We explored the outcomes of germline BRCA1/2 pathogenic/likely pathogenic variants (PVs/LPVs) in the endocrine-sensitive disease treated with first line standard of care cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Three studies retrospectively showed a reduction in overall survival (OS) and progression free survival (PFS) in gBRCA1/2m patients compared to both germinal BRCA1/2 wild type (gBRCA1/2wt) and to the untested population. Regarding the efficacy of PI3K inhibitors, there are no subgroup or biomarker analyses in which germinal BRCA status was explored. However, the biological interactions between the PIK3CA/AKT/mTOR pathway and BRCA1/2 at a molecular level could help us to understand the activity of these drugs when used to treat BC in BRCA1/2 PVs/LPVs carriers. The efficacy of trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate (ADC) targeting HER2 for HER2-low and HER2-positive (HER2+) BC, has been increasingly described. Unfortunately, data on T-DXd in HER2+ or HER2-low metastatic BC harboring germinal BRCA1/2 PVs/LPVs is lacking. Including germinal BRCA1/2 status in the subgroup analysis of the registration trials of this ADC would be of great interest, especially in the phase III trial DESTINY-breast04. This trial enrolled patients with HER2-negative (HER2-) and both HR+ and HR- metastatic disease, which can now be categorized as HER2-low. The HER2-low subgroup includes tumors that were previously classified as triple negative, so it is highly likely that some women were germline BRCA1/2 PVs/LPVs carriers and this data was not reported. Germline BRCA1/2 status will be available for a higher number of individuals with BC in the near future and data on the prognostic and predictive role of these PVs/LPVs is needed in order to choose the best treatment options.

Inherited mutations in BRCA1 and BRCA2 genes increase risks for breast, ovarian, and other cancers. Both genes encode proteins for accurately repairing chromosome breaks. If mutations inactivate this function, broken chromosomes may not be restored correctly, allowing breaks to persist or rearrange chromosomes. These abnormalities are potentially catastrophic events that can originate from viral infections. I used bioinformatic analyses of publicly available breast cancer patient data to show that the distribution of chromosome breaks in hereditary breast cancers differs markedly from sporadic breast cancers. Then I tested hereditary breast cancer sequence data around chromosome breaks for DNA similarity to all known viruses. Human DNA flanking breakpoints usually had decisive matches to Epstein-Barr virus (EBV / HHV4) tumor variants HKHD40 and HKNPC60. Many breakpoints were near EBV genome anchor sites, human EBV tumor-like sequences, EBV-associated epigenetic marks, and some fragile sites. On chromosomes 2 and 12, sequences near EBV genome anchor sites accounted for 90% and 88% of breakpoints (p<0.0001), respectively. On chromosome 4, 51/52 inter-chromosomal breakpoints were close to EBV-like sequences in 19 hereditary breast cancers. In contrast, 19 sporadic breast cancers only had 12 interchromosomal breakpoint regions on chromosome 4 near EBV-like sequences. On various other chromosomes, five EBV genome anchor sites were near hereditary breast cancer breakpoints at precisely defined, disparate gene or LINE locations. Independent evidence further implicating EBV in hereditary breast cancer breakpoints is that 25 breast cancer break positions are within 1.25% of breakpoints in model EBV cancers. In addition to BRCA1 or BRCA2 mutations, all the hereditary breast cancers had mutated genes essential for immune responses. This compromise facilitates reactivation of herpes viruses which produce nucleases capable of breaking chromosomes. EBV also causes other deleterious effects: anchored EBV episomes can interfere with normal replication and obstruct DNA break repairs; even very early infection causes massive transcription changes. The results, therefore, imply proactive treatment and prevention of herpes viral infections may prevent some chromosome breaks and benefit BRCA mutation carriers.

Inherited mutations in BRCA1 and BRCA2 genes increase risks for breast, ovarian, and other cancers. Both genes encode proteins for accurately repairing chromosome breaks. If mutations inactivate this function, chromosome fragments may not be restored correctly. Resulting chromosome rearrangements can become critical breast cancer drivers. Because I had data from thousands of cancer structural alterations that matched viral infections, I wondered whether infections contribute to chromosome breaks and rearrangements in hereditary breast cancers. There are currently no interventions to prevent chromosome breaks because they are thought to be unavoidable. However, if chromosome breaks come from infections, they can be treated or prevented. I used bioinformatic analyses to test publicly available breast cancer sequence data around chromosome breaks for DNA similarity to all known viruses. Human DNA flanking breakpoints usually had the strongest matches to Epstein-Barr virus (EBV) tumor variants HKHD40 and HKNPC60. Many breakpoints were near sites that anchor EBV genomes, human EBV tumor-like sequences, EBV-associated epigenetic marks, and fragile sites. On chromosome 2, sequences near EBV genome anchor sites accounted for 90% of breakpoints (p<0.0001). On chromosome 4, 51/52 inter-chromosomal breakpoints were close to EBV-like sequences. Five EBV genome anchor sites were near breast cancer breakpoints at precisely defined, disparate gene or LINE locations. Breakpoint flanking regions resembled known EBV-cancers. Twenty-five breakpoints in breast cancers were within 1.25% of EBV cancer breakpoints. In addition to BRCA1 or BRCA2 mutations, all the breast cancers had mutated genes essential for immune responses. Because of this immune compromise, herpes viruses can activate and produce nucleases that break chromosomes. Alternatively, anchored viral episomes can obstruct break repairs, whatever the cause. The results, therefore, imply proactive treatment and prevention of herpes viral infections may prevent some chromosome breaks and benefit BRCA mutation carriers.

Genetic testing allows for identification of germline DNA variations which are associated with a significant increase in risk of developing breast and ovarian cancer. Detection of a BRCA1 or BRCA2 pathogenic variant triggers several clinical management actions, which may include increased surveillance and prophylactic surgery for healthy carriers or treatment with PARP inhibitor therapy for carriers diagnosed with cancer. Thus, standardized validated criteria for annotation of BRCA1 and BRCA2 variants according to their pathogenicity are necessary to support clinical decision making and ensure improved outcomes. Upon detection, variants whose pathogenicity can be inferred by the genetic code are typically classified as pathogenic, likely pathogenic, likely benign, or benign. Variants whose impact on function cannot be directly inferred by the genetic code are labeled as Variants of Uncertain Clinical Significance (VUS) and are evaluated by multifactorial likelihood models that use personal and family history of cancer, segregation data, prediction tools, and co-occurrence with a pathogenic BRCA variant. Missense variants, coding alterations that replace a single amino acid residue with another, are a class of variants for which determination of clinical relevance is particularly challenging. Here, we discuss current issues in variant classification by following a typical life cycle of a BRCA1 missense variant through detection, annotation and information dissemination. Advances in massively parallel sequencing have led to a substantial increase in VUS findings. Although comprehensive assessment and classification of missense variants according to their pathogenicity remains the bottle neck, new developments in functional analysis, high throughput assays, data sharing, and statistical models are rapidly changing this scenario.

Germline mutations in Breast cancer susceptibility gene 1 and 2 (BRCA1 and BRCA2) cause breast, ovarian and other cancers, and the chemotherapeutic drug doxorubicin (Dox) is widely used to treat these cancers. However, Dox use is limited by latent induction of severe cardiotoxicity known as Dox-induced cardiomyopathy, for which there are no specific treatments currently available. Dox is administered into the systemic circulation, where it readily translocates into sub-cellular compartments, and disrupts the integrity of DNA. Accumulating evidence indicates that oxidative stress, DNA damage, inflammation and apoptosis all play a central role in Dox-induced cardiomyopathy. The BRCA1 and BRCA2 proteins are distinct as they perform crucial yet separate roles in the homologous recombination repair of DNA double-strand breaks, thereby maintaining genomic integrity. Additionally, both BRCA1 and BRCA2 mitigate oxidative stress and apoptosis in both cardiomyocytes and endothelial cells. Accordingly, BRCA1 and BRCA2 are essential regulators of pathways that are central to the development of cardiomyopathy induced by Doxorubicin. Despite extensive investigations, there exists a gap in knowledge about the role of BRCA1 and BRCA2 in Doxorubicin-induced cardiomyopathy. Here, we review the previous findings and associations about the expected role and associated mechanisms of BRCA1 and 2 in Dox-induced cardiomyopathy and future perspectives.

Coordinated sets of extremely numerous digital data, on a given social or economic event, are treated by Artificial Intelligence tools to obtain reasonably accurate, valuable predictions. The same approach, applied to biomedical issues, as how to choose the right drug to completely cure a given cancer patient, does not reach satisfactory results. It is the “organized biological complexity”, which requires a different systems approach, to integrate, in an Augmented Intelligence strategy, statistical computations of digital data, network construction of “omics” findings, well-designed mathematical models and new experiments in an iterative pathway to reconstruct the “logic” beneath the “organized complexity”, as shown here for Systems Metabolomics of cancer. On this basis new diagnostic approaches, able to identify precision drug treatments, as well as new discovery strategy for more effective anti-cancer drugs are described.

BRCA1 and 2 pathogenic variants increase lifetime risks of breast (50-75%) and ovarian cancer (15-20%). Guidelines recommend breast screening (MRI and mammogram) or risk-reducing mastectomy with salpingo-oophorectomy for ovarian cancer prevention. We sought to 1) characterize the population of BRCA1/2 carriers in Newfoundland and Labrador (NL) 2) evaluate risk-reducing interventions 3) identify factors influencing screening and prevention adherence. Methods: This is a retrospective study from a population-based provincial cohort of BRCA1/2 carriers. Eligibility criteria for risk-reducing interventions were defined for each case and patients were categorized based on their level of adherence with recommended screening or prevention. Chi-squared and regression analyses were used to determine which factors influenced uptake and level of adherence. Results: 276 BRCA1/2 carriers were identified; 156 living NL females composed the study population. Unaffected females were younger at testing than those with a cancer diagnosis (44.4 y versus 51.7 y; p=0.002). Categorized by eligibility, 61.0%, 61.6%, 39.0% and 75.7% of patients underwent MRI, mammogram, risk-reducing mastectomy, and risk-reducing salpingo-oophorectomy, respectively. Individuals with breast cancer were more likely to have risk-reducing mastectomy (64.7% versus 35.3%; p<0.001), and those who attended specialty hereditary cancer clinic were more likely to be adherent with breast/ovarian cancer recommendations (73.2% versus 13.4%; p<0.001) and to undergo risk-reducing salpingo-oophorectomy(84.1% versus 15.9%; p<0.001). Conclusions: Nearly 40% of female BRCA1/2 carriers were not receiving breast surveillance according to evidence-based recommendations. Cancer risk reduction and uptake of breast imaging and prophylactic breast and pelvic surgeries are significantly higher in patients who receive dedicated specialty care. Organized hereditary cancer prevention programs will be a valuable component of Canadian health care systems and have the potential to reduce the burden of disease country-wide.

Background: Several hereditary-familial syndromes associated with various types of tumors have been identified to date, evidencing that hereditary cancers caused by germline mutations account for 5-10% of all tumors. Advances in genetic technology and the implementation of Next Generation Sequencing (NGS) have accelerated the discovery of several susceptibility cancer genes, allowing the detection of cancer-predisposing mutations in a larger number of cases. The aim of this study is to highlight how the application of an NGS-multi gene panel to a group of oncological patients subsequently leads to the improvement of healthy pathogenic variants/likely pathogenic variants (PVs/LPVs) carriers' identification and prevention of the disease in these cases. Methods: Starting from a total of 110 cancer patients carrying PVs/LPVs in genes involved in cancer susceptibility detected by a customized NGS panel of 27 cancer-associated genes, we enrolled 250 healthy collateral family members from January 2020 to July 2022. The specific PVs/LPVs identified in each proband were tested in healthy collateral family members by Sanger sequencing. Results: 131 out of the 250 cases (52%) weren’t carriers of the mutation detected in the affected relative, while 119 were carriers. Of these, 81/250 patients carried PVs/LPVs on BRCA1/2 (33%), 35/250 harbored PVs/LPVs on other genes beyond BRCA1 and BRCA2 (14%), and 3/250 (1%) were PVs/LPVs carriers both on BRCA1/2 and on another susceptibility gene. Conclusion: Our results show that the analysis of BRCA1/2 genes only would have resulted in a missed diagnosis in a number of cases and in the lack of prevention of the disease in a considerable percentage of healthy carriers with a genetic mutation (14%).

Rapid and continuing advances in biomarker testing are not being matched by take-up in health systems, and this is hampering both patient care and innovation. It also risks costing health systems the opportunity to make their services more efficient and, over time, more economical. The potential that genomics has brought to biomarker testing in diagnosis, prediction and research is being realised, pre-eminently in many cancers, but also in an ever-wider range of conditions. One of the paradigmatic examples is BRCA1/2 testing in ovarian, breast, pancreatic and prostate cancers. Nevertheless, development is impeded by data deficiencies, and lack of policy alignment on standards, approval – and the role of real-world evidence in the process - and reimbursement. The acute nature of the problem is compellingly illustrated by the particular challenges facing the development and use of tumour agnostic therapies, where the gaps in preparedness for taking advantage of this innovative approach to cancer therapy are sharply exposed. Europe should already have in place a guarantee of universal access to a minimum suite of biomarker tests and should be planning for an optimum testing scenario with a wider range of biomarker tests integrated into a more sophisticated health system articulated around personalised medicine. Improving healthcare and winning advantages for Europe's industrial competitiveness and innovation require an appropriate policy framework – starting with an update to outdated recommendations.

Epidemiological data highlight prostate cancer as a significant global health issue, with high incidence and substantial impact on patients' quality of life. The prevalence of this disease is associated with various factors, including age, heredity, and race. Recent research in prostate cancer genetics has identified several genetic variants that may be associated with an increased risk of developing the disease. However, despite the significance of these findings, genetic markers for prostate cancer are not currently utilized in clinical practice as reliable indicators of the disease. In addition to genetics, epigenetic alterations also play a crucial role in prostate cancer development. Aberrant DNA methylation, changes in chromatin structure, and microRNA (miRNA) expression are major epigenetic events that influence oncogenesis. Existing markers for prostate cancer, such as prostate-specific antigen (PSA), have limitations in terms of sensitivity and specificity. The cost of testing, follow-up procedures, and treatment for false-positive results and overdiagnosis contributes to the overall healthcare expenditure. Improving the effectiveness of prostate cancer diagnosis and prognosis requires either narrowing the risk group by identifying new genetic factors or enhancing the sensitivity and specificity of existing markers. Immunological biomarkers (both circulating and intra-tumoral), including markers of immune response and immune dysfunction, represent a potentially useful area of research for enhancing the diagnosis and prognosis of prostate cancer. Our review emphasizes the need for developing novel immunological biomarkers to improve the diagnosis, prognosis, and management of prostate cancer. We highlight the most recent achievements in the identification of biomarkers provided by circulating monocytes and tumor-associated macrophages (TAMs). We highlight that monocytes-derived and TAMs-derived biomarkers can enable to establish the missing links between genetic predisposition, hormonal metabolism and immune responses in prostate cancer.

Apoptosis, also known as the programmed death of cells, is responsible for maintaining the homeostasis of tissues and this function is carried out by caspases. The process of apoptosis is carried out via two distinct pathways: the extrinsic pathway, which is governed by death receptors, and the intrinsic pathway, also known as the mitochondrial pathway. The BCL-2 protein family encoded by the BCL-2 gene, located at the 18q21.33 chromosomal location, is in charge of regulating the intrinsic pathway, which is responsible for inducing cell death via the permeabilization of the mitochondrial membrane and the release of apoptosis - inducing components. The BCL-2 homology (BH1, BH2, BH3, BH4) domains of this family proteins are crucial for their functioning and their common BH domains allow interactions between members of the same family and can also serve as indications of pro- or anti-apoptotic activity. A direct correlation may be shown between the overexpression of BCL-2 and the postponement of cell death. It has been determined that a change in the expression of BCL-2 is the root cause of a variety of malignancies, including lung, breast, melanoma, and chronic lymphocytic leukemia, Multiple Sclerosis, Diabetes. In this review, we discuss the therapeutic potential of regulating BCL-2 family connections and their relevance to health and disease.

Tobacco use, most people would say. Smoking tobacco increases the risk of developing many types of cancer and is responsible for approximately one-third of all cancer deaths. The association between tobacco use and lung cancer is well known; lung cancer occurs about 20 times more often in heavy smokers than in nonsmokers [1]. However, many lung cancers are diagnosed in never smokers [2], and most smokers do not develop lung cancer [3,4].

We have been encouraging practicing gynecologists to adopt molecular diagnostics tests, PCR, and cancer biomarkers, as an alternative enabled by these platforms to traditional Papanicolaou and colposcopy tests, respectively. An aliquot of liquid-based cytology was used for the molecular test [high-risk HPV types, (HR HPV)], another for the PAP test and still one more for the p16/Ki67 dual stain cytology. A total of 4,499 laboratory samples were evaluated, and we found that 25.1% of low-grade samples and 47.9% of high-grade samples after PAP testing had a negative HR HPV-PCR result. In those cases, reported as Pap-negative, 22.1% got a positive HR HPV-PCR result. Dual staining with the p16/Ki67 biomarkers in samples was positive for HR HPV, and 31.7% were also positive for these markers. Of the PCR results positive for any of these high-risk HPV subtypes, n 68.3% we did not to find evidence for the presence of cancerous cells, highlighting the importance of performing dual staining with p16/Ki67 after PCR, to avoid unnecessary colposcopies. Encountered challenges are a deep-rooted social reluctance in Mexico to abandon traditional Pap smears and the opinion of many specialists, we still believe that colposcopy continues to be a preferred procedure over dual staining protocol.

In the era of nanotechnology, researchers are implementing point to care service to cancer patients to detect malignancy beforehand and to reduce the mortality rate of cancers. Cancer is known to be the most fatal disease among all other diseases and the survivability from cancer is quite impossible if the stage of the cancer is an advanced level. Though the early detection of cancer can increase the chances of survival with a double fold. Biosensor is a part of nanotechnology which is capable to provide point to care service in the field of medicine. With the rising number of cancer occurrences being identified around the world and the increasing number of deaths because of the identification of advanced cancer, biosensors can play a significant part in the early detection of cancer. New molecular methods, including as genomic and proteomic approaches, are increasingly being used to study patient molecular profiles. When such diagnosis method is paired with bioinformatics tools, they generate new data that can be used to discover new disease biomarkers. Finding precise and sensitive indicators that are corelated to a specific disease, as with many other diseases, can be challenging. Furthermore, the concentration of biomarkers in biological fluids varies according to illness states and phases. Peptides, proteins, up or down regulated expression of gene markers, and gene alternation are all examples of molecular markers that are commonly used to diagnose cancer. In this article, we have highlighted six different deadliest cancers such as Ovarian, Breast, Prostrate, Lung, Colorectal and Liver cancer. The article contains distinct types of biomarkers which are normally found in these kinds of cancer and generally used as a potential diagnostic target in the medicine field. The article mainly summarized the application of different types of biosensors devices in the detection of the mostly found biomarkers in the above cancer types.

Background: Micro-RNAs (miRNA) are emerging as biomarkers in the detection and prognosis of cancers due to their inherent stability and resilience. Methods: To summarize evidence regarding urinary miRNA (umiRNAs) role in the detection, prognosis and therapeutic management of urological cancers, we performed a systematic review of the most important scientific databases using the following keywords: (urinary mir-na)AND(prostate cancer); (urinary mirna)AND(bladder cancer); (urinary mirna)AND(renal cancer); (urinary mirna)AND(testicular cancer); (urinary mirna)AND(urothelial cancer). Results: Of all, 1364 articles were initially selected. Only original studies in the English language on human specimens were considered for inclusion in our systematic review. Thus, a convenient sample of 60 original articles was identified. Urinary miRNA (UmiRNAs) are downregulated in prostate cancers and may serve as potential non-invasive molecular biomarkers. Several umiR-NAs have been identified as diagnostic biomarkers of urothelial carcinoma and bladder cancer (BCa), allowing to discriminate malignant from non-malignant forms of haematuria. UmiRNAs could serve as therapeutic targets or recurrence markers of non-muscle invasive BCa and could predict the aggressivity and prognosis of muscle-invasive BCa. In renal cell carcinoma, miRNAs have been identified as predictors of tumour detection, aggressiveness, and progression to metastasis. Conclusion: umiRNAs could play an important role in the diagnosis, prognosis, and therapy of urological cancers.

Extremely low-frequency electromagnetic fields (ELF-EMFs) are non-ionizing radiations typically emitted by power lines, electrical wiring and electrical appliances. Epidemiological studies have repeatedly shown a positive association between ELF-EMFs and childhood leukemia. Exposures greater than 0.3-0.4 µT increase the risk by approximately 1.5-2 fold, and estimates indicate that up to 2% of childhood leukemia cases in Europe may be attributable to ELF-EMFs. However, it is considered unlikely that ELF-EMFs can cause cancer, because carcinogenesis requires the accumulation of DNA alterations and ELF-EMFs do not have enough energy to damage the DNA. Lack of biological plausibility is a barrier to accept the evidence of carcinogenicity in human studies and to take measures to protect pregnant women and children from ELF-EMFs. Recent evidence indicates that non-mutagenic agents can cause DNA alterations and increase the risk of cancer by promoting the accumulation of cell divisions in stem cells. Cell division generates DNA alterations (e.g., mutations arising during DNA replication), which occur even in the absence of DNA-damaging agents. Importantly, ELF-EMFs can trigger the division of stem cells; this effect is under development in the field of regenerative medicine. A possible mechanism by which ELF-EMFs induce the malignant transformation of hematopoietic stem cells is discussed.

Selectins are responsible for the early stages of cell migration as they control cell adhesion. They make the microenvironment permissive for metastatic events by promoting the activation of other cell adhesion molecules (CAMs). We employed several robust bioinformatics tools to evaluate gene sequence; single nucleotide polymorphisms (SNPs) in intronic and UTR regions; and missense SNPs with amino acid change in L-selectin (SELL), E-selectin (SELE), P-selectin (SELP) and PSGL-1 (SELPLG). We demonstrated that gene polymorphisms rs2229569, rs1131498, rs4987360, rs4987301 and rs2205849; polymorphisms rs3917777, rs2205894 and rs2205893 of SELP gene; rs7138370, rs7300972 and rs2228315 variants of SELPLG gene; and rs1534904 and rs5368 polymorphisms of SELE gene may produce important alterations in the DNA structure and consequent alterations in the morphology and function of the corresponding proteins. These Selectin polymorphic variants deserve further investigation in cancer patients, as they may become useful clinical markers for risk determination, diagnostic and prognostic biomarkers or even targets for targeted therapies.

Lynch syndrome (LS) is an inherited cancer predisposition disorder associated with an elevated risk of various epithelial cancers. Despite sharing the same pathogenic variant (PV), Lynch syn-drome variant heterozygotes (LSVH) exhibit considerable phenotypic variability in cancer risk. The role of Human Leukocyte Antigen (HLA) in modifying cancer risk prompted our investiga-tion into whether HLA variations act as genetic modifiers influencing age at cancer diagnosis in a unique cohort of LSVH carrying a PV in the hMLH1 gene in South Africa. Within our extensive LS cohort, 426 individuals carried the same hMLH1 PV (MLH1:c.1528C>T). We selected 100 indi-viduals with the greatest diversity in age at cancer diagnosis and the oldest unaffected individu-als for high-throughput HLA genotyping of 12 HLA class I and II loci using next-generation se-quencing. Statistical analyses employed Kaplan-Meier survival analyses with Logrank tests and Cox proportional hazards. Following the robust application of statistical correction methods, six HLA alleles (3.2%) were significantly associated with a young age at cancer diagnosis. Notably, HLA-B*15:17 and HLA-DPB1*55:01 correlated significantly with very young colorectal cancer (CRC) diagnosis (Mean age: 21y [17-25]; HR = 71.59; q

It is estimated that pancreatic cancer will be the 2^nd leading cause of cancer-related deaths globally by 2030, highlighting the ongoing lack of effective treatment options in this devastating condition. There is a lack of reliable prognostic or predictive markers in pancreatic cancer to guide management decisions, whether for systemic chemotherapy, molecularly targeted therapies, or immunotherapies. To date, the results for targeted agents and immunotherapies in unselected populations of chemo-refractory pancreatic cancer have not met expectations. The reasons for this lack of efficacy of immunotherapy in pancreatic cancer are incompletely understood. The challenges in pancreatic cancer include the physical barrier created by the dense desmoplastic stroma surrounding the tumor, chemokine-mediated exclusion of T cells, poor antigenicity, paucity of infiltrating T cells within the tumor, ultimately leading to an immunosuppressive microenvironment. A better understanding of the role of inflammation in pancreatic cancer, its tumor microenvironment and individualized patient-related features, be they molecular, clinical or histopathological would enable a more effective tailored approach to the management of pancreatic cancer. In this review, the role of inflammation, the immune tumor microenvironment and potential immune biomarkers in pancreatic cancer are explored.

Backgound: Exosomes are extracellular nanovesicles, carriers of different biomolecules such as lipids, proteins, nucleic acids. Their composition and the fact that their release dramatically increases in case of tumorigenesis, opens different scenarios on the possible application in the research for new biomarkers.Methods: The most widely applied methodologies include ultracentrifugation techniques, size-based techniques, immunoaffinity capture-based techniques (mainly ELISA) and precipitation. To optimize the acquisition of exosomes from the reference sample, more techniques can be applied in sequence for a single extraction, determining an increase in labor time and costs. Results: The analysis of PSA-expressing exosomes provides an incredibly accurate way to discriminate between healthy patients and those with prostate disease. Specifically, IC-ELISA alone method achieved 98.57% sensitivity and 80.28% specificity in discriminating prostate cancer (PC) from benign prostatic hyperplasia (BPH).An immunocapture-based ELISA assay was performed to quantify and characterize carbonic anhydrase (CA) IX expression in exosomes. The results revealed that CA IX positive exosomes were 25-fold higher in plasma samples from PC patients than in those from healthy control. Conclusions: The analysis of PC-linked exosomes represents a promising diagnostic model that can effectively distinguish patients with PC from those with non-malignant prostatic disease, However, the use of exosome analysis in clinical practice is currently limited by several issues, including a lack of standardization in the analytical process and high costs, which are still too high for a large-scale use.

Blood-based circulating cell free DNA(cfDNA) detection offers a non-invasive and easily accessible way for early cancer detection. Despite the extensive utility of cfDNA, there are still many challenges to develop the clinical biomarkers. For example, cfDNA with genetic alterations often compose a small portion of the DNA circulating in plasma, which can be confounded by cfDNA contributed by normal cells. Therefore, filtering out the potential false-positive cfDNA mutations from health population will be important for the cancer-based biomarkers. Additionally, many low-frequency genetic alterations are easily overlooked in small amount of cfDNA-based cancer test. We hypothesize that, the combination of diverse types of cancer studies on cfDNA can provide us a new insight to identify low-frequency genetic variant across cancer types for early clinical detection of cancers. By building a standardized computational pipeline for 1358 cfDNA samples across seven cancer types, we prioritize 129 shard genetic variants in the major cancer types. Further functional analysis of the 129 variants found that they are mainly enriched in ribosome pathways such as cotranslational protein targeting to membrane, some of which are tumor suppressor, oncogene and related to cancer initiation. In summary, our integrative analysis revealed the important roles of ribosome proteins as the common biomarkers in early cancer diagnosis.

Though early-stage colorectal cancer has a high 5-year survival rate of 65-92% depending on the specific stage, this probability drops to 13% after the cancer metastasizes. Frontline treatments for colorectal cancer such as chemotherapy and radiation often produce dose-limiting toxicities in patients and acquired resistance in cancer cells. Additional targeted treatments are needed to improve patient outcomes and quality of life. Immunotherapy involves treatment with peptides, cells, antibodies, viruses, or small molecules to engage or train the immune system to kill cancer cells. Preclinical and clinical investigations of immunotherapy for treatment of colorectal cancer including immune checkpoint blockade, adoptive cell therapy, monoclonal antibodies, oncolytic viruses, anti-cancer vaccines, and immune system modulators have been promising, but demonstrate limitations for patients with proficient mismatch repair enzymes. In this review, we discuss preclinical and clinical studies investigating immunotherapy for treatment of colorectal cancer and predictive biomarkers for response to these treatments. We also consider open questions including optimal combination treatments to maximize efficacy, minimize toxicity, and prevent acquired resistance and approaches to sensitize mismatch repair proficient patients to immunotherapy.

Epidemiological data indicate that 5.8% of cancer deaths world-wide are attributable to alcohol consumption. The risk of cancer is higher in tissues in closest contact on ingestion of alcohol, such as the oral cavity, pharynx and esophagus. The risk of these cancers is increased even in people who have only one alcoholic drink per day. However, since ethanol is not mutagenic and the carcinogenic metabolite of ethanol (acetaldehyde) is mostly produced in the liver, it is not clear why alcohol use preferentially exerts a local carcinogenic effect. It is well known that ethanol causes cell death at the concentrations present in alcoholic beverages; however, this effect has been overlooked probably because dead cells cannot give rise to cancer. Here I discuss that the cytotoxic effect of ethanol on the cells lining the oral cavity, pharynx and esophagus activates the division of the stem cells located in deeper layers of the mucosa to replace the dead cells. Every time stem cells divide, they become exposed to unavoidable errors associated with cell division (e.g., mutations arising during DNA replication and chromosomal alterations occurring during mitosis) and also become highly vulnerable to the genotoxic activity of endogenous and exogenous DNA-damaging agents (e.g., reactive oxygen species, acetaldehyde and tobacco carcinogens). Alcohol consumption probably increases the risk of developing cancer of the oral cavity, pharynx and esophagus by promoting the accumulation of cell divisions in the stem cells that maintain these tissues in homeostasis. Because the cytotoxic activity of ethanol is concentration-dependent, the risk of these cancers will not only increase with increasing amounts of ethanol, but also with increasing concentrations; an ounce of whisky is probably more carcinogenic when taken undiluted than when taken mixed with non-alcoholic beverages. The local cytotoxic effect of ethanol can also explain the known synergistic effect of alcohol and tobacco use on the risk of these cancers. Understanding the mechanisms of carcinogenicity of alcohol is important to reinforce the epidemiological evidence and to raise public awareness of the strong link between alcohol consumption and cancer.

MicroRNAs (miRNAs) are single-stranded, noncoding RNA molecules that regulate gene expression post-transcriptionally by binding to messenger RNAs. miRNAs are important regulators of gene expression, and their dysregulation is implicated in many human and dog diseases. Most cancers tested, to date, have been shown to express altered miRNA levels, which indicates their potential importance in the oncogenic process. Based on this evidence, numerous miRNAs have been suggested as potential cancer biomarkers for both diagnosis and prognosis. miRNA-based therapies have also been tested in different cancers and have provided measurable clinical benefits to patients. In addition, understanding miRNA biogenesis and regulatory mechanisms in cancer can provide important knowledge about resistance to chemotherapies, leading to more personalized cancer treatment. In this review, we have comprehensively summarized the importance of miRNA in human and dog cancer research. We have discussed the current state of development and potential for miRNA as both a diagnostic marker and a therapeutic target.

An emerging picture in cancer biology is that, paradoxically, chemotherapy can actively induce changes that favor cancer progression. These pro-cancer changes can be either inside (intrinsic) or outside (extrinsic) the cancer cells. In this review, we will discuss the extrinsic pro-cancer effect of chemotherapy; that is, the effect of chemotherapy on the non-cancer host cells to promote cancer progression. We will focus on metastasis, and will first discuss recent data from mouse models of breast cancer. Intriguingly, despite reducing the size of primary tumors, chemotherapy changes the tumor microenvironment, resulting in an increased escape of cancer cells into the blood stream. Furthermore, chemotherapry changes the tissue microenvironment at the distant sites, making it more hospitable to cancer cells upon their arrival. We will then discuss the idea and evidence that these devastating pro-metastatic effects of chemotherapy can be explained in the context of stress response. At the end, we will discuss the potential relevance of these mouse data to human breast cancer and their implication on chemotherapy in the clinic.

Bladder cancer (BC) diagnosis is reliant on cystoscopy, an invasive procedure associated with urinary tract infections. This has sparked interest in identifying non-invasive biomarkers in body fluids such as blood and urine. A source of biomarkers in these biofluids are extracellular vesicles (EVs), nanosized vesicles that contain a wide array of molecular cargo, including small non-coding RNA such as microRNA and transfer RNA-derived fragments (tRF). Here we performed small-RNA next-generation sequencing for urine EVs, serum EVs and serum supernatant from 41 patients with non-muscle invasive BC (27 stage Ta, 14 stage T1) and 15 non-cancer patients (NCP) with benign cystoscopy findings. Serum and urine samples were collected before transurethral resection of bladder tumors (TUR-b) and at routine postsurgery check-ups. Expression levels of tRFs in presurgery samples were compared to those at postsurgery check-ups and to NCPs. To strengthen the reliability of our results, samples from 10 patients with stage T1 disease were resequenced. When comparing tRF expression in urine EVs between BC patients with stage T1 disease and NCPs, 14 differentially expressed tRFs (DEtRFs) were identified. In serum supernatant, six DEtRFs were identified among stage T1 patients when comparing presurgery to postsurgery samples, and four DEtRFs were found when comparing presurgery samples to NCPs. By performing a blast search, we found that sequences of DEtRFs aligned with genomic sequences pertaining to processes relevant to cancer development, such as enhancers, regulatory elements and CpG islands. Our findings display a number of tRFs that may hold potential as biomarkers for the diagnosis and recurrence-free survival of BC.

Cervical cancer (CC) is the most common cancer in women worldwide and is almost always associated with repeated infections by human papillomavirus (HPV). Screening by traditional tests combined with biomarker identification techniques for low- or high-grade injuries, are becoming increasingly important in diagnosis and prognosis, avoiding countless deaths. This article explores existing literature on the main serum biomarkers and the identification of biomarkers associated with the oncogenesis of HPV expression in the identification of pre-cancerous lesions and of CC for an effective treatment, with reduction of recurrence, as well as we explain strategies for the development of biomarkers based on DNA, proteins and other markers. We also describe how markers of chromosomal instability host DNA, promoting hypo- or hypermethylation of DNA, as well as polymorphisms and epigenetic events in the p53 gene. Finally, we discuss changes in gene expression using cDNA microarray techniques and changes in the expression of proteins and markers identified through mass spectrometry.

Transfer RNA fragments (tRFs) have gene silencing effects similarly to miRNAs, can be sorted into extracellular vesicles (EVs) and are emerging as potential circulating biomarkers for cancer diagnosis. We aimed at analyzing the expression of tRFs in gastric cancer (GC) and understanding their potential as biomarkers. We explored miRNA datasets from gastric tumors and normal adjacent tissues (NAT) from TCGA repository, and proprietary 3D-cultured GC cell lines and corresponding EVs, in order to identify differentially represented tRFs using MINTmap and R/Bioconductor packages. Selected tRFs were validated in patient-derived EVs. We found 613 Differentially Expressed (DE)-tRFs in the TCGA dataset, of which 19 were concomitantly upregulated in TCGA gastric tumors and present in 3D-cells and EVs, but barely expressed in NAT. Moreover, 20 tRFs were expressed in 3D-cells and EVs and downregulated in TCGA gastric tumors. Of these 39 DE-tRFs, 9 tRFs were also detected in patient-derived EVs. Interestingly, the targets of these 9 tRFs affect neutrophil activation and degranulation, cadherin binding, focal adhesion and cell-substrate junction, highlighting these pathways as major targets of EV-mediated crosstalk with the tumor microenvironment. Furthermore, as they are present in four distinct GC datasets and can be detected even in low quality patient-EV derived samples, they hold promise as GC biomarkers. By repurposing already available NGS data, we could identify and cross-validate a set of tRFs holding potential as GC diagnosis biomarkers.

Background: Oral cancer (OC) is serious health concerning issue that has a high fatality rate. The oral cavity has seven kinds of OC, including the lip, tongue, and floor of the mouth, as well as the buccal, hard palate, alveolar, retromolar trigone, and soft palate. The goal of this study is to look into new biomarkers and important pathways that might be used as diagnostic biomarkers and therapeutic candidates in OC. Methods: Publicly available repository the Gene Expression Omnibus (GEO) was responsible to collect OC-related datasets. GSE74530, GSE23558, and GSE3524 microarray datasets were collected to apply analysis. Minimum cut-off criteria of |log fold-change (FC)| > 1 and adjusted p < 0.05 were applied to figure out the up-regulated and down-regulated differential expression genes (DEGs) from the three datasets. After that only common DEGs in all three datasets were collected to apply further analysis. Gene ontology (GO) and Pathway analysis were implemented to explore the functional behaviors of DEGs. Then protein-protein interaction (PPI) networks were built to identify the most performed genes, clustering algorithm was also implemented to identify complex parts of PPI. TF-miRNA networks were also constructed to study deeply about OC-associated DEGs. Finally, top gene performers from PPI networks were used to apply drug signature analysis. Results: After applying filtration and cut-off criteria 2508, 3377, and 670 DEGs were found for GSE74530, GSE23558, and GSE3524 respectively, and 166 common DEGs were found in every dataset. The GO annotation remarks that most of the DEGs were associated with the terms of type I interferon signaling pathway. The pathways of KEGG reported that the common DEGs are related to the Cell cycle and Influenza A. The PPI network holds 88 nodes and 492 edges and CDC6 had the highest number of connections. 4 clusters were identified from the PPI. Drug signatures doxorubicin and resveratrol showed high significance according to the hub genes. We anticipate that our bioinformatics research will aid in the definition of the pathophysiology and the development of new therapies for OC.

There is a major clinical need for accurate biomarkers for prostate cancer prognosis, to better inform treatment strategies and disease monitoring. Current clinically recognised prognostic factors, including prostate-specific antigen (PSA) levels, lack sensitivity and specificity in distinguishing aggressive from indolent disease, particularly in patients with localised intermediate grade prostate cancer. There has therefore been a major focus on identifying molecular biomarkers that can add prognostic value to existing markers, including investigation of DNA methylation, which has a known role in tumorigenesis. In this review, we will provide a comprehensive overview of the current state of DNA methylation biomarker studies in prostate cancer prognosis, and highlight the advances that have been made in this field. We cover the numerous studies into well-established candidate genes, and explore the technological transition that has enabled hypothesis-free genome-wide studies and the subsequent discovery of novel prognostic genes.

Cancer is a complex and devastating disease that has engaged scientists and researchers for decades. Despite tremendous efforts, previous hypotheses about cancer development have not achieved significant breakthroughs. Evolutionary Cancer Cell Biology (ECCB) is a novel and emerging branch of oncological science that provides an evolutionary perspective on the origin of cancer. It reveals that the cancer genome evolved hundreds of millions of years ago, long before multicellular organisms such as metazoans and humans emerged. ECCB aims to unify all evolutionary insights, hypotheses, and theories into a cohesive framework. It investigates the intricate relationship between cancer genomics and ancient pre-metazoan genes that emerge when normal cells transform into cancer cells. It challenges the conventional wisdom of cancer research by suggesting that cancer could arise through intrinsic cellular mechanisms without genetic alterations and mutations. Furthermore, it postulates that somatic mutations are only secondary, downstream events in the process of oncogenesis.

Immune Checkpoint Inhibitors are monoclonal antibodies that are used to treat over one in three cancer patients. While they have changed the natural history of disease, prolonging life and preserving quality of life, they are highly active in less than 40% of patients, even in the most responsive malignancies such as melanoma, and cause significant autoimmune side effects. Licenced biomarkers include tumour Programmed Death Ligand 1 expression by immunohistochemistry, microsatellite instability, and Tumour Mutational Burden, none of which are particularly sensitive or specific. Emerging tumour and immune tissue biomarkers such as novel immunohistochemistry scores, tumour, stromal and immune cell gene expression profiling, and liquid biomarkers such as systemic inflammatory markers, kynurenine/tryptophan ratio, circulating immune cells, cytokines and DNA are discussed in this review. We also examine the influence of the faecal microbiome on treatment outcome and its use as a biomarker of response and toxicity.

Background: The incidence of prostate cancer (PC) has been risen annually. Despite the diagnosis is made mainly with non-metastatic PC, mortality is explained by the metastatic disease (mPC). Without a doubt there is an intermediate scenario in which patients have no mPC but will have initiated a metastatic cascade through an epithelial-mesenchymal transition. There is indeed a need for more and better tools to predict what patients will progress in the future to non-localized clinical disease or already have micrometastatic disease, and therefore, will clinically progress after primary treatment. Biomarkers for predicting mPC are still under development; there are few studies and not much evidence of their usefulness. Summary: This review is focused on tissue-based genomic biomarkers (TBGB) for predicting metastatic disease. We developed four main research questions that will attempt to answer according to the current evidence. Why is important to predict metastatic disease? Which tests are available to predict metastatic disease? What impact should there be on clinical guidelines and clinical practice in predicting metastatic disease? What are current prostate cancer treatments? Key Messages: Knowing useful predict tools could help determine which patients may need multimodal or adjuvant treatment even with a localized disease, and in consequence, what patients do not need more than a single modality of treatment. The importance of predicting metastasis is fundamental, given that once metastasis is diagnosed, the quality of life (QoL) and survival drop dramatically.

Background: Biomarker profiles should represent a coherent description of the colorectal cancer (CRC) stage and its evolution. Methods: Using droplet digital PCR, we detected the allelic frequencies (AF) of KRAS, NRAS, BRAF and EGFR mutations from 60 tumors. We employed a pair-wise association approach to estimate the risk involving AF mutations as outcome variables for clinical data and as predicting variables for tumor-staging. We evaluated correlations between mutations AFs and also between the mutations and histopathology features (tumor staging, inflammation, differentiation and invasiveness). Results: KRAS G12/G13 mutations were present in all patients. KRAS Q61 was significantly associated with poor differentiation, high desmoplastic reaction, invasiveness (ypT4) and metastasis (ypM1). NRAS and BRAF were associated with the right-side localization of tumors. Diabetic patients had a higher risk to exhibit NRAS G12/G13 mutations. BRAF’s presence limited the invasiveness in the submucosa, co-existing with NRAS G12/G13 mutations. Conclusions: The associations we found and the mutational AF we reported may help to understand disease processes and may be considered as potential CCR biomarker candidates. In addition, we propose representative mutation panels associated with specific clinical and histopathological features of CRC, as a unique opportunity to refine the degree of personalization of CRC treatment.

Objective: The aim of study is to find key genes and enriched pathways associated with lung cancer. Participants and Methods: Differentially expressed genes (DEGs) data of 54674 genes based on stage, tumor and status of lung cancer was taken from 66 patients of African American (AAs) origin. 2392 DEGs were found based on stage, 13502 DEGs were found based on tumor, 2927 DEGs were found based on status having p value (p<0.05). Results: Total 33 common DEGs were found from stage, tumor and status of lung cancer. Gene ontology (GO) and KEGG pathway enrichment analysis was performed and 49 significant pathways were obtained, out of which 10 pathways were found to be exclusively involved in lung cancer development. Protein-protein interaction (PPI) network analysis found 69 nodes and 324 edges and identified 10 hub genes based on their highest degrees. Module analysis of PPI found that ‘Viral carcinogenesis’, ‘pathways in cancer’, ‘notch signaling pathway’, ‘AMPK signaling pathways’ had a close association with lung cancer. Conclusion: These identified DEGs regulate other genes which play important role in growth of lung cancer. The key genes and enriched pathways identified can thus help in better identification and prediction of lung cancer.

Background: So far, vaccination has been considered the most crucial defense against viral infection, including SARS-CoV-2. Numerous reports have demonstrated the effectiveness of the above vaccines in oncology patients. It has also been proven that, apart from vaccinations and oncological therapy, the course of the cancer process itself influences the magnitude of the humoral response, especially in people after infection with SARS-CoV-2. Objective: This study aimed to answer the question about the impact of the cancer process on the humoral response in oncological patients vaccinated against SARS-CoV-2 infection and in patients after COVID-19. Material and methods: 1,668 people were observed. Over two years, 5,082 SARS-CoV-2 IgG and IgM antibody samples were determined. The concentration of antibodies was assessed in three groups of oncological patients: those undergoing anticancer therapy after contracting COVID-19 and those after vaccination against the SARS-CoV-2 infection. Results: The obtained results indicate a naturally more significant humoral response in oncological patients who have not been vaccinated and have not undergone anticancer therapy, such as radiotherapy, chemotherapy, or surgical intervention. The above observation applies to patients with breast, lung, and colon cancer, although the response varies significantly depending on the type of cancer. Summary: The size of the humoral response and the presence of specific antibodies directed against the SARS-CoV-2, IgM, and IgG, in response to the supply of the vaccine antigen or assessed after COVID-19, is an indicator of adequate immune protection against reinfection. This study highlights for the first time the phenomenon of increased humoral response in response to a viral infection in patients with certain types of cancer that are assumed to be sensitive to oncological therapy, the initiation of which, according to generally accepted principles, was blocked by infection with the SARS-CoV-2. The phenomenon we observe seems to confirm the presence of a "natural" defence potential in a cancer patient's body, in this case, directed against infection with a viral pathogen. A "stronger" antiviral response also seems to explain the asymptomatic course of SARS-CoV-2 infection in some of the above patients. It remains an open question to what extent the SARS-CoV-2 infection weakened the "natural" potential of the anticancer response in these patients.

Lung cancer is one of the leading causes of cancer-related mortality globally. Pulmonary nodules are one of the risk factors and their discovery rate has been increasing. Based on the nodule size and growth rate, their malignancy propensity is determined; however, it is very challenging to distinguish between benign and cancerous nodules. Many tumour-associated antigens (TAA) have been studied as blood biomarkers for lung cancer, most commonly the Cytokeratin 19 fragment (CYFRA 21-1), squamous cell carcinoma antigen (SCC Ag), carbohydrate antigen (CA19-9) and carcinoembryonic antigen (CEA). Due to their low sensitivity, TAAs are not recommended as tools for the early detection of lung cancer. However, cancer testis antigens (CTAs) are highly specific for carcinomas but their expression is more commonly associated with advanced stages of cancer and poor prognosis. Despite the fact that TAAs may provide useful insights for the diagnosis and prognosis of early lung cancer, their potential to do so has yet to be demonstrated.

Lung cancer remains the leading cause of cancer-related mortality worldwide. The main issue is the absence of a screening test available in clinical practice; the identification of non-invasive biomarkers is thus an urgent clinical necessity. Currently, low-dose computed tomography (LD-CT) demonstrates a 20% reduction of lung cancer mortality. However, it is not particularly suitable for clinical practice because of the costs, radiation, and the false positive rate. Several studies have therefore focused on research into biomarkers in body fluids. Despite the power of certain molecules to distinguish lung cancer patients from healthy subjects, no biomarker has yet been shown to significantly and reliably influence clinical decisions or to be translated from the laboratory to clinical practice. We performed an overview of the peer-reviewed biomedical literature published in the last 10 years on the research regarding biomarkers for the early diagnosis of lung cancer via a comprehensive analysis of the reviews published this past year. Our main aim was to bring to light the limitations and strengths of the research already conducted. Furthermore, future prospectives have been explored, bearing in mind the management of clinical trials and their integration into clinical practice.

Iron (Fe) is a trace element that plays essential roles in various biological processes such as DNA synthesis and repair, as well as cellular energy production, or oxygen transport, and it is currently widely recognized that iron homeostasis is dysregulated in many cancers. Indeed, several iron homeostasis proteins may be responsible for malignant tumor initiation, proliferation, and for metastatic spread of tumors. A large number of studies demonstrated the potential clinical value of turning these deregulated proteins as prognostic and/or predictive biomarkers of malignancy and /or response to anticancer treatments. Additionally, the iron addiction of cancer cells and the importance of iron in ferroptosis cell death signaling pathways prompted the development of therapeutic strategies against advanced stage or resistant cancers. In this review, we selected relevant and promising studies in the field of iron metabolism in cancer research and clinical oncology. Besides, we discuss some co-existing discrepant findings. We will also present and discuss the latest lines of research related to targeting iron, or its regulatory pathways, as potential promising anti-cancer strategies for human therapy. Iron chelators, such as deferoxamine or iron-oxide based nanoparticles, which are already tested in clinical trials, alone or in combination with chemotherapy will also be reported.

Nowadays, cervical cancer (CC) is treated as the leading cancer among women throughout the world. Despite effective vaccination and improved surgery and treatment, CC remains its fatality rate about half of the infected populations globally. The major screening biomarkers and therapeutic target identification have now become a global concern. The present study, we have employed systems biology approaches to retrieve the potential biomarkers and pathways from the transcriptomic profiling. Initially, we have identified 76 of each up-regulated and down-regulated gene from a total of 4,643 differentially expressed genes. The up-regulatory genes are mainly concentrating on immune-inflammatory response and the down-regulatory genes are on receptor binding and gamma-glutamyltransferase. The involved pathways associated with these genes were also assessed through pathway enrichment and they were mainly focused on different cancer pathways, immunoresponse, and cell cycle pathways. After the subsequent enrichment of these genes, we have identified 12 hub genes, which play a crucial role in CC. Furthermore, the survival of the hub genes was also assessed, and among them, finally, CXCR4 has identified as one of the most potential differentially expressed gene that might play a vital role to the survival of CC patients. Thus CXCR4 could be used as a prognostic biomarker and development of a drug target for CC.

Purpose: Recently introduced molecules namely long non-coding RNAs (lncRNAs) are associated with various diseases, including breast cancer, and they may have the potential to act as biomarkers. Invasive ductal carcinoma (IDC) is a frequently observed type of breast cancer that diagnosis through immunohistochemical methods. However, no reliable non-invasive markers such as circulating markers have been introduced for it, so far. Materials and methods: The relative quantitation (RQ) of two lncRNAs, RP11-445H22.4 and TINCR, was measured in tumoral tissues and paired adjacent non-tumoral tissues (PANTs) as well as in plasma samples using real-time polymerase chain reaction (RT-PCR). Furthermore, promoter methylation of the two lncRNAs genes was assessed using methylation-specific PCR (MSP). In order to compare the diagnostic values, plasma levels of CA 15-3 were measured as a conventional circulating biomarker using ELISA. The receiver operating characteristic (ROC) curve was used to illustrate the sensitivity and specificity of the potential biomarkers. Results: The RP11-445H22.4 and TINCR genes were upregulated in tumor tissues compared to PANTs (RQ_{RP11-445H22.4} = 2.7, RQ_TINCR = 4.4). Furthermore, the presence of RP11-445H22.4 and TINCR in the plasma of patients was significantly more than healthy controls (RQ_{c.RP11-445H22.4} = 4.12, RQ_c.TINCR = 4.16, P<0.001). The promoters of RP11-445H22.4 and TINCR genes were hypomethylated in the tumoral tissues with a negative correlation with their gene expression. Conclusion: Based on the findings, it can be speculated that the expression levels of these two lncRNAs as well as their promoter methylation can be considered as a therapeutic target and potential biomarker for breast carcinoma.

Radiomics refers to the extraction and analysis of a wide range of medical imaging features in a non-invasive and cost-effective manner to comprehensively characterise tumours. In this study, machine learning models combining radiomics and clinical factors were developed to predict retroperitoneal lymph node metastasis in testicular germ cell tumours (TGCTs), with the aim of reducing unnecessary treatment in this group of young patients. Ninety-one patients with surgically proven testicular germ cell tumours and contrast-enhanced CT were included in this retrospective study. After segmenting 273 retroperitoneal lymph nodes using dedicated radiomics software, we developed machine-learning prediction models using Random Forest (RF), Light Gradient Boosting Machine (LGBM), Support Vector Machine Classifier (SVC), and K-Nearest Neighbours (KNN). For each classifier, we developed a radiomics-only, clinical-only, and combined radiomics-clinical prediction model. The models’ performances were evaluated using the area under the receiver operating characteristic curves (AUCs). The RF-based combined clinical and radiomic model showed the most robust performance in predicting LNM with an area under the curve (AUC) of 0.95 (±0.03; 95% CI), accuracy 87%, precision 89%, recall 86% and F1 score 87%, followed by the LGBM model with an area under the curve (AUC) of 0.93 (±0.05; 95% CI), accuracy 83%, precision 87%, recall 80% and F1 score 82%. Decision curve analysis demonstrated the clinical utility of our proposed RF-based combined clinical–radiomics model. Our study has identified reliable and predictive machine-learning techniques for predicting lymph node metastasis in early-stage testicular cancer. Identifying the most effective machine-learning approaches for predictive analysis based on radiomics integrating clinical risk factors can expand the applicability of radiomics in precision oncology and cancer treatment. Multi-centre validation is required to provide high-quality evidence for clinical application.

Frontal Temporal Dementia (FTD) is a neurological disorder known to have less therapeutic options. So far only a few biomarkers are available for FTD that can be used as potential comorbidity targets. To this end, in the present study we aim to identify potential biomarkers or susceptible genes for FTD that show comorbidities with diseases such as COVID-19 and Breast Cancer. Gene expression Omnibus datasets containing FTD expression profiles from African American and white ethnicity background were included in our study. In FTD samples of GSE193391 dataset, we identified 305 DEGs with 168 genes being up-regulated and 137 genes being down-regulated. We conducted comorbidity analysis for COVID-19 and Breast cancer followed by analysis of potential drug interactions, pathogenicity, analysis of genetic variants and functional enrichment analysis. Resulting genes AKT3, GFAP, ADCYAP1R1, VDAC1, and C4A showed significant transcriptomic alterations in FTD and significant comorbidity status with COVID-19 and Breast cancer. Functional pathway analysis revealed that these comorbid genes were significantly enriched in the pathways such as glioma, JAK/STAT signaling, systematic lupus erythematosus, neurodegeneration-multiple diseases and neuroactive ligand-receptor interaction. Overall, from these results, we concluded that these genes could be recommended as potential therapeutic targets for the treatment of comorbidities in FTD.

Pancreatic cancer is the most lethal cancer, it has lowest 5-year survival rate among other types of cancers. More than half of pancreatic cancer are diagnosed at distant stage due to its insidious and non-specific symptoms. Surgery is the most effective treatment to date, but only 10-20% are resectable upon diagnosis. Currently, the only biomarker approved by the United States Food and Drug Administration (US-FDA) for pancreatic cancer is carbohydrate antigen 19-9 (CA19-9); however, it has limited use for early diagnosis. An increasing number of studies have a combination of biomarkers. Recently, the application for liquid biopsy has drawn a lot of attention, such as the use of microRNA (miRNA), circulating tumor DNA (ctDNA), and circulating tumor cells (CTC). Screening for pancreatic cancer is indicated for high-risk patients; studies of new diagnostic models combined with biomarkers for early detection also showed promising results to aid clinicians in deciding on whether to start screening. This review aims to summarize the progress on current biomarkers and new potential strategies for early detection of pancreatic cancer.

Background: Identification of cancer biomarkers that are differentially expressed (DE) under two biological conditions is an important task in many microarray studies. There exist several methods in the literature in this regards and most of these methods designed especially for unpaired samples, which does not satisfy the requirements of paired samples where the gene expressions are taken from the same patients before and after treatment. Furthermore, the traditional biomarker identification methods based on either p-values or fold change (FC) values. However, sometimes, p-value based results do not comply with FC based results due to the smaller variance of gene expressions. There are some methods that combine both p-values and FC values to solve this problem. But, these methods also show weak performance for small-sample case in presence of outlying expressions. To overcome this problem, in this paper an attempt is made to develop a hybrid robust SAM-FC approach by combining rank of FC values and rank of p-values based on SAM statistic using minimum β-divergence method, which is designed for paired samples. This method introduces a weight function known as β-weight function. This weight function produces larger weights corresponding to usual/normal expressions and smaller weights for unusual/outlying expressions. The β-weight function plays the significant role on the performance of the proposed method. Results: The proposed method uses β-weight function as a measure of outlier detection by setting β=0.2. We unify both classical and robust estimates using β-weight function such that maximum likelihood estimators (MLEs) are used in absence of outliers and minimum β-divergence estimators are used in presence of outliers to obtain reasonable p-values and FC values in the proposed method. We examined the performance of proposed method in a comparison of some popular methods (t-test, SAM, LIMMA, Wilcoxon, WAD, RP and FCROS) using both simulated and real gene expression profiles for both small-and large-sample cases. From the simulation and a real spike in data analysis results we observed that the proposed method outperforms other methods for small-sample case in presence of outliers and it keeps almost equal performance with other robust methods (Wilcoxon, RP and FCROS) otherwise. From a head-and-neck cancer (HNC) dataset the proposed method identified 2 genes (CYP3A4, NOVA1) that are significantly enriched in linoleic acid metabolism, drug metabolism, steroid hormone biosynthesis and metabolic pathways. The survival analysis through Kaplan-Meier curve revealed that combined effect of these 2 genes has prognostic capability and they might be promising biomarker of HNC. Moreover, we retrieved the 12 candidate drugs based on gene interaction from glad4u and drug bank databases. Conclusion The identified drugs showed statistical significance and critical role of the proteins indicate that these proteins might be therapeutic target in cancer. Thus, elucidating the associations between the drugs identified in the present study require further investigations.

Breast cancer (BC) is the second leading cause of death in the United States in women. 1 in 8 women in their lifetime has a risk of developing breast cancer. With advances in omics technology, more data is available for diagnosis, treatment, and prognosis. The help of Machine Learning algorithms, a subdomain of Artificial Intelligence, would allow for a better clinical support tool. Machine Learning could be the key to answering a complex problem in BC. The methodology of this research question involves collecting and finding data such as RNA-Seq datasets, selecting and training appropriate machine learning algorithms, and evaluating the performance of the algorithms in predicting BC prognosis. Also, the study explores and tries to identify the most relevant genes and pathways through feature selection extraction and dimensionality reduction techniques. After applying feature extraction, the top 10 genes were extracted using the Univariate Feature Selection (UFS) method, precisely the SelectKBest technique. After employing different machine learning algorithms, such as Networks, Random Forest, Linear SVM, Logistic Regression, and Quadratic Discriminant Analysis (QDA), we found QDA was the best model in classifying the RNA-seq dataset with a 96% accuracy rate and 94% ROC AUC. This study suggests that AK2 and CD68 have a positive correlation with each other, and it could potentially be a biomarker and therapeutic target for BC.

Lung cancer is the leading cause of cancer related mortality worldwide. In order to improve its overall survival, early diagnosis is required. Since current screening methods still face some pitfalls, such as high false positive rates for low-dose computed tomography, researchers are still looking for early biomarkers to complement existing screening techniques in order to provide a safe, faster and more accurate diagnosis. Biomarkers are biological molecules found in body fluids, such as plasma, that can be used to diagnose a condition or disease. Metabolomics has already shown to be a powerful tool in the search for cancer biomarkers since cancer cells are characterised by impaired metabolism, resulting in an adapted plasma metabolite profile. The metabolite profile can be determined using nuclear magnetic resonance, or NMR. Although metabolomics and NMR metabolite profiling of blood plasma are still under investigation, there is already evidence for its potential for early-stage lung cancer diagnosis, therapy response, and follow-up monitoring. This review highlights some key breakthroughs in this research field, where the most significant biomarkers will be discussed in relation with their metabolic pathways and in light of the altered cancer metabolism.

Cancer is a common illness with a high mortality. Compared to traditional technologies, biomarkers detection, with low cost and simple operation, has higher sensitivity and faster speed in early screening and prognosis of cancer. Therefore, extensive research has been focused on the development of biosensors and the construction of sensing interfaces. Molybdenum disulfide (MoS2) is a promising two-dimensional (2D) nanomaterial, whose unique adjustable bandgap shows excellent electronic and optical properties in the construction of biosensor interfaces. It not only has the advantages of high catalytic activity and low manufacturing costs, but also can further expand the application of hybrid structures by different functionalization, and is widely used in various biosensors fields. Herein, the application of electrochemical and optical sensing platforms based on MoS2 in the detection of cancer biomarkers was comprehensively reviewed. Firstly, the structure and preparation method of MoS2 were introduced, and its applicable characteristics in the field of biosensors were explored. Secondly, we comprehensively reviewed the recent construction and application of sensing platform based on MoS2 in the field of cancer biomarkers detection in both electrochemical and optical aspects. The prime characteristics and application performances of MoS2 and its composites were emphasized. Additionally, we also involved some other types of biosensors based on MoS2. Finally, we summarized the challenges and development prospects of MoS2 in the application of cancer biomarkers detection, and provided some insights for the application potential of this kind of emerging nano-materials in a broader field.

Pharmacists must acquire the necessary knowledge to provide better drug therapy to patients. In other words, educational programs need to facilitate behavioral changes among pharmacists. Therefore, this study aimed to evaluate how the behavior of pharmacists changed after attending a palliative care educational program. We conducted a web-based questionnaire survey examining the behavior of pharmacists regarding palliative care before participating in the program, two months after participating in the program, and eight months after participating in the program, to determine the behavior and changes over time. For all questions, scores were higher at two and eight months after attending the program than before attending the program (P &lt;0.05). In addition, no significant difference was observed between two and eight months after attending the program for all questions (P =0.504-1.000). The knowledge gained from the educational program was used to repeatedly intervene with patients with cancer, to address the various symptoms they experienced and maintain their behavior. The proven effectiveness of this program serves as a stepping stone for a nationwide rollout across Japan’s 47 prefectures.

Pancreatic cancer (PC) is the most lethal type of cancer, it has the lowest 5-year survival rate among all other types of cancers. More than half of PC cases are diagnosed at an advanced stage due to PC’s insidious and non-specific symptoms. Surgery remains the most efficacious treatment option currently available, but only 10-20% of PC cases are resectable upon diagnosis. As of now, the sole biomarker approved by the United States Food and Drug Administration (US-FDA) for PC is carbohydrate antigen 19-9 (CA19-9); however, its use is limited use for early diagnosis. An in-creasing number of studies have investigated a combination of biomarkers. Lately, there has been considerable interest in the application of a liquid biopsy, including the utilization of microRNAs (miRNAs), circulating tumor DNA (ctDNA), and circulating tumor cells (CTCs). Screening for PC is indicated for high-risk patients; studies on new diagnostic models combined with biomarkers for early detection have also shown promising results for the ability of these models and biomarkers to aid clinicians in deciding on whether to start screening. This review seeks to provide a concise overview of the advancements in existing biomarkers and explore novel strategies for the early detection of PC.

Introduction: Lymph-nodal prostate cancer oligometastases are differently treated according to their site: pelvic are locoregional lymph-nodes, instead para-aortic lymph-nodes are considered as distant metastases. Aim of the study was a comparison between para-aortic and pelvic oligometastases treated with stereotactic body radiation therapy (SBRT). Material/methods: This is a retrospective analysis. De-novo metastatic or extra-nodal disease were excluded. Univariate and multivariate analyses were performed; pattern of recurrence was evaluated too. A propensity score matching (PSM) was applied to create comparable cohorts. Primary end-point was the progression-free survival (PFS). Secondary end-points were biochemical relapse-free survival (BRFS), ADT-free survival (ADTFS), polymetastases-free survival (PMFS), local progression-free survival (LPFS) and pattern of relapse. Results: 240 lymph-nodal oligometastases in 164 patients (127 pelvic and 37 para-aortic) were treated. Median PFS was 20 and 11 months in pelvic and para-aortic patients respectively (p=0.042). The difference was not confirmed at the multivariate analysis (p=0.06). Median BRFS was 16 and 9 months respectively in pelvic and para-aortic group (p=0.07). No statistically significant differences for ADTFS or PMFS were detected. The cumulative 5-years LPFS was 90.5%. At PSM no statistically significant differences for all the study end-points were detected. Conclusions: Patients affected by para-aortic disease might have PFS comparable to pelvic disease; local control is high in both cohorts. Our results support the use of SBRT also to para-aortic metastases.

The concept and policies of multiple early cancer detection (MCED) have gained significant attention from governments worldwide in recent years. In the era of burgeoning artificial intelligence (AI) technology, the integration of MCED with AI has become a prevailing trend, giving rise to a plethora of MCED AI products. However, due to the heterogeneity of both the detection targets and the AI technologies, the overall diversity of MCED AI products remains considerable. The types of detection targets encompass protein biomarkers, cell-free DNA, or combinations of these biomarkers. In the development of AI models, different model training approaches are employed, including datasets of case-control researches or real-world cancer screening datasets. Various validation techniques, such as cross-validation, location-wise validation, and time-wise validation are used. All of the factors show significant impacts on the predictive efficacy of MCED AIs. After the completion of AI model development, deploying the MCED AIs in clinical practice presents numerous challenges, including presenting the predictive reports, identifying the potential locations and types of tumor, and addressing cancer-related information such as clinical follow-up and treatment. This study reviews several mature MCED AI products currently available in the market, detecting their composing factors from serum biomarkers detection, MCED AIs training/validation, and the clinical application. The review illuminates the challenges encountered by existing MCED AI products across these stages, offering insights into the continued development and obstacles within the field of MCED AI.

MicroRNAs are used as biomarkers for classification of cancer subtypes since certain miRNAs are differentially expressed in normal and patient samples. Moreover, miRNAs target mRNAs and can heavily influence Gene Expressions. Thus, deregulation of miRNAs is linked to various disorders. Thus, miRNAs can be used for prognosis and developing personalized health solutions for patients. Given the importance of miRNAs, there has been substantial work done in the field. In this paper, recent works in the field of using miRNAs expressions of patients were considered. A total of 20 papers were surveyed which utilized feature selection ensembles, fuzzy logic as well as deep learning. 10 papers have been reported which offer insight into how miRNAs can be utilized for subtype-specific or generalized cancer diagnosis.

1) Background: One of the most common cancer that affects men worldwide and North American men is prostate cancer. Gleason score is a pathological grading system to examine the potential aggressiveness of the disease in the prostate tissue. The advancement in computing and next-generation sequencing technology now allow us to study the genomic profiles of patients in association with their different Gleason score more accurately and effectively. 2) Methods: In this study, we used a novel machine learning method to analyze gene expression of prostate tumors with different Gleason scores, and identify potential genetic biomarkers for each Gleason group. We obtained a publicly-available RNA-Seq dataset of a cohort of 104 prostate cancer patients from the National Center for Biotechnology Information’s (NCBI) Gene Expression Omnibus (GEO) repository, and categorized patients based on their Gleason scores to create a hierarchy of disease progression. A hierarchical model with standard classifiers in different Gleason groups, also known as nodes, was developed to identify and predict nodes based on their mRNA or gene expression. In each node, patient samples were analyzed via class imbalance and hybrid feature selection techniques to build the prediction model. The outcome from analysis of each node is a set of genes that can differentiate each Gleason group from the remaining groups. To validate the proposed method, the set of identified genes are used to classify a second dataset of 499 prostate cancer patients collected from cBioportal [1]. 3) Results: The overall accuracy of applying this novel method to the first dataset was 93.3%, and further validated to 87% accuracy using the second dataset. This method also identified genes that were not previously reported as potential biomarkers for specific Gleason groups. In particular, PIAS3 was identified as a potential biomarker for Gleason score 4+3=7, and UBE2V2 for Gleason score 6. 4) Insight: Previous reports show that the genes predicted by this newly proposed method strongly correlate with prostate cancer development and progression. Furthermore, pathway analysis shows that both PIAS3 and UBE2V2 share similar protein interaction pathways, the JAK/STAT signaling process.

Intermediate filaments constitute the third component of the cellular skeleton. Unlike actin and microtubule cytoskeletons, the intermediate filaments are composed of wide variety of structurally related proteins showing distinct expression patterns in tissues and cell types. Changes in expression patterns of intermediate filaments are often associated with cancer progression, in particular with phenotypes leading to increased cellular migration and invasion. In this review we will describe the role of vimentin intermediate filaments in cancer cell migration, cell adhesion structures, and metastasis formation. The potential for targeting vimentin in cancer treatment and the development of drugs targeting vimentin will be reviewed.

Lung cancer remains the main cause of global cancer-related deaths. Currently low-dose computed tomography (LD-CT) shows a 20% reduction of mortality. However, its clinical suitability is hindered by cost, radiation, and some false positives. Thus, the discovery non-invasive and less-expensive biomarker is urgent needed. In this scenario, proteins released in biological fluids could be considered interesting biomarkers for their role in cancer development. We conducted a pioneering case-control pilot study aimed at assessing the usefulness of Raf Kinase Inhibitory Protein (RKIP) and its phosphorylated form (pRKIP) as potential early-stage lung cancer biomarkers. Urine and Blood samples of two consecutive and independent cohorts of lung cancer patients and healthy controls were screened by means of a novel experimental ELISA assay designed to evaluate both forms of the biomarker. Although urinary levels of RKIP were not statistically different between the lung cancer group and high-risk healthy group, serum ones instead increased significantly in early stage LC patients and permitted to discriminate LC patients from both low-risk (HS) and high-risk healthy subjects (HR-HS) with an overall 93% accuracy (AUC 0.93) when LC was compared to HS and 74% (AUC 0.73) when it was compared to high-risk group. Of note, the analysis of RKIP/pRKIP ratio also showed a high accuracy (90% - AUC 0.95) in discriminating LC patients from HS and more importantly, it allowed to identify LC patients compared to HR-HS, with a higher accuracy (79% - AUC 0.79) than RKIP alone. We hypothesize that serum RKIP levels may be correlated to the activation of the immune systems against the tumor during the first phases of its development. Our study identified a preliminary, non-invasive, RKIP and pRKIP profile able to discriminate with high specificity and sensitivity the early-stage lung cancer patients from high-risk Healthy Subjects. These results, although preliminary, suggest the utility of measuring RKIP/pRKIP as potential new screening test for lung cancer and provide the basis for future validation studies.

Next-generation sequencing (NGS) has actualized human papillomavirus (HPV) virome profiling for in-depth investigation of viral evolution and pathogenesis. However, viral computational analysis remains a bottleneck due to semantic discrepancies between computational tools and curated reference genomes. To address this, we developed and tested automated workflows for HPV taxonomic profiling and visualization using a customized Papillomavirus database in CLC Microbial Genomics Module. HPV genomes from Papilloma Virus Episteme were customized and incorporated into CLC “ready-to-use” workflows for stepwise data processing to include: 1) Taxonomic Analysis, 2) Estimate Alpha/Beta Diversities, and 3) Map Reads to Reference. Low-grade (n = 95) and high-grade (n = 60) Pap smears were tested with ensuing collective runtimes: Taxonomic Analysis (36 min); Alpha/Beta Diversities (5 sec); Map Reads (45 min). Tabular output conversion to visualizations entailed 1-2 keystrokes. Biodiversity analysis between low- (LSIL) and high-grade squamous intraepithelial lesions (HSIL) revealed loss of species richness and gain of dominance by HPV-16 in HSIL. Integrating clinically relevant, taxonomized HPV reference genomes within automated workflows proved to be an ultra-fast method of virome profiling. The entire process named “HPV DeepSeq” provides a simple, accurate and practical means of NGS data analysis for a broad range of applications in viral research.

Introduction: Colorectal cancer (CRC) is a disease of colon or rectum the part of digestive system. DNA methylation is a process of gene expression by recruiting protein which involve in gene repression, or inhibiting the binding of transcription factors to DNA. MicroRNAs (miRNAs) have been attracting major interest as potential biomarker in cancer. Hereditary nonpolyposis of colorecta cancer (HNPCC) is a type of genetic change (mutation) in a family. Our aims to do a systematic review on DNA methylation and miRNAs serve as candidate clinical biomarkers in HNPCC. Materials and methods: Electronic databases (Medline, PubMed and Scopus data bases). We searched to identify publication all over the world related colorectal cancer and miRNA. Selection was based on the design (CRC, invasive CRC, Colon or rectum, HNPCC, microRNA, circulating miRNA, non-coding RNA), 87 papers from PubMed and 15 papers from Scopus were selected all over the world. CRC, target antigens, methodologies used for detection and miRNA expression were identified and summarized. Results: A total of 96 articles were searched, 87 articles from scopus and 9 articles from PubMed. 20 duplicates removed and remain 76, 52 excluded after screened the titles and abstracts; and remain 24, 10 full texts articles were excluded with reason, and 14 identifications were included in the studies. Conclusion: The findings of this systematic review showed that DNA methylation and mircroRNA in HNCC patients as a genetic mutation or a promoter in colorectal cancer.

Background and objectives: TSC1 is a crucial component of the mTOR pathway, impacting cell growth, proliferation, and autophagy, while TSC2 is a tumor suppressor gene that regulates cell growth and is associated with the mTOR signaling pathway. In the present study, we analyzed TSC1 and TSC2 mRNA expression levels in rectal cancer, and evaluated the clinicopathological and prognostic characteristics of TSC1 and TSC2. Materials and Methods: TSC1 and TSC2 mRNA expression was examined in various cancer types. We further evaluated survival to determine the prognostic significance of TSC1 and TSC2 mRNA in CRC using The Cancer Genome Atlas (TCGA) data. Results: The study focused on rectal cancer, as it exhibited the most promising results. The patients were split into two subgroups, each comprising 50% of the total, based on the TSC gene expression levels. This division was made to assess the clinical characteristics associated with the expression of TSC1 and TSC2 genes. In the study, lower TSC1 expression was linked to venous invasion in rectal cancer patients, and there was also a related trend with lymphatic invasion, although it didn't reach statistical significance. Lower TSC2 expression was observed in younger patients and had some associations with sex and M stage, but these correlations were not statistically significant. When it came to survival analysis, TSC1 expression did not significantly impact overall survival, while higher TSC2 expression was associated with a poorer prognosis in rectal cancer. To enhance our comprehension, additional research, especially in larger case studies, is needed to explore the molecular mechanisms and clinical characteristics of TSC genes in colorectal cancer.

Despite the recent availability of immune checkpoint inhibitors, not all patients affected by Non-Small Cell Lung Cancer (NSCLC) benefit from immunotherapy. The reason for this variability relies to a variety of factors which may allow the identification of novel biomarkers. Presently, a variety of biomarkers are under investigation, including the PD1/PDL1 axis, the tumor mutational burden, and the Microbiota. This latter is made by all bacteria and other microorganisms hosted in our body. The gut microbiota is the most represented and has been involved in different physiological and pathological events, including cancer. In this light, it appears that all conditions modifying gut microbiota can influence cancer, its treatment, and its treatment-related toxicities. The aim of this review is to analyze all conditions influencing the gut microbiota and, therefore, affecting response to immunotherapy, iRAEs and their management in NSCLC patients. The investigation of the landscape of these biological events can allow novel insights for optimal management of NSCLC immunotherapy.

This work aims to investigate the expression levels of four preselected miRNAs previously linked to Cancer and/or Obesity, with the purpose of finding potential biomarkers in the clinical management of Colorectal Cancer (CRC) developed by obese and non-obese patients. We analyzed samples from a total of 65 subjects, 43 affected by CRC and 22 without cancer. Serum and both subcutaneous and omental adipose tissues (SAT and OAT) were analyzed, as well as tumor and non-tumor colorectal tissues in the case of the CRC patients. The relative expression (2-∆∆Ct) levels of 4 miRNAs (miR-181a-5p, miR-143-3p, miR-132-3p and miR-23a-3p) were measured by RT-qPCR. Serum, SAT and OAT expression levels of these miRNAs showed significant differences between subjects with and without CRC, especially in the group of overweight/obese subjects. In CRC serum levels of miR-181a-5p, miR-143-3p and miR-23a-3p correlated with their levels in both SAT and OAT. Moreover, in the case of miR-181a-5p, these correlations were significantly influenced by the body mass index (BMI). From these data, we can conclude that both adiposity and CRC induce changes in the expression of the miRNAs investigated, demonstrating the potential utility of this panel of miRNAs in the diagnosis and prognosis of CRC patients.

Background: Pancreatic neuroendocrine tumors (pNETs) represents a rare subset of pancreatic cancer. Functional tumors caused hormonal changes and clinical syndromes, while non-functional ones are often diagnosed late. Surgical management need a multidisciplinary planning, involving enucleation, distal pancreatectomy with or without spleen preserving, cen-tral pancreatectomy, pancreaticoduodectomy or total pancreatectomy. Minimally invasive ap-proach increased in the last decade compared to the open technique. The aim of this study is to analyze current diagnostic and surgical trends for pNETs, to identify better interventions and their outcomes. Methods: The study adhered to PRISMA guidelines, conducting a systematic review of literature from May 2008 to March 2022 across multiple databases. Several combinations of keywords was used ("NET", "pancreatic", "surgery", "laparoscopic", "minimally invasive", "robotic”, “enuclea-tion”,“parenchima sparing”) and relevant article references was manually checked. Manuscript quality was evaluated. Results: The study screened 3867 manuscripts, twelve studies were selected, primarily from Ita-ly, the United States, and China. A total of 7767 surgical treated patients was collected from 160 included centers. The mean age was 56,3 y.o. Enucleations (EN) and distal pancreatectomy (DP) was the most common performed surgery and represents 43.4% and 38.6% of the total interven-tions, respectively. Pancreatic fistula, post operative bleeding, re-operation and follow up was recorded and analyzed. Conclusions: Enucleation show better postoperative outcomes and lower mortality rates com-pared to pancreaticoduodenectomy (PD) or distal pancreatectomy (DP), despite similar risks of postoperative pancreatic fistula (POPF). DP was preferred over enucleation for pancreas body-tail, while laparoscopic enucleation is better for head pNETs.

(1) Background: This study aimed to investigate the effect of increased HER-2 expression on tumor-infiltrating lymphocytes (TILs) and determine its impact on the prognosis of colorectal cancer (CRC) patients; (2) Methods: HER-2, CD4, CD8, CD19, LY6G, CD56, CD68, CD11b, and EpCam expression in CRC tissues and adjacent paracancerous tissues were assessed using multiplex fluorescence immunohistochemical staining. The correlation between HER-2 expression and the number of TILs in CRC tissues was analyzed. Kaplan-Meier and Cox proportional hazards models were used to analyze survival outcomes; (3) Results: The expression of HER-2 in tumor tissues was higher than that in paracancerous tissues (1.31 ± 0.45 vs. 0.86 ± 0.20, P < 0.05). Additionally, there was an increase in the numbers of CD4+, CD8+, CD19+, and CD68+ cells in CRC tissues (14.11 ± 1.10 vs. 3.40 ± 0.18, P < 0.005; 0.16 ± 0.12 vs. 0.04 ± 0.04, P < 0.005; 0.71 ± 0.46 vs. 0.25 ± 0.13, P < 0.0005; 0.27 ± 0.24 vs. 0.03 ± 0.11, P < 0.05). The increase in HER-2 expression was positively correlated with an increase in CD4, CD8, and CD19 (p < 0.0001). In HER-2-positive CRC tissues, CD68 expression was increased (0.80 ± 0.55 vs. 0.25 ± 0.22, P < 0.05). In HER-2-upregulated CRC tissues, CD4, CD8, CD19, CD68, CD11b, Ly6G, and CD56 expressions were elevated (0.70 ± 0.37 vs. 0.32 ± 0.17, P = 0.03; 0.22 ± 0.13 vs. 0.09 ± 0.06, P = 0.03; 0.31 ± 0.19 vs. 0.12 ± 0.08, P = 0.02; 1.05 ± 0.62 vs. 0.43 ± 0.21, P < 0.01; 1.34 ± 0.81 vs. 0.53 ± 0.23, P < 0.01; 0.50 ± 0.31 vs. 0.19 ± 0.10, P < 0.01; 1.26 ± 0.74 vs. 0.52 ± 0.24, P < 0.01). Furthermore, increased HER-2 expression is an independent risk factor for recurrence-free survival (RFS) in patients (P < 0.01, HR = 3.421); (4) Conclusions: The increased expression of HER-2 and its relationship with immune cells will provide new insights for immunotherapy in CRC patients.

(1) Background: Among the chronic complications of type 2 diabetes mellitus, cancer became the leading cause of death in several countries. Our objective was the determination of whether prevalent type 2 diabetes mellitus is associated with a higher incidence of cancer. (2) Methods: This study is a nationwide analysis performed in Hungary. Study population was divided into a group with type 2 diabetes mellitus and into a non-diabetic group. The primary outcome was the risk related to overall cancer incidence. A key secondary outcome was the overall incidence of cancer in distinct study years. Further outcomes were the annual percent changes. (3) Results: The odds ratio related to the overall incidence of cancer was 2.50 (95% confidence interval: 2.46-2.55, P&lt;0.0001) in patients with diabetes as related to controls. The odds ratio was higher in males than in females. The highest risk was found in the 18-39-year-old subgroup. The annual cancer incidence rate declined in controls, but not in patients with diabetes. Several types of cancer showed a decreasing tendency in non-diabetic controls.; (4) Conclusions: type 2 diabetes is associated with a higher risk of cancer. High risk in young patients with type 2 diabetes suggests that these young individuals should be considered as a risk group.

Recent reports suggest that dysregulation of lipid metabolism is a key feature of the most invasive cancers. To identify potential biomarkers of tumor aggressiveness, we compared the proteomes of two experimental models of malignant mesothelioma in rats exhibiting different invasive properties. Quantitative changes between the most invasive, M5-T1, versus the least invasive, F4-T2, first led to a list of 424 proteins. A second step, cross-comparing this list with 433 proteins distinguishing invasive vs non-invasive tumors, led to identifying 88 proteins that specifically increased and 157 that decreased, respectively, characterizing the most aggressive M5-T1 tumor. Among the 15 mitochondrial proteins found in these lists, the very long-chain specific acyl-CoA dehydrogenase, encoded by the Acadvl gene and involved in fatty acid beta oxidation, appeared to play an important role in the metabolic reprogramming of the tumor microenvironment. Immunohistochemical staining of tumor sections confirmed increased expression of Acadvl in the M5-T1 tumor. Finally, the dramatic increase and decrease, observed in 25 and 17 proteins, respectively, suggested the existence of a strong link between mitochondrial events and modifications of the extracellular matrix, immune cell components or other subcellular compartments. These findings highlight some important aspects of the tumor microenvironment changes linked to aggressiveness.

Praeruptorin A(PA), a naturally existing pyranocumarin, is isolated from the dried root of Peucedanum praeruptorum Dunn. So far the anti-cancer effect and molecular mechanism behind Praeruptorin A action in human cervical cancer HeLa cells remain unknown. In the present study, we find that PA reduces cell proliferation and colony formation of human cervical cancer HeLa cells through inducing cell cycle arrest at G0/G1 phase. PA-upregulated p21 and p27 proteins are observed, accompanied with inhibition of cyclin D1 and S-phase kinase-associated protein 2(Skp2) proteins expression. PA could significantly inhibit migration and invasion of human HeLa cells. Meanwhile, PA significantly reduces invasive protein expression of matrix metalloproteinase-2 (MMP-2), and increases protein expression of tissue inhibitor of metalloproteinase-2 (TIMP-2). PA is observed to possess the capacity in suppressing ERK1/2 activation. PD98059 (ERK specific inhibitor) significantly enhances PA-induced downregulation of MMP-2 expression, and upregulation of TIMP-2 expression. Moreover, we found that PA treatment notably inhibits 12-O-tetradecanoylphorbol-13-acetate(TPA)-upregulated ERK1/2 activation, MMP-2 expression, cellular migration and invasion in human HeLa cells. Taken together, these findings are the first to demonstrate the anti-cancer activity of PA, which may act as a promising therapeutic agent for the treatment of human cervical cancer.

De-escalation is currently taking place both in surgical and systemic treatment of breast cancer. The introduction of trastuzumab, the first monoclonal antibody against the HER2 receptor over 20 years ago was a milestone in the treatment of HER2 positive breast cancer and marked the beginning of a new era in targeted tumor therapy. In the sense of de-escalation, omitting non-targeted cytotoxic chemotherapy altogether is often hailed as the ultimate goal of oncological research. Especially in case of small, node-negative, HER2 positive early breast cancer, it remains a challenge for clinicians to establish the safest and most efficient treatment plan while considering the significant potential for toxic side effects associated with chemotherapy and HER2 targeted therapy, and the generally excellent prognosis. In this context, several ongoing studies are currently assessing chemotherapy-free regimens as part of strategies aimed at de-escalating therapy in the field of HER2 positive early breast cancer. Despite promising early results from these studies, combination of anti-HER2 treatment with chemotherapy backbone remains standard of care.

In an effort to discover an effective and selective antitumour agent, synthesis and anti-cancer potential of 4-(pyridin-4-yl)-6-(thiophen-2-yl)pyrimidin-2(1H)-one (SK-25), which has been reported earlier by us with significant cytotoxicity towards MiaPaCa-2 malignant cells, with an IC₅₀ value of 1.95 μM and was found to instigate apoptosis. In the present study, the antitumour efficacy of SK-25 was investigated on Ehrlich ascites tumour (solid), Sarcoma 180 (solid) tumour and Ehrlich ascites carcinoma. The compound was found to inhibit tumour development by 94.71% in Ehrlich ascites carcinoma (EAC), 59.06% in Ehrlich tumour (ET, solid) and 45.68% in Sarcoma-180 (solid) at 30 mg/kg dose. Additionally, SK-25 was established to be non-toxic at a maximum tolerated dose of 1000 mg/kg in acute oral toxicity in Swiss-albino mice. Computer-based predictions also show that the compounds could have an interesting DMPK profile. The current study provides insight for further investigation of the antitumour potential of the molecule.

Background: Myometrial invasion (MI) is a parameter currently used in transvaginal ultrasound (TVS) in endometrial cancer (EC) to determine local staging, however, without molecular diagnostics, it is insufficient for selection of high-risk cases, i.e., those with a high risk of lymph node metastases (LNM). Methods: One hundred sixteen consecutive EC patients, who had received 2D transvaginal ultrasound examinations in their preoperative workup and final histopathology results as a reference standard, were included in this prospective study. Univariate and multivariate logistic models of analyzed TVS biomarkers (tumor [T] size, T area [AREA], T volume [SPE-VOL], MI, T-free distance to serosa [TFD], endo-myometrial irregularity, [EMIR], cervical stromal involvement, CSI) were evaluated to assess the relative accuracy of the possible LNM predictors. To avoid a potential bias in assuming linear relations between LNM and continuous predictors, spline functions were applied. Calculations were made in R with the use of libraries splines, glmulti, and pROC. Results: LNM was found in 20 out of 116 (17%) patients. In univariate analysis, only uMI, EMIR, uCSI and uTFD were significant predictors of LNM. Accuracy was 0.707 (AUC 0.684, 95% CI 0.568-0.801) for uMI (p<0.01), 0.672 (AUC 0.664, 95% CI 0.547-0.781) for EMIR (p<0.01), 0.776 (AUC 0.647, 95% CI 0.529-0.765) for uCSI (p<0.01), and 0.638 (AUC 0.683, 95% CI 0.563-0.803) for uTFD (p<0.05). The cut-off value for uTFD was 5.2 mm. However, AREA and VOL revealed significant relation by non-linear analysis as well. Among all possible multivariate models, the one comprising interactions of splines of uTFD with uMI and splines of SPE-VOL with uCSI showed most usefulness. Accuracy was 0.802 (AUC 0.791, 95% CI 0.673-0.91) Conclusions: A combination of uTFD for patients with uMI>50%, and SPE-VOL for patients with uCSI, allows for the most accurate prediction of LNM in EC, rather than uMI alone.

Cervical cancer is the fourth most common type of cancer in the world that causes death in women. It is mainly caused by persistent infection by human papillomavirus (HPV) that triggers a chronic inflammatory process. Therefore, the use of anti-inflammatory drugs is a potential treatment option. The effects of piperine, an amino alkaloid derived from Piper nigrum, are poorly understood in cervical cancer inflammation, making it a target of research. This work aimed to investigate the antitumor effect of piperine on cervical cancer and to determine whether this effect is modulated by the cyclooxygenase 2 (PTGS2) pathway using in vitro model of cervical cancer (HeLa, SiHa, CaSki), and non-tumoral (HaCaT) cell lines. The results showed that, piperine reduces in vitro parameters associated with neoplastic evolution such proliferation, viability and migration by cell cycle arrest in the G1/G0 and G2/M phases, with subsequent induction of apoptosis. This action was modulated by downregulated of cyclooxygenase 2 (PTGS2) pathway, which in turn regulates the secretion of cytokines and the expression of mitogen activated protein kinases (MAPKs), metalloproteinases (MMPs), and their antagonists (TIMPs). These findings indicate the phytotherapeutic potential of piperine as complementary treatment in cervical cancer.

Objectives: This study aimed to assess the impact of a predictive model for detecting extracapsular extension on pathology (pECE+) on biochemical recurrence-free survival (BCRFS) within 4 years after robotic-assisted radical prostatectomy (RARP). Methods: Retrospective data analysis from a single center between 2015 to 2022. Variables under consideration included prostate-specific antigen (PSA) levels, patient age, prostate volume, MRI semantic features and Gleason score (GS). We also assessed the influence of pECE+ and positive surgical margins on BCRFS. using the Kaplan-Meier survival function and Cox regression model were assessed. Additionally, we analyzed the MRI features on BCR (biochemical recurrence) in low/intermediate risk patients. Results: 177 participants with a follow-up exceeding 6 months post-RARP were included. The 1-year, 2-year, and 4-year risks of BCR after curative prostatectomy were 5%, 13%, and 21%, respectively. The survival analysis showed that adverse MRI features as macroscopic ECE on MRI (mECE+), capsular disruption, high tumor capsular contact length (TCCL), GS≥8, positive surgical margins (PSM), and pECE+ on pathology were risk factors for BCR. In low/intermediate-risk patients (pECE- and GS &lt;(4+4)) the presence of adverse MRI features, has been shown to increase the risk of BCR. Conclusions: The study highlights the importance of incorporating predictive MRI features for detecting extracapsular extension pre-surgery in influencing early outcomes and clinical decision-making; mECE+, TCCL, capsular disruption, and GS≥8 based on pre-surgical biopsy were independent prognostic factors for early BCR. The presence of adverse features on MRI can assist in identifying low/intermediate-risk patients who would benefit from closer monitoring.

Objective: The aim of our study was to perform a retrospective analysis of the volume of cervical screening tests, the number of patients treated with an excision method, and the incidence of invasive and non-invasive cervical during a pandemic and pre-pandemic period of 24 months. Results: There was a statistically significant age difference between the two study periods, both by the average age of patients and by age group. The mean difference was 32 years before the pan-demic and 35 years during the pandemic (p-value >0.05). The majority of patients presenting for investigations before and during the pandemic were in the 30-39-year-old age group (31.95%, respectively; 34.2% (p-value = 0.003). The biggest patient loss ratio identified by age group was in the 50–59 years: 14,53% in the pre-pandemic period and 9,1% in the pandemic period. In the pan-demic period, patients from rural areas presented in the clinical trial with a lower rate of 39.52% (83 patients) vs. 60.47% (127 patients) in urban areas. A higher percentage of patients experiencing cervicorrhagia as a clinical manifestation in the pandemic period vs. the prepandemic period, with an increase in more severe lesions in the pandemic period, has a statistical significance of 8% more newly diagnosed compared to the pre-pandemic period. Conclusion: The addressability of the patients during the COVID period was not affected in a drastic way in our study. We encountered a decrease in appointments in the age group 50–59 years and a decrease in patients with rural residence. In our study, we found an increase in cervicorrhagia as a reason for consultation in the pandemic period with a higher lesion degree, both on a pap smear and on a cervical biopsy.

Background and Objective: Type 2 diabetes mellitus (DM2) and breast cancer (BC) are diseases of high prevalence worldwide. Both alter lung function separately. So suffering both tables would increase this decrease in lung function. The objetive was to determine the effects of DM2 and BC on ventilation volumes and pressures in adult women. Material and Methods: Forty-two women patients were recruited, of whom 40 were accepted under the exclusion criteria. They were divided into four groups: control group (CG), DM2, BC and DM2+BC. Body plethysmography was used to measure forced vital capacity, lung volumes, airway resistance and muscle pressures. Finally the normality of the data was determined using Student's t test or the Mann-Whitney U test; the threshold of significance was p<0.05. Results: No significant differences were observed in the anthropometric variables between the control group and the other groups. The ventilation flows showed no significant differences, while the lung volumes presented significant differences in the inspiratory capacity (IC) variables (p<0,002). Maximum inspiratory and expiratory pressures (MIP-MEP) also presented significant diminution (p<0,001; p<0,041, respectively). Conclusions: From the results obtained we can conclude that the combination of type 2 diabetes mellitus with breast cancer caused a diminution in ventilation volumes and pressures, specifically in IC, MIP and MEP.

Hypoxia — reduction in oxygen availability—plays key roles in both physiological and pathological processes. Given the importance of oxygen for cell and organism viability, mechanisms to sense and respond to hypoxia are in place. A variety of enzymes utilise molecular oxygen, but of particular importance to oxygen sensing are the 2-oxoglutarate (2-OG) dependent dioxygenases (2-OGDs). Of these, Prolyl-hydroxylases have long been recognised to control the levels and function of Hypoxia Inducible Factor (HIF), a master transcriptional regulator in hypoxia, via their hydroxylase activity. However, recent studies are revealing that dioxygenases are involved in almost all aspects of gene regulation, including chromatin organisation, transcription and translation. We highlight the relevance of HIF and 2-OG dioxyenases in the control of gene expression in response to hypoxia and their relevance to human cancers.

In comparison to the general population, lung cancer patients are more likely to suffer from severe Coronavirus disease (COVID-19) and mortality associated with it. Considering this increased risk, and in order to prevent symptoms and severe disease, patients with lung cancer have been prioritized for COVID-19 vaccinations, primary and booster doses. Despite this, the pivotal clinical trials did not include these patients, which leaves open questions regarding vaccine efficacy and humoral immune response. This review outlines the findings of recent investigations into the humoral responses of lung cancer patients to COVID-19 vaccination, particularly the primary doses and first boost.

The Bcl-2 family plays a crucial role in regulating cell apoptosis, making it an attractive target for cancer therapy. In this study, a series of indole-based compounds, U1-6, were designed, synthesized, and evaluated for their anticancer activity against BCL-2-expressing cancer cell lines. The binding affinity, safety profile, cell cycle arrest, and apoptosis effects of the compounds were tested. The designed compounds exhibited potent inhibitory activity at sub-micromolar IC50 concentrations against MCF-7, MDA-MB-231, and A549 cell lines. Notably, U2 and U3 demonstrated the highest activity, particularly against MCF-7 cells. Respectively, both U2 and U3 showed potential Bcl-2 inhibition activity with IC50 values of 1.2 ± 0.02 and 11.10 ± 0.07 µM using an ELISA binding assay compared to 0.62 ± 0.01 µM for gossypol, employed as positive control. Molecular docking analysis suggested stable interactions of compound U2 at the Bcl-2 binding site through hydrogen bonding, pi-pi stacking, and hydrophobic interactions. Furthermore, U2 demonstrated significant induction of apoptosis and cell cycle arrest at G1/S phase. Importantly, U2 displayed a favorable safety profile on HDF human dermal normal fibroblast cells at 10-fold greater IC50 compared to MDA-MB-231 cells. These findings underscore the therapeutic potential of compound U2 as a Bcl-2 inhibitor and provide insights into its molecular mechanisms of action.

Matrix metalloproteases (MMPS) are a family of well-known enzymes which operate prevalently in the extracellular domain, where they fulfil the function of remodeling the extracellular matrix. Within the about 26 family members, encoded by 24 genes in humans, MMP-2 and MMP-9, have been regarded as the primary responsibility for the basement membrane and pericellular ECM rearrangement. In cases of infiltrating carcinomas, which arise from the epithelial tissues of a gland or of an internal organ, a marked alteration of the expression and the activity levels of both MMPs is known to occur. Present investigation represents the continuation and upgrading of our previous studies, now focusing on the occurrence and intensity levels of MMP-2 and -9, and their proteomic correlations, in a cohort of 80 breast cancer surgical tissues

Beyond factors such as smoking and obesity, the risk of getting gastrointestinal cancer is passed down from parents to offspring, inherited by a gene mutation, predisposing them to develop cancer in their lifetime. Here we describe the clinical history of family members affected by gastrointestinal pathologies often leading to cancer. In the epidemiological study, the cohort of members of this family shared a high risk of developing gastrointestinal diseases. The subjects were monitored from May 2006 to December 2017 by collecting periodically clinical and endoscopic data, and determining both auto-modification of lymphocyte Poly(ADP-ribose)Polymerase as early signal of DNA damage, and erythrocyte membrane lipid composition (Fat Profile). Both biomarkers were demonstrated to be non invasive and easy tools, to monitor over time family members, first the oldest members (nine siblings), and thereafter their offspring, whose cell status evolved from physiological even to cancerous one. All subjects developed gastrointestinal pathologies of different kind and seriousness. Some diseases evolved to cancer, sometimes as a sudden and lethal event. The results of the two molecular approaches, agreed and even predicted the clinical and imaging paths. This cohort study supported the hypothesis that both noninvasive molecular analyses can predict altered cell states and support clinical and imaging tests.

The cell stress response is an essential system present in every cell for responding and adapting to extracellular environmental stimulations. A major program for stress response is the heat shock factor (HSF)–heat shock protein (HSP) system that maintains proteostasis in cells and promotes cancer progression. However, less is known about how the cell stress response is regulated by alternative transcription factors. Here, we show that the SCAN domain-containing transcription factors (SCAN-TFs) are involved in repressing the stress response in cancer. SCAND1 and SCAND2 are SCAN-TFs that can hetero-oligomerize with SCAN-zinc finger transcription factors, such as MZF1(ZSCAN6), for accessing DNA and transcriptionally co-repressing target genes. We found that heat stress induced the expression of both SCAND1 and MZF1(ZSCAN6) bound to HSP90 gene promoter regions in prostate cancer cells. SCAND1 and MZF1 blocked the heat shock responsiveness of HSP90 in prostate cancer cells. Gene expression of SCAND2, SCAND1 and MZF1 was negatively correlated with HSP90 expression in patients-derived prostate adenocarcinoma. MZF1 and SCAND2 were more highly expressed in paired normal tissues than in tumor tissues in several cancer types. High expression of SCAND2, SCAND1 and MZF1 correlated with enhanced prognoses of pancreatic cancer and head and neck cancers. Additionally, high expression of SCAND2 was correlated with better prognoses of lung adenocarcinoma and sarcoma. In contrast, high expression of HSP90AA1 correlated with poorer prognoses in several cancer types. These data suggest that the stress-inducible SCAN-TFs can function as a feedback system, suppressing excessive stress response and inhibiting cancers.

Enzalutamide is a second-generation androgen-receptor inhibitor that increases overall survival (OS) rates in patients with metastatic castration-resistant prostate cancer (mCRPC). This study evaluates the efficacy of circulating tumor cell (CTC) status as a prognostic biomarker after enzalutamide administration. A retrospective subgroup analysis and prognostic survey of 43 patients with mCRPC and bone metastases, treated in Juntendo University-affiliated hospitals from 2015–2022, were conducted. Patients were treated with 160 mg enzalutamide daily. CTC analyses on blood samples were performed regularly before and every three months post-treatment. Relationship between the patients' clinical factors and the OS rate was analyzed using the log-rank test; the median OS was 37 months. Patients with no detected CTCs at baseline showed significantly longer OS than those with CTCs at baseline. Furthermore, patients showing negative reversion of CTCs during enzalutamide treatment had significantly longer OS than patients with CTC-positive continuation. Two biomarkers–higher hemoglobin at baseline and achieving negative-reversion of CTCs–were significantly associated with prolonged OS. This study suggests that patients achieving CTC-negative reversion during treatment for mCRPC with bone metastases exhibit improved long-term OS. Chronological measurement of CTC status might be clinically useful in treatment of mCRPC.

Most pivotal clinical trials in advanced non-small cell lung cancer (NSCLC) have excluded patients with poor performance status (PS), and data on the efficacy and safety of pharmacotherapy have not been fully accumulated. For NSCLC patients with PS 2 and without druggable genetic alterations, monotherapy with cytotoxic agents or carboplatin-based combination therapy is usually administered based on the results of several randomized trials. However, the evidence of cytotoxic chemotherapy for patients with PS 2 is insufficient, with limited efficacy and toxicity concerns. Immune checkpoint inhibitors (ICIs) are a promising treatment for patients with PS 2 because of lower incidence of severe toxicity compared to cytotoxic chemotherapy. Meanwhile, several reports suggest that anti-PD-1 antibodies monotherapy is less effective for patients with PS 2, especially for those with PS 2 caused by disease burden. Although the combination therapy of nivolumab and ipilimumab is a promising treatment option, there is a divergence in efficacy data between clinical trials. The standard of care for advanced NSCLC with PS 2 has not been established, and future therapeutic strategies should take into account the heterogeneity of the PS 2 population.

Cathepsins (Caths) are lysosomal proteases that participate in various physiological and pathological processes. Accumulating evidence suggests that cathepsins play a multifaceted role in radiotherapy response. Firstly, cathepsins contribute to the remodelling of the tumor microenvironment by degrading extracellular matrix components, promoting angiogenesis, and facilitating tumor invasion and metastasis. Their proteolytic activity influences the tumor's response to radiation by affecting oxygenation, nutrient availability, and immune cell infiltration within the tumor microenvironment. Furthermore, cathepsins have been implicated in DNA damage repair processes, including non-homologous end joining and homologous recombination. Cathepsin-mediated DNA repair mechanisms can promote radioresistance in cancer cells, limiting the efficacy of radiotherapy. Additionally, cathepsins have been associated with the activation of prosurvival signalling pathways, such as PI3K/Akt and NF-κB, which can confer resistance to radiation-induced cell death. Radiotherapy plays a crucial role in the treatment of various malignancies. However, the effectiveness of radiotherapy can be limited by intrinsic or acquired resistance mechanisms in cancer cells. In recent years, there has been growing interest in understanding the role of cathepsins, a family of proteases, in modulating the response of tumor cells to radiotherapy. In this study, we shed light on the regulation and expression of cathepsin B in colon carcinoma cell line (Caco-2) before and after exposure to radiation were investigated. Radiation-induced upregulation of cathepsin B in dose-independent manner. Proteolytic inhibition of cathepsin B by cathepsin B specific inhibitor CA074 has increased the cytotoxic effect of ionizing irradiation in caco-2 cells. Similar results were also obtained after cathepsin B knockout by CRISPR CAS9. These results showed that cathepsin B could contribute to ionizing radiation resistance and abolishing of cathepsin B either by inhibition its proteolytic activity or expression has increased in caco-2 cells susceptibility to ionizing irradiation.

(1) Background: Patients with type 2 diabetes mellitus (T2DM) are at higher risk of cancer but how these two diseases associate is still debated. The goal was the assessment of the overall incidence of cancer among patients with newly diagnosed T2DM in Hungary. Summarizing, incident T2DM is associated with a significantly higher overall risk of incident cancer, with a reverse correlation of age. Newly registered T2DM patients were suggested to be screened for cancer within 6 months. (2) Methods: A nationwide, retrospective, longitudinal study was performed using a Hungarian database. The incident T2DM and diabetes free Hungarian population were included in the study. The primary endpoints were the overall and site-specific incidence and annual percentage change of the incidence of cancer in both populations. (3) Results: The overall incidence of cancer in patients amounted to 29.4/1000 and 6.6/1000 with or without T2DM, respectively, and the OR (95%CI) of cancer of the T2DM group was 4.32 (4.14-4.53), p&lt;0.0001. The risk of having cancer was age-dependent, having the highest odd in the age group 18-39. The incidence of cancer was declining in the non-diabetic but was unchanged in T2DM population. The average lag time of diagnosing a cancer after the detection of T2DM was 3.86 months.; (4) Conclusions: Iincident T2DM is associated with a significantly higher overall risk of incident cancer, with a reverse correlation of age. Newly registered T2DM patients were suggested to be screened for cancer within 6 months.

Overexpression of human epidermal growth factor receptor 2 (HER2) in breast and gastric cancers is an important target for monoclonal antibody (mAb) therapy. All therapeutic mAbs, including anti-HER2 mAbs, exhibit adverse effects probably due to the recognition of antigens expressed in normal cells. Therefore, tumor-selective or specific mAbs can be beneficial in reducing the adverse effects. In this study, we established a novel cancer-specific anti-HER2 antibody, named H₂Mab-250/H₂CasMab-2 (IgG₁, kappa). H₂Mab-250 reacted with HER2-positive breast cancer BT-474 and SK-BR-3 cells. Importantly, H₂Mab-250 did not react with non-transformed normal epithelial cells (HaCaT and MCF 10A) and immortalized normal epithelial cells in flow cytometry. In contrast, most anti-HER2 mAbs including H₂Mab-119 (IgG₁, kappa) reacted with both cancer and normal epithelial cells. Furthermore, a core-fucose deleted IgG_2a-type H₂Mab-250 (H₂Mab-250-mG_2a-f) could trigger the antibody-dependent cellular cytotoxicity activity to BT-474, but not to HaCaT cells. Furthermore, H₂Mab-250-mG_2a-f exhibited an in vivo antitumor effect against BT-474 xenograft. Immunohistochemical analysis demonstrated that H₂Mab-250 possesses much higher reactivity to the HER2-positive breast cancer tissues compared to H₂Mab-119, and did not react with normal tissues, including heart, breast, stomach, lung, colon, kidney, and esophagus. The epitope mapping demonstrated that the Trp614 of HER2 domain IV mainly contributes to the recognition by H₂Mab-250. H₂Mab-250 could contribute to the development of chimeric antigen receptor-T or antibody-drug conjugates without adverse effects for breast cancer therapy.

Obesity, type 2 diabetes, and different forms of cancers are among the leading human diseases and highly complex in terms of diagnostic and therapeutic approaches. Diabetes and cancer are among the most frequent and complex diseases and based on epidemiological evidence and study it can be concluded that the patients suffering from diabetes are considered to be significantly at higher risk for a number of cancer types. Both these diseases are among the highly complex and heterogeneous in nature. There are a number of evidences which support the hypothesis that these diseases interlinked and obesity may aggravate the risk(s) of both these diseases type 2 diabetes and different types of cancers. Multi-level unwanted alterations such as (epi-)genetic alterations, changes at the transcriptional level, and altered signaling pathways (receptor, cytoplasmic, and nuclear level) are the major source which promotes a number of complex diseases and such heterogeneous level of complexities are considered as the major barrier in the development of therapeutic. With so many known challenges, it is critical to understand the relationships and the common shared causes between type 2 diabetes and cancer which is difficult to unravel and understand. Furthermore, the real complexity arises during diagnosis from contended corroborations that specific drug(s) (individually or in combination) during diagnosis process of type 2 diabetes may increase or decrease the cancer risk or affect cancer prognosis. In this review article, we have presented the recent and most updated evidences from the studies where the origin, biological background, correlation between them have been presented or proved. Furthermore, we have summarized the methodological challenges and tasks that are frequently encountered. we have also outlined the physiological links between type 2 diabetes and cancers. Finally, we have presented and summarized the outline of the hallmarks for both these diseases diabetes and cancer.

Curcumin and trans-cinnamaldehyde are acrolein-based Michael acceptor compounds that are commonly found in domestic condiments, and known to cause cancer cell death via redox mechanisms. Based on the structural features of these compounds we designed and synthesized several 2-cinnamamido-N-substituted-cinnamamide (bis-cinnamamide) compounds. One of the derivatives, (Z)-2-[(E)-cinnamamido]-3-phenyl-N-propylacrylamide 1512 showed a moderate antiproliferative potency (HCT-116 cell line inhibition of 32.0 µM), good selectivity profile (no inhibition of normal cell lines), and proven cellular activities leading to apoptosis. SAR studies led to more than 10-fold increase in activity. Our most promising compound, [(Z)-3-(1H-indol-3-yl)-N-propyl-2-[(E)-3-(thien-2-yl)propenamido)propenamide] 4112 killed colon cancer cells at IC50 = 0.89 µM (Caco-2), 2.85 µM (HCT-116) and 1.65 µM (HT-29), while exhibiting much weaker potency on C-166 and BHK normal cell lines (IC50 = 71 µM and 77.6 µM, respectively). Cellular studies towards identifying the compounds mechanism of cytotoxic activities revealed that apoptotic induction occurs in part as a result of oxidative stress. Importantly, the compounds showed inhibition of cancer stem cells that are critical for maintaining the potential for self-renewal and stemness. The results presented here show discovery of covalently-acting Michael addition compounds that potently kill cancer cells by a defined mechanism, with minimal effect on normal noncancerous cell.

In previous clinical studies, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with cancer has a high risk of aggravation and mortality than in healthy infected individuals. The inoculation with the COVID-19 vaccine reduces the risk of SARS-CoV-2 infection and COVID- 19 severity. However, vaccination-induced production of anti-SARS-CoV-2 antibodies is said to be lower in patients with cancer than in healthy individuals. Additionally, the rationale for why patients with cancer become more severe with COVID-19 is not well understood. Therefore, we examined the infection status of SARS-CoV-2 in primary tumor and micrometastasis tissues of patients with cancer and COVID-19. In this study, angiotensin-converting enzyme 2 (ACE2) expression was observed, and SARS-CoV-2 particles were detected in ovarian tissue cells in contact with the micrometastatic niche of high-grade serous ovarian cancer. We believe that more severe COVID-19 cases in patients with cancer may be attributed to these pathological features.

Breast cancer (BC) ranks among the most prevalent cancers diagnosed in women. Its treatment necessitates precision tailored to the cancer's genetic makeup for enhanced efficacy. Research has been directed towards natural compounds for their anti-BC properties, aiming to augment existing treatment modalities. Chromolaena tacotana (Klatt) R.M. King and H. Rob, commonly referred to as Ch. tacotana, is a notable source of bioactive hydroxy-methylated flavonoids. However, the specific anti-BC mechanisms of these flavonoids, particularly those present in the plant's inflorescences, remain partly undefined. This study focuses on assessing a chalcone derivative extracted from Ch. tacotana inflorescences for its potential to concurrently activate regulated autophagy and intrinsic apoptosis in Luminal A and triple-negative BC cells. We determined the chemical composition of the chalcone using ultraviolet (UV) and nuclear magnetic resonance (NMR) spectroscopy. Its selective cytotoxicity against BC cell lines was assessed using the MTT assay. Flow cytometry and western blot analysis were employed to examine the modulation of proteins governing autophagy and the intrinsic apoptosis pathway. Additionally, in silico simulations were conducted to predict interactions between the chalcone and various anti-apoptotic proteins, including the mTOR protein. The chalcone was identified as 2',4-dihydroxy-4',6'-dimethoxy-chalcone (DDC), also known as Flavokavain C (FKC). This compound demonstrated selective inhibition of BC cell proliferation and triggered autophagy and intrinsic apoptosis. It induced cell cycle arrest in the G0/G1 phase and altered mitochondrial outer membrane potential (∆ψm). The study observed the activation of autophagic LC3-II and mitochondrial pro-apoptotic proteins in both BC cell lines. The regulation of Bcl-XL and Bcl-2 proteins varied according to BC subtype, yet they showed promising molecular interactions with DDC. Among the examined pro-survival proteins, mTOR and Mcl-1 exhibited the most favorable binding energies and were downregulated in MCF-7 and MDA-MB-231 cell lines. Further research is needed to fully understand the molecular dynamics involved in the activation and interaction of autophagy and apoptosis pathways in cancer cells in response to potential anticancer agents like the hydroxy-methylated flavonoids from Ch. tacotana.

The C-type lectin-like receptor 2 (CLEC-2) is expressed on platelets and mediates binding to podoplanin (PDPN) on various cell types. The binding to circulating tumor cells (CTCs) leads to platelet activation and promote metastatic spread. The increased level of soluble CLEC-2 (sCLEC-2), presumably, released from activated platelets was shown in patients with thromboinflammatory and malignant disease. However, the functional role of sCLEC-2 and the mechanism of sCLEC-2 release is not known. In this study, we focused on the effect of platelet activation on CLEC-2 expression and the sCLEC-2 plasma level in cancer patients. First, citrated blood from healthy volunteer donors (n=20) was used to measure the effect of platelet stimulation by classical agonists and PDPN on aggregation, CLEC-2 expression on platelets by flow cytometry, sCLEC-2 release to the plasma by ELISA and total CLEC-2 expression by Western blot analysis. Second, sCLEC-2 was determined in plasma samples from healthy donors (285) and patients with colorectal carcinoma (CRC; 194), melanoma (160), breast cancer (BC; 99) or glioblastoma (49). PDPN caused a significant increase of the aggregation response induced by classical agonists. ADP or PDPN stimulation of platelets caused a significant decrease of CLEC-2 on platelets and sCLEC-2 in the plasma, whereas, total CLEC-2 in platelet lysates remained the same. Thus, the increased plasma level of sCLEC-2 is not a suitable biomarker of platelet activation. In patients with CRC (median 0.9 ng/mL), melanoma (0.9 ng/mL) or BC (0.7 ng/mL) we found significantly lower sCLEC-2 levels (p&lt;0.0001), whereas, glioblastoma patients displayed higher levels (2.6 ng/mL; p=0.0233) compared to healthy controls (2.1 ng/mL). The low sCLEC-2 plasma level observed in most of the tumor entities of our study, presumably, results from the internalization of sCLEC-2 by activated platelets or binding of sCLEC-2 to CTC.

Green products have excellent potential for discovering and producing new medicinal products. In recent years, there is a growing interest towards the green synthesis of metal nanoparticles, particularly from plants sources. This eco-friendly approach was used in the recent research to biosynthesize zinc oxide nanoparticles (ZnO NPs) from Cissus antractica plant. The present study aims to examine the cell cytotoxicity, cell death, and pathways of apoptosis in lung cancer cells (A549) and inflammation properties treated with biosynthesized ZnO NPs. Additionally, synthe-sized ZnO nanoparticles were characterized using UV–vis spectroscopy, X-ray diffraction (XRD), Transmission electron microscopy (TEM), Fourier-transform infrared spectroscopy (FT-IR), and Energy-dispersive X-ray spectroscopy (EDS). The XRD and TEM analyses exhibited 31 nm as the size of synthesized nanoparticles, the pure crystal form of ZnO NPs, and the shape of the NPs as nearly spherical and hexagonal quartzite. The MTT assay used for cytotoxicity evaluation de-picted the significant toxic effect of CA-ZnONPs against the A549 lung cancer cells at concentra-tions up to 20 µg/mL than non-cancerous cells. Furthermore, we observed an elevated ROS level in cancer cells. These NPs also demonstrated dose-dependent ability to suppress colony for-mation and cell migration, which increases their potential as a lung cancer treatment. Further-more, The NPs formulation's ability to induce apoptosis in cancer cells was further supported by Hoechst and propidium iodide dye. Further, CA ZnO NPs increased the gene expression of BAX, Cyto-c, Caspase 3 and 9, but decreased the expression of Bcl-2, indicating that the nanoformulation triggered mitochondrial-mediated apoptosis. Besides, this study showed that NPs suppressed in-flammatory responses by subsequently decreasing reactive oxygen species (ROS) generation, downregulating the expression of the pro-inflammatory cytokines TNF-α, iNOS, COX-2, IL-6, IL-8, and NO. Moreover, the study's findings imply that Cissus antractica are a potential source with biosynthesize nanoparticles that can might be further investigated for the progress of an-ti-inflammatory and anti-cancer drugs with further study.

Background: Comorbidities have been frequently reported in COVID-19 patients, which often lead to more severe outcomes. The underlying molecular mechanisms behind these clinical observations have not yet been explained. Herein, we investigated the disease-specific gene expression signatures that may induce susceptibility to SARS-CoV-2 infection. Methods: We studied 30 frequently occurring acute, chronic, or infectious diseases of recent times that have shown comorbidity in one or another respiratory disease(s) caused by pathogenic human infecting coronaviruses, especially SARS-CoV-2. We retrieved array-based gene expression data for each disease and control from relevant datasets. Subsequently, all the datasets were quantile normalized, and log-2 transformed data was used for analysis. Results The expression of ACE2 receptor and host proteases, namely FURIN and TMPRSS2 that are essential for cellular entry of SARS-CoV-2, was upregulated in all six studied subtypes of leukemia (hereafter, referred as leukemia). The expression of ACE2 was also increased in psoriasis, lung cancer, Non-alcoholic fatty liver disease (NAFLD), breast cancer, and pulmonary arterial hypertension patients. The expression of FURIN was higher in psoriasis, NAFLD, lung cancer, and in type II diabetic liver, whereas it was lowered in breast cancer. Similarly, the expression of TMPRSS2 was increased during lung cancer and type II diabetes; it was decreased during psoriasis, NAFLD, lung cancer, breast cancer, and cervical cancer.Furthermore, a heightened expression of genes that are involved in immune response was observed in leukemia patients, as shown by the higher expression of IFNA2, IFNA8, IFNA10, IFNA14, IFNA16, IFNA21, IFNB1, CXCL10, and IL6. The expression of JAK1, STAT1, IL6, and CXCL10 was higher in NAFLD. Besides, JAK1 and STAT1 were upregulated in type II diabetic muscles. In addition, most of the upregulated genes in COVID-19 patients showed a similar trend in leukemia, NAFLD, and psoriasis. Furthermore, SARS-CoV-2, SARS-CoV and MERS CoV, were found to commonly alter two genes, namely, CARBONIC ANHYDRASE 11 and CLUSTERIN.Conclusions: The genes that may confer susceptibility to SARS-CoV-2 infection are mostly upregulated in leukemia patients; hence, leukemia patients are relatively more susceptible to develop COVID-19, followed by other chronic disorders, such as, NAFLD, type II diabetes, psoriasis, and hypertension. This study identifies key genes that are altered in the studied diseases types, which may aid in the infection of SARS-CoV-2 and underlie COVID-19 associated comorbidities.

Never in mitosis gene A-related kinase 2 (NEK2) a member of serine-threonine kinase protein mainly involved in the cell cycle process. Clinical studies revealed NEK2 overexpression in various tumour types, also NEK2 was reported for their association with genetic abnormalities like mitotic machinery deregulation and chromosomal instability. Besides NEK2 plays a key role in maintaining the transformed phenotype of cancer cells and chemo-resistance of several tumour types. Thus, NEK2 transcriptional profile is important for diagnosis, treatment, and prognosis stages of cancer studies. Screening of novel NEK2 inhibitor would be beneficial in developing the specific lead molecules. Our studies involved NEK2 transcriptional profile search, screening of druggable cavities in NEK2, Drug likeliness of mangrove derived naphthoquinone derivatives avicennoneA , avicennoneB , avicennoneC , avicennoneD , avicenoneE , avicennone F , and avicennone G , avicequinone A, stenocarpoquinone B , avicequinone C , avicenol A , avicenol C,brugine, apigenin, chrysin and molecular docking studies to assess MNC compounds binding efficacy towards NEK2. Mangrove derived compounds conferred the intermolecular hydrogen bond, Pi-alkyl,pi-cation interactions with NEK2 kinase domain region residues Tyr 19, Lys 37, Arg 164, Lys174. Nearly 200 kinase proteins contained this promising Cys 22 residue as its positioned in the catalytic site like NEK family proteins. Avicenna A, Avicennone G, Chrysin and Brugine formed the irreversible covalent binding with NEK2 through Cys 22, thus they can be considered as potential kinase inhibitors with the limited off-target response. But these MNC compounds need to be tested further in invitro and invivo studies to propose as potent NEK2 inhibitors.

Although mammography has been the gold standard for early detection of breast cancer, if a woman has dense breast tissue, a false negative diagnosis may occur. Breast ultrasound, whether hand-held or automated, is a useful adjunct to mammography but adds extra time and cost. The primary aim was to demonstrate that our second-generation Aceso system, which combines full-field digital mammography (FFDM) and automated breast ultrasound (ABUS) in a single platform, is able to produce improved quality images that provide clinically meaningful results. Aceso was first tested using two industry standards: a CDMAM phantom to assess the FFDM images; and the CIRS 054GS phantom to evaluate the ABUS images. In addition, 25 women participated in a clinical trial: 14 were healthy volunteers while 11 were patients referred by the breast clinic at Groote Schuur Hospital. The CDMAM phantom results showed the FFDM results were better than EUREF’s standard of “acceptable” and were approaching “achievable”. The ABUS results showed lateral and axial spatial resolution of 0.5 mm and adequate depth penetration of 80 mm. Our second-generation Aceso system, with its improved quality of clinical FFDM and ABUS images, has demonstrated its potential for early detection of breast cancer in a busy clinic.

Three new compounds (1, 11 and 12), together with 32 known ones, were isolated from the root bark of Morus alba L. using various chromatographic methods. The structures of the undescribed compounds were elucidated based on 1D, 2D NMR and HRESIMS data analysis, while the known ones were identified by comparison of their spectroscopic data with those reported in the literature. All the isolates were evaluated for their cytotoxic activities against human gastric cancer HGC27 cells by CCK-8 assay. Among them, compounds 5, 8, 10 and 30 exhibited cytotoxic activities on HGC27 cells with IC50 values of 10.24 ± 0.89 μM, 28.94 ± 0.72 μM, 6.08 ± 0.34 μM and 33.76 ± 2.64 μM, respectively. Furthermore, compound 10 was confirmed to reduce proliferation ability, increase apoptosis rate and inhibit cell migration pathway by annexin V/PI double staining experiment, transwell experiment and western blot analysis.

Objectives: To evaluate the relationship between the type of conization, the volume and dimensions of the cone, with the persistence/recurrence of CIN 2-3, presence of affected margins and post-cone HR-HPV positivity. Methods: 227 women treated with LLETZ and histologically confirmed CIN2-3 were evaluated between 1996 and 2006 and followed up until June 2016. Age, type of resection according to IFCPC 2011, volume, cone dimensions, margins were studied. of resection, post-cone high-risk human papillomavirus (HR-HPV) status and viral load. Determinants of HR-HPV positivity were estimated using unconditional logistic regression and time to recurrence was assessed using Kaplan-Meier curves. Results: Persistent/recurrent CIN2-3 was found in 12 cases (5.2%), type 1 conization was performed in 81 patients, with 5 recurrences (6.1%), type 2 in 101 patients, with 6 recurrences (5 .9%) and type 3 resection in 45 women, with 1 recurrence (2.2%). Volume and dimensions were not associated with recurrence. The Log-Rank Test did not show a significant difference between the 3 treatments (p= 0.18). The free margins in type 1 were 37%, in type 2 resection 61% and in type 3 71% (p=0.001). Resection type 1 had 15% HR-HPV post positive cone, type 2 reached 16% and type 3 had 9%, this difference being non-significant (p=0.58). The incidence of recurrence at 36 months in type 1 resection was 0.08%, in type 2 treatment it was 0.04% and in type 3 resection it was 0.0%. Conclusions : Type 3 resection had a higher proportion of free margins and lower post-cone HR-HPV positivity, with a lower incidence of persistence/recurrence.

Some bispecific radiotracers have been developed to overcome the limitations of monospecific tracers and improve detection sensitivity for heterogeneous tumor lesions. Here we aim to synthesize two bispecific tracers targeting prostate-specific membrane antigen (PSMA) and fibroblast activation protein (FAP), which are key markers expressed in prostate cancer. A pyridine-based FAP-targeted ligand was synthesized through multi-step organic synthesis, and then connected to the 2-Nal-containing PSMA-targeted motif. Ki(PSMA) values of Ga-complexed bispecific ligands, Ga-AV01084 and Ga-AV01088, were 11.6 ± 3.25 and 28.7 ± 6.05 nM, respectively, and the IC50(FAP) values of Ga-AV01084 and Ga-AV01088 were 10.9 ± 0.67 and 16.7 ± 1.53 nM, respectively. The uptake values for PSMA-expressing LNCaP tumor xenografts were 9.05 ± 1.54 and 8.85 ± 1.25 %ID/g for [68Ga]Ga-AV010184 and [68Ga]Ga-AV01088, respectively, which were lower than the monospecific PSMA-targeted tracer [68Ga]Ga-PSMA-617 (16.7 ± 2.30 %ID/g). The uptake values for FAP-expressing HEK293T:hFAP tumor xenografts were 1.90 ± 0.41 and 1.20 ± 0.25 %ID/g for [68Ga]Ga-AV01084 and [68Ga]Ga-AV01088, respectively, which were also lower than the monospecific FAP-targeted tracer, [68Ga]Ga-AV02070 (7.93 ± 1.88 %ID/g). Further investigations are needed to optimize the selection of linkers and targeted pharmacophores to improve the tumor uptake of PSMA/FAP bispecific tracers for prostate cancer imaging.

The molecular structure and vibrational spectra of six 1,2,3-triazoles-containing molecules with possible anticancer activity were investigated. In two of them, the optimized geometry was determined in the monomer, cyclic dimer and staking forms using the B3LYP, M06-2X and MP2 methods. The effect of the para-substitution in the aryl ring was evaluated based on the changes in the molecular structure and atomic charge distribution of the triazole ring. Several relationships were obtained that could facilitate the selection of the substituents on the triazole ring for their further synthesis. The observed IR and Raman bands in the solid state of two of these compounds were accurately assigned according to the functional calculations on the monomer and dimer forms, together with the polynomic scaling equation procedure (PSE).

A series of 2-phenylamino-3-acyl-1,4-naphtoquinones were evaluated regarding their in vitro antiproliferative activities using DU-145, MCF-7 and T24 cancer cells. Such activities were discussed in terms of molecular descriptors like half-wave potentials, hydrophobicity and molar refractivity. Compounds 4 and 11 display the highest antiproliferative activity against the three cancer cells, therefore, they were subject to further studies. The in silico prediction of drug likeness, using pkCSM and SwissADME explorer online, shows that compound 11 is a suitable lead molecule to be developed. Furthermore, the expression of some key genes was studied in DU-145 cancer cells. They include genes involved in apoptosis (Bcl-2), tumor metabolism regulation (mTOR), redox homeostasis (GSR), cell cycle regulation (CDC25A), cell cycle progression (TP53), epigenetic (HDAC4), cell-cell communication (CCN2) and inflammatory pathways (TNF). Compound 11 displays an interesting profile because among these genes, mTOR was significantly less expressed as compared to control conditions. Molecular docking show that compound 11 has good affinity with mTOR, unraveling a potential inhibitory effect on this protein. Due to the key role of mTOR on tumor metabolism, we suggest that impaired DU-145 cells proliferation by compound 11 is caused by a reduced mTOR expression (less mTOR protein) and inhibitory activity on mTOR protein.

Sinulariolide, a natural product extracted from cultured-type soft coral Sinularia flexibilis, possesses bioactivity against the movement of several types of cancer cell. However, the molecular pathway of its effects on human bladder cancer remain poorly understood. Using a human bladder cancer cell line as an in vitro model, this study investigated the underlying mechanism of sinulariolide against cell migration/invasion in TSGH-8301 cells. We found that sinulariolide inhibited TSGH-8301 cell migration/invasion, and the effect was concentration-dependent. Furthermore, the protein expressions of matrix metalloproteinases (MMPs) MMP-2 and MMP-9, as well as urokinase, were significantly decreased after 24-h sinulariolide treatment. Meanwhile, the increased expressions of tissue inhibitors of metalloproteinases (TIMPs) TIMP-1 and TIMP-2 were in parallel with an increased concentration of sinulariolide. Finally, the expressions of several key phosphorylated proteins in the mTOR signaling pathway were also downregulated by sinulariolide treatment. Our results demonstrated that sinulariolide has significant effects against TSGH-8301 cell migration/invasion, and its effects were associated with decreased levels of MMP-2/-9 and urokinase expression, as well as increased TIMP-1/TIMP-2 expression. The inhibitory effects were mediated by reducing phosphorylation proteins of the PI3K, AKT and mTOR signaling pathway. The findings suggested that sinulariolide is a good candidate for advanced investigation with the aim of developing a new drug for the treatment of human bladder cancer.

Tspo is a receptor involved in the regulation of cellular proliferation, apoptosis and mitochondrial functions. Previous studies showed the expression of TSPO protein correlated positively with tumour malignancy and negatively with patient survival. The aim of this study was to determine the transcription of Tspo mRNA in various types of normal and cancer tissues. In situ hybridization was performed to localise the Tspo mRNA in various human normal and cancer tissues. The relative level of Tspo mRNA was quantified using fluorescent intensity and visual estimation of colorimetric staining. RT-PCR was used to confirm these mRNA levels in normal lung, lung cancer, liver cancer and cervical cancer cell lines. There was a significant increase in the level of transcription in liver, prostate, kidney and brain cancers while a significant decrease was observed in cancers of the colon and lung. Quantitative RT-PCR confirmed that the mRNA levels of Tspo are higher in a normal lung cell line than in a lung cancer cell line. An increase in the expression levels of TSPO makes it a good diagnostic biomarker and TSPO could serve as a target for anticancer drug development.