The development of a fast and accurate intraoperative method that enables the differentiation and stratification of cancerous lesions is still a challenging problem in laboratory medicine. Therefore, it is important to find and optimize a simple and effective analytical method that enables the selection of distinctive metabolites. This study aims to assess the usefulness of solid-phase microextraction (SPME) probes as a sampling method for the lipidomic analysis of brain tumors. To this end, SPME was applied to sample brain tumors immediately after excision, followed by lipidomic analysis via liquid chromatography-high resolution mass spectrometry (LC-HRMS). The results showed that long fibers were a good option for extracting analytes from an entire lesion to obtain an average lipidomic profile. Moreover, significant differences between tumors of different histological origin were observed. In-depth investigation of the glioma samples revealed that malignancy grade and isocitrate dehydrogenase (IDH) mutation status impact the lipidomic composition of the tumor, whereas 1p/19q co-deletion did not appear to alter the lipid profile. This first on-site lipidomic analysis of intact tumors proved that chemical biopsy with SPME is a promising tool for the simple and fast extraction of lipid markers in neurooncology.

Liquid biopsy via isolation of circulating tumour cells (CTCs) represents a promising diagnostic tool capable of supplementing state-of-the-art for prostate cancer (PC) prognosis. Unfortunately, most of CTC technologies, such as AdnaTest or Cellsearch, critically rely on the Epithelial-Cell-Adhesion-Molecule (EpCAM) marker, limiting the possibility of detecting stem-like cells (CSCs) and mesenchymal-like cells (EMT-CTCs) that are present during PC progression. In this tontext, dielectrophoresis (DEP) is an epCAM independent, label-free, enrichment system, separating rare cells simply on the basis of their specific electrical properties. As compared to other technollgies, DEP represents a superior technique in terms of running costs, cells yield and specificity, but due to its higher complexity, requires still further technical as well as clinical development. Interestingly, DEP can be improved by the use of microfluid, nanostructured materials and fluoroimaging in order to increase its potential applications. In the context of PC, the utility of DEP can be translated in its capacity to detect CTC in the bloodstream in their epithelial, mesenchymal, or epithelial-mesenchymal phenotypes, which should be taken into account when choosing CTC enrichment and analysis methods for PC prognosis and early diagnosis.

Background/Aim: Uterine leiomyoma, also known as fibroids, is the most common benign neoplasm of the female genital tract. Leiomyoma, including its subtypes, is the most common uterine tumor. The subtypes account for approximately 10% of leiomyomas. Intravenous leiomyomatosis, a uterine leiomyoma subtype, is an intravascular growth of benign smooth muscle cells, occasionally with pelvic or extrapelvic extension. Uterine leiomyosarcoma, a malignant tumor, tends to metastasize hematogenously, and distant metastasis to the lungs and liver is common. Therefore, this intravenous leiomyomatosis’ oncological features resemble those of the malignant tumor uterine leiomyosarcoma. Cancer stem cells migrate to distant organs via intravascular infiltration, leading to micrometastases. Materials and Methods: We examined the oncological properties of intravenous leiomyomatosis using molecular pathological techniques on tissue excised from patients with uterine leiomyoma. Result: CD44-positive mesenchymal tumor stem-like cells were detected in both intravenous leiomyomatosis and uterine leiomyosarcoma. The oncological nature of intravenous leiomyomatosis was found to be similar to the oncological properties of uterine leiomyosarcoma. However, in intravenous leiomyomatosis, Cyclin E and Ki-67-positive cells were rare, and no pathological findings suspected to be malignant were observed. Conclusion: It is expected that establishing a treatment method targeting cancer stem cells will lead to the treatment of malignant tumors with a low risk of recurrence and metastasis.

Breast cancer, although the most frequently diagnosed malignant tumour in humans, has a less clear aetiology compared to other frequent cancer types. Mouse-mammary tumour virus (MMTV) is involved in breast cancer in mice and dogs and might play a role in the aetiology of some breast cancers in humans, since it has been identified in 20-40% of breast cancer samples in Western Europe, USA, Australia and some other parts of the world population. The purpose of our study was to identify MMTV DNA sequences in breast tissue samples from breast cancer patients operated in our regional centre from Romania. We have selected 75 patients with non-metastatic breast cancer treated with curative intent and searched with PCR the MMTV-like DNA sequence in the breast cancer tissue and normal breast tissue obtained from the same patients. Since none of the examined samples was positive for MMTV-like target sequences on PCR we could not prove that MMTV plays a role in the aetiology of breast cancer in our patient group. This finding is similar to publications of other geographically related research groups and might be due to the fact that only the Mus musculus domesticus mouse species was proven to carry infectious MMTV, but not the Mus musculus musculus species, which is specific to South-Eastern Europe (including Romania) and some parts of Asia.

Tumor microenvironment (TME) represents a complex network between tumor cells and a variety of components including immune, stromal and vascular endothelial cells as well as extracellular matrix. A wide panel of signals and interactions here take place, resulting in a bi-directional modulation of cellular functions. Many stimuli, on one hand, induce tumor growth and spread of metastatic cells and, on the other hand, contribute to the establishment of an immunosuppressive environment. The latter feature is achieved by soothing immune effector cells, mainly cytotoxic T lymphocytes, B and NK cells, and/or through expansion of regulatory cell populations, including regulatory T and B cells, tumor-associated macrophages and myeloid-derived suppressor cells. In this context, immune checkpoints (IC) are key players in the control of T cell activation and anti-cancer activities, leading to the inhibition of tumor cell lysis and of pro-inflammatory cytokine production. Thus, these pathways represent promising targets for the development of effective and innovative therapies both in adults and childhood. Here we address the role of different cell populations homing the TME and of well-known and recently characterized IC in the context of pediatric solid tumors. We also discuss preclinical and clinical data available using IC inhibitors alone, in combination each other or administered with standard therapies.

Proper and timely segregation of cellular genome is an important and a prime requirement of all cell division programmes. Mis-segregation of chromosomes and resulting aneuploidy leads to several clinical consequences. Over the years, shugoshin emerges as a key protein factor involved in the segregation of genetic material in dividing cells. Deletion or altered level of shugoshin is reported in several human malignancies, as a result, shugoshin now emerges as an important tumour associated gene and a possible target for cancer therapy. Apart from the role in cancer, recent studies also showed the involvement of shugoshin in several other clinical disorders. Through this review, we tried to highlight the clinical relevance of shugoshin.

MicroRNAs (miRNAs) are a kind of conserved small non-coding RNAs that participate in regulating gene expression by targeting multiple molecules. Early studies have shown that the expression of miRNAs changes significantly in different tumor tissues and cancer cell lines. It is well acknowledged that such variation is involved in almost all biological processes, including cell proliferation, mobility, survival and differentiation. Increasing experimental data indicate that miRNA dysregulation is a biomarker of several pathological conditions including cancer, and that miRNA can exert a causal role, as oncogenes or tumor suppressor genes, in different steps of the tumorigenic process. Anticancer therapies based on miRNAs are currently being developed with a goal to improve outcomes of cancer treatment. In our present study, we review the function of miRNAs in tumorigenesis and development, and discuss the latest clinical applications and strategies of therapy targeting miRNAs in cancer.

Abstract: (1) Background: Cancer immune escape is associated with the metabolic reprogramming of TME, and combining metabolic targets with immunotherapy has great potential to improve clinical outcomes. Among all metabolic processes, lipid metabolism, especially fatty acid (FA) metabolism, has a huge role in cancer cell survival, migration, and proliferation, but its mechanism and role in the tumor immune microenvironment remain to be investigated. (2) Methods: We comprehensively analyzed 309 fatty acid-related genes, screened 121 different genes, and used one-way COX regression to select 15 genes with prognostic impact. Systematically evaluated the correlation between FMGs modification patterns and Tumor Microenvironment Infiltration, prognosis, and Immunotherapy. The FMGs-Score was constructed to quantify the FMGs modification patterns using principal component analysis. (3) Results: Three clusters based on FMGs-related genes were demonstrated in breast cancer, with three patterns of distinct immune cell infiltration and biological behavior. An FMGsScore signature was constructed to reveal that patients with a low FMGsScore had higher immune checkpoint expression, higher immune checkpoint inhibitor (ICI) scores, increased immune microenvironment infiltration, better survival advantage, and were more sensitive to immunotherapy than those with a high FMGsScore. Finally, the expression and function of the signature key gene NDUFAB1 were examined by in vitro experiments. (4) Conclusions: This study significantly demonstrates the non-negligible role of FMGs in the immune microenvironment of breast cancer, and that FMGsScores can be used to guide the prediction of immunotherapy in breast cancer patients. In in vitro experiments, knockdown of the NDUFAB1 gene resulted in reduced proliferation and migration of MCF-7 cell lines.

The problem of drug resistance in terms of antifungal therapy, unknown until a few years ago, is assuming increasing importance. Particularly in immunosuppressed patients and subject to chemotherapy and radiotherapy. In the last years the use of essential oils as approach to improving the effectiveness of antifungal agents and reducing the antibiotic resistant has been proposed. Our research aimed to evaluate the antifungal activity of Colombian essential oil of Ruta graveolens (REO) against clinical strains of Candida albicans, Candida parapsilopsis, C. glabrata and Candida tropicalis. The data obtained showed that Candida tropicalis and Candida albicans were most sensible strains showing minimum inhibitory concentrations (MIC) of 0.5 and 1.0 µg/ml of REO. The Time Kill Kinetics assay demonstrated that REO showed fungicide effect against C. tropicalis and fungistatic effect against C. albicans. In addition, the 40% of the biofilm formed by C. albicans was eradicated using 1% of REO after 1 hour of exposure.

The central reason behind emergence of clinically-detectable tumors is evasion from immune surveillance due to lack of cancer cells surface membrane expression of tumor-specific peptides in association with MHC class I molecules, concealment of natural killer cells-activating molecules, and absence of inflammation resulting from inefficient stimulation of innate immunity receptors and co-stimulatory molecules. The tumor microenvironment (TME) also contributes to tumor initiation, progression and resistance to therapeutic interventions because of its dense, fibrogenic, barrier-like composition, aberrant vasculature, and production of cytokines and chemokines responsible for recruitment of immune suppressive cells, notably myeloid-derived suppressor cells, M2 macrophages, regulatory T cells, extracellular trap-forming neutrophils, and cancer-associated fibroblasts. We herein show that the relentless efforts and strategies to overcome the TME elusive tumor-promoting impact produced contrasting, opposed, controversial effects, characterized by limited efficacy and proven adversity, and most importantly deterred from attempts to discover and counteract the fundamental inherent mechanisms initiating, and not consequent to, carcinogenesis.

Introduction: Obstructive sleep apnea (OSA) is not only common in the general population but even more so in patients with tumors of the head and neck region. Untreated, it leads to reduced quality of life, increased daytime sleepiness, and other comorbidities. The aim of this study was to determine the difference in the occurrence of OSA in the patient population with head and neck tumors compared to the general population as represented by the Trend cohort of the Study of Health in Pomerania (SHIP) , and to assess the influence of tumor treatment. Methods: Between July 2018 and December 2021, preoperative polysomnography was conducted in 47 patients with histologically confirmed squamous cell carcinoma in the oropharynx, hypo-pharynx, or larynx. A follow-up polysomnography was performed in 23 patients 2-11 months af-ter completing treatment. The collected data was correlated with tumor treatment and tumor size. Results: Of the included patients, 43 were male and four were female. Age ranged from 54 to 90 years. The pretherapeutic measurement found no significant difference in the prevalence of a pathologically elevated apnea-hypopnea index (AHI) in our patients compared to the SHIP-Trend cohort. In the follow-up measurement after treatment completion, a significant deterioration in AHI was observed. Initially, 70 % of patients had an AHI > 5, after therapy this increased to 87 %. The effect was particularly pronounced in the group of patients with advanced tumor stages who had received primary chemoradiation. Conclusion: OSA is a relevant condition in patients with head and neck cancer. Tumor treatment can lead to an increased occurrence of sleep-related breathing disorders, especially in patients with advanced tumor stages undergoing primary chemoradiation. Additional studies are neces-sary to better understand the exact mechanism involved.

Central adiposity is one of the significant determinants of obesity-related hypertension risk, which may arise due to the abdominal fat depot's pathogenic inflammatory nature. Pro-inflammatory cytokines and adipokines up-regulation through nuclear factor-kappa B (NF-κB) activation in adipose tissue has been considered an essential function in the pathogenesis of obesity-related hypertension. This study aimed to ascertain the NF-κB inhibitor (SN50) effect on TNF-α and angiotensinogen (AGT) secretion and expression in mediating the anti-inflammatory effect through its impact on NF-κB activity in humans adipose tissue. Primary human adipocytes were isolated from 20 subjects among 10 overweight and 10 obese with and without hypertension and treated with 10ng/ml LPS in the presence and absence of NF-κB inhibitor, SN50 (50μg/ml). TNF-α secretion and NF-κB p65 activity were detected in supernatants extracted from cultured cells treated and untreated with LPS (10ng/ml) and SN50 (50μg/ml) using enzyme-linked immunosorbent assay (ELISA). The western blot technique detected the protein of NF-κB p65 and AGT. Gene expression of TNF-α and AGT was detected in cells and performed using quantitative real-time polymerase chain reaction (RT-PCR). Treatment of AbdSc adipocytes with LPS (10ng/ml) caused a significant increase in NF-κB p65 among overweight and obese subjects with and without hypertension (P= 0.001) at 24 hours incubation. In contrast, SN50-NF-κB inhibitor causes a reduction of NF-κB p65 in overweight (P= <0.001) and obese subjects with and without hypertension (P= 0.001) at 24 hours incubation. Treatment of AbdSc adipocytes with 10ng/ml LPS caused a significant increase in TNF-α secretion in overweight and obese subjects at all-time points (P= <0.001), whereas SN50 leads to a decrease in TNF-α secretion at 3 and 12 hours incubation. Treatment of AbdSc adipocytes with LPS (10ng/ml) caused increased TNF-α and AGT gene expression twofold compared with untreated cells, whereas, in the presence of SN50, it reduces mRNA AGT levels in both groups. Taken together, these adipokines with NF-κB activation may represent essential biomarkers to evaluate hypertension risk and to provide insight into the pathogenesis of obesity-related hypertension.

Background: Glioblastoma remains a challenging brain tumor to treat due to its infiltrative nature. Accurately identifying tumor boundaries during surgery is crucial for successful tumor resection. This study introduces an innovative intraoperative visualization method utilizing a surgical fluorescence microscope to precisely locate tumor cells. The focus of the study is on IR-Glint, a novel preparation comprising Cy7.5-labeled aptamers Gli-233nt and Gli-55_3L specific to human glioblastoma. Methods: The aptamers were modified using molecular modeling and quantum chemical techniques. The effectiveness of the preparation was assessed using flow cytometry and microscopy on primary cultures of human glioblastoma. In vivo studies were conducted on mouse and rabbit models, employing orthotopic xenotransplantation of human brain glioblastoma with various imaging techniques, including PET/CT, in vivo fluorescence visualization, confocal laser scanning, and surgical microscopy. Results: The experiments validated the potential of IR-Glint for intraoperative visualization of glioblastoma using infrared imaging. Surface application of the aptamer-based formulation on the brain allowed clear visualization of the tumor, aiding surgeons in tumor resection. This approach also reduces the dosage required and mitigates potential toxic effects on the patient. Conclusions: This study demonstrates the promising potential of using in-frared dye-labeled aptamers for intraoperative visualization of glioblastoma. By improving surgical treatment outcomes in neurosurgery, this novel approach may pave the way for future advancements in the field.

Cancer is a devastating disease, causing tremendous morbidity and mortality each year. Cancer can be considered as a genetic disease in the sense that instabilities in protooncogenes and tumor suppressor genes are among the hallmarks of cancer progression and metastasis. However, a particular cancer can express different proteins in different patients, making cancer a heterogeneous disease. This heterogeneity in part influences treatment resistance and failure. Therefore, it is crucial to understand the mechanism by which cancer cells develop and enhance resistance to different agents. This review aims to present the general paradigm and recent updates on cancer cell resistance to different antitumor agents. It demonstrates that tumor resistance results from a myriad of factors, including tumor microenvironment, supporting immune cells, and cancer stem cells. This interaction contributes to cancer cells overcoming the therapeutic effects of different classes of antitumor agents, such as cytotoxic chemotherapeutics, targeted agents, and immunotherapies. With the development of advanced molecular analysis, specialized genomic assessment has assisted clinicians and researchers in choosing selected agents combating cancer cells. Together, this approach can potentially reduce treatment toxicity, health system burden, and financial costs while improving patient quality of life. Understanding the exact mechanism of drug resistance in cancer cells can open the way to new effective and less toxic therapeutics.

Vascular endothelial growth factor receptor 2 (VEGFR2) mediates VEGFA signaling mainly through the PI3K/AKT/mTOR and PLCγ/ERK1/2 pathways. Here we unveil a peptidomimetic (VGB3) based on the interaction between VEGFB and VEGFR1 that unexpectedly binds and neutralizes VEGFR2. Investigation of the cyclic and linear structures of VGB3 using receptor binding and cell proliferation assays, molecular docking, and evaluation of antiangiogenic and antitumor activities in the 4T1 mouse mammary tumor model showed that loop formation is essential for peptide functionality. VGB3 inhibited proliferation and tubulogenesis of human umbilical vein endothelial cells (HUVECs), accounting for the abrogation of VEGFR2, p-VEGFR2 and, subsequently, PI3K/AKT/mTOR and PLCγ/ERK1/2 pathways. In 4T1 cells, VGB3 inhibited cell proliferation, VEGFR2 expression and phosphorylation, PI3K/AKT/mTOR pathway, FAK/Paxillin, and epithelial-to-mesenchymal transition cascade. The apoptotic effects of VGB3 on HUVE and 4T1 cells were inferred from annexin-PI and TUNEL staining and activation of P53, caspase-3, caspase-7, and PARP1, which mechanistically occurred through the intrinsic pathway mediated by Bcl2 family members, Cytochrome c, Apaf-1 and caspase-9, and extrinsic pathway via death receptors and caspase-8. These data indicate that binding regions shared by VEGF family members may be important in developing novel pan-VEGFR inhibitors that are highly relevant in the pathogenesis of angiogenesis-related diseases.

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.

Although oncolytic viruses are currently being evaluated for cancer treatment in clinical trials, systemic administration is hindered by many factors that prevent them from reaching the tumor cells. When administered systemically, mesenchymal stem cells (MSCs) target tumors, and therefore constitute good cell carriers for oncolytic viruses. Methods: MSCs were primed with trichostatin A under hypoxia, which upregulated the expression of CXCR4, a chemokine receptor involved in tumor tropism, and coxsackievirus and adenovirus receptor that plays an important role in adenoviral infection. After priming, MSCs were loaded with conditionally replicative adenovirus that exhibits limited proliferation in cells with a functional p53 pathway and encodes Escherichia coli nitroreductase (NTR) enzymes (CRAdNTR) for targeting tumor cells. Results: Primed MSCs increased tumor tropism and susceptibility to adenoviral infection, and successfully protected CRAdNTR from neutralization by anti-Adenovirus antibodies both in vitro and in vivo, and specifically targeted p53-deficient colorectal tumors when infused intravenously. Analyses of deproteinized tissues by UPLC-MS/QTOF revealed that these MSCs converted the co-administered prodrug CB1954 into cytotoxic metabolites, such as 4-hydroxylamine and 2-amine, inducing oncolysis and tumor growth inhibition without being toxic for the host vital organs. Conclusion: This study shows that the combination of oncolytic viruses delivered by MSCs with the activation of prodrugs is a new cancer treatment strategy that provides a new approach for the development of oncolytic viral therapy for various cancers.

Triple-negative breast cancer (TNBC) is characterized by an active immune response. We evalu-ated intratumoral interrelation between FOXP3+ tumor-infiltrating lymphocytes and other cy-tokines in TNBC. Network analysis refined cytokines significantly correlate with FOPX3 in TNBC. Treatment response and prognosis imformation of patients and survival data from the TGCA and METABRIC databases were analyzed according to refined cytokines. Interleukin (IL)-33 was sig-nificantly expressed by TNBC cell lines than luminal cell lines (log2 fold change: 5.31, p <0.001) and IL-33 and TGFB2 showed a strong correlation with FOXP3 in the TNBC cell line. Immunohisto-chemistry demonstrated IL-33 high group was a significant predictor of complete response of neoadjuvant chemotherapy (odds ratio (OR) 4.12, p<0.05) and a favorable survival compared to IL-33 low group (OR 6.48, p<0.05) in TNBC. Survival data from TGCA and METABRIC revealed that FOXP3 was a significantly favorable marker in IL-33 high group com-pared to the low IL-33 low group (hazard ratio (HR) 2.1, p=0.02), and IL-33 high/TGFB2 high subgroup showed significant favorable prognosis in the FOXP3 high group compared to the FOPX3 low group in TNBC (HR 3.5, p=0.01). IL-33 and TGFB2 were key cytokines of intratumoral interrelation among FOXP3 in TNBC.

This study investigated the inhibitory effect of Siegesbeckia orientalis ethanolic extract (SOE) on growth and metastasis of hepatic tumors in C57BL/6JNarl mice, which is the model of tumor-igenesis induced by subcutaneous injection of Hepa1-6 murine hepatoma cells on the back of mice. Feeding 25 mg SOE/kg BW daily for 14 days effectively reduced the hepatoma weight in tu-mor-bearing mice by 59.7%. SOE intervention reduced the expression of anti-apoptotic Bcl-2 gene in tumor tissue by 48.5% and down-regulated the antioxidant system, by reducing the gene ex-pression of catalase (48.0%), glutathione peroxidase (46.3%), and superoxide dismutase (32.0%). In addition, SOE intervention increased the production of ROS by 21.4%, and the gene expression of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 by 135.3%, 179.3% and 91.7%, respectively, indicating that SOE intervention promoted the acute inflammatory response. Results of H&E staining analysis showed that SOE had the ability to inhibit angiogenesis in tumor tissue. Fur-thermore, SOE treatment inhibited the expression of migration-related genes, such as MMP-2, MMP-7, MMP-9 and β-catenin, and the inhibition rates were 24.8%, 27.4%, 10.4% and 21.9%, respectively. These results imply that SOE had the ability to suppress tumor metastasis. On the other hand, SOE intervention decreased the serum contents of inflammatory cytokines, such as TNF-α, IL-1β and IL-6 by 27.4%, 30.4%, and 30.7%, respectively, indicating that SOE intervention has an anti-inflammatory effect on normal tissues of mice. Since SOE intervention had no signif-icant effect on liver and kidney weights, and no mice died throughout the experiment, it shows that it is safe to feed SOE under this experimental condition. Based on the above results, SOE has a great potential to be used in the treatment of hepatoma.

Introduction: Osteosarcomas of the jaw (OSJ) are rare tumors with a different behavior from osteosarcomas of other bones. This study aims to analyze the clinical, pathological, and therapeutic characteristics of this type of sarcoma. Methods: a retrospective observational study of cases diagnosed with OSJ registered at the “La Paz” University Hospital (Madrid). Results: Eight cases with a diagnosis of OSJ were obtained in a study period of 22 years (2000-2022). The mean age was 41 years. The distribution was 1:1 between the maxilla and mandible. Painful inflammation was the most frequent clinical manifestation. Conventional osteoblastic osteosarcoma was the most common. Survival at 5 years was 50%, while at 10 years, it decreased to 25%. Conclusions: OSJ differs from conventional osteosarcomas of long tubular bones. Surgery continues to be the mainstay of treatment; more studies are needed in which more standardized protocols can be proposed for adjuvant therapeutic management.

Circulating tumor cells (CTC) and circulating tumor microemboli (CTM) have been shown to correlate negatively with patient survival. Actual CTC counts before and after treatment can be used to aid in prognosis of patient outcomes. The presence of circulating tumor materials (CTMat) can advertise the presence of metastasis before clinical presentation, enabling early detection of relapse. Importantly, emerging evidence is indicating that cancer treatments can actually increase the incidence of CTCs and metastasis in pre-clinical models. Subsequently, the study of CTCs, their biology and function are of vital importance. Emerging technologies for the capture of CTC/CTMs and CTMat are elucidating vitally important biological and functional information that can lead to important alterations in how therapies are administered. This paves the way for the development of a “liquid biopsy” where treatment decisions can be informed by information gleaned from tumor cells and tumor cell debris in the blood.

Background: Patients undergoing brain tumor resection experience changes to their neurocognitive abilities, many of which can be difficult to predict. We hypothesized that changes in brain connectivity could predict changes in neurocognitive functioning, demonstrating the potential for brain connectivity aware surgical planning to provide enhanced outcomes for patients. Methods: Patients underwent functional and diffusion MR scanning and neuropsychological testing before tumor resection and two weeks post-resection. Using this functional and diffusion imaging, we measured changes in the topology of the functional and structural graph networks, respectively. From the neuropsychological testing scores, we derived a composite score that describes a patient’s overall level of neurocognitive functioning. We then used a multiple linear regression model to test if structural and functional connectivity measures could predict changes in composite scores. Results: Twenty-one subjects completed imaging and neuropsychological evaluation both before and after surgery. The multiple linear regression model showed that changes in functional local efficiency were inversely correlated with changes in composite score (p

Erastin (ER) induces cell death by utilizing the process of ferroptosis via generation of reactive oxygen species (ROS). Ferroptosis is characterized by accumulation of ROS within the cell, leading to an iron-dependent oxidative damage-mediated cell death. Here, we have examined ferroptosis-dependent mechanism(s) of cytotoxicity of ER in K-RAS mutant human ovarian tumor OVCAR-8 and NCI/ADR-RES cell lines. We used these cell lines to decipher the mechanisms of ER as NCI/ADR-RES cells express higher activities of SOD, glutathione peroxidase and transferases than OVCAR-8 cells. We found that ER was equally cytotoxic to both cells; ER formed more ROS in OVCAR-8 cells than in NIH/ADR-RES cells. Ferrostatin-1, an inhibitor of ferroptosis, inhibited ER-induced cell death in both cell lines. In contrast, RSL3 (RAS-selective lethal 3), an inducer of ferroptosis, significantly enhanced cell death in both cell lines. ER induced significant lipid peroxidation only in OVCAR-8 cells. We found that RSL3 was more cytotoxic to NCI/ADR-RES cells and significantly enhanced ER-induced lipid peroxidation in both cells, indicating GPX4 was involved in the process of ER-mediated ferroptosis. ER treatment also differentially modulated several ferroptosis related genes (e.g., HMOX1/OH1, and CHAC1) in these cells, indicating ER-induced cell death may be mediated differently in OVCAR-8 and NCI/ADR-RES ovarian cells. Our studies suggest that combinations of ER and RSL3 may contribute significantly to the treatment of ovarian cancers, including those that are resistant to other therapeutic agents due to the presence of P-gp or tumors with Ras mutation in the clinic. ER induced ferroptosis may also be an important treatment modality for resistant tumors expressing MDR1 in the clinic.

Lambert-Eaton myasthenic syndrome is a primary autoimmune or paraneoplastic neuromuscular disorder, which causes muscle weakness, areflexia and autonomic disorders through the production of antibodies to voltage-gated calcium channels. Diagnosis may be challenging, yet at the same time extremely important, allowing the detection of a possible underlying malignancy, in cases of paraneoplastic presentation. Some antibodies have good sensitivity and specificity for malignancy and are also discussed. Although most of times being correlated to small cell lung cancer, other types of tumors may be also found in the paraneoplastic syndrome. Misdiagnosis with Myasthenia Gravis may occur and differences between these two disorders are discussed. Therapy choice may vary from each patient depending on drug response and the situation in which the patient is encounter. Overall, the present paper brings a review of Lambert-Eaton, involving the diagnosis, as well as, the pathophysiology, differential diagnosis, tumor investigation and treatment. Also, a brief overview through guidance on therapy during the Corona Virus Disease 2019 pandemic is analyzed.

Aims: This systematic review aims to evaluate the influence of Environmental Enrichment (EE) on oncological factors in experimental studies involving various types of cancer models. Methods: A comprehensive search was conducted in three databases: PubMed (161 articles), Embase (335 articles), and Scopus (274 articles). Eligibility criteria were applied based on the PICOS strategy to minimize bias. Two independent researchers performed the searches, with a third participant resolving any discrepancies. The selected articles were analyzed, and data regarding sample characteristics and EE protocols were extracted. The outcomes focused solely on cancer and tumor-related parameters, including cancer type, description of the cancer model, angiogenesis, tumor occurrence, volume, weight, mice with tumors, and tumor inhibition rate. Key-findings: A total of 770 articles were identified across the three databases, with 12 studies meeting the inclusion criteria for this systematic review. The findings demonstrated that different EE protocols were effective in significantly reducing various aspects of tumor growth and development, such as angiogenesis, volume, weight, and the number of mice with tumors. Furthermore, EE enhanced the rate of tumor inhibition in mouse cancer models. Findings: This systematic review highlights the significant impact of EE protocols on multiple parameters associated with tumor growth and development, including angiogenesis, occurrence, volume, weight, and tumor incidence. Moreover, EE demonstrated the potential to increase the rate of tumor inhibition. These findings underscore the importance of EE as a valuable tool in the management of cancer.

Clinical management in neuro-oncology has changed to an integrative approach that incorporates molecular profile alongside histopathology and imaging findings. While the WHO guideline recommends genotyping of informative alterations as a routine clinical practice for central nervous system (CNS) tumors, acquisition of tumor tissue in the CNS is invasive and not always possible. Liquid biopsy is a non-invasive approach that provides the opportunity to capture the complex molecular heterogeneity of the whole tumor through detection of circulating tumor biomarkers in body fluids, such as blood or cerebrospinal fluid. Despite all the advantages, the low abundance of tumor-derived biomarkers, particularly in CNS tumors, as well as their short half-life has limited the application of liquid biopsy in clinical practice. Thus, it is crucial to identify factors that are associated with the presence of these biomarkers and explore possible strategies that can increase the shedding of these tumoral components into biological fluids. In this review, we first describe the clinical applications of liquid biopsy in CNS tumors including its roles in early detection of recurrence and monitoring of treatment response. We then discuss the utilization of imaging in identifying factors that affect the detection of circulating biomarkers as well as how image-guided interventions such as focused ultrasound can help enhance the presence of tumor biomarkers through blood-brain barrier disruption.

Primary central nervous system and brain tumors are one of the global burdens that are continuously increasing in cases and requiring more treatment options. Surgery has been the leading treatment option for tumors, however, the localization of the tumor and its infiltrating nature make this option challenging. DNA microarray expression profiles of different CNS tumors provide insight into potential biomarkers for identifying different tumor types and subtypes. Here, we utilized the differentially expressed genes common in four expression profiles, GSE66354, GSE68848, GSE74195, and GSE43290 to reconstruct the gene co-expression network. In this study, we were able to identify preserved cluster genes, hub genes, co-regulating transcription factors, miRNA families, and candidate repurposed drugs. Fourteen identified hub genes, which were, CACNA1A, DNM1, GABRA1, GRIA2, MAPT, SLC17A7, SNAP25, SNAP91, STXBP1, SYT1, COL1A1, COL6A2, FBN2, and FN1 appeared to play a role in tumor progression and may serve as drug targets. We also reported the DEGs in each tumor type, which were ATRT, EPN, PA, MED, PNET, MEN, ACM, ODG, and GBM. Five identified miRNA families, which were, let-7 family, mir-124 family, mir-1 family, mir-103 family, and mir-27 family described in the literature to have tumor-suppressing characteristics. Drug-gene and drug-transcription factor network revealed 32 candidate repurposed drugs and 13 were validated through connectivity map analysis. Here, two main repurposed drugs fit the regulatory requirement for gene interaction, these were, quercetin and vorinostat. Future validation in experimental studies may utilize the future use of the candidate repurposed drugs. Our study provides insights into drug repurposing prospects and understanding tumor expressions.

Two-stage surgery is unintentionally necessary when total tumor removal cannot be accomplished in the first surgery, although, it has not yet been established how to leave the tumor for the next surgery. There is a risk of postoperative hemorrhage in the residual tumor, especially in hypervascular tumors. We report a case of hypervascular choroid plexus papilloma in which preservation of intratumoral venous drainage was considered important to avoid hemorrhagic complications during a two-stage surgery. In hypervascular tumor resection, to prevent postoperative hemorrhage associated with a residual tumor, it may be important to preserve venous drainage of the tumor.

Background: About 10% of Wilms Tumor (WT) patients have a malformation or cancer predisposition syndrome (CPS) with causative germline genetic or epigenetic variants. Knowledge on CPS is essential for genetic counselling. Methods: This retrospective analysis focused on 2927 consecutive patients with WTs registered between 1989 and 2017 in the SIOP/GPOH studies. Results: (GU, N=66, 2,3%), Beckwith-Wiedemann spectrum (BWS, N=32, 1,1%), isolated hemihypertrophy (IHH, N=29, 1,0%), Denys-Drash syndrome (DDS, N=24, 0,8%) and WAGR syndrome (N=20, 0,7%) were reported most frequently. Compared to others, these patients were younger at WT diagnosis (median age 24,5 months vs. 39,0 months), had smaller tumors (334,8mL vs. 496,9mL), less often metastasis (8,2% vs. 18%), but more often nephroblastomatosis (12,9% vs. 1,9%). WT with IHH was associated with blastemal WT and DDS with stromal subtype. Bilateral WTs were common in WAGR (30%), DDS (29%) and BWS (31%). Chemotherapy induced reduction in tumor volume was poor in DDS (7,7% increase) and favorable in BWS (84,6% reduction). The event-free survival (EFS) of patients with BWS was significantly (p=0,002) worse than in others. Conclusions: CPS should be considered in WTs with specific clinical features resulting in referral to a geneticist. Their outcome was not always favorable.

Meningioma (MGM) is the most common type of intracranial tumor in adults. The validation of novel prognostic biomarkers to better inform tumor stratification and clinical prognosis is urgently needed. Many molecular and cellular alterations have been described in MGM tumors over the past few years, providing a rational basis for the identification of biomarkers and therapeutic targets. The role of receptor tyrosine kinase (RTKs), including those of the ErbB family of receptors, as oncogenes has been well established in several cancer types. Here, we review histological, molecular, and clinical evidence suggesting that RTKs, including the epidermal growth factor receptor (EGFR, ErbB 1), as well as other members of the ErbB family, may be useful as biomarkers in MGM.

Several treatment guidelines for sporadic, nonmetastatic nonfunctioning neuroendocrine tumors of the pancreas (NF-pNETs) have recommended resection, however, tumors ≤ 2 cm do not necessarily need surgery. This study aimed to establish a surgical treatment plan for NF-pNETs ≤ 2 cm. From 2000 to 2017, 483 patients who underwent resection for NF-pNETs ≤ 2cm in 18 institutions from Korea and China were enrolled and their medical records were reviewed. Median age was 56 (range 16- 80) years. The 10-year overall survival rate (10Y-OS) and recurrence-free survival rate (10Y-RFS) were 89.8 and 93.1%, respectively. In multivariable analysis, tumor size (> 1.5cm; p = 0.001) and nodal metastasis (p = 0.013) were independent adverse prognostic factors for OS. Perineural invasion (p = 0.008) and high Ki-67 index (≥3%; p < 0.001) were independent prognostic factors for poor RFS. NF-pNETs ≤ 2 cm showed unfavorable prognosis after resection when the tumor was larger than 1.5cm, Ki-67 index ≥ 3%, or nodal metastasis was present. NF-pNET patients with tumors ≤ 1.5cm can be observed if the preoperative Ki-67 index is under 3%, and if nodal metastasis is not suspected in preoperative radiologic studies. These findings support the clinical use to make decision about small NF-pNETs.

In this paper, we propose methods for brain tumor detection in MRI images based on ensemble learning. We build upon prior research on ensemble methods by testing the concatenation of pre-trained models: features extracted via transfer learning are merged and segmented by classification algorithms or a stacked ensemble of those algorithms. The proposed approach achieved accuracy scores of 0.98 , outperforming a benchmark VGG-16 model. Considerations to granular computing are given in the paper as well.

A surgical microscope is large in size, which makes it impossible to be portable. The distance between the surgical microscope and the observation tissue is 15–30 cm, and the adjustment range of the right and left of the camera is a maximum of 30°. Therefore, the surgical microscope is generated attenuation (above 58%) of irradiation optical source owing to the long working distance. Moreover, the observation of tissue is affected because of dazzling by ambient light as the optical source power is strong (55 to 160 mW/cm2). Further, observation blind spot phenomena will occur due to the limitations in adjusting the right and left of the camera. Therefore, it is difficult to clearly observe the tumor. In this study, a compact pen-type probe with a portable surgical microscope is presented. The proposed surgical microscope comprises a small and portable pen-type probe that can adjust the working distance between the probe and the observed tissue. In addition, it allows the adjustment of the viewing angle and fluorescence brightness. The proposed probe has no blind spots or optical density loss.

A surgical microscope is large in size, making portability impossible. The distance between the surgical microscope and the observation tissue is 15 to 30 cm, while the maximum adjustment range of the camera to the right and left is 30°. Therefore, surgical microscopes cause attenuation (above 58%) of the irradiation optical source owing to the long working distance. Moreover, the observation of tissue was dazzled with ambient light because the optical power source was strong (50 to 160 mW/cm2). Owing to the limited ability to adjust the camera to the right and left, a blind spot occurs with a surgical microscope. Therefore, it is difficult to clearly observe a tumor. In this study, a compact pen-type probe with a portable surgical microscope is proposed. The pen-type probe is small with a portable shape, and is capable of adjusting the working distance between itself and the observed tissue. It is also possible to adjust the viewing angle and fluorescence brightness. The proposed pen-type probe has no blind spots or optical density loss.

The heterogeneity of tumor infiltrating lymphocytes is not well characterized in brain metastasis. To address this, we performed a targeted analysis of immune cell subsets in brain metastasis tissues to test which immunosuppressive routes are involved in brain metastasis. We performed multiplex immunofluorescence (mIF), using commercially available validated antibodies on twenty formalin-fixed paraffin embedded whole sections. We quantitated the subsets of immune cells utilizing a targeted panel of proteins including PanCK, CD8, CD4, VISTA and Iba1, and analyzed an average of 15000 cells per sample. We classified tumours as either high (>30%) or low (<30%) tumour infiltrating lymphocytes (TILs) and found that increased TILs density correlated with survival. We next sought out to phenotype these TILs using mIF. The tumours with low TILs (n=9) had significantly higher expression of the immune-checkpoint molecule VISTA in tumor cells (p<0.01) as well as in their microenvironment (p<0.001). Contrastingly, the brain metastatic tumours with high TILs (n=8) displayed higher levels of activated microglia, as measured by Iba1 expression. Low TILs-tumours displayed CD8+ T-cells that co-express VISTA (p<0.01) significantly more compared to high TILs group, where CD8+ T-cells significantly co-express Iba1 (p<0.05). Interestingly, no definite phenotypes of CD4+ subsets were observed. These results were supported by RNA analysis of a publicly available, independent cohort. In conclusion, our work contributes to a growing understanding of the immune surveillance escape routes active in brain metastasis.

Several studies have suggested that pre and/or postdiagnosis physical activity can reduce the risk of recurrence in breast cancer patients, however its effect according to follow-up time has not yet been investigated. We analyzed recurrence and mortality dynamics in randomized clinical trials (RCTs) from Australia and Canada. The combined Australian RCTs evaluated, at median follow-up of 8.3 years, an 8-month pragmatic exercise intervention in 337 women with newly diagnosed breast cancer, while the Canadian RCT evaluated, at median follow-up of 7.4 years, supervised aerobic or resistance exercise during chemotherapy in 242 patients. For each RCT, the control arm consisted of patients undergoing usual care. We estimated the event dynamics by the discrete hazard function, through flexible regression of yearly conditional event probabilities with generalized additive models. In the considered RCTs, the recurrence and mortality risk of patients enrolled in the physical activity arm was stably reduced at medium/long term after five year of follow-up. In the Australian RCTs where patients were recruited by urban versus rural area, the latter group did not display benefit from physical activity. Estimated Odds Ratios (95% Confidence Intervals) for Disease Free Survival (DFS) in urban women were 0.63 (0.22-1.85); 0.27 (0.079-0.90); 0.11 (0.013-0.96) at the 3rd, 5th and 7th year of follow-up, respectively. For rural women, DFS patterns were overlapping with ORs approximating 1 at the different years of follow-up. Although not reaching statistical evidence, the estimates in the Canadian trial were in line with the results from the Australian urban women with ORs (95% CI) forDFS of 0.70 (0.33-1.50); 0.47 (0.19-1.18); 0.32 (0.077-1.29) at 3rd, 5th, 7th follow-up year, respectively. While we acknowledge that the analyzed RCTs were not designed for investigating disease recurrence over time, these results support the evidence that physical activity reduces the risk of developing medium/long-term metastases. Additional translational research is needed to clarify the mechanisms underlying these observations.

Development of novel anti-cancer peptides requires a rapid screening process which can be accelerated by using appropriate in vitro tumor models. Breast carcinoma tissue is a three dimensional (3D) microenvironment, which contains a hypoxic center surrounded by dense proliferative tissue. Biochemical clues provided by such 3D cell mass cannot be recapitulated in conventional 2D culture systems. In this experiment, we evaluate the efficacy of the sandalwood peptide, cyclosaplin on established in vitro 3D silk breast cancer model using invasive MDA-MB-231 cell line. The anti-proliferative effect of the peptide on 3D silk tumor model is monitored by alamar blue assay, with conventional 2D culture as control. The proliferation rate, glucose consumed, LDH, and MMP-9 activity of Human breast cancer cells are higher in 3D constructs compared to 2D. A higher concentration of drug is required to achieve 50% cell death in 3D culture than 2D cultures. The cyclosaplin treated MDA-MB-231 cells showed significant decrease in MMP-9 activity in 3D constructs. Microscopic analysis revealed the formation of cell clusters evenly distributed in the scaffolds. The drug treated cells were less in number, smaller and showed unusual morphology. Overall, these findings indicate the role of cyclosaplin as a promising anti-cancer therapeutics.

Cyclin E2, a member of the cyclin family, is a key cell cycle-related protein. This protein plays essential roles in cancer progression, and as such, an inhibitor of cyclin E2 has been approved to treat several types of cancers. Even so, mechanisms underlying how to regulate cyclin E2 expression in cancer remain largely unknown. The current study found that miR-3687 is up-regulated in clinical bladder cancer (BC) tumor tissues, TCGA database and human BC cell lines. Inhibition of miR-3687 expression significantly reduces human BC cell proliferation in vitro and tumor growth in vivo, which are concurrently with the induction of G0/G1 cell cycle arrest and downregulation of cyclin E2 protein expression. Interestingly, overexpression of cyclin E2 reversed the inhibition of BC proliferation induced by miR-3687. Mechanistic studies suggest that miR-3687 could bind to the 3'-UTR of foxp1 mRNA, downregulates FOXP1 protein expression, and in turn promotes the transcription of cyclin E2, thereby promoting the growth of BC cells. Collectively, the current study not only establishes a novel regulatory axis of miR-3687/FOXP1 in regard to regulation of cyclin E2 expression in BC cells, but also provides strong suggestive evidence that miR-3687 and FOXP1 may be potentially promising targets in therapeutic strategies of human BC.

Photodynamic therapy (PDT) with a suitable photosensitizer molecule is a promising anticancer treatment. We evaluated two chlorin molecules as potential photosensitizers, methyl pyropheophorbide a (MPPa) and N-methoxyl purpurinimide (NMPi), against A549 human lung adenocarcinoma cells in vitro as well as in A549 tumor-bearing mice in vivo. Cell viability, microscopy, and FACS analyses were performed for the in vitro studies. MPPa and NMPi showed high phototoxicity in vitro, which was dependent on the concentration of the photosensitizers as well as the light irradiation time. In the animal study, tumor volume change, tumor surface alterations, and H&E and TUNEL staining analyses were performed and compared between small (tumor volume of <50 mm³) and large (tumor volume of >50 mm³) size of initial tumors. MPPa and NMPi showed high anticancer efficacy against small-size tumors, indicating that early treatment with PDT is effective. Especially, repeated two times PDT with NMPi allowed almost complete eradication against small-size tumors. However, MPPa and NMPi were not effective against large-size tumors. In conclusion, the two chlorin derivatives, MPPa and NMPi, show good anticancer efficacy as promising photosensitizers for PDT in vitro and in vivo. Moreover, their activity in vivo was significantly dependent on the initial tumor size in mice, which confirms the importance of early cancer treatment.

The Na+/K+ ATPase is a protein involved in the active transport of ions across the cellular membrane. Ouabain is a cardiotonic glycoside that, by inhibiting the Na+/K+ pump, interferes with cell processes mediated directly by the pump, but also indirectly influences other cellular processes, such as cellular cycle and proliferation, growth, cell differentiation, angiogenesis, migration, adhesion and invasion. We used the SK-BR-3 breast cancer cell line, mesenchymal stem cells (MSCs), and tumor-associated fibroblasts (TAFs) in vitro for determining the changes induced by Ouabain in concentration of 10-5 M, 10-6 M, 10-8 M, 10-9 M on these cellular types, employing specific methods: SEM for morphological evaluation; immunocytochemistry, flowcytometry to assess immunophenotypical markers expression, cell cycle and Annexin V/PI assay for cellular proliferation and viability testing; flowchamber assay to evaluate functional adhesion behavior; RT-PCR for Na+/K+ ATPase subunits molecular expression. Being indicative of the pro-apoptotic and inhibitory effect of Ouabain on tumor invasion and metastasis, the results support the addition of Ouabain to the oncological therapeutic arsenal, trailing the “repurposing drugs” approach.

Three-dimensional (3D) cell culture systems can be regarded as suitable platforms to bridge the huge gap between animal studies and two-dimensional (2D) monolayer cell culture to study chronic diseases such as cancer. In particular, the preclinical platforms for multicellular spheroid formation and culture can be regarded as ideal in vitro tumor models. The complex tumor microenvironment such as hypoxic region and necrotic core can be recapitulated in 3D spheroid configuration. Cells aggregated in spheroid structures can better illustrate the performance of anti-cancer drugs as well. Various methods have been proposed so far to create such 3D spheroid aggregations. Both conventional techniques and microfluidic methods can be used for generation of multicellular spheroids. In this review paper, we first discuss various spheroid formation phases. Then, the conventional spheroid formation techniques such as bioreactor flasks, liquid overlay and hanging droplet technique are explained. Next, a particular topic of the hydrogel in spheroid formation and culture is explored. This topic has received less attention in the literature. Hydrogels entail some advantages to the spheroid formation and culture such as size uniformity, the formation of porous spheroids or hetero-spheroids as well as chemosensitivity and invasion assays and protecting from shear stress. Finally, microfluidic methods for spheroid formation and culture are briefly reviewed.

A teratoma is a neoplasm composed of cell populations or tissues that remind, in their appearance, normal elements derived from at least two embryonic layers. Fetal mature teratomas are normally benign, cystic, and typically occur along the midline, while they are rare in the posterior mediastinum. Teratomas are frequently solitary, however they may sometimes be associated with other congenital anomalies and/or with chromosomal abnormalities. Clinically, they are often asymptomatic but can occasionally cause compression symptoms. Prenatal diagnoses are uncommon and made with ultrasonography; differential diagnosis with other congenital conditions is mandatory. We report the case of a 21 weeks of gestational age-old fetus with a Mature Triphyllic Fetal Cystic Teratoma, grade 0, located in the right posterior mediastinum.

Recently concluded, large-scale cancer genomics studies involving multiregion sequencing of primary tumors and paired metastases appear to indicate that many or most cancer patients have one or more “clonal" mutations in their tumors. Clonal mutations are those that are present in all of a patient’s cancer cells. Achilles Therapeutics is currently the only company specifically targeting clonal mutations. However, they are doing so with tumor-derived T cells. To address the potential limitations of immunotherapy, I have devised another approach for exploiting clonal mutations, which I call “Oncolytic Vector Efficient Replication Contingent on Omnipresent Mutation Engagement” (OVERCOME). The ideal version of OVERCOME would likely employ a bioengineered facultative intracellular bacterium. The bacterium would initially be attenuated, but (transiently) reverse its attenuation upon clonal mutation detection.

(1) Background: The typical transporter protein, P-glycoprotein (P-gp), has been proven to be associated with multidrug resistance (MDR). Pyxinol and 24S-Pyxinol amino acid ester derivatives had been demonstrated to be promising P-gp inhibitors for reversal of tumor MDR in KBV cells, however, their roles in MDR reversal in other tumor-resistant cells are still unclear. (2) Methods: In the present study, we synthesized 40 amino acid ester derivatives of Pyxinol and 24S-Pyxinol. The MDR reversal effects of these derivatives were evaluated in A549/Tax, MCF-7/ADR, and HCT-8/VCR cells using the CCK-8 assay. Subsequently, western blot assay, intracellular Rhodamine123 (Rh123) accumulation assay and P-gp ATPase activity assay were utilized to investigate the effects of active compound on P-gp. Molecular docking was used to predict the possible binding patterns of active compound to P-gp. Moreover, based on UPLC-Q/TOF-MS cellular metabolomics technology to identify endogenous differential metabolites and metabolic pathways associated with tumor MDR effects of the active compound. (3) Results: The results of the CCK-8 assay showed that compounds 8, 14, 16, 17, 18, 23, 25, 34, 36, 37 exhibited strong MDR reversal effect in A549/Tax, MCF-7/ADR and HCT-8/VCR cells, which were screened by reversal fold (RF) greater than 5. Among them, 10 μM of derivative 37 (new compound) showed the outstanding activity (RF: 15.31) in reversing MDR in A549/Tax cells. Compound 37 could act as a substrate for P-gp and inhibit the efflux function of P-gp by competitively binding to the binding site of antitumor drugs. Meanwhile, the molecular docking results confirmed that compound 37 was identified to under-go high-affinity binding to the drug binding site of P-gp. In addition, 14 endogenous differential metabolites and 6 metabolic pathways involved closely associated with the reversal of tumor MDR effects of compound 37 were identified. (4) Conclusions: Overall, a new candidate compound 37 (24S-3-L-threonyl-Pyxinol) could be provided for reversing tumor MDR by this study.

Alphaviruses, flaviviruses, measles viruses and rhabdoviruses are enveloped single-stranded RNA viruses, which have been engineered as expression vector systems for recombinant protein expression and vaccine development. Due to the presence of non-structural genes encoding the replicase complex, a 200,000-fold amplification of viral RNA occurs in the cytoplasm of infected cells providing extreme transgene expression levels, which is why they are named self-replicating RNA viruses. Expression of surface proteins of pathogens causing infectious disease and tumor antigens provide the basis for vaccine development against infectious diseases and cancer. The self-replicating RNA viral vectors can be administered as replicon RNA, recombinant viral particles, or layered DNA/RNA replicons. Self-replicating RNA viral vectors have been applied for vaccine development against influenza virus, HIV, hepatitis B virus, human papilloma virus, Ebola virus and recently coronaviruses, especially SARS-CoV-2 the causative agent of the COVID-19 pandemic. Measles virus and rhabdovirus vector-based SARS-CoV-2 vaccine candidates have been subjected to clinical trials. Moreover, RNA vaccine candidates based on self-amplifying alphaviruses have also been evaluated in clinical settings. Various cancers such as brain, breast, lung, ovarian, prostate cancer and melanoma have also been targeted for vaccine development. Robust immune responses and protection have been demonstrated in animal models. Clinical trials have shown good safety and target-specific immune responses. Ervebo, the VSV-based vaccine against Ebola virus disease has been approved for human use.

Metastasis is the leading cause of cancer-related death and drives patient morbidity as well as healthcare costs. For several cancers, breast and prostate in particular, bone is the primary site of metastasis. Efforts to treat bone metastases have been stymied by a lack of models to study the progression and cellular players and signaling pathways driving bone metastasis. In this review, we examine the newly described and classic models of bone metastasis. Through the use of current in vivo, microfluidic and in silico computational models bone metastasis models we may eventually understand how cells escape the primary tumor and how these circulating tumor cells then home to and colonize the bone marrow. Further, future models may uncover how cell enter and escape dormancy to develop into overt metastases. Recreating the metastatic process will lead to the discovery of therapeutic targets for disrupting and treating bone metastasis.

More than 1 million women are diagnosed annually worldwide with a gynecological cancer. Most gynecological cancers are diagnosed at late stage, either because lack of symptoms such as in ovarian cancer or limited accessibility to primary prevention in low-resource countries such as in cervical cancer. Here, we extend the studies of AR2011, a stroma-targeted and tumor microenvironment responsive oncolytic adenovirus (OAdV) whose replication is driven by a triple hybrid promoter. We show that AR2011 was able to replicate and lyse in vitro fresh explants obtained from human ovarian cancer. uterine cancer, and cervical cancer. AR2011 was also able to strongly inhibit the in vitro growth of ovarian malignant cells obtained from human ascites fluid. The virus could synergize in vitro with cisplatin even on ascites-derived cells obtained from patients heavily pretreated with neoadjuvant chemotherapy. AR2011(h404) a dual transcriptionally targeted derived virus armed with hCD40L and h41BBL under the regulation of the hTERT promoter, showed a strong efficacy in vivo both on subcutaneous and intraperitoneally established human ovarian cancer in nude mice. Preliminary studies in an immunocompetent murine tumor model showed that AR2011(m404) expressing the murine cytokines was able to induce an abscopal effect. The present studies suggest that AR2011(h404) is a likely candidate as a novel medicine for intraperitoneal disseminated ovarian cancer.

Glucocorticoid administration is a common clinical practice in attempt to decrease inflammation associated with, and improve resectability of, canine mast cell tumors (MCTs). However, the impact of neoadjuvant glucocorticoids on histological features and proliferation indices of canine MCTs is unknown. The objective of this study was to evaluate changes in tumor grade, mitotic count, Ki67, AgNOR, and AgNORxKi67 scores following short-course, anti-inflammatory neoadjuvant prednisone in canine patients with MCTs. This was a prospective, single-arm pilot study. Client-owned dogs with treatment-naïve, cytologically-confirmed MCTs were enrolled. Patients underwent an initial incisional biopsy followed by a 10-14 day course of anti-inflammatory prednisone, and surgical resection. All histological samples were randomized, masked, and evaluated by a single pathologist. Unstained paired pre- and post-treatment samples were submitted to a commercial laboratory for Ki67 and AgNOR immunohistochemical analysis. There were 11 dogs enrolled with 11 tumors. There were no statistical differences between the pre- and post-treatment histological parameters of mitotic index, Ki67, AgNOR, or Ki67xAgNOR. There were no clinically-significant alterations between pre-treatment and post-treatment in the assignment of tumor grades. A short-course of anti-inflammatory prednisone does not appear to alter the histological parameters that affect grade-determination, nor significantly alter the proliferation indices in canine MCTs.

LOXL2, a copper-dependent amine oxidase, has emerged as a promising therapeutic target in hepatocellular carcinoma (HCC). Increased LOXL2 expression in HCC has been linked with aggressive phenotype and represents a poor prognostic factor. Here, we focus on mechanisms by which LOXL2 orchestrates multiple oncogenic functions in HCC development. We are reviewing current knowledge about the roles of LOXL2 in the modulation of the HCC tumor microenvironment, formation of premetastatic niches, and epithelial-mesenchymal transition. Also, we are highlighting the complex interplay between LOXL2 and hypoxia, angiogenesis, and vasculogenic mimicry in HCC. At the end of the review, we summarize current LOXL2 inhibitors and discuss their potential in HCC precision treatment.

Tumorigenesis is a complex and dynamic process involving cell-cell and cell-extracellular matrix (ECM) interactions that allow tumor cell growth, drug resistance and metastasis. This review provides an updated summary of the role played by the tumor microenvironment (TME) components and hypoxia in tumorigenesis and highlight various ways through which tumor cells reprogram normal cells including into phenotypes that are pro-tumorigenic including cancer associated- fibroblasts, -macrophages and -endothelial cells. Tumor cells secrete numerous factors leading to transformation of a previously anti-tumorigenic environment into a pro-tumorigenic environment. Once formed, solid tumors continue to interact with various stromal cells including local and infiltrating fibroblasts, macrophages, mesenchymal stem cells, endothelial cells, pericytes, and secreted factors and the ECM within the tumor microenvironment (TME). The TME is key to tumorigenesis, drug response and treatment outcome. Importantly, stromal cells and secreted factors can initially be anti-tumorigenic but over time promote tumorigenesis and induce therapy resistance. To counter hypoxia, increased angiogenesis leads to formation of new vascular networks in order to actively promote and sustain tumor growth via supply of oxygen and nutrients whilst removing metabolic waste. Angiogenic vascular network formation aid in tumor cell metastatic dissemination. Successful tumor treatment and novel drug development require the identification and therapeutic targeting of pro-tumorigenic components of the TME including cancer-associated- fibroblasts (CAFs) and -macrophages (CAMs), hypoxia, blocking ECM-receptor interactions, in addition to targeting of tumor cells. Re-programming of stromal cells and the immune response to be anti-tumorigenic is key to therapeutic success. Lastly, this review highlights potential TME- and hypoxia-centred therapies under investigations.

Conventional radiation therapy uses white X-rays that consist of a mixture of X-ray waves with various energy levels. In contrast, a monochromatic X-ray (monoenergetic X-ray) has a single energy level. Irradiation of high Z elements with a synchrotron generated monochromatic X-ray with the energy at or higher than the K-edge energy of the element results in the production of the Auger electrons that cause DNA damage leading to cell killing. Delivery of high Z elements into cancer cells and tumor mass can be facilitated by the use of nanoparticles. Mesoporous silica nanoparticles (MSNs) have been shown to be effective in delivering high Z elements to cancer cells. A proof of principle experiment was reported that demonstrated the feasibility of this approach. This opens up a possibility to pursue the Auger cancer therapy by the combined use of MSNs loaded with high Z elements and monochromatic X-rays. Similar cancer therapies using other types of quantum beams such as neutron, proton and carbon ion beams can be envisioned.

Understanding clinical significance of variants of unknown significance (VUS) reported in next-generation sequencing (NGS) has become essential in cancer treatment. Our study examined six widely used in silico tools: PolyPhen-2, Align-GVGD, MutationTaster2, CADD, REVEL, and Chat-GPT. We utilized a dataset of gene variants known to potentially affect immune therapy. No single tool could comprehensively determine mutation variant pathogenicity. MutationTaster2021 showed the highest overall accuracy and MCC among the tools. Notably, REVEL and Chat-GPT exhibited 100% specificity, suggesting their proficiency in accurately identifying pathogenic variants and minimizing false positives. In contrast, CADD displayed optimal sensitivity, making it suitable for effectively ruling out benign variants.

The management of brain tumors presents numerous challenges, despite the employment of multimodal therapies including surgical intervention, radiotherapy, chemotherapy, and immunotherapy. Owing to the distinct location of brain tumors and the presence of the blood-brain barrier (BBB), these tumors exhibit considerable heterogeneity and invasiveness at a histological level. Recent advancements in hydrogel research for the local treatment of brain tumors have sought to overcome the primary challenge of delivering therapeutics past the BBB, thereby ensuring efficient accumulation within brain tumor tissues. This article elaborates on various hydrogel-based delivery vectors, examining their efficacy in the local treatment of brain tumors. Additionally, it reviews the fundamental principles involved in designing intelligent hydrogels that can circumvent the BBB and penetrate larger tumor areas, thereby facilitating precise, controlled drug release. Hydrogel-based drug delivery systems (DDSs) are posited to offer a groundbreaking approach in addressing the challenges and limitations inherent in traditional oncological therapies, which are significantly impeded by the unique structural and pathological characteristics of brain tumors.

Currently, the most promising work seems to be aimed not so much at the development of new drugs, but rather at creating ways of targeted delivery of existing drugs. In this paper, we show that polymeric micelles based on chitosan, heparin grafted with lipoic and oleic acids residues demonstrate the potential for doxorubicin delivery to tumors due to pH-, glutathione-sensitivity. Smart delivery systems use the Aikido principle, i.e. they target tumor cells according to their features. Natural polysaccharides (heparin and chitosan) provide the pH sensitivity of micelles: the release of doxorubicin (Dox) is enhanced in a slightly acidic environment (model tumor microenvironment). Fatty acid residues are necessary for the formation of micelles and solubilization of cytostatics in a hydrophobic core. Lipoic acid residues formed a labile S-S cross-linking between polymer chains (the first method), and also covalently attached doxorubicin molecules through glutathione-sensitive S-S bridges (the second option) – determine Redox sensitivity of micelles to tumors. The characterization of polymeric micelles and prodrugs (Dox-polymer) was carried out using FTIR spectroscopy. The release of doxorubicin from micelles occurs slowly (20% / 6h) in an environment with a pH of 7.4 and the absence of glutathione, while in a slightly acidic environment and in the presence of 10 mM glutathione, the rate increases up 6 times, with an increase in the effective concentration up to 5 times after 7 h. The permeability of free doxorubicin, micellar formulations (covalent S-S crosslinked and not) into Raji, K562, A875 cancer cells was studied using confocal laser scanning microscopy (CLSM), demonstrated an increase in the permeability of micellar formulations based on Dox. Thus, we have presented micellar formulations of doxorubicin for targeted delivery to tumor, what is important in the aspects of reducing non-target toxicity, increasing the selectivity of cytostatics against tumors and overcome multidrug resistance.

Prostate cancer (PC) is a common malignancy of elderly men, characterized by great heterogeneity in its clinical course, ranging from an indolent to a highly aggressive disease. The aggressive variant prostate cancer (AVPC) clinically shows an atypical pattern of disease progression, similar to that of small cell PC (SCPC), and also shares the chemo-responsiveness of SCPC. The term AVPC does not describe a specific histologic subtype of PC but rather the group of tumors that, irrespective of morphology, show an aggressive clinical course, dictated by androgen receptor (AR) indifference. AR indifference represents an adaptive response to androgen deprivation therapy (ADT), driven by epithelial plasticity, an inherent ability of tumor cells to adapt to their environment by changing their phenotypic characteristics in a bi-directional way. The molecular profile of AVPC entails combined alterations in tumor suppressor genes retinoblastoma protein 1 (RB1), tumor protein 53 (TP53) and phosphatase and tensin homolog (PTEN). The understanding of the biologic heterogeneity of castration-resistant PC (CRPC) and the need to identify the subset of patients that would potentially benefit from specific therapies necessitate the development of prognostic and predictive biomarkers. This review aims to discuss the possible pathophysiologic mechanisms of AVPC development and the potential use of emerging tissue-based biomarkers in clinical practice.

Lipid nanoparticles (LNPs) have attracted extensive attention in tumor immunotherapy in recent years. The strategy of targeting immune cells in cancer therapy has become a research area of great interest. mRNA vaccines are a potential choice for tumor immunotherapy due to their ability to directly encode antigen proteins and stimulate a strong immune response. However, the mode of delivery and lack of stability of mRNA are key issues limiting its application. LNPs are an excellent mRNA delivery vector, and their structural stability and biocompatibility make them an effective means to deliver mRNA to specific targets. This study summarizes the research progress in LNP delivery vector-assisted targeted controlled release mRNA vaccines in tumor immunity. The role of LNPs in improving mRNA stability, immunogenicity and targeting is discussed. In addition, combined with the cutting-edge research results, the potential mechanisms and application prospects of LNP-mRNA vaccines in tumor immunotherapy were further analyzed. This review aims to systematically summarize the latest research progress in LNP delivery carrier-assisted targeted controlled-release mRNA vaccines in tumor immunity to provide new ideas and strategies for tumor immunotherapy and provide more effective treatment plans for patients.

Cancer remains as a worldwide cause of death. Investigational research efforts have included the administration of tumors-derived extracts to healthy animals. Having previously demonstrated that administration of non-transmissible, human cancers-derived homogenates induced malignant tumors in mice; we examined here the consequences of administering 50 or 100 µg of protein of crude homogenates from samples of mammary carcinoma, pancreatic adenocarcinoma, and melanoma. The protocol conceived six inoculations per week during three months. Concurrent control group received homogenates of healthy donor skin cosmetic surgery fragments. Mammary carcinoma homogenate administration did not provoke animals’ deterioration or mortality. Multiple foci of lung adenocarcinomas with broad expression of malignity histomarkers, coexisting with small cell-like carcinomas were found. Disseminated cells, positive to classic epithelial markers were detected in lymphoid nodes. Pancreas tumor and melanoma homogenates administrations severely deteriorated animals’ health. Pancreas tumor induced lung poorly-differentiated adenocarcinomas, as a remarkable pancreatic islets hyperplasia. Melanoma affected lungs with atypical adenomatous hyperplasia and solid pseudopapillary adenocarcinoma. Giant atypical hepatocytes with variegated nuclei were also observed. Kidney parenchyma exhibited dispersed foci of neoplastic cells within a desmoplastic matrix. A noticeable nuclear overlapping with hyperchromatic nuclei, mitotic figures, and prominent nuclear atypia was identified in epidermal cells. None of these changes were ever detected in any mouse of the control groups. This study confirms and extends our hypothesis that tumor homogenates contain and may act as a vector for “malignancy drivers”, which ultimately implement a carcinogenesis process in otherwise healthy mice.

Current treatments in patients with pancreatic cancer offer limited benefits. In this report, we applied “alkalization therapy”, which was efficacious for other solid tumors at our clinic, to stage 4 pancreatic cancer patients, and investigated its effect on disease prognosis. Patients with metastatic pancreatic cancer who were treated at Karasuma Wada Clinic in Kyoto, Japan, between 2011 and 2022 were included in the study. All patients received alkalization therapy (combination of an alkaline diet, bicarbonate, and citric acid administration), alongside standard chemotherapy. Urine samples were collected to assess urine pH as a marker for whole-body alkalization. In the 98 patients analyzed, the median overall survival (OS) from the time of diagnosis was 13.2 months. Patients with a mean urine pH of 7.5 or greater had a median OS of 29.9 months, compared with 15.2 months for those with a mean urine pH of 6.5 to 7.5, and 8.0 months for those with a mean urine pH of less than 6.5, which suggests a trend of a longer OS in patients with a higher urine pH. Conclusions: Alkalization therapy may offer a viable approach to enhance the survival of stage 4 pancreatic cancer patients, who typically have an unfavorable prognosis.

Background: Muscle wasting is a common phenomenon in oncology and appears to be alleviated by exercise training. This study aims to determine the degree of aggressiveness of cancer-induced muscle wasting in two different phenotypic muscles, and whether exercise training can attenuate this muscle dysfunction. Methods: Fifty Sprague-Dawley rats were randomly assigned to four experimental groups, two control groups (sedentary and exercised) and two breast cancer model groups (sedentary and exercised) induced by 1-methyl-1-nitrosoureia (MNU). After 35 weeks of endurance training the animals were sacrificed and the gastrocnemius and soleus muscles were harvested for morphometric analysis. Results: A significant reduction in cross-sectional area (P < 0.05) was found in both muscles of sedentary tumor-bearing animals. Interstitial fibrosis was significantly higher in the gastrocnemius of sedentary tumor-bearing animals (P < 0.05), but not in the soleus. A shift from large to small fibers was observed in the gastrocnemius of sedentary tumor-bearing animals. Long-term exercise training was able to prevent this cancer-related mus-cle dysfunction. Conclusions: The Gastrocnemius muscle showed a very pronounced reduction in cross-sectional area and marked interstitial fibrosis in sedentary animals with tumors. The soleus muscle showed a less pronounced but significant reduction in cross-sectional area, and collagen deposition did not differ between tumor groups. These contrasting results confirm that can-cer-induced muscle wasting can affect specific fiber types, and specific muscles, namely fast glycolytic muscles, and that exercise training can act to improve it.

Research has shown the role of growth factors in lung cancer angiogenesis. Angiogenesis promotes lung cancer progression by stimulating tumor growth, enhancing tumor invasion, contributing to metastasis, and modifying immune system responses within the tumor microenvironment. As a result, new treatment techniques based on the anti-angiogenic characteristics of compounds have been developed. These compounds selectively block the growth factors themselves, their receptors, or the downstream signaling pathways activated by these growth factors. The EGF and VEGF families are the primary targets in this approach, and several studies are being conducted to propose anti-angiogenic drugs that are increasingly suitable for the treatment of lung cancer, either as monotherapy or as combined therapy. The efficacy results are encouraging, but a caution must be placed on the higher risk of toxicity, outlining the importance of personalized follow-up in the management of these patients.

Aim: This study was to evaluate the predictive value of tumor marker (TM) score in patients with hepatocellular carcinoma (HCC) treated with Atezolizumab plus Bevacizumab (Atez/Bev) as a first-line chemotherapy. Materials/Methods: From September 2020 to December 2022, 371 HCC patients treated with Atez/Bev, in whom alpha-fetoprotein (AFP), fucosylated AFP (AFP-L3) and des gamma-carboxy prothrombin (DCP) were measured at introducing Atez/Bev. Elevations of AFP (≥100 ng/ml), AFP-L3 (≥10%), and DCP (≥100 mAU/ml) were treated as positive, and the number of positive tumor marker was summed up and used as the previously proposed TM score. Hepatic reserve function was assessed with modified albumin-bilirubin grade (mALBI). Predictive values for prognosis were evaluated, retrospectively. Results: TM score 0 was in 81 (21.8%), score 1 in 110 (29.6%), score 2 in 112 (29.9%), and score 3 in 68 (18.3%), respectively. Median overall survival (OS) was not applicable [NA] (95% CI NA-NA), 24.0 months (95% CI 17.8-NA), 16.7 months (95% CI 17.8-NA) and NA (95%CI 8.3-NA) for TM scores 0, 1, 2 and 3, respectively (p<0.001). Median progression free survival (PFS) was also 16.5 months (95% CI 8.0-not applicable [NA]), 13.8 months (95% CI 10.6-21.3) and 7.7 months (95% CI 5.3-8.9), 5.8 months (95%CI 3.0-7.6), respectively (p<0.001). OS was stratified well in mALBI 1/2a as well as in mALBI 2a/2b. Whereas, PFS was well stratified in mALBI 2a/2b, while not in mALBI 1/2a. Conclusion: The TM score was a simple and useful prognostic marker in HCC patients treated with Atez/Bev.

Considering tumors from an evolucionary perspective, successive tumor cells undergo turnover in response to stressful conditions which pressures tumor cells to adapt to a new environment. Tumor cells uses parts of themselves to communicate and share biological information, known as extracellular vesicles (EV) secretion to promote their survival and “survive to each and every metabolic cost”. Tumor microenvironment (TME) is a miscellaneous of cells, factors, extracellular matrix proteins and EVs. EVs include smalls (<160nm, exosomes) and larger (100-1,000nm, microvesicles) lipid bilayer enclosed packages of biomolecules that are shed by tumors to TME. Tumor-derived extracellular vesicles transfer adaptative stress signaling to recipient cells, reprograming these cells. Heat Shock Proteins (HSP) are more prominent stress response regulators found in exosomes. HSP-loaded exosomes actively reprogram tumor and TME cells to acquire mechanisms that contribute to tumor progression and therapy resistance. The intercellular communication mediated by HSP-loaded EVs favors the escape of tumor cells from, endoplasmic reticulum (ER) stress, hypoxia, apoptosis and anti-cancer therapies. Extracellular HSPs activate and deactivate immune response, induce cell differentiation, changes vascular homeostasis, and help to augment the pre-metastatic niche formation. Here we will explore the EV mechanism of HSP transmission among TME cells and the relevance of these intercellular communications for resistance to therapies in cancer.

Purposes: To provide abdominal contrast-enhanced MR image synthesis, we developed an image gradient regularized multi-modal multi-discrimination sparse-attention fusion generative adversarial network (GRMM-GAN) to avoid repeated contrast injections to patients and facilitate adaptive monitoring. Methods: With IRB approval, 165 abdominal MR studies from 61 liver cancer patients were retrospectively solicited from our institutional database. Each study included T2, T1 pre-contrast (T1pre), and T1 contrast-enhanced (T1ce) images. The GRMM-GAN synthesis pipeline consists of a sparse attention fusion network, an image gradient regularizer (GR), and a generative adversarial network with multi-discrimination. The studies were randomly divided into 115 for training, 20 for validation, and 30 for testing. The two pre-contrast MR modalities, T2 and T1pre images, were adopted as inputs in the training phase. The T1ce image at the portal venous phase was used as an output. The synthesized T1ce images were compared with the ground truth T1ce images. The evaluation metrics include peak signal-to-noise ratio (PSNR), structural-similarity-index (SSIM), and mean-squared-error (MSE). A Turing test and experts’ contours evaluated the image synthesis quality. Results: The proposed GRMM-GAN model achieved a PSNR of 28.56, an SSIM of 0.869, and an MSE of 83.27. The proposed model showed statistically significant improvements in all metrics tested with p-values <0.05 over the state-of-the-art model comparisons. The average Turing test score was 52.33%, close to random guessing, supporting the model's effectiveness for clinical application. In the tumor-specific region analysis, the average tumor contrast-to-noise ratio (CNR) of the synthesized MR images was not statistically significant from the real MR images. The average DICE from real vs. synthetic images was 0.90, compared to the inter-operator DICE of 0.91. Conclusion: We demonstrated the function of a novel multi-modal MR image synthesis neural network, GRMM-GAN, for T1ce MR synthesis based on pre-contrast T1 and T2 MR images. GRMM-GAN shows promise for avoiding repeated contrast injections during radiation therapy treatment.

Uveal melanoma (UM) is the most common primary cancer of the eye and is associated with a high rate of metastatic death. UM can be stratified into two main classes based on metastatic risk, with class 1 UM having a low metastatic risk and class 2 UM having a high metastatic risk. Class 2 UM have a distinctive genomic, transcriptomic, histopathologic, and clinical phenotype characterized by biallelic inactivation of the BAP1 tumor suppressor gene, an immune suppressive microenvironment enriched for M2-polarized macrophages, and poor response to checkpoint inhibitor immunotherapy. To identify potential mechanistic links between BAP1 loss and immune suppression in class 2 UM, we performed an integrated analysis of UM samples, as well as genetically engineered UM cell lines and uveal melanocytes (UMC). Using RNA sequencing (RNA-seq), we found that the most highly up-regulated gene associated with BAP1 loss across these datasets was PROS1, which encodes a ligand that triggers phosphorylation and activation of the immunosuppressive macrophage receptor MERTK. The inverse association between BAP1 and PROS1 in class 2 UM was confirmed by single-cell RNA-seq, which also revealed that MERTK was up-regulated in CD163+ macrophages in class 2 UM. Using ChIP-seq, BAP1 knockdown in UM cells resulted in an accumulation of H3K27ac at the PROS1 locus, suggesting epigenetic regulation of PROS1 by BAP1. Phosphorylation of MERTK in RAW 264.7 monocyte-macrophage cells was increased upon co-culture with BAP1-/- UMCs, and this phosphorylation was blocked by depletion of PROS1 in the UMCs. These findings were corroborated by multi-color immunohistochemistry, where class 2/BAP1-mutant UMs demonstrated increased PROS1 expression in tumor cells and increased MERTK phosphorylation in CD163+ macrophages compared to class 1/BAP1-wildtype UMs. Taken together, these findings provide a mechanistic link between BAP1 loss and suppression of the tumor immune microenvironment in class 2 UMs, and they implicate the PROS1-MERTK pathway as a potential target for immunotherapy in UM.

Findings of new targeted treatments with adequate safety evaluations is essential for better cancer cures and mortality rates. Immunotherapy holds promise for patients with relapsed disease, with the ability to elicit long-term remissions. Emerging promising clinical results in B-cell malignancy using gene-altered T-lymphocytes uttering chimeric antigen receptors have sparked a lot of interest. This treatment could open the path for a major difference in the way we treat tumors that are resistant or recurring. Genetically altered T cells used to produce tumor-specific chimeric antigen receptors are resurrected field of adoptive cell therapy by demonstrating remarkable success in the treatment of malignant tumors. Because of the molecular complexity of chimeric antigen receptors -T cells, a variety of engineering approaches to improve safety and effectiveness are necessary to realize larger therapeutic uses. In this study, we investigate at new strategies for enhancing chimeric antigen receptors-T cell therapy by altering chimeric antigen receptors proteins, T lymphocytes, and their relations with other solid tumor microenvironment (TME) aspects.

Mechanical properties of tumor cytoskeleton are extremely vital for any phases of cancer, especially in tumor invasion and metastasis. However, in current category of anticancer drugs, the cytoskeleton-targeting drugs are limited and its role in tumor progression is unclear. Here, we present the mechanical characteristics of tumor stiffness are tightly regulated by cancer cytoskeleton including actin filaments and microtubule during tumor initiation, growth and metastasis, and review the natural drugs that target cancer cytoskeleton. We define cytoskeleton dynamics as target mechanisms for anticancer drug, and summary the plant, microbial and marine sources of natural products. Furthermore, the material approaches to active cancer mechanics are supplied in this review. We aim to promote the development of anticancer drugs that target tumor mechanics by using those material approaches in future and find its pharmacological application.

Lineage plasticity, the switching of cells from one lineage to another has been recognized to be a cardinal property essential for embryonic development, tissue repair and homeostasis. However, such a highly regulated process goes awry when cancer cells exploit this inherent ability to their advantage, resulting in tumorigenesis, relapse, metastasis and therapy resistance. In this review, we summarize our current understanding on the role of lineage plasticity in tumor progression and therapeutic resistance in multiple cancers. Lineage plasticity can be triggered by treatment itself and is reported across various solid as well as liquid tumors. Here we focus on the importance of lineage switching in tumor progression and therapeutic resistance of solid tumors such as the prostate, lung, hepatocellular and colorectal carcinoma and the myeloid and lymphoid lineage switch observed in leukemias. Besides this, we also discuss the role of Epithelial-Mesenchymal Transition (EMT) in facilitating the lineage switch in biphasic cancers such as aggressive carcinosarcomas. We also discuss the mechanisms involved, current therapeutic approaches and challenges that lie ahead in taming the scourge of lineage plasticity in cancer.

: Annona squamosa L. is an important medicinal plant used in traditional medicine for the treatment of various diseases. Different parts of A. squamosa L. have various therapeutic effects; however, the anticancer activity of the leaves has not yet been identified. In vitro, MTT, nuclear staining, and LDH assays were used to evaluate cell survival and proliferation in cells exposed to the extracts. The effect of the extracts on cell migration was investigated using a monolayer wound repair assay, and the apoptotic effects were evaluated using flow cytometry. A breast cancer model was used to study the effect of the extract on the tumor size, and the expression of different proliferative and apoptotic markers was evaluated by immunohistochemical analysis. At a concentration of 100 µg/mL, A. squamosa leaf extracts exerted strong antiproliferative and cytotoxic effects against various cell lines. The extracts reduced wound closure and strongly induced apoptosis. In vivo study, rats were sacrificed 24 h after the last injection, and tumor size, as well as the expression of proliferative and apoptotic markers, were observed to be greatly affected by treatment with the extracts. Therefore, A. squamosa leaf extract may be developed as a potential novel drug to treat breast cancer in the future

Chronic myelogenous leukemia (CML) was the first malignancy for which clinical outcome was drastically improved by kinase inhibitor therapy. Kinase inhibitors targeting other well-known oncogenes have been introduced into clinical practice, but none have shown the same magnitude of clinical benefit as ABL1 inhibition in CML. We argue that early detection is an underappreciated, but critically important factor in success of ABL1 inhibitors in treatment of CML. We show that CML provides a window into how many types of cancer may look and behave at an early stage, prior to diagnosis and the development of additional genomic alterations. The remarkable clinical benefits of ABL1 inhibition is likely due to early detection of CML at a stage in which the tumor is driven by single oncogenic alteration which can be successfully controlled by the inhibitor. Thinking of CML as a prototype for effective systemic treatment based on early cancer detection may help to develop strategies for improving treatment for other types of cancer.

Cholangiocarcinoma is an epithelial malignancy arising in the region between the intrahepatic bile ducts and the ampulla of Vater at the distal end of the common bile duct. The effect of current chemotherapy regimens against cholangiocarcinoma is limited, and the prognosis of patients with cholangiocarcinoma is poor. Aberrant DNA methylation and histone modification induce silencing of tumor suppressor genes and chromosomal instability during carcinogenesis. Studies have shown that the tumor suppressor genes and microRNAs (miRNAs) including MLH1, p14, p16, DAPK, miR-370 and miR-376c are frequently methylated in cholangiocarcinoma. Silencing of these tumor suppressor genes and miRNAs plays critical roles in the initiation and progression of cholangiocarcinoma. In addition, recent studies have demonstrated that DNA methylation inhibitors induce expression of endogenous retroviruses and exert the anti-tumor effect of via an anti-viral immune response. Aberrant DNA methylation of tumor suppressor genes and miRNAs could be a powerful biomarker for diagnosis and treatment of cholangiocarcinoma. Epigenetic therapy with DNA methylation inhibitors hold considerable promise for the treatment of cholangiocarcinoma through re-activation of tumor suppressor genes and miRNAs as well as induction of an anti-viral immune response.

Tumor-associated macrophages are a key component in the tumor microenvironment, secreting extracellular vesicles (EVs) such as exosomes and other various factors for intercellular communication. However, macrophage-derived EVs heterogeneity and their cytotoxicity to cancer cells has not been well understood. Here, we aimed to separately isolate various types of macro-phage-EVs by size exclusion chromatography (SEC) method and investigate EV transmission and cytotoxicity to oral cancer cells. For fluorescence-labeling of cellular and EV membranes, palmitoylation signal-fused GFP and tdTomato were expressed in THP-1 monocytic cells and HSC-3 oral cancer cells, respectively. We found that fluorescence-labeled EVs secreted by macrophages were highly transmissive to oral cancer cells than those from parental monocytic cells. In a co-culture system and conditioned medium (CM), a macrophage-secreted unidentified factor was cytotoxic to oral cancer cells. We fractionated macrophage-derived EVs by the SEC method and performed western blotting to characterize various EV types. Three fractions were characterized: small exosomes (EXO-S: < 50 nm) fraction containing HSP90α, HSP90β, CD63 (EV marker) and β-actin; large exosomes (EXO-L: 50-200 nm) fraction containing CD9 (EV marker) and HSP90β; large EVs (100-500 nm) fraction. Notably, the macrophage-derived small exosomes fraction was cytotoxic to oral cancer cells, while large exosomes and large EVs were not. There-fore, it was implicated that macrophage-derived small exosomes are cytotoxic with high trans-mission potential to cancer cells.

Breast cancer (BC) is the most common type of cancer in both men and women alike, but it is more prevalent in women. Natural compounds that can modulate the oncogenic process can be considered a significant anti-cancer agent for treating BC. These natural compounds are more effective than synthetic drugs, which have profound side effects on the normal cell and resistance to cancer cells. Genistein is a type of dietary phytoestrogen included in the flavonoid group with a similar structure of estrogen that might provide a strong alternative and complementary medicine to existing chemotherapeutics drugs. Several research studies demonstrated that it can target the estrogen receptor (ER), Human epidermal growth factor receptor-2 (HER2), and Breast cancer gene-1 (BRCA-1) in multiple BC cell lines, as well as sensitize cancer cell lines to this compound when used at an optimal inhibitory concentration. Genistein effectively showed anti-cancer activities through apoptosis induction, arresting cell cycle, inhibiting angiogenesis with metastasis, reducing inflammation, mammosphere formation, tumor growth, up-regulating tumor suppressor gene, and downregulating oncogene in suppressing cancer progression in vitro and animal model study. In addition, research studies have also suggested that these phytochemicals synergistically reverse the resistance mechanism of chemotherapeutic drugs, increasing the efficacy of some chemoinformatics drugs. Our review article aims to unbox and validate the molecular pharmacology in breast tissue, cell-specific anti-cancer mechanism with synergistic activity, and possible pharmacokinetic parameters of Genistein as a potential alternative therapeutic option for the treatment of BC.

Background: Atypical teratoid/rhabdoid tumor (AT/RT) is an uncommon and aggressive pediatric central nervous system neoplasm. However, a universal clinical consensus or reliable prognostic evaluation system for this malignancy is lacking. Our study aimed to develop a risk model based on comprehensive clinical data to assist in clinical decision-making. Methods: We conducted a retrospective study by examining data from the Surveillance, Epidemiology, and End Results (SEER) repository, spanning 2000 to 2019. The external validation cohort was sourced from the Children's Hospital Affiliated to Chongqing Medical University, China. To discern independent factors affecting overall survival (OS) and cancer-specific survival (CSS), we applied Least Absolute Shrinkage and Selection Operator (LASSO) and Random Forest (RF) regression analyses. Based on these factors, we structured nomogram survival predictions and initiated a dynamic online risk-evaluation system. To contrast survival outcomes among diverse treatments, we used propensity score matching (PSM) methodology. Molecular data with the most common mutations in AT/RT were extracted from the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Results: The annual incidence of AT/RT showed an increasing trend (APC, 2.86%; 95% CI:0.75-5.01). Our prognostic study included 316 SEER database participants and 27 external validation patients. The entire group had a median OS of 18 months (range 11.5 to 24 months) and median CSS of 21 months (range 11.7 to 29.2). Evaluations involving C-statistics, DCA, and ROC analysis underscored the distinctive capabilities of our prediction model. An analysis via PSM highlighted that individuals undergoing triple therapy (integrating surgery, radiotherapy, and chemotherapy) had discernibly enhanced OS and CSS. The most common mutations of AT/RT identified in the COSMIC database were SMARCB1, BRAF, SMARCA4, NF2, and NRAS. Conclusions: In this study, we devised a predictive model that effectively gauges the prognosis of AT/RT and briefly analyzed its genomic features, which might offer a valuable tool to address existing clinical challenges.

Immune checkpoint blockade (ICB) has revolutionized the prognosis of several advanced-stage solid tumors. However, its success has been far more limited in hematological malignancies and is mostly restricted to classical Hodgkin lymphoma (cHL) and primary mediastinal B cell lymphoma (PMBCL). In patients with non-Hodgkin lymphoma (NHL), response to PD-1/PD-L1 ICB monotherapy has been relatively limited, although some subtypes are more sensitive than others. Numerous predictive biomarkers have been investigated in solid malignancies, such as PD-L1 expression, tumor mutational burden (TMB) and microsatellite instability (MSI), among others. This case-illustrated review aims to appraise the current knowledge on PD-1/PD-L1 ICB efficacy in lymphoid malignancies, when used either as monotherapy or combined with other agents, and describes potential biomarkers of response in this specific setting.

Therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC) can be attributed, in part, to a dense extracellular matrix containing excessive collagen deposition. Here, we describe a novel Salmonella typhimurium (ST) vector expressing the bacterial collagenase Streptomyces omiyaensis trypsin (SOT), a serine protease known to hydrolyze collagens I and IV, which are predominantly found in PDAC. Utilizing aggressive models of PDAC, we show that ST-SOT selectively degrades intratumoral collagen leading to enhancement of immune checkpoint blockade (ICB) therapy in tumor-bearing mice. Ultimately, we found that ST-SOT treatment significantly modifies the intratumoral immune landscape to generate a microenvironment more conducive to ICB.

Although decision making strategy based on clinico-histopathological criteria is well established, renal cell carcinoma (RCC) represents a spectrum of biological ecosystems characterized by distinct genetic and molecular alterations, diverse clinical courses and potential specific therapeutic vulnerabilities. Given the plethora of drugs available, the subtype-tailored treatment to RCC subtype holds the potential to improve patient outcome, shrinking treatment-related morbidity and cost. The emerging knowledge of the molecular taxonomy of RCC is evolving, whilst the antiangiogenic and immunotherapy landscape maintained and reinforced their potential. Although several prognostic factors of survival in patients with RCC have been described, no reliable predictive biomarkers of treatment individual sensitivity or resistance have been identified. In this review, we summarize the available evidence able to prompt more precise and individualized patient selection in well-designed clinical trials, covering the unmet need of medical choices in the era of next-generation anti-angiogenesis and immunotherapy.

18F-fluorodeoxyglucose positron emission tomography and computed tomography (18F-FDG PET-CT) is increasingly used in the diagnosis, prognosis, staging, and treatment monitoring of many tumor types. However, only a small number of studies have reported the use of 18F-FDG PET-CT in intrahepatic cholangiocarcinoma (ICC). This study aimed to examine the accuracy of tumor staging in ICC by using 18F-FDG PET-CT. Between January 2009 and December 2020, patients with suspected ICC were retrospectively enrolled in the study and underwent imaging. The sensitivity and specificity of 18F-FDG PET-CT, CT, and magnetic resonance imaging (MRI) in detecting tumors, satellite focus, vascular invasion, and lymph node metastases were analyzed. The efficacy of 18F-FDG PET-CT for tumor staging was evaluated. Of the 110 patients who were enrolled in the study, 52 underwent surgical treatment and 45 were histologically diagnosed with ICC. When compared with CT or MRI, 18F-FDG PET-CT had similar sensitivity and specificity values for diagnosing satellite focus and vascular and bile duct invasion; however, PET-CT showed higher accuracy in diagnosing regional lymph node metastases. The accuracy of tumor staging by 18F-FDG PET-CT was higher than that by CT/MRI. Thus, 18FDG PET-CT may support tumor staging in ICC.

Iron oxide nanozymes are a form of nanomaterial with both superparamagnetic and enzyme-mimicking properties. Given the multifunctional nature of iron oxide nanozymes, it is attractive for creating iron oxide hybrid nanozymes through biomolecular modifications to imbue with auxillary properties. Such iron oxide hybrid nanozymes can be useful for rapid and cost-effective analysis of circulating tumor nucleic acids (ctNAs) in patient liquid biopsies during minimal residual disease (MRD) monitoring of cancer recurrence. Herein, the use of streptavidin-modified iron oxide hybrid nanozymes is reported for magnetic enrichment and bioelectrocatalytic sensing of three prostate cancer (PCa) ctRNA biomarkers with high detection specificity and sensitivity (10 copies) over an ultrabroad dynamic range (five orders of magnitude). Furthermore, the feasibility of ctRNA analysis for pre- and post-cancer treatment MRD monitoring is demonstrated using PCa urinary liquid biopsy samples.

Circulating tumor cells (CTC) have shown to be prognostic in advanced colorectal cancer (advCRC), but their value for predicting response to treatment or as a source of molecular data is debated. We compared CellSearch® (Janssen Diagnostics, LLC) and IsoFlux^TM (Fluxion Biosciences Inc, South San Francisco, CA) systems for the enumeration of CTC in patients with newly diagnosed advCRC (group 1; n=34). Using castPCR^TM we studied KRAS status in CTC isolated with IsoFlux^TM and compared it with that of the primary tumor in patients from group 1 and in KRAS wild-type (KRAS^WT) patients with progressive disease (group 2; n=22). Median number of CTC detected with CellSearch® (groups 1 and 2) was 1 (range: 0-78) and with IsoFlux^TM (group 1) was 8 (range: 0-419), showing a modest correlation (r=0.345, P=0.036), which improved if lung metastases (r=0.805, P=0.016) or if lung and liver metastases were present (r=0.812, P=0.05). A Bland-Altman plot showed that the higher the number of CTC detected the larger the difference between both methods in favor of IsoFlux^TM. After a median follow-up since CTC collection of 16 months (range: 1-30) CellSearch® ≥ 3 CTC (HR 2.77, 95% CI 0.77-9.95) and IsoFlux^TM ≥ 11 CTC (HR 4.14, 95% CI 1.05-16.19) were established as the best cutoff points for predicting survival. Using castPCR^TM we found KRAS mutations in CTC in 4 out of 8 patients from group 1 and in 2 out of 3 patients from group 2. None of these mutations were found in the primary tumor using standard methods, possibly reflecting intratumor heterogeneity or treatment selection pressure. We conclude that IsoFlux^TM is more efficient than CellSearch® in the isolation of CTC in patients with advCRC, achieving, in a majority of cases, the established minimum of CTC for castPCR^TM-based genetic analyses.

Background: PRAME, NY-ESO-1 and SSX2 are cancer testis antigens (CTAs), which in normal tissues are expressed in testicular germ cells with re-expression in numerous cancer types. Their ability to elicit humoral and cellular immune responses have rendered them promising targets for cancer immunotherapy, but they have never been studied in a large and well-characterized cohort soft tissue sarcomas (STS). Methods: On protein level, we examined PRAME, NY-ESO-1 and SSX2 expression in tumour tissues of 249 STS using immunohistochemistry. We correlated expression levels with clinicopathological parameters including Tumour-infiltrating lymphocyte (TIL) counts, grading and long- term survival. Results: Expression of PRAME, NY-ESO-1 and SSX2 was observed in 25 (10%), 19 (8%), and 11 (4%) of 249 specimens with distinct patterns for histo subtypes. Expression of PRAME was associated with shorter patient survival (p=0.005) and higher grade (G2 vs G3, p=0.001) while NY-ESO-1 expression was correlated with more favourable survival (p=0.037) and low grade (G2 vs G3, p=0.029). Both PRAME and NY-ESO-1 expression was more frequent in STS with low TILs counts. Conclusions: CTAs PRAME, NY-ESO-1 and SSX2 show distinct expression patterns in different STS subtypes. These results may guide future immunotherapeutic approaches in STS.

Psoriatic arthritis (PsA) is a persistent, inflammatory disease that affects individuals with psoriasis, arthritis, and enthesitis. Research has demonstrated that inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-23 (IL-23), and interleukin-17 (IL-17) play a pivotal role in both the onset and progression of PsA. These cytokines are generated by activated immune cells and stimulate the attraction of inflammatory cells to the synovium and joint tissues, resulting in the deterioration of cartilage and bone. The blocking of these cytokines has become a successful treatment strategy for PsA, as biological drugs that inhibit TNF-α, IL-23, and IL-17 have demonstrated notable clinical benefits. The association between PsA and other types of inflammatory cytokines or chemokines, excluding TNF-α, IL-23, and IL-17, has been extensively investigated in numerous studies. These findings may provide a chance for the discovery of novel therapeutic agents targeting other molecules, distinct from the currently approved biologics and targeted synthetic disease-modifying antirheumatic drugs. In this review, we discuss the current understanding of the role of inflammatory cytokines in PsA pathogenesis and clinical implications of targeting these cytokines for PsA treatment.

The extracellular matrix (ECM) is a ubiquitous member of the body and is key to the maintenance of tissues and organs integrity. Initially thought to be a by-stander in many cellular processes, the extracellular matrix has been shown to have diverse components that regulate and activate many cellular processes and ultimately influence cell phenotype. Importantly, the ECM composition, architecture, and stiffness/elasticity influence cellular phenotypes. Under normal conditions and during development, the synthesized ECM is constantly undergoing degradation and remodeling processes via the action of matrix proteases that maintain tissue homeostasis. In many pathological conditions including fibrosis and cancer, the ECM synthesis, remodeling, and degradation is dysregulated causing its integrity to be altered. Both physical and chemical cues from the ECM are sensed via receptors including integrins and play key roles in driving cellular proliferation and differentiation and in various disease progression such as cancers. Advances in ‘omics’ technologies have seen an increase in studies focussing on bi-directional cell-matrix interactions and here we highlight emerging knowledge on the role played by the ECM during normal development and in pathological conditions. This review summarizes current ECM-targeted-therapies that can modify tumor ECM to overcome drug resistance and better cancer treatment.

The tumor organoid (tumoroid) model in three-dimensional (3D) culture systems has been developed to reflect more closely the in vivo tumors than 2D-cultured tumor cells. Notably, extracellular vesicles (EVs) are efficiently collectible from the culture supernatant of gel-free tumoroids. Matrix metalloproteinase (MMP) 3 is a multi-functional factor playing crucial roles in tumor progression. However, roles of MMP3 within tumor growth and EVs have not unveiled. Here, we investigated the protumorigenic roles of MMP3 on integrities of tumoroids and EVs. We generated MMP3-knockout (KO) cells using the CRISPR/Cas9 system from rapidly metastatic LuM1 tumor cells. Moreover, we established fluorescent cell lines with palmitoylation signal-fused fluorescent proteins (tdTomato and enhanced GFP). Then we confirmed the exchange of EVs between cellular populations and tumoroids. LuM1-tumoroids released large EVs (300-1000 nm) and small EVs (50-200 nm) while the knockout of MMP3 resulted in the additional release of broken EVs from tumoroids. The loss of MMP3 leads to a significant reduction in tumoroid size and to the development of the necrotic area within tumoroids. MMP3 and CD9 (a category-1 EV marker tetraspanin protein) were significantly down-regulated in MMP3-KO cells and their EV fraction. These weakened phenotypes by MMP3 KO were markedly rescued by the addition of MMP3-rich EVs or conditioned medium (CM) collected from LuM1-tumoroids, which caused a dramatic rise in the expression of MMP3, CD9, and Ki-67 (a marker of proliferating cells) in the MMP3-null/CD9-low tumoroids. Notably, MMP3 enriched in tumoroids-derived EVs and CM deeply penetrated into recipient MMP3-KO tumoroids, resulting in a remarkable enlargement of solid tumoroids, while MMP3-null EVs did not. These data demonstrate that EVs can mediate molecular transfer of MMP3 resulting in increasing the proliferation and CD9+ tumorigenesis, indicating crucial roles of MMP3 in tumor progression.

Ral-interacting protein 76 (RLIP76) is a potential factor with vascular endothelial growth factor (VEGF) in the corpus luteum and tumor angiogenesis. RLIP76, VEGF, and hypoxia-inducible factor-1 (HIF-1) are proteins that activate angiogenic functions in tumor and endothelial cells. RLIP76 is a main factor in tumor growth, and VEGF is a major endothelial cell protein for angiogenesis. Also, RLIP76 regulates a small GTPase (R-Ras, oncogene) in cell survival, spreading, and migration. HIF-1 is important in the corpus luteum, tumor angiogenesis, and tumor growth. VEGF and HIF-1 regulate the angiogenic function of RLIP76, and RLIP76 controls vascular growth in endothelial and tumor cells. RLIP76, R-Ras, VEGF, and HIF-1 may be useful in the research of corpus luteum and cancer therapy and the study of mechanisms of tumor angiogenesis. This review will help to elucidate the roles of RLIP76/R-Ras and VEGF via HIF-1 in corpus luteum and tumor angiogenesis, tumorigenesis, and the specific regulation of RLIP76 in luteal, tumor, and endothelial cells. Thus, we reviewed the angiogenesis of the corpus luteum and tumor in the ovarian and tumor microenvironment.

With its unique properties and potential applications, nanoparticle-based delivery platforms for vac-cines have gained significant attention in recent years. Nanoparticles have the advantages of enhancing immunogenicity, targeting delivery and improving stability, providing a new solution for drug and vaccine delivery. And in some clinical studies, a variety of nanoparticle delivery platforms have been gradually applied to a wide range of vaccine applications. Current research priorities are exploring various types of nanoparticles as vaccine delivery system to enhance vaccine stability and immunogen-icity. Lipid nanoparticles have shown promising potential in preclinical and clinical studies to efficiently deliver antigens to immune cells. Moreover, lipid nanoparticles (LNPs) and other nanoparticles as nu-cleic acids especially mRNA delivery system, have shown vast potential for vaccine development. In this review, we present various vaccine platforms with an emphasis on nanoparticles for mRNA nano-vaccine delivery vehicles. We introduce several novel nanoparticles delivery platforms for mRNA vac-cine such as lipid, polymer, protein-based nanoparticle and so on. In addition, we overview the an-ti-tumor immunity of nanovaccine against different tumors in cancer immunotherapy. Finally, we give an outlook future perspectives and remaining challenges for this promising technolo-gy-nanoparticle-based delivery platforms for vaccines.

Hyperplastic nodules (HNs) are benign polypoid lesions of the colorectal mucosa reportedly caused by hyperplasia of the crypt epithelial cells. They differ from hyperplastic polyps because the crypts do not have histologically serrated changes. HNs often occur in the rectal mucosa and tend to be multifocal. We have proposed a new colitis nucleomigrans (CN) concept as the third type of microscopic colitis. Our histopathological criteria of CN include: i) chained nuclear migration to the middle part of the surface-lining columnar epithelium, ii) apoptotic nuclear debris scattered in the eosinophilic cytoplasm underneath the nuclei, and iii) mild to moderate chronic inflammation in the lamina propria. Immunostaining for cleaved-caspase 3 revealed apoptotic bodies. In this study, we report that most HN lesions share the histological features with CN, representing polypoid CN. We evaluated 108 lesions of HN in total, and 94 (87%) were reclassified as polypoid CN. In the polypoid CN, the lamina propria mucosae were uniformly edematous, suggesting that accelerated apoptosis of the mucosal surface epithelium may cause osmotic dysregulation to form localized mucosal elevations.

Conventional MRI sequences are standard methods to monitor patients with brain tumors but have significant limitations especially after irradiation. Currently, the role of FET-PET in radiotherapy of glioblastoma is emerging, starting from target definition, response assessment and in distinguishing progression from post-irradiation changes. Recently a PET RANO criteria have been published providing optimal strategy for treatment evaluation with amino-acid PET. Earlier, a PET/RANO group reported contribution of PET imaging to radiotherapy planning and monitoring in glioma patients. Also, increasing evidence have showed advantages of amino-acid PET vs. RANO MRI for prediction of overall survival. In this narrative review we aimed to summarize published data on FET-PET based treatment response assessment to radiotherapy and focused on details in protocols.

Neuroblastoma is an embryonal tumor arising from the sympathetic central nervous system. The epidermal growth factor (EGF) plays a role in neuroblastoma growth and metastatic behavior. Recently, we have demonstrated that cathepsin D (CD) contrasts EGF-induced neuroblastoma cell growth in 2D by downregulating EGFR/MAPK signaling. Aggressive NB is highly metastatic to the bone and the brain. In the metastatic process, adherent cells detach to form clusters of suspended cells that once reached the metastatic site adhere and form secondary colonies. Whether CD involves in survival of metastatic NB clones is not known. Therefore, in this study we addressed how CD differentially affects cell growth in suspension versus adherent condition. To mimic tumor heterogeneity, we co-cultured transgenic clones silenced for or overexpressing CD. We compared the growth kinetics of such mixed clones in 2D and 3D models in response to EGF, and we found that Over CD clone was advantaged for the growth in suspension, while the CD knocked-down clone was favored for the adherent growth as 2D. The fact that CD plays a dual role in cancer cell growth in 2D and 3D conditions indicates that during clonal evolution subclones expressing different level of CD may arise, which confers survival and growth advantages depending on the metastatic step. Whether CD involves in survival of metastatic NB clones is not known. We propose that epigenetic regulation of CD expression could be an additional strategy to prevent NB metastases.

Oral squamous cell carcinoma (OSCC) remains an under-studied and significant global cancer killer and dismal survival rates have not changed in decades. A better understanding of the molecular basis of OSCC progression and metastasis is needed to develop new approaches for treating this disease. The supportive network surrounding cancer tumor cells known as the tumor microenvironment (TME) has gained increasing interest lately since it performs essential pro-tumorigenic functions. Cancer-associated fibroblasts (CAFs) are one of the main cell types in the TME and are known to play a key role in influencing the biological behavior of tumors. CAFs present a heterogeneity both in phenotype as well as functions, leading to the suggestion of different CAF subtypes in several cancer forms. The task to subtype CAFs in OSCC has however just begun and there is today no united way of subtyping CAFs in this disease. This review aims to define the features of CAFs and to summarize CAF subtype research in OSCC including aspects as disease prognosis and therapeutic opportunities.

The research presents a novel synthetic photosensitizer for photodynamic therapy (PDT) of malignant tumors - meso-tetra(3-pyridyl) bacteriochlorin, which absorbs at 747 nm (in the long-wavelength region of the spectrum) and is stable when stored in the dark. H2Py4BC demonstrates pronounced photoinduced activity in vitro against tumor cells of various genesis (IC50 varies from 21 to 68 nM for НЕр2, EJ, S37, CТ26, and LLC cultured cells) and provides in vivo pronounced antitumor efficacy in the treatment of mice bearing small or large S37, Colo26, and LLC metastatic tumors, as well as in the treatment of rats bearing RS-1 liver cholangioma. As a result, total regress of primary tumor nodules and cure of 40 to 100% of the animals were proved by the experiment criteria, MRI, and histological analysis. Meso-tetra(3-pyridyl) bacteriochlorin quickly penetrates and accumulates in the tumor tissue and internal organs of mice, and after 24 hours 80% of the dye is excreted from skin as well as 87% - 92% from liver, kidneys, and spleen.

Heat shock factor 1 (HSF1) is a transcription factor crucial for regulating heat shock response (HSR), one of the significant cellular protective mechanisms. When cells are exposed to proteotoxic stress, HSF1 induces the expression of heat shock proteins (HSPs) to act as chaperones, correcting the protein-folding process and maintaining proteostasis. In addition to its role in HSR, HSF1 is overexpressed in multiple cancer cells, where its activation promotes malignancy and leads to poor prognosis. The mechanisms of HSF1-induced tumorigenesis are complex and involve diverse signaling pathways, dependent on cancer type. With its important roles in tumorigenesis and tumor progression, targeting HSF1 offers a novel cancer treatment strategy. In this article, we examine the basic function of HSF1 and its regulatory mechanisms, focus on the mechanisms involved in HSF1’s roles in different cancer types, and examine current HSF1 inhibitors as novel therapeutics to treat cancers.

Endoscopic submucosal dissection (ESD) is almost always performed with a sedative because of the longer procedure times involved. The risk of post-ESD deep vein thrombosis (DVT) has been reported as relatively high, and D-dimer levels are sometimes elevated after ESD. This retrospective study evaluated factors affecting changes in D-dimer levels from before to after ESD to identify causes of elevated D-dimer levels after ESD. This retrospective analysis included 117 patients with gastrointestinal tumors resected using ESD. After excluding 8 patients with pre-ESD levels of D-dimer >1.5 μg/mL, factors correlating with changes in D-dimer from before to after ESD were analyzed using logistic regression analysis in 109 patients. Sedation was accomplished primarily using midazolam, but because the sedative effect of midazolam shows marked inter-individual variability, a “corrected midazolam dose” was determined by dividing the total midazolam dose by the initial dose to correct for inter-individual differences in the sedative effect of midazolam. This value was used as one potential explanatory variable in subgroup analysis of the 103 patients who received midazolam. In subgroup analysis using the corrected midazolam dose as an explanatory variable, only corrected midazolam dose correlated with a change in D-dimer ≥ 1.0 μg/mL in multivariate analysis (odds ratio [OR]=1.5, 95% confidence interval [CI] 0.43–0.95; P=0.030). Corrected midazolam dose correlated with increases in post-ESD D-dimer levels. This potential relationship indicates that patients undergoing ESD and requiring extended sedation may be at increased risk of DVT.

“Gray zone” category tumors in thyroid follicular tumors are difficult to diagnose, especially to distinguish between follicular thyroid adenoma (FTA) and follicular thyroid carcinoma (FTC). This study aimed to assess the diagnostic performance of metabolite enzymes using imaging mass spectrometry to distinguish FTA from FTC and determine the association between metabolite enzyme expression with thyroid follicular borderline tumor diagnosis. Air flow-assisted desorption electrospray ionization mass spectrometry imaging (AFAIDESI-MSI) was used to develop a classification model for the characteristics of thyroid follicular tumors among 24 samples. We analyzed the expression of metabolic enzyme markers in an independent validation set of 133 cases and evaluated the potential biological behavior of 19 borderline thyroid lesions. Phospholipids and fatty acids (FAs) were more abundant in FTA than in FTC (P<0.001). The metabolic enzyme panel—including FA synthase and Ca²⁺-independent PLA2, which are closely associated with altered metabolic pathways—was further identified in follicular thyroid tumors. The marker combination showed optimal performance in the validation group (area under the receiver operating characteristic curve, sensitivity, and specificity: 73.6%, 82.1%, 60.6%, respectively). The diagnostic strategy suggested considering a putative role of AFAIDESI-MSI in routine clinical triage for strict follow-up, with low metabolic enzyme expression combined with diagnostic in patients with a thyroid follicular borderline tumor diagnosis.

Liquid biopsy is a rapidly emerging field which involves the minimal/non-invasive assessment of signature somatic mutations through analysis of circulating tumor DNA (ctDNA) shed by tumor cells in bodily fluids. The broad, unmet need for liquid biopsy lung cancer detection is the lack of multiplex platform that can detect a mutation panel of lung cancer genes using minimum amount of sample, especially for ultra-short ctDNA (usctDNA). Here we developed a non-PCR and non-NGS-based single droplet based multiplexing microsensor technology “Electric Field-Induced Released and Measurement (EFIRM) Liquid Biopsy” (m-eLB) for lung can-cer-associated usctDNA. The m-eLB provides multiplexable assessment of usctDNA within a single droplet of biofluid in only one well of micro-electrodes, as each electrode coated with dif-ferent probes for the ctDNA. In this m-eLB prototype, it demonstrates accuracy for 3 tyrosine ki-nase inhibitor related EGFR target sequences in synthetic nucleotides. The accuracy for the multi-plexing assay has an AUC of 0.98 for L858R, Ex19del, AUC of 0.94 for Ex19 deletion and AUC of 0.93 for T790M. By combining the 3 EGFR assay together, the AUC was 0.97 for the multiplexing assay.

During the progression from ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC), cells have to overcome the physically restraining basement membrane (BM) which compartmentalizes the epithelium from the stroma. Since the extracellular matrix (ECM) of the epithelial and stromal compartment is biochemically and physically distinct from one another, the progression demands a certain degree of cellular plasticity being essentially required for a primary tumor to become invasive. The Epithelial-to-Mesenchymal Transition depicts such a cell program equipping cancer cells with features allowing for dissemination from the epithelial entity and stromal invasion on the single-cell level. Here, we investigated the reciprocal interference between an altering tumor microenvironment and the EMT-phenotype in vitro. BM-typical collagen IV and stroma-typical collagen I coatings were applied as provisional 2-D matrices. Pro-inflammatory growth factors were introduced to improve tissue mimicry. Whereas the growth on coated surfaces did only slightly affect the EMT-phenotype, the combinatorial action of collagen with growth factor TGF-β1 induced prominent phenotypic changes. However, the EMT-induction was independent of the collagen type and cellular accessibility for EMT-like changes was strongly cell line dependent. Summarizing the entire body of data, we computed an EMT-phenotyping model that was used to decide on cellular EMT-status and estimate EMT-like changes. We confirmed that miR200c-mediated reversion of mesenchymal MDA-MB-231 cells is reflected by our EMT-phenotype model emphasizing its potential to predict the therapeutic efficacy of EMT-targeting drugs in the future.

Tumor necrosis factor (TNF) inhibitors (anti-TNFs) represent a cornerstone of the treatment of various immune-mediated inflammatory diseases and are among the most commercially successful therapeutic agents. Knowledge of TNF binding partners is critical for identification of the factors able to affect clinical efficacy of the anti-TNFs. Here we report that among eighteen representatives of the multifunctional S100 protein family only S100A11, S100A12 and S100A13 interact with the soluble form of TNF (sTNF) in vitro. The lowest equilibrium dissociation constants (Kd) for the complexes with monomeric sTNF determined using surface plasmon resonance spectroscopy range from 2 nM to 28 nM. The apparent Kd values for the complexes of multimeric sTNF with S100A11/A12 estimated from fluorimetric titrations are 0.1-0.3 µM. S100A12/A13 suppress the cytotoxic activity of sTNF against Huh-7 cells, as evidenced by the MTT assay. Structural modeling indicates that the sTNF-S100 interactions may interfere with the sTNF recognition by the therapeutic anti-TNFs. Bioinformatic analysis reveals dysregulation of TNF and S100A11/A12/A13 in numerous disorders. Overall, we have shown a novel potential regulatory role of the extracellular forms of specific S100 proteins that may affect efficacy of anti-TNF treatment in various diseases.

ATP and other nucleoside phosphates have specific receptors named purinergic receptors. Purinergic receptors and ectonucleotidases regulate various signaling pathways that play a role in physiological and pathological processes. Extracellular ATP in the tumor microenvironment (TME) has a higher level than in normal tissues and plays a role in cancer cell growth, survival, angiogenesis, metastasis, and drug resistance. In this review, we investigated the role of purinergic receptors in the development of resistance to therapy through changes in tumor cell metabolism. When a cell transforms to neoplasia, its metabolic processes change. The metabolic reprogramming modified metabolic feature of the TME, that can cause impeding immune surveillance and promote cancer growth. The purinergic receptors contribute to therapy resistance by modifying cancer cells' glucose, lipid, and amino acid metabolism. Limiting the energy supply of cancer cells is one approach to overcoming resistance. Glycolysis inhibitors which reduce intracellular ATP levels, may make cancer cells more susceptible to anti-cancer therapies. The loss of the P2X7R through glucose intolerance and decreased fatty acid metabolism reduces therapeutic resistance. Potential metabolic blockers that can be employed in combination with other therapies will aid in the discovery of new anti-cancer immunotherapy to overcome therapy resistance. Therefore, therapeutic interventions that are considered to inhibit cancer cell metabolism and purinergic receptors simultaneously can potentially reduce resistance to treatment.

Background and Aims: Of all primary liver tumors, primary hepatic angiosarcoma (PHA) is a rare and aggressive malignant vascular tumor. The standard therapeutic care for hepatic angiosarcoma remains unclear. This study compared the survival outcomes of aggressive treatment (resection and liver transplant) and nonaggressive treatment (chemotherapy, transarterial chemoembolization [TACE], and conservative treatments) for patients with PHA and analyzed the prognostic factors influencing survival. Materials and Methods: Data of patients diagnosed as having PHA at our facility were retrospectively reviewed. The primary outcome was survival time. The secondary outcome was calculated baseline characteristics. Results: We included a total of 19 patients, who were divided into 2 treatment groups: aggressive (8 patients had undergone resection or transplants) and nonaggressive (11 patients had undergone TACE, chemotherapy, or conservative treatment). The mean survival time was 233.1 ± 189.7 days in the aggressive treatment group and 146.5 ± 115.8 days in the nonaggressive treatment group. A Kaplan-Meier plot revealed no significant difference in survival time between the 2 treatment groups (P = .3256). Conclusions: The survival time of patients receiving aggressive treatment was longer than that of those receiving nonaggressive treatment. The long term survival time in some selective cases of aggressive treatment will be achieved. Thought a difference was not significant between the groups. Because the number of patients was limited, more cases are required to confirm these findings.

Uveal melanoma (UM) is characterized by relatively few, highly incident molecular alterations and their association with metastatic risk is deeply understood. Nevertheless, this knowledge has so far not led to innovate therapies for the successful treatment of UM metastases or for adjuvant therapy, leaving survival after diagnosis of metastatic UM almost unaltered in decades. The driver mutations of UM, mainly in the G-protein genes GNAQ and GNA11, activate the MAP-kinase pathway as well as the YAP/TAZ pathway. At present, there are no drugs that target the latter and this likely explains the failure of MEK-inhibitors. Immune checkpoint blockers, despite the game changing effect in cutaneous melanoma (CM) show only marginal effects in UM probably because of the low mutational burden of 0.5 per megabase and the unavailability of antibodies targeting the main immune checkpoint active in UM. The highly pro-tumorigenic microenvironment of UM also contributes to therapy resistance. However, T-cell redirection by a soluble T cell receptor that is fused to an anti-CD3 single-chain variable fragment, local, liver specific therapy, new immune checkpoint blockers and YAP/TAZ specific drugs give new hope to repeat the success of innovative therapy obtained for CM.

Background: Ultrasonography’s usefulness in endometrial cancer (EC) diagnosis consists of its staging and predictive roles. Ultrasound-measured tumor-free distance from the tumor to the uterine serosa (uTFD) is a promising marker for this variable. The aim of the study was to determine the usefulness of this biomarker in locoregional staging, and thus in the prediction of lymph node metastasis (LNM). Methods: We conducted a single-institutional, prospective study on 116 consecutive patients with EC who underwent 2D transvaginal ultrasound examination. The uTFD marker was compared with the depth of ultrasound-measured myometrial invasion (uMI). Univariate and multivariate logit models were evaluated to assess the predictive power of the uTFD and uMI in regard to LNM. The reference standard was a final histopathology result. Survival was assessed by the Kaplan-Meyer method. Results: LNM was found in 17% of the patients (20/116). In the univariate analysis, uMI and uTFD were significant predictors of LNM. Accuracy was 70.7%, and NPV was 92.68% (OR 4.746, 95% CI 1.710-13.174) for uMI (p = 0.002), and 63.8%, and 89.02% (OR 0.842, 95% CI 0.736 – 0.963), respectively, for uTFD (p = 0.01). The cut-off value for uTFD in the prediction of LNM was 5.2 mm. The absence of LNM was associated more with biomarker values uMI &lt;1/2 and uTFD &gt;=5.2 mm than with the presence of metastases with uMI &gt;1/2 and uTFD values &lt;5.2 mm. In the multivariate analysis, the accuracy of the uMI-uTFD model was 74%, and NPV was 90.24% (p = NS). Neither uMI nor uTFD are surrogates for overall and recurrence-free survivals in endometrial cancer. Conclusions: Both uMI and uTFD, either alone or in combination, are valuable tools for gaining additional preoperative information on expected lymph node status. Negative lymph nodes status is better described by ultrasound biomarkers than a positive status. It is easier to use uTFD measurement as a biomarker of EC invasion than uMI, and the former still maintains a similar predictive value for lymph node metastases to the latter at diagnosis.