Publically available (own) transcriptomic data were re-analyzed to quantify the alteration of functional pathways in the thyroid cancer, establish the gene hierarchy, identify potential gene targets and predict the effects of their manipulation. The expression data were generated from one case of papillary thyroid carcinoma (PTC) and from genetically manipulated BCPAP (papillary) and 8505C (anaplastic) human thyroid cancer cell lines. The study used the genomic fabric perspective that considers the transcriptome as a multi-dimensional mathematical object based on the three independent characteristics that can be derived for each gene from the expression data. We found remarkable remodeling of the thyroid hormone synthesis, cell cycle, oxidative phosphorylation and apoptosis pathways. Serine peptidase inhibitor, Kunitz type, 2 (SPINT2) was identified as the Gene Master Regulator of the investigated PTC. The substantial increase of the expression synergism of SPINT2 with apoptosis genes in the cancer nodule with respect to the surrounding normal tissue (NOR) suggests that its experimental overexpression may force the PTC cells into apoptosis with negligible effect on the NOR cells. The predictive value of the expression coordination for the expression regulation was validated with data from 8505C and BCPAP cells before and after lentiviral transfection with DDX19B.

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.

Amino acid metabolism promotes cancer cell proliferation and survival by supporting building block synthesis, producing reducing agents to mitigate oxidative stress, and generating immunosuppressive metabolites for immune evasion. Malignant cells rewire amino acid metabolism to maximize their access to nutrients. Amino acid transporter expression is upregulated to acquire amino acids from the extracellular environment. Under nutrient depleted conditions, macropinocytosis can be activated where proteins from the extracellular environment are engulfed and degraded into the constituent amino acids. The demand for non-essential amino acids (NEAAs) can be met through de novo synthesis pathways. Cancer cells can alter various signaling pathways to boost amino acid usage for the generation of nucleotides, reactive oxygen species (ROS) scavenging molecules and oncometabolites. The importance of amino acid metabolism in cancer proliferation makes it a potential target for therapeutic intervention, including via small molecules and antibodies. In this review, we will delineate the targets related to amino acid metabolism and promising therapeutic approaches.

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.

Development of targeted therapies for triple-negative breast cancer (TNBC) is an unmet medical need. Cisplatin has demonstrated its promising potential for the treatment of TNBC in clinical trials; however, cisplatin treatment is associated with hypoxia that in turn promotes cancer stem cell (CSC) enrichment and drug resistance. Therapeutic approaches to attenuate this may lead to increased cisplatin efficacy in the clinic for the treatment of TNBC. In this report, we analyzed clinical dataset of TNBC and found that TNBC patients possessed higher levels of EGFR and hypoxia gene expression. A similar expression pattern was also observed in cisplatin-resistant ovarian cancer cells. We thus developed a new therapeutic approach to inhibit EGFR and hypoxia by combination of metformin and gefitinib that sensitized TNBC cells to cisplatin and led to the inhibition of both CD44+/CD24- and ALDH+ CSCs. We demonstrated a similar inhibition efficacy on organotypic cultures of TNBC patient samples ex vivo. Since these drugs have already been used frequently in the clinic, this study illustrates a novel, clinically translatable therapeutic approach to treat patients with TNBC.

Despite advances in the understanding of its molecular pathophysiology, prostate cancer remains largely incurable, highlighting the need for novel therapies. We developed a chimeric antigen receptor (CAR) specific for prostate specific membrane antigen (PSMA), a glycoprotein that is overexpressed in prostate cancer, which expression involves neovasculature of several tumor entities, thus envisaging an additional antiangiogenic effect. To optimize the CAR design, we compared two CARs with signaling domains containing one or two T cell costimulatory elements, in addition to CD3ζ. Conversely, what has been described for other CARs, a third-generation CAR (containing CD28 and 41BB co-signaling domains) induced a potent antitumor effect similar to a second-generation CAR (containing CD28 co-signaling domain), though we observed a detrimental effect of the additional costimulatory domain that was attributed to increased activation-induced cell death (AICD). This “super-stimulation” resulted in exhaustion of cells, higher frequencies of cell death and, more importantly, the impossibility of sufficiently expanding the CAR cells to obtain the minimum number of cells requested for in vivo therapies. While the superiority of 2nd and 3rd generation over 1st generation CAR T cells has been clearly shown in both preclinical and clinical studies, the optimal combination of costimulatory domains for 3rd generation CAR-T cells must still be defined and should be evaluated case-by-case in order to fine-tune immunotherapy approaches.

Colorectal cancer (CRC) is considered as one of the leading types of cancer in the world. CD133, as a cancer stem cell marker, has a pivotal role in the development of drug resistance, migration, and stemness properties of CRC cells. This study designed to check the combined effect of CD133siRNA and Oxaliplatin on proliferation, migration, apoptosis, and stemness properties of CRC cells in HT-29 cell line.MTT assay was performed to define the combined effect of CD133siRNA and Oxaliplatin on the viability of HT-29 cells. In order to figure out the effect of this combination therapy on CD133 expression at the gene and protein level, qRT-PCR and western blot were exploited, respectively. The ability of cell migration was tested by wound healing assay as well. Also, colony formation and sphere formation were conducted to assess the stemness properties in the combination group. Flow cytometry was conducted to investigate the apoptosis, cell cycle, and surface expression of CD133 in different groups. Finally, the expression of migration-, and stemness-associated genes were measured by qRT-PCR. We indicated that silencing of CD133 reduces the migration and stemness properties of colorectal cancerous cells. This suppression makes HT-29 cells more sensitive to Oxaliplatin and reduces the effective dose of this chemical drug. Therefore, the suppression of CD133 in combination with Oxaliplatin treatment might be a promising therapeutic approach in the treatment of colorectal cancer.

Over the last two months, as oncology specialists, we have frequently been contacted for estimating prognosis for cancer patients affected by COVID-19 infection. Until now, there have been no clear markers to guide decision making regarding the appropriateness of invasive ventilation in cancer patients affected by COVID-19 infection. Therefore, we developed a practical tool encompassing a prognostic score. We aimed at identifying a subgroup of patients likely to have a better outcome and therefore may be potential candidates for invasive ventilation, "The Milano Policlinico ONCOVID-ICU score". The score is composed by three groups of variables: patient’s characteristics such as sex, age, BMI and comorbidities; oncological variables (treatment intent, life expectancy, on or off-treatment status) and clinical parameters in association with laboratory values (SOFA score and D-dimer). The SOFA score includes six different clinical parameters and during the first few days of ICU admissions has an important prognostic role. The oncological history should never represent, per se, a contraindication to intensive care and must be considered together with other variables, such as laboratory values, clinical parameters and patient characteristics, in order to make the hardest but best possible choice. The Milano Policlinico ONCOVID-ICU score, to our knowledge, is the first prognostic score proposed in this setting of patients and may be a useful tool to assess the prognosis of cancer patients being in this critical condition.

Although sarcopenia is characterized by a loss of muscle strength and skeletal muscle mass, few studies have evaluated the effect of muscle strength on hepatocellular carcinoma (HCC) patients. We separately evaluated the impact of sarcopenia-related factors (grip strength [GS] and the skeletal muscle index [SMI]) on the survival among lenvatinib-treated unresectable HCC (u-HCC) patients. This single-center cohort study was conducted at a university hospital. The study population included 63 lenvatinib-treated u-HCC patients managed between April 2018 and April 2020. A decreased GS and decreased SMI were found in 21 (33.3%) and 22 (34.9%) patients, respectively. The overall survival (OS) of the normal GS group was significantly higher than that of the decreased GS group, while that of the normal and decreased SMI groups did not differ markedly. There were no significant differences in the progression-free survival between the normal GS and decreased GS groups or the normal SMI and decreased SMI groups. A multivariate Cox proportional hazards model showed that ALBI2b (hazard ratio [HR] 4.39) and a decreased GS (HR 3.55) were independently associated with an increased risk of poor prognosis. In addition to the hepatic functional reserve, a decreased GS was a poor prognostic factor in lenvatinib-treated u-HCC patients.

Colorectal cancer (CRC) is the third most common cancer, with rising incidence due to lifestyle and diet. 40% of CRC cases are found to have KRAS mutations. In this study, we investigate the survival outcome of metastatic Colorectal cancer mCRC) patients in Brunei Darussalam restrospectively. Chi-squared test was used to compare the survival outcomes of mCRC patients, and Mann-Whitney U test was used to compare the median ages of both groups. Kaplan-Meier survival curves were drawn and logrank test was used to compare the survival outcome between two groups. There was a total of 105 patients with stage IV CRC being treated during the study period. 81.6% (n=62) of mCRC patients were found to have the primary tumours on the left side of the colon. 19 of these 26 (73.1%) mutant KRAS mCRC patients died, while 23 of 50 (46.0%) wild-type KRAS mCRC patients died at the end of the study period, contributing to death rates of 45.2% and 54.8%, correspondingly. 30.3% (n=23) of the study population had a single metastatic site detected (either liver, or lung or any other organs), while 69.7% (n=53) of the 76 mCRC patients had two (double) or more metastatic sites. 69.2% (n=18) and 30.8% (n=8) of the mutant KRAS mCRC patients had mutations within codons 12 and 13, respectively. To our knowledge, this is the first study in Brunei Darussalam to analyse both the survival outcomes of metastatic CRC patients and those of mutant KRAS mCRC patients. Chi-squared analysis showed a significant difference between the survival outcomes of wild-type KRAS and mutant KRAS mCRC patients (p-value = 0.024). There was a significant difference in the survival outcome between the mutant KRAS mCRC patients with RCC and mutant KRAS mCRC with LCC patients. There was no significant difference between the survival outcomes of mutant KRAS patients with mutations in either codon 12 or 13 of the KRAS gene (Table 3). However, there is a significant difference in the median survival periods between the mutant KRAS mCRC patients with mutations in codon 12 and those with mutation in codon 13 of the KRAS gene (p-value = 0.003). In conclusion, we found that mutant KRAS mCRC patients had a significantly poorer OS, which was shown to be worse when the primary tumours were found at the left side of the colon. Mutant KRAS mCRC patients with mutations in codon 12 were found to have shorter survival median periods than those with mutations within codon 13.

Immune checkpoint inhibitors (ICI) have been widely used in melanoma, but to identify melanoma patients with survival benefit from ICI is still a big challenge. There is an urgent need for prognostic signatures improving the prediction of immunotherapy responses of cancer patients. We used data from EMBL-EBI database and analyzed RNA-seq information and clinical profiles in melanoma. Weighted gene co-expression network analysis (WGCNA) was used to identify the key module, then nonnegative matrix factorization (NMF) was conducted to cluster patients into two different cluster and compared them regarding overall survival (OS) and progression-free survival (PFS). Subsequently, the differentially expressed genes (DEGs) between different clusters were identified, and their function and pathway annotation were performed. 91 melanoma biopsies with complete survival information were included in our analyses and we first identified the key module (magenta) by WGCNA, then identified nine prognostic lncRNAs (ENSG00000258869, ENSG00000179840, ENSG00000206344, ENSG00000226777, ENSG00000205018, ENSG00000204261, ENSG00000163597, ENSG00000197536, and ENSG00000263069) signature that predicted for OS and PFS in patients treated with ICI by NMF. Finally, enrichment analysis showed that the functions of DEGs between two consensus clusters were mainly related to the immune process and treatment. In summary, the nine lncRNAs signature is a novel effective predictor for OS and PFS in melanoma patients treated with ICI.

Motivation: UCSC Xena platform provides huge amounts of processed cancer omics data from big public projects like TCGA or individual reserach groups for enabling unprecedented research opportunities. In 2019, we developed UCSCXenaTools, an R package for retrieval of UCSC Xena data. However, an easier dataset exploration and analysis tool is still lack, especially for researchers without programming experience. Results: We develop UCSCXenaShiny, an R Shiny package to quickly explore, download all datasets from UCSC Xena data hubs. In addiction, a module based analysis framework is constructed to analyze and visualize data. Availability: https://github.com/openbiox/UCSCXenaShiny or https://cran.r-project.org/package=UCSCXenaShiny.

Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL), accounting for about 40% of all cases NHL. Analysis of the tumour microenvironment is an important aspect of the assessment of the progression of DLBCL. In this review article, we have analyzed the role of different cellular components of the tumour microenvironment, including mast cells, macrophages, lymphocytes, in tumour progression of DLBCL. We examined several approaches to confront the available pieces of evidence; three key points emerged. DLBCL is a disease of malignant B-cells spreading and accumulating both at nodal and in extranodal sites. Both in patients with nodal and extranodal lesions, the subsequent induction of a cancer-friendly environment appears pivotal. DLBCL cell interaction with mature stromal cells and vessels confers tumour protection and inhibition of immune response while delivering nutrients and oxygen supply. Single cells may also reside and survive in protected niches in the nodal and extranodal sites as a source for residual disease and relapse. This review aims to molecularly and functionally recapitulate the DLBCL-milieu crosstalk, to relate niche and pathological angiogenic constitution and interaction factors to DLBCL progression.

Cellular therapy has emerged as an attractive option for the treatment of cancer, and adoptive transfer of chimeric antigen receptor (CAR) expressing T cells has gained FDA approval in hematologic malignancy. However, limited efficacy has been observed utilizing CAR-T therapy in solid tumors. Natural killer (NK) cells are crucial for tumor surveillance and exhibit potent killing capacity of aberrant cells in an antigen-independent manner. Adoptive transfer of unmodified allogeneic or autologous NK cells has shown limited clinical benefit due to factors including low cell number, low cytotoxicity and failure to migrate to tumor sites. To address these problems, immortalized and autologous NK cells have been genetically engineered to express high affinity receptors (CD16), CARs directed against surface proteins (PD-L1, CD19, Her2, etc.) and endogenous cytokines (IL-2 and IL-15) that are crucial for NK cell survival and cytotoxicity, with positive outcomes reported by several groups both preclinically and clinically. With a multitude of NK cell-based therapies currently in clinic trials, it is likely they will play a crucial role in next-generation cell therapy-based treatment. In this review we will highlight the recent advances and limitations of allogeneic, autologous and genetically enhanced NK cells used in adoptive cell therapy.

The recent COVID-19 outbreak in China led to a worldwide pandemic associated with a severe acute respiratory illness. A higher incidence of COVID-19 infection was demonstrated in cancer patients, including patients with lung cancer. This study was conducted to get insights into the reasons for this enhanced frequency of COVID-19 infection. Methods: Using different bioinformatic tools, the expression and methylation pattern of ACE2 and TMPRSS2 gene were analyzed in healthy and malignant tissues with a focus on lung adenocarcinoma (LUAD) and correlated to clinical parameters and smoking history. Results: ACE2 and TMPRSS2 were heterogeneously expressed across 36 healthy tissues with the highest expression in digestive, urinary and reproductive organs, while their expression was significantly lower in 36 cancer tissues. In LUAD, ACE2, but not TMPRSS2 was overexpressed, which inversely correlated to the promoter methylation. An age-dependent upregulation of ACE2 expression was found in LUAD compared to normal lung tissues. In a healthy lung, TMPRSS2 expression was dependent on sex and smoking history and downregulated in LUAD of smokers. Cancer progression was associated with decreased TMPRSS2, but unaltered ACE2 expression, while ACE2 expression in lung metastases of different cancers was higher than in metastasis of other sites. TMPRSS2, but not ACE2 expression, was associated with LUAD patients’ survival. Conclusions: Comprehensive molecular analyses revealed a heterogeneous, distinct expression and methylation profile of ACE2 and TMPRSS2 in healthy lung vs LUAD tissues across sex, age and smoking history, which is associated with clinical parameters and might have implications for COVID-19 disease.

The majority of cellular responses to external stimuli are mediated by receptors such as G protein-coupled receptors (GPCRs) and systems including endoplasmic reticular stress (ER stress). Since GPCR signalling is pivotal in numerous malignant pathologies, they are targeted by a number of clinically used drugs. Cancer cells often negatively modulate GPCRs in order to survive, proliferate and to disseminate. Similarly, numerous branches of the unfolded protein response (UPR) act as pro-survival mediators and are involved in promoting cancer progression via mechanisms such as epithelial mesenchymal transition (EMT). However, there are a few proteins among these groups which impede deleterious effects by orchestrating the pro-apoptotic phenomenon and paving a therapeutic pathway. The present review exposes and discusses such critical mechanisms and some of the key processes involved in carcinogenesis.

The lytic bone disease is a hallmark of multiple myeloma, being present in about 80% of patients with newly diagnosed MM, and in more during the disease course. The myeloma associated bone disease (MBD) severely affects the morbidity and quality of life of the patients. MBD defines treatment demanding MM. In recent years, knowledge of the underlying pathophysiology has increased, and novel imaging technologies, medical and non-pharmaceutical treatments have improved. In this review, we highlight the major achievements in understanding, diagnosing and treating MBD. For diagnosing MBD, low-dose whole-body CT is now recommended over conventional skeletal survey, but also more advanced functional imaging modalities, such as diffusion-weighted MRI and PET/CT are increasingly important in the assessment and monitoring of MBD. Bisphosphonates have, for many years, played a key role in management of MBD, but denosumab is now an alternative to bisphosphonates, especially in patients with renal impairment. Radiotherapy is used for uncontrolled pain, for impeding fractures and in treatment of impeding or symptomatic spinal cord compression. Cement augmentation has been shown to reduce pain from vertebral compression fractures. Cautious exercise programs are safe and feasible and may have the potential to improve the status of patients with MM.

The recent COVID-19 outbreak in China led to a worldwide pandemic associated with a severe acute respiratory illness. A higher incidence of COVID-19 infection was demonstrated in cancer patients, including patients with lung cancer. This study was conducted to get insights into the reasons for this enhanced frequency of COVID-19 infection. Methods: Using different bioinformatic tools, the expression and methylation pattern of ACE2 and TMPRSS2 gene were analyzed in healthy and malignant tissues with a focus on lung adenocarcinoma (LUAD) and correlated to clinical parameters and smoking history. Results: ACE2 and TMPRSS2 were heterogeneously expressed across 36 healthy tissues with the highest expression in digestive, urinary and reproductive organs, while their expression was significantly lower in 36 cancer tissues. In LUAD, ACE2, but not TMPRSS2 was overexpressed, which inversely correlated to the promoter methylation. An age-dependent upregulation of ACE2 expression was found in LUAD compared to normal lung tissues. In a healthy lung, TMPRSS2 expression was dependent on sex and smoking history and downregulated in LUAD of smokers. Cancer progression was associated with decreased TMPRSS2, but unaltered ACE2 expression, while ACE2 expression in lung metastases of different cancers was higher than in metastasis of other sites. TMPRSS2, but not ACE2 expression, was associated with LUAD patients’ survival. Conclusions: Comprehensive molecular analyses revealed a heterogeneous, distinct expression and methylation profile of ACE2 and TMPRSS2 in healthy lung vs LUAD tissues across sex, age and smoking history, which is associated with clinical parameters and might have implications for COVID-19 disease.

Pheochromocytoma is a rare neuroendocrine tumor that affects people in the 4th and 5th decades of life. It can be benign or malignant, and present as isolated tumors or along with other neuroendocrine syndromes. We present a case of an elderly man who underwent laparoscopic adrenalectomy for pheochromocytoma when he was 58 years only to have a recurrence of metastatic malignant pheochromocytoma in his seventies. We also conducted a literature review to understand the epidemiology and presentation of the tumor and to emphasize that there should be a low threshold of suspicion for timely diagnosis and management of recurrent pheochromocytoma.

Nicotine exposure may affect NSCLC is associated with lung cancer in humans. Whether nicotine exhibits carcinogenesis promoted activities in tumor growth still unknown. Nicotine is known to have dichotomous effects on cancer biology, acting like a pro- or anti-carcinogenesis agent. There are different functions between adenocarcinoma and squamous NSCLC cancer cells. Excess generation of nicotine may inhibit mitochondrial metabolism, protein modification, and DNA cleavage. Materials and Methods: We used the H520 NSCLC line obtained from human lung epithelial cells to detected nicotine growth and toxicity using MTT assay and western blotting. The concentration of nicotine stimulated cell growth to correspond to low concentration, while high concentration was cytotoxic. Results: According to MTT assay results, at 1.0 μM nicotine has significantly enhanced the H520 cell viability (%). Nicotine induced lung cancer carcinogenesis through mechanisms of α7nAchR, EGFR, HDAC2/4/5, Cyclin D/Cyclin E, Bcl-2, p-Akt, and inflammatory proteins of NF-KappaB and COX2 increases at 1.0 μM. Apoptosis proteins were decreases at 1.0 μM nicotine by p21, p27, c-jun, and p38α using western blotting. Nicotine stimulates tumor growth is mediated through α7nicotinic-acetylcholine receptors (α7nAChR), possibly involving inflammation. On the other hand, at high nicotine concentrations (> 1.0 μM) with consistent cytotoxic effects and appeared to be due to direct cell kill. Nicotine can prevent apoptosis induced by NSCLC. Conclusion: Therefore, the effects on chemotherapeutics by NSCLC malignant cell lines, nicotine in concentrations as low as 1.0 μM decreased. These mechanisms are responsible for the genotoxic effects caused by nicotine. This leads to downstream effects on decreased apoptosis, increased cell proliferation and transformation. The malignant NSCLC cells respond to the treatment with nicotine in lung cancer, the nicotine-mediated induction of growth may provide one of its links to α7nAchR or EGFR.

Background: The hedgehog (HH) signaling pathway is a key regulator of embryonic patterning, tissue regeneration, stem cell renewal, and cancer growth. The smoothened (SMO) protein regulates the HH signaling pathway and has demonstrated oncogenic activity. Methods: To clarify the role of the HH signaling pathway in tumorigenesis, the expression profile of key HH signaling molecules, including SMO, PTCH1, GLI1, GLI2, and GLI3, were determined in thirty-three cancer cell lines. We performed a computational analysis of the upstream region of the SMO gene to identify the regulatory elements. Results: Three potential CpG islands and several putative SMO promoter elements were identified. Luciferase reporter assays mapped key SMO promoter elements, and functional binding sites for SP1, AP1, CREB, and AP-2a transcription factors in the core SMO promoter region were confirmed. A hypermethylated SMO promoter was identified in several cancer cell lines suggesting an important role for epigenetic silencing of SMO expression in certain cancer cells. Discussion: These results have important implications for our understanding of regulatory mechanisms controlling HH pathway activity and the molecular basis of SMO gene function. Moreover, this study may prove valuable for future research aimed at producing therapeutic downregulation of SMO expression in cancer cells.

Background: Prostate cancer (PCa) is characterized by significant heterogeneity in its molecular, genomic, and immunologic characteristics. Methods: Whole transcriptome RNAseq data from The Cancer Genome Atlas of prostate adenocarcinomas (n=496) was utilized. The immune microenvironment was characterized using the CIBERSORTX tool to identify immune cell type composition. Unsupervised hierarchical clustering was performed based on immune cell type content. Analyses of progression-free survival (PFS), distant metastases, and overall survival (OS) were performed using Kaplan-Meier estimates and Cox-regression multivariable analyses. Results: Four immune clusters were identified, largely defined by plasma cell, CD4+ Memory Resting T Cells (CD4 MR), M0 and M2 macrophage content (CD4 MRHighPlasma CellHighM0LowM2Low, CD4 MRLowPlasma CellHighM0LowM2Low, CD4 MRHighPlasma CellLowM0HighM2Low, and CD4 MRHighPlasma CellLowM0LowM2High). The two macrophage-enriched/plasma cell non-enriched clusters (3&4) demonstrated worse PFS (HR 2.24, 95% CI 1.46–3.45, p=0.0002) than the clusters 1&2. No metastatic events occurred in the non-macrophage-enriched clusters. Comparing clusters 3 vs 4, in patients treated by surgery alone, cluster 3 had zero progression events (p<0.0001). However, cluster 3 patients had worse outcomes after post-operative radiotherapy (p=0.018). Conclusion: Distinct tumor immune clusters with a macrophage-enriched phenotype and reduced plasma cell enrichment independently characterize an aggressive phenotype in localized prostate cancer that may differentially respond to treatment.

Oral cancer cells (TYS) and the signalling pathways involved in metastasis, in response to cancer-associated fibroblasts (CAFs, COM) and normal oral mucosal fibroblasts (MM1) was studied. Metastatic cell behaviour was observed by cell-scatter, 3D-collagen gel migration and 3D-spheroid invasion assays. Akt, MAPK, EGFR, TGFβRii and CXCR4 inhibitors were used to identify the signalling pathways involved. Signalling pathway protein expression and activation were assessed by SDS-PAGE and Western Blotting. COM-CM (conditioned medium) and MM1-CM stimulated cancer cell scattering, which was blocked only by the Akt inhibitor. COM-CM induced scattered cancer cells showed higher levels of Akt phosphorylation than the negative control and MM1-CM. Migration and invasion of TYS cells into the collagen gels from the spheroids was stimulated by CM from both sources, compared to the negative control. COM cells stimulated TYS, cancer cell invasion into the collagen more than MM1 and the control. Akt and EGFR inhibitors effectively blocked CM and COM cell-induced invasion. Akt-silenced cancer cells were not stimulated to migrate and invade by fibroblast-CM and did not survive addition of the EGFR inhibitor. This suggests that CAFs stimulate oral cancer cell migration and invasion in an Akt- dependent manner. EGFR and Akt are potential therapy targets in metastatic oral cancer.

Background: Three drug-combinations, ipilimumab-nivolumab (Ipi-Nivo), pembrolizumab-axitinib (Pembro-Axi) and avelumab-axitinib (Ave-Axi), have received regulatory approvals in USA and Europe for the treatment of metastatic renal cell carcinoma with clear cell component (mRCC). However, no head-to-head comparison data are available to identify the best option. Therefore, we aimed to compare these new treatments in the first-line setting. Methods: We conducted a systematic search in Pubmed, the Cochrane library and clinicaltri-al.gov website from January 2015 to October 2019, for any randomized controlled trials of treatment-naïve patients with mRCC. The process was performed according to PRISMA guide-lines. We performed a Bayesian network meta-analysis with two different approaches. The out-comes for analysis were overall survival, progression-free survival, and objective response rate. Results: Our search identified 3 published phase 3 randomized clinical trials (2835 patients). In the contrast-based model, Ave-Axi (SUCRA: 83%) and Pembro-Axi (SUCRA: 80%) exhibited the best ranking probabilities for PFS. For OS, Pembro-Axi (SUCRA: 96%) was the most pref-erable option against Ave-Axi and Ipi-Nivo. Objective response rate analysis showed Ave-Axi as the best (SUCRA= 94%) and Pembro-Axi as second best option. In the parametric models, risk of progression was comparable for Ave-Axi and Ipi-Nivo, whereas Pembro-Axi exhibited a lower risk during the first 6 months of treatment and a higher risk afterward. Furthermore, Pembro-Axi exhibited a net advantage in terms of OS over the two other regimens, while Ave-Axi was the least preferable option. Conclusions: Overall evidences suggested pembrolizumab plus axitinib may be the best option.

Background: Coffee is the second most popular drink in the worldwide, and it has different components with antioxidant and antitumor properties. The objective of this study was to explore the relationship between coffee consumption and the incidence and mortality of stomach cancer in the main consuming countries. Methods: An observational study was performed. Dataset of coffee consumption was obtained from WorldAtlas, and incidence and mortality rates from GLOBOCAN database. Spearman's rank correlation coefficient was calculated. All statistical analysis were performed using STATA software. Results: A total of 25 countries were included in the study. There was a significant linear correlation between coffee consumption kg per person per year and an estimated age-adjusted incidence (r=0.5984, p=0.0016) and mortality (r=0.5877, p=0.0020). Conclusion: Coffee consumption could potentially have beneficial effects on incidence and mortality by stomach cancer.

Prostate cancer (PCa) has become the most common tumor among males in Europe and the USA. Adoptive immunotherapy appears as a promising strategy to control the advanced stages of the disease by specific targeting the tumor, in particular through chimeric antigen receptor T (CAR-T) cell therapy. Despite the advancements of CAR-T technology in the treatment of hematological malignancies, solid tumors still represent a challenge. To overcome current limits, other cellular effectors than T lymphocytes are under study as possible candidates for CAR-engineered cancer immunotherapy. A novel approach involves the NK-92 cell line, which mediates strong cytotoxic responses against a variety of tumor cells but has no effect on non-malignant healthy counterparts. Here, we report a therapeutic approach against PCa based on engineering of NK-92 cells with a CAR recognizing the human prostate-specific membrane antigen (PSMA), which is overexpressed in prostatic neoplastic cells. Upon CAR transduction, NK-92/CAR cells acquired high and specific lytic activity against PSMA-expressing prostate cancer cells in vitro, and also underwent degranulation and produced high levels of IFN-γ in response to antigen recognition. Lethal irradiation of the effectors, a safety measure requested for the clinical application of retargeted NK-92 cells, fully abrogated replication but did not impact on phenotype and short-term functionality. PSMA-specific recognition and antitumor activity were retained in vivo, as adoptive transfer of irradiated NK-92/CAR cells in prostate cancer-bearing mice restrained tumor growth and improved survival. Anti-PSMA CAR-modified NK-92 cells represent a universal, off-the-shelf, renewable and cost-effective product endowed with relevant potentialities as a therapeutic approach for PCa immunotherapy.

Immune checkpoint inhibitors (ICIs) – anti-programmed death-1 (PD-1) and their ligands (PD-L1 and PD-L2) have become widely used in the treatment of several malignancies. Many immune-related adverse events have been linked to these agents. However, tuberculosis (TB) reactivation during their use is increasingly reported. Herein, we present a 58-year-old lady with advanced non-small cell lung cancer (NSCLC) ALK-negative, EGFR wild, and PD-L1 Immune histochemistry (IHC) strongly positive in 95% of tumor cells. The patient presented with high-grade fever and a history of productive cough for a 1-week duration. A few days later, she was diagnosed with pulmonary tuberculosis following the 6th cycle of Pembrolizumab, an anti-PD-1 monoclonal antibody. AFB smear and TB PCR from BAL were positive (rifampin resistance not detected), and she was accordingly started on Anti-TB medications. Immunotherapy was held. Of note, the patient had a history of sick contact with a patient with active TB infection ten years ago, but there was no documentation of latent TB or previous TB infection. Her HIV status is negative. Her sputum AFB smear continued to be positive after four weeks of anti-TB medications. Later, the patient was discharged after her sputum was cleared from AFB (negative x 2 sets). We assumed that our patient developed reactivation of pulmonary tuberculosis secondary to an immune checkpoint inhibitor (Pembrolizumab). She was not re-challenged with Pembrolizumab following TB diagnosis. To our knowledge, this is the first reported case from the Arab and the Middle East; it reinforces the previous observations of the association between ICIs administration and the development of MTB. Nevertheless, further studies in the clinical setting are necessary to establish the exact mechanism involved in this association. Oncologists' awareness & prompt recognition of this potential hazardous consequence are essential. Since there is no clear evidence whether LTBT prior PD-1/PD targeted immunotherapy is required, targeted LTBT before starting ICIs immunotherapy with TB chemoprophylaxis; yet to be explored, particularly in the regions where the MTB prevalence is high.

Breast cancer (BC) is among the leading causes of mortality from cancer in women. Many of the available anticancer drugs have various side effects. Therefore, researchers are seeking novel anticancer agents particularly from natural compounds and in this regard, snake venom is still one of the main sources of drug discovery. Previous studies showed potential anticancer effects of Cytotoxin II (CTII) from Naja naja oxiana against the different types of cancers. In this study, a pET-SUMO-CTII vector was transformed into SHuffle® T7 Express, an Escherichia coli strain, for recombinant protein expression (rCTII) and the cytotoxic effects of this protein was assessed in MCF-7 cells. The flow cytometry assay was applied to measure the apoptosis and cell cycle. Also, mRNA levels of the Bax, Bcl2, P53, caspase-3, caspase-8, caspase-9, caspase-10, matrix metalloproteinases (MMP)-3, and MMP-9 were analyzed by quantitative real-time PCR to determine the underlying cellular pathways affected by rCTII. The results of this study showed that treatment with 4 µg mL-1 of rCTII enhanced apoptosis through the intrinsic and extrinsic pathways. Also, the increase of the cells' proportion in the sub-G1 phase as well as a reduction in S phase was observed. In addition, the expression of MMP-3 and MMP-9 was decreased in the treated group in comparison to the control group that may contribute to the reduced migratory ability of tumor cells. These experimental results indicate that rCTII has anti-proliferative potential, and so this protein could be a potential drug for BC therapy in combination with other drugs.

The signal transduction pathways of estrogen receptors (ER) mainly includes gene pathway and non-gene pathway. Studies have shown that the gene pathway of ER is related with the expression of nuclear proteins, and this is the key issue for our current research. With the GEO database analysis, Human centromere protein F (CENPF) is highly expressed in adenocarcinoma of lung (LUAD), and the co-expression of CENPF and ERβ was found in the nucleus of LUAD cells. Meanwhile, CENPF and ERβ2/5 were related with T stage and poor prognosis (P<0.05). Knockdown of CENPF gene significantly inhibited the biological effects of LUAD cells, the tumor growth of mice and the expression of ERβ2/5 (P<0.05). Further, group experiments showed that knockdown CENPF inhibits biological effects of LUAD cells mediated by ERβ pathway. All the results indicated that both CENPF and ERβ2/5 play important roles in the progression of LUAD, and knockdown of CENPF can inhibit the progression of LUAD by inhibiting the expression of ER2/5. Thus, the development of inhibitors against ERβ2/5 subtype and CENPF remained more effective in improving the therapeutic effect of LUAD.

The standard of care for metastatic breast cancer (MBC) is systemic therapies with imbrication of focal treatment in case of symptomatology onset. Recently, thanks to implementation of radiological and metabolic exams and development of new target therapies, oligometastatic and oligoprogressive disease presentations are even more common, leading to a change of paradigm of focal treatments. In fact, acknowledgement of behaviour of disease in these setting of patients is carrying aim of radiotherapy towards modalities with radical intent. The aim of this literature review is to analyse available clinical data regarding disease behaviour, imaging, radiotherapy and chemo-radiotherapy integration outcomes for understanding bone metastasis from breast cancer and the potential impact of targeting it.

Metastases cause high mortality in several cancers and immunotherapies are expected to be effective in the prevention and treatment of metastatic disease. However, only a minority of patients benefit from immunotherapies. This creates a need for novel therapies that are efficacious regardless of the cancer types and metastatic environments they are growing in. Preclinical immuno-oncology models for studying metastases have long been limited to syngeneic or carcinogenesis-inducible models that have murine cancer and immune cells. However, the translational power of these models has been questioned. Interactions between tumor and immune cells are often species-specific and regulated by different cytokines in mice and humans. For increased translational power, mice engrafted with functional parts of human immune system have been developed. These humanized mice are utilized to advance understanding the role of immune cells in the metastatic process, but increasingly also to study the efficacy and safety of novel immunotherapies. From these aspects, this review will discuss the role of immune cells in the metastatic process and the utility of humanized mouse models in immuno-oncology research for metastatic cancers, covering several models from the perspective of efficacy and safety of immunotherapies.

Abstract: This brief policy is written after experience treating COVID-19 positive radiation therapy patients to reduce risk to therapy staff and patients in radiation oncology department. It is important to prioritize the safety of staff and non-infected patients while ensuring the continuation of radiation oncology services. Radiation therapists have sustained contact with covid-19 patients in an enclosed vault. Protocols for correct disinfecting of equipment and room and therapists following methods for less transmission of virus is crucial. This policy covers prevention methods from COVID-19 transmission from patient to patient, patient to staff, staff to patient and staff to staff as follows A.Risk reduction by screening and preparing staff and rooms B.Radiation Therapist Policy for COVID-19 positive patient with CCC (Critical Cancer Care)

Background: Nodal peripheral T-cell lymphomas (nPTCLs) encompass a heterogeneous group of mature and aggressive lymphoid malignancies, including peripheral T-cell lymphoma, not otherwise specified (PTCL/NOS), angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large cell lymphoma (ALCL) ALK-positive and ALK-negative. Their differential diagnosis and prognosis are an issue in the clinical practice. Accurate biomarkers to refine the different subtypes of nPTCLs and to stratify their prognosis are essential to improve their treatment approach. The aim of this study was to test the prognostic impact of GATA3 gene expression, and its capability to discriminate the different subtypes of nPTCLs. Patients and Methods: From 2000 to 2017, 80 patients with nPTCLs were eligible for GATA3 gene expression analysis that was assessed retrospectively by quantitative real time PCR (qRT-PCR) of neoplastic biopsies in Formalin-Fixed Paraffin-Embedded samples (FFPE). Results: Median age was 49 years old (IqR 34-59), 43/80 (53.7%) were male. Median follow-up was 1.72 years. Of them, 36.3% were classified as PTCL/NOS, 31.2% ALK-negative ALCL, 21.2% ALK-positive ALCL and 11.3% AITL. The majority of cases had advanced stage (III/IV). Two-year estimated overall survival (OS) and progression-free survival (PFS) were 52.2% and 39.5%, respectively. The median GATA3 gene expression level was 0.49% (range 0 – 7.07) in all cohort, it was 0.11% for ALK-positive ALCL, 0.46% for ALK-negative ALCL, 0.86% for PTCL/NOS and 0.67% for AITL. The difference of GATA3 gene expression among distinct variants of nPTCLs was statistically significant (p < 0.001). GATA3 gene expression levels ≥ 0.71% discriminate PTCL/NOS from ALK-negative ALCL and AITL with sensitivity of 62% and specificity of 80.3%. GATA3 gene expression levels ≥ median was associated with poor 2-year OS for PTCL/NOS (46.7% x 21.4%, p=0.04) and for ALK-negative ALCL (85.7% x 54.5%, p=0.04). Conclusion: Despite the relative small and heterogeneous group of patients with nPTCLs, GATA3 gene overexpression may be an important biomarker associated with poor prognosis in PTCL/NOS and ALK-negative ALCL. Moreover it may also discriminate different subtypes of nPTCLs. Further studies with larger series of patients should confirm our findings.

Angiogenesis is a term that describes the formation of new blood and lymphatic vessels from a pre-existing vasculature. This allows tumour cells to acquire sustenance in the form of nutrients and oxygen and the ability to evacuate metabolic waste. As one of the hallmarks of cancer, angiogenesis has been studied extensively in animal and human models to enable better understanding of cancer biology and the development of new anti-cancer treatments. Angiogenesis plays a crucial role in the process of tumour genesis, because solid tumour need a blood supply if they are to grow beyond a few millimeters in size. On the other hand, there is growing evidence that some solid tumour exploit existing normal blood supply and do not require a new vessel formation to grow and to undergo metastasis. This review of the literature will present the current understanding of this intricate process and the latest advances in the use of angiogenesis-targeting therapies in the fight against cancer.

Cervical cancer is known as one of the most important cancers in women worldwide. Chemotherapy is a standard treatment for advanced/recurrent cervical cancer in which the prognosis of the disease is really poor and the 1-year survival chance in these patients is maximally 20%. However, resistance to anticancer drugs is a major problem in treating cancer. Cervical cancer stem cells are considered as a fundamental cause of chemo and radio-resistance and also relapse after primary successful treatment. Signaling pathways include a wide range of molecular mechanisms contribute to drug resistance. Recently, microRNAs (miRNAs) are announced as a group of molecular biomarkers involving in response to chemotherapy in cancer patients. As the miRNAs, there are some long non-coding RNAs (LncRNAs) which their aberrant expression is considered as a biomarker for monitoring chemoresistance. In this review, we summarized current reports about the involvement of signaling pathways during chemoresistance in cervical cancer. Then, genes that have been demonstrated their involvement during drug resistance in cervical cancer were tabulated. Further, miRNAs that have been reported as biomarkers during treatment are listed. By bioinformatic analysis, we predictedmiR-335-5p and miR-16-5p as the most potential biomarkers for monitoring resistance to chemotherapy. Finally, long non-coding RNAs that have been introduced in recent studies as novel biomarkers during the response to chemotherapy were mentioned.

Mammary neoplasm affects a population of intact and elderly female dogs and 50% are malignant. In order to study this disease, cell culture is as a promising preclinical model, creating the opportunity to deposit cell lines at a cell bank, allowing a great reproducibility of the assays and making the validation of the results more reliable. Another important aspect is the possibility to establish models for better understanding tumour characteristics, such as vasculogenic mimicry. Due the importance of cancer cell lines in preclinical models, this study aimed to establish and characterize primary cell lines from canine mammary gland tumours according to immunophenotype and tumorigenicity, and with its ability to form vasculogenic mimicry-like structures in vitro and in vivo. Cell cultures were evaluated for morphology, phenotype, vasculogenic mimicry and tumorigenicity abilities. We collected 17 primary mammary carcinoma and 3 metastasis and had a satisfactory result in 10 of them. All cell lines presented spindle shape or polygonal morphology and expressed concomitant pan-cytokeratin and cytokeratin 8/18. Four cell lines had vasculogenic mimicry ability in vitro and two of them showed in vivo tumorigenic potential and forming VM in the xenotransplant tumour. Cell characterization of those lines will help to create a database for more knowledge of mammary carcinomas in dogs, including studies of tumour behaviour and new therapeutic targets.

Acute myeloid leukemia (AML) is an incurable hematological malignancy. To treat the disease successfully, new therapeutic strategies are urgently needed. One of these strategies can be the use of neurokinin-1 receptor (NK-1R) antagonists (e.g., aprepitant), because the substance P (SP)/NK-1R system is involved in cancer progression, including AML. AML patients show an up-regulation of the NK-1R mRNA expression; human AML cell lines show immunoreactivity for both SP and the NK-1R (it is overexpressed: the truncated isoform is more expressed than the full-length form) and, via this receptor, SP and NK-1R antagonists (aprepitant, in a concentration-dependent manner) respectively exert a proliferative action or an antileukemic effect (apoptotic mechanisms are triggered by promoting oxidative stress via mitochondrial Ca++ overload). Aprepitant inhibits the formation of AML cell colonies and, in combination with chemotherapeutic drugs, is more effective in inducing cytotoxic effects and AML cell growth blockade. NK-1R antagonists also exert an antinociceptive effect in myeloid leukemia-induced bone pain. The antitumor effect of aprepitant is diminished when the NF-κB pathway is overactivated and the damage induced by aprepitant in cancer cells is higher than that exerted in non-cancer cells. Thus, the SP/NK-1R system is involved in AML and aprepitant is a promising antitumor strategy against this hematological malignancy. In this review, the involvement of this system in solid and non-solid tumors (in particular in AML) is up-dated and the use of aprepitant as an anti-leukemic strategy for the treatment of AML is also mentioned (a dose of aprepitant (> 20 mg/kg/day) for a period of time according to the response to treatment is suggested).

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.

Triple negative breast cancers (TNBCs) are molecularly heterogeneous, and the link between their aggressiveness with African ancestry is not established. We investigated primary TNBCs for gene expression among self-reported race (SRR) groups of African American (AA, n=42) and European American (EA, n=33) women. Using The Cancer Genome Atlas (TCGA) approaches, we analyzed RNA sequencing data to measure changes in genome-wide expression and used logistic regressions to identify ancestry-associated gene expression signatures. To determine global ancestry, GATK best practices were followed for variant calling, and used the 1000 Genomes Project as reference data. We identified >150 African ancestry-associated genes and found that, compared to SRR, quantitative genetic analysis was a more robust method to identify racial/ethnic-specific genes that were differentially expressed. A subset of African ancestry-specific genes that were upregulated in TNBCs of our AA patients were validated in TCGA data. In AA patients, there was a higher incidence of basal-like 2 tumors and altered TP53, NFB1, and AKT pathways. The distinct distribution of TNBC subtypes and altered oncologic pathways show that the ethnic variations in TNBCs are driven by shared genetic ancestry. Thus, to appreciate the molecular diversity of TNBCs, tumors from patients of various ancestral origins should be evaluated.

Glioblastoma multiforme (GBM) is the most common high-grade intracranial tumor in adults. It is characterized by uncontrolled proliferation, diffuse infiltration due to high invasive and migratory capacities, as well as intense resistance to chemo- and radiotherapy. With a five-year survival of less than 3% and an average survival rate of 12 months after diagnosis, GBM has become a focus of current research to urgently develop new therapeutic approaches in order to prolong survival of GBM patients. The methylation status of the promoter region of the O6-methylguanine–DNA methyltransferase (MGMT) is nowadays routinely analyzed, since a methylated promoter region is beneficial for an effective response to temozolomide-based chemotherapy. Furthermore, several miRNAs were identified regulating MGMT expression, apart from promoter methylation, by degrading MGMT mRNA before protein translation. These miRNAs could be a promising innovative treatment approach to enhance Temozolomide (TMZ) sensitivity in MGMT unmethylated patients and to increase progression-free survival as well as long-term survival. In this review, the relevant miRNAs are systematically reviewed.

Background: Lung cancer is one of the common causes of death worldwide. Although the incidence rate of lung cancer in Western countries is decreasing, it presents a growing trend in developed countries. Since there is no accurate enough information about the epidemiological and Histopathologic features of lung cancer in central Iran, Isfahan, we were motivated to conduct this research. Materials and Methods: This was a descriptive, cross-sectional study carried out in central Iran, Isfahan. All demographic, histopathological and clinical data of the lung cancer patients registered in MACSA, a referral charity-based cancer center in central Iran, was analyzed within 2012-2018 using SPSS v.22 software. Results: Altogether 260 patients with lung cancer were included in this study from 6127 cancer patients registered within 2012-2018 (4.2%). Out of them, 66.2% were men, and 18.8 % of the patients were alive at the time of the study. The mean age of the patients at diagnosis was 61.56 (SD=14.11, range: 9-93). Altogether, 63.1% of patients had metastasis of whom 57.6% were in stage IV at diagnosis. The Frequency of different types of lung cancer was 36.9% adenocarcinomas, 14.2% squamous cell carcinoma, 9.6% bronchogenic carcinoma and 8.1% small cell lung cancer, respectively. Altogether, 128 cases were smokers with an average 35.45 ± 14 pack- years. Only in 36.2% of the patients, the diagnostic and therapeutic biomarkers had been checked, and CK7 was positive in 88.9% of the cases in which the biomarker had been checked. Conclusion: Despite to similar Iranian studies, the most common histopathologic type of lung cancer among the patients was adenocarcinoma that it may be attributed to the lower consumption of smoking in our population and their different genetic context. Molecular biomarkers had been checked in a small portion of the patients. More education of the clinicians along with the development of cancer molecular testing may lead to promote the personalized-based approach.

The cyclic lipopeptide produced from Bacillus pumilus strain HY1 was isolated from Korean soybean sauce. The chemical structures of the surfactin isomers were analyzed using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) and electrospray ionization tandem mass spectrometry (ESI-MS/MS). The five potential surfactin isoforms were detected with protonated masses of m/z 994.7, 1,008.7, 1022.7, 1036.7, and 1,050.7 and different structures in combination with Na+, K+, and Ca2+ ions. ESI-MS/MS analysis revealed that the isolated surfactin possessed the precise amino acid sequence LLVDLL and hydroxyl fatty acids with 12 to 16 carbons. The surfactin content during cheonggukjang fermentation increased from 0.3 to 51.2 mg/kg over 60 h of fermentation. The surfactin extraction of cheonggukjang inhibited the growth of two cancer cell lines. The growth of both MCF-7 and Caco-2 cells was strongly inhibited with 100 μg/μL surfactin. These results suggest that surfactins produced from strain HY1 have anticancer properties.

We performed a systematic review and meta-analysis to evaluate the role of gastric acid suppressant use on outcomes of tyrosine kinase inhibitors (TKIs) and oral chemotherapy. We identified all researches evaluating the effect of GAS use on patients receiving oral chemotherapy or TKIs for solid tumors. The pooled hazard ratios (HRs) and 95% confidence interval (95% CI) for overall survival (OS) and progression-free survival (PFS) were calculated with fixed-effects or random-effects model. The study population included n=16 retrospective studies and 372,418 patients. Series concerned gastrointestinal tract tumors (n=5 studies), renal cell carcinomas (RCC, n=3 studies), non-small cell lung cancers (NSCLC, n=5 studies), and soft tissue sarcomas or mixed histologies solid tumors in n=3 studies. The pooled HRs for OS and PFS were 1.31 (95% CI: 1.20–1.43; P<01) and 1.3 (95%CI 1.07-1.57; P<0.01) for GAS and no GAS users, respectively. Only studies of EGFR mutated NSCLC patients receiving TKIs and those with colorectal cancer receiving oral chemotherapy showed a significant correlation between GAS and poor survival. Our study supports the evidence of a possible negative impact of concomitant GAS therapy on survival outcomes of patients receiving oral anti-cancer drugs.

Antibiotics (ABs) are common medications used for treating infections. In cancer patients treated with immune checkpoint inhibitors (ICIs), concomitant exposure to ABs may impair the efficacy of ICIs and lead to a poorer outcome compared to AB non-users. We report here the results of a meta-analysis evaluating the effects of ABs on the outcome of patients with solid tumors treated with ICIs. PubMed, the Cochrane Library, and Embase were searched from inception until September 2019 for observational or prospective studies reporting prognosis of adult patients with cancer treated with ICIs and with or without ABs. Overall survival (OS) was the primary endpoint, and progression-free survival (PFS) was the secondary endpoint. The effect size was reported as hazard ratios (HRs) with a 95% confidence interval (CI), and an HR > 1 associated with a worse outcome in ABs users compared to no-ABs users. Fifteen publications were retrieved for a total of 2363 patients. In the main analysis (n = 15 studies reporting data), OS was reduced in patients exposed to ABs before or during treatment with ICIs (HR = 2.07, 95%CI 1.51–2.84; P<.01). Similarly, PFS was inferior in ABs users in n = 13 studies with data available (HR = 1.53, 95%CI 1.22–1.93; p<.01). In cancer patients treated with ICIs, AB use significantly reduces OS and PFS. Short duration/course of ABs may be considered in clinical situations in which they are strictly needed.

The effect of proteolytic enzymes including Cathepsin K, a cysteine cathepsin, in onset and progression of cancers in human has been research intensive. Cathepsin K involves in many aspects and stages of cancers including apoptosis, cell proliferation, cancer immunology, inflammatory cell recruitment to tumors and aiding in the process of mobilization of normal healthy cells from their tissue compartments assisting in metastasis and angiogenesis. The objective of this review is to collect together and summarize and analyze the biochemical and physiological pathways of how cathepsin K is involved in onset and progression of cancers with more emphasis on breast and prostate cancers and cathepsin K regulated mechanisms underlying metastasis of such cancers to bones. Information for the review was gathered through published literature from global databases such as Google Scholar, PUBMED and NCBI on different studies on physiological interactions between enzymatic activity of cathepsin K with cancers and metastasis to bones. Analysis of published studies reveal that immunohistochemical studies of breast cancer cells indicate that they overexpress cathepsin K resulting in induction of aberrant mechanisms of cell signaling in breast cancers, creating a higher tendency for their metastasis to bones. Immunohistochemical, immunoprecipitation and fluorgenic assays of several studies done on the association of the same enzymatic activity on prostate cancers shows elevated levels of cathepsin K. Lesions derived from prostate cancer cell masses were observed to undergo increased bone formation and resorption levels. Such resorption levels cause secretion of biological factors promoting tumor expansion. In addition, studies indicate that Cathepsin K was observed to be a key component promoting higher bone resorption levels in patients suffering from cancer. Authors suggest that, to completely understand the association of cathepsin K on cancerous cells and their mechanism in metastasis, distributary patterns of cathepsin K in healthy human tissues needs to be extensively studied initially. It is also suggested that metastasis of breast and prostate cancers to bone could be terminated and overcome by successful production of efficient and precise inhibitory therapeutics targeting the enzymatic activity of Cathepsin K with minimum unintended adverse health effects.

The COVID-19 pandemic is placing unprecedented stress on healthcare systems around the world. Although Radiation Oncology Departments are not at the frontline of fighting this infectious disease, it is important to implement COVID-19 policies to reduce risk of staff and patient exposure, and to limit the risk of department shutdown or downtime. This brief report describes the policy implemented at George Washington University Radiation Oncology to manage the risks of COVID-19. This includes a General Statement related to the priorities of the Radiation Oncology department, a screening procedure for new and follow-up patients, management policies for critical and non-critical patients with COVID-19 or under quarantine, a policy for the management of patients currently under treatment who are diagnosed or placed in quarantine, a clinical escalation action plan, guidelines for staff meetings and travel, and procedure management. This policy was implemented at George Washington University Radiation Oncology after the first case of COVID-19 was reported in Washington DC on March 7, 2020.

HIF-1α is a master regulator of oxygen homeostasis involved in different stages of cancer development. Thus, HIF-1α inhibition represents an interesting target for anti-cancer therapy. It was recently shown that HIF-1α interaction with NQO1 inhibits its proteasomal degradation, thus suggesting that targeting the stability of NQO1 could led to destabilization of HIF-1α as a therapeutic approach. Since the molecular interactions of NQO1 with HIF-1α are beginning to be unraveled, we review here our current knowledge on the intracellular functions and stability of NQO1, its pharmacological modulation by small ligands, and the molecular determinants of its roles as a chaperone of many different proteins including cancer-associated factors such as p53 and p73α. This knowledge is then discussed in the context of potentially targeting the intracellular stability of HIF-1α by acting on its chaperone, NQO1. This could result in novel anti-cancer therapies.

We performed a systematic review and meta-analysis to evaluate the role of gastric acid suppressant use on outcomes of tyrosine kinase inhibitors (TKIs) and oral chemotherapy. We identified all researches evaluating the effect of GAS use on patients receiving oral chemotherapy or TKIs for solid tumors. The pooled hazard ratios (HRs) and 95% confidence interval (95% CI) for overall survival (OS) and progression-free survival (PFS) were calculated with fixed-effects or random-effects model. The study population included n=16 retrospective studies and 372,418 patients. Series concerned gastrointestinal tract tumors (n=5 studies), renal cell carcinomas (RCC, n=3 studies), non-small cell lung cancers (NSCLC, n=5 studies), and soft tissue sarcomas or mixed histologies solid tumors in n=3 studies. The pooled HRs for OS and PFS were 1.31 (95% CI: 1.20–1.43; P<01) and 1.3 (95%CI 1.07-1.57; P<0.01) for GAS and no GAS users, respectively. Only studies of EGFR mutated NSCLC patients receiving TKIs and those with colorectal cancer receiving oral chemotherapy showed a significant correlation between GAS and poor survival. Our study supports the evidence of a possible negative impact of concomitant GAS therapy on survival outcomes of patients receiving oral anti-cancer drugs.

Cell death resistance is a key feature of tumor cells. One of the main anti-cancer therapies is increasing the susceptibility of cells to death. Cancer cells have developed a capability of tumor immune escape. Hence, restoring the immunogenicity of cancer cells can be suggested as an effective approach against cancer. Accumulating evidence proposes that several anticancer agents provoke the release of danger-associated molecular patterns (DAMPs) that are determinants of immunogenicity and stimulate immunogenic cell death (ICD). It has been suggested that ICD inducers are two different types according to their various activities. Here, we review the well-characterized DAMPs and focus on the different types of ICD inducers and recent combination therapies that can augment the immunogenicity of cancer cells.

Cancer is a leading cause of death worldwide. It is theorized that underlying genetic and epigenetic changes enable cells to proliferate out of control by escaping regulatory mechanisms. The progression of cancer is associated with increased cell proliferation, metabolic modifications, resistance to apoptosis, genetic instability, induction of angiogenesis and augmented migratory capability. Recent developments in DNA and RNA analysis have made it possible to study these genetic changes systematically. These advances have enabled us to possess a deeper knowledge of the signaling pathways and involved processes. In-depth studies of the pathways involved in carcinogenesis have led to the identification of pathways that may be targeted for therapeutic purposes. In this review, we provide an overview of the relevant mechanisms and pathways involved in the development and progression of cancer.

Cancer is a leading cause of death worldwide. It is theorized that underlying genetic and epigenetic changes enable cells to proliferate out of control by escaping regulatory mechanisms. The progression of cancer is associated with increased cell proliferation, metabolic modifications, resistance to apoptosis, genetic instability, induction of angiogenesis and augmented migratory capability. Recent developments in DNA and RNA analysis have made it possible to study these genetic changes systematically. These advances have enabled us to possess a deeper knowledge of the signaling pathways and involved processes. In-depth studies of the pathways involved in carcinogenesis have led to the identification of pathways that may be targeted for therapeutic purposes. In this review, we provide an overview of the relevant mechanisms and pathways involved in the development and progression of cancer.

Androgen receptor signaling is crucial for prostate cancer growth and is positively regulated in part by intratumoral CYP3A5. As African American (AA) men often carry the wild type CYP3A5 and express high level of CYP3A5 protein, we blocked the wild type CYP3A5 in AA origin prostate cancer cells and tested its effect on androgen receptor signaling. q-PCR based profiler assay identified several AR regulated genes known to regulate AR nuclear translocation, cell cycle progression and cell growth. CYP3A5 processes several commonly prescribed drugs and many of these are CYP3A5 inducers or inhibitors. In this study, we test the effect of these commonly prescribed CYP3A5 inducers/inhibitors on AR signaling. The results show that the CYP3A5 inducers promoted AR nuclear translocation, downstream signaling and cell growth whereas CYP3A5 inhibitors abrogated them. The observed changes in AR activity is specific to alterations in CYP3A5 activity. Both the inducers tested demonstrated increased cell growth of prostate cancer cells, whereas the inhibitors showed reduced cell growth. Further, characterization and utilization of the observation that CYP3A5 inducers and inhibitors alter AR signaling may provide guidance to physicians prescribing CYP3A5 modulating drugs to treat comorbidities in elderly patients undergoing ADT, particularly AA.

MicroRNAs (miRNAs) are small and non-coding RNAs displaying aberrant expression in the tissue and plasma of cancer patients in comparison to healthy individuals. In past decades, accumulating data proposed that miRNAs could be diagnostic and prognostic biomarkers in cancer patients. It has been identified that miRNAs can act either as oncogenes through silencing of tumor inhibitors or tumor suppressor via targeting oncoproteins. MiR-144 is located in chromosomal region 17q11.2 that was widely destroyed in many types of cancers. Several studies revealed that miR-144 has different target genes including rapamycin, zonula occludens1, SFRP1, and ANO1. MiR-144 acts as a tumor suppressor or oncogene by targeting specific genes. In this review, we define the role of miR‐144 and its targets in different cancers and provide understanding in tumor proliferation, migration, and apoptosis.

Breast cancer (BC) is the most frequent form of malignancy and the second only to lung cancer as common cause of cancer-causing deaths in women. Notwithstanding many progresses in the field, metastatic BC has a very poor prognosis. As therapies are becoming more personalized to meet patients‘ needs, a better knowledge of the molecular biology leading to the disease unfolds the possibility to project more precise compounds or antibodies targeting definite alteration at the molecular level expressed in cancer cells of patients or as antigens on the surface of cell membranes. Fibroblast growth factor receptor (FGFR) is a druggable target -which is activated by its own ligands -namely the Fibroblast Growth Factors (FGFs). This pathway provides a vast range of interesting molecular targets pursued at different levels of clinical investigation. Herein we provide an update on the knowledge on genetic alterations of the receptors in breast cancer, their role in tumorigenesis and the most recent drugs against this particular receptor to treat the disease.

Natural killer (NK) cell therapy is one of the most promising treatments for Glioblastoma Multiforme (GBM). However, this emerging technology is limited by the availability of sufficient numbers of fully functional cells. Here, we investigated the efficacy of NK cells that were expanded and treated by interleukin-2 (IL-2) and heat shock protein70 (HSP70), both in vitro and in vivo. Proliferation and cytotoxicity assays were used to assess the functionality of NK cells in vitro, after which treated and naïve NK cells were administrated intra-cranially and systemically to compare the potential antitumor activities in our in vivo rat GBM models. In vitro assays provided strong evidence of NK cell efficacy against C6 tumor cells. In vivo tracking of NK cells showed efficient homing around and within the tumor site. Furthermore, significant amelioration of the tumor in rats treated with HSP70/Il-2 treated NK cells as compared to those subjected to non-treated NK cells, as confirmed by MRI, proved the efficacy of adoptive NK cell therapy. Moreover, results obtained with systemic injection confirmed migration of activated NK cells over the blood brain barrier and subsequent targeting of GBM tumor cells. Our data suggest that administration of HSP70/Il-2 treated NK cells may be a promising therapeutic approach to be considered in the treatment of GBM.

Matrix metalloproteinase 3 (MMP3) plays multiple roles in pro-tumorigenic proteolysis and in intracellular transcription. These include inducing connective tissue growth factor [CTGF, also known as cellular communication network factor 2 (CCN2)] and prompting a new definition of MMP3 as a moonlighting metalloproteinase. Members of the MMP family have been found within tumor-derived extracellular vesicles (EVs) such as oncosomes or exosomes. We here investigated the roles of MMP3-rich oncosomes in tumor progression, molecular transmission, and gene regulation. MMP3 and CCN2/CTGF were significantly co-expressed in tumor samples derived from patients suffering from colorectal adenocarcinoma. We found that oncosomes derived from a rapidly metastatic colon cancer cells (LuM1) were enriched in MMP3 and a C-terminal half fragment of CCN2/CTGF. MMP3-rich oncosomes were highly transmissive into recipient cells and were pro-tumorigenic in an allograft mouse model. Oncosome-derived MMP3 was transmissive into recipient cell nuclei, trans-activated CCN2/CTGF promoter, and induced CCN2/CTGF production at 1 to 6 hours after the addition of oncosomes to culture media. In addition, CRISPR/Cas9-mediated knockout of MMP3 showed significant anti-tumor effects, including inhibition of migration and invasion of LuM1 cells in vitro, inhibition of tumor growth in vivo, and reduction of CCN2/CTGF and its promoter activity in vitro. These data newly demonstrate that the oncosome-derived moonlighting metalloproteinase promotes metastasis and is pro-tumorigenic at distant sites as well as a transmissive trans-activator for the cellular communication network gene.

Tumor cells exhibit a resistance-associated secretory phenotype involving extracellular vesicles (EVs) and heat shock proteins (HSPs). This response occurs in response to cell stress and cancer therapeutics. HSPs are stress-responsive molecular chaperones promoting proper protein folding, while also being released from cells with EVs as well as in free form as alarmins. We have here investigated the secretory phenotype of castration-resistant prostate cancer (CRPC) cells using proteome analysis. We have also examined the roles of the key co-chaperone CDC37 in stressome release, epithelial-to-mesenchymal transition (EMT), and tumor progression. A number of HSP family members and their common receptor CD91/LRP1 were enriched at high levels in CRPC cell-derived EVs among over 700 other protein species. The small EVs (30 to 200 nm in size, potentially exosomes) were released even in a non-heated condition from the prostate cancer cells, whereas EMT-coupled release of EVs (200 to 500 nm, likely ectosomes) with associated HSP90α was increased after heat shock stress (HSS). Lactate dehydrogenase, a marker of membrane leakage/damage of cells, was also released upon HSS from the prostate cancer cells. During this stress response, intracellular CDC37 was also transcriptionally inducible by heat shock factor 1, and knockdown of CDC37 decreased EMT-coupled release of EVs. Triple knockdown of CDC37, HSP90α, and HSP90β was required for efficient reduction of the chaperone trio and to reduce tumorigenicity of the CRPC cells in vivo. Taken together, the data indicated that CDC37 and HSP90 are essential for stressome release and for tumorigenesis in resistant cancer.

Patient derived model systems are important tools for studying novel anti-cancer therapies. Patient derived xenografts (PDXs) have gained favor over the last 10 years as newer mouse strains have improved the success rate of establishing PDXs from patient biopsies. PDXs can be engrafted from head and neck cancer (HNC) samples across a wide range of cancer stages, retain the genetic features of their human source, and can be treated with both chemotherapy and radiation, allowing for clinically relevant studies. Not only do PDXs allow for study of patient tissues in an in vivo model, they can also provide a renewable source of cancer cells for organoid cultures. Herein, we review the uses of HNC patient derived models for radiation research including approaches to establishing both orthotopic and heterotopic PDXs, approaches and potential pitfalls to delivering chemotherapy and radiation to these animal models, biological advantages and limitations, and alternatives to animal studies that still use patient-derived tissues.

Epithelial-mesenchymal transition (EMT) has been well recognized for its essential role in cancer progression as well as normal tissue development. In cancer cells, activation of EMT permits the cells to acquire migratory and invasive abilities and stem-like properties. However, simple categorization of cancer cells into epithelial and mesenchymal phenotypes misleads the understanding of the complicated metastatic process, and contradictory results from different studies also indicate the limitation of application of EMT theory in cancer metastasis. Nowadays, growing evidence suggests the existence of an intermediate status between epithelial and mesenchymal phenotypes, i.e., the “hybrid epithelial-mesenchymal (hybrid E/M)”state, provides a possible explanation for those conflicting results. Appearance of hybrid E/M phenotype offers a more plastic status for cancer cells to adapt the stressful environment for proceeding metastasis. In this article, we review the biological importance of the dynamic changes between the epithelial and the mesenchymal states. The regulatory mechanisms encompassing the translational, post-translational, and epigenetic control for this complex and plastic status are also discussed .

Autophagy is a multistep catabolic process through which misfolded, aggregated or mutated proteins and damaged organelles are internalized in membrane vesicles called autophagosomes and ultimately fused to lysosomes for degradation of sequestered components. The multi-step nature of the process offers multiple regulation points prone to be deregulated and cause different human disease, but also offers multiple targetable points for designing therapeutic strategies. Cancer cells have evolved to use autophagy as an adaptive mechanism to survive under extremely stressful conditions within tumor microenvironment, but also to increase invasiveness and resistance to anti-cancer drugs such as chemotherapy. This review collects all clinical evidences of autophagy deregulation during cholangiocarcinogenesis together with all pre-clinical reports evaluating compounds that modulate autophagy to induce cholangiocarcinoma (CCA) cell death. Altogether, experimental data suggests an impairment of autophagy during initial steps of CCA development and increased expression of autophagy markers on established tumors and in invasive phenotypes. Pre-clinical efficacy of autophagy modulators promoting CCA cell death, reducing invasiveness capacity and resensitizing CCA cells to chemotherapy open novel therapeutic avenues to design more specific and efficient strategies to treat this aggressive cancer

Previously, we demonstrated that IR triggers the invasion/migration of A549 cells via activation of an EGFR–p38/ERK–STAT3/CREB-1–EMT pathway. Here, we have demonstrated the involvement of a novel intracellular signaling mechanism in γ-ionizing radiation (IR)-induced migration/invasion. Expression of receptor-interacting protein (RIP) 1 was initially increased upon exposure of A549, a non-small cell lung cancer (NSCLC) cell line, to IR. IR-induced RIP1 is located downstream of EGFR and involved in the expression/activity of matrix metalloproteases (MMP-2 and MMP-9) and vimentin, suggesting a role in epithelial-mesenchymal transition (EMT). Our experiments showed that IR-induced RIP1 sequentially induces Src-STAT3-EMT to promote invasion/migration. Inhibition of RIP1 kinase activity and expression blocked induction of EMT by IR and suppressed the levels and activities of MMP-2, MMP-9, and vimentin. IR-induced RIP1 activation was additionally associated with stimulation of the transcriptional factor NF-κB. Specifically, exposure to IR triggered NF-κB activation and inhibition of NF-κB suppressed IR-induced RIP1 expression followed by a decrease in invasion/migration as well as EMT. Based on the collective results, we propose that IR concomitantly activates EGFR and NF-κB and subsequently triggers the RIP1–Src/STAT3–EMT pathway, ultimately promoting metastasis.

Abstract: Cancer survivors are at an increased risk for cardiovascular disease (CVD). However, the association between particulate matter (PM) and CVD risk among cancer survivors (alive >5 years since diagnosis) is unclear. We investigated the risk of CVD among 40,899 cancer survivors within the Korean National Health Insurance Service database. Exposure to PM was determined by assessing yearly average PM levels obtained from the Air Korea database from 2008 to 2011. PMs with sizes <2.5 (PM2.5), <10 (PM10), or 2.5-10 (PM2.5-10) μm in diameter were compared, with each PM level exposure further divided into quintiles. Patients were followed up from January 2012 to date of CVD event, death, or December 2017, whichever came earliest. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for CVD were calculated using Cox proportional hazards regression by PM exposure levels. Compared with cancer survivors in the lowest quintile of PM2.5 exposure, those within the highest quintile had a greater risk for CVD (aHR 1.31, 95% CI 1.07-1.59). Conversely, increasing PM10 and PM2.5-10 levels were not associated with increased CVD risk (p for trend 0.078 and 0.361, respectively). Cancer survivors who reduce PM2.5 exposure may reduce their risk of developing CVD.

Patient derived model systems are important tools for studying novel anti-cancer therapies. Patient derived xenografts (PDXs) have gained favor over the last 10 years as newer mouse strains have improved the success rate of establishing PDXs from patient biopsies. PDXs can be engrafted from head and neck cancer (HNC) samples across a wide range of cancer stages, retain the genetic features of their human source, and can be treated with both chemotherapy and radiation, allowing for clinically relevant studies. Not only do PDXs allow for study of patient tissues in an in vivo model, they can also provide a renewable source of cancer cells for organoid cultures. Herein, we review the uses of HNC patient derived models for radiation research including approaches to establishing both orthotopic and heterotopic PDXs, approaches and potential pitfalls to delivering chemotherapy and radiation to these animal models, biological advantages and limitations, and alternatives to animal studies that still use patient-derived tissues.

Mammary neoplasms affect a population of intact and elderly female dogs and 50% of these neoplasms are malignant. In order to study this disease, cell culture is as a promising preclinical model, creating the opportunity to deposit cell lines at a cell bank, allowing a great reproducibility of the assays and making the validation of the results more reliable. Another important aspect is the possibility to establish models for the better understanding of tumour characteristics, such as vasculogenic mimicry. VM is related to cancer cells able to generate vascular-like structures from epithelial cells, mimicking the vasculogenic process and it is closely related to patient’s prognosis. Due the importance of cancer cell lines in preclinical models, this study aimed to establish and characterize ten cell lines from canine mammary gland tumours according to immunophenotype and tumorigenicity, and with its ability to form vasculogenic mimicry-like structures in vitro and in vivo. Cell cultures were evaluated for morphology, phenotype, vasculogenic mimicry and tumorigenicity abilities. All cell lines presented spindle shape morphology and expressed concomitant pan-cytokeratin and cytokeratin 8/18. Four cell lines had vasculogenic mimicry ability in vitro and two of them showed in vivo tumorigenic potential and forming VM in the xenotransplant tumour. Cell characterization of those lines will help to create a database for more knowledge of mammary carcinomas in dogs, including studies of tumor behavior and new therapeutic targets.

Background: Lung cancer is one of the leading causes of morbidity and mortality worldwide with 25% of deaths due to lung cancer occurring in Europe. This study therefore sought to assess the burden of lung cancer by country and to evaluate the magnitude of fine Particulate Matter (PM2.5) and cigarette smoking by country in Europe. Methods: An ecological study nested on the World Health Organization air pollution database 2016 was conducted. We sampled 30 European Countries, with a total of 1625 mean annual samples of Particulate Matter (PM2.5) collected from 1625 designated sites (n = 1625). We further used the ‘World Health Disease Rankings’ database to extract Lung Cancer Morbidity and Mortality Rate by country. We used SAS version 9.4 to indicate the distribution of PM2.5 and Lung Cancer Mortality Rate. Results: Lung cancer Relative Risk (RR) was 1.0 in all never- smokers. RR for Ex-smokers for Adeno carcinoma was 3.5 in males and 1.1 in females, small cell carcinoma was 16.2 in males and 3.8 in females. RR for current smokers for Adeno carcinoma was 8.0 in males and 4.1 in females, small cell carcinoma was 57.9 in males and 18.2 in females. Mean annual PM2.5 by country ranged from 6.01 to 37.28µg/m3 whereas lung cancer mortality rate by country ranged from 19.67 to 54.26 deaths per 100,000 population. Conclusion: Cigarette smoking and exposure to both second hand smoke and high concentration of PM2.5 resulted into increased burden of lung cancer in Europe. Countries should re-strategize to reduce the burden of lung cancer in Europe.

Imatinib became the standard treatment for chronic myeloid leukemia (CML) about 20 years ago, which was a major breakthrough in stabilizing the pathology and improving the quality of life of patients. However, the emergence of resistance to imatinib and other tyrosine kinase inhibitors leads researchers to characterize new therapeutic targets. Several studies have highlighted the role of histone deacetylase 6 (HDAC6) in various pathologies, including cancer. This protein effectively intervenes in cellular activities by its primarily cytoplasmic localization. In this review, we will discuss the molecular characteristics of the HDAC6 protein, as well as its overexpression in CML leukemic stem cells, which make it a promising therapeutic target for the treatment of CML.

Thoracotomy is one of the most painful types of incision a patient can experience. Pain is a very complex pathophysiological entity. Neuronal pathophysiological mechanisms are integrated with the immunological response, which amplify inflammation and pain. Prolonged inflammation induces a pathological response of the immune-system and constantly stimulate the nociceptive pathways generating chronic pain. The mechanisms are particularly altered in lymphomas, where pain following chest surgery often becomes chronic and reduces the quality of life. In this study 51 elderly patients who had undergone a transthoracic biopsy to verify the suspect of mediastinal lymphoma were examined for pain reduction with oral opioids, effect of epidural analgesia and paravertebral block. Subsequently, patients underwent tensed torsion exercises, progressively intensified. After the first few days, patients walked progressively for 20 minutes a day. Once discharged a program of patients started aerobic exercises to increase muscle endurance and to strengthen the extensor muscles of the legs and of the upper limbs. The systemic administration of opioids is the simplest and most common method of providing analgesia for postoperative pain, but early mobilization, respiratory rehabilitation, and muscle toning exercises are excellent support devices both for physical and psychological recovery.

The incidence of post transplantation lymphoproliferative disorders (PTLDs) and other neoplasms in organ transplant patients is higher than in the non-transplanted population. This event is more frequent in older subjects, due, at least in part, to the immune dysfunction induced by immunosuppressants administered to prevent rejection. Alterations of the immune system mechanisms of protection against carcinogenesis appear to be the key role in the in the pathogenesis of these neoplasms. The data of our study on the incidence of neoplasms occurred during a long-term follow-up in an elderly population after they underwent cardiac transplantation. This study gives, also evidence of the favorable effect of physical activity programs on cardiorespiratory and psychomotor function.

PcALCL mainly concerns elderly patients. It is a large CD30+ T-cell neoplasm composed of large cells with anaplastic, pleomorphic or immunoblastic morphology, with exclusively cutaneous onset and localization. The clinical course of pcALCL is predominantly indolent. Most elderly patients with lymphoma tend to have a sedentary lifestyle, which has a negative effect on their quality of life (QoL) and on their survival. Several studies indicate that exercise has a positive impact on QoL because it reduces peak oxygen consumption, improves physical capacity, increases self-esteem, reduces accumulated stress and promotes relaxation. Therefore, particularly in indolent lymphomas, it is necessary to indicate a program of physical activity to be practiced systematically. The complete surgical excision and local radiotherapy are the first line gold standard in pcALCL with solitary lesion.

The incidence of cancer in organ transplant patients is higher than in the non-transplanted population. The incidence increases with increasing age. The use of Fludeoxyglucose positron emission tomography/CT (PET/CT) is sensitive and specific to detect PTLD LD compared with conventional CT imaging. We analyzed the medical data of 127 patients aged over 60 years, who underwent heart transplantation in the above period, who have been practicing early CT-PET for diagnostic purposes between February 2007 and October 2018. Of 127 consecutive patients who underwent CT-PET, SUVs up than 4, were found in 84 patients of which 20 were affected by PTLDs, seven patients were affected by chronic non neoplastic inflammatory diseases, the remainder were affected by other neoplasms. The favorable effect of physical activity programs on cardiorespiratory and psychomotor function occur in all patients. In conclusion, CT-PET at the first doubts about the possibility of the development of neoplasms has allowed a diagnosis and then a treatment more quickly. Education in behavioral norms that improve the patient's quality of life is necessary.

Cancer risk is known to increase tremendously when the immune system is suppressed, e.g., as observed in young organ-transplant recipients and AIDS patients. Based on such data, it may be hypothesized that the main reason for the development of clinical cancer is the weakening or suppression of the immune system, and that uncontrolled multiplication of cancer cells occurs when some aspects of the immune system fall below certain critical levels. Therefore, cancer may be prevented and treated by boosting these critical aspects of the immune system so that they are maintained above the critical levels. If multiple immune system boosting interventions are utilized, more aspects of the immune system would be boosted, increasing the likelihood of enhancing the critical aspects of the immune system and generating a cancer preventive and/or therapeutic effect. Clinical trials are needed to validate this approach for cancer prevention and treatment. If validated, the proposed approach could result in a major reduction of the death and suffering caused by cancer in the world.

Background: Pancreatic invasive ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality in Japan. The early diagnosis of pancreatic cancer, which will increase the number of patients with resectable tumors, is urgently needed. The purpose of the present study was to examine the earliest signs of pancreatic abnormalities on CT in order to facilitate the diagnosis and treatment of PDAC. Methods: Forty-one patients with pancreatic cancer and their 154 CTs were selected for the present study. We used the images that were acquired prior to the diagnosis and examined the pancreas in these images to observe serial changes in the morphology of the pancreas after selecting CT images in which PDAC was suspected. We also confirmed whether the main pancreatic duct was observed around that area of the pancreas. Four thousand two hundred seventy-seven patients without pancreato-biliary disease with 4630 CTs were selected for the control group. Results: Two pancreas shapes were detected: localized constriction of the pancreatic parenchyma referred to as the K-shaped sign, and localized fatty changes. Twenty-four (58.5%) of 41 patients showed the K-shaped sign. The main pancreatic duct without dilatation was noted around the K-shaped sign in 9 of the 24 patients. Eight of 41 patients (19.5%) showed localized fatty changes. Nine of 41 patients (21.9%) showed no abnormality. In the control group, only seven of 4277 patients (0.16%) showed the K-shaped sign. Conclusions: The K-shaped sign including localized fatty changes is the earliest CT sign that presents with pancreatic abnormalities. The K-shaped sign does not indicate PDAC itself but may predict its future development.

Background: This retrospective study evaluates the survival effects of metronomic maintenance therapy with fluoropyrimidine in patients with stage III colorectal cancer (CRC) according to epidermal growth factor receptor (EGFR) expression. Methods: We enrolled 197 patients with stage III CRC who had undergone radical resection and FOLFOX regimen adjuvant chemotherapy. The clinicopathological features and effects of metronomic maintenance therapy on survival according to treatment group and EGFR expression were analyzed. By conducting an in vitro cell line study and in vivo study through knockdout of EGFR gene, we analyzed the capacities of cell proliferation and migration. Results: Postoperative relapse and mortality were significantly more common in the FOLFOX group. Metronomic maintenance therapy was a significantly independent predictive factor of postoperative relapse and mortality, as well as a prognostic factor of disease-free survival and overall survival. The significant differences of survival between the two groups were only observed in patients with positive EGFR expression. Conclusions: The present study suggested EGFR expression as the prognostic factor in patients with stage III CRC receiving metronomic maintenance therapy. By analyzing EGFR expression, we can identify the potential candidates with optimal survival benefit from metronomic maintenance therapy in patients with stage III CRC.

Animal-assisted interventions (AAI) are a unique class of complementary medical treatments that can improve a patient’s quality of life, both physically and psychologically. Part I of this two-paper systematic literature review series focused on the study methods and quantitative results of researchers in this field. We continue this in-depth review here in Part II by discussing the common theories associated with AAI in the context of cancer. Of all the factors at work in human-animal interactions, researchers explicitly cite compatible animal personality, physical touch, physical movement, distraction/entertainment, and increased human interaction as the mechanisms responsible for the positive clinical outcomes observed in AAI. In various combinations, these mechanisms group under broader theoretical frameworks that attempt to fully explain the AAI context as it relates to cancer care. The social support hypothesis and the conception of a human-animal bond are the most referenced overarching frameworks. The cognitive activation theory of stress, the science of unitary human beings, and the self-object hypothesis are also referenced. We briefly consider other relevant theories commonly noted in the human-animal interactions literature that have the potential to clarify aspects of cancer-related AAI. We also discuss the neurobiological transduction mechanisms needed to connect theoretical frameworks and their mechanisms directly to the observed clinical outcomes. To advance the field, researchers should consider overarching theories with testable hypotheses when designing studies, and use consistent terminology when reporting results. This review lays a foundation for progress towards a unified theoretical framework and for effective treatment of the whole cancer patient.

Animal-assisted interventions (AAI) use human-animal interactions to positive effect in various contexts including cancer care. This systematic literature review is the first part of a two-part paper series focusing on the research methods and quantitative results of AAI studies in oncology. We find methodological consistency in the use of canines as therapy animals, in the types of high-risk patients excluded from studies, and in the infection precautions taken with therapy animals throughout cancer wards. The investigated patient endpoints are not significantly affected by AAI, with the exceptions of improvements in oxygen consumption, quality of life, depression, mood, and satisfaction with therapy. The AAI field in oncology has progressed significantly since its inception and has great potential to positively impact future patient outcomes. To advance the field, AAI research in oncology should consistently improve the methodological design of studies, report data more completely, and focus on the therapy animal’s well-being.

In Taiwan, colorectal cancer is ranked second and third in terms of mortality and cancer incidence, respectively. In addition, medical expenditures related to colorectal cancer are considered to be the third highest. While advances in treatment strategies have provided cancer patients with longer survival, potentially harmful second primary cancers can occur. Therefore, second primary colorectal cancer analysis is an important issue with regard to clinical management. In this study, a novel predictive scheme was developed for predicting the risk factors associated with second colorectal cancer in patients with colorectal cancer by integrating five data mining classification techniques, including support vector machine, random forest, multivariate adaptive regression splines, extreme learning machine, and extreme gradient boosting. In total, 4,287 patients in the datasets provided by three hospital tumor registries were used. Our empirical results revealed that this proposed predictive scheme provided promising classification results and the identification of important risk factors for predicting second colorectal cancer based on accuracy, sensitivity, specificity, and area under the curve metrics. Collectively, our clinical findings suggested that the most important risk factors were the combined stage, age at diagnosis, BMI, surgical margins of the primary site, tumor size, sex, regional lymph nodes positive, grade/differentiation, primary site, and drinking behavior. Accordingly, these risk factors should be monitored for the early detection of second primary tumors in order to improve treatment and intervention strategies.

This study aimed to rank cancers by the strength of relationship between comprehensive mRNA expression of the most harmful or protective genes and patient survival. Using TCGA dataset including RNA-SEQ and clinical data, we investigated not only gene specific prognostic availability, but also comprehensive prognostic availability of prognostic genes filtered by cox coefficient, and ranked cancers by specially designed prognostic indicator. Through Kaplan-Meier plots, we checked that cancers vary in the strength of influence of prognostic genes, and they follow as the rank. Developing treatment with method to reduce or increase expression of biomarkers for specific cancer which ranked bottom, it would be not efficient in high probability. The results of this study can be a scientific evidence for that.

Mammary neoplasms affect a population of uncastrated and elderly female dogs and most of these neoplasms are malignant. In order to study this disease cell culture presents itself as a promising preclinical model, creating the opportunity to deposit cell lines at a cell bank, allowing a great repetition of the assays and making the validation of the results more reliable. Including, in vitro experiments for vasculogenic mimicry (VM) evaluation. VM is related to cancer cells capable of generate vascular-like structures without endothelial cells, mimicking the vasculogenic process. The aim of this study was to establish and characterize ten cell lines from canine mammary gland tumour according to immunophenotype and tumorigenicity, and with its ability to form vasculogenic mimicry-like structures in vitro. Fifteen samples from canine mammary gland carcinoma were collected and cultured in vitro and ten cell lines were established and characterized. Cells were evaluated for morphology, phenotype, vascular mimicry and tumorigenicity. All cell lines presented spindle shape morphology and expressed concomitant pan-cytokeratin and CK8/18. Four cell lines had vasculogenic mimicry ability and two cell showed in vivo tumorigenic potential. Cell characterization of those lines will help to create a database for more knowledge of mammary gland carcinomas in dogs, including studies of tumor behavior and new therapeutic targets.

Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem tumor with a 5-year survival of <1%. Up to 80% of DIPG tumors contain a specific K27M mutation in one of two genes encoding histone H3 (H3K27M). Furthermore, p53 mutations found in >70-80% of H3K27M DIPG, and mutant p53 status is associated with a decreased response to radiation treatment and worse overall prognosis. Recent evidence indicates that H3K27M mutation disrupts tri-methylation at H3K27 leading to aberrant gene expression. Jumonji family histone demethylases collaborates with H3K27 mutation in DIPG by erasing H3K27 trimethylation and thus contributing to derepression of genes involved in tumorigenesis. Since the first line treatment for pediatric DIPG is fractionated radiation, we investigated the effects of Jumonji demethylase inhibition with GSK-J4, and mutant p53 targeting/oxidative stress induction with APR-246, on radio-sensitization of human H3K27M DIPG cells. Both APR-246 and GSK-J4 displayed growth inhibitory effects as single agents in H3K27M DIPG cells. Furthermore, both of these agents elicited mild radiosensitizing effects in human DIPG cells (sensitizer enhancement ratios (SERs) of 1.12 and 1.35, respectively; p<0.05). Strikingly, a combination of APR-246 and GSK-J4 displayed a significant enhancement of radiosensitization, with SER of 1.50 (p<0.05) at sub-micro-molar concentrations of the drugs (0.5 μM). The molecular mechanism of the observed radiosensitization appears to involve DNA damage repair deficiency triggered by APR-246/GSK-J4, leading to the induction of apoptotic cell death. Thus, a therapeutic approach of combined targeting of mutant p53, oxidative stress induction, and Jumonji demethylase inhibition with radiation in DIPG warrants further investigation.

The aim of the following paper was to determine the influence of soft tissue therapy on respiratory efficiency and chest mobility of women suffering from breast cancer. This study was a controlled randomized trial. Tests were carried out in a group of patients (n=49), who were hospitalized in the Province Polyclinic Hospital, Konin, Poland. In the study group, irrespective of the standard physical therapy program, an additional therapy program was run. The program consisted in applying specific techniques of soft tissue treatment. All patients in the each term were subject to pulmonary function test, chest mobility and pain assessment. Statistical analysis of the obtained results of spirometry and chest mobility assessment have revealed no differences in the analyzed parameters between the examined groups in the period of joint therapeutic treatment. In the period between the 3rd examination and the end of the 11-month- rehabilitation treatment, statistically significant differences were observed in the analyzed spirometry parameters, however, there was no difference in the parameters describing airflow in small airways (MEF₅₀,PEF) between individual groups, during consecutive examinations in the course of diversified therapeutic treatment. Chest mobility assessment of the patients, performed during diversified therapeutic treatment, revealed statistically significant differences between the groups. However, there was no difference between the examined groups, as far as pain sensation is concerned. Enhancing the regular rehabilitation program by including additional therapeutic methods, which are based on myofascial release and post-isometric relaxation techniques, had a beneficial effects regarding respiratory system efficiency.

Breast cancer is the most common cause of death for women worldwide. Thus, the ability of artificial intelligence systems to predict and classify breast cancer is very important. In this paper, a hybrid ensemble method classification mechanism is proposed based on a majority voting mechanism. First, the performance of different state-of-the-art machine learning classification algorithms for the Wisconsin Breast Cancer Dataset (WBCD) were evaluated. The three best classifiers were then selected based on their F3 score. F3 score is used to emphasize the importance of false negatives (recall) in breast cancer classification. Then, these three classifiers, simple logistic Regression learning, stochastic gradient descent learning and multilayer perceptron network, are used for ensemble classification using a voting mechanism. We also evaluated the performance of hard and soft voting mechanism. For hard voting, majority-based voting mechanism was used and for soft voting we used average of probabilities, product of probabilities, maximum of probabilities and minimum of probabilities-based voting methods. The hard voting (majority-based voting) mechanism shows better performance with 99.42% as compared to the state-of-the-art algorithm for WBCD.

We examined special roles of the Central Nervous System (CNS) in an attempt to resolve the puzzle that chronic diseases cannot be cured by medicine. By exploring a skill-learning model, we found that the CNS is able to remember certain information reflecting biochemical and cellular (B&C) processes in the body. From the skill using ability, we found that the CNS is able to control basic B&C processes that drive and power the skill. From the ability to adjust forces and force direction of a physical act, we found that the CNS is able to adjust B&C processes that drive the physical act. From this adjustment capability, we further inferred that the CNS must also store information on the baseline B&C processes. As a whole, we found that the CNS can maintain information on baseline B&C processes, up-regulate or down-regulate the processes, and make comparisons in performing its regulatory functions. We found that chronic diseases are the results of deviated baseline B&C processes. Per the proved hypothesis, the CNS maintains deviated baseline B&C processes, and thus protects the body states of fully developed diseases. We then used the three CNS roles to explain that cancer progresses with increasing malignancy, cancer quickly returns after a surgery, cancer cells repopulate after chemotherapy and radiotherapy, cancer develops drug resistance inevitably, immune cells rebound after suppression, generally poor benefits of cancer drugs such as beta-blockers, etc. We further showed that long-term exercises generally push most, if not all, baseline B&C processes in diametrical opposing directions against the diseased B&C processes, implying that exercises play unique roles in reversing chronic diseases. Finally, we proposed several strategical approaches to resetting the CNS’ state memory as the essential condition for curing chronic diseases.

After reviewing cancer theories, cancer treatment development histories, randomized clinical trial's performance, cancer treatment strategy, trial follow-up times, and conducting numerous simulations using existing data, the authors found: (1) medical treatments come with three to four lethal factors: treatment side-effects, emotional distress and chronic dress, lack of exercises or physical inactivity, and excessive nutrition in some cases; (2) clinical trial exaggerates the benefits of fast-acting treatments and underestimates the slow-delivering adverse side effects as a result of statistical averaging, interfering effects of personal lifestyle factors, and insufficient follow-up times; (3) the benefits of medical treatments are limited by chain comparison, where surgery sets up a negative standard relative to the best way for resolving cancer; (4) the strategy of destroying the tumor is unworkable; (5) medical treatments can turn natural cancer growth curve into approximately doubly exponential curve; (6) multiple factor non-medical measures are much more powerful than medical treatments in controlling cancer growth and metastasis rates; and (7) cancer early diagnosis and over treatments are bad strategies that have great adverse impacts on cancer patients. Based on huge increases in cancer growth rate constants, substantial of loss of organ functional capacity, and severe systemic aging-like cellular damages, the authors concluded that medical treatments promote cancer growth and metastasis rates and shorten patient lives in most cases, and the claimed benefits are caused by triple biases of clinical trials. The authors believe that the better strategy for ending the global cancer epidemic is abandoning clinical trails as the research model, changing caner treatment strategy from killing cancer cells to slowing down cancer growth rates by using multiple factors optimization approach in personalized medicine.

BRCA-associated hereditary breast and ovarian cancer syndrome (HBOC) implies increased absolute risk also for other malignancies such as cholangiocarcinoma (CCA). However, even if somatic mutations in CCA have been reported, there are no data on its utilization as predisposing genetic factor in a family. For the first time, we utilized CCA somatic BRCA mutation to individualize a family with HBOC. A 47-year-old woman (daughter of a patient died for CCA) accessed to our Genetic Councelling to evaluate her personal cancer risk. We performed a somatic BRCA1/2 NGS analysis on DNA extracted from formalin-fixed, paraffin-embedded CCA-tissue of her mother. After demonstration of pathogenic variant c.6468_6469delTC in BRCA2 gene mutation, the same germline pathogenic variant was found in DNA blood of one of two daugthers. So far, CCA tissue can be utilized, in addition to patient’s selection to specific therapeutic strategies, also to individualize families belonging to HBOC syndrome.

The purpose of this prospective study was to evaluate the usefulness of interstitial magnetic resonance lymphography (MRL) with superparamagnetic iron oxide (SPIO) in sentinel lymph node (SLN) mapping of clinically N0 early oral cancer, and to conduct a comparative study of this MRL with computed tomography lymphography (CTL). CTL and MRL was performed for SLN mapping before surgery for 24 patients with clinically N0 early oral cancer. SLNs were detected by CTL in 21 (87.5%) patients, and the total and mean number of SLN were 45 and 1.9, respectively. All SLNs could be detected 2 min and 3.5-5 min after contrast medium injection. In all patients, SLNs were detected by MRL at 10 min after SPIO injection, and the total and mean number of SLN was 66 and 2.8, respectively. MRL at 30 min after the injection showed additional 2 secondary lymph nodes. Interstitial MRL with SPIO is safe and useful imaging for detection of SLNs in clinically N0 early oral cancer, and the optimal imaging timing is 10 min after SPIO injection.

Incident rates of neurodegenerative diseases have steadily increased globally, but there is no therapeutic access available. We newly prescribed medicinal herbal remedy including five different herbal plants called, Chen-Ma-Dan-Sam-Ga-Mi-Bang (CMST), purposed to prove for pharmacological properties and corresponded actions on hippocampus neuronal cell injury by hypoxia-induced mice model. Mice were adapted to normoxia or hypoxia with or without CMST for 5 days. We gathered pharmacological effects of CMST on cell injury by enhancement of dihydroethidium and 4-hydroxynonenal signals which were correlated with abnormal redox status in the protein or gene expression levels (abnormal elevations of nitric oxide, reactive oxygen species, lipid peroxidation and deteriorations of total glutathione, total antioxidant capacity, and activities of superoxide dismutase and catalase) due to hypoxia. CMST also notably exerted to attenuates molecules for neuronal cell injury markers such as p-tau, cleaved caspase-3 due to DNA oxidations (53bp1and phosphor-histone H2AX), inflammatory cytokines, and hemeoxigenase-1. We further figured out the underlying actions of CMST by in vitro experiment through inactivation of microglial cell which can mediate neuronal cell injury. Collectively, CMST prevented from hippocampal neuronal cells via inactivation of microglial cell with normalization of redox status on hypoxia-induced hippocampus neuronal cell injury.

In comparison to other human cancer types, malignant melanoma exhibits the greatest amount of heterogeneity. After DNA-based detection of the BRAF V600E mutation in melanoma patients, targeted inhibitor treatment is the current recommendation. This approach, however, does not take the abundance of the therapeutic target, i.e., the B-raf V600E protein, into consideration. As shown by immunohistochemistry, the protein expression profiles of metastatic melanomas do clearly reveal the existence of inter- and intra-tumor variability. Nevertheless, the technique is only semi-quantitative. To quantitate the mutant protein there is a fundamental need for more precise techniques that are aimed at defining the currently non-existent link between the levels of the target protein and subsequent drug efficacy. Using cutting-edge mass spectrometry combined with DNA and mRNA sequencing, the mutated B-raf protein within metastatic tumors was quantitated for the first time. B-raf V600E protein analysis revealed a subjacent layer of heterogeneity for mutation-positive metastatic melanomas. These were characterized into two distinct groups with different tumor morphologies, protein profiles and patient clinical outcomes. This study provides evidence that a higher level of expression for the mutated protein is associated with a more aggressive tumor progression. Our study design that is comprised of surgical isolation of tumors, histopathological characterization, tissue biobanking, and protein analysis may enable the eventual delineation of patient responders/non-responders and the subsequent therapy of malignant melanoma.

Gold nanoparticles (GNPs) have demonstrated significant dose enhancement with kilovoltage (kV) X-rays however recent studies have shown inconsistent findings with megavoltage (MV) X-rays. We proposed to evaluate the radiosensitization effect in U87 glioblastoma (GBM) cells in the presence of 42 nm GNPs and irradiated with a clinical 6 MV photon beam. Cytotoxicity and radiosensitization was observed using MTS and clonogenic cellular radiation sensitivity assays respectively. Sensitization enhancement ratio was calculated for 2 Gy (SER2Gy) with GNP (100 μg/mL). Dark field and MTS assay revealed high co-localization and good biocompatibility of the GNPs with GBM cells. Significant sensitization enhancement of 1.45 (P = 0.001) was observed with GNP 100 μg/mL. Similarly, at 6 Gy there was significant difference in the survival fraction between GBM alone group (Mean (M) = 0.26, Standard Deviation (SD) = 0.008) and GBM plus GNP group (M = 0.07, SD = 0.05, P = 0.03). GNPs enable radiosensitization in U87 GBM cells at 2 Gy when irradiated using a clinical platform. In addition to the potential clinical utility of GNPs, these studies demonstrate the effectiveness of a robust and easy to standardise in-vitro model that can be employed for future studies involving metal nanoparticle plus irradiation.

The nuclear receptor superfamily comprises a large group of proteins with functions essential for cell signaling, survival and proliferation. There are multiple distinctions between nuclear superfamily classes defined by hallmark differences in function, ligand binding, tissue specificity, and DNA binding. In this review, we utilize the initial classification system, which defines subfamilies based on structure and functional difference. The defining feature of the nuclear receptor superfamily is that these proteins function as transcription factors. The loss of transcriptional regulation or gain of functioning of these receptors is a hallmark in numerous diseases. For example, in prostate cancer the androgen receptor is a primary target for current prostate cancer therapies. Targeted cancer therapies for nuclear hormone receptors have been more feasible than others to develop due to ligand availability and cell permeability of hormones. To better target these receptors, it is critical to understand their structural and functional regulation. Given that late-stage cancers often develop hormone insensitivity, we will explore the strengths and pitfalls of targeting other transcription factors outside of the nuclear receptor superfamily such as the signal transducer and activator of transcription (STAT).

Glioblastoma (GBM) is the most lethal form of brain tumor, characterized by rapid growth and surrounding tissue invasion. The current standard treatment is surgery followed by radiotherapy, and concurrent chemotherapy, typically with temozolomide. Although extensive research has been performed over the past years to develop an effective therapeutic strategy for the treatment of GBM, efforts have not provided major improvements in the overall survival of patients with GBM. Thus, new therapeutic approaches are urgently needed. A major challenge in the development of therapies for central nervous system (CNS) disorders is overcoming the blood–brain barrier (BBB). In this context, the intranasal (IN) route of drug administration has been proposed as a non-invasive alternative route to directly targeting the CNS. In fact, this route of drug administration may bypass the blood-brain barrier and reduce systemic side effects. Recently, formulations have been developed to further enhance nose-to-brain transport, mainly with the use of nano-sized and nanostructured drug delivery systems. The focus of this review will be on the strategies developed to deliver a number of anticancer compounds for the treatment of GBM using the nasal administration. In particular, the specific properties of nanomedicines proposed for the nose-to-brain delivery will be critically evaluated. The number of preclinical and clinical data reviewed support the idea that nasal delivery of anticancer drugs might represent a breakthrough advancement in the fight against GBM.

PDEF is expressed in luminal epithelial cells of the prostate gland and associates with luminal phenotype. Hippo pathway regulates cell growth/proliferation, cellular homeostasis, and organ development by modulating phosphorylation of its downstream effectors. In previous studies, we observed decreased levels of PDEF during prostate cancer progression. In the present studies, we evaluated the effects of PDEF on total and phospho (Ser-127)YAP1 protein(a downstream effector of the Hippo pathway) levels in PC3 cells, a line of castrate resistant prostate cancer. We observed that the expression of PDEF in PC3 cells resulted in increased increased phospho(Ser127) -YAP1 protein levels. Our immunofluorescence analysis for YAP1 revealed an increased cytoplasmic/nuclear ratio of YAP1 in PDEF-PC3 cells as compared to VC-PC3 cells, suggesting PDEF may play a critical role in modulating YAP1 phosphorylation, and by extension in the regulation of the Hippo pathway. We also observed a decrease in YAP1 protein levels in prostate cancer tissues as compared to normal prostate tissues. Our analysis of multiple publicly available clinical cohorts revealed a gradual decrease in YAP1 mRNA expression during prostate cancer progression and metastasis. This decrease was similar to the decrease in PDEF levels which we reported earlier. In addition we observed further decreased in PDEF and YAP1 expression in Neuro-Endocrine Prostate Cancer (NEPC), and a direct correlation between PDEF and YAP1 expression. To the best of our knowledge, these results provide the first demonstration of modulation of YAP1 by PDEF in any system and suggest a cross-talk between PDEF and the Hippo pathway.

Cancer stem cells (CSCs) have been identified in many cancer types. This study identified and characterized CSCs in head and neck metastatic malignant melanoma (HNmMM) to regional lymph nodes using induced pluripotent stem cell (iPSC) markers. Immunohistochemical (IHC) staining performed on 20 HNmMM tissue samples demonstrated expression of iPSC markers OCT4, SOX2, KLF4 and c-MYC in all samples while NANOG was expressed at low levels in two samples. Immunofluorescence (IF) staining demonstrated an OCT4+/SOX2+/KLF4+/c-MYC+ CSC subpopulation within the tumor nests (TNs) and another within the peritumoral stroma (PTS) of HNmMM tissues. IF also showed expression of NANOG by some OCT4+/SOX2+/KLF4+/c-MYC+ cells within the TNs in an HNmMM tissue sample that expressed NANOG on IHC staining. In situ hybridization (n=6) and reverse-transcription quantitative polymerase chain reaction (n=5) on the HNmMM samples confirmed expression of all five iPSC markers. Western blotting of four primary cell lines derived from four of the 20 HNmMM tissue samples showed expression of SOX2, KLF4, and c-MYC but not OCT4 and NANOG, and three of these cell lines formed tumorspheres in vitro. We demonstrate the presence of two putative CSC subpopulations within HNmMM, which may be a novel therapeutic target in the treatment of this aggressive cancer.

Background: Glioblastomas (GBM) is generally burdened, to date, by a dismal prognosis, although Long Term Survivors have a relatively significant incidence. Our specific aim was to determine the exact impact of many surgery-, patient- and tumor-related variable on Survival parameters. Methods: The surgical, radiological and clinical outcomes of patients have been retrospectively reviewed for the present study. All the patients have been operated on in our Institution and classified according their Overall Survival in LTS (Long Term Survivors) and STS (Short Term Survivors). A thorough Review of our surgical series was conducted to compare the oncologic results of the patients in regards to 1. Surgical , 2. Molecular, and 3.Treatment related features. Results: A total of 177 patients were included in the final cohort. Extensive statistical analysis by means of univariate, multivariate and survival analyses disclosed a survival advantage for patients presenting a younger age, a smaller lesion and a better functional status at presentation. From the Histochemical point of view, Ki67(%) was the strongest predictor of better oncologic outcomes. A stepwise analysis of variance outlines the existence of 8 prognostic subgroups according to the molecular patterns of Ki67 overexpression and EGFR, p53 and IDH mutations. Conclusions: On the ground of our statistical analyses we can affirm that the following factors were significant predictors of survival advantage: KPS, Age, Volume of the lesion, Motor disorder at presentation, a Ki67 overexpression. A fine molecular profiling is feasible to precisely stratify the prognosis of GBM patients.

The use of circulating cell-free (cf) DNA to monitor cancer progression and response to therapy has significant potential but there is only limited data on whether this technique can detect the presence of low frequency subclones that may ultimately confer therapy resistance. In this study, we sought to evaluate whether whole-exome sequencing of cfDNA can accurately profile the mutation landscape of metastatic melanoma. We used whole-exome sequencing (WES) to identify variants in matched tumor-derived genomic (g) DNA and plasma-derived cfDNA isolated from a cohort of 10 metastatic cutaneous melanoma patients. WES parameters such as sequencing coverage and total sequencing reads were comparable between gDNA and cfDNA. There was significant concordance between gDNA and cfDNA based on the total number of variants identified and the degree of overlap in variants which was independent of the site of tumor biopsy. The mutant allele frequency of common single nucleotide variants was lower in cfDNA reflecting lower read depth and dilution of circulating tumor DNA in the circulation by other cfDNA species. In addition to known melanoma driver mutations, several other melanoma-associated mutations were found to be concordant between matched gDNA and cfDNA. This study highlights that WES of cfDNA can capture clinically-relevant mutations present in melanoma metastases, but does not appear to provide any additional unique information on tumor heterogeneity. Targeted deep sequencing may be required to detect low frequency genomic aberrations known for predicting therapy resistance.

Objectives: To demonstrate the efficacy of Gemtuzumab ozogamicin in refractory AML patients with organ dysfunctions and poor performance status. Three refractory AML patients with are described. One of them was pretreated by intensive chemotherapy, two other patients progressed during Azacitidine treatment. WHO performance status III . Two patients had respiratory failure grade 2, the other one suffered from acute kidney insufficiency. Two patients were highly febrile with elevated CRP level. Gemtuzumab ozogamicin administration was performed in three patients followed by further switch to Gemtuzumab ozogamicin + Azacitidine or “7+3” treatment. Results: Gemtuzumab ozogamicin administration resulted in abrupt fever cessation in two febrile patients simultaneously with CRP level decrease and fast gradual resolution of respiratory failure. Recovery of kidney function was noticed in patient with renal insufficiency. WHO performance status have elevated in all three patients. No adverse effects grade II-III were noticed. Further treatment made two patients eligible for intensive chemotherapy, one patient was transplanted, patient with kidney failure obtained complete remission. Conclusions: Gemtuzumab ozogamicin therapy appeared to be safe and highly efficacious in relapsed/refractory AML patients with organ dysfunctions and poor performance status.

Patients with glioblastoma (GB), a highly aggressive brain tumor, have a median survival of 14.6 months following neurosurgical resection with adjuvant chemoradiotherapy. Quiescent GB cancer stem cells (CSCs) invariably cause local recurrence. These GB CSCs that can be identified by embryonic stem cell markers express components of the renin-angiotensin system and are associated with circulating CSCs. Despite the presence of circulating CSCs, GB rarely develops distant metastasis outside the central nervous system. This paper reviews the current literature on GB growth inhibition in relation to CSCs, circulating CSCs, the RAS and the novel therapeutic approach by repurposing drugs that target the renin-angiotensin system to improve overall symptom-free survival and maintain quality of life.