Molecular impact of NOTCH signaling dysregulation on ovarian cancer progression, chemoresistance, and taxane response.

Patients with epithelial ovarian cancer (EOC) face high mortality due to late diagnosis, recurrence, metastasis, and drug resistance. The NOTCH signaling pathway plays a critical role in cancer progression. This study analyzed NOTCH pathway deregulation in EOC patients and its response to taxane treatment in vitro and in vivo.

Therapeutic pancreatic cancer biomarkers and pharmacogenetics.

FOLFIRINOX and gemcitabine plus nab-paclitaxel represent the most effective chemotherapy regimens for metastatic pancreatic cancer patients nowadays, but the median overall survival remains less than one year. Pharmacogenomics and the individualization of therapy represent a promising strategy, including identifying patients at increased risk of toxicity. This review summarizes contemporary knowledge about genetic variability and putative biomarkers with published associations to therapy responses of pancreatic cancer not only for gold standard treatment regimens (FOLFIRINOX, gemcitabine/nab-paclitaxel and nal-IRI/5-fluorouracil) but also for other therapeutic options regarding targeted therapy and immunotherapy.

Genetic differences between primary colorectal cancer and its paired synchronous and metachronous metastases.

As the second most deadly cancerous disease worldwide, colorectal cancer (CRC) stands in the center of scientific interest in hope to develop novel approaches for precise diagnostics and prognosis determination. Metastatic disease remains the main cause of CRC mortality. To investigate the underlying genetic differences between CRC patients with synchronous and metachronous liver metastases, we performed whole-exome sequencing of 210 patient samples using formalin-fixed paraffin-embedded samples from primary tumors and the paired liver metastatic tissue.

Functional validation of somatic variability in and for prediction of platinum sensitivity and prognosis in epithelial ovarian carcinoma patients.

Concerning the dismal prognosis of chemoresistant patients with epithelial ovarian carcinoma (EOC), we aimed to follow up the findings of a previous whole-exome sequencing study using an orthogonal Sanger sequencing on the same patients and a separate set of 127 EOC patients ( = 177, all fresh frozen tumor samples). We focused on TP53 as a frequently mutated gene relevant for chemosensitivity, included KRAS as an additional therapeutically relevant target, complemented the study with transcript levels of both genes, and compared results with clinical parameters. All variants in TP53 and KRAS detected by exome sequencing were confirmed.

Integrative miRNOMe profiling reveals the miR-195-5p-CHEK1 axis and its impact on luminal breast cancer outcomes.

The luminal subtype (estrogen receptor-positive, ER+) is the most common and the most heterogeneous type of breast carcinoma (BC) in women. During our study, we determined expression levels of all microRNAs (miRNome) in 101 ER+ BC samples and identified 25 miRNAs being associated with proliferative markers. Using comprehensive in silico analyses we prioritized CHEK1, CDC25A, and CCNE1 as candidate genes affecting the proliferation of ER+ BC, with two microRNAs from the miR-497∼195 cluster identified as their potential regulators.

Potential for Clinical Management of Pancreatic Cancer Through Whole Exome Profiling of Site-Specific Metastases and Matched Primary Tumors.

Considering the lack of molecular background of the metastatic process in pancreatic ductal adenocarcinoma (PDAC) and the fact that the location of the metastasis may carry prognostic information and potential therapeutic opportunities, we aimed to explore genomic profiles of metastases from diverse loci and their value for the patients' therapeutic management. DNA samples from paired primary and metastatic tissue of 20 patients were microdissected and sequenced using whole exome target enrichment. Somatic genetic variability, copy number variations (CNVs), and mutational signatures were assessed for associations with clinical data of patients.

The relationship of the microbiome, associated metabolites and the gut barrier with pancreatic cancer.

Pancreatic cancers have high mortality and rising incidence rates which may be related to unhealthy western-type dietary and lifestyle patterns as well as increasing body weights and obesity rates. Recent data also suggest a role for the gut microbiome in the development of pancreatic cancer. Here, we review the experimental and observational evidence for the roles of the oral, gut and intratumoural microbiomes, impaired gut barrier function and exposure to inflammatory compounds as well as metabolic dysfunction as contributors to pancreatic disease with a focus on pancreatic ductal adenocarcinoma (PDAC) initiation and progression.

A current knowledge of the undifferentiated carcinoma of the pancreas with osteoclast-like giant cells: a narrative review.

Background And Objective: Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells (UCOGC) is a rare variant of malignant pancreatic tumor. There is still no standardized treatment for this uncommon subtype, as surgical resection with lymphadenectomy is the only potentially curative treatment so far. In this paper, we describe the current knowledge of this very rare specific subtype of pancreatic cancer (PC) as a narrative review.

Synthesis, Purification, and Characterization of Molten Salt Fuel for the SALIENT-03 Irradiation Experiment.

This work presents the synthesis, purification, and characterization of a molten salt fuel for the irradiation experiment SALIENT-03 (SALt Irradiation ExperimeNT), a collaborative effort between the Nuclear Research and Consultancy Group and the Joint Research Centre, European Commission. The primary objective of the project is to investigate the corrosion behavior of selected Ni-alloy based structural materials which are being considered for the construction of fluoride molten salt reactors. During the test, these materials will be exposed to selected liquid molten fuel salts under irradiation in the High Flux Reactor in Petten, the Netherlands.

The use of patient-derived xenografts and patient-derived organoids in the search for new therapeutic regimens for pancreatic carcinoma. A review.

Patient-derived organoids (PDOs) and xenografts (PDXs) are powerful tools for personalized medicine in pancreatic cancer (PC) research. This study explores the complementary strengths of PDOs and PDXs in terms of practicality, genetic fidelity, cost, and labor considerations. Among other models like 2D cell cultures, spheroids, cancer-on-chip systems, cell line-derived xenografts (CDX), and genetically engineered mouse models (GEMMs), PDOs and PDXs uniquely balance genetic fidelity and personalized medicine potential, offering distinct advantages over the simplicity of 2D cultures and the advanced, but often resource-intensive, GEMMs and cancer-on-chip systems.

Polymorphisms within autophagy-related genes as susceptibility biomarkers for pancreatic cancer: A meta-analysis of three large European cohorts and functional characterization.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with patients having unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Given that genetic variation within autophagy-related genes influences autophagic flux and susceptibility to solid cancers, we decided to investigate whether 55,583 single nucleotide polymorphisms (SNPs) within 234 autophagy-related genes could influence the risk of developing PDAC in three large independent cohorts of European ancestry including 12,754 PDAC cases and 324,926 controls. The meta-analysis of these populations identified, for the first time, the association of the BID variant with an increased risk of developing the disease (OR = 1.

Targeted panel sequencing of pharmacogenes and oncodrivers in colorectal cancer patients reveals genes with prognostic significance.

Background: Colorectal cancer is still the second leading cause of cancer-related deaths and thus biomarkers allowing prediction of the resistance of patients to therapy and estimating their prognosis are needed. We designed a panel of 558 genes with pharmacogenomics records related to 5-fluorouracil resistance, genes important for sensitivity to other frequently used drugs, major oncodrivers, and actionable genes. We performed a target enrichment sequencing of DNA from tumors and matched blood samples of patients, and compared the results with patient prognosis stratified by systemic adjuvant chemotherapy.

Artificial Intelligence-Driven Prediction Revealed CFTR Associated with Therapy Outcome of Breast Cancer: A Feasibility Study.

Introduction: In silico tools capable of predicting the functional consequences of genomic differences between individuals, many of which are AI-driven, have been the most effective over the past two decades for non-synonymous single nucleotide variants (nsSNVs). When appropriately selected for the purpose of the study, a high predictive performance can be expected. In this feasibility study, we investigate the distribution of nsSNVs with an allele frequency below 5%.

Genes divided according to the relative position of the longest intron show increased representation in different KEGG pathways.

Despite the fact that introns mean an energy and time burden for eukaryotic cells, they play an irreplaceable role in the diversification and regulation of protein production. As a common feature of eukaryotic genomes, it has been reported that in protein-coding genes, the longest intron is usually one of the first introns. The goal of our work was to find a possible difference in the biological function of genes that fulfill this common feature compared to genes that do not.

A pleiotropy scan to discover new susceptibility loci for pancreatic ductal adenocarcinoma.

Pleiotropic variants (i.e. genetic polymorphisms influencing more than one phenotype) are often associated with cancer risk.

A Long-Term Study on the Bactericidal Effect of ZrN-Cu Nanostructured Coatings Deposited by an Industrial Physical Vapor Deposition System.

ZrN-Cu coatings containing two different amounts of Cu (~11 at.% and ~25 at.%) were deposited using an industrial physical vapor deposition (PVD) system.

Targeted DNA sequencing of high-grade serous ovarian carcinoma reveals association of TP53 mutations with platinum resistance when combined with gene expression.

High-grade serous ovarian carcinoma (HGSC) is the most common subtype of ovarian cancer and is among the most fatal gynecological malignancies worldwide, due to late diagnosis at advanced stages and frequent therapy resistance. In 47 HGSC patients, we assessed somatic and germline genetic variability of a custom panel of 144 known or suspected HGSC-related genes by high-coverage targeted DNA sequencing to identify the genetic determinants associated with resistance to platinum-based therapy. In the germline, the most mutated genes were DNAH14 (17%), RAD51B (17%), CFTR (13%), BRCA1 (11%), and RAD51 (11%).

Third-generation taxanes SB-T-121605 and SB-T-121606 are effective in pancreatic ductal adenocarcinoma.

Pancreatic cancer is a severe malignancy with increasing incidence and high mortality due to late diagnosis and low sensitivity to treatments. Search for the most appropriate drugs and therapeutic regimens is the most promising way to improve the treatment outcomes of the patients. This study aimed to compare (1) efficacy and (2) antitumor effects of conventional paclitaxel and the newly synthesized second (SB-T-1216) and third (SB-T-121605 and SB-T-121606) generation taxanes in wild type BxPC-3 and more aggressive G12V mutated Paca-44 pancreatic cancer cell line models.

Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk.

Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci.

Prognostic potential of whole exome sequencing in the clinical management of metachronous colorectal cancer liver metastases.

Background: Colorectal cancer is a highly prevalent and deadly. The most common metastatic site is the liver. We performed a whole exome sequencing analysis of a series of metachronous colorectal cancer liver metastases (mCLM) and matched non-malignant liver tissues to investigate the genomic profile of mCLM and explore associations with the patients' prognosis and therapeutic modalities.

Evaluation of human papillomavirus DNA in colorectal cancer and adjacent mucosal tissue samples.

Background: Although the role of viral agents, such as human papillomavirus (e.g. HPV16, HPV18) in colorectal cancer (CRC) has been previously investigated, results remain inconclusive.

Protein expression and localization of ABC transporters in pancreatic adenocarcinoma: Prognostic role of ABCC8.

Background: ATP-binding cassette (ABC) transporters translocate various substances across cellular membranes. Their deregulation may cause cancer drug resistance or perturbations in the supply of building blocks for cancer cells and modify patients' prognosis. This study investigated protein expression and cellular localization of the previously suggested putative prognostic biomarkers - ABCB2/TAP1, ABCC7/CFTR, ABCC8/SUR1, and ABCD4 in patients with pancreatic ductal adenocarcinoma (PDAC).

The potential of exome sequencing of paired colorectal tumors and synchronous liver metastases to improve treatment.

Tweetable abstract Sequencing exomes of synchronous and metachronous liver metastases of colorectal cancer has potential to enhance treatment, since they can have molecular profiles distinct from primary tumors.

A scan of all coding region variants of the human genome, identifies 13q12.2-rs9579139 and 15q24.1-rs2277598 as novel risk loci for pancreatic ductal adenocarcinoma.

Coding sequence variants comprise a small fraction of the germline genetic variability of the human genome. However, they often cause deleterious change in protein function and are therefore associated with pathogenic phenotypes. To identify novel pancreatic ductal adenocarcinoma (PDAC) risk loci, we carried out a complete scan of all common missense and synonymous SNPs and analysed them in a case-control study comprising four different populations, for a total of 14 538 PDAC cases and 190 657 controls.