Predicting Survival in Patients with Advanced NSCLC Treated with Atezolizumab Using Pre- and on-Treatment Prognostic Biomarkers.

Existing survival prediction models rely only on baseline or tumor kinetics data and lack machine learning integration. We introduce a novel kinetics-machine learning (kML) model that integrates baseline markers, tumor kinetics, and four on-treatment simple blood markers (albumin, C-reactive protein, lactate dehydrogenase, and neutrophils). Developed for immune-checkpoint inhibition (ICI) in non-small cell lung cancer on three phase II trials (533 patients), kML was validated on the two arms of a phase III trial (ICI and chemotherapy, 377 and 354 patients).

Cytidine Deaminase Resolves Replicative Stress and Protects Pancreatic Cancer from DNA-Targeting Drugs.

Unlabelled: Cytidine deaminase (CDA) functions in the pyrimidine salvage pathway for DNA and RNA syntheses and has been shown to protect cancer cells from deoxycytidine-based chemotherapies. In this study, we observed that CDA was overexpressed in pancreatic adenocarcinoma from patients at baseline and was essential for experimental tumor growth. Mechanistic investigations revealed that CDA localized to replication forks where it increased replication speed, improved replication fork restart efficiency, reduced endogenous replication stress, minimized DNA breaks, and regulated genetic stability during DNA replication.

Combining the antianginal drug perhexiline with chemotherapy induces complete pancreatic cancer regression .

Pancreatic ductal adenocarcinoma (PDAC) remains one of the human cancers with the poorest prognosis. Interestingly, we found that mitochondrial respiration in primary human PDAC cells depends mainly on the fatty acid oxidation (FAO) to meet basic energy requirements. Therefore, we treated PDAC cells with perhexiline, a well-recognized FAO inhibitor used in cardiac diseases.

Pancreatic ductal adenocarcinoma ubiquitination profiling reveals specific prognostic and theranostic markers.

Background: Pancreatic ductal adenocarcinoma (PDAC) has been widely studied at multiomics level. However, little is known about its specific ubiquitination, a major post-translational modification (PTM). As PTMs regulate the final function of any gene, we decided to establish the ubiquitination profiles of 60 PDAC.

Menin inhibition suppresses castration-resistant prostate cancer and enhances chemosensitivity.

Disease progression and therapeutic resistance of prostate cancer (PC) are linked to multiple molecular events that promote survival and plasticity. We previously showed that heat shock protein 27 (HSP27) acted as a driver of castration-resistant phenotype (CRPC) and developed an oligonucleotides antisense (ASO) against HSP27 with evidence of anti-cancer activity in men with CRPC. Here, we show that the tumor suppressor Menin (MEN1) is highly regulated by HSP27.

A glycosyltransferase gene signature to detect pancreatic ductal adenocarcinoma patients with poor prognosis.

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an important heterogeneity, reflected by different clinical outcomes and chemoresistance. During carcinogenesis, tumor cells display aberrant glycosylated structures, synthetized by deregulated glycosyltransferases, supporting the tumor progression. In this study, we aimed to determine whether PDAC could be stratified through their glycosyltransferase expression profiles better than the current binary classification (basal-like and classical) in order to improve detection of patients with poor prognosis.

Discovery and 3D imaging of a novel ΔNp63-expressing basal cell type in human pancreatic ducts with implications in disease.

Objective: The aggressive basal-like molecular subtype of pancreatic ductal adenocarcinoma (PDAC) harbours a ΔNp63 (p40) gene expression signature reminiscent of a basal cell type. Distinct from other epithelia with basal tumours, ΔNp63 basal cells reportedly do not exist in the normal pancreas.

Design: We evaluated ΔNp63 expression in human pancreas, chronic pancreatitis (CP) and PDAC.

Metabolomic profiling of pancreatic adenocarcinoma reveals key features driving clinical outcome and drug resistance.

Background: Although significant advances have been made recently to characterize the biology of pancreatic ductal adenocarcinoma (PDAC), more efforts are needed to improve our understanding and to face challenges related to the aggressiveness, high mortality rate and chemoresistance of this disease.

Methods: In this study, we perform the metabolomics profiling of 77 PDAC patient-derived tumor xenografts (PDTX) to investigate the relationship of metabolic profiles with overall survival (OS) in PDAC patients, tumor phenotypes and resistance to five anticancer drugs (gemcitabine, oxaliplatin, docetaxel, SN-38 and 5-Fluorouracil).

Findings: We identified a metabolic signature that was able to predict the clinical outcome of PDAC patients (p < 0.

A metagenomics investigation of carbohydrate-active enzymes along the goat and camel intestinal tract.

Studies of the digestive microbiota of ruminant animals most often focus on the bacterial diversity in the rumen or the feces of the animals, but little is known about the diversity and functions of their distal intestine. Here, the bacterial microbiota of the distal intestinal tract of two goats and two camels was investigated by metagenomics techniques. The bacterial taxonomic diversity and carbohydrate-active enzyme profile were estimated for samples taken from the small intestine, the large intestine, and the rectum of each animal.

Regulation of the positive transcriptional effect of PLZF through a non-canonical EZH2 activity.

The transcription factor PLZF (promyelocytic leukemia zinc finger protein) acts as an epigenetic regulator balancing self-renewal and differentiation of hematopoietic cells through binding to various chromatin-modifying factors. First described as a transcriptional repressor, PLZF is also associated with active transcription, although the molecular bases underlying the differences are unknown. Here, we reveal that in a hematopoietic cell line, PLZF is predominantly associated with transcribed genes.

Binding to RNA regulates Set1 function.

The Set1 family of histone H3 lysine 4 (H3K4) methyltransferases is highly conserved from yeast to human. Here we show that the Set1 complex (Set1C) directly binds RNA through the regions that comprise the double RNA recognition motifs (dRRM) and N-SET domain within Set1 and its subunit Spp1. To investigate the functional relevance of RNA binding, we performed UV RNA crosslinking (CRAC) for Set1 and RNA polymerase II in parallel with ChIP-seq experiments.

JAM-C Identifies Src Family Kinase-Activated Leukemia-Initiating Cells and Predicts Poor Prognosis in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) originates from hematopoietic stem and progenitor cells that acquire somatic mutations, leading to disease and clonogenic evolution. AML is characterized by accumulation of immature myeloid cells in the bone marrow and phenotypic cellular heterogeneity reflective of normal hematopoietic differentiation. Here, we show that JAM-C expression defines a subset of leukemic cells endowed with leukemia-initiating cell activity (LIC).

A Metagenomics Investigation of Carbohydrate-Active Enzymes along the Gastrointestinal Tract of Saudi Sheep.

The digestive microbiota of humans and of a wide range of animals has recently become amenable to in-depth studies due to the emergence of DNA-based metagenomic techniques that do not require cultivation of gut microbes. These techniques are now commonly used to explore the feces of humans and animals under the assumption that such samples are faithful proxies for the intestinal microbiota. Sheep () are ruminant animals particularly adapted to life in arid regions and in particular Najdi, Noaimi (Awassi), and Harrei (Harri) breeds that are raised in Saudi Arabia for milk and/or meat production.

[Gut microbiota and digestion of polysaccharides].

The distal gut microbiota corresponds to all the microorganisms, essentially bacteria, that reside commonly in the colon. The microbial population is characterized by a large taxonomical diversity, counting approximately a thousand distinct bacterial species for a single individual. The pace of investigations of this microbial system has greatly accelerated these last few years, fuelled by the advent of metagenomics techniques, which do not rely on bacterial cultivation, but utilize high throughput DNA sequencing.

Development and validation of a microarray for the investigation of the CAZymes encoded by the human gut microbiome.

Distal gut bacteria play a pivotal role in the digestion of dietary polysaccharides by producing a large number of carbohydrate-active enzymes (CAZymes) that the host otherwise does not produce. We report here the design of a custom microarray that we used to spot non-redundant DNA probes for more than 6,500 genes encoding glycoside hydrolases and lyases selected from 174 reference genomes from distal gut bacteria. The custom microarray was tested and validated by the hybridization of bacterial DNA extracted from the stool samples of lean, obese and anorexic individuals.

The abundance and variety of carbohydrate-active enzymes in the human gut microbiota.

Descriptions of the microbial communities that live on and in the human body have progressed at a spectacular rate over the past 5 years, fuelled primarily by highly parallel DNA-sequencing technologies and associated advances in bioinformatics, and by the expectation that understanding how to manipulate the structure and functions of our microbiota will allow us to affect health and prevent or treat diseases. Among the myriad of genes that have been identified in the human gut microbiome, those that encode carbohydrate-active enzymes (CAZymes) are of particular interest, as these enzymes are required to digest most of our complex repertoire of dietary polysaccharides. In this Analysis article, we examine the carbohydrate-digestive capacity of a simplified but representative mini-microbiome in order to highlight the abundance and variety of bacterial CAZymes that are represented in the human gut microbiota.