Immune checkpoint inhibitors as first-line treatment for brain metastases in stage IV NSCLC patients without driver mutations.

Immune checkpoint inhibitors (ICI) therapy with or without chemotherapy has been established as the first-line treatment for patients with non-oncogene addicted advanced Non-Small Cell Lung Cancer (NSCLC). Yet some clinical settings, such as the treatment sequence in patients with brain metastases, have barely been evidenced. Although ICIs cannot directly cross the blood-brain barrier (BBB), evidence suggests that BBB damage could allow ICIs into the central nervous system, or that they can have an indirect effect on the tumor immune microenvironment (TIME) and cause an anti-tumor response.

Glucose 6 phosphate dehydrogenase overexpression rescues the loss of cognition in the double transgenic APP/PS1 mouse model of Alzheimer's disease.

Mice models of Alzheimer's disease (APP/PS1) typically experience cognitive decline with age. G6PD overexpressing mice (G6PD-Tg) exhibit better protection from age-associated functional decline including improvements in metabolic and muscle functions as well as reduced frailty compared to their wild-type counterparts. Importantly G6PD-Tg mice show diminished accumulation of DNA oxidation in the brain at different ages in both males and females.

Metabolomics of Plasma in XLH Patients with Arterial Hypertension: New Insights into the Underlying Mechanisms.

X-linked hypophosphatemia (XLH) is a rare genetic disorder that increases fibroblast growth factor 23 (FGF23). XLH patients have an elevated risk of early-onset hypertension. The precise factors contributing to hypertension in XLH patients have yet to be identified.

miRNAs Related to Immune Checkpoint Inhibitor Response: A Systematic Review.

The advent of immune checkpoint inhibitors (ICIs) has represented a breakthrough in the treatment of many cancers, although a high number of patients fail to respond to ICIs, which is partially due to the ability of tumor cells to evade immune system surveillance. Non-coding microRNAs (miRNAs) have been shown to modulate the immune evasion of tumor cells, and there is thus growing interest in elucidating whether these miRNAs could be targetable or proposed as novel biomarkers for prognosis and treatment response to ICIs. We therefore performed an extensive literature analysis to evaluate the clinical utility of miRNAs with a confirmed direct relationship with treatment response to ICIs.

Sex Differences in the Efficacy of Immune Checkpoint Inhibitors in Neoadjuvant Therapy of Non-Small Cell Lung Cancer: A Meta-Analysis.

Non-small cell lung cancer (NSCLC) is one of the world's leading causes of morbidity and mortality. ICIs alone or combined with chemotherapy have become the standard first-line treatment of metastatic NSCLC. The impressive results obtained have stimulated our interest in applying these therapies in early disease stage treatments, as neoadjuvant immunotherapy has shown promising results.

Changes in lipid metabolism driven by steroid signalling modulate proteostasis in C. elegans.

Alzheimer's, Parkinson's and Huntington's diseases can be caused by mutations that enhance protein aggregation, but we still do not know enough about the molecular players of these pathways to develop treatments for these devastating diseases. Here, we screen for mutations that might enhance aggregation in Caenorhabditis elegans, to investigate the mechanisms that protect against dysregulated homeostasis. We report that the stomatin homologue UNC-1 activates neurohormonal signalling from the sulfotransferase SSU-1 in ASJ sensory/endocrine neurons.

FAMetA: a mass isotopologue-based tool for the comprehensive analysis of fatty acid metabolism.

The use of stable isotope tracers and mass spectrometry (MS) is the gold standard method for the analysis of fatty acid (FA) metabolism. Yet, current state-of-the-art tools provide limited and difficult-to-interpret information about FA biosynthetic routes. Here we present FAMetA, an R package and a web-based application (www.

Translation of a tissue epigenetic signature to circulating free DNA suggests BCAT1 as a potential noninvasive diagnostic biomarker for lung cancer.

Lung cancer patients are diagnosed at late stages when curative treatments are no longer possible; thus, molecular biomarkers for noninvasive detection are urgently needed. In this sense, we previously identified and validated an epigenetic 4-gene signature that yielded a high diagnostic performance in tissue and invasive pulmonary fluids. We analyzed DNA methylation levels using the ultrasensitive digital droplet PCR in noninvasive samples in a cohort of 83 patients.

LipidMS 3.0: an R-package and a web-based tool for LC-MS/MS data processing and lipid annotation.

Motivation: LipidMS was initially envisioned to use fragmentation rules and data-independent acquisition (DIA) for lipid annotation. However, data-dependent acquisition (DDA) remains the most widespread acquisition mode for untargeted LC-MS/MS-based lipidomics. Here, we present LipidMS 3.

Calorie restriction improves metabolic state independently of gut microbiome composition: a randomized dietary intervention trial.

Background: The gut microbiota has been suggested to play a significant role in the development of overweight and obesity. However, the effects of calorie restriction on gut microbiota of overweight and obese adults, especially over longer durations, are largely unexplored.

Methods: Here, we longitudinally analyzed the effects of intermittent calorie restriction (ICR) operationalized as the 5:2 diet versus continuous calorie restriction (CCR) on fecal microbiota of 147 overweight or obese adults in a 50-week parallel-arm randomized controlled trial, the HELENA Trial.

Prediagnostic alterations in circulating bile acid profiles in the development of hepatocellular carcinoma.

Bile acids (BAs) play different roles in cancer development. Some are carcinogenic and BA signaling is also involved in various metabolic, inflammatory and immune-related processes. The liver is the primary site of BA synthesis.

Mild Muscle Mitochondrial Fusion Distress Extends Lifespan through an Early and Systemic Metabolome Reorganization.

In a global aging population, it is important to understand the factors affecting systemic aging and lifespan. Mitohormesis, an adaptive response caused by different insults affecting the mitochondrial network, triggers a response from the nuclear genome inducing several pathways that promote longevity and metabolic health. Understanding the role of mitochondrial function during the aging process could help biomarker identification and the development of novel strategies for healthy aging.

c-MYC Triggers Lipid Remodelling During Early Somatic Cell Reprogramming to Pluripotency.

Metabolic rewiring and mitochondrial dynamics remodelling are hallmarks of cell reprogramming, but the roles of the reprogramming factors in these changes are not fully understood. Here we show that c-MYC induces biosynthesis of fatty acids and increases the rate of pentose phosphate pathway. Time-course profiling of fatty acids and complex lipids during cell reprogramming using lipidomics revealed a profound remodelling of the lipid content, as well as the saturation and length of their acyl chains, in a c-MYC-dependent manner.

Tumor Microenvironment-Derived Metabolites: A Guide to Find New Metabolic Therapeutic Targets and Biomarkers.

Metabolic reprogramming is a hallmark of cancer that enables cancer cells to grow, proliferate and survive. This metabolic rewiring is intrinsically regulated by mutations in oncogenes and tumor suppressors, but also extrinsically by tumor microenvironment factors (nutrient and oxygen availability, cell-to-cell interactions, cytokines, hormones, etc.).

Reviewing the metabolome coverage provided by LC-MS: Focus on sample preparation and chromatography-A tutorial.

Metabolomics has become an invaluable tool for both studying metabolism and biomarker discovery. The great technical advances in analytical chemistry and bioinformatics have considerably increased the number of measurable metabolites, yet an important part of the human metabolome remains uncovered. Among the various MS hyphenated techniques available, LC-MS stands out as the most used.

The Potential Role of Efficacy and Safety Evaluation of N-Acetylcysteine Administration During Liver Procurement. The NAC-400 Single Center Randomized Controlled Trial.

Background: N-acetylcysteine infusions have been widely used to reduce ischemia/reperfusion damage to the liver; however, convincing evidence of their benefits is lacking.

Objective: To perform the largest randomized controlled trial to compare the impact of N-acetylcysteine infusion during liver procurement on liver transplant outcomes.

Methods: Single center, randomized trial with patients recruited from La Fe University Hospital, Spain, from February 2012 to January 2016.

Endothelin-1-Mediated Drug Resistance in -Mutant Non-Small Cell Lung Carcinoma.

Progression on therapy in non-small cell lung carcinoma (NSCLC) is often evaluated radiographically, however, image-based evaluation of said therapies may not distinguish disease progression due to intrinsic tumor drug resistance or inefficient tumor penetration of the drugs. Here we report that the inhibition of mutated promotes the secretion of a potent vasoconstrictor, endothelin-1 (EDN1), which continues to increase as the cells become resistant with a mesenchymal phenotype. As EDN1 and its receptor (EDNR) is linked to cancer progression, EDNR-antagonists have been evaluated in several clinical trials with disappointing results.

Methods for analysis of specific DNA methylation status.

Methylation of CpG dinucleotides plays a crucial role in the regulation of gene expression and therefore in the development of different pathologies. Aberrant methylation has been associated to the majority of the diseases, including cancer, neurodegenerative, cardiovascular and autoimmune disorders. Analysis of DNA methylation patterns is crucial to understand the underlying molecular mechanism of these diseases.

A small molecule G6PD inhibitor reveals immune dependence on pentose phosphate pathway.

Glucose is catabolized by two fundamental pathways, glycolysis to make ATP and the oxidative pentose phosphate pathway to make reduced nicotinamide adenine dinucleotide phosphate (NADPH). The first step of the oxidative pentose phosphate pathway is catalyzed by the enzyme glucose-6-phosphate dehydrogenase (G6PD). Here we develop metabolite reporter and deuterium tracer assays to monitor cellular G6PD activity.

Glutamine/glutamate metabolism rewiring in reprogrammed human hepatocyte-like cells.

Human dermal fibroblasts can be reprogrammed into hepatocyte-like (HEP-L) cells by the expression of a set of transcription factors. Yet, the metabolic rewiring suffered by reprogrammed fibroblasts remains largely unknown. Here we report, using stable isotope-resolved metabolic analysis in combination with metabolomic-lipidomic approaches that HEP-L cells mirrors glutamine/glutamate metabolism in primary cultured human hepatocytes that is very different from parental human fibroblasts.

Identification of a novel synthetic lethal vulnerability in non-small cell lung cancer by co-targeting TMPRSS4 and DDR1.

Finding novel targets in non-small cell lung cancer (NSCLC) is highly needed and identification of synthetic lethality between two genes is a new approach to target NSCLC. We previously found that TMPRSS4 promotes NSCLC growth and constitutes a prognostic biomarker. Here, through large-scale analyses across 5 public databases we identified consistent co-expression between TMPRSS4 and DDR1.

Prediagnostic Plasma Bile Acid Levels and Colon Cancer Risk: A Prospective Study.

Background: Bile acids have been proposed to promote colon carcinogenesis. However, there are limited prospective data on circulating bile acid levels and colon cancer risk in humans.

Methods: Associations between prediagnostic plasma levels of 17 primary, secondary, and tertiary bile acid metabolites (conjugated and unconjugated) and colon cancer risk were evaluated in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC.

Although EGFR mutant-selective tyrosine kinase inhibitors (TKI) are clinically effective, acquired resistance can occur by reactivating ERK. We show using models of acquired EGFR TKI resistance with a mesenchymal phenotype that CXCR7, an atypical G protein-coupled receptor, activates the MAPK-ERK pathway via β-arrestin. Depletion of CXCR7 inhibited the MAPK pathway, significantly attenuated EGFR TKI resistance, and resulted in mesenchymal-to-epithelial transition.