Comprehensive histopathological analysis of gastric cancer in European and Latin America populations reveals differences in PDL1, HER2, p53 and MUC6 expression.

Introduction: Gastric cancer (GC) burden is currently evolving with regional differences associated with complex behavioural, environmental, and genetic risk factors. The LEGACy study is a Horizon 2020-funded multi-institutional research project conducted prospectively to provide comprehensive data on the tumour biological characteristics of gastroesophageal cancer from European and LATAM countries.

Material And Methods: Treatment-naïve advanced gastroesophageal adenocarcinoma patients were prospectively recruited in seven European and LATAM countries.

MMPred: a tool to predict peptide mimicry events in MHC class II recognition.

We present MMPred, a software tool that integrates epitope prediction and sequence alignment algorithms to streamline the computational analysis of molecular mimicry events in autoimmune diseases. Starting with two protein or peptide sets (e.g.

The pan-cancer landscape of aldo-keto reductase1B10 reveals that its expression is diminished in gastric cancer.

Introduction: Aldo-keto reductase 1B10 (AKR1B10) is a multifunctional enzyme, which is important in cancer development and progression, but the landscape of AKR1B10 in pan-cancers and in tumor microenvironment is unclear.

Method: This study integrated the sequencing data of 33 cancer types, including gastric cancer, from TCGA project to explored the expression pattern and genetic and epigenetic alterations of AKR1B10. The association of AKR1B10 expression with clinical progression of cancers was evaluated by Kaplan-Meier analysis; the potential role of AKR1B10 in tumor microenvironment (TME) and immune-related gene expression were analyzed by PURITY, ESTIMATE, TIMER and CIBERSORT algorithms.

Targeting Retinaldehyde Dehydrogenases to Enhance Temozolomide Therapy in Glioblastoma.

Glioblastoma (GB) is an aggressive malignant central nervous system tumor that is currently incurable. One of the main pitfalls of GB treatment is resistance to the chemotherapeutic standard of care, temozolomide (TMZ). The role of aldehyde dehydrogenases (ALDHs) in the glioma stem cell (GSC) subpopulation has been related to chemoresistance.

Aldo-keto reductase 1B10 as a Carcinogenic but Not a Prognostic Factor in Colorectal Cancer.

Colorectal cancer (CRC) is the leading cause of cancer death, but little is known about its etiopathology. Aldo-keto reductase 1B10 (AKR1B10) protein is primarily expressed in intestinal epithelial cells, but lost in colorectal cancer tissues. This study revealed that AKR1B10 may not be a prognostic but an etiological factor in colorectal tumorigenesis.

A decision support system based on artificial intelligence and systems biology for the simulation of pancreatic cancer patient status.

Oncology treatments require continuous individual adjustment based on the measurement of multiple clinical parameters. Prediction tools exploiting the patterns present in the clinical data could be used to assist decision making and ease the burden associated to the interpretation of all these parameters. The goal of this study was to predict the evolution of patients with pancreatic cancer at their next visit using information routinely recorded in health records, providing a decision-support system for clinicians.

The mechanism of macroautophagy: The movie.

This animated movie presents the mechanism of macroautophagy, hereafter autophagy, by showing the molecular features of the formation of autophagosomes, the hallmark organelle of this intracellular catabolic pathway. It is based on our current knowledge and it also illustrates how autophagosomes can recognize and eliminate selected cargoes.

The LEGACy study: a European and Latin American consortium to identify risk factors and molecular phenotypes in gastric cancer to improve prevention strategies and personalized clinical decision making globally.

Background: Gastric Cancer (GC) is the fourth most deadly cancer worldwide. Enhanced understanding of its key epidemiological and molecular drivers is urgently needed to lower the incidence and improve outcomes. Furthermore, tumor biology in European (EU) and Latin American (LATAM) countries is understudied.

Structural and biochemical evidence that ATP inhibits the cancer biomarker human aldehyde dehydrogenase 1A3.

Human aldehyde dehydrogenase (ALDH) participates in the oxidative stress response and retinoid metabolism, being involved in several diseases, including cancer, diabetes and obesity. The ALDH1A3 isoform has recently elicited wide interest because of its potential use as a cancer stem cell biomarker and drug target. We report high-resolution three-dimensional ALDH1A3 structures for the apo-enzyme, the NAD complex and a binary complex with ATP.

Expansion of the 4-(Diethylamino)benzaldehyde Scaffold to Explore the Impact on Aldehyde Dehydrogenase Activity and Antiproliferative Activity in Prostate Cancer.

Aldehyde dehydrogenases (ALDHs) are overexpressed in various tumor types including prostate cancer and considered a potential target for therapeutic intervention. 4-(Diethylamino)benzaldehyde (DEAB) has been extensively reported as a pan-inhibitor of ALDH isoforms, and here, we report on the synthesis, ALDH isoform selectivity, and cellular potencies in prostate cancer cells of 40 DEAB analogues; three analogues (, , and ) showed potent inhibitory activity against ALDH1A3, and two analogues ( and ) showed potent inhibitory activity against ALDH3A1. Significantly, 16 analogues displayed increased cytotoxicity (IC = 10-200 μM) compared with DEAB (>200 μM) against three different prostate cancer cell lines.

Perspective on the Structural Basis for Human Aldo-Keto Reductase 1B10 Inhibition.

Human aldo-keto reductase 1B10 (AKR1B10) is overexpressed in many cancer types and is involved in chemoresistance. This makes AKR1B10 to be an interesting drug target and thus many enzyme inhibitors have been investigated. High-resolution crystallographic structures of AKR1B10 with various reversible inhibitors were deeply analyzed and compared to those of analogous complexes with aldose reductase (AR).

Identification of the most vulnerable populations in the psychosocial sphere: a cross-sectional study conducted in Catalonia during the strict lockdown imposed against the COVID-19 pandemic.

Design And Objectives: A cross-sectional study to evaluate the impact of COVID-19 on the psychosocial sphere in both the general population and healthcare workers (HCWs).

Methods: The study was conducted in Catalonia (Spain) during the first wave of the COVID-19 pandemic when strict lockdown was in force. The study population included all people aged over 16 years who consented to participate in the study and completed the survey, in this case a 74-question questionnaire shared via social media using snowball sampling.

Design, Synthesis, Biological Evaluation and In Silico Study of Benzyloxybenzaldehyde Derivatives as Selective ALDH1A3 Inhibitors.

Aldehyde dehydrogenase 1A3 (ALDH1A3) has recently gained attention from researchers in the cancer field. Several studies have reported ALDH1A3 overexpression in different cancer types, which has been found to correlate with poor treatment recovery. Therefore, finding selective inhibitors against ALDH1A3 could result in new treatment options for cancer treatment.

Targeting autophagy in disease: established and new strategies.

Macroautophagy/autophagy is an evolutionarily conserved pathway responsible for clearing cytosolic aggregated proteins, damaged organelles or invading microorganisms. Dysfunctional autophagy leads to pathological accumulation of the cargo, which has been linked to a range of human diseases, including neurodegenerative diseases, infectious and autoimmune diseases and various forms of cancer. Cumulative work in animal models, application of genetic tools and pharmacologically active compounds, has suggested the potential therapeutic value of autophagy modulation in disease, as diverse as Huntington, infection, or pancreatic cancer.

CuBlock: a cross-platform normalization method for gene-expression microarrays.

Motivation: Cross-(multi)platform normalization of gene-expression microarray data remains an unresolved issue. Despite the existence of several algorithms, they are either constrained by the need to normalize all samples of all platforms together, compromising scalability and reuse, by adherence to the platforms of a specific provider, or simply by poor performance. In addition, many of the methods presented in the literature have not been specifically tested against multi-platform data and/or other methods applicable in this context.

Systems biology drug screening identifies statins as enhancers of current therapies in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is a B lymphoid malignancy highly dependent on the microenvironment. Despite new targeted therapies such as ibrutinib and venetoclax, disease progression and relapse remain an issue. CLL cell interactions with the supportive tissue microenvironment play a critical role in disease pathogenesis.

In-silico drug repurposing study predicts the combination of pirfenidone and melatonin as a promising candidate therapy to reduce SARS-CoV-2 infection progression and respiratory distress caused by cytokine storm.

From January 2020, COVID-19 is spreading around the world producing serious respiratory symptoms in infected patients that in some cases can be complicated by the severe acute respiratory syndrome, sepsis and septic shock, multiorgan failure, including acute kidney injury and cardiac injury. Cost and time efficient approaches to reduce the burthen of the disease are needed. To find potential COVID-19 treatments among the whole arsenal of existing drugs, we combined system biology and artificial intelligence-based approaches.

Synthesis of C11-to-C14 methyl-shifted all-trans-retinal analogues and their activities on human aldo-keto reductases.

Human aldo-keto reductases (AKRs) are enzymes involved in the reduction, among other substrates, of all-trans-retinal to all-trans-retinol (vitamin A), thus contributing to the control of the levels of retinoids in organisms. Structure-activity relationship studies of a series of C11-to-C14 methyl-shifted (relative to natural C13-methyl) all-trans-retinal analogues as putative substrates of AKRs have been reported. The synthesis of these retinoids was based on the formation of a C10-C11 single bond of the pentaene skeleton starting from a trienyl iodide and the corresponding dienylstannanes and dienylsilanes, using the Stille-Kosugi-Migita and Hiyama-Denmark cross-coupling reactions, respectively.

Structural and kinetic features of aldehyde dehydrogenase 1A (ALDH1A) subfamily members, cancer stem cell markers active in retinoic acid biosynthesis.

Aldehyde dehydrogenases catalyze the NAD(P)-dependent oxidation of aldehydes to their corresponding carboxylic acids. The three-dimensional structures of the human ALDH1A enzymes were recently obtained, while a complete kinetic characterization of them, under the same experimental conditions, is lacking. We show that the three enzymes, ALDH1A1, ALDH1A2 and ALDH1A3, have similar topologies, although with decreasing volumes in their substrate-binding pockets.

Engineering aldo-keto reductase 1B10 to mimic the distinct 1B15 topology and specificity towards inhibitors and substrates, including retinoids and steroids.

The aldo-keto reductase (AKR) superfamily comprises NAD(P)H-dependent enzymes that catalyze the reduction of a variety of carbonyl compounds. AKRs are classified in families and subfamilies. Humans exhibit three members of the AKR1B subfamily: AKR1B1 (aldose reductase, participates in diabetes complications), AKR1B10 (overexpressed in several cancer types), and the recently described AKR1B15.

Coordinated signals from the DNA repair enzymes PARP-1 and PARP-2 promotes B-cell development and function.

Poly (ADP-ribose) polymerase (PARP)-1 and PARP-2 regulate the function of various DNA-interacting proteins by transferring ADP-ribose emerging from catalytic cleavage of cellular β-NAD. Hence, mice lacking PARP-1 or PARP-2 show DNA perturbations ranging from altered DNA integrity to impaired DNA repair. These effects stem from the central role that PARP-1 and PARP-2 have on the cellular response to DNA damage.

Inhibitors of aldehyde dehydrogenases of the 1A subfamily as putative anticancer agents: Kinetic characterization and effect on human cancer cells.

Aldehyde dehydrogenases (ALDHs) are enzymes catalyzing the NAD(P)-dependent oxidation of aldehydes to their corresponding carboxylic acids. High ALDH activity has been related to some important features of cancer stem cells. ALDH1A enzymes, involved in the retinoic acid signaling pathway, are promising drug targets for cancer therapy, and the design of selective ALDH1A inhibitors has a growing pharmacological interest.

Efficacy of aldose reductase inhibitors is affected by oxidative stress induced under X-ray irradiation.

Human aldose reductase (hAR, AKR1B1) has been explored as drug target since the 1980s for its implication in diabetic complications. An activated form of hAR was found in cells from diabetic patients, showing a reduced sensitivity to inhibitors in clinical trials, which may prevent its pharmacological use. Here we report the conversion of native hAR to its activated form by X-ray irradiation simulating oxidative stress conditions.

Characterization of inflammatory response in hepatorenal syndrome: Relationship with kidney outcome and survival.

Background: Several lines of evidence indicate that decompensated cirrhosis is characterized by the presence of systemic inflammation. Hepatorenal syndrome (HRS-AKI) is a unique type of renal failure that occurs at late stages of cirrhosis. However, confirmation of the presence and significance of such inflammatory response in HRS-AKI is lacking.

Driving next-generation autophagy researchers towards translation (DRIVE), an international PhD training program on autophagy.

The European autophagy consortium (DRIVE) held its kick-off meeting in Groningen on the 14 and 15 of June 2018. This Marie Skłodowska-Curie Early Training Network was approved under the European Union's Horizon 2020 Research and Innovation Program and is funded for 4 years. Within DRIVE, 14 European research teams from academia and industry will train 15 PhD students through applied, cross-disciplinary and collaborative macroautophagy/autophagy research.