Using machine learning to identify risk factors for pancreatic cancer: a retrospective cohort study of real-world data.

Objectives: This study aimed to identify the risk factors for pancreatic cancer through machine learning.

Methods: We investigated the relationships between different risk factors and pancreatic cancer using a real-world retrospective cohort study conducted at West China Hospital of Sichuan University. Multivariable logistic regression, with pancreatic cancer as the outcome, was used to identify covariates associated with pancreatic cancer.

Membrane remodeling by FAM92A1 during brain development regulates neuronal morphology, synaptic function, and cognition.

The Bin/Amphiphysin/Rvs (BAR) domain protein FAM92A1 is a multifunctional protein engaged in regulating mitochondrial ultrastructure and ciliogenesis, but its physiological role in the brain remains unclear. Here, we show that FAM92A1 is expressed in neurons starting from embryonic development. FAM92A1 knockout in mice results in altered brain morphology and age-associated cognitive deficits, potentially due to neuronal degeneration and disrupted synaptic plasticity.

Antimicrobial activities of natural flavonoids against foodborne pathogens and their application in food industry.

The application of natural alternatives as food preservatives has gained much attention due to the escalating negative perception of synthetic preservatives among consumers and the spread of drug-resistance foodborne pathogens. Natural flavonoids have the potential to be employed for food safety due to their antimicrobial properties against a wide range of foodborne pathogenic microorganisms. In this perspective, we reviewed the antimicrobial activities of natural flavonoids, the mechanism of action, as well as their application for food safety and quality.

Tumor biomarkers for diagnosis, prognosis and targeted therapy.

Tumor biomarkers, the substances which are produced by tumors or the body's responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management.

Erratum: [Corrigendum] Chloroquine potentiates the anticancer effect of sunitinib on renal cell carcinoma by inhibiting autophagy and inducing apoptosis.

[This corrects the article DOI: 10.3892/ol.2017.

STK19 is a DNA/RNA-binding protein critical for DNA damage repair and cell proliferation.

STK19 was originally identified as a manganese-dependent serine/threonine-specific protein kinase, but its function has been highly debated. Here, the crystal structure of STK19 revealed that it does not contain a kinase domain, but three intimately packed winged helix (WH) domains. The third WH domain mediated homodimerization and double-stranded DNA binding, both being important for its nuclear localization.

Neurodevelopmental defects in human cortical organoids with -acetylneuraminic acid synthase mutation.

Biallelic genetic variants in -acetylneuraminic acid synthase (), a critical enzyme in endogenous sialic acid biosynthesis, are clinically associated with neurodevelopmental disorders. However, the mechanism underlying the neuropathological consequences has remained elusive. Here, we found that mutation resulted in the absence of both sialic acid and protein polysialylation in the cortical organoids and notably reduced the proliferation and expansion of neural progenitors.

Hippocampal circAnk3 Deficiency Causes Anxiety-like Behaviors and Social Deficits by Regulating the miR-7080-3p/IQGAP1 Pathway in Mice.

Background: Circular RNAs are highly enriched in the synapses of the mammalian brain and play important roles in neurological function by acting as molecular sponges of microRNAs. circAnk3 is derived from the 11th intron of the ankyrin-3 gene, Ank3, a strong genetic risk factor for neuropsychiatric disorders; however, the function of circAnk3 remains elusive. In this study, we investigated the function of circAnk3 and its downstream regulatory network for target genes in the hippocampus of mice.

Discovery and Optimization of Novel DHODH Inhibitors for the Treatment of Inflammatory Bowel Disease.

As a key rate-limiting enzyme in the synthesis of pyrimidine nucleotides, human dihydroorotate dehydrogenase (DHODH) is considered a known target for the treatment of autoimmune diseases, including inflammatory bowel disease (IBD). Herein, BAY 41-2272 with a 1-pyrazolo[3,4-]pyridine scaffold was identified as an DHODH inhibitor by screening an active compound library containing 5091 molecules. Further optimization led to 2-(1-(2-chloro-6-fluorobenzyl)-1-pyrrolo[2,3-]pyridin-3-yl)-5-cyclopropylpyrimidin-4-amine (, which was found to be the most promising and drug-like compound with potent inhibitory activity against DHODH (IC = 173.

Methamphetamine exposure drives cell cycle exit and aberrant differentiation in rat hippocampal-derived neurospheres.

Methamphetamine (METH) abuse by pregnant drug addicts causes toxic effects on fetal neurodevelopment; however, the mechanism underlying such effect of METH is poorly understood. In the present study, we applied three-dimensional (3D) neurospheres derived from the embryonic rat hippocampal tissue to investigate the effect of METH on neurodevelopment. Through the combination of whole genome transcriptional analyses, the involved cell signalings were identified and investigated.

Synthesis and biological evaluation of novel pyrazole amides as potent mitochondrial complex I inhibitors.

Targeting mitochondrial complex I (CI) is emerging as an attractive anticancer strategy, and CI inhibitor IACS-010759 has achieved breakthrough success. However, the narrow therapeutic index of IACS-010759 seriously hinders its further application. In this study, a series of novel pyrazole amides were designed and optimized based on IACS-010759, and their potential CI inhibitory effects were biologically evaluated.

Pharmacological inhibition of LSD1 suppresses growth of hepatocellular carcinoma by inducing GADD45B.

Lysine-specific histone demethylase 1 (LSD1) is an attractive target for malignancies therapy. Nevertheless, its role in hepatocellular carcinoma (HCC) progression and the potential of its inhibitor in HCC therapy remains unclear. Here, we show that LSD1 overexpression in human HCC tissues is associated with HCC progression and poor patient survival.

Morphine Re-arranges Chromatin Spatial Architecture of Primate Cortical Neurons.

The expression of linear DNA sequence is precisely regulated by the three-dimensional (3D) architecture of chromatin. Morphine-induced aberrant gene networks of neurons have been extensively investigated; however, how morphine impacts the 3D genomic architecture of neurons is still unknown. Here, we applied digestion-ligation-only high-throughput chromosome conformation capture (DLO Hi-C) technology to investigate the effects of morphine on the 3D chromatin architecture of primate cortical neurons.

Cardiolipin and OPA1 Team up for Methamphetamine-Induced Locomotor Activity by Promoting Neuronal Mitochondrial Fusion in the Nucleus Accumbens of Mice.

Mitochondria are highly dynamic organelles with coordinated cycles of fission and fusion occurring continuously to satisfy the energy demands in the complex architecture of neurons. How mitochondria contribute to addicted drug-induced adaptable mitochondrial networks and neuroplasticity remains largely unknown. Through liquid chromatography-mass spectrometry-based lipidomics, we first analyzed the alteration of the mitochondrial lipidome of three mouse brain areas in methamphetamine (METH)-induced locomotor activity and conditioned place preference.

β-hydroxybutyrate reduces reinstatement of cocaine conditioned place preference through hippocampal CaMKII-α β-hydroxybutyrylation.

Studies have shown the therapeutic effects of a ketogenic diet (KD) on epilepsy, but the effect of a KD on drug reinstatement is largely unclear. This study aims to investigate whether KD consumption possesses therapeutic potential for cocaine reinstatement and the molecular mechanism. We find that a KD significantly reduces cocaine-induced reinstatement in mice, which is accompanied by a markedly elevated level of β-hydroxybutyrate (β-OHB), the most abundant ketone body, in the hippocampus.

Dissecting the genetic and microenvironmental factors of gastric tumorigenesis in mice.

Gastric cancer (GC) is one of the most frequent and lethal malignancies in the world. However, our understanding of the mechanisms underlying its initiation and progression is limited. Here, we generate a series of primary GC models in mice with genome-edited gastric organoids, which elucidate the genetic drivers for sequential transformation from dysplasia to well-differentiated and poorly differentiated GC.

Discovery of potent human dihydroorotate dehydrogenase inhibitors based on a benzophenone scaffold.

Blocking the de novo biosynthesis of pyrimidine by inhibiting human dihydroorotate dehydrogenase (hDHODH) is an effective way to suppress the proliferation of cancer cells and activated lymphocytes. Herein, eighteen teriflunomide derivatives and four ASLAN003 derivatives were designed and synthesized as novel hDHODH inhibitors based on a benzophenone scaffold. The optimal compound 7d showed a potent hDHODH inhibitory activity with an IC value of 10.

Acquired semi-squamatization during chemotherapy suggests differentiation as a therapeutic strategy for bladder cancer.

Cisplatin-based chemotherapy remains the primary treatment for unresectable and metastatic muscle-invasive bladder cancers (MIBCs). However, tumors frequently develop chemoresistance. Here, we established a primary and orthotopic MIBC mouse model with gene-edited organoids to recapitulate the full course of chemotherapy in patients.

A novel series of teriflunomide derivatives as orally active inhibitors of human dihydroorotate dehydrogenase for the treatment of colorectal carcinoma.

Human dihydroorotate dehydrogenase (hDHODH) is a key enzyme in the de novo synthesis pathway of pyrimidine nucleotide in cells. The moderate efficiency of teriflunomide, an approved hDHODH inhibitor for the treatment of multiple sclerosis, limited its therapeutic application of malignancy. Herein, thirty-seven novel teriflunomide derivatives with a biphenyl scaffold were designed, synthesized and evaluated.

Neonatal exposure to sevoflurane induces adolescent neurobehavioral dysfunction by interfering with hippocampal glycerophoslipid metabolism in rats.

Sevoflurane exposure in the neonatal period causes long-term developmental neuropsychological dysfunction, including memory impairment and anxiety-like behaviors. However, the molecular mechanisms underlying such effects have not been fully elucidated. In this study, we investigated the effect of neonatal exposure to sevoflurane on neurobehavioral profiles in adolescent rats, and applied an integrated approach of lipidomics and proteomics to investigate the molecular network implicated in neurobehavioral dysfunction.

Synapse differentiation-induced gene 1 regulates stress-induced depression through interaction with the AMPA receptor GluA2 subunit of nucleus accumbens in male mice.

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are key regulators during the process of synaptic plasticity in major depression disorder (MDD). Synapse differentiation-induced gene 1 (SynDIG1) functions as an atypical AMPAR auxiliary subunit and regulates synaptic AMPAR content; however, the role of SynDIG1 in MDD remains elusive. In this study, we found that the SynDIG1 expression was significantly increased in the neurons of the nucleus accumbens (NAc) of male mice after chronic social defeat stress (CSDS).

KMT2C deficiency promotes small cell lung cancer metastasis through DNMT3A-mediated epigenetic reprogramming.

Small cell lung cancer (SCLC) is notorious for its early and frequent metastases, which contribute to it as a recalcitrant malignancy. To understand the molecular mechanisms underlying SCLC metastasis, we generated SCLC mouse models with orthotopically transplanted genome-edited lung organoids and performed multiomics analyses. We found that a deficiency of KMT2C, a histone H3 lysine 4 methyltransferase frequently mutated in extensive-stage SCLC, promoted multiple-organ metastases in mice.