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Deficient mismatch repair (dMMR) results in microsatellite instability (MSI), a pronounced mutator phenotype. High‐frequency MSI (MSI‐H)/dMMR is gaining increasing interest as a biomarker for advanced cancer patients to determine their eligibility for immune checkpoint inhibitors (ICIs). Various methods based on next‐generation sequencing (NGS) have been developed to assess the MSI status. Comprehensive genomic profiling (CGP) testing can precisely ascertain the MSI status as well as genomic alterations in a single NGS test. The MSI status can be also ascertained through the liquid biopsy‐based CGP assays. MSI‐H has thus been identified in various classes of tumors, resulting in a greater adoption of immunotherapy, which is hypothesized to be effective against malignancies that possess a substantial number of mutations and/or neoantigens. NGS‐based studies have also characterized MSI‐driven carcinogenesis, including significant rates of fusion kinases in colorectal cancers (CRCs) with MSI‐H that are targets for therapeutic kinase inhibitors, particularly in MLH1‐methylated CRCs with wild‐type KRAS/BRAF. NTRK fusion is linked to the colorectal serrated neoplasia pathway. Recent advances in investigations of MSI‐H malignancies have resulted in the development of novel diagnostic or therapeutic techniques, such as a synthetic lethal therapy that targets the Werner gene. DNA sensing in cancer cells is required for antitumor immunity induced by dMMR, opening up novel avenues and biomarkers for immunotherapy. Therefore, clinical relevance exists for analyses of MSI and MSI‐H‐associated genomic alterations in malignancy. In this article, we provide an update on MSI‐driven carcinogenesis, with an emphasis on unique landscapes of diagnostic and immunotherapeutic strategies. High‐frequency microsatellite instability (MSI‐H)/deficient mismatch repair (dMMR) is gaining increasing interest as a biomarker for patients with advanced cancer to determine their eligibility for immune checkpoint inhibitors (ICIs). This review provides an update on MSI‐driven carcinogenesis, with an emphasis on unique landscapes of diagnostic and immunotherapeutic strategies.

Deficient DNA mismatch repair (MMR) results in a strong mutator phenotype known as microsatellite instability (MSI), which is a hallmark of Lynch syndrome-associated cancers. MSI is characterized by length alterations within simple repeated sequences that are called microsatellites. Lynch syndrome is primarily caused by mutations in the MMR genes, mainly MLH1 and MSH2, and less frequently in MSH6, and rarely PMS2, and large genomic rearrangements account for 5–20 % of all mutations. Germ line hemiallelic methylations of MLH1 or MSH2 are termed as epimutations and have been identified as causative of Lynch syndrome. Moreover, germ line 3′ deletions of EPCAM gene is involved in MSH2 methylation. MSI is also observed in about 15 % of sporadic colorectal cancer (CRC), gastric cancer (GC), and endometrial cancer (EC), and at lower frequencies in other cancers, often in association with hypermethylation of the MLH1 gene. Trimethylation of histone H3 on Lys36 (H3K36 me3) is an epigenetic histone mark that was required for DNA MMR in vivo. Thus, mutations in the H3K36 trimethyltransferase SETD2 have been reported as a potential cause of MSI. Genetic, epigenetic, and transcriptomic differences have been identified between cancers with and without MSI. Recent comprehensive molecular characterizations of CRC, EC, and GC by The Cancer Genome Atlas indicate that MSI+ cancers are distinct biological entities. The BRAF V600E mutation is specifically associated with sporadic MSI+ CRCs with methylated MLH1, but is not associated with Lynch syndrome-related CRCs. Accumulating evidence indicates a role of interactions between MSI and microRNA (miRNA) in the pathogenesis of MSI-positive (MSI+) cancer. As another new mechanism underlying MSI, overexpression of miR-155 or miR-21 has been shown to downregulate the expression of the MMR genes. Gene targets of frameshift mutations caused by MSI are involved in various cellular functions, including DNA repair (MSH3 and MSH6), cell signaling (TGFBR2 and ACVR2A), apoptosis (BAX), epigenetic regulation (HDAC2 and ARID1A), and miRNA processing (TARBP2 and XPO5), and a subset of MSI+ CRCs reportedly shows the mutated miRNA machinery phenotype. Moreover, microsatellite repeats in miRNA genes, such as hsa-miR-1273c, may be novel MSI targets for CRC, and mutations in noncoding regulatory regions of MRE11, BAX (BaxΔ2), and HSP110 (HSP110ΔE9) may affect the efficiency of chemotherapy. Thus, analyses of MSI and its related molecular alterations in cancers are increasingly relevant in clinical settings, and MSI is a useful screening marker for identifying patients with Lynch syndrome and a prognostic factor for chemotherapeutic interventions. In this review, we summarize recent advances in the pathogenesis of MSI and focus on genome-wide analyses that indicate the potential use of MSI and related alterations as biomarkers and novel therapeutic targets.

Abstract Transthyretin cardiac amyloidosis (ATTR-CA) demonstrates progressive, potentially fatal, and infiltrative cardiomyopathy caused by extracellular deposition of transthyretin-derived insoluble amyloid fibrils in the myocardium. Two distinct types of transthyretin (wild type or variant) become unstable, and misfolding forms aggregate, resulting in amyloid fibrils. ATTR-CA, which has previously been underrecognized and considered to be rare, has been increasingly recognized as a cause of heart failure with preserved ejection fraction among elderly persons. With the advanced technology, the diagnostic tools have been improving for cardiac amyloidosis. Recently, the efficacy of several disease-modifying agents focusing on the amyloidogenic process has been demonstrated. ATTR-CA has been changing from incurable to treatable. Nevertheless, there are still no prognostic improvements due to diagnostic delay or misdiagnosis because of phenotypic heterogeneity and co-morbidities. Thus, it is crucial for clinicians to be aware of this clinical entity for early diagnosis and proper treatment. In this mini-review, we focus on recent advances in diagnosis and treatment of ATTR-CA.

HIV and simian immunodeficiency virus (SIV) infections are known for impaired neutralizing antibody (NAb) responses. While sequential virus–host B cell interaction appears to be basally required for NAb induction, driver molecular signatures predisposing to NAb induction still remain largely unknown. Here we describe SIV-specific NAb induction following a virus–host interplay decreasing aberrant viral drive of phosphoinositide 3-kinase (PI3K). Screening of seventy difficult-to-neutralize SIV mac239 -infected macaques found nine NAb-inducing animals, with seven selecting for a specific CD8 + T-cell escape mutation in viral nef before NAb induction. This Nef-G63E mutation reduced excess Nef interaction-mediated drive of B-cell maturation-limiting PI3K/mammalian target of rapamycin complex 2 (mTORC2). In vivo imaging cytometry depicted preferential Nef perturbation of cognate Envelope-specific B cells, suggestive of polarized contact-dependent Nef transfer and corroborating cognate B-cell maturation post-mutant selection up to NAb induction. Results collectively exemplify a NAb induction pattern extrinsically reciprocal to human PI3K gain-of-function antibody-dysregulating disease and indicate that harnessing the PI3K/mTORC2 axis may facilitate NAb induction against difficult-to-neutralize viruses including HIV/SIV.

Proopiomelanocortin (POMC), a precursor with multiple bioactive peptides, is expressed by keratinocytes and regulates various pathophysiological responses, including pruritus associated with atopic dermatitis (AD). In the skin, POMC is extracellularly processed into peptides like α-melanocyte-stimulating hormone (α-MSH); however, the processing and functional role of β-endorphin (β-END) remain unclear. Here, we investigated the molecular form and biological activity of β-END generated in the context of AD. We analyzed skin extracts from AD lesions using immunoprecipitation and MALDI-TOF MS, identifying β-END(1–9), a truncated peptide, as a major derivative. To explore opioid receptor expression in fetal rat skin keratinocytes (FRSK) using RT-PCR. Delta opioid receptor (DOR) was detected in FRSK cells. Functional assays showed β-END(1–9) reduced cAMP levels via DOR signaling, acting as a full agonist with about half the potency of methionine-enkephalin. To further explore its biological effects, DNA microarray analysis was conducted on β-END(1–9)-treated FRSK cells. Differential gene expression analysis revealed modulation of genes involved in collagen maturation and hyaluronic acid synthesis, suggesting roles in skin barrier function. Collectively, these findings suggest that POMC is processed into β-END(1–9) in atopic-inflammatory skin, and this peptide acts via DOR expressed in keratinocytes to promote the expression of skin-protective factors.

Background and purposeThe spread of COVID-19 has restricted the delivery of standard medical care to surgical patients dramatically. Surgical triage is performed by considering the type of disease, its severity, the urgency for surgery, and the condition of the patient, in addition to the scale of infectious outbreaks in the region. The purpose of this study was to evaluate the impact of the COVID-19 pandemic on the number of surgical procedures performed and whether the effects were more prominent during certain periods of widespread infection and in the affected regions.MethodsWe selected 20 of the most common procedures from each surgical field and compared the weekly numbers of each operation performed in 2020 with the respective numbers in 2018 and 2019, as recorded in the National Clinical Database (NCD). The surgical status during the COVID-19 pandemic as well as the relationship between surgical volume and the degree of regional infection were analyzed extensively.ResultsThe rate of decline in surgery was at most 10–15%. Although the numbers of most oncological and cardiovascular procedures decreased in 2020, there was no significant change in the numbers of pancreaticoduodenectomy and aortic replacement procedures performed in the same period.ConclusionThe numbers of most surgical procedures decreased in 2020 as a result of the COVID-19 pandemic; however, the precise impact of surgical triage on decrease in detection of disease warrants further investigation.

We report a computational approach (implemented in MS-DIAL 3.0; http://prime.psc.riken.jp/) for metabolite structure characterization using fully 13C-labeled and non-labeled plants and LC–MS/MS. Our approach facilitates carbon number determination and metabolite classification for unknown molecules. Applying our method to 31 tissues from 12 plant species, we assigned 1,092 structures and 344 formulae to 3,604 carbon-determined metabolite ions, 69 of which were found to represent structures currently not listed in metabolome databases.A computational approach facilitates molecular formula, metabolite class, and structure assignment for plant metabolites on the basis of LC–MS analysis of fully 13C-labeled and unlabeled plants.

Background Comprehensive metabolomic analyses have been conducted in various institutes and a large amount of metabolomic data are now publicly available. To help fully exploit such data and facilitate their interpretation, metabolomic data obtained from different facilities and different samples should be integrated and compared. However, large-scale integration of such data for biological discovery is challenging given that they are obtained from various types of sample at different facilities and by different measurement techniques, and the target metabolites and sensitivities to detect them also differ from study to study. Results We developed iDMET, a network-based approach to integrate metabolomic data from different studies based on the differential metabolomic profiles between two groups, instead of the metabolite profiles themselves. As an application, we collected cancer metabolomic data from 27 previously published studies and integrated them using iDMET. A pair of metabolomic changes observed in the same disease from two studies were successfully connected in the network, and a new association between two drugs that may have similar effects on the metabolic reactions was discovered. Conclusions We believe that iDMET is an efficient tool for integrating heterogeneous metabolomic data and discovering novel relationships between biological phenomena.

BackgroundDespite interest in surgeon and hospital volume effects on distal gastrectomy, clinical significance has not been confirmed in a large-scale population. We studied to clarify the effects of surgeon and hospital volume on postoperative mortality after distal gastrectomy for gastric cancer among Japanese patients in a nationwide web-based data entry system.MethodsWe extracted data on distal gastrectomy for gastric cancer from the National Clinical Database between 2011 and 2015. The primary outcome was operative mortality. Hospital volume was divided into 3 tertiles: low (1–22 cases per year), medium (23–51) and high (52–404). Surgeon volume was divided into the 5 groups: 0–3, 4–10, 11–20, 21–50, 51 + cases per year. We calculated the 95% confidence interval (CI) for the mortality rate based on odds ratios (ORs) estimated from a hierarchical logistic regression model.ResultsWe analyzed 145,523 patients at 2182 institutions. Operative mortality was 1.9% in low-, 1.0% in medium- and 0.5% in high-volume hospitals. The operative mortality rate decreased definitively with surgeon volume, 1.6% in the 0–3 group and 0.3% in the 51 + group. After risk adjustment for surgeon and hospital volume and patient characteristics, hospital volume was significantly associated with operative morality (medium: OR 0.64, 95% CI 0.56–0.73, P < 0.001; high: OR 0.42, 95% CI 0.35–0.51, P < 0.001).ConclusionsWe demonstrate that hospital volume can have a crucial impact on postoperative mortality after distal gastrectomy compared with surgeon volume in a nationwide population study. These findings suggest that centralization may improve outcomes after distal gastrectomy.