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Adjuvant chemotherapy after surgery improves survival of patients with stage II–III, resectable gastric cancer. However, the overall survival benefit observed after adjuvant chemotherapy is moderate, suggesting that not all patients with resectable gastric cancer treated with adjuvant chemotherapy benefit from it. We aimed to develop and validate a predictive test for adjuvant chemotherapy response in patients with resectable, stage II–III gastric cancer. In this multi-cohort, retrospective study, we developed through a multi-step strategy a predictive test consisting of two rule-based classifier algorithms with predictive value for adjuvant chemotherapy response and prognosis. Exploratory bioinformatics analyses identified biologically relevant candidate genes in gastric cancer transcriptome datasets. In the discovery analysis, a four-gene, real-time RT-PCR assay was developed and analytically validated in formalin-fixed, paraffin-embedded (FFPE) tumour tissues from an internal cohort of 307 patients with stage II–III gastric cancer treated at the Yonsei Cancer Center with D2 gastrectomy plus adjuvant fluorouracil-based chemotherapy (n=193) or surgery alone (n=114). The same internal cohort was used to evaluate the prognostic and chemotherapy response predictive value of the single patient classifier genes using associations with 5-year overall survival. The results were validated with a subset (n=625) of FFPE tumour samples from an independent cohort of patients treated in the CLASSIC trial (NCT00411229), who received D2 gastrectomy plus capecitabine and oxaliplatin chemotherapy (n=323) or surgery alone (n=302). The primary endpoint was 5-year overall survival. We identified four classifier genes related to relevant gastric cancer features (GZMB, WARS, SFRP4, and CDX1) that formed the single patient classifier assay. In the validation cohort, the prognostic single patient classifier (based on the expression of GZMB, WARS, and SFRP4) identified 79 (13%) of 625 patients as low risk, 296 (47%) as intermediate risk, and 250 (40%) as high risk, and 5-year overall survival for these groups was 83·2% (95% CI 75·2–92·0), 74·8% (69·9–80·1), and 66·0% (60·1–72·4), respectively (p=0·012). The predictive single patient classifier (based on the expression of GZMB, WARS, and CDX1) assigned 281 (45%) of 625 patients in the validation cohort to the chemotherapy-benefit group and 344 (55%) to the no-benefit group. In the predicted chemotherapy-benefit group, 5-year overall survival was significantly improved in those patients who had received adjuvant chemotherapy after surgery compared with those who received surgery only (80% [95% CI 73·5–87·1] vs 64·5% [56·8–73·3]; univariate hazard ratio 0·47 [95% CI 0·30–0·75], p=0·0015), whereas no such improvement in 5-year overall survival was observed in the no-benefit group (72·9% [66·5–79·9] in patients who received chemotherapy plus surgery vs 72·5% [65·8–79·9] in patients who only had surgery; 0·93 [0·62–1·38], p=0·71). The predictive single patient classifier groups (chemotherapy benefit vs no-benefit) could predict adjuvant chemotherapy benefit in terms of 5-year overall survival in the validation cohort (pinteraction=0·036 in univariate analysis). Similar results were obtained in the internal evaluation cohort. The single patient classifiers validated in this study provide clinically important prognostic information independent of standard risk-stratification methods and predicted chemotherapy response after surgery in two independent cohorts of patients with resectable, stage II–III gastric cancer. The single patient classifiers could complement TNM staging to optimise decision making in patients with resectable gastric cancer who are eligible for adjuvant chemotherapy after surgery. Further validation of these results in prospective studies is warranted. Ministry of ICT and Future Planning; Ministry of Trade, Industry, and Energy; and Ministry of Health and Welfare.

Background Pediatric hypertrophic cardiomyopathy (HCM) is a rare condition, particularly in neonates, and is characterized by rapid and extensive myocardial hypertrophy, often leading to severe clinical outcomes. HCM can arise from variants in sarcomeric genes, which are essential for myocardial contractions, as well as non-sarcomeric gene variants. Although genetic modifiers and oligogenic inheritance have been implicated in congenital heart disease and cardiomyopathy, their complexity in HCM has not been fully elucidated, especially in familial cases with variable phenotypes. Hence, this study aims to investigate the genetic architecture in a family with a history of cardiac disease and neonatal HCM, focusing on oligogenic inheritance of non-sarcomeric variants. Methods Clinical data and blood samples were collected for genetic analysis. Whole genome sequencing (WGS) and bioinformatic analyses identified compound heterozygous variants in the MYO19 gene. Maternally inherited variants were analyzed because the proband’s mother was also diagnosed with HCM. WGS was performed on the patient’s maternal grandfather and aunt, who have cardiac disease, revealing candidate genetic variants that may contribute to the cardiac phenotype. Results Compound heterozygous MYO19 variants were identified in the neonatal patient. Missense c.203C > G (p.A68G) and frameshift c.275_276del (p.E92Vfs*19) variants were identified, which were located in the myosin motor domain, a functionally crucial region of the MYO19 protein. Maternally inherited missense variants were identified in SURF1 and ETFDH . All three genes are associated with mitochondrial function, and in silico prediction tools suggest that these variants are likely damaging. Other candidate genetic variants possibly contributing to the cardiac phenotype were also detected in the extended maternal family. Conclusions To the best of our knowledge, this study represents the first report proposing MYO19 as a candidate gene for HCM and highlights the potential role of oligogenic inheritance in the etiology of the disease. Furthermore, plausible candidate variants of other mitochondria-related genes, such as MYO19 , SURF1 , and ETFDH , were identified, and other family members were investigated to support the pathogenesis of HCM further. Given the limited understanding of the genetics of pediatric HCM, these findings contribute valuable insights into its genetic basis in pediatric patients.

The mesenchymal cancer phenotype is known to be clinically related to treatment resistance and a poor prognosis. We identified gene signature-based molecular subtypes of gastric cancer (GC, n  = 547) based on transcriptome data and validated their prognostic and predictive utility in multiple external cohorts. We subsequently examined their associations with tumor microenvironment (TME) features by employing cellular deconvolution methods and sequencing isolated GC populations. We further performed spatial transcriptomics analysis and immunohistochemistry, demonstrating the presence of GC cells in a partial epithelial-mesenchymal transition state. We performed network and pharmacogenomic database analyses to identify TGF-β signaling as a driver pathway and, thus, a therapeutic target. We further validated its expression in tumor cells in preclinical models and a single-cell dataset. Finally, we demonstrated that inhibition of TGF-β signaling negated mesenchymal/stem-like behavior and therapy resistance in GC cell lines and mouse xenograft models. In summary, we show that the mesenchymal GC phenotype could be driven by epithelial cancer cell-intrinsic TGF-β signaling and propose therapeutic strategies based on targeting the tumor-intrinsic mesenchymal reprogramming of medically intractable GC. Gastric cancer: Growth factor target for intractable cancer subtypes Targeting a growth factor protein could reprogram tumor cells in difficult-to-treat gastric cancer, improving chemotherapy responses and prognosis. Several subtypes of gastric cancer are intractable and chemo-resistant. These often display elevated levels of genes expressed in mesenchymal stem cells, multipotent cells that are frequently involved in cancer progression. Jae-Ho Cheong and Yong-Min Huh at Yonsei University, Seoul, South Korea, and co-workers used gene expression profiling on samples from 547 patients to clarify gastric cancer molecular subtypes and their associated gene signatures. They validated their results against multiple external patient groups, and examined the association betweenf different subtypes and the tumour microenvironment. Experiments on mouse models showed that the transforming growth factor-beta pathway (TGF-β) drives the switch from normal to mesenchymal stem cell state of cancer cells not stormal cells. Inhibiting TGF-β signaling in gastric cancer cells blocked this transition and reduced chemotherapy resistance. Introduction

Motile cells manifest increased migration speed and directionality in gradients of stimuli, including chemoattractants, electrical potential, and substratum stiffness. Here, we demonstrate that Dictyostelium cells move directionally in response to an electric field with specific acceleration/deceleration kinetics of directionality and migration speed. Detailed analyses of the migration kinetics suggest that migration speed and directionality are separately regulated by Gβ and RasG, respectively, in EF-directed cell migration. Cells lacking Gβ, which is essential for all chemotactic responses in Dictyostelium, showed EF-directed cell migration with the same increase in directionality in an EF as wild-type cells. However, these cells failed to show induction of the migration speed upon EF stimulation as much as wild-type cells. Loss of RasG, a key regulator of chemoattractant-directed cell migration, resulted in almost complete loss of directionality, but similar acceleration/deceleration kinetics of migration speed as wild-type cells. These results indicate that Gβ and RasG are required for the induction of migration speed and directionality, respectively, in response to an EF, suggesting separation of migration speed and directionality even with intact feedback loops between mechanical and signaling networks.

We study invariant metrics on unbounded strongly pseudoconvex domains with non-compact automorphism group. The main result is that the corresponding Bergman and K a ¨ hler–Einstein metrics are metrically equivalent. We also determine the comparisons among invariant metrics, including the Carathéodory and Kobayashi pseudo-metrics additionally.

FERM domain-containing proteins are involved in diverse biological and pathological processes, including cell-substrate adhesion, cell-cell adhesion, multicellular development, and cancer metastasis. In this study, we determined the functions of FrmB, a FERM domain-containing protein, in the cell morphology, cell adhesion, and multicellular development of Dictyostelium cells. Our results show that FrmB appears to play an important role in regulating the size of developmental structures. frmB null cells showed prolonged aggregation during development, resulting in increased size of developmental structures, such as mounds and fruiting bodies, compared to those of wild-type cells, whereas FrmB overexpressing cells exhibited decreased size of developmental structures. These results suggest that FrmB may be necessary for limiting the sizes of developmental structures. Loss of FrmB also resulted in decreased cell-substrate adhesion and slightly increased cell area, suggesting that FrmB had important roles in the regulation of cell adhesion and cell morphology. These studies would contribute to our understanding of the intertwined and overlapped functions of FERM domain-containing proteins.

Establishment of cell polarity is mediated by a series of signaling molecules that are asymmetrically activated or localized in the cell upon extracellular stimulation. To understand the mechanism that mediates anterior/posterior asymmetric localization of RapGAP3 during migration, we determined the minimally required amino acids in the I/LWEQ domain that cause posterior localization and found that the minimal region of the F-actin binding domain for posterior localization could, with some additional deletion at the C-terminal, localize to the anterior. Analysis of the localization and translocation kinetics to the cell cortex of the truncated proteins suggests that the required regions for anterior/posterior localization might have a preferential binding affinity to preexisting F-actins at the rear and lateral sides of the cell or newly formed F-actins at the front of the cell, leading to distinct differential sites of the cell.

Alzheimer’s disease (AD) is an age-related disorder that causes a loss of brain function. Hyperphosphorylation of tau and the subsequent formation of intracellular neurofibrillary tangles (NFTs) are implicated in the pathogenesis of AD. Hyperphosphorylated tau accumulates into insoluble paired helical filaments that aggregate into NFTs; therefore, regulation of tau phosphorylation represents an important treatment approach for AD. Heat shock protein 27 (Hsp27) plays a specific role in human neurodegenerative diseases; however, few studies have examined its therapeutic effect. In this study, we induced tau hyperphosphorylation using okadaic acid, which is a protein phosphatase inhibitor, and generated a fusion protein of Hsp27 and the protein transduction domain of the HIV Tat protein (Tat-Hsp27) to enhance the delivery of Hsp27. We treated Tat-Hsp27 to SH-SY5Y neuroblastoma cells for 2 h; the transduction level was proportional to the Tat-hsp27 concentration. Additionally, Tat-Hsp27 reduced the level of hyperphosphorylated tau and protected cells from apoptotic cell death caused by abnormal tau aggregates. These results reveal that Hsp27 represents a valuable protein therapeutic for AD.

Seventy-six species of fishes, representing 60 genera and 34 families, were recorded from tidal pools on Jeju Island, southern Korea. The major families in terms of species were the Gobiidae (11 species), Pomacentridae (8 species), Blenniidae (6 species), and Labridae (5 species). Thirty-nine species were classified as tropical, 26 as temperate and 11 as subtropical.