Real-World Evidence of FOLFIRI Combined with Anti-Angiogenesis Inhibitors or Anti-EGFR Antibodies for Patients with Early Recurrence Colorectal Cancer After Adjuvant FOLFOX/CAPOX Therapy: A Japanese Claims Database Study.

BACKGROUND: Oxaliplatin-containing adjuvant regimens (folinic acid, fluorouracil, and oxaliplatin/capecitabine and oxaliplatin [FOLFOX/CAPOX]) are used after curative resection of colorectal cancer (CRC). However, real-world evidence regarding treatment sequences and outcomes in patients with early recurrence CRC after adjuvant chemotherapy is limited. OBJECTIVE: We aimed to describe the patient characteristics, treatment sequence, and overall duration of second-line (2L) therapy in patients with early recurrence CRC who received adjuvant chemotherapy (FOLFOX/CAPOX) followed by folinic acid, fluorouracil, and irinotecan (FOLFIRI) + anti-angiogenesis drugs (AA) or FOLFIRI + anti-epidermal growth factor receptor (EGFR) antibodies. METHODS: This retrospective study analyzed Japanese administrative data from November 2014 to March 2023 of adult patients who underwent CRC resection surgery, started FOLFOX/CAPOX ≤3 months (mo) after surgery, and had early CRC recurrence. Early recurrence was defined as initiation of FOLFIRI+AA or FOLFIRI+anti-EGFR antibodies as 2L therapy, ≤12 mo of discontinuing adjuvant chemotherapy. Patient characteristics, treatment sequence, median time to treatment discontinuation (mTTD), i.e., duration between the start and end dates of 2L therapy (Kaplan-Meier method), and factors associated with 2L time to treatment discontinuation constituted the study outcomes (Cox regression model). Subgroup analyses were performed for timing of early CRC recurrence (≤6 mo and 6-12 mo) and tumor sidedness. RESULTS: Among the 832 selected patients (median age [minimum-maximum] 67 (24-86) years, 56.4% male), CAPOX (71.3%) was more commonly used than FOLFOX (28.7%) as adjuvant therapy. FOLFIRI+AA (72.5%) was used more commonly than FOLFIRI+anti-EGFR antibodies (27.5%) in 2L. AA and anti-EGFR antibodies groups had similar mTTD: 6.2 mo (95% confidence interval 5.8, 6.9) and 6.1 mo (95% confidence interval 5.2, 7.4). Age ≥70 years showed significant association with shorter 2L treatment duration (hazard ratio 1.2, 95% confidence interval 1.0, 1.4; p = 0.03). The AA cohort's mTTD was numerically shorter in the ≤6 mo recurrence subgroup compared with the 6-12 mo recurrence subgroup (6.1 mo vs 8.1 mo); the anti-EGFR antibodies cohort had similar mTTD (5.8 mo vs 6.2 mo). The AA and anti-EGFR antibodies cohorts also had similar mTTD in the left-sided CRC subgroup (6.5 mo vs 6.2 mo), but not in the right-sided subgroup (5.6 mo vs 3.9 mo). CONCLUSIONS: This is the first administrative data-based real-world evidence on treatment sequence and outcomes for patients with early recurrence CRC treated with FOLFIRI+AAs or FOLFIRI+ anti-EGFR antibodies after adjuvant FOLFOX/CAPOX therapy in Japan. Both regimens had similar TTD, but relapse timing and tumor sidedness may influence their efficacy.

Targeting Super-Enhancer-Driven Transcriptional Dependencies Suppresses Aberrant Hedgehog Pathway Activation and Overcomes Smoothened Inhibitor Resistance.

Aberrant activation of the Hedgehog (Hh) signaling pathway plays important roles in oncogenesis and therapeutic resistance in several types of cancer. The clinical application of FDA-approved Hh-targeted Smoothened inhibitors (SMOi) is hindered by the emergence of primary or acquired drug resistance. Epigenetic and transcriptional targeted therapies represent a promising direction for developing improved anti-Hh therapies. In this study, we integrated epigenetic/transcriptional-targeted small-molecule library screening with CRISPR/Cas9 knockout library screening and identified CDK9 and CDK12, two transcription elongation regulators, as therapeutic targets for antagonizing aberrant Hh activation and overcoming SMOi resistance. Inhibition of CDK9 or CDK12 potently suppressed Hh signaling and tumor growth in various SMOi responsive or resistant Hh-driven tumor models. Systemic epigenomic profiling elucidated the Hh-driven super-enhancer (SE) landscape and identified IRS1, encoding a critical component and cytoplasmic adaptor protein of the IGF pathway, as an oncogenic Hh-driven SE target gene and effective therapeutic target in Hh-driven tumor models. Collectively, this study identifies SE-driven transcriptional dependencies that represent promising therapeutic vulnerabilities for suppressing the Hh pathway and overcoming SMOi resistance. As CDK9 and IRS inhibitors have already entered human clinical trials for cancer treatment, these findings provide comprehensive preclinical support for developing trials for Hh-driven cancers.

Comprehensive analyses and experimental verification of NETs and an EMT gene signature for prognostic prediction, immunotherapy, and chemotherapy in pancreatic adenocarcinoma.

Pancreatic adenocarcinoma (PAAD) is an aggressive malignancy with high mortality and poor prognosis. Neutrophil extracellular traps (NETs) and the epithelial-mesenchymal transition (EMT) significantly influence on the progression of various cancers. However, the underlying relevance of NETs- and EMT-associated genes on the outcomes of patients with PAAD remains to be elucidated. Transcriptome RNA sequencing data, together with clinical information and single-cell sequencing data of PAAD were collected from public databases. In the TCGA-PAAD cohort, ssGSEA was used to calculate NET and EMT scores. WGCNA was used to determine the key gene modules. A risk model with eight NET- and EMT-related genes (NERGs) was established using LASSO and multivariate Cox regression analysis. Patients in the reduced risk (RR) group showed better prognostic values compared with those in the elevated risk (ER) group. The prognostic model exhibited reliable and robust prediction when validated using an external database. The distributions of risk genes were explored in a single-cell sequencing data set. Immune infiltration, immune cycle, and immune checkpoints were compared between the RR and ER groups. Moreover, potential chemotherapeutic drugs were examined. DCBLD2 was identified as a key gene in PAAD cell lines by qRT-PCR, and was highly expressed in PAAD tissues. GSEA demonstrated that DCBLD2 induced the EMT. Transwell assays and western blotting showed that cell invasion and EMT induction were significantly reduced after DCBLD2 knockdown. Collectively, we constructed a prognosis model based on a NET and EMT gene signature, providing a valuable perspective for the prognostic evaluation and management of PAAD patient.

Bowel Urgency in Patients with Ulcerative Colitis and Crohn's Disease: A Cross-Sectional Real-World Survey in Japan.

INTRODUCTION: Bowel urgency (BU) is among the most disruptive of inflammatory bowel disease (IBD) symptoms. However, data on its prevalence and association with disease activity are limited. This real-world study of Japanese patients with IBD evaluated BU prevalence and compared clinical outcomes and health-related quality of life (HRQoL) between patients with and without BU. METHODS: Data were drawn from the Adelphi IBD Disease Specific Programme™, a cross-sectional survey of physicians and their patients with ulcerative colitis (UC) and Crohn's disease (CD). Physicians reported demographic and clinical data, including disease activity measures (Mayo score and CD Activity Index [CDAI]), for consulting patients, who voluntarily completed a patient-reported questionnaire, including HRQoL measures (Short IBD Questionnaire [SIBDQ] and EQ-5D-5L). Outcomes were compared between patients with and without BU using t-, Fisher exact and Mann-Whitney U tests as appropriate. RESULTS: Of 120 UC patients, 27.5% (n = 33) self-reported BU; physicians were unaware of BU in 54.5% (n = 18) of these patients. Patients with BU had higher mean Mayo scores (p < 0.01) and lower mean SIBDQ scores (47.9 vs 56.6, p < 0.01) than patients without BU, with mean EQ-5D-5L scores 0.83 and 0.87, respectively (p = 0.06). Physicians were satisfied with treatment but believed better control could be achieved for 39.4% of patients with BU and 35.6% without. Of 114 CD patients, 17.5% (n = 20) self-reported BU; physicians were unaware of BU in 75.0% (n = 15) of these patients. Patients with BU had higher mean CDAI scores (p < 0.01) and lower mean SIBDQ (48.7 vs 56.2, p < 0.01) and EQ-5D-5L scores (0.81 vs 0.88, p < 0.01) than patients without BU. Physicians were satisfied but believed better control could be achieved for 40.0% of patients with BU vs 19.1% without. CONCLUSIONS: Patients with BU have worse clinical outcomes and HRQoL than patients without, underlining the need for improved physician-patient communication regarding BU and new IBD therapeutic options.

A novel AluYb8 insertion-associated non-coding RNA, lncMUTYH, impairs mitochondrial function and dampens the M2-like polarization of macrophages.

An inverted AluYb8 insertion in the MUTYH intron 15 (AluYb8MUTYH variant) has been reported to be associated with reduced MUTYH1 expression and mitochondrial dysfunction with age. However, the underlying mechanism remains unknown. In this study, we identified a novel transcript associated with the AluYb8MUTYH variant, which revealed that this transcript is about 780 nucleotides in length with a poly-A tail, lacks protein-coding potential, referred to as lncMUTYH. The results from the reporter gene system confirmed that the lncMUTYH down-regulates MUTYH1 expression at the translational level. Site-directed mutagenesis on the 5'-terminal exon sequences of α-MUTYH and lncMUTYH constructs revealed that lncMUTYH can act as a trans-regulator that depends on the partial base pairing between its exonized AluYb8 sequence and the 5'UTR of α-MUTYH to impede MUTYH 1 expression. Furthermore, we have demonstrated a correlation between decreased mitochondrion-localized MUTYH1 caused by lncMUTYH and lowered levels of mitochondrial biological function indicators, such as mtDNA content, mitochondrial regulatory gene expression, oxygen consumption rate, ATP product, and mitochondrial respiratory capacity. Notably, we found that lncMUTYH inhibited the M2-like polarization of macrophages, and CD68/CD206-positive cell fractions were significantly lower in lncMUTYH ectopically expressing cells. The results confirmed that the AluYb8MUTYH-associated lncMUTYH, derived from an AluYb8 insertion mutation, acts as a trans-regulatory factor that inhibits the MUTYH1 protein expression, leading to a progressive mitochondrial dysfunction that may disrupt macrophage differentiation. In summary, lncMUTYH can contribute to AluYb8MUTYH-associated mitochondrial dysfunction with age and hamper the macrophage polarization process, potentially increasing the risk of developing age-related diseases.

A novel non-coding RNA was identified derived from the AluYb8 insertion in the MUTYH gene, namely lncMUTYH.LncMUTYH selectively decreased the MUTYH1 protein localized in mitochondrial, which is dependent on the sequence and orientation derived from AluYb8 insertion.Overexpression of lncMUTYH dampens the mitochondrial function and M2-like polarization of macrophages, partly due to the suppression of the MUTYH1 protein.

Treatment patterns in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma post covalent Bruton tyrosine kinase inhibitor treatment: a Japanese claims database study.

Standard treatment has not been established for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after discontinuation of covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy. This retrospective, administrative database (Medical Data Vision) study described the patient characteristics, treatment patterns, and factors associated with receiving post-first-cBTKi treatment in Japanese patients with CLL/SLL. Patients aged ≥18 years with confirmed CLL/SLL diagnosis and treated with anti-neoplastic drugs indicated for CLL/SLL between March 2013 and February 2022 were included. Patient characteristics at baseline (first line), first cBTKi exposure (first-cBTKi), post-first-cBTKi treatment received, and the treatment sequence of CLL drugs received first line through third line, were described. Time-to-event analyses used the Kaplan-Meier method. Multivariable logistic regression analysis was used to explore factors associated with receiving post-first-cBTKi treatment among patients who discontinued first-cBTKi treatment. Among 2,424 eligible patients (median age: 72.0 years, 61.9% male), 450 (18.6%) received cBTKi in any treatment line. Among patients treated with cBTKi, 273 (60.7%) discontinued treatment; 56.0% of them (n = 153/273) received subsequent treatment. Median duration of post-first-cBTKi treatment was 2.2 months (95% confidence interval [CI]: 1.8, 3.5). The most common regimens post-first-cBTKi were cBTKi therapy (47.7%), bendamustine-based therapy (17.0%), and venetoclax-based therapy (13.1%). Patients aged <75 years (odds ratio [OR] [95% CI]: 2.0 [1.2, 3.4]) and those who did not receive blood transfusion during cBTKi treatment (OR [95% CI]: 2.3 [1.3, 4.1]) were more likely to receive post-first-cBTKi treatment. In conclusion, Japanese patients with CLL/SLL received various treatments for short duration after first-cBTKi discontinuation.

Treatment persistence of interleukin-17 inhibitor class drugs among patients with psoriasis in Japan: a retrospective database study.

BACKGROUND AND OBJECTIVE: Real-world evidence on persistence of interleukin-17 inhibitors (IL-17i) as a drug class among Japanese patients with psoriasis is lacking. Hence, we aimed to describe persistence rates of IL-17is among patients with psoriasis including psoriasis vulgaris (PsO), psoriatic arthritis (PsA), and generalized pustular psoriasis (GPP) or erythrodermic psoriasis (EP) in Japan. METHODS: We analyzed claims data from the Medical Data Vision database. Patients ≥15 years old with a psoriasis diagnosis and an IL-17i prescription between November 2016 and August 2020 were included and followed through August 2021. Persistence rates of the IL-17i class among patients with psoriasis and its subtypes (PsO, PsA, and GPP or EP), and persistence rates of ixekizumab, secukinumab, or brodalumab among patients with PsO or PsA were analyzed using Kaplan-Meier method. Analyses were conducted in the bio-naïve and bio-experienced subgroups. RESULTS: The IL-17i class had >50% persistence rates up to 36 months among patients with psoriasis and its subtypes (PsO, PsA, and GPP or EP). 36-Month persistence rates for ixekizumab, secukinumab, and brodalumab were 46.2% to 57.7% in patients with PsO and 43.0% to 48.4% in patients with PsA. Across analyses, bio-naïve patients demonstrated similar or greater persistence rates than bio-experienced patients. CONCLUSION: IL-17is' persistence rates over 36 months were >50% among patients with psoriasis and its subtypes (PsO, PsA, and GPP or EP) in Japan.

Body mass index and esophageal and gastric cancer: A pooled analysis of 10 population-based cohort studies in Japan.

The effect of body mass index (BMI) on esophageal and gastric carcinogenesis might be heterogeneous, depending on subtype or subsite. However, findings from prospective evaluations of BMI associated with these cancers among Asian populations have been inconsistent and limited, especially for esophageal adenocarcinoma and gastric cardia cancer. We performed a pooled analysis of 10 population-based cohort studies to examine this association in 394,247 Japanese individuals. We used Cox proportional hazards regression to estimate study-specific hazard ratios (HRs) and 95% confidence intervals (CIs), then pooled these estimates to calculate summary HRs with a random effects model. During 5,750,107 person-years of follow-up, 1569 esophageal cancer (1038 squamous cell carcinoma and 86 adenocarcinoma) and 11,095 gastric (728 cardia and 5620 noncardia) cancer incident cases were identified. An inverse association was observed between BMI and esophageal squamous cell carcinoma (HR per 5-kg/m2 increase 0.57, 95% CI 0.50-0.65), whereas a positive association was seen in gastric cardia cancer (HR 1.15, 95% CI 1.00-1.32). A nonsignificant and significant positive association for overweight or obese (BMI ≥25 kg/m2 ) relative to BMI <25 kg/m2 was observed with esophageal adenocarcinoma (HR 1.32, 95% CI 0.80-2.17) and gastric cardia cancer (HR 1.24, 95% CI 1.05-1.46), respectively. No clear association with BMI was found for gastric noncardia cancer. This prospective study-the largest in an Asian country-provides a comprehensive quantitative estimate of the association of BMI with upper gastrointestinal cancer and confirms the subtype- or subsite-specific carcinogenic impact of BMI in a Japanese population.

Clinicopathological and prognostic significance of elevated BTF3 expression in gastric cancer.

The purpose of this paper was to explore the significance of basic transcription factor 3 (BTF3) in the process and clinicopathological parameters of gastric cancer (GC) patients. GC tissues were collected in our hospital to detect the mRNA expression of BTF3 by quantitative real-time polymerase chain reaction (Q-PCR). Western blot analysis was performed to detect the protein expression of BTF3. Kaplan-Meier method and Log-rank analysis were used to analyze the progression-free survival time and overall time of GC patients, while the Chi-square test was used to investigate the association between BTF3 and clinicopathological parameters of GC patients. SiRNA was designed to suppress the expression of BTF3. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay and transwell assay were conducted to determine the viability and invasion ability of GC cells. BTF3 was found abnormally up-regulated in GC tissues and cells and was related to the Grade, Lymph node metastasis and stage of GC patients, as well as the poor progression-free survival and overall survival of them. Besides, inhibition of BTF3 in GC cells could trigger the reduction of cell viability and invasion ability. Our results demonstrated that BTF3 played an important role in the process of GC and could be regarded as a new target for the diagnosis and therapy of GC.

[Mechanism of Kaixin Powder prescriptions Buxin Decoction regulating PI3K/AKT signaling pathway to protect cardiovascular system: based on network pharmacology and experimental verification].

This study established the EA.hy926 cell myocardial ischemia model to compare the effects of two Kaixin Powder prescriptions, Buxin Decoction(BXD) and Dingzhi Pills(DZP), at three dosages(500, 200, and 100 µg·mL~(-1)) on the cell viability. Further, the public databases(TCMSP, TCMID, SYMMAP, and STRING) and the network pharmacology methods such as KEGG pathway enrichment were employed to decipher the possible molecular mechanism of BXD in exerting the cardioprotective effect. The pharmacological effect of BXD was evaluated with the rat model of isoprenaline(ISO)-induced myocardial ischemia. The expression levels of proteins involved in the phosphatidylinositol-3-kinase/protein kinase B(PI3 K/AKT) signaling pathway were measured by Western blot. BXD significantly increased the viability of EA.hy926 cells, showing the performance superior to DZP. The network pharmacology analysis predicted that BXD might exert cardiac protection through the PI3 K/AKT signaling pathway. The in vivo experiment on rats showed that BXD treatment significantly increased the cardiac ejection fraction(EF), fractional shortening(FS), diastolic left ventricular anterior wall(LVAWd), systolic left ventricular anterior wall(LVAWs), and diastolic left ventricular posterior wall(LVPWd), significantly decreased the beat per minute(BPM) and diastolic left ventricular internal diameter(LVIDd), and significantly improved the ST segment in the electrocardiogram. The pathological results(Masson staining) showed that BXD restored the myocardial thickness, decreased the collagen fiber, increased the muscle fiber, and reduced the infarct area to alleviate myocardial ischemia. Furthermore, BXD lowered the serum levels of inflammatory cytokines [tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6)] and myocardial enzymes [creatine kinase(CK) and lactate dehydrogenase(LDH)], increased the p-AKT/AKT ratio, up-regulated the protein levels of PI3 K, NF-κB, IKK-α, and Bcl-xl, and down-regulated that of the apoptotic protein Bax. In conclusion, BXD may exert cardiac protection effect by regulating the PI3 K/AKT signaling pathway.

Dissecting super-enhancer driven transcriptional dependencies reveals novel therapeutic strategies and targets for group 3 subtype medulloblastoma.

BACKGROUND: Medulloblastoma is the most common malignant pediatric brain tumor and group 3 subtype medulloblastoma (G3-MB) exhibits the worst prognosis. Super enhancers (SEs) are large clusters of enhancers that play important roles in cancer through transcriptional control of cell identity genes, oncogenes and tumor-dependent genes. Dissecting SE-driven transcriptional dependencies of cancer leads to identification of novel oncogenic mechanisms, therapeutic strategies and targets. METHODS: Integrative SE analyses of primary tissues and patient-derived tumor cell lines of G3-MB were performed to extract the conserved SE-associated gene signatures and their oncogenic potentials were evaluated by gene expression, tumor-dependency and patient prognosis analyses. SE-associated subtype-specific upregulated tumor-dependent genes, which were revealed as members of SE-driven core transcriptional regulatory network of G3-MB, were then subjected to functional validation and mechanistic investigation. SE-associated therapeutic potential was further explored by genetic or pharmaceutical targeting of SE complex components or SE-associated subtype-specific upregulated tumor-dependent genes individually or in combination, and the underlying therapeutic mechanisms were also examined. RESULTS: The identified conserved SE-associated transcripts of G3-MB tissues and cell lines were enriched of subtype-specifically upregulated tumor-dependent genes and MB patients harboring enrichment of those transcripts exhibited worse prognosis. Fourteen such conserved SE-associated G3-MB-specific upregulated tumor-dependent genes were identified to be members of SE-driven core transcriptional regulatory network of G3-MB, including three well-recognized TFs (MYC, OTX2 and CRX) and eleven newly identified downstream effector genes (ARL4D, AUTS2, BMF, IGF2BP3, KIF21B, KLHL29, LRP8, MARS1, PSMB5, SDK2 and SSBP3). An OTX2-SE-ARL4D regulatory axis was further revealed to represent a subtype-specific tumor dependency and therapeutic target of G3-MB via contributing to maintaining cell cycle progression and inhibiting neural differentiation of tumor cells. Moreover, BET inhibition with CDK7 inhibition or proteasome inhibition, two combinatory strategies of targeting SE complex components (BRD4, CDK7) or SE-associated effector gene (PSMB5), were shown to exhibit synergistic therapeutic effects against G3-MB via stronger suppression of SE-associated transcription or higher induction of ER stress, respectively. CONCLUSIONS: Our study verifies the oncogenic role and therapeutic potential of SE-driven transcriptional dependencies of G3-MB, resulting in better understanding of its tumor biology and identification of novel SE-associated therapeutic strategies and targets.

A redox-activated Pt(IV) pro-probe: From G-quadruplex imaging to cancer therapy.

Efficient uptake to both cytoplasm and nucleus in live cells remains a key obstacle for G-quadruplex targeting fluorophores. We developed a Pt(IV) complex by oxidizing a bisphenanthrolinyl Pt(II) complex, which is our first generation G-quadruplex specific fluorogenic probe.15 The axial lipophilic ligand assists Pt(IV) pro-probe to enter live cells and reach the nucleus rapidly. In situ reduction of Pt(IV) pro-probe restores parental Pt(II) complex, and sequentially lights up both RNA and DNA G-quadruplexes in live cancerous cells simultaneously. Pt(IV) pro-probe shows potent cytotoxicity after long time incubation as a dual-functional theranostic agent.

HMGN5 Escorts Oncogenic STAT3 Signaling by Regulating the Chromatin Landscape in Breast Cancer Tumorigenesis.

Cancer progression is highly dependent on the ability of cancer cell tumor formation, in which epigenetic modulation plays an essential role. However, the epigenetic factors promoting breast tumor formation are less known. Screened from three-dimensional (3D)-sphere tumor formation model, HMGN5 that regulates chromatin structures became the candidate therapeutic target in breast cancer, though its role is obscure. HMGN5 is highly expressed in 3D-spheres of breast cancer cells and clinical tumors, also an unfavorable prognostic marker in patients. Furthermore, HMGN5 controls tumor formation and metastasis of breast cancer cells in vitro and in vivo. Mechanistically, HMGN5 is governed by active STAT3 transcriptionally and further escorts STAT3 to shape the oncogenic chromatin landscape and transcriptional program. More importantly, interference of HMGN5 by nanovehicle-packaged siRNA effectively inhibits tumor growth in breast cancer cell-derived xenograft mice model. IMPLICATIONS: Our findings reveal a novel feed-forward circuit between HMGN5 and STAT3 in promoting breast cancer tumorigenesis and suggest HMGN5 as a novel epigenetic therapeutic target in STAT3-hyperactive breast cancer.

A universal co-expression gene network and prognostic model for hepatic-biliary-pancreatic cancers identified by integrative analyses.

Hepatic, biliary and pancreatic cancers are a diverse set of malignancies with poor prognoses. It is possible that common molecular mechanisms are involved in the carcinogenesis of these cancers. Here, we identified LINC01537 and seven protein-coding genes by integrative analysis of transcriptomes of mRNAs, microRNAs and long non-coding RNAs from cholangiocarcinoma, hepatocellular carcinoma and pancreatic adenocarcinoma cohorts in TCGA. A predictive model constructed from seven biomarkers was established to successfully predict the survival rate of patients, which was then further verified in external cohorts. Additionally, patients with high-risk scores in our model were prone to epithelial-mesenchymal transition. Finally, activation of the biomarker PDE2A significantly attenuated migration and epithelial-mesenchymal transition in the HepG2 liver cancer cell line.

Histone methyltransferase KMT2D contributes to the protection of myocardial ischemic injury.

Histone H3 lysine 4 (H3K4) methyltransferase 2D (KMT2D) plays an important role in cell development in early life. However, the function of KMT2D in adult cells such as cardiomyocytes or neurons has not been reported. In this study, cardiomyocyte-specific KMT2D knockout (KMT2D-cKO) and control (KMT2D-Ctl) mice were exposed to sham or myocardial ischemia (MI) surgery. Depletion of KMT2D aggravated the ischemic area, led to the increased mortality (26.5% in KMT2D-cKO vs 12.5% in KMT2D-Ctl) of the mice, and weakened the left ventricular systolic function. RNA-seq analysis in cardiac tissues identified genes whose expression was changed by MI and KMT2D deletion. Combined with the genome-wide association study (GWAS) analysis, cardiac disease-associated genes Rasd1, Thsd7a, Ednra, and Tns1 were identified. The expression of the Rasd1 was significantly decreased by MI or the loss of KMT2D in vivo. Meanwhile, ChIP assays demonstrated that either MI or loss of KMT2D attenuated monomethylated H3K4 (H3K4me1) enrichment on the enhancer of Rasd1. By generating a KMT2D knockout (H9C2-KO) H9C2 monoclone, we verified that the expression of Rasd1 was controlled by KMT2D, and the expression of Rasd1 was decreased by serum starvation but not low-(O2) treatment in H9C2 cells. KMT2D has a protective effect on ischemic myocardium by regulating cardiac disease-associated genes including Rasd1. KMT2D is required for the H3K4me1 deposition on the enhancer of Rasd1. Our data for the first time suggest that KMT2D-mediated Rasd1 expression may play an important protective effect on adult cells during nutritional deficiency caused by ischemic injury.

Relative risk of gastric cancer between those with and without Helicobacter pylori infection history in Japan.

Background and Aim: The causal relationship between Helicobacter pylori (H. pylori) infection and gastric cancer has been established. Although the magnitude of the carcinogenic effect of H. pylori is the next concern, it has not been sufficiently evaluated in Japan. Spontaneous disappearance of H. pylori infection may have provoked underestimation of the carcinogenic effect of the infection. To reduce the influence, a comparison should be carried out between subjects with and without the infection history. Cutoff values of H. pylori antibody lower than the manufacturer's recommendation are known to be more appropriate to diagnose history of H. pylori infection. The aim was to evaluate the carcinogenic effect of H. pylori. Methods: A case-control study consisting of 275 gastric cancer patients and 275 age- and sex-matched controls was performed. Serum H. pylori antibody was measured using the "JHM-Cap" kit with a domestic antigen (cut value of the manufacturer's recommendation was 2.3 EV: ELISA value). Using a conditional logistic model, the odds ratios (ORs) for five cutoff values adjusted for smoking and drinking doses were calculated. Results: For cutoff values of 1.25, 1.5, 1.75, 2.0, and 2.3 EV, the ORs (95% confidence intervals) were 67.7 (9.1, 502), 37.2 (8.8, 157), 21.3 (9.0, 60.2), 25.5 (9.0, 72.7), and 25.9 (9.2, 73.2), respectively. Conclusions: These results suggest that the risk ratio of gastric cancer between subjects with and without history of H. pylori infection in Japan may exceed 20.

Lifetime incidence risk for gastric cancer in the Helicobacter pylori-infected and uninfected population in Japan: A Monte Carlo simulation study.

Helicobacter pylori (H. pylori) infection is considered the leading cause of gastric cancer. Gastric cancer is currently a common cancer with high incidence and mortality rates, but it is expected that the incidence rate will gradually decrease as the H. pylori infection prevalence decreases in the future. When evaluating the effectiveness of gastric cancer prevention strategies, it is essential to note the differences in long-term cumulative risks between H. pylori-infected and uninfected populations, but this has not yet been precisely evaluated. In our study, we aimed to estimate the cumulative incidence risks of developing gastric cancer from birth to 85 years among H. pylori-infected and uninfected populations by using population-based cancer registry data and birth year-specific H. pylori infection prevalence rates. Death from gastric cancer and other causes of death were considered in the estimations of the adjusted cumulative incidence risks stratified by sex and H. pylori infection status. After performing 5000 Monte Carlo simulations with repeated random sampling using observed cancer incidence in selected three prefectures (Fukui, Nagasaki, Yamagata) of prefectural population-based cancer registry in Japan, the mean adjusted cumulative incidence risk for gastric cancer in the H. pylori-infected population was 17.0% for males and 7.7% for females and 1.0% for males and 0.5% for females in the uninfected population. These results calculated with Japanese cancer registry data may be useful in considering and evaluating future prevention strategies for gastric cancer in Japan.

Low-intensity cigarette smoking and mortality risks: a pooled analysis of prospective cohort studies in Japan.

BACKGROUND: Increasing proportions of smokers in Japan smoke <10 cigarettes per day (CPD). Yet, the health risks of low-intensity smoking in Asia are poorly understood. METHODS: We performed a pooled analysis of 410 294 adults from nine population-based prospective cohort studies participating in the Japan Cohort Consortium. Cigarette-use data were collected at each study baseline in 1983-1994. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality were calculated using multivariable-adjusted Cox regression by CPD among current smokers and by age at cessation among former smokers, with never smokers as the referent group. Pooled HRs and CIs were computed using a random-effect model. RESULTS: The smoking prevalence was 54.5% in men and 7.4% in women. About 15.5% of male and 50.4% of female current smokers smoked 1-10 CPD (low-intensity). Both male and female low-intensity smokers had higher all-cause mortality risks than never smokers. Risks were further higher with increasing CPD in a dose-response manner. HRs (95% CIs) were 1.27 (0.97-1.66), 1.45 (1.33-1.59) and 1.49 (1.38-1.62) for 1-2, 3-5 and 6-10 CPD, respectively, in men; 1.28 (1.01-1.62), 1.49 (1.34-1.66) and 1.68 (1.55-1.81) for 1-2, 3-5 and 6-10 CPD, respectively, in women. Similar associations were observed for smoking-related causes of death. Among former low-intensity smokers, younger age at cessation was associated with lower mortality risk. CONCLUSIONS: Smoking very low amounts was associated with increased mortality risks in Japan. All smokers should quit, even if they smoke very few CPD.