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Microvascular angina (MVA) is the most common cause of cardiac ischemic chest pain in patients without obstructive coronary artery disease (CAD) and lacks of effective treatment means. Medicine food homology (MFH) involves substances with both nutritional and medicinal qualities that have the potential to improve MVA symptoms as medicines, dietary supplements. However, research on MFH formula (MFHF) for MVA is not available. The study aims to generate a core MFHF for MVA through data mining and offer scientific backing for the utilization of edible medications in the prevention and alleviation of MVA. 11 databases were utilized to construct a database of MFH drugs, and the MFHF was generated through frequency analysis, association rule analysis, and clustering analysis. The composition of the formula is Codonopsis Radix, Astragali Radix, Platycodonis Radix, Persicae Semen, Glycyrrhizae Radix Et Rhizoma, Angelicae Sinensis Radix, and Allii Macrostemonis Bulbus. Through network pharmacology and molecular docking, we identified five major active components of MFHF: Adenosine, Nonanoic Acid, Lauric Acid, Caprylic Acid, and Enanthic Acid, along with nine core targets (NFKB1, ALB, AKT1, ACTB, TNF, IL6, ESR1, CASP3, and PTGS) for the improvement of MVA. These 5 active components have various biological activities, such as reducing oxidative stress, anti-inflammation, analgesia effect, inhibiting platelet aggregation, vasodilatation, vascular endothelial protection, and cardio-protection. GO and KEGG enrichment analyses revealed that MFHF mainly acted on the response to xenobiotic stimulus, integrative component of the plasma membrane, RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding, pathways in cancer, lipid and atherosclerosis, human cytomegalovirus infection, and the PI3K-Akt signaling pathway, which are the main pathogenesis of MVA.

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BACKGROUND: Breast cancer (BC) poses significant burdens on women globally. While past research suggests a potential link between bone mineral density (BMD) and BC risk, findings remain inconsistent. Our study aims to elucidate the causal relationship between BMD and BC in East Asians using bidirectional Mendelian randomization (MR). METHODS: Genetic association data for bone mineral density T-scores (BMD-T) and Z-scores (BMD-Z) (Sample size = 92,615) and BC from two different sources (Sample size1 = 98,283; Sample size2 = 79,550) were collected from publicly available genome-wide association studies (GWAS). Single-nucleotide polymorphisms (SNPs) associated with BMD-T and BMD-Z as phenotype-related instrumental variables (IVs) were used, with BC as the outcome. As the primary means of causal inference, the inverse variance weighted (IVW) approach was employed. Heterogeneity analysis was conducted using Cochran's Q test, while MR-Egger regression analysis was implemented to assess the pleiotropic effects of the IVs. Sensitivity analyses were performed using methods such as MR-Egger, weighted median, and weighted mode to analyze the robustness and reliability of the results. The MR-PRESSO method and the RadialMR were used to detect and remove outliers. The PhenoScanner V2 website was utilized to exclude confounding factors shared between BMD and BC. Besides, the Bonferroni correction was also used to adjust the significance threshold. Then, the meta-analysis method was applied to combine the MR analysis results from the two BC sources. Finally, a reverse MR analysis was conducted. RESULTS: The results of the IVW method were consolidated through meta-analysis, revealing a positive correlation between genetically predicted BMD-T ([Formula: see text], [Formula: see text], [Formula: see text]) and BMD-Z ([Formula: see text],[Formula: see text], [Formula: see text]) with increased BC risk. The Cochran's [Formula: see text] test and MR-Egger regression suggested that neither of these causal relationships was affected by heterogeneity or horizontal pleiotropy. The sensitivity analyses supported the IVW results, indicating the robustness of the findings. Reverse MR analysis showed no causal relationship between BC and BMD. CONCLUSION: Our MR study results provide evidence for the causal relationship between BMD and BC risk in East Asian populations, suggesting that BMD screening is of great significance in detecting and preventing BC.

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Objective: The present study aimed to explore the potential causal relationship between childhood asthma and chronic obstructive pulmonary disease (COPD) in European and East Asian populations with Mendelian randomization (MR) analysis. Methods: Based on summary data from genome-wide association studies, single nucleotide polymorphisms (SNPs) associated with childhood asthma were used as instrumental variables. The MR analysis employed the inverse variance weighting, MR-Egger regression and weighted median method to estimate the causal effect between childhood asthma and COPD in European and East Asian populations. Cochran's Q test, MR-PRESSO method and MR-Egger intercept were used to detect heterogeneity, outliers and horizontal pleiotropy, respectively. Leave-one-out analysis applied to assess the effect of removing individual SNP on the estimate of causal association. Results: The MR analysis showed no genetic causal relationship between childhood asthma and COPD. The results of Cochran's Q test, MR-PRESSO and MR-Egger regression indicated the absence of heterogeneity, outliers and horizontal pleiotropy, respectively. Leave-one-out analysis showed no significant difference in the statistical results after exclusion of single SNPs. Conclusions: The MR analysis revealed that there is no causal relationship between childhood asthma and COPD at the genetic level in both European and East Asian populations. Additionally, due to the presence of shared confounding factors and pathogenic genes, further research is needed to comprehensively assess the relationship between childhood asthma and COPD.

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In this paper, we present a comprehensive guide for implementing artificial intelligence (AI) techniques in traditional East Asian medicine (TEAM) research. We cover essential aspects of the AI model development pipeline, including research objective establishment, data collection and preprocessing, model selection, evaluation, and interpretation. The unique considerations in applying AI to TEAM datasets, such as data scarcity, imbalance, and model interpretability, are discussed. We provide practical tips and recommendations based on best practices and our own experience. The potential of large language models in TEAM research is also highlighted. Finally, we discuss the challenges and future directions of AI application in TEAM, emphasizing the need for standardized data collection and sharing platforms.

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Introduction: Following acute enterovirus (EV) infection, outcomes vary based on factors like the immune response, viral cell entry receptor expression levels, tissue tropism, and genetic factors of both the host and virus. While most individuals exhibit mild, self-limited symptoms, others may suffer severe complications or prolonged infections that can lead to autoimmune disorders. Methods: To elucidate host responses to EV infection, we performed whole exome sequencing on blood samples from both infected and uninfected individuals. Our initial focus was on genes encoding EV entry receptors-PSGL-1, SCARB2, and ANAXA2 for EV-A71, and CD155 for poliovirus-and on host genes ACBD3 and PI4KΒ, crucial for EV replication. Results: Although no specific genetic variants directly associated with EV infection were identified, we discovered 118 variants across 116 genes enriched in East Asian populations through multi-layered variant filtering. These variants were further analyzed for their potential impacts on organs, biological processes, and molecular pathways. Phenome-wide association studies were conducted to refine our understanding of their contributions to EV infection susceptibility. Discussion: Our findings aim to develop a predictive panel based on these 118 variants, which could help susceptible individuals during EV outbreaks, guiding targeted clinical interventions and preventative strategies.

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Background: Conventional medicine (CM) for paroxysmal atrial fibrillation (PAF) have limitations and side effects. Integrative approaches, including traditional herbal medicines like Liriope Tuber, are being explored for potential benefits, although evidence remains limited. Methods: In April 2023, a literature search was conducted across nine databases, focusing on randomized controlled trials assessing the effects of Liriope Tuber in traditional herbal medicine (LTHM) on PAF. The risk of bias was evaluated using Version 2 of the Cochrane risk-of-bias tool for randomized trials. A random-effects model was employed for the meta-analysis. Results: A total of 43 studies with 3,743 participants were included. The meta-analysis indicated that adding LTHM to CM reduced PAF frequency (SMD = -0.99, 95 % CI = -1.40 to -0.57, I² = 88 %, N = 16, n = 1266), left atrium diameter (LAD) (MD = -2.39 mm, 95 % CI = -3.09 to -1.68), P-wave dispersion (Pd) (MD = -6.41 ms, 95 % CI = -8.44 to -4.37), high sensitive C-Reactive Protein (hs-CRP) (MD = -1.10 mg/l, 95 % CI = -1.73 to -0.47), and improved left ventricular ejection fraction (LVEF) (MD = 4.71 %, 95 % CI = 3.17 to 6.25). Thirty-four studies raised concerns about bias, with eight showing high risk. Certainty of evidence was rated as "low" for PAF frequency, LAD, Pd, hs-CRP, and LVEF. Conclusion: LTHM combined with CM may reduce PAF frequency. However, due to the complexity of interventions, with Liriope Tuber being only one component of the regimen, high risk of bias, substantial heterogeneity, and indirectness, interpretations should be cautious. Study registration: PROSPERO (ID: CRD42023477926).

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BACKGROUND AND HYPOTHESIS: While genetic correlations, pleiotropic loci, and shared genetic mechanisms of psychiatric disorders have been extensively studied in European populations, the investigation of these factors in East Asian populations has been relatively limited. STUDY DESIGN: To identify novel pleiotropic risk loci for depression and schizophrenia (SCZ) in East Asians. We utilized the most comprehensive dataset available for East Asians and quantified the genetic overlap between depression, SCZ, and their related traits via a multitrait genome-wide association study. Global and local genetic correlations were estimated by LDSC and ρ-HESS. Pleiotropic loci were identified by the multitrait analysis of GWAS (MTAG). STUDY RESULTS: Besides the significant correlation between depression and SCZ, our analysis revealed genetic correlations between depression and obesity-related traits, such as weight, BMI, T2D, and HDL. In SCZ, significant correlations were detected with HDL, heart diseases and use of various medications. Conventional meta-analysis of depression and SCZ identified a novel locus at 1q25.2 in East Asians. Further multitrait analysis of depression, SCZ and related traits identified ten novel pleiotropic loci for depression, and four for SCZ. CONCLUSIONS: Our findings demonstrate shared genetic underpinnings between depression and SCZ in East Asians, as well as their associated traits, providing novel candidate genes for the identification and prioritization of therapeutic targets specific to this population.

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Background: Menopausal insomnia significantly impacts the quality of life in women. East Asian herbal medicines (EAHMs) have been traditionally used in Asian countries, but their efficacy and safety require systematic evaluation. This systematic review and meta-analysis aimed to evaluate the effectiveness and safety of EAHM for treating menopausal insomnia. Methods: A comprehensive literature search was conducted across 10 electronic databases from inception until 19 July 2023. Randomized controlled trials (RCTs) investigating EAHM for menopausal insomnia were included. Two reviewers independently screened studies, extracted data, and assessed the risk of bias using the Cochrane risk of bias tool. The primary outcome was sleep quality, insomnia severity, and sleep architecture. Secondary outcomes included total effective rate (TER), menopausal symptoms, and adverse effects. Meta-analysis was conducted using a random-effects model, and the results were calculated as mean differences (MDs) or risk ratios (RRs) and their 95% confidence intervals (CIs). Also, the certainty of evidence was assessed using the GRADE approach. Results: A total of 70 RCTs involving 6,035 participants met the inclusion criteria. The most frequently used EAHMs were modified Suan Zao Ren Tang, and the most frequently used herbal component was Zizyphus jujuba Miller var. spinosa Hu ex H. F. Chou [Rhamnaceae; Zizyphi Semen]. Compared with sedative-hypnotics, EAHM significantly improved sleep quality, as measured by the Pittsburgh Sleep Quality Index (PSQI) (MD -2.18, 95% CI -2.56 to -1.80), and reduced menopausal symptoms, as assessed by the Kupperman Index (MD -4.92, 95% CI -6.03 to -3.80). Similar results were seen when EAHM was added to sedative-hypnotics. When EAHM was additionally used in sedative-hypnotics, similar benefits were shown for PSQI (MD -2.46, 95% CI -3.09 to -1.82) and the Kupperman Index (MD -4.64, 95% CI -5.07 to -4.21). EAHM was generally safer than sedative-hypnotics, with significantly fewer adverse reactions (RR 0.15, 95% CI 0.07-0.34). However, the certainty of evidence was moderate to low. Conclusion: EAHMs, alone or with sedative-hypnotics, may be effective and safe for improving sleep quality and managing menopausal symptoms. Future studies should include diverse populations, rigorous methodologies, and explore mechanisms of action to confirm these findings. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?], identifier [CRD42023446708].

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OBJECTIVE: This study investigated the clinical details and usage of Sa-am acupuncture in Korean medicine clinics and explored how practicing Korean medicine doctors (KMDs) think about Sa-am acupuncture. METHODS: We conducted a questionnaire-based survey of KMDs who utilize Sa-am acupuncture in their practice. The study comprehensively investigated issues related to clinical application of Sa-am acupuncture, needling techniques used during treatment, training methods, and directions for its future improvement. RESULTS: We analyzed 572 responses. An average of 50% of the patients visiting Korean medicine clinics were receiving Sa-am acupuncture. The most prevalent indication for Sa-am acupuncture use was digestive disorders. The patients' appetite level and digestive function were most frequently used indicators for selecting acupuncture points. Regarding prescription compositions, Jung-Gyuk formulas were more frequently used than Seung-Gyuk formulas. Inserting the needle along the flow of the channel or against the flow of the channel was most popular. The acupuncture style most frequently used in combination with Sa-am acupuncture was Ashi point acupuncture. Strengths of Sa-am acupuncture included its versatility, easy application, and good outcomes. Limitations included the lack of rigorous education and training programs, difficulty in applying the principles for beginners, and insufficient clinical research evidence. CONCLUSION: In clinics where Sa-am acupuncture is available, KMDs were providing Sa-am acupuncture to about half of their patients. Practitioners were not using all of the tonification and sedation techniques which may be due to time constraints or simply a lack of necessity. Sa-am acupuncture demonstrated high utility in clinical practice and high satisfaction based on the efficacy and safety. More training programs and high-quality research are needed to help expand the use of Sa-am acupuncture. Please cite this article as: Park JY, Lee YS, Park HJ, Lee SK, Lee JW, Kim SY. A survey on the real-world clinical utilization of a traditional acupuncture in Republic of Korea: Sa-am acupuncture. J Integr Med. 2024; Epub ahead of print.

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Osteoarthritis (OA), characterized by chronic pain and joint degradation, is a progressive joint disease primarily induced by age-related systemic inflammation. Angelica gigas Nakai (AG), a medicinal plant widely used in East Asia, exhibits promising results for such conditions. This study aimed to evaluate the potential of AG as a drug candidate for modulating the multifaceted pathology of OA based on its anti-inflammatory properties. We evaluated the efficacy of AG in pain relief, functional improvement, and cartilage erosion delay using monosodium iodoacetate-induced OA rats and acetic acid-induced writhing mice, along with its anti-inflammatory effects on multiple targets in the serum and cartilage of in vivo models and lipopolysaccharide-stimulated RAW 264.7 cells. In vivo experiments demonstrated significant analgesic and chondroprotective effects of AG, along with functional recovery, in model animals compared with the active controls. AG dose-dependently modulated inflammatory OA pathology-related targets, including interleukin-1ß, tumor necrosis factor-α, matrix metalloproteinase-13, and cyclooxygenase-2, both in vitro and in vivo. In conclusion, AG could be a potential drug candidate for modulating the multifaceted pathology of OA. Nevertheless, further comprehensive investigations, involving a broader range of compounds, pathologies, and mechanisms, are warranted to validate these findings.

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Rosacea is a chronic inflammatory disorder primarily affecting the facial skin, prominently involving the cheeks, nose, chin, forehead, and periorbital area. Cutaneous manifestations encompass persistent facial erythema, phymas, papules, pustules, telangiectasia, and flushing. The pathogenesis of rosacea is associated with various exacerbating or triggering factors, including microbial infestation, temperature fluctuations, sunlight exposure, physical exertion, emotional stress, consumption of hot beverages and spicy foods, and exposure to airborne pollen. These environmental factors interact with genetic predispositions in the development of rosacea. The roles of the lipophilic microbiome, ultraviolet radiation, nociceptive responses, and vascular alterations have been proposed as significant factors in the pathogenesis. These insights contribute to understanding the anatomical specificity of facial involvement and the progressive nature of rosacea. East Asian skin, predominantly classified as Fitzpatrick skin phototypes III to IV, is characterized by relatively diminished skin barrier function and increased sensitivity to irritants. Airborne pollen exposure may particularly act as a trigger in East Asian individuals, possibly mediated through toll-like receptors. The lack of specificity in objective clinical and histopathological findings leads to diagnostic challenges for individuals with colored skin, including East Asians, particularly when erythema is the sole objective manifestation. An alternative diagnostic scheme may thus be necessary. A diagnostic approach emphasizing vascular manifestations and nociceptive symptoms potentially holds promise for individuals with darker skin tones. More research focusing on potential variations in skin physiology across different racial groups is essential to establish more effective diagnostic schemes applicable to both dark and light skin colors.

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BACKGROUND: Height is associated with increased cancer risk, but most studies focus on Western populations. We aimed to evaluate this relationship in East Asians. METHOD: Observational analyses were performed utilizing data from China Kadoorie Biobank (CKB) prospective cohort. Adjusted hazard ratios (HRs) and corresponding 95 % confidence intervals (CIs) were estimated using Cox proportional hazards models. Two-sample Mendelian randomization (MR) analyses explored causal effects between height and cancer using data from Korean Genome and Epidemiology Study (KoGES), Biobank Japan (BBJ), and CKB. RESULTS: Over a median 10.1-years follow-up, 22,731 incident cancers occurred. In observational analyses, after Bonferroni correction, each 10 cm increase in height was significantly associated with higher risk of overall cancer (HR 1.16, 95 % CI 1.14-1.19, P < 0.001), lung cancer (1.18, 95 % CI 1.12-1.24, P < 0.001), esophageal cancer (1.21, 95 % CI 1.12-1.30, P < 0.001), breast cancer (1.41, 95 % CI 1.31-1.53, P < 0.001), and cervix uteri cancer (1.29, 95 % CI 1.15-1.45, P < 0.001). Each 10 cm increase in height was suggestively associated with increased risk for lymphoma (1.18, 95 % CI 1.04-1.34, P = 0.010), colorectal cancer (1.09, 95 % CI 1.02-1.16, P = 0.010), and stomach cancer (1.07, 95 % CI 1.00-1.14, P = 0.044). In MR analyses, genetically predicted height (per 1 standard deviation increase, 8.07 cm) was suggestively associated with higher risk of lung cancer (odds ratio [OR] 1.17, 95 % confidence interval [CI] 1.02-1.35, P = 0.0244) and gastric cancer (OR 1.14, 95 % CI 1.02-1.29, P = 0.0233). CONCLUSIONS: Taller height was significantly related to a higher risk for overall cancer, lung cancer, esophageal cancer, breast cancer, and cervix uteri cancer. Our findings suggest that height may be a potential causal risk factor for lung and gastric cancers among East Asians.

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Acral peeling skin syndrome (APSS; MIM 609796) is a rare genodermatosis characterized by painless focal cutaneous exfoliation of the dorsal hands and feet, typically displaying autosomal recessive inheritance. While cases associated with a founder mutation in TGM5 are relatively common in European Caucasian populations, no APSS cases have been reported from Japan or other East Asian countries. In contrast, Nagashima-type palmoplantar keratosis (NPPK; MIM 615598), caused by variants in SERPINB7, is relatively common in East Asia due to founder mutations. We describe a 27-year-old Japanese woman with spontaneous focal cutaneous exfoliation of the dorsal hand following prolonged glove use, indicative of APSS. Histopathological examination revealed a cleft between the stratum corneum and stratum granulosum and within the horny layer of the epidermis, supporting this diagnosis. However, her mother and maternal uncle exhibited similar symptoms, and there was no reported consanguinity in the patient's parents or grandparents, prompting suspicion of an autosomal dominant genodermatosis. Whole-genome sequencing (WGS) revealed compound heterozygous variants in TGM5 (c.1037G>A and c.684 + 1G>A) as suspected causative variants in the patient, leading to an APSS diagnosis, the first reported in East Asia. On the other hand, her mother and maternal uncle were diagnosed with NPPK due to compound heterozygous pathogenic variants in SERPINB7 (c.796C>T and c.455-1G>A). This case highlights the complexity of diagnosing skin disorders when multiple genodermatoses with similar phenotypes exist within a pedigree. Comprehensive genetic analyses, such as whole-exome sequencing and WGS, are invaluable for identifying causative variants in such complex cases.

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Psoriasis is a chronic, immune-mediated inflammatory skin disease with many complications and a poor prognosis that imposes a significant burden on individuals and society. Narrowband ultraviolet B (NB-UVB) represents a cost-effective non-drug therapeutic intervention for psoriasis. East Asian herbal medicine (EAHM) is currently being investigated for its potential as a safe and effective psoriasis treatment. Consequently, it has the potential to be employed as a combination therapy with NB-UVB. The objective was to ascertain the efficacy and safety of the EAHM with NB-UVB combination therapy and to identify important drugs for further research. In this study, randomized controlled trials (RCTs) were retrieved from ten databases in Korea, China, and Japan. All statistical analyses were conducted using R software version 4.3.0. The primary outcomes were the Psoriasis Area and Severity Index (PASI) and the incidence rate of adverse events (AEs), while the secondary outcomes were hematologic markers and the Dermatology Life Quality Index (DLQI), which reflect the immune-mediated inflammatory pathology of psoriasis. The analysis of 40 RCTs, including 3521 participants, demonstrated that EAHM with NB-UVB combination therapy exhibited a statistically significant superiority over NB-UVB monotherapy with respect to primary and secondary outcomes. The Bayesian network meta-analysis revealed that Investigator Presciption 3 and Ziyin Liangxue Decoction exhibited a consistent relative advantage with respect to each PASI-based efficacy metric. The network analysis estimated the potential influence ranking for all individual herbs according to PageRank centrality. The findings of this study suggest that EAHMs co-administered with NB-UVB may provide additional efficacy and safety-related benefits for patients with psoriasis. However, the quality of evidence is still low, and further high-quality trials are needed to reach more definitive conclusions.

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East Asian Passiflora virus (EAPV) causes passionfruit woodiness disease, a major threat limiting passionfruit production in eastern Asia, including Taiwan and Vietnam. In this study, an infectious cDNA clone of a Taiwanese severe isolate EAPV-TW was tagged with a green fluorescent protein (GFP) reporter to monitor the virus in plants. Nicotiana benthamiana and yellow passionfruit plants inoculated with the construct showed typical symptoms of EAPV-TW. Based on our previous studies on pathogenicity determinants of potyviral HC-Pros, a deletion of six amino acids (d6) alone and its association with a point mutation (F8I, simplified as I8) were conducted in the N-terminal region of the HC-Pro gene of EAPV-TW to generate mutants of EAPV-d6 and EAPV-d6I8, respectively. The mutant EAPV-d6I8 caused infection without conspicuous symptoms in N. benthamiana and yellow passionfruit plants, while EAPV-d6 still induced slight leaf mottling. EAPV-d6I8 was stable after six passages under greenhouse conditions and displayed a zigzag pattern of virus accumulation, typical of a beneficial protective virus. The cross-protection effectiveness of EAPV-d6I8 was evaluated in both N. benthamiana and yellow passionfruit plants under greenhouse conditions. EAPV-d6I8 conferred complete cross-protection (100%) against the wild-type EAPV-TW-GFP in both N. benthamiana and yellow passionfruit plants, as verified by no severe symptoms, no fluorescent signals, and PCR-negative status for GFP. Furthermore, EAPV-d6I8 also provided complete protection against Vietnam's severe strain EAPV-GL1 in yellow passionfruit plants. Our results indicate that the attenuated mutant EAPV-d6I8 has great potential to control EAPV in Taiwan and Vietnam via cross-protection.

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Introduction: Type 2 diabetes mellitus (T2DM) was associated with digestive system tumors. We analyzed publicly available data from GWAS studies using Mendelian randomization methods to clarify its causal relationship and mechanisms. Five common digestive system tumors and four diabetes-related phenotypes were included. Methods: Inverse variance weighted method was the main analytical method. Meta-analysis was used to summarize results of multiple data sources. Horizontal pleiotropy was tested using Egger-intercept method and validated by MRPRESSO method. Heterogeneity and sensitivity analysis were conducted by Cochran's Q test and leave-one-out method, respectively. Results: T2DM is associated with a reduced risk of esophageal (OR: 0.77, 95% CI: 0.71 to 0.83, P< 0.001), gastric (OR: 0.87, 95% CI: 0.84 to 0.90, P< 0.001) and colorectal cancer (OR: 0.88, 95% CI: 0.85 to 0.91, P< 0.001) and hepatocellular carcinoma (OR: 0.92, 95% CI: 0.86 to 0.97, P = 0.005) and an increased risk of pancreatic cancer (OR: 1.92, 95% CI: 1.47 to 2.50, P< 0.001) in East Asian population. T2DM causes decreased fasting insulin levels (OR = 0.966, 95% CI: 0.95 to 0.98, P< 0.001) and increased glycated hemoglobin levels (OR=1.41, 95% CI: 1.39 to 1.44, P<0.001). Elevated fasting insulin levels increase the risk of esophageal cancer (OR = 10.35, 95% CI: 1.10 to 97.25, P = 0.041), while increased glycated hemoglobin levels increase pancreatic cancer risk (OR=2.33, 95% CI: 1.37 to 3.97, P=0.002) but decrease gastric cancer risk (OR=0.801, 95% CI: 0.65 to 0.99, P=0.044). Conclusion: T2DM is associated with a reduced risk of esophageal, gastric and colorectal cancer and hepatocellular carcinoma in East Asian populations. The causal relationships between T2DM with esophageal and gastric cancer are partially mediated by decreased fasting insulin and increased glycated hemoglobin levels, respectively. T2DM indirectly increases the risk of pancreatic cancer by increasing glycated hemoglobin levels.

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PURPOSE: Although meningiomas are the most common primary intracranial tumors, their genetic etiologies have not been fully elucidated. To date, only two genome-wide association studies (GWASs) have focused on European ancestries, despite ethnic differences in the incidence of meningiomas. The aim of this study was to conduct the first GWAS of Japanese patients with meningiomas to identify the SNPs associated with meningioma susceptibility. METHODS: In this multicenter prospective case-control study, we studied 401 Japanese patients with meningioma admitted in five institutions in Japan, and 50,876 control participants of Japanese ancestry enrolled in Biobank Japan. RESULTS: The quality control process yielded 536,319 variants and imputation resulted in 8,224,735 variants on the autosomes and 224,820 variants on the X chromosomes. This GWAS eventually revealed no genetic variants with genome-wide significance (P < 5 × 10 - 8) and observed no significant association in the previously reported risk variants rs11012732 and rs2686876 due to low minor allele frequency in the Japanese population. CONCLUSION: This is the first GWAS of meningiomas in East Asian populations and is expected to contribute to the development of GWAS research for meningiomas.

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Needle-leaved junipers (Juniperus sect. Juniperus, Cupressaceae) are coniferous trees and shrubs with red or blue fleshy cones. They are distributed across Asia, Macaronesia and the Mediterranean Basin, with one species (J. communis) having a circumboreal distribution. Here we aim to resolve the phylogeny of this clade to infer its intricate evolutionary history. To do so, we built a comprehensive, time-calibrated phylogeny using genotyping-by-sequencing (GBS) and combine it with species occurrence using phylogeographic tools. Our results provide solid phylogenetic resolution to propose a new taxonomic classification and a biogeographical history of the section. Specifically, we confirm the monophyly of two groups within J. sect. Juniperus: the Asian (blue-cone) species including the circumboreal J. communis, and the Mediterranean-Macaronesian (red-cone) species. In addition, we provide strong phylogenetic evidence for three distinct species (J. badia, J. conferta, J. lutchuensis) previously considered subspecies or varieties, as well as for the differentiation between the eastern and western Mediterranean lineages of J. macrocarpa. Our findings suggest that the Mediterranean basin was the primary center of diversification for Juniperus sect. Juniperus, followed by an East Asian-Tethyan disjunction resulting from uplifts of the Qinghai-Tibetan Plateau and climatic shifts. The colonization history of Macaronesia by red-cone junipers from the western Mediterranean appears to have taken place independently in two different geological periods: the Miocene (Azores) and the Pliocene (Madeira-Canary Islands). Overall, genomic data and phylogenetic analysis are key to consider a new taxonomic proposal and reconstruct the biogeographical history of the iconic needle-leaved junipers across the Paleartic.

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PIK3CA-related overgrowth spectrum (PROS) is an umbrella term to describe a diverse range of developmental disorders. Research to date has predominantly emerged from Europe and North America, resulting in a notable scarcity of studies focusing on East Asian populations. Currently, the prevalence and distribution of PIK3CA variants across various genetic loci and their correlation with distinct phenotypes in East Asian populations remain unclear. This study aims to elucidate the phenotype-genotype correlations of PROS in East Asian populations. We presented the phenotypes and genotypes of 82 Chinese patients. Among our cohort, 67 individuals carried PIK3CA variants, including missense, frameshift, and splice variants. Six patients presented with both PIK3CA and an additional variant. Seven PIK3CA-negative patients exhibited overlapping PROS manifestations with variants in GNAQ, AKT1, PTEN, MAP3K3, GNA11, or KRAS. An integrative review of the literature pertaining to East Asian populations revealed that specific variants are uniquely associated with certain PROS phenotypes. Some rare variants were exclusively identified in cases of megalencephaly and diffuse capillary malformation with overgrowth. Non-hotspot variants with undefined oncogenicity were more common in CNS phenotypes. Diseases with vascular malformation were more likely to have variants in the helical domain, whereas phenotypes involving adipose/muscle overgrowth without vascular abnormalities predominantly presented variants in the C2 domain. Our findings underscore the unique phenotype-genotype patterns within the East Asian PROS population, highlighting the necessity for an expanded cohort to further elucidate these correlations. Such endeavors would significantly facilitate the development of PI3Kα selective inhibitors tailored for the East Asian population in the future.

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CagA is a significant oncogenic factor injected into host cells by Helicobacter pylori, which is divided into two subtypes: East Asian type (CagAE), characterized by the EPIYA-D motif, and western type (CagAW), harboring the EPIYA-C motif. CagAE has been reported to have higher carcinogenicity than CagAW, although the underlying reason is not fully understood. SHIP2 is an intracellular phosphatase that can be recruited by CagA to perturb the homeostasis of intracellular signaling pathways. In this study, we found that SHIP2 contributes to the higher oncogenicity of CagAE. Co-Immunoprecipitation and Pull-down assays showed that CagAE bind more SHIP2 than CagAW. Immunofluorescence staining showed that a higher amount of SHIP2 recruited by CagAE to the plasma membrane catalyzes the conversion of PI(3,4,5)P3 into PI(3,4)P2. This alteration causes higher activation of Akt signaling, which results in enhanced IL-8 secretion, migration, and invasion of the infected cells. SPR analysis showed that this stronger interaction between CagAE and SHIP2 stems from the higher affinity between the EPIYA-D motif of CagAE and the SH2 domain of SHIP2. Structural analysis revealed the crucial role of the Phe residue at the Y + 5 position in EPIYA-D. After mutating Phe of CagAE into Asp (the corresponding residue in the EPIYA-C motif) or Ala, the activation of downstream Akt signaling was reduced and the malignant transformation of infected cells was alleviated. These findings revealed that CagAE hijacks SHIP2 through its EPIYA-D motif to enhance its carcinogenicity, which provides a better understanding of the higher oncogenic risk of H. pylori CagAE.

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