miR-622 Increases miR-30a Expression through Inhibition of Hypoxia-Inducible Factor 1α to Improve Metastasis and Chemoresistance in Human Invasive Breast Cancer Cells.

Hypoxia-inducible factor 1α (HIF-1α) plays a pivotal role in the survival, metastasis, and response to treatment of solid tumors. Autophagy serves as a mechanism for tumor cells to eliminate misfolded proteins and damaged organelles, thus promoting invasiveness, metastasis, and resistance to treatment under hypoxic conditions. MicroRNA (miRNA) research underscores the significance of these non-coding molecules in regulating cancer-related protein synthesis across diverse contexts. However, there is limited reporting on miRNA-mediated gene expression studies, especially with respect to epithelial-mesenchymal transition (EMT) and autophagy in the context of hypoxic breast cancer. Our study reveals decreased levels of miRNA-622 (miR-622) and miRNA-30a (miR-30a) in invasive breast cancer cells compared to their non-invasive counterparts. Inducing miR-622 suppresses HIF-1α protein expression, subsequently activating miR-30a transcription. This cascade results in reduced invasiveness and migration of breast cancer cells by inhibiting EMT markers, such as Snail, Slug, and vimentin. Furthermore, miR-30a negatively regulates beclin 1, ATG5, and LC3-II and inhibits Akt protein phosphorylation. Consequently, this improves the sensitivity of invasive MDA-MB-231 cells to docetaxel treatment. In conclusion, our study highlights the therapeutic potential of inducing miR-622 to promote miR-30a expression and thus disrupt HIF-1α-associated EMT and autophagy pathways. This innovative strategy presents a promising approach to the treatment of aggressive breast cancer.

Genetic insights into carbohydrate sulfotransferase 8 and its impact on the immunotherapy efficacy of cancer.

Immune checkpoint blockade (ICB) is a promising therapy for solid tumors, but its effectiveness depends on biomarkers that are not precise. Here, we utilized genome-wide association study to investigate the association between genetic variants and tumor mutation burden to interpret ICB response. We identified 16 variants (p < 5 × 10-8) probed to 17 genes on 9 chromosomes. Subsequent analysis of one of the most significant loci in 19q13.11 suggested that the rs111308825 locus at the enhancer is causal, as its A allele impairs KLF2 binding, leading to lower carbohydrate sulfotransferase 8 (CHST8) expression. Breast cancer cells expressing CHST8 suppress T cell activation, and Chst8 loss attenuates tumor growth in a syngeneic mouse model. Further investigation revealed that programmed death-ligand 1 (PD-L1) and its homologs could be sulfated by CHST8, resulting in M2-like macrophage enrichment in the tumor microenvironment. Finally, we confirmed that low-CHST8 tumors have better ICB response, supporting the genetic effect and clinical value of rs111308825 for ICB efficacy prediction.

Genome-Wide Association Studies for Albuminuria of Nondiabetic Taiwanese Population.

INTRODUCTION: Chronic kidney disease, which is defined by a reduced estimated glomerular filtration rate and albuminuria, imposes a large health burden worldwide. Ethnicity-specific associations are frequently observed in genome-wide association studies (GWAS). This study conducts a GWAS of albuminuria in the nondiabetic population of Taiwan. METHODS: Nondiabetic individuals aged 30-70 years without a history of cancer were enrolled from the Taiwan Biobank. A total of 6,768 subjects were subjected to a spot urine examination. After quality control using PLINK and imputation using SHAPEIT and IMPUTE2, a total of 3,638,350 single-nucleotide polymorphisms (SNPs) remained for testing. SNPs with a minor allele frequency of less than 0.1% were excluded. Linear regression was used to determine the relationship between SNPs and log urine albumin-to-creatinine ratio. RESULTS: Six suggestive loci are identified in or near the FCRL3 (p = 2.56 × 10-6), TMEM161 (p = 4.43 × 10-6), EFCAB1 (p = 2.03 × 10-6), ELMOD1 (p = 2.97 × 10-6), RYR3 (p = 1.34 × 10-6), and PIEZO2 (p = 2.19 × 10-7). Genetic variants in the FCRL3 gene that encode a secretory IgA receptor are found to be associated with IgA nephropathy, which can manifest as proteinuria. The PIEZO2 gene encodes a sensor for mechanical forces in mesangial cells and renin-producing cells. Five SNPs with a p-value between 5 × 10-6 and 5 × 10-5 are also identified in five genes that may have a biological role in the development of albuminuria. CONCLUSION: Five new loci and one known suggestive locus for albuminuria are identified in the nondiabetic Taiwanese population.

Midterm Outcomes of Kissing Covered Self-Expanding Stents for Reconstruction of Complex Aortoiliac Occlusive Disease.

BACKGROUND: We sought to investigate the midterm results of kissing self-expanding covered stents (SECSs) for the reconstruction of aortic bifurcation in complex aortoiliac occlusive disease. METHODS: Data of consecutive patients who had undergone endovascular treatment for aortoiliac occlusive disease were screened. Only patients with TransAtlantic Inter-Society Consensus (TASC) class C and D lesions treated by bilateral iliac kissing stents (KSs) were included. Midterm primary patency, risk factors, and limb salvage rates were analyzed. Follow-up results were analyzed using the Kaplan-Meier curves. Cox proportional hazards models were used to identify the predictors of primary patency. RESULTS: A total of 48 patients (95.8% men; mean age, 65.3 ± 10.2 years) were treated with kissing SECSs. Of them, 17 patients had TASC-II class C lesions and 31 had class D lesions. There were 38 total occlusive lesions, with a mean occlusive lesion length of 108.2 ± 57.3 mm. The overall mean lesion length was 140.3 ± 60.5 mm, and the mean length of implanted stents in the aortoiliac arteries was 141.9 ± 59.9 mm. The mean diameter of the deployed SECSs was 7.8 ± 0.5 mm. The mean follow-up time was 36.5 ± 15.8 months, and the follow-up rate was 95.8%. At 36 months, the overall primary patency, assisted primary patency, secondary patency, and limb salvage rates were 92.2%, 95.7%, 97.8%, and 100%, respectively. Univariate Cox regression analysis revealed that stent diameter ≤7 mm (hazard ratio [HR]: 9.53; 95% confidence interval [CI] 1.56-57.94, P = 0.014) and severe calcification (HR: 12.66; 95% CI 2.04-78.45, P = 0.006) were significantly associated with restenosis. Multivariate analysis showed severe calcification to be the only significant determinant of restenosis (HR: 12.66; 95% CI 2.04-78.45, P = 0.006). CONCLUSIONS: Kissing SECSs provide good midterm results for the treatment of aortoiliac occlusive disease. A stent diameter >7 mm is a potent protective factor against restenosis. Because severe calcification appears to be the only significant determinant of restenosis, patients with severe calcification require close follow-up.

Iatrogenic arteriovenous fistula after lumbar discectomy surgery: a case report.

Iatrogenic arteriovenous fistula (IAVF) is an unusual and potentially fatal complication of lumbar spinal surgery. A 62-year-old patient presented with a history of dyspnea, left lower limb edema and coughing. A physical exam showed bilateral basal rales in the lungs, abdominal bruit and bilateral lower limb pitting edema. A computed tomography angiograph revealed an arteriovenous communication between the right internal iliac artery and the left common iliac vein. The patient was diagnosed with an IAVF, which developed post-lumbar disc surgery. The patient underwent a successful endovascular treatment by using covered stent at the common iliac artery with embolism of lumbar artery. The patient's symptoms were relieved 2 months after surgery.

Upregulation of PD-L1 by SARS-CoV-2 promotes immune evasion.

Patients with severe COVID-19 often suffer from lymphopenia, which is linked to T-cell sequestration, cytokine storm, and mortality. However, it remains largely unknown how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces lymphopenia. Here, we studied the transcriptomic profile and epigenomic alterations involved in cytokine production by SARS-CoV-2-infected cells. We adopted a reverse time-order gene coexpression network approach to analyze time-series RNA-sequencing data, revealing epigenetic modifications at the late stage of viral egress. Furthermore, we identified SARS-CoV-2-activated nuclear factor-κB (NF-κB) and interferon regulatory factor 1 (IRF1) pathways contributing to viral infection and COVID-19 severity through epigenetic analysis of H3K4me3 chromatin immunoprecipitation sequencing. Cross-referencing our transcriptomic and epigenomic data sets revealed that coupling NF-κB and IRF1 pathways mediate programmed death ligand-1 (PD-L1) immunosuppressive programs. Interestingly, we observed higher PD-L1 expression in Omicron-infected cells than SARS-CoV-2 infected cells. Blocking PD-L1 at an early stage of virally-infected AAV-hACE2 mice significantly recovered lymphocyte counts and lowered inflammatory cytokine levels. Our findings indicate that targeting the SARS-CoV-2-mediated NF-κB and IRF1-PD-L1 axis may represent an alternative strategy to reduce COVID-19 severity.

Genome- and transcriptome-wide association studies of 386,000 Asian and European-ancestry women provide new insights into breast cancer genetics.

By combining data from 160,500 individuals with breast cancer and 226,196 controls of Asian and European ancestry, we conducted genome- and transcriptome-wide association studies of breast cancer. We identified 222 genetic risk loci and 137 genes that were associated with breast cancer risk at a p < 5.0 × 10-8 and a Bonferroni-corrected p < 4.6 × 10-6, respectively. Of them, 32 loci and 15 genes showed a significantly different association between ER-positive and ER-negative breast cancer after Bonferroni correction. Significant ancestral differences in risk variant allele frequencies and their association strengths with breast cancer risk were identified. Of the significant associations identified in this study, 17 loci and 14 genes are located 1Mb away from any of the previously reported breast cancer risk variants. Pathways analyses including 221 putative risk genes identified multiple signaling pathways that may play a significant role in the development of breast cancer. Our study provides a comprehensive understanding of and new biological insights into the genetics of this common malignancy.

The Genetic Diversity and the Divergence Time in Extant Primitive Mayfly, Siphluriscus chinensis Ulmer, 1920 Using the Mitochondrial Genome.

In this study, the mitochondrial (mt) genomes of Siphluriscus chinensis (Ephemeroptera: Siphluriscidae) were evaluated in specimens collected from two sites in China: Niutou Mountain, Zhejiang Province (S. chinensis NTS) and Leigong Mountain, Guizhou Province (S. chinensis LGS) and were successfully sequenced. The lengths of the mt genomes of S. chinensis NTS and S. chinensis LGS were 15,904 bp (ON729390) and 15,212 bp (ON729391), respectively. However, an in-depth comparison of the two mt genomes showed significant differences between the specimens collected from the two sites. A detailed analysis of the genetic distance between S. chinensis NTS and S. chinensis LGS was undertaken to further achieve an accurate delimitation of S. chinensis. The genetic distance between S. chinensis NTS and the other three species within Siphluriscidae was a high value, above 12.2%. The two mt genomes were used to reconstruct phylogenetic relationships and estimate divergence time. The results demonstrated robust differences between S. chinensis NTS and S. chinensis LGS, which revealed that a kind of cryptic species existed. Maximum likelihood (ML) and Bayesian inference (BI) analyses produced well-supported phylogenetic trees that showed evolutionary relationships between Siphluriscidae (((S. chinensis HQ875717 + S. chinensis MF352165) + S. chinensis LGS) + S. chinensis NTS). The most recent common ancestor (MRCA) of four species within Siphluriscidae began to diversify during the Neogene [11.80 million years ago (Mya); 95% highest posterior densities (HPD) = 6.17-19.28 Mya], and S. chinensis NTS was first to diverge from the branches of S. chinensis LGS. In short, based on mitochondrial genomes, our results showed that the specimens collected from Leigong Mountain, Guizhou Province (S. chinensis LGS) belonged to S. chinensis, and the specimens collected from Niutou Mountain, Zhejiang Province (S. chinensis NTS) were a cryptic species of S. chinensis.

Relevance of the MHC region for breast cancer susceptibility in Asians.

BACKGROUND: Human leukocyte antigen (HLA) genes play critical roles in immune surveillance, an important defence against tumors. Imputing HLA genotypes from existing single-nucleotide polymorphism datasets is low-cost and efficient. We investigate the relevance of the major histocompatibility complex region in breast cancer susceptibility, using imputed class I and II HLA alleles, in 25,484 women of Asian ancestry. METHODS: A total of 12,901 breast cancer cases and 12,583 controls from 12 case-control studies were included in our pooled analysis. HLA imputation was performed using SNP2HLA on 10,886 quality-controlled variants within the 15-55 Mb region on chromosome 6. HLA alleles (n = 175) with info scores greater than 0.8 and frequencies greater than 0.01 were included (resolution at two-digit level: 71; four-digit level: 104). We studied the associations between HLA alleles and breast cancer risk using logistic regression, adjusting for population structure and age. Associations between HLA alleles and the risk of subtypes of breast cancer (ER-positive, ER-negative, HER2-positive, HER2-negative, early-stage, and late-stage) were examined. RESULTS: We did not observe associations between any HLA allele and breast cancer risk at P < 5e-8; the smallest p value was observed for HLA-C*12:03 (OR = 1.29, P = 1.08e-3). Ninety-five percent of the effect sizes (OR) observed were between 0.90 and 1.23. Similar results were observed when different subtypes of breast cancer were studied (95% of ORs were between 0.85 and 1.18). CONCLUSIONS: No imputed HLA allele was associated with breast cancer risk in our large Asian study. Direct measurement of HLA gene expressions may be required to further explore the associations between HLA genes and breast cancer risk.

A genome-wide association study for melatonin secretion.

Melatonin exerts a wide range of effects among various tissues and organs. However, there is currently no study to investigate the genetic determinants of melatonin secretion. Here, we conducted a genome-wide association study (GWAS) for melatonin secretion using morning urine 6-hydroxymelatonin sulfate-to-creatinine ratio (UMCR). We initially enrolled 5000 participants from Taiwan Biobank in this study. After excluding individuals that did not have their urine collected in the morning, those who had history of neurological or psychiatric disorder, and those who failed to pass quality control, association of single nucleotide polymorphisms with log-transformed UMCR adjusted for age, sex and principal components of ancestry were analyzed. A second model additionally adjusted for estimated glomerular filtration rate (eGFR). A total of 2373 participants underwent the genome-wide analysis. Five candidate loci associated with log UMCR (P value ranging from 6.83 × 10-7 to 3.44 × 10-6) encompassing ZFHX3, GALNT15, GALNT13, LDLRAD3 and intergenic between SEPP1 and FLJ32255 were identified. Similar results were yielded with further adjustment for eGFR. Interestingly, the identified genes are associated with circadian behavior, neuronal differentiation, motor disorders, anxiety, and neurodegenerative diseases. We conducted the first GWAS for melatonin secretion and identified five candidate genetic loci associated with melatonin level. Replication and functional studies are needed in the future.

Genome-wide association study identifies genetic risk loci for adiposity in a Taiwanese population.

Overweight and obese are risk factors for various diseases. In Taiwan, the combined prevalence of overweight and obesity has increased dramatically. Here, we conducted a genome-wide association study (GWAS) on four adiposity traits, including body-mass index (BMI), body fat percentage (BF%), waist circumference (WC), and waist-hip ratio (WHR), using the data for more than 21,000 subjects in Taiwan Biobank. Associations were evaluated between 6,546,460 single-nucleotide polymorphisms (SNPs) and adiposity traits, yielding 13 genome-wide significant (GWS) adiposity-associated trait-loci pairs. A known gene, FTO, as well as two BF%-associated loci (GNPDA2-GABRG1 [4p12] and RNU6-2-PIAS1 [15q23]) were identified as pleiotropic effects. Moreover, RALGAPA1 was found as a specific genetic predisposing factor to high BMI in a Taiwanese population. Compared to other populations, a slightly lower heritability of the four adiposity traits was found in our cohort. Surprisingly, we uncovered the importance of neural pathways that might influence BF%, WC and WHR in the Taiwanese (East Asian) population. Additionally, a moderate genetic correlation between the WHR and BMI (γg = 0.52; p = 2.37×10-9) was detected, suggesting different genetic determinants exist for abdominal adiposity and overall adiposity. In conclusion, the obesity-related genetic loci identified here provide new insights into the genetic underpinnings of adiposity in the Taiwanese population.

A common variant in 11q23.3 associated with hyperlipidemia is mediated by the binding and regulation of GATA4.

Large-scale genome-wide associations comprising multiple studies have identified hundreds of genetic loci commonly associated with hyperlipidemia-related phenotypes. However, single large cohort remains necessary in aiming to investigate ethnicity-specific genetic risks and mechanical insights. A community-based cohort comprising 23,988 samples that included both genotype and biochemical information was assembled for the genome-wide association analysis (GWAS) of hyperlipidemia. The analysis identified fifty genetic variants (P < 5 × 10-8) on five different chromosomes, and a subsequent validation analysis confirmed the significance of the lead variants. Integrated analysis combined with cell-based experiments of the most statistically significant locus in 11q23.3 revealed rs651821 (P = 4.52 × 10-76) as the functional variant. We showed transcription factor GATA4 preferentially binds the T allele of rs651821, the protective allele for hyperlipidemia, which promoted APOA5 expression in liver cells and individuals with the TT genotype of rs651821. As GATA4-APOA5 axis maintains triglyceride homeostasis, GATA4 activation by phenylephrine implies synergism for lowering triglyceride levels in hyperlipidemia patients. Our study demonstrates that rs651821 mediates APOA5 activation via allele-specific regulation by GATA4. We suggest elevating GATA4 activity could provide a therapeutic potential for treating the development of hyperlipidemia.

Inhibitory Effects of Ursolic Acid on the Stemness and Progression of Human Breast Cancer Cells by Modulating Argonaute-2.

The stemness and metastasis of cancer cells are crucial features in determining cancer progression. Argonaute-2 (AGO2) overexpression was reported to be associated with microRNA (miRNA) biogenesis, supporting the self-renewal and differentiation characteristics of cancer stem cells (CSCs). Ursolic acid (UA), a triterpene compound, has multiple biological functions, including anticancer activity. In this study, we find that UA inhibits the proliferation of MDA-MB-231 and MCF-7 breast cancer cell lines using the CCK-8 assay. UA induced a significant decrease in the fraction of CSC in which it was examined by changes in the expression of stemness biomarkers, including the Nanog and Oct4 genes. UA altered invasion and migration capacities by significant decreases in the levels of epithelial-to-mesenchymal transition (EMT) proteins of slug and vimentin. Furthermore, the co-reduction in oncogenic miRNA levels (miR-9 and miR-221) was a result of the down-modulation in AGO2 in breast cancer cells in vitro. Mechanically, UA increases PTEN expression to inactivate the FAK/PI3K/Akt/mTOR signaling pathway and the decreased level of c-Myc in quantitative RT-PCR and Western blot imaging analyses. Our current understanding of the anticancer potential of UA in interrupting between EMT programming and the state of CSC suggests that UA can contribute to improvements in the clinical practice of breast cancer.

Polygenic risk scores for prediction of breast cancer risk in Asian populations.

PURPOSE: Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups. METHODS: The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases). RESULTS: The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk. CONCLUSION: PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry.

Taiwan Biobank: A rich biomedical research database of the Taiwanese population.

The Taiwan Biobank (TWB) is an ongoing prospective study of >150,000 individuals aged 20-70 in Taiwan. A comprehensive list of phenotypes was collected for each consented participant at recruitment and follow-up visits through structured interviews and physical measurements. Biomarkers and genetic data were generated from blood and urine samples. We present here an overview of TWB's genetic data quality, population structure, and familial relationship, which consists of predominantly Han Chinese ancestry, and highlight its important attributes and genetic findings thus far. A linkage to Taiwan's National Health Insurance database of >25 years and other registries is underway to enrich the phenotypic spectrum and enable deep and longitudinal genetic investigations. TWB provides one of the largest biobank resources for biomedical and public health research in East Asia that will contribute to our understanding of the genetic basis of health and disease in global populations through collaborative studies with other biobanks.

Genome-Wide Association Study of Lithium-Induced Dry Mouth in Bipolar I Disorder.

Dry mouth is a rather common unpleasant adverse drug reaction (ADR) to lithium treatment in bipolar disorders that often lead to poor adherence or early dropout. The aim of this study was to identify the genetic variants of dry mouth associated with lithium treatment in patients with bipolar I (BPI) disorder. In total, 1242 BPI patients who had ever received lithium treatment were identified by the Taiwan Bipolar Consortium for this study. The proportions of patients who experienced impaired drug compliance during lithium medication were comparable between those only with dry mouth and those with any other ADR (86% and 93%, respectively). Dry mouth appeared to be the most prevalent (47.3%) ADR induced by lithium treatment. From the study patients, 921 were included in a genome-wide association study (GWAS), and replication was conducted in the remaining 321 patients. The SNP rs10135918, located in the immunoglobulin heavy chain locus (IGH), showed the strongest associations in the GWAS (p = 2.12 × 10-37) and replication groups (p = 6.36 × 10-13) (dominant model) for dry mouth with a sensitivity of 84.9% in predicting dry mouth induced by lithium. Our results may be translated into clinical recommendation to help identify at-risk individuals for early identification and management of dry mouth, which will improve medication adherence.

Targeting conserved N-glycosylation blocks SARS-CoV-2 variant infection in vitro.

BACKGROUND: Despite clinical success with anti-spike vaccines, the effectiveness of neutralizing antibodies and vaccines has been compromised by rapidly spreading SARS-CoV-2 variants. Viruses can hijack the glycosylation machinery of host cells to shield themselves from the host's immune response and attenuate antibody efficiency. However, it remains unclear if targeting glycosylation on viral spike protein can impair infectivity of SARS-CoV-2 and its variants. METHODS: We adopted flow cytometry, ELISA, and BioLayer interferometry approaches to assess binding of glycosylated or deglycosylated spike with ACE2. Viral entry was determined by luciferase, immunoblotting, and immunofluorescence assays. Genome-wide association study (GWAS) revealed a significant relationship between STT3A and COVID-19 severity. NF-κB/STT3A-regulated N-glycosylation was investigated by gene knockdown, chromatin immunoprecipitation, and promoter assay. We developed an antibody-drug conjugate (ADC) that couples non-neutralization anti-spike antibody with NGI-1 (4G10-ADC) to specifically target SARS-CoV-2-infected cells. FINDINGS: The receptor binding domain and three distinct SARS-CoV-2 surface N-glycosylation sites among 57,311 spike proteins retrieved from the NCBI-Virus-database are highly evolutionarily conserved (99.67%) and are involved in ACE2 interaction. STT3A is a key glycosyltransferase catalyzing spike glycosylation and is positively correlated with COVID-19 severity. We found that inhibiting STT3A using N-linked glycosylation inhibitor-1 (NGI-1) impaired SARS-CoV-2 infectivity and that of its variants [Alpha (B.1.1.7) and Beta (B.1.351)]. Most importantly, 4G10-ADC enters SARS-CoV-2-infected cells and NGI-1 is subsequently released to deglycosylate spike protein, thereby reinforcing the neutralizing abilities of antibodies, vaccines, or convalescent sera and reducing SARS-CoV-2 variant infectivity. INTERPRETATION: Our results indicate that targeting evolutionarily-conserved STT3A-mediated glycosylation via an ADC can exert profound impacts on SARS-CoV-2 variant infectivity. Thus, we have identified a novel deglycosylation method suitable for eradicating SARS-CoV-2 variant infection in vitro. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Dose-Response Relationship Between Physical Activity and the Incidence of Peripheral Artery Disease in General Population: Insights From the National Health and Nutrition Examination Survey 1999-2004.

Purpose: A low ABI, ≦0.9, indicates peripheral artery disease (PAD) and physical activity (PA) represents an important non-surgical treatment for patients with PAD. However, as for the general population, the associations between PA, PAD, and their mutual dependence are not well-defined. Here we aimed to determine whether there is a dose-response relationship between PA and incidence of PAD in the general population using restricted cubic spline (RCS). Patients and methods: This study analyzed 1,370 adults aged ≧40 years who had participated in the National Health and Nutrition Examination Survey (NHANES) during 1999-2004. The ABI of the participants were measured by trained technicians, and PAD was defined as ABI ≦0.9. PA was obtained with a standard questionnaire, and metabolic equivalents (MET) were used to quantify the PA level. Logistic regression was used to assess the association between PA and incidence of PAD, and the dose-response relationship was analyzed with RCS. Results: PAD was present in 6.2% of the participants: 5.6% of males and 6.9% of females. After adjusting for potential confounders, compared with the first quartile (Q1) of MET, the odds ratios (ORs) of PAD for those with Q2, Q3, and Q4 of MET were 0.688 [95% confidence interval (CI) = 0.684-0.692], 0.463 (95% CI = 0.460-0.466), 0.816 (95% CI = 0.812-0.821), respectively (all p < 0.0001). The RCS regression showed that physical activity was related to the incidence of PAD in a non-linear manner (p for non-linearity < 0.0001). For females, the prevalence of PAD decreased as physical activity increased, reaching the minimum for activity at ~5,800 MET-min month-1 (OR = 0.425, 95% CI = 0.424-0.426), and for males, no plateau was found in this study. Conclusion: The prevalence of PAD is inversely associated with PA, and vigorous activities might help decrease PAD risk for general population. The prevalence of PAD reaches the minimum at ~5,800 MET-min month-1, representing a recommended PA value.

Intracellular Accumulation of IFN-λ4 Induces ER Stress and Results in Anti-Cirrhotic but Pro-HCV Effects.

IFNL3/IFNL4 polymorphisms are inversely associated with the risk of chronic hepatitis C virus (HCV) infection and cirrhosis, two major risk factors for developing hepatocellular carcinoma (HCC). To further explore these inverse associations and their molecular underpinnings, we analyzed IFNL3/IFNL4 polymorphisms represented by the IFNL4 genotype (presence of rs368234815-dG or rs12979860-T alleles) in HCV patients: 2969 from Japan and 2931 from Taiwan. IFNL4 genotype was associated with an increased risk of HCV-related HCC (OR=1.28, 95%CI=1.07-1.52, P=0.0058) in the general population of Japanese patients, but not in Taiwanese patients who achieved treatment-induced viral clearance. IFNL4 genotype was also associated with a decreased risk of cirrhosis (OR=0.66, 95%CI=0.46-0.93, P=0.018, in Taiwanese patients). We then engineered HepG2 cells to inducibly express IFN-λ4 in the presence or absence of interferon lambda receptor 1 (IFNLR1). Induction of IFN-λ4 resulted in its intracellular accumulation, mainly in lysosomes and late endosomes, and increased ER stress, leading to apoptosis and reduced proliferation. We identified the very-low-density lipoprotein receptor (VLDLR), which facilitates HCV entry into hepatocytes, as a transcript induced by IFN-λ4 but not IFN-λ3. Our results suggest that the molecular mechanisms underlying the anti-cirrhotic but pro-HCV associations observed for IFNL3/IFNL4 polymorphisms are, at least in part, contributed by intracellular accumulation of IFN-λ4 causing ER stress in hepatic cells.

Body mass index and type 2 diabetes and breast cancer survival: a Mendelian randomization study.

The causal relationship between body mass index (BMI) and type 2 diabetes (T2D) and breast cancer prognosis is still ambiguous. The aim of this study was to investigate the prognostic effect of BMI and T2D on breast cancer disease-free survival (DFS) among Asian individuals. In this two-sample Mendelian randomization (MR) study, the instrumental variables (IVs) were identified using a genome-wide association study (GWAS) among 24,000 participants in the Taiwan Biobank. Importantly, the validity of these IVs was confirmed with a previous large-scale GWAS (Biobank Japan Project, BBJ). In this study, we found that a genetic predisposition toward higher BMI (as indicated by BMI IVs, F = 86.88) was associated with poor breast cancer DFS (hazard ratio [HR] = 6.11; P < 0.001). Furthermore, higher level of genetically predicted T2D (as indicated by T2D IVs) was associated with an increased risk of recurrence of and mortality from breast cancer (HR = 1.43; P < 0.001). Sensitivity analyses, including the weighted-median approach, MR-Egger regression, Radial regression and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) supported the consistency of our findings. Finally, the causal relationship between BMI and poor breast cancer prognosis was confirmed in a prospective cohort study. Our MR analyses demonstrated the causal relationship between the genetic prediction of elevated BMI and a greater risk of T2D with poor breast cancer prognosis. BMI and T2D have important clinical implications and may be used as prognostic indicators of breast cancer.