Addressing causal relationship between drinking behavior and metabolic syndrome: one-sample Mendelian randomization analysis.

AIMS: Alcohol drinking is associated with central obesity, hypertension, and hyperlipidemia, which further causes metabolic syndrome (MetS). However, prior epidemiological studies on such associations lack experimental evidence for a causal relationship. This study aims to explore the causal relationship between drinking behavior and MetS in Taiwan population by using Mendelian randomization (MR) analysis. METHODS: A cross-sectional study was conducted using the Taiwan Biobank database, which comprised 50 640 Han Chinese who were 30-70 years old without cancer from 2008 to 2020. In MR analysis, we constructed weighted and unweighted genetic risk scores by calculating SNP alleles significantly associated with alcohol drinking. We calculated odds ratios and 95% confidence interval (CI) by using a two-stage regression model. RESULTS: A total of 50 640 participants were included with a mean age of 49.5 years (SD: 1.67 years), 36.6% were men. The adjusted odds ratio (aOR) of MetS per 5% increase in the likelihood of genetic predisposition to drink based on weighted genetic risk score with adjustment was 1.11 (95% CI: 1.10, 1.12, P < .001). Analysis was also conducted by grouping the likelihood of genetic predisposition to drink based on quartiles with multivariate adjustment. Using Q1 as the reference group, the aORs of MetS for Q2, Q3, and Q4 were 1.19 (1.12, 1.27, p < .001), 1.31 (1.23, 1.40, p < .001), and 1.87 (1.75, 2.00, p < .001), respectively, for the weighted genetic risk score. CONCLUSIONS: This study shows a modest relationship between drinking behavior and MetS by using MR analysis.

Increased plasma levels of monocyte chemoattractant protein-1 in patients with hepatitis B virus pre-S2 gene deletion mutation predict a higher risk of hepatocellular carcinoma recurrence after curative surgical resection.

BACKGROUND: Despite resection surgery as a curative therapy for hepatocellular carcinoma (HCC), the high rate of postoperative HCC recurrence remains a big challenge for patient survival. Chronic hepatitis B virus (HBV) infection is the most important risk factor for HCC. Deletion mutation in the HBV pre-S2 gene leads to expression of an essential viral oncoprotein called pre-S2 mutant and represents an independent prognostic biomarker for HCC recurrence after curative surgical resection. Additionally, cytokines are multifunctional secreted proteins and implicated in all stages of HBV-related HCC tumorigenesis. METHODS: This study aimed to identify the cytokines whose plasma levels were associated with pre-S2 gene deletion mutation and HCC recurrence and evaluate their potential to be combined with pre-S2 gene deletion mutation in predicting HCC recurrence. RESULTS: Among a panel of 27 cytokines examined, plasma levels of monocyte chemoattractant protein-1 (MCP-1) were significantly upregulated in patients with pre-S2 gene deletion mutation or HCC recurrence. MCP-1 was validated as an independent prognostic biomarker for HCC recurrence. Moreover, patients with both the presence of pre-S2 gene deletion mutation and high levels of MCP-1 displayed a higher risk of HCC recurrence than patients with either one or none of these two biomarkers. The combination of pre-S2 gene deletion mutation and MCP-1 levels exhibited a better prognostic performance for HCC recurrence than each biomarker alone. CONCLUSIONS: This study discovered that MCP-1 levels had a significance to be as a combination biomarker with pre-S2 gene deletion mutation providing an improved performance in predicting HCC recurrence after curative surgical resection.

Combination of Hepatitis B Virus Pre-S2 Gene Deletion Mutation and Tumor-Node-Metastasis Stage Predicts Higher Hepatocellular Carcinoma Recurrence after Curative Surgical Resection.

Hepatocellular carcinoma (HCC) is one of the most frequent and life-threatening human cancers worldwide. Despite curative resection surgery, the high recurrence rate of HCC leads to poor patient survival. Chronic hepatitis B virus (HBV) infection is a major etiological factor for HCC. HBV pre-S2 gene deletion mutation leads to the expression of an important oncoprotein called a pre-S2 mutant. It represents an independent prognostic biomarker for HCC recurrence. This study aimed to identify other independent prognostic biomarkers from clinicopathological characteristics of 75 HBV-related HCC patients receiving resection surgery and to validate their potential to be combined with pre-S2 gene deletion mutation as a combination biomarker for HCC recurrence. Patients with both the presence of pre-S2 gene deletion mutation and tumor-node-metastasis (TNM) stage IIIA-IIIC had a higher HCC recurrence risk than patients with either one or none of these two factors. Moreover, the combination of pre-S2 gene deletion mutation and TNM stage exhibited better performance than either of these two factors alone in discriminating patients from patients without HCC recurrence. Collectively, this study proposed that the TNM stage held significance as a combination biomarker with pre-S2 gene deletion mutation with a greater performance in predicting HCC recurrence after curative surgical resection.

Association of Increased Programmed Death Ligand 1 Expression and Regulatory T Cells Infiltration with Higher Hepatocellular Carcinoma Recurrence in Patients with Hepatitis B Virus Pre-S2 Mutant after Curative Surgical Resection.

Although surgical resection is available as a potentially curative therapy for hepatocellular carcinoma (HCC), high recurrence of HCC after surgery remains a serious obstacle for long-term patient survival. Therefore, the discovery of valuable prognostic biomarkers for HCC recurrence is urgently needed. Pre-S2 mutant is a mutant form of hepatitis B virus (HBV) large surface protein which is expressed from the HBV surface gene harboring deletion mutations spanning the pre-S2 gene segment. Pre-S2 mutant-positive HCC patients have been regarded as a high-risk population of HCC recurrence after resection surgery and display increased immune checkpoint programmed death ligand 1 (PD-L1) expression and pro-tumor regulatory T cells (Tregs) infiltration in tumor tissues. In this study, the association of higher levels of PD-L1 expression and Tregs infiltration in tumor tissues with post-operative HCC recurrence in pre-S2 mutant-positive HCC patients was evaluated. We found that patients with pre-S2 mutant in combination with higher levels of PD-L1 expression and Tregs infiltration in tumor tissues were independently associated with a higher risk of HCC recurrence (hazard ratio, 4.109; p value = 0.0011) and poorer recurrence-free survival (median, 8.2 versus 18.0 months; p value = 0.0004) than those of patients with either one or two of these three biomarkers. Furthermore, a combination of pre-S2 mutant, intra-tumoral PD-L1 expression, and tumor-infiltrating Tregs exhibited superior performance in identifying patients at a higher risk of HCC recurrence (area under the receiver operating characteristic curve, 0.8400). Collectively, this study suggests that higher levels of PD-L1 expression and Tregs infiltration in tumor tissues predicted a higher risk of HCC recurrence in pre-S2 mutant-positive HCC patients after curative surgical resection.

Role of Coptis chinensis in antibiotic susceptibility of carbapenem-resistant Klebsiella pneumoniae.

BACKGROUND: The incidence of carbapenem-resistant Klebsiella pneumoniae (CRKP) has rapidly increased. This study aimed to assess the effect of Coptis chinensis and its compounds on the minimal inhibitory concentrations (MICs) of eight antibiotics against CRKP. METHODS: Cell cultures were used to investigate the effects of C. chinensis and its compounds on the MICs of eight antibiotics against CRKP. The MICs for antibiotics alone and antibiotics with C. chinensis or compounds were measured and compared. Furthermore, the effects of C. chinensis on cell membrane injury and intracellular adenosine triphosphate (ATP) CRKP concentration were also measured. The Mann-Whitney rank-sum test was used to analyze the differences between means. RESULTS: C. chinensis exhibits a notable MIC bacteriostatic effect at 5 mg/mL on CRKP. A significant MIC reduction against CRKP exists when C. chinensis was added to colistin and colistin-containing two-antibiotic combinations. Moreover, C. chinensis could damage cell membrane integrity and decrease intracellular ATP concentration in CRKP. Thus, C. chinensis exhibits antimicrobial activity superiority with colistin against CRKP. Furthermore, the effects of identified compounds in C. chinensis on the MICs of colistin, four-to eight-, two-to four-, and one-to two-fold reductions were found in ferulic acid, magnoflorine, and jatrorrhizine hydrochloride, respectively. Among these compounds, ferulic acid destroys membrane integrity and decreases intracellular ATP concentration. CONCLUSION: C. chinensis and ferulic acid can potentiate the antimicrobial activity of colistin and may represent a promising component of combination therapy against CRKP infections in a clinical setting.

Derivation and validation of a clinical prediction model for risks of venous thromboembolism in diabetic and general populations.

ABSTRACT: Most studies on the prediction of venous thromboembolism (VTE) focused on hospitalized, surgery, and cancer patients or women receiving hormonal contraceptives or menopausal hormone therapy. No study considered diabetic and general populations to establish a VTE prediction model, especially in Asia. We developed a predictive model for VTE among type 2 diabetic patients and the general population.This study considered 2 nationwide retrospective cohort studies consisting of 52,427 diabetic participants and 508,664 participants from the general population aged 30 to 85 years during 2001 to 2004 in Taiwan. All participants were followed up until VTE event, death, or December 2011. The outcome event was VTE, including deep venous thrombosis and pulmonary embolism. Candidate predictors consisted of socio-demographic factors, diabetes-related factors and biomarkers, comorbidities, and medicine use. Our study followed the procedures proposed by the Framingham Heart Study to develop prediction models by using a Cox regression model. The predictive accuracy and performance characteristics were assessed using the area under curve of receiver operating characteristics curve and calibration of a risk score were performed by Hosmer-Lemeshow goodness-of-fit test.The common factors for persons with type 2 diabetes and general population included age, hospitalization status 1 year before the baseline, hypertension, chronic kidney disease, chronic obstructive pulmonary disease, and anti-diabetes medications; the specific factors for persons with type 2 diabetes consisted of body mass index, glycosylated hemoglobin A1C, and creatinine; and the factors for general population included gender, peripheral vascular disease, cancer, hypertension medication, cardiovascular medication, and non-steroidal anti-inflammatory drug. The area under curve of 3-, 5-, and 8-year VTE prediction models were 0.74, 0.71, and 0.69 in the diabetic population and 0.77, 0.76, and 0.75 in the general population, respectively.The new clinical prediction models can help identify a high risk of VTE and provide medical intervention in diabetic and general populations.

Association of Low Serum Albumin Level with Higher Hepatocellular Carcinoma Recurrence in Patients with Hepatitis B Virus Pre-S2 Mutant after Curative Surgical Resection.

Hepatocellular carcinoma (HCC) is, globally, one of the most prevalent and deadly human cancers; despite curative surgical resection, its high recurrence rate after surgery remains a large threat, resulting in poor patient survival. The hepatitis B virus (HBV) pre-S2 mutant that harbors deletions spanning the pre-S2 gene segment has emerged as an important oncoprotein for HCC development and a valuable prognostic biomarker for HCC recurrence; however, its relationship with clinicopathological factors is largely unexplored. In this study, the correlation of the deletion spanning the pre-S2 gene segment with clinicopathological factors and the association of such correlation with HCC recurrence after curative surgical resection were examined in HBV-related HCC patients. Inverse correlation between serum albumin level and the deletion spanning the pre-S2 gene segment was identified. HCC patients with the presence of the deletion spanning the pre-S2 gene segment and a low serum albumin level were associated with higher HCC recurrence than patients with either factor alone or neither factor were. Moreover, a combination of the serum albumin level and the deletion spanning the pre-S2 gene segment exhibited better performance than that of either factor alone in predicting HCC recurrence. Collectively, this study shows an association of low serum albumin level with pre-S2 mutant-positive HCC patients, and validates the prognostic value of this association in identifying patients with higher HCC recurrence after curative surgical resection.

Renal markers and risks of all cause and cardiovascular mortality from the Taichung community based cohort study.

This study aimed to explore the associations between renal-related and arterial stiffness biomarkers with all-cause and expanded cardiovascular disease (CVD) mortality in a general Taiwanese population. This prospective community-based cohort study included 4883 subjects aged ≥ 20 years who were followed up until December 31, 2016. Renal-related biomarkers consisted of blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), and urine albumin-to-creatinine ratio (UACR). Arterial stiffness biomarker consisted of brachial-ankle pulse wave velocity (baPWV). The death status of the subjects was ascertained by matching information from death records with the identification number and date of birth of the subjects. Cox proportional hazard models with restricted cubic splines estimated the hazard ratios and 95% confidence intervals for all-cause mortality and expanded CVD mortality. During a mean 8.3 years of follow up, 456 deaths were recorded, 146 of which were due to expanded CVD mortality. The multivariable-adjusted hazard ratios of all-cause mortality was 1.53 (95% CI 1.21-1.94) for BUN (≥ 20 mg/dL vs. < 20 mg/dL), 1.57 (1.15-2.14) for eGFR (< 90 mL/min/1.73 m2 vs. ≥ 90 mL/min/1.73 m2), 1.55 (1.25-1.92) for UACR (≥ 30 mg/g vs. < 30 mg/g), and 1.75 (1.14-2.67) for baPWV (≥ 1400 cm/s vs. < 1400 cm/s). The expanded CVD mortality was 1.89 (95% CI 1.30-2.73) for BUN (≥ 20 mg/dL vs. < 20 mg/dL), 2.28 (1.13-4.57) for eGFR (< 90 mL/min/1.73 m2 vs. ≥ 90 mL/min/1.73 m2), 2.13 (1.52-2.99) for UACR (≥ 25 mg/g vs. < 25 mg/g), and 15.73 (2.14-115.61) for baPWV (≥ 1400 cm/s vs. < 1400 cm/s). High levels of BUN, UACR, and baPWV and low levels of eGFR showed high risks with all-cause and expanded CVD mortality. Our study provides insights into screening tests to target populations at high risk of premature death due to CVD.

Increased infiltration of regulatory T cells in hepatocellular carcinoma of patients with hepatitis B virus pre-S2 mutant.

Hepatocellular carcinoma (HCC) is a frequent and deadly human cancer worldwide that is intimately associated with chronic hepatitis B virus (HBV) infection. Pre-S2 mutant is a HBV oncoprotein that plays important roles in HCC development and is linked to poor prognosis in HCC patients. However, the profiles of tumor-infiltrating lymphocytes in HCC tissues of pre-S2 mutant-positive patients remain unknown. In this study, we performed fluorescent immunohistochemistry staining to detect the infiltration of 'anti-tumor' cytotoxic T lymphocytes (CTLs) and 'pro-tumor' regulatory T cells (Tregs) in pre-S2 mutant-positive and -negative HCC patients. We showed that pre-S2 mutant-positive patients had a significantly higher infiltration of CD4+CD25+ cells and forkhead box P3 (Foxp3)-expressing cells but similar CTLs and lower granzyme B-expressing cells in HCC tissues compared with pre-S2 mutant-negative patients. Moreover, the percentage of pre-S2 plus pre-S1 + pre-S2 deletion (pre-S2 mutant) was positively correlated with the density of CD4+CD25+ cells and Foxp3-expressing cells but negatively with granzyme B-expressing cells in HCC tissues. Considering that increased intratumoral Tregs have been shown to promote tumor immune evasion, our data may provide new insights into the pathogenesis of HBV pre-S2 mutant-induced HCC and suggest that therapeutics targeting Tregs may be a promising strategy for treating pre-S2 mutant-positive high-risk patient population.

Increased Expression of Programmed Death Ligand 1 in Hepatocellular Carcinoma of Patients with Hepatitis B Virus Pre-S2 Mutant.

PURPOSE: Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC), a leading cause of cancer-related death worldwide. The HCC patients who harbor HBV pre-S2 mutant, an oncoprotein that plays key roles in HCC development, have been closely associated with a worse prognosis after curative surgical resection, suggesting an urgent need for alternative therapeutic options to improve their survival. In this study, we aimed to evaluate the expression profiles of programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1), two of the most well-studied immune checkpoint molecules that promote tumor immune evasion, in tumor of the pre-S2 mutant-positive/high HCC patients. METHODS: We classified 40 HBV-related HCC patients into the pre-S2-positive/high and -negative/low groups by a next-generation sequencing-based approach. The fluorescent immunohistochemistry staining was performed to detect the expression of PD-1 and PD-L1 in HCC tissues of patients. RESULTS: We showed that patients with either deletion spanning pre-S2 gene segment or high percentage of pre-S2 plus pre-S1+pre-S2 deletion (the pre-S2 mutant-positive/high group) exhibited a significantly higher density of PD-L1-positive cells in HCC tissues than those without. Moreover, the percentage of pre-S2 plus pre-S1+pre-S2 deletion displayed a high positive correlation with the density of PD-L1-positive cells in HCC tissues. CONCLUSION: The increased expression of PD-L1 in tumor tissues of the pre-S2 mutant-positive HCC patients suggest that pre-S2 mutant may play a potential role in dysregulation of tumor immune microenvironment in the progression of HBV-related HCC, implicating for the development of future therapeutic strategies.

Hepatitis B virus pre-S2 deletion (nucleotide 1 to 54) in plasma predicts recurrence of hepatocellular carcinoma after curative surgical resection.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Despite curative surgical resection, high recurrence of HCC after surgery results in poor patient survival. To develop prognostic markers is therefore important for better prevention and therapy of recurrent HCC to improve patient outcomes. Deletion mutations over the pre-S1 and pre-S2 gene segments of hepatitis B virus (HBV) have been closely associated with recurrence of HCC after curative surgical resection. In this study, we applied a next-generation sequencing-based approach to further evaluate the association of pre-S deletion regions with HCC recurrence. We demonstrated that the pre-S2 deletion (nucleotide 1 to 54) was the most predominant deletion regions of pre-S gene in plasma of HBV-related HCC patients. Moreover, patients with the pre-S2 deletion (nucleotide 1 to 54) exhibited a significantly higher risk of HCC recurrence after curative surgical resection than those without. The pre-S2 deletion (nucleotide 1 to 54) in plasma represented a prognostic factor that independently predicted HCC recurrence with greater performance than other clinicopathological and viral factors. Our data suggest that detection of the pre-S2 deletion (nucleotide 1 to 54) in plasma may be a promising noninvasive strategy for identifying patients at high risk for HCC recurrence after curative surgical resection.

Independent associations of urinary albumin-to-creatinine ratio and serum cystatin C with carotid intima-media thickness in community-living Taiwanese adults.

BACKGROUND: Renal function is a key factor of cardiovascular disease. Carotid intima-media thickness (IMT) has been widely used as a marker of early subclinical atherosclerosis. The determinants of cystatin C, a novel marker of renal function, have not been extensively studied in the Asian population. This study aimed to assess the determinants of cystatin C and explore whether carotid thickening was associated with urinary albumin-creatinine ratio and cystatin C in community-living Taiwanese adults. METHODS: A cross-sectional study was conducted on participants from Taichung City, Taiwan. All the participants underwent carotid ultrasonography. Carotid IMT-mean and IMT-maximum were derived. Kidney biomarkers were measured on the basis of urinary albumin-to-creatinine ratio (ACR) and cystatin C. Multiple linear regression analysis was used. RESULTS: A total of 1032 individuals were recruited, and 469 (45.44%) of them were men. An increased cystatin C level was significantly associated with older age, male gender, lack of physical activity, low HDL cholesterol, abdominal obesity, high hs-CRP, and high ACR. The multivariate-adjusted mean carotid IMT-mean and IMT-maximum values significantly increased by 80.49 and 195.23 µm for every one unit of increase in cystatin C level and by 0.07 and 0.14 µm for every one unit of increase in ACR, respectively (all p < 0.001 except ACR on IMT-maximum with p < 0.01). Lack of physical activity, low HDL, abdominal obesity, high hs-CRP, and high ACR were the determinants of cystatin C. CONCLUSION: Cystatin C and ACR were strongly and linearly associated with carotid thickening, a marker of subclinical atherosclerosis.

Derivation and validation of 10-year all-cause and cardiovascular disease mortality prediction model for middle-aged and elderly community-dwelling adults in Taiwan.

Prediction model mainly focused on specific diseases, such as diabetes, hypertension, cardiovascular disease, or patients with cancer, or populations of Europe and America, thereby limiting its generalization. This study aimed to develop and validate a 10-year mortality risk score by using data from a population-representative sample of adults. Data were collected from 2,221 Taichung Community Health study participants aged ≥40 years. The baseline period of the study was 2004, and all participants were followed up until death or in 2016. Cox's proportional hazards regression analyses were used to develop the prediction model. A total of 262 deaths were ascertained during the 10-year follow-up. The all-cause mortality prediction model calculated the significant risk factors, namely, age, sex, marital status, physical activity, tobacco use, estimated glomerular filtration rate, and albumin-to-creatinine ratio, among the baseline risk factors. The expanded cardiovascular disease (CVD) mortality prediction model consisted of six variables: age, sex, body mass index, heart disease plus heart disease medication use, stroke plus medication use, and ankle-brachial index. The areas under receiver operating curves of the 3-, 5- and 10-year predictive models varied between 0.97, 0.96, and 0.88 for all-cause mortality, and between 0.97, 0.98, and 0.84 for expanded CVD mortality. These mortality prediction models are valid and can be used as tools to identify the increased risk for mortality.

Interactions among IGF-1, AKT2, FOXO1, and FOXO3 variations and between genes and physical activities on physical performance in community-dwelling elders.

This study assessed the interactions among IGF-1, AKT2, FOXO1, and FOXO3 variations and the interactions of gene and physical activity on handgrip strength, arm muscle mass-adjusted handgrip (armGrip), gait speed (GS), timed up and go (TUG), and leg press strength (LPS). Nine single nucleotide polymorphisms (SNPs) containing three IGF-1 SNPs (rs6214, rs5742692, and rs35767), two AKT2 SNPs (rs892119 and rs35817154), two FOXO1 SNPs (rs17446593 and rs10507486), and two FOXO3 SNPs (rs9480865 and rs2153960) were genotyped in 472 unrelated elders with a mean age of 73.8 years. We observed significant interactions of IGF-1 SNP rs6214 and rs35767 with regular physical activity on TUG and GS; and AKT2 SNP rs892119 and FOXO3 SNP rs9480865 with regular physical activity on armGrip. Genotype GG of IGF-1 rs6214 and rs35767 in individuals without regular physical activity had poor performance in TUG and GS, as well as GG of AKT2 rs892119 decreased armGrip in individuals without regular physical activity. After FDR adjustment, no significant gene-gene interactions were found. A sedentary lifestyle may increase the risk of impairing physical performance and regular physical activity is a remedy for sarcopenia, even a little regular physical activity can overcome carrying some risk alleles in this pathway.

Diabetes mellitus associated with an increased risk of percutaneous coronary intervention long-term adverse outcomes in Taiwan: A nationwide population-based cohort study.

AIMS: This study compared the incidence rates of patients with diabetes mellitus (DM) and patients without DM with percutaneous coronary intervention (PCI) in a national population-based cohort to determine if the patients with DM have an increased risk of adverse outcomes. METHODS: We performed a retrospective cohort study among 92,624 patients with and without DM, who underwent PCI for the first time in 2000-2008. The patients were identified from National Health Insurance Program Database through propensity score matching. Endpoints were the occurrence of PCI adverse outcomes, including myocardial infarction (MI), need for target vessel revascularization by either bypass surgery or repeat PCI, all-cause mortality or 2011/12/31. Incidence rate was calculated and hazard ratios of PCI adverse events were estimated using Cox's proportional hazard regression model. RESULTS: During the mean six-year follow up, the rates of MI (incidence rate 20.96 vs. 15.59 per 1000 person-years), bypass surgery (incidence rate 8.15 vs. 5.15 per 1000 person-years), all-cause mortality (incidence rate 6.20 vs. 4.72 per 1000 person-years), and the composite measure of MI, repeat PCI, bypass surgery, all-cause mortality (incidence rate 37.31 vs. 28.14 per 1000 person-years) were higher in patients with DM. The corresponding hazard ratios (HRs) and their 95% confidence intervals (CIs) were 1.34 (95% CI: 1.29, 1.39), 1.46 (1.38, 1.56), 1.34 (1.25, 1.44), and 1.31 (1.27, 1.35). However, the repeat PCI rate (incidence rate 2.65 vs. 2.70 per 1000 person-years); with an adjusted HR of 0.97 (0.88, 1.07) was not statistically different. CONCLUSIONS: This nationwide retrospective cohort study determined a positive correlation between PCI adverse events and DM. As the prevalence of DM and PCI continues to increase, novel treatments and intensified surveillance coronary angiography for high risk patients are needed.

Next-Generation Sequencing-Based Quantitative Detection of Hepatitis B Virus Pre-S Mutants in Plasma Predicts Hepatocellular Carcinoma Recurrence.

Hepatocellular carcinoma (HCC) is among the most common and lethal human cancers worldwide. Despite curative resection, high recurrence of HCC remains a big threat, leading to poor patient outcomes. Hepatitis B virus (HBV) pre-S mutants, which harbor deletions over pre-S1 and pre-S2 gene segments of large surface proteins, have been implicated in HCC recurrence. Therefore, a reliable approach for detection of pre-S mutants is urgently needed for predicting HCC recurrence to improve patient survival. In this study, we used a next-generation sequencing (NGS)-based platform for quantitative detection of pre-S mutants in the plasma of HBV-related HCC patients and evaluated their prognostic values in HCC recurrence. We demonstrated that the presence of deletions spanning the pre-S2 gene segment and the high percentage of pre-S2 plus pre-S1 + pre-S2 deletions, either alone or in combination, was significantly and independently associated with poor recurrence-free survival and had greater prognostic performance than other clinicopathological and viral factors in predicting HCC recurrence. Our data suggest that the NGS-based quantitative detection of pre-S mutants in plasma represents a promising approach for identifying patients at high risk for HBV-related HCC recurrence after surgical resection in a noninvasive manner.

Detection of hepatitis B virus pre-S mutants in plasma by a next-generation sequencing-based platform determines their patterns in liver tissues.

Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death worldwide. Patients with hepatitis B virus (HBV) pre-S mutants in liver tissues or blood have been regarded as a high-risk population for HCC development and recurrence. Detection of pre-S mutants in clinical specimens is thus important for early diagnosis and prognosis of HCC to improve patient survival. Recently, we have developed a next-generation sequencing (NGS)-based platform that can quantitatively detect pre-S mutants in patient plasma with superior sensitivity and accuracy. In this study, we compared the pre-S genotyping results from plasma by the NGS-based analysis with those from liver tissues by the immunohistochemistry (IHC)-based analysis in 30 HBV-related HCC patients. We demonstrated that the detection rate of pre-S mutants was significantly higher by NGS- than by IHC-based analysis. There was a moderate to good agreement between both analyses in detection of pre-S mutants. Compared with the IHC, the NGS-based detection of pre-S mutants in patient plasma could determine the patterns of pre-S mutants in liver tissues more efficiently in a noninvasive manner. Our data suggest that the NGS-based platform may represent a promising approach for detection of pre-S mutants as biomarkers of HBV-related HCC in clinical practice.

Important gene-gene interaction of TNF-α and VDR on osteoporosis in community-dwelling elders.

Gene effects on osteoporosis have been studied separately and may have been masked by gene-gene and gene-environment interactions. We evaluated gene-gene and gene-physical activity interactions of the variants of tumor necrosis factor-α (TNF-α) and vitamin D receptor (VDR) genes on osteoporosis. A total of 472 elders were included. Seven variants (TNF-α: rs1799964, rs1800629, rs3093662; VDR: rs7975232, rs1544410, rs2239185, rs3782905) were genotyped. Bone mineral densities of the lumbar spine, femoral neck, and total hip were measured by dual-energy X-ray absorptiometry. Predictive models' ability to discriminate osteoporosis status was evaluated by areas under the receiver operating characteristics (AUROC) curve. After multivariable adjustment, significant interactions of TNF-α rs1800629 and VDR rs3782905 were observed on overall and lumbar spine osteoporosis. In elderly women, we found that those carrying the CG/CC genotype of VDR rs3782905 were significantly associated with increased odds of overall osteoporosis compared with those carrying the GG genotype of VDR rs3782905 among those carrying TNF-α rs1800629 GG genotype. The adjusted odds ratios (ORs) for VDR rs3782905 CG/CC genotype in elderly women carrying TNF-α rs1800629 AG/AA and GG genotypes were 0.1 (0.01, 0.98) and 3.54 (1.51, 8.30), respectively. We observed significant differences in AUROCs between the model with traditional covariates plus variants and their interaction term and the model with traditional covariates only (AUROCs: 0.77 and 0.81; p = 0.028). Although the sample size of this study may have been relatively small, our results suggest that the interaction of the CG/CC genotype of VDR rs3782905 with TNF-α rs1800629 GG genotype was associated with increased odds of overall and lumbar spine osteoporosis in elderly women.

A qualitative study of attitudes to and perceptions of betel quid consumption and its oral health implications in Taiwan.

OBJECTIVES: Betel quid (BQ) chewing is extremely prominent in South and Southeast Asia because it considered by users to be of social, cultural and religious importance. BQ chewing has been recognized as a risk factor for oral premalignant lesions and oral cancer. Because BQ chewing has become a severe health risk in Taiwan, the development of prevention and cessation programmes is essential. The purpose of this study was to explore the attitudes and perceptions associated with BQ consumption and its oral health implications in an attempt to inform the development of health promotion initiatives and BQ cessation efforts in Taiwan, where the dental profession could have a pivotal role in preventing and controlling BQ use among persons at risk. METHODS: This qualitative study used data gathered from focus groups and individual interviews. A convenience sample of 41 adults from Jhushan and Lugu Townships (Nantou County) and Taichung City, Taiwan, participated in this study (27 men, 14 women; 31 Han, 10 aboriginals from the Paiwan tribe; mean age 40.3, SD 9.2 years). RESULTS: Among the seven themes that emerged from the original study, five (Initiation, Health Risk Perception, Health Consequences, Withdrawal Symptoms and Help from Healthcare Providers) had oral/dental implications. CONCLUSIONS: Our study highlights research areas relevant to further investigation, such as incorporating brief BQ prevention and cessation counselling when early oral and dental signs associated with BQ consumption are detected. Undertaking behavioural interventions in dental settings might help to reduce the prevalence of BQ chewing in Taiwan.

A Next-Generation Sequencing-Based Platform for Quantitative Detection of Hepatitis B Virus Pre-S Mutants in Plasma of Hepatocellular Carcinoma Patients.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Early diagnosis and treatment of HCC remain a key goal for improving patient survival. Chronic hepatitis B virus (HBV) infection is a major risk factor for HCC development. Pre-S mutants harboring deletions in HBV large surface antigen have been well demonstrated as HBV oncoproteins that dysregulate multiple signaling pathways in hepatocytes, leading to HCC formation. The presence of pre-S mutants in plasma represents important predictive and prognostic markers for HCC in patients with chronic HBV infection. However, the method to detect pre-S mutants remains to be optimized. In this study, we developed a platform, based on the next-generation sequencing (NGS) technology, for detection of pre-S mutants in plasma of HBV-related HCC patients. Compared to the current TA cloning-based analysis, the NGS-based analysis could detect pre-S deletion quantitatively, and the detection rate was significantly more sensitive in 49 plasma analyzed (McNemar's paired proportion test, P value < 0.0001; simple kappa coefficient, κ = 0.29 (95% CI, 0.12 to 0.46)). Our data suggest that the NGS-based platform may hold a promise for improving the clinical application of pre-S mutants in serving as predictive and prognostic markers for HBV-related HCC.