The largest genome-wide association study for breast cancer in Taiwanese Han population.

PURPOSE: Breast cancer is a molecularly heterogeneous disease, and multiple genetic variants contribute to its development and prognosis. Most of previous genome-wide association studies (GWASs) and polygenic risk scores (PRSs) analyses focused on studying breast cancers of Caucasian populations, which may not be applicable to other population. Therefore, we conducted the largest breast cancer cohort of Taiwanese population to fill in the knowledge gap. METHODS: A total of 152,534 Participants recruited by China Medical University Hospital between 2003 and 2019 were filtered by several patient selection criteria and GWAS quality control steps, resulting in the inclusion of 2496 cases and 9984 controls for this study. We then conducted GWAS for all breast cancers and PRS analyses for all breast cancers and the four breast cancer subtypes, including luminal A, luminal B, basal-like, and HER2-enriched. RESULTS: The GWAS analyses identified 113 SNPs, 50 of which were novel. The PRS models for all breast cancers and the luminal A subtype showed positively correlated trends between the PRS and the risk of developing breast cancer. The odds ratios (95% confidence intervals) for the groups with the highest PRS in all breast cancers and the luminal A subtype were 5.33 (3.79-7.66) and 3.55 (2.13-6.14), respectively. CONCLUSION: In summary, we explored the association of genetic variants with breast cancer in the largest Taiwanese cohort and developed two PRS models that can predict the risk of developing any breast cancer and the luminal A subtype in Taiwanese women.

Your height affects your health: genetic determinants and health-related outcomes in Taiwan.

BACKGROUND: Height is an important anthropometric measurement and is associated with many health-related outcomes. Genome-wide association studies (GWASs) have identified hundreds of genetic loci associated with height, mainly in individuals of European ancestry. METHODS: We performed genome-wide association analyses and replicated previously reported GWAS-determined single nucleotide polymorphisms (SNPs) in the Taiwanese Han population (Taiwan Biobank; n = 67,452). A genetic instrument composed of 251 SNPs was selected from our GWAS, based on height and replication results as the best-fit polygenic risk score (PRS), in accordance with the clumping and p-value threshold method. We also examined the association between genetically determined height (PRS251) and measured height (phenotype). We performed observational (phenotype) and genetic PRS251 association analyses of height and health-related outcomes. RESULTS: GWAS identified 6843 SNPs in 89 genomic regions with genome-wide significance, including 18 novel loci. These were the most strongly associated genetic loci (EFEMP1, DIS3L2, ZBTB38, LCORL, HMGA1, CS, and GDF5) previously reported to play a role in height. There was a positive association between PRS251 and measured height (p < 0.001). Of the 14 traits and 49 diseases analyzed, we observed significant associations of measured and genetically determined height with only eight traits (p < 0.05/[14 + 49]). Height was positively associated with body weight, waist circumference, and hip circumference but negatively associated with body mass index, waist-hip ratio, body fat, total cholesterol, and low-density lipoprotein cholesterol (p < 0.05/[14 + 49]). CONCLUSIONS: This study contributes to the understanding of the genetic features of height and health-related outcomes in individuals of Han Chinese ancestry in Taiwan.

A Study to Evaluate Accuracy and Validity of the EFAI Computer-Aided Bone Age Diagnosis System Compared With Qualified Physicians.

Study Objectives: In previous research, we built a deep neural network model based on Inception-Resnet-v2 to predict bone age (EFAI-BAA). The primary objective of the study was to determine if the EFAI-BAA was substantially concordant with the qualified physicians in assessing bone ages. The secondary objective of the study was to determine if the EFAI-BAA was no different in the clinical rating (advanced, normal, or delayed) with the qualified physicians. Method: This was a retrospective study. The left-hand X-ray images of male subjects aged 3-16 years old and female subjects aged 2-15 years old were collected from China Medical University Hospital (CMUH) and Asia University Hospital (AUH) retrospectively since the trial began until the included image amount reached 368. This was a blinded study. The qualified physicians who ran, read, and interpreted the tests were blinded to the values assessed by the other qualified physicians and the EFAI-BAA. Results: The concordance correlation coefficient (CCC) between the EFAI-BAA (EFAI-BAA), the evaluation of bone age by physician in Kaohsiung Veterans General Hospital (KVGH), Taichung Veterans General Hospital (TVGH2), and in Taipei Tzu Chi Hospital (TZUCHI-TP) was 0.9828 (95% CI: 0.9790-0.9859, p-value = 0.6782), 0.9739 (95% CI: 0.9681-0.9786, p-value = 0.0202), and 0.9592 (95% CI: 0.9501-0.9666, p-value = 0.4855), respectively. Conclusion: There was a consistency of bone age assessment between the EFAI-BAA and each one of the three qualified physicians (CCC = 0.9). As the significant difference in the clinical rating was only found between the EFAI-BAA and the qualified physician in TVGH2, the performance of the EFAI-BAA was considered similar to the qualified physicians.

Analysis of HLA Variants and Graves' Disease and Its Comorbidities Using a High Resolution Imputation System to Examine Electronic Medical Health Records.

Hyperthyroidism is a prevalent endocrine disorder, and genetics play a major role in the development of thyroid-associated diseases. In particular, the inheritance of HLA has been demonstrated to induce the highest susceptibility to Graves' disease (GD). However, thus far, no studies have reported the contribution of HLA to the development of GD and the complications that follow. Thus, in the present study, to the best of our knowledge, for the first time, a powerful imputation method, HIBAG, was used to predict the HLA subtypes among populations with available genome-wide SNP array data from the China Medical University Hospital (CMUH). The disease status was extracted from the CMUH electronic medical records; a total of 2,998 subjects with GD were identified as the cases to be tested and 29,083 subjects without any diagnosis of thyroid disorders were randomly selected as the controls. A total of 12 HLA class I genotypes (HLA-A*02:07-*11:01, HLA-B*40:01-*46:01 and *46:01-*46:01, and HLA-C*01:02-*01:02, *01:02-*03:04, and *01:02-*07:02) and 17 HLA class II genotypes (HLA-DPA1*02:02-*02:02, HLA-DPB1*02:01-*05:01, *02:02-*05:01, and *04:01-*05:01, HLA-DQA1*03:02, HLA-DRB1*09:01-*15:01, and *09:01-*09:01) were found to be associated with GD in the Taiwanese population. Moreover, the HLA subtypes HLA-A*11:01, HLA-B*46:01, HLA-DPA1*01:03, and HLA-DPB1*05:01 were found to be associated with heart disease, stroke, diabetes, and hypertension among subjects with GD. Our data suggest that several HLA alleles are markedly associated with GD and its comorbidities, including heart disease, hypertension, and diabetes.

Genetic factors of idiopathic central precocious puberty and their polygenic risk in early puberty.

OBJECTIVE,: To investigate the genetic characteristics of idiopathic central precocious puberty (ICPP) and validate its polygenic risk for early puberty. DESIGN AND METHODS: A bootstrap subsampling and genome-wide association study were performed on Taiwanese Han Chinese girls comprising 321 ICPP patients and 148 controls. Using previous GWAS data on pubertal timing, a replication study was performed. A validation group was also investigated for the weighted polygenic risk score (wPRS) of the risk of early puberty. RESULTS: A total of 105 SNPs for the risk of ICPP were identified, of which 22 yielded an area under the receiver operating characteristic curve of 0.713 for the risk of early puberty in the validation group. A replication study showed that 33 SNPs from previous GWAS data of pubertal timing were associated with the risk of ICPP (training group: P-value < 0.05). In the validation group, a cumulative effect was observed between the wPRS and the risk of early puberty in a dose-dependent manner (validation group: Cochran-Armitage trend test: P-value < 1.00E-04; wPRS quartile 2 (Q2) (odds ratio (OR) = 5.00, 95% CI: 1.55-16.16), and wPRS Q3 (OR = 11.67, 95% CI: 2.44-55.83)). CONCLUSIONS: This study reveals the ICPP genetic characteristics with 22 independent and 33 reported SNPs in the Han Chinese population from Taiwan. This study may contribute to understand the genetic features and underlying biological pathways that control pubertal timing and pathogenesis of ICPP and also to the identification of individuals with a potential genetic risk of early puberty.

Chinese Herbal Medicine Usage Reduces Overall Mortality in HIV-Infected Patients With Osteoporosis or Fractures.

The survival of patients with HIV has greatly improved, due to Anti-Retroviral Therapy (ART). However, long-term HIV survivors often develop serious bone abnormalities, possibly due to the interplay of osteoblasts, osteoclasts, HIV ad ART. We evaluated in a nation-wide study in Taiwan the effect of Chinese herbal medicine (CHM) on overall mortality in HIV patients with osteoporosis or fractures. Enrollment period was between 1998 and 2011. Patients with osteoporosis or fractures before the HIV infection, and those with less than 14 days CHM use, were excluded. This left 498 patients, 160 CHM users, 338 without CHM. Univariate Kaplan-Meier and multivariate Cox regression analysis were used to compare the overall mortality in these 2 groups. Due to the nature of Chinese medicine, CHMs inevitably varied. We therefore also used rule mining and network analysis to determine which major CHM clusters were prescribed to the patients. CHM users had a much Lower mortality (hazard ratio (HR) = 0.43, 95% confidence interval (CI): 0.24-0.77, p < 0.005) and higher survival (p = 0.004, log-rank test). Although the CHMs greatly varied, network analysis identified one main cluster of strongly related CHM combinations (Chuan-Xiong-Cha-Tiao-San (CXCTS), Gan-Cao (GC; Glycyrrhiza uralensis Fisch.), Liu-He-Tang (LHT), Huang-Qin-Tang (HQT), Jia-Wei-Ping-Wei-San (JWPWS), and Dang-Gui-Long-Hui-Wan (DGLHuiW)). CHM as an additional treatment strongly improves overall survival in HIV-infected patients with osteoporosis and fractures.

Timing, Dosage, and Adherence of Antiretroviral Therapy and Risk of Osteoporosis in Patients With Human Immunodeficiency Virus Infection in Taiwan: A Nested Case-Control Study.

The progression of acquired immunodeficiency syndrome is delayed in patients with human immunodeficiency virus (HIV) infection receiving antiretroviral therapy (ART). However, long-term ART is associated with adverse effects. Osteoporosis is one of the adverse effects and is a multifactorial systemic skeletal disease associated with bone fragility and an increased risk of fracture. We performed a longitudinal, comprehensive, nested case-control study to explore the effect of ART on the risk of osteoporosis in 104 osteoporotic and 416 non-osteoporotic patients with HIV infection at their average age about 29 years old in Taiwan. Patients with history of ART, current exposure to ART, higher cumulative defined daily doses (DDDs), or higher ART adherence were at a higher risk of osteoporosis (p < 0.05). Patients receiving nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-containing regimen (zidovudine-lamivudine combination, lamivudine-abacavir combination, and abacavir alone) and protease inhibitor (PI)-containing regimen (lopinavir-ritonavir combination, ritonavir, and atazanavir) had a higher risk of osteoporosis (p < 0.05). Especially, patients receiving high doses of the PIs lopinavir-ritonavir combination had an increased risk of osteoporosis (p < 0.05). In conclusion, history of ART, current exposure to ART, higher cumulative DDDs, and higher ART adherence were associated with an increased risk of osteoporosis. Furthermore, NRTI- and PI-containing regimens and high doses of PIs lopinavir-ritonavir combination may be associated with an increased risk of osteoporosis in patients with HIV infection in Taiwan.

Genome-Wide and Candidate Gene Association Analyses Identify a 14-SNP Combination for Hypertension in Patients With Type 2 Diabetes.

BACKGROUND: High blood pressure is common and comorbid with type 2 diabetes (T2D). Almost 50% of patients with T2D have high blood pressure. Patients with both conditions of hypertension (HTN) and T2D are at risk for cardiovascular diseases and mortality. The study aim was to investigate genetic risk factors for HTN in T2D patients. METHODS: This study included 999 T2D (cohort 1) patients for the first genome scan stage and 922 T2D (cohort 2) patients for the replication stage. Here, we investigated the genetic susceptibility and cumulative weighted genetic risk score for HTN in T2D patients of Han Chinese descent in Taiwan. RESULTS: Thirty novel genetic single nucleotide polymorphisms (SNPs) were associated with HTN in T2D after adjusting for age and body mass index (P value <1 × 10-4). Eight blood pressure-related and/or HTN-related genetic SNPs were associated with HTN in T2D after adjusting for age and body mass index (P value <0.05). Linkage disequilibrium and cumulative weighted genetic risk score analyses showed that 14 of the 38 SNPs were associated with risk of HTN in a dose-dependent manner in T2D (Cochran-Armitage trend test: P value <0.0001). The 14-SNP cumulative weighted genetic risk score was also associated with increased regression tendency of systolic blood pressure in T2D (SBP = 122.05 + 0.8 × weighted genetic risk score; P value = 0.0001). CONCLUSIONS: A cumulative weighted genetic risk score composed of 14 SNPs is important for HTN, increased tendency of systolic blood pressure, and may contribute to HTN risk in T2D in Taiwan.

Report of clinical bone age assessment using deep learning for an Asian population in Taiwan.

INTRODUCTION: A deep learning-based automatic bone age identification system (ABAIs) was introduced in medical imaging. This ABAIs enhanced accurate, consistent, and timely clinical diagnostics and enlightened research fields of deep learning and artificial intelligence (AI) in medical imaging. AIM: The goal of this study was to use the Deep Neural Network (DNN) model to assess bone age in months based on a database of pediatric left-hand radiographs. METHODS: The Inception Resnet V2 model with a Global Average Pooling layer to connect to a single fully connected layer with one neuron using the Rectified Linear Unit (ReLU) activation function consisted of the DNN model for bone age assessment (BAA) in this study. The medical data in each case contained posterior view of X-ray image of left hand, information of age, gender and weight, and clinical skeletal bone assessment. RESULTS: A database consisting of 8,061 hand radiographs with their gender and age (0-18 years) as the reference standard was used. The DNN model's accuracies on the testing set were 77.4%, 95.3%, 99.1% and 99.7% within 0.5, 1, 1.5 and 2 years of the ground truth respectively. The MAE for the study subjects was 0.33 and 0.25 year for male and female models, respectively. CONCLUSION: In this study, Inception Resnet V2 model was used for automatic interpretation of bone age. The convolutional neural network based on feature extraction has good performance in the bone age regression model, and further improves the accuracy and efficiency of image-based bone age evaluation. This system helps to greatly reduce the burden on clinical personnel.

Genetic risk score constructed from common genetic variants is associated with cardiovascular disease risk in type 2 diabetes mellitus.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) experience a two-fold increased risk of cardiovascular diseases. Genome-wide association studies (GWAS) have identified T2DM susceptibility genetic variants. Interestingly, the genetic variants associated with cardiovascular disease risk in T2DM Han Chinese remain to be elucidated. The present study aimed to investigate the genetic variants associated with cardiovascular disease risk in T2DM. METHODS: We performed bootstrapping, GWAS and an investigation of genetic variants associated with cardiovascular disease risk in a discovery T2DM cohort and in a replication cohort. The discovery cohort included 326 cardiovascular disease patients and 1209 noncardiovascular disease patients. The replication cohort included 68 cardiovascular disease patients and 317 noncardiovascular disease patients. The main outcome measures were genetic variants for genetic risk score (GRS) in cardiovascular disease risk in T2DM. RESULTS: In total, 35 genetic variants were associated with cardiovascular disease risk. A GRS was generated by combining risk alleles from these variants weighted by their estimated effect sizes (log odds ratio [OR]). T2DM patients with weighted GRS ≥ 12.63 had an approximately 15-fold increase in cardiovascular disease risk (odds ratio = 15.67, 95% confidence interval [CI] = 10.33-24.00) compared to patients with weighted GRS < 10.39. With the addition of weighted GRS, receiver-operating characteristic curves showed that area under the curve with conventional risk factors was improved from 0.719 (95% CI = 0.689-0.750) to 0.888 (95% CI = 0.866-0.910). CONCLUSIONS: These 35 genetic variants are associated with cardiovascular disease risk in T2DM, alone and cumulatively. T2DM patients with higher levels of weighted genetic risk score have higher cardiovascular disease risks.

Decreased overall mortality rate with Chinese herbal medicine usage in patients with decompensated liver cirrhosis in Taiwan.

BACKGROUND: Liver cirrhosis is one of the main causes of the morbidity and mortality in liver diseases. Chinese herbal medicine (CHM) has long been used for the clinical treatment of liver diseases. This study was designed to explore the usage frequency and prescription patterns of CHM for patients with decompensated liver cirrhosis and to evaluate the long-term effects of CHM on overall mortality. METHODS: Two thousand four hundred sixty-seven patients with decompensated liver cirrhosis (ICD-9-CM code: 571.2, 571.5, and 571.6) diagnosed between 2000 and 2009 in Taiwan were identified from the registry for catastrophic illness patients. Of these, 149 CHM users and 298 CHM non-users were matched for age, gender, and Charlson comorbidity index score. The chi-squared test, paired Student's t-test, Cox proportional hazard model, and Kaplan-Meier method were applied for various comparisons between these groups of patients. RESULTS: CHM-treated patients showed a lower overall mortality risk compared with non-treated patients (Multivariable: p < 0.0001; HR: 0.54, 95% CI: 0.42-0.69). The cumulative incidence of overall mortality was lower in the CHM-treated group (stratified log-rank test, p = 0.0002). The strongest CHM co-prescription pattern- Yin-Chen-Hao-Tang (YCHT) → Long-Dan-Xie-Gan-Tang (LDXGT) had the highest support, followed by Zhi-Zi (ZZ) → Yin-Chen-Wu-Ling-San (YCWLS) and Bai-Hua-She-She-Cao (BHSSC) → Da-Huang (DaH). CONCLUSION: CHM, as adjunct therapy, might decrease the risk of overall mortality in patients with decompensated liver cirrhosis. CHM co-prescription patterns and network analysis showed that comprehensive herbal medicines have a protective role against liver fibrosis. Further studies are required to enhance the knowledge of safety and efficacy of CHM in patients with decompensated liver cirrhosis.

Lower rates of mortality, readmission and reoperation in patients receiving acupuncture after hip fracture: a population-based analysis.

BACKGROUND: Studies on the effects of acupuncture on mortality and complication rates in hip fracture patients are limited by small sample size and short follow-up time. We aimed to assess the associations of acupuncture use with mortality, readmission and reoperation rates in hip fracture patients using a longitudinal population-based database. METHODS: A retrospective matched cohort study was conducted using data for the years 1996-2012 from Taiwan's National Health Insurance Research Database. Hip fracture patients were divided into an acupuncture group consisting of 292 subjects who received at least 6 acupuncture treatments within 183 days of hip fracture, and a propensity score matched "no acupuncture" group of 876 subjects who did not receive any acupuncture treatment and who functioned as controls. The two groups were compared using survival analysis and competing risk analysis. RESULTS: Compared to non-treated subjects, subjects treated with acupuncture had a lower risk of overall death (hazard ratio (HR): 0.41, 95% confidence interval (CI): 0.24-0.73, p = 0.002), a lower risk of readmission due to medical complications (subdistribution HR (sHR): 0.64, 95% CI: 0.44-0.93, p = 0.019) and a lower risk of reoperation due to surgical complications (sHR: 0.62, 95% CI: 0.40-0.96, p = 0.034). CONCLUSION: This is the first study to suggest that postoperative acupuncture in hip fracture patients is associated with significantly lower mortality, readmission and reoperation rates compared with those of matched controls.

Genetic Architecture Associated With Familial Short Stature.

CONTEXT: Human height is an inheritable, polygenic trait under complex and multilocus genetic regulation. Familial short stature (FSS; also called genetic short stature) is the most common type of short stature and is insufficiently known. OBJECTIVE: To investigate the FSS genetic profile and develop a polygenic risk predisposition score for FSS risk prediction. DESIGN AND SETTING: The FSS participant group of Han Chinese ancestry was diagnosed by pediatric endocrinologists in Taiwan. PATIENTS AND INTERVENTIONS: The genetic profiles of 1163 participants with FSS were identified by using a bootstrapping subsampling and genome-wide association studies (GWAS) method. MAIN OUTCOME MEASURES: Genetic profile, polygenic risk predisposition score for risk prediction. RESULTS: Ten novel genetic single nucleotide polymorphisms (SNPs) and 9 reported GWAS human height-related SNPs were identified for FSS risk. These 10 novel SNPs served as a polygenic risk predisposition score for FSS risk prediction (area under the curve: 0.940 in the testing group). This FSS polygenic risk predisposition score was also associated with the height reduction regression tendency in the general population. CONCLUSION: A polygenic risk predisposition score composed of 10 genetic SNPs is useful for FSS risk prediction and the height reduction tendency. Thus, it might contribute to FSS risk in the Han Chinese population from Taiwan.

Protective effects and network analysis of natural compounds obtained from Radix dipsaci, Eucommiae cortex, and Rhizoma drynariae against RANKL-induced osteoclastogenesis in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Osteoporosis is one of the most common bone diseases; it is characterized by bone loss and is a risk factor for hip fracture. Chinese herbal medicines (CHMs) and their related natural compounds have been used for treating many diseases, including bone diseases, since ancient times in China and are regarded as a cost-effective complementary therapy. AIM OF THE STUDY: The goal of this study was to investigate the osteoprotective mechanisms of these three Chinese herbs and their related natural compounds. The effects of CHMs and related natural compounds on RANKL-induced osteoclastogenesis in vitro were investigated. MATERIALS AND METHODS: A network pharmacology method was applied to study CHM-related natural compounds and their osteoporosis targets. In addition, their effect on RANKL-induced osteoclastogenesis in RAW264.7 cells was also investigated in vitro. RESULTS: Radix dipsaci, Eucommiae cortex, and Rhizoma drynariae exhibited protective effects against mortality in hip fracture patients. Furthermore, these three herbs inhibited RANKL-induced TRAP activities and reduced the expression of bone resorption-related genes in RAW264.7 cells. Network analysis of natural compound (ingredient)-target interactions identified 11 natural compounds. Signal pathway analyses suggested that these compounds may target cytokine-cytokine receptor interactions, including RANKL-induced osteoclastogenesis. Five novel natural compounds exhibited reduced RANKL-induced TRAP activities and bone resorption-related gene expression. CONCLUSION: The clinically used CHMs, Radix dipsaci, Eucommiae cortex, and Rhizoma drynariae, and natural compounds obtained from them may suppress RANKL-induced osteoclastogenesis in vitro.

Effects of Chinese Herbal Medicines on the Risk of Overall Mortality, Readmission, and Reoperation in Hip Fracture Patients.

Hip fracture is a major public health concern, with high incidence rates in the elderly worldwide. Hip fractures are associated with increased medical costs, patient dependency on families, and higher rates of morbidity and mortality. Chinese herbal medicine (CHM) is typically characterized as cost-effective and suitable for long-term use with few side effects. To better understand the effects of CHM on hip fracture patients, we utilized a population-based database to investigate the demographic characteristics, cumulative incidence of overall mortality, readmission, reoperation, and patterns of CHM prescription. We found that CHM usage was associated with a lower risk of overall mortality [P = 0.0009; adjusted hazard ratio (HR): 0.47, 95% confidence interval (CI): 0.30-0.73], readmission (P = 0.0345; adjusted HR: 0.67, 95% CI: 0.46-0.97), and reoperation (P = 0.0009; adjusted HR: 0.57, 95% CI: 0.40-0.79) after adjustment for age, type of hip fracture, surgical treatment type, and comorbidities. We also identified the herbal formulas, single herbs, and prescription patterns for the treatment of hip fracture by using association rule mining and network analysis. For hip fracture patients, the most common CHM coprescription pattern was Du-Zhong (DZ) → Xu-Duan (XD), followed by Du-Huo-Ji-Sheng-Tang (DHJST) → Shu-Jing-Huo-Xue-Tang (SJHXT), and Gu-Sui-Bu (GSB) → Xu-Duan (XD). Furthermore, XD was the core prescription, and DZ, GSB, SJHXT, and DHJST were important prescriptions located in cluster 1 of the prescription patterns. This study provides evidence for clinical CHM use as an adjunctive therapy that offers benefits to hip fracture patients.

Network analysis and mechanisms of action of Chinese herb-related natural compounds in lung cancer cells.

BACKGROUND: Chinese herbal medicines (CHMs) are a resource of natural compounds (ingredients) and their potential chemical derivatives with anticancer properties, some of which are already in clinical use. Bei-Mu (BM), Jie-Geng (JG), and Mai-Men-Dong-Tang (MMDT) are important CHMs prescribed for patients with lung cancer that have improved the survival rate. HYPOTHESIS/PURPOSE: The aim of this study was to systemically investigate the mechanisms of action of these CHM products in lung cancer cells. METHODS: We used a network pharmacology approach to study CHM product-related natural compounds and their lung cancer targets. In addition, the underlying anti-lung cancer effects of the natural compounds on apoptosis, cell cycle progression, autophagy, and the expression of related proteins was investigated in vitro. RESULTS: Ingredient-lung cancer target network analysis identified 20 natural compounds. Three of these compounds, ursolic acid, 2-(3R)-8,8-dimethyl-3,4-dihydro-2H-pyrano(6,5-f)chromen-3-yl)-5-methoxyphenol, and licochalcone A, inhibited the proliferation of A549 lung cancer cells in a dose-dependent manner. Signal pathway analyses suggested that these three ingredients may target cellular apoptosis, anti-apoptosis, and cell cycle-related proteins. These three ingredients induced apoptosis through the regulation of the expression of apoptotic and anti-apoptotic proteins, including B-cell lymphoma-2 and full-length and cleaved poly(ADP-ribose) polymerase proteins. They also induced cell cycle arrest in S and G2/M phases and autophagy in A549 cells. CONCLUSION: The pharmacological mechanisms of ingredients from MMDT on lung cancer may be strongly associated with their modulatory effects on apoptosis, autophagy, cell cycle progression, and cell proliferation.

Effects of Chinese herbal medicine therapy on survival and hepatic outcomes in patients with hepatitis C virus infection in Taiwan.

BACKGROUND: Chinese herbal medicine (CHM) is a complementary natural medicine that is used widely for the treatment of hepatic diseases. The aim of this study was to investigate the effects of the long-term use of CHM for the treatment of liver diseases, as prescribed by TCM doctors, on overall mortality and hepatic outcomes in patients with HCV. PATIENTS AND METHODS: We identified 98788 patients with HCV. Of these, 829 and 829 patients who were users and non-users of CHM, respectively, were matched for age, gender, CCI, and comorbidities prior to CHM treatment. The chi-squared test, Cox proportional hazard model, Kaplan--Meier method, and log-rank test were used for comparisons. RESULTS: CHM users had a lower risk of overall mortality than non-users after adjustment for comorbidities by using a multivariate Cox proportional hazard model (p-value < 0.001; HR: 0.12, 95% CI: 0.06-0.26). In addition,the CHM users had a lower risk of liver cirrhosis than non-users after adjustment for comorbidities (p-value = 0.028; HR: 0.29, 95% CI: 0.09-0.88). The 12-year cumulative incidences of overall mortality and liver cirrhosis were lower in the CHM group (p-value < 0.05 for both, log rank test). The CHM co-prescription for Dan-Shen, Bie-Jia, Jia-Wei-Xiao-Yao-San => E-Shu was found to occur most often associated for the specific treatment of HCV infection. CONCLUSION: CHM as adjunctive therapy may reduce the overall mortality and the risk of liver cirrhosis in patients with HCV. The comprehensive list of the herbal medicines that may be used for the treatment of patients with HCV may be useful in future scientific investigations or for future therapeutic interventions to prevent negative hepatic outcomes in patients with HCV.

The Temporal Relationship between Selected Mental Disorders and Substance-Related Disorders: A Nationwide Population-Based Cohort Study.

Introduction. Previous studies have examined the association between specific mental disorders, particularly mood and anxiety disorders, and substance-related disorders; but the temporal link between them remains unclear. This study aimed to examine whether individuals with specific mental disorders, including affective psychoses, neurotic disorders, schizophrenia, personality disorders, and adjustment reaction, have higher risks for subsequently developing substance-related disorders compared to those without. Methods. A large-scale study with longitudinal data was conducted using the Taiwan National Health Insurance Research Database (NHIRD) consisting of 2,000,118 patients' medical records from 2000 to 2009. A total of 124,423 people diagnosed with selected mental disorders and the same number of people without the diagnoses of the selected disorders were identified between January 1, 2001, and December 31, 2006, and followed up for the diagnoses of substance-related disorders till the end of 2009. We estimated the risk for subsequently developing substance-related disorders among patients with the selected mental disorders compared to those without by using Cox proportional hazard models. The cumulative incidence of substance-related disorders was calculated using the Kaplan-Meier method. Results. The risk for developing substance-related disorders in patients with selected mental disorders is about 5 times (HR=5.09, 95% CI: 4.74-5.48) higher than those without after adjusting for potential confounding variables. From the multivariate analyses of subsamples stratified by age, sex, and urban and income levels, we found all adjusted hazard ratios were significantly higher than 1.0, ranging from 2.12 (95% CI: 1.72-2.62) to 14.55 (95% CI: 7.89-26.83). For children and adolescents aged 10-19 years, those with specific mental disorders had 14.55-fold higher risk for developing substance-related disorders in later life compared to their counterparts. Furthermore, patients with personality disorders had the highest risk (HR=25.05). Conclusions. The earlier onset of the selected mental disorders is a potential risk for developing substance-related disorders in later life, particularly for personality disorders. Health professionals should pay more attention to this at-risk population, especially to adolescents with mental disorders.

Evaluation of Oral Antiretroviral Drugs in Mice With Metabolic and Neurologic Complications.

Antiretroviral (ART) drugs has previously been associated with lipodystrophic syndrome, metabolic consequences, and neuropsychiatric complications. ART drugs include three main classes of protease inhibitors (PIs), nucleoside analog reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Our previous work demonstrated that a high risk of hyperlipidemia was observed in HIV-1-infected patients who received ART drugs in Taiwan. Patients receiving ART drugs containing either Abacavir/Lamivudine (Aba/Lam; NRTI/NRTI), Lamivudine/Zidovudine (Lam/Zido; NRTI/NRTI), or Lopinavir/Ritonavir (Lop/Rit; PI) have the highest risk of hyperlipidemia. The aim of this study was to investigate the effects of Aba/Lam (NRTI/NRTI), Lam/Zido (NRTI/NRTI), and Lop/Rit (PI) on metabolic and neurologic functions in mice. Groups of C57BL/6 mice were administered Aba/Lam, Lam/Zido, or Lop/Rit, orally, once daily for a period of 4 weeks. The mice were then extensively tested for metabolic and neurologic parameters. In addition, the effect of Aba/Lam, Lam/Zido, and Lop/Rit on lipid metabolism was assessed in HepG2 hepatocytes and during the 3T3-L1 preadipocyte differentiation. Administration with Aba/Lam caused cognitive and motor impairments in mice, as well as their metabolic imbalances, including alterations in leptin serum levels. Administration with Lop/Rit also caused cognitive and motor impairments in mice, as well as their metabolic imbalances, including alterations in serum levels of total cholesterol, and HDL-c. Treatment of mice with Aba/Lam and Lop/Rit enhanced the lipid accumulation in the liver, and the decrease in AMP-activated protein kinase (AMPK) phosphorylation and/or its downstream target acetyl-CoA carboxylase (ACC) protein expression. In HepG2 hepatocytes, Aba/Lam, Lam/Zido, and Lop/Rit also enhanced the lipid accumulation and decreased phosphorylated AMPK and ACC proteins. In 3T3-L1 pre-adipocyte differentiation, Aba/Lam and Lop/Rit reduced adipogenesis by decreasing expression of transcription factor CEBPb, implicating the lipodystrophic syndrome. Our results demonstrate that daily oral administration of Aba/Lam and Lop/Rit may produce cognitive, motor, and metabolic impairments in mice, regardless of HIV-1 infection.

Effects of Chinese herbal medicine on hyperlipidemia and the risk of cardiovascular disease in HIV-infected patients in Taiwan.

ETHNOPHARMACOLOGICAL RELEVANCE: Due to the development of antiretroviral therapy (ART), HIV/AIDS is now regarded as a treatable chronic disease. Chinese herbal medicine (CHM) is a type of complementary and alternative medicine (CAM) that has been widely applied in the healthcare system in Taiwan. AIM OF THE STUDY: The aim of this study was to investigate the frequency of use and patterns of prescription for the CHM-based treatment of HIV-infected patients and to assess the long-term effects of CHM on hyperlipidemia and cardiovascular disease events in these patients. MATERIALS AND METHODS: We identified 21,846 HIV-infected patients (ICD-9-CM: 042-044, 079, and V08 codes). Of these, 1083 and 2166 patients who used CHM and were non-users, respectively, were matched for age, gender, and ART use before CHM. The chi-squared test, Cox proportional hazard model, Kaplan-Meier method, and the log-rank test were used for comparisons between these two groups. RESULTS: CHM users had a lower risk of hyperlipidemia compared with non-users after adjusting for comorbidities by using a multivariate Cox proportional hazard model (P = 0.0011; HR: 0.66, 95% CI: 0.52-0.85). In addition, the CHM users had a lower risk of cardiovascular disease compared with non-users after adjusting for comorbidities (P = 0.0004; HR: 0.67, 95% CI: 0.53-0.83). The 10-year cumulative incidences of hyperlipidemia and cardiovascular disease were lower in the CHM group (P < 0.0001 for both, log rank test). Among the 12 most commonly used CHMs in these patients, Jia-Wei-Xiao-Yao-San (JWXYS) (46.1%), Ge-Gen-Tang (GGT) (40.6%), and Yin-Qiao-San (YQS) (38.0%) were the most common herbal formulas used. Huang-Qin (HQin) (44.6%), Yan-Hu-Suo (YHS) (40.5%), and Jie-Geng (JG) (39.5%) were the most commonly used single herbs. A CHM network analysis showed that JG was the core CHM in one cluster, and BM, MXSGT, and HQin were important CHMs in that cluster. In the other cluster, YHS was the core CHM, and SYGCT and JWXYS were important CHMs. CONCLUSION: CHM as adjunctive therapy may reduce hyperlipidemia and the risk for cardiovascular disease in HIV-infected patients. The list of the comprehensive herbal medicines that the patients used might be useful in further scientific investigations or therapeutic interventions for preventing atherosclerosis among HIV-infected patients.