National Defense Medical Center

Abstract The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes) 1 . In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

Lists of authors and their affiliations appear in the online version of the paper Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry 1 . We identified 65 new loci that are associated with overall breast cancer risk at P < 5 10 -8 . The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genomewide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

The objective of this study was to identify and characterize a self-renewing subpopulation of human ovarian tumor cells (ovarian cancer-initiating cells, OCICs) fully capable of serial propagation of their original tumor phenotype in animals. Ovarian serous adenocarcinomas were disaggregated and subjected to growth conditions selective for self-renewing, nonadherent spheroids previously shown to derive from tissue stem cells. To affirm the existence of OCICs, xenoengraftment of as few as 100 dissociated spheroid cells allowed full recapitulation of the original tumor (grade 2/grade 3 serous adenocarcinoma), whereas >10(5) unselected cells remained nontumorigenic. Stemness properties of OCICs (under stem cell-selective conditions) were further established by cell proliferation assays and reverse transcription-PCR, demonstrating enhanced chemoresistance to the ovarian cancer chemotherapeutics cisplatin or paclitaxel and up-regulation of stem cell markers (Bmi-1, stem cell factor, Notch-1, Nanog, nestin, ABCG2, and Oct-4) compared with parental tumor cells or OCICs under differentiating conditions. To identify an OCIC cell surface phenotype, spheroid immunostaining showed significant up-regulation of the hyaluronate receptor CD44 and stem cell factor receptor CD117 (c-kit), a tyrosine kinase oncoprotein. Similar to sphere-forming OCICs, injection of only 100 CD44(+)CD117(+) cells could also serially propagate their original tumors, whereas 10(5) CD44(-)CD117(-) cells remained nontumorigenic. Based on these findings, we assert that epithelial ovarian cancers derive from a subpopulation of CD44(+)CD117(+) cells, thus representing a possible therapeutic target for this devastating disease.

BACKGROUND: The presence of hepatitis B e antigen (HBeAg) in serum indicates active viral replication in hepatocytes. HBeAg is thus a surrogate marker for the presence of hepatitis B virus DNA. We conducted a prospective study to determine the relation between positivity for hepatitis B surface antigen (HBsAg) and HBeAg and the development of hepatocellular carcinoma. METHODS: In 1991 and 1992, we enrolled 11,893 men without evidence of hepatocellular carcinoma (age range, 30 to 65 years) from seven townships in Taiwan. Serum samples obtained at the time of enrollment were tested for HBsAg and HBeAg by radioimmunoassay. The diagnosis of hepatocellular carcinoma was ascertained through data linkage with the computerized National Cancer Registry in Taiwan and with death certificates. We performed a multiple regression analysis to determine the relative risk of hepatocellular carcinoma among men who were positive for HBsAg alone or for HBsAg and HBeAg, as compared with those who were negative for both. RESULTS: There were 111 cases of newly diagnosed hepatocellular carcinoma during 92,359 person-years of follow-up. The incidence rate of hepatocellular carcinoma was 1169 cases per 100,000 person-years among men who were positive for both HBsAg and HBeAg, 324 per 100,000 person-years for those who were positive for HBsAg only, and 39 per 100,000 person-years for those who were negative for both. After adjustment for age, sex, the presence or absence of antibodies against hepatitis C virus, cigarette-smoking status, and use or nonuse of alcohol, the relative risk of hepatocellular carcinoma was 9.6 (95 percent confidence interval, 6.0 to 15.2) among men who were positive for HBsAg alone and 60.2 (95 percent confidence interval, 35.5 to 102.1) among those who were positive for both HBsAg and HBeAg, as compared with men who were negative for both. CONCLUSIONS: Positivity for HBeAg is associated with an increased risk of hepatocellular carcinoma.

BACKGROUND: The time to initiate intravenous thrombolysis for acute ischemic stroke is generally limited to within 4.5 hours after the onset of symptoms. Some trials have suggested that the treatment window may be extended in patients who are shown to have ischemic but not yet infarcted brain tissue on imaging. METHODS: We conducted a multicenter, randomized, placebo-controlled trial involving patients with ischemic stroke who had hypoperfused but salvageable regions of brain detected on automated perfusion imaging. The patients were randomly assigned to receive intravenous alteplase or placebo between 4.5 and 9.0 hours after the onset of stroke or on awakening with stroke (if within 9 hours from the midpoint of sleep). The primary outcome was a score of 0 or 1 on the modified Rankin scale, on which scores range from 0 (no symptoms) to 6 (death), at 90 days. The risk ratio for the primary outcome was adjusted for age and clinical severity at baseline. RESULTS: After 225 of the planned 310 patients had been enrolled, the trial was terminated because of a loss of equipoise after the publication of positive results from a previous trial. A total of 113 patients were randomly assigned to the alteplase group and 112 to the placebo group. The primary outcome occurred in 40 patients (35.4%) in the alteplase group and in 33 patients (29.5%) in the placebo group (adjusted risk ratio, 1.44; 95% confidence interval [CI], 1.01 to 2.06; P = 0.04). Symptomatic intracerebral hemorrhage occurred in 7 patients (6.2%) in the alteplase group and in 1 patient (0.9%) in the placebo group (adjusted risk ratio, 7.22; 95% CI, 0.97 to 53.5; P = 0.05). A secondary ordinal analysis of the distribution of scores on the modified Rankin scale did not show a significant between-group difference in functional improvement at 90 days. CONCLUSIONS: Among the patients in this trial who had ischemic stroke and salvageable brain tissue, the use of alteplase between 4.5 and 9.0 hours after stroke onset or at the time the patient awoke with stroke symptoms resulted in a higher percentage of patients with no or minor neurologic deficits than the use of placebo. There were more cases of symptomatic cerebral hemorrhage in the alteplase group than in the placebo group. (Funded by the Australian National Health and Medical Research Council and others; EXTEND ClinicalTrials.gov numbers, NCT00887328 and NCT01580839.).

In this study, we reveal a mechanism by which plants regulate inorganic phosphate (Pi) homeostasis to adapt to environmental changes in Pi availability. This mechanism involves the suppression of a ubiquitin-conjugating E2 enzyme by a specific microRNA, miR399. Upon Pi starvation, the miR399 is upregulated and its target gene, a ubiquitin-conjugating E2 enzyme, is downregulated in Arabidopsis thaliana. Accumulation of the E2 transcript is suppressed in transgenic Arabidopsis overexpressing miR399. Transgenic plants accumulated five to six times the normal Pi level in shoots and displayed Pi toxicity symptoms that were phenocopied by a loss-of-function E2 mutant. Pi toxicity was caused by increased Pi uptake and by translocation of Pi from roots to shoots and retention of Pi in the shoots. Moreover, unlike wild-type plants, in which Pi in old leaves was readily retranslocated to other developing young tissues, remobilization of Pi in miR399-overexpressing plants was impaired. These results provide evidence that miRNA controls Pi homeostasis by regulating the expression of a component of the proteolysis machinery in plants.

BACKGROUND: Loss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with decreased plasma levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. It is not known whether such variants or therapeutic antagonism of ANGPTL3 are associated with a reduced risk of atherosclerotic cardiovascular disease. METHODS: We sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human genetics study. We performed tests of association for loss-of-function variants in ANGPTL3 with lipid levels and with coronary artery disease in 13,102 case patients and 40,430 controls from the DiscovEHR study, with follow-up studies involving 23,317 case patients and 107,166 controls from four population studies. We also tested the effects of a human monoclonal antibody, evinacumab, against Angptl3 in dyslipidemic mice and against ANGPTL3 in healthy human volunteers with elevated levels of triglycerides or LDL cholesterol. RESULTS: In the DiscovEHR study, participants with heterozygous loss-of-function variants in ANGPTL3 had significantly lower serum levels of triglycerides, HDL cholesterol, and LDL cholesterol than participants without these variants. Loss-of-function variants were found in 0.33% of case patients with coronary artery disease and in 0.45% of controls (adjusted odds ratio, 0.59; 95% confidence interval, 0.41 to 0.85; P=0.004). These results were confirmed in the follow-up studies. In dyslipidemic mice, inhibition of Angptl3 with evinacumab resulted in a greater decrease in atherosclerotic lesion area and necrotic content than a control antibody. In humans, evinacumab caused a dose-dependent placebo-adjusted reduction in fasting triglyceride levels of up to 76% and LDL cholesterol levels of up to 23%. CONCLUSIONS: Genetic and therapeutic antagonism of ANGPTL3 in humans and of Angptl3 in mice was associated with decreased levels of all three major lipid fractions and decreased odds of atherosclerotic cardiovascular disease. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT01749878 .).

BACKGROUND: occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population. METHODS: exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy. RESULTS: As of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% confidence interval [CI], 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% (95% CI, 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment. CONCLUSIONS: exon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.).

Research on liposome formulations has progressed from that on conventional vesicles to new generation liposomes, such as cationic liposomes, temperature sensitive liposomes, and virosomes, by modulating the formulation techniques and lipid composition. Many research papers focus on the correlation of blood circulation time and drug accumulation in target tissues with physicochemical properties of liposomal formulations, including particle size, membrane lamellarity, surface charge, permeability, encapsulation volume, shelf time, and release rate. This review is mainly to compare the therapeutic effect of current clinically approved liposome-based drugs with free drugs, and to also determine the clinical effect via liposomal variations in lipid composition. Furthermore, the major preclinical and clinical data related to the principal liposomal formulations are also summarized.

Recent studies have demonstrated the important role of plant microRNAs (miRNAs) under nutrient deficiencies. In this study, deep sequencing of Arabidopsis (Arabidopsis thaliana) small RNAs was conducted to reveal miRNAs and other small RNAs that were differentially expressed in response to phosphate (Pi) deficiency. About 3.5 million sequence reads corresponding to 0.6 to 1.2 million unique sequence tags from each Pi-sufficient or Pi-deficient root or shoot sample were mapped to the Arabidopsis genome. We showed that upon Pi deprivation, the expression of miR156, miR399, miR778, miR827, and miR2111 was induced, whereas the expression of miR169, miR395, and miR398 was repressed. We found cross talk coordinated by these miRNAs under different nutrient deficiencies. In addition to miRNAs, we identified one Pi starvation-induced DICER-LIKE1-dependent small RNA derived from the long terminal repeat of a retrotransposon and a group of 19-nucleotide small RNAs corresponding to the 5' end of tRNA and expressed at a high level in Pi-starved roots. Importantly, we observed an increased abundance of TAS4-derived trans-acting small interfering RNAs (ta-siRNAs) in Pi-deficient shoots and uncovered an autoregulatory mechanism of PAP1/MYB75 via miR828 and TAS4-siR81(-) that regulates the biosynthesis of anthocyanin. This finding sheds light on the regulatory network between miRNA/ta-siRNA and its target gene. Of note, a substantial amount of miR399* accumulated under Pi deficiency. Like miR399, miR399* can move across the graft junction, implying a potential biological role for miR399*. This study represents a comprehensive expression profiling of Pi-responsive small RNAs and advances our understanding of the regulation of Pi homeostasis mediated by small RNAs.

BACKGROUND: Most of the ectopic beats initiating paroxysmal atrial fibrillation (PAF) originate from the pulmonary vein (PV). However, only limited data are available on PAF originating from the non-PV areas. METHODS AND RESULTS: Two hundred forty patients with a total of 358 ectopic foci initiating PAF were included. Sixty-eight (28%) patients had AF initiated by ectopic beats (73 foci, 20%) from the non-PV areas, including the left atrial posterior free wall (28, 38.3%), superior vena cava (27, 37.0%), crista terminalis (10, 3.7%), ligament of Marshall (6, 8.2%), coronary sinus ostium (1, 1.4%), and interatrial septum (1, 1.4%). Catheter ablation eliminated AF with acute success rates of 63%, 96%, 100%, 50%, 100%, and 0% in left atrial posterior free wall, superior vena cava, crista terminalis, ligament of Marshall, coronary sinus ostium, and interatrial septum, respectively. During a follow-up period of 22+/-11 months, 43 patients (63.2%) were free of antiarrhythmic drugs without AF recurrence. CONCLUSIONS: Ectopic beats initiating PAF can originate from the non-PV areas, and catheter ablation of the non-PV ectopy has a moderate efficacy in treatment of PAF.

BACKGROUND: Enterovirus 71 infection causes hand-foot-and-mouth disease in young children, which is characterized by several days of fever and vomiting, ulcerative lesions in the oral mucosa, and vesicles on the backs of the hands and feet. The initial illness resolves but is sometimes followed by aseptic meningitis, encephalomyelitis, or even acute flaccid paralysis similar to paralytic poliomyelitis. METHODS: We describe the neurologic complications associated with the enterovirus 71 epidemic that occurred in Taiwan in 1998. At three major hospitals we identified 41 children with culture-confirmed enterovirus 71 infection and acute neurologic manifestations. Magnetic resonance imaging (MRI) was performed in 4 patients with acute flaccid paralysis and 24 with rhombencephalitis. RESULTS: The mean age of the patients was 2.5 years (range, 3 months to 8.2 years). Twenty-eight patients had hand-foot-and-mouth disease (68 percent), and 6 had herpangina (15 percent). The other seven patients had no skin or mucosal lesions. Three neurologic syndromes were identified: aseptic meningitis (in 3 patients); brain-stem encephalitis, or rhombencephalitis (in 37); and acute flaccid paralysis (in 4), which followed rhombencephalitis in 3 patients. In 20 patients with rhombencephalitis, the syndrome was characterized by myoclonic jerks and tremor, ataxia, or both (grade I disease). Ten patients had myoclonus and cranial-nerve involvement (grade II disease). In seven patients the brain-stem infection produced transient myoclonus followed by the rapid onset of respiratory distress, cyanosis, poor peripheral perfusion, shock, coma, loss of the doll's eye reflex, and apnea (grade III disease); five of these patients died within 12 hours after admission. In 17 of the 24 patients with rhombencephalitis who underwent MRI, T2-weighted scans showed high-intensity lesions in the brain stem, most commonly in the pontine tegmentum. At follow-up, two of the patients with acute flaccid paralysis had residual limb weakness, and five of the patients with rhombencephalitis had persistent neurologic deficits, including myoclonus (in one child), cranial-nerve deficits (in two), and ventilator-dependent apnea (in two). CONCLUSIONS: In the 1998 enterovirus 71 epidemic in Taiwan, the chief neurologic complication was rhombencephalitis, which had a fatality rate of 14 percent. The most common initial symptoms were myoclonic jerks, and MRI usually showed evidence of brainstem involvement.

We investigated the interaction between angiogenic and osteogenic factors in bone formation and bone healing with ex vivo gene therapy using muscle-derived stem cells genetically engineered to express human bone morphogenetic protein-4 (BMP4), VEGF, or VEGF-specific antagonist (soluble Flt1). Our results show that although VEGF alone did not improve bone regeneration, it acted synergistically with BMP4 to increase recruitment of mesenchymal stem cells, to enhance cell survival, and to augment cartilage formation in the early stages of endochondral bone formation. These early effects, coupled with accelerated cartilage resorption, eventually led to a significant enhancement of bone formation and bone healing. The beneficial effect of VEGF on bone healing elicited by BMP4 depends critically on the ratio of VEGF to BMP4, with an improper ratio leading to detrimental effects on bone healing. Finally, we show that soluble Flt1 inhibits bone formation elicited by BMP4. Thus, VEGF plays an important role in bone formation elicited by BMP4, and it can significantly enhance BMP4-elicited bone formation and regeneration through multiple mechanisms. This study has important implications for the formulation of new strategies to improve bone healing through increasing mesenchymal stem cell recruitment and survival, in combination with muscle-derived stem cell-based gene therapy.

Federated learning (FL) is a method used for training artificial intelligence models with data from multiple sources while maintaining data anonymity, thus removing many barriers to data sharing. Here we used data from 20 institutes across the globe to train a FL model, called EXAM (electronic medical record (EMR) chest X-ray AI model), that predicts the future oxygen requirements of symptomatic patients with COVID-19 using inputs of vital signs, laboratory data and chest X-rays. EXAM achieved an average area under the curve (AUC) >0.92 for predicting outcomes at 24 and 72 h from the time of initial presentation to the emergency room, and it provided 16% improvement in average AUC measured across all participating sites and an average increase in generalizability of 38% when compared with models trained at a single site using that site's data. For prediction of mechanical ventilation treatment or death at 24 h at the largest independent test site, EXAM achieved a sensitivity of 0.950 and specificity of 0.882. In this study, FL facilitated rapid data science collaboration without data exchange and generated a model that generalized across heterogeneous, unharmonized datasets for prediction of clinical outcomes in patients with COVID-19, setting the stage for the broader use of FL in healthcare.

Nitrogen accounts for approximately 60% of the fertilizer consumed each year; thus, it represents one of the major input costs for most nonlegume crops. Nitrate is one of the two major forms of nitrogen that plants acquire from the soil. Mechanistic insights into nitrate transport and signaling have enabled new strategies for enhancing nitrogen utilization efficiency, for lowering input costs for farming, and, more importantly, for alleviating environmental impacts (e.g., eutrophication and production of the greenhouse gas N 2 O). Over the past decade, significant progress has been made in understanding how nitrate is acquired from the surroundings, how it is efficiently distributed into different plant tissues in response to environmental changes, how nitrate signaling is perceived and transmitted, and how shoot and root nitrogen status is communicated. Several key components of these processes have proven to be novel tools for enhancing nitrate- and nitrogen-use efficiency. In this review, we focus on the roles of NRT1 and NRT2 in nitrate uptake and nitrate allocation among different tissues; we describe the functions of the transceptor NRT1.1, transcription factors, and small signaling peptides in nitrate signaling and tissue communication; and we compile the new strategies for improving nitrogen-use efficiency.

We recently demonstrated that microRNA399 (miR399) controls inorganic phosphate (Pi) homeostasis by regulating the expression of UBC24 encoding a ubiquitin-conjugating E2 enzyme in Arabidopsis (Arabidopsis thaliana). Transgenic plants overexpressing miR399 accumulated excessive Pi in the shoots and displayed Pi toxic symptoms. In this study, we revealed that a previously identified Pi overaccumulator, pho2, is caused by a single nucleotide mutation resulting in early termination within the UBC24 gene. The level of full-length UBC24 mRNA was reduced and no UBC24 protein was detected in the pho2 mutant, whereas up-regulation of miR399 by Pi deficiency was not affected. Several characteristics of Pi toxicity in the pho2 mutant were similar to those in the miR399-overexpressing and UBC24 T-DNA knockout plants: both Pi uptake and translocation of Pi from roots to shoots increased and Pi remobilization within leaves was impaired. These phenotypes of the pho2 mutation could be rescued by introduction of a wild-type copy of UBC24. Kinetic analyses revealed that greater Pi uptake in the pho2 and miR399-overexpressing plants is due to increased Vmax. The transcript level of most PHT1 Pi transporter genes was not significantly altered, except PHT1;8 whose expression was enhanced in Pi-sufficient roots of pho2 and miR399-overexpressing compared with wild-type plants. In addition, changes in the expression of several organelle-specific Pi transporters were noticed, which may be associated with the redistribution of intracellular Pi under excess Pi. Furthermore, miR399 and UBC24 were colocalized in the vascular cylinder. This observation not only provides important insight into the interaction between miR399 and UBC24 mRNA, but also supports their systemic function in Pi translocation and remobilization.

In this study, 221 phytocompounds were evaluated for activity against anti-severe acute respiratory syndrome associated coronavirus (SARS-CoV) activities using a cell-based assay measuring SARS-CoV-induced cytopathogenic effect on Vero E6 cells. Ten diterpenoids (1-10), two sesquiterpenoids (11 and 12), two triterpenoids (13 and 14), five lignoids (15-19), curcumin (20), and reference controls niclosamide (21) and valinomycin (22) were potent inhibitors at concentrations between 3.3 and 10 microM. The concentrations of the 22 compounds to inhibit 50% of Vero E6 cell proliferation (CC50) and viral replication (EC50) were measured. The selective index values (SI = CC50/EC50) of the most potent compounds 1, 5, 6, 8, 14, and 16 were 58, >510, 111, 193, 180, and >667, respectively. Betulinic acid (13) and savinin (16) were competitive inhibitors of SARS-CoV 3CL protease with Ki values = 8.2 +/- 0.7 and 9.1 +/- 2.4 microM, respectively. Our findings suggest that specific abietane-type diterpenoids and lignoids exhibit strong anti-SARS-CoV effects.

Background & Aims: This study investigated whether obesity, diabetes, and other metabolic factors are independently associated with hepatocellular carcinoma (HCC), stratified by hepatitis B virus (HBV) and hepatitis C virus (HCV) serostatus, and explored the possible joint influence of obesity/diabetes and HBV/HCV infections on the risk of HCC. Methods: A total of 23,820 residents in Taiwan were recruited and followed up for 14 years. All analyses were stratified by hepatitis B surface antigen (HBsAg) and antibody to HCV (anti-HCV) at enrollment, and 218 subjects positive for both seromarkers were excluded. Incident HCC cases were identified via linkage to the national cancer registry. Multivariate-adjusted relative risk (RRa) and 95% confidence interval (95% CI) were estimated using Cox proportional hazards models. Results: Extreme obesity (body mass index ≥30 kg/m2) was independently associated with a 4-fold risk of HCC (RRa, 4.13; 95% CI, 1.38–12.4) among anti-HCV–seropositive subjects and a 2-fold risk (RRa, 2.36; 95% CI, 0.91–6.17) in persons without HBV and HCV infections, after controlling for other metabolic components, but not in HBsAg-seropositive subjects (RRa, 1.36; 95% CI, 0.64–2.89). Diabetes was associated with HCC in all 3 groups, with the highest risk in those with HCV infection (RRa, 3.52; 95% CI, 1.29–9.24) and lowest in HBV carriers (RRa, 2.27; 95% CI, 1.10–4.66). We found more than 100-fold increased risk in HBV or HCV carriers with both obesity and diabetes, indicating synergistic effects of metabolic factors and hepatitis. Conclusions: The finding that both obesity and diabetes are predictors of HCC risk, possibly differently depending on HBV and HCV infection status, may shed some light in preventing HCC. Background & Aims: This study investigated whether obesity, diabetes, and other metabolic factors are independently associated with hepatocellular carcinoma (HCC), stratified by hepatitis B virus (HBV) and hepatitis C virus (HCV) serostatus, and explored the possible joint influence of obesity/diabetes and HBV/HCV infections on the risk of HCC. Methods: A total of 23,820 residents in Taiwan were recruited and followed up for 14 years. All analyses were stratified by hepatitis B surface antigen (HBsAg) and antibody to HCV (anti-HCV) at enrollment, and 218 subjects positive for both seromarkers were excluded. Incident HCC cases were identified via linkage to the national cancer registry. Multivariate-adjusted relative risk (RRa) and 95% confidence interval (95% CI) were estimated using Cox proportional hazards models. Results: Extreme obesity (body mass index ≥30 kg/m2) was independently associated with a 4-fold risk of HCC (RRa, 4.13; 95% CI, 1.38–12.4) among anti-HCV–seropositive subjects and a 2-fold risk (RRa, 2.36; 95% CI, 0.91–6.17) in persons without HBV and HCV infections, after controlling for other metabolic components, but not in HBsAg-seropositive subjects (RRa, 1.36; 95% CI, 0.64–2.89). Diabetes was associated with HCC in all 3 groups, with the highest risk in those with HCV infection (RRa, 3.52; 95% CI, 1.29–9.24) and lowest in HBV carriers (RRa, 2.27; 95% CI, 1.10–4.66). We found more than 100-fold increased risk in HBV or HCV carriers with both obesity and diabetes, indicating synergistic effects of metabolic factors and hepatitis. Conclusions: The finding that both obesity and diabetes are predictors of HCC risk, possibly differently depending on HBV and HCV infection status, may shed some light in preventing HCC. See CME quiz on page 293. The incidence of liver cancer is increasing in several developed countries and would continue to increase for some decades.1Bosch F.X. Ribes J. Diaz M. et al.Primary liver cancer: worldwide incidence and trends.Gastroenterology. 2004; 127: S5-S16Abstract Full Text Full Text PDF PubMed Scopus (2139) Google Scholar The estimated attributable risk for the combined effects of hepatitis B and C viral infections accounts for more than 80% of liver cancer cases worldwide.1Bosch F.X. Ribes J. Diaz M. et al.Primary liver cancer: worldwide incidence and trends.Gastroenterology. 2004; 127: S5-S16Abstract Full Text Full Text PDF PubMed Scopus (2139) Google Scholar Obesity and diabetes have been found to be associated with an increased risk of hepatocellular carcinoma (HCC) in several epidemiologic studies.2Moller H. Mellemgaard A. Lindvig K. et al.Obesity and cancer risk: a Danish record-linkage study.Eur J Cancer. 1994; 30A: 344-350Abstract Full Text PDF PubMed Scopus (398) Google Scholar, 3Wolk A. Gridley G. Svensson M. et al.A prospective study of obesity and cancer risk (Sweden).Cancer Causes Control. 2001; 12: 13-21Crossref PubMed Scopus (506) Google Scholar, 4Rapp K. Schroeder J. Klenk J. et al.Obesity and incidence of cancer: a large cohort study of over 145,000 adults in Austria.Br J Cancer. 2005; 93: 1062-1067Crossref PubMed Scopus (270) Google Scholar, 5Calle E.E. Rodriguez C. Walker-Thurmond K. et al.Overweight, obesity and mortality from cancer in a prospective studied cohort of US adults.N Engl J Med. 2003; 348: 1625-1638Crossref PubMed Scopus (5870) Google Scholar, 6Samanic C. Gridley G. Chow W.H. et al.Obesity and cancer risk among white and black United States veterans.Cancer Causes Control. 2004; 15: 35-43Crossref PubMed Scopus (263) Google Scholar, 7Nair S. Mason A. Eason J. et al.Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis?.Hepatology. 2002; 36: 150-155Crossref PubMed Scopus (286) Google Scholar Five large population studies, 3 in Europe2Moller H. Mellemgaard A. Lindvig K. et al.Obesity and cancer risk: a Danish record-linkage study.Eur J Cancer. 1994; 30A: 344-350Abstract Full Text PDF PubMed Scopus (398) Google Scholar, 3Wolk A. Gridley G. Svensson M. et al.A prospective study of obesity and cancer risk (Sweden).Cancer Causes Control. 2001; 12: 13-21Crossref PubMed Scopus (506) Google Scholar, 4Rapp K. Schroeder J. Klenk J. et al.Obesity and incidence of cancer: a large cohort study of over 145,000 adults in Austria.Br J Cancer. 2005; 93: 1062-1067Crossref PubMed Scopus (270) Google Scholar and 2 in the United States,5Calle E.E. Rodriguez C. Walker-Thurmond K. et al.Overweight, obesity and mortality from cancer in a prospective studied cohort of US adults.N Engl J Med. 2003; 348: 1625-1638Crossref PubMed Scopus (5870) Google Scholar, 6Samanic C. Gridley G. Chow W.H. et al.Obesity and cancer risk among white and black United States veterans.Cancer Causes Control. 2004; 15: 35-43Crossref PubMed Scopus (263) Google Scholar observed that obesity is associated with an increase in HCC incidence2Moller H. Mellemgaard A. Lindvig K. et al.Obesity and cancer risk: a Danish record-linkage study.Eur J Cancer. 1994; 30A: 344-350Abstract Full Text PDF PubMed Scopus (398) Google Scholar, 3Wolk A. Gridley G. Svensson M. et al.A prospective study of obesity and cancer risk (Sweden).Cancer Causes Control. 2001; 12: 13-21Crossref PubMed Scopus (506) Google Scholar, 4Rapp K. Schroeder J. Klenk J. et al.Obesity and incidence of cancer: a large cohort study of over 145,000 adults in Austria.Br J Cancer. 2005; 93: 1062-1067Crossref PubMed Scopus (270) Google Scholar, 6Samanic C. Gridley G. Chow W.H. et al.Obesity and cancer risk among white and black United States veterans.Cancer Causes Control. 2004; 15: 35-43Crossref PubMed Scopus (263) Google Scholar and mortality,5Calle E.E. Rodriguez C. Walker-Thurmond K. et al.Overweight, obesity and mortality from cancer in a prospective studied cohort of US adults.N Engl J Med. 2003; 348: 1625-1638Crossref PubMed Scopus (5870) Google Scholar but a study conducted in an Asian country failed to obtain similar results.8Lai M.S. Hsieh M.S. Chiu Y.H. et al.Type 2 diabetes and hepatocellular carcinoma: a cohort study in high prevalence area of hepatitis virus infection.Hepatology. 2006; 43: PubMed Scopus Google Scholar A of and cohort have diabetes to a 2-fold increased risk of M.S. Hsieh M.S. Chiu Y.H. et al.Type 2 diabetes and hepatocellular carcinoma: a cohort study in high prevalence area of hepatitis virus infection.Hepatology. 2006; 43: PubMed Scopus Google Scholar, Chow W.H. et risk of liver cancer in with diabetes PubMed Scopus Google Scholar, Gridley G. et incidence in a cohort of with diabetes in PubMed Scopus Google Scholar, C. A. et and the risk of liver J Cancer. PubMed Scopus Google Scholar, H. et of diabetes in the of hepatocellular PubMed Scopus Google Scholar, The of diabetes in hepatocellular carcinoma: a study among United States J 2001; PubMed Google Scholar, Diabetes the risk of liver and hepatocellular 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, et the risk of hepatocellular carcinoma in the United a population 2005; PubMed Scopus Google Scholar, et factors for hepatocellular carcinoma: of with viral hepatitis and diabetes 2002; 36: PubMed Scopus Google Scholar, H. et and cancer risk in and 2005; PubMed Scopus Google Scholar, E.E. et a of cancer mortality in a large cohort of US J 2004; PubMed Scopus Google Scholar, S. K. et of diabetes, and viral hepatitis on risk of hepatocellular carcinoma in and in the 2004; PubMed Scopus Google Scholar, M. M. et and the risk of cancer: from a cohort study in Med. 2006; PubMed Scopus Google Scholar, H. The diabetes and hepatocellular carcinoma: a of epidemiologic 2006; Full Text Full Text PDF PubMed Scopus Google Scholar large cohort study in M.S. Hsieh M.S. Chiu Y.H. et al.Type 2 diabetes and hepatocellular carcinoma: a cohort study in high prevalence area of hepatitis virus infection.Hepatology. 2006; 43: PubMed Scopus Google Scholar studies, 3 M.S. Hsieh M.S. Chiu Y.H. et al.Type 2 diabetes and hepatocellular carcinoma: a cohort study in high prevalence area of hepatitis virus infection.Hepatology. 2006; 43: PubMed Scopus Google Scholar, et the risk of hepatocellular carcinoma in the United a population 2005; PubMed Scopus Google Scholar, S. K. et of diabetes, and viral hepatitis on risk of hepatocellular carcinoma in and in the 2004; PubMed Scopus Google Scholar whether diabetes and HCC hepatitis infection status, but investigated the of a of hepatitis on the increasing prevalence of obesity and diabetes, is to the 2 factors other metabolic and and HCC hepatitis B and is a risk factor for is to whether metabolic factors are associated with HCC differently depending on hepatitis B virus (HBV) and hepatitis C virus (HCV) infection We conducted the using from a J. et of hepatocellular carcinoma a of hepatitis B virus 2006; PubMed Scopus Google Scholar, et B antigen and the risk of hepatocellular Engl J Med. 2002; PubMed Scopus Google Scholar, J. et risk on the of hepatitis B viral 2006; Full Text Full Text PDF PubMed Scopus Google Scholar that been followed up for more than in Taiwan and in cohort hepatitis B surface antigen (HBsAg) and antibody to HCV (anti-HCV) at We to whether obesity and diabetes other metabolic factors are independently associated with stratified by HBV and HCV to the possible joint influence of obesity/diabetes and HBV/HCV infections on the risk of HCC to the the in HCC risk is associated with is the study that the obesity/diabetes other metabolic factors and risk of HCC by and serostatus, the of HBV and HCV A of the and and was J. et of hepatocellular carcinoma a of hepatitis B virus 2006; PubMed Scopus Google Scholar, et B antigen and the risk of hepatocellular Engl J Med. 2002; PubMed Scopus Google Scholar, J. et risk on the of hepatitis B viral 2006; Full Text Full Text PDF PubMed Scopus Google Scholar and residents of that the and of Taiwan were to in a cancer and a total of and to with on and factors was via a by were at and on hepatitis B HBV and were using and J. et of hepatocellular carcinoma a of hepatitis B virus 2006; PubMed Scopus Google Scholar, et B antigen and the risk of hepatocellular Engl J Med. 2002; PubMed Scopus Google Scholar, J. et risk on the of hepatitis B viral 2006; Full Text Full Text PDF PubMed Scopus Google Scholar All to in and the were and by the of the of Taiwan The metabolic factors for obesity, of diabetes and and of total and The of obesity was by of mass index kg/m2) and obesity was a for and for to in the Asian S. et the of the metabolic to 2004; PubMed Scopus Google Scholar was to to and on the for the Asian index for Asian and for and 2004; Scholar A of diabetes and was from the of and were to be of on and were at study positive for or for liver cancer via was national were to with the national cancer in Taiwan to HCC cases and liver cancer identified linkage to the national cancer or from or at were from the The cancer was in in and in not all liver to the national cancer were on liver cancer cases in carriers to the HCC a all HCC cases in at of the by at 2 or for were from the of to the of HCC or were and not with HCC were on factors that may be associated with both metabolic factors and HCC in a and that were 3 All analyses were stratified by of and and persons were both and positive and were from the to of HCC cases The relative risk and 95% confidence interval were estimated by Cox proportional hazards models. and obesity obesity and of diabetes were in the with for and to whether the of HBV or HCV infections the obesity/diabetes and HCC risk in a to the joint of obesity, diabetes, and of or was estimated by the of HCC cases with metabolic factor and viral risk factor diabetes and that was to the of attributable to the combined of J PubMed Scopus Google Scholar The of from was estimated from the 95% of an on the by of attributable to the combined of J PubMed Scopus Google Scholar and the of indicating with both HBV and HCV infections were the was on of of or diabetes and both factors in with were for both and and A of metabolic obesity, and of diabetes and were among those without HBV and HCV infections to whether the was associated with increasing HCC risk in a of were by the of a the of the and other HCC risk an using a with a was HBV HCC of liver and the metabolic factors obesity, and of diabetes and were all in to the of and HCC after for the effects of other metabolic All analyses were using Scholar All analyses were without a of liver at and the the indicating that may not be for the HCC cases that of may be but at and and of metabolic factors may be to HCC. We analyses HCC cases of and the the The that HCC cases may be and with metabolic and may influence the risk be the of to the was found to have with and to the in increased HCC on to all study subjects in the the in the the was for both and were for and were for at The or of HCC risk factors in 3 is in for were were in were and the highest of diabetes and of liver HBsAg-seropositive were were in and of and the lowest of and and to be than the other 2 were for both the highest total and the highest with and A total of HCC cases were identified the The HCC was similar in 2 with HBV or HCV infection and but in the with an incidence of HCC of and of for HCC by HBV and HCV and positive and and at high or at total in and in of diabetes of at at of liver HCC in and in in a without HBV and HCV infections and or were associated with an increased risk of HCC. Extreme obesity and of diabetes were associated with an increased risk of HCC 95% CI, for ≥30 95% CI, for HBsAg-seropositive and or were associated with an increased risk of HCC. Diabetes was associated with a relative HCC risk of (95% CI, obesity were to HCC was associated with a risk of HCC 95% CI, in HBsAg-seropositive and of Incident HCC in to by HBV and HCV and positive and and positive (95% (95% (95% at high or at total for in and in of diabetes of at at in and in in a anti-HCV–seropositive subjects a HCC risk factor but not was associated with a relative HCC risk of (95% CI, and were associated with HCC but not Obesity 95% CI, for ≥30 obesity 95% CI, and of diabetes 95% CI, were associated with the risk of HCC in anti-HCV–seropositive 3 the relative HCC risk associated with metabolic factors after for other and stratified by and and obesity were were in models. were for both and of the metabolic factors were associated with HCC risk a 2-fold HCC risk observed for obesity 2.36; 95% CI, for ≥30 and diabetes 95% CI, HBsAg-seropositive of diabetes was the HCC risk factor with an of (95% CI, obesity was associated with a increased risk of HCC 95% CI, was found with increasing was associated with a risk of HCC 95% CI, anti-HCV–seropositive obesity was associated with an of (95% CI, and was associated with an increasing HCC risk in a with the highest of (95% CI, for Diabetes was associated with a increased risk of HCC in both 95% CI, 3.52; 95% CI, and were associated with HCC risk in but not of HCC in to by HBV and HCV and positive and and positive total ≥30 for obesity of diabetes of All are (95% are for in at at and high and in a All are (95% are for in at at and high and the effects of the of obesity, diabetes, and HBV and HCV infections on HCC risk, with the of HBV and HCV infections, diabetes, and The relative HCC risk was (95% CI, for the of and obesity and (95% CI, for the of and The was (95% CI, for the of and diabetes and (95% CI, for the of and all factors the relative HCC risk was high (95% CI, for HBsAg-seropositive subjects with obesity and diabetes and (95% CI, for anti-HCV–seropositive subjects with obesity and of HCC by and Extreme and of hepatitis (95% for and at high and of diabetes of and for and at high and obesity ≥30 of and for and at high and of and was HCC for and at high and of diabetes of and for and at high and obesity ≥30 of and for and at high and of and was HCC in a the of synergistic effects in an of diabetes on both 95% CI, and 95% CI, obesity HCC risk to 95% CI, but not to 95% CI, to of the were in for without HBV and HCV infections, the of metabolic factors obesity, and of diabetes and was associated with increasing HCC risk in a 95% CI, for metabolic risk The was (95% CI, the was to the and of Incident HCC in to of HBV and HCV of of for in at at and high and of metabolic factors for to those than at of metabolic factors for for in at at and high and in a analyses were to whether were associated with factors to liver and metabolic the HBV and found a of HBV and of with those for was an HBV and those with the highest HBV on were with HCC at than those not HCC All other at obesity, obesity, and of diabetes and were associated with of and of at and of HBV and of in to HCV HBV were subjects with viral obesity of diabetes of for in at and high and were subjects with viral in a for in at and high and prospective the several metabolic factors and risk of HCC was on HBV and HCV obesity and obesity ≥30 kg/m2) were independently associated with 2-fold and 4-fold increased risk of HCC among Extreme obesity was associated with 2-fold increased risk in those without HBV and HCV infections, was HBV was not associated with HCC Diabetes was associated with to increased risk of of HBV and HCV The risk was highest among those with HCV infection and lowest in HBV carriers and not in those without those without HBV and HCV infections, of metabolic factors were to for the to HCC and were We found more than 100-fold increased risk of HCC among HBV or HCV carriers with both obesity and diabetes, with those without all indicating synergistic effects of metabolic factors and hepatitis have that obesity is associated with an increased risk of H. Mellemgaard A. Lindvig K. et al.Obesity and cancer risk: a Danish record-linkage study.Eur J Cancer. 1994; 30A: 344-350Abstract Full Text PDF PubMed Scopus (398) Google Scholar, 3Wolk A. Gridley G. Svensson M. et al.A prospective study of obesity and cancer risk (Sweden).Cancer Causes Control. 2001; 12: 13-21Crossref PubMed Scopus (506) Google Scholar, 4Rapp K. Schroeder J. Klenk J. et al.Obesity and incidence of cancer: a large cohort study of over 145,000 adults in Austria.Br J Cancer. 2005; 93: 1062-1067Crossref PubMed Scopus (270) Google Scholar, 5Calle E.E. Rodriguez C. Walker-Thurmond K. et al.Overweight, obesity and mortality from cancer in a prospective studied cohort of US adults.N Engl J Med. 2003; 348: 1625-1638Crossref PubMed Scopus (5870) Google Scholar, 6Samanic C. Gridley G. Chow W.H. et al.Obesity and cancer risk among white and black United States veterans.Cancer Causes Control. 2004; 15: 35-43Crossref PubMed Scopus (263) Google Scholar, 7Nair S. Mason A. Eason J. et al.Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis?.Hepatology. 2002; 36: 150-155Crossref PubMed Scopus (286) Google Scholar but 2 of failed to for other metabolic factors and HCC risk factors to of H. Mellemgaard A. Lindvig K. et al.Obesity and cancer risk: a Danish record-linkage study.Eur J Cancer. 1994; 30A: 344-350Abstract Full Text PDF PubMed Scopus (398) Google Scholar, 3Wolk A. Gridley G. Svensson M. et al.A prospective study of obesity and cancer risk (Sweden).Cancer Causes Control. 2001; 12: 13-21Crossref PubMed Scopus (506) Google Scholar study observed a increased risk among the population in with the H. Mellemgaard A. Lindvig K. et al.Obesity and cancer risk: a Danish record-linkage study.Eur J Cancer. 1994; 30A: 344-350Abstract Full Text PDF PubMed Scopus (398) Google Scholar the incidence for liver cancer was (95% CI, in in A. Gridley G. Svensson M. et al.A prospective study of obesity and cancer risk (Sweden).Cancer Causes Control. 2001; 12: 13-21Crossref PubMed Scopus (506) Google Scholar of liver cancer among kg/m2) was with of in a large US E.E. Rodriguez C. Walker-Thurmond K. et al.Overweight, obesity and mortality from cancer in a prospective studied cohort of US adults.N Engl J Med. 2003; 348: 1625-1638Crossref PubMed Scopus (5870) Google Scholar et S. Mason A. Eason J. et al.Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis?.Hepatology. 2002; 36: 150-155Crossref PubMed Scopus (286) Google Scholar that obesity was an independent risk factor for HCC in with 95% CI, for kg/m2) and 95% CI, but not in with HCV HBV and hepatitis. of to increased risk of HCC associated with of diabetes was with M.S. Hsieh M.S. Chiu Y.H. et al.Type 2 diabetes and hepatocellular carcinoma: a cohort study in high prevalence area of hepatitis virus infection.Hepatology. 2006; 43: PubMed Scopus Google Scholar, Chow W.H. et risk of liver cancer in with diabetes PubMed Scopus Google Scholar, Gridley G. et incidence in a cohort of with diabetes in PubMed Scopus Google Scholar, C. A. et and the risk of liver J Cancer. PubMed Scopus Google Scholar, H. et of diabetes in the of hepatocellular PubMed Scopus Google Scholar, The of diabetes in hepatocellular carcinoma: a study among United States J 2001; PubMed Google Scholar, Diabetes the risk of liver and hepatocellular 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, et the risk of hepatocellular carcinoma in the United a population 2005; PubMed Scopus Google Scholar, et factors for hepatocellular carcinoma: of with viral hepatitis and diabetes 2002; 36: PubMed Scopus Google Scholar, H. et and cancer risk in and 2005; PubMed Scopus Google Scholar, E.E. et a of cancer mortality in a large cohort of US J 2004; PubMed Scopus Google Scholar, S. K. et of diabetes, and viral hepatitis on risk of hepatocellular carcinoma in and in the 2004; PubMed Scopus Google Scholar, M. M. et and the risk of cancer: from a cohort study in Med. 2006; PubMed Scopus Google Scholar, H. The diabetes and hepatocellular carcinoma: a of epidemiologic 2006; Full Text Full Text PDF PubMed Scopus Google Scholar of H. The diabetes and hepatocellular carcinoma: a of epidemiologic 2006; Full Text Full Text PDF PubMed Scopus Google Scholar et the risk of hepatocellular carcinoma in the United a population 2005; PubMed Scopus Google Scholar a HCV and diabetes with an of (95% CI, for those with HCV and diabetes, with those without factor in a large study in the United study found a similar with an of (95% CI, for those with HCV and diabetes, was than the of diabetes 95% CI, and HCV 95% CI, but the not S. K. et of diabetes, and viral hepatitis on risk of hepatocellular carcinoma in and in the 2004; PubMed Scopus Google Scholar synergistic effects of diabetes and viral hepatitis with an of (95% CI, but combined hepatitis B and C a study by et M.S. Hsieh M.S. Chiu Y.H. et al.Type 2 diabetes and hepatocellular carcinoma: a cohort study in high prevalence area of hepatitis virus infection.Hepatology. 2006; 43: PubMed Scopus Google Scholar found that 2 diabetes increased risk of HCC in those were HCV 95% CI, or 95% CI, The may be to HCV persons with HBV infections and to the risk from The synergistic of kg/m2) and diabetes on the risk of HCC been We found that kg/m2) not increase HCC risk to an with diabetes a synergistic in the not This is with the from that is not associated with increased risk of HCC in the with obesity ≥30 kg/m2) in to diabetes, the synergistic to in the in The of of with risk of HCC among those with HBV or HCV infections were with 2 other H. et of diabetes in the of hepatocellular PubMed Scopus Google Scholar, M. et in with hepatocellular Med. 2001; Google Scholar We HBV in a and a was observed of HBV and The and was by study conducted in Chiu Y.H. et al.A study the metabolic and hepatitis infection study J 2006; Scholar but been a on the of HBV and liver is to increase the risk of would that be associated with of the have the that may the and HCC risk study and the study by et Chiu Y.H. et al.A study the metabolic and hepatitis infection study J 2006; Scholar is associated with HBV been that in HBV may the of is the of the et hepatitis B virus of B by the of 2004; PubMed Scopus Google Scholar of B B would in of all the in the was to viral increasing of viral M. 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Severe acute respiratory syndrome (SARS) is an infectious disease caused by a novel human coronavirus. Currently, no effective antiviral agents exist against this type of virus. A cell-based assay, with SARS virus and Vero E6 cells, was developed to screen existing drugs, natural products, and synthetic compounds to identify effective anti-SARS agents. Of >10,000 agents tested, approximately 50 compounds were found active at 10 microM; among these compounds, two are existing drugs (Reserpine 13 and Aescin 5) and several are in clinical development. These 50 active compounds were tested again, and compounds 2-6, 10, and 13 showed active at 3 microM. The 50% inhibitory concentrations for the inhibition of viral replication (EC(50)) and host growth (CC(50)) were then measured and the selectivity index (SI = CC(50)/EC(50)) was determined. The EC(50), based on ELISA, and SI for Reserpine, Aescim, and Valinomycin are 3.4 microM (SI = 7.3), 6.0 microM (SI = 2.5), and 0.85 microM (SI = 80), respectively. Additional studies were carried out to further understand the mode of action of some active compounds, including ELISA, Western blot analysis, immunofluorescence and flow cytometry assays, and inhibition against the 3CL protease and viral entry. Of particular interest are the two anti-HIV agents, one as an entry blocker and the other as a 3CL protease inhibitor (K(i) = 0.6 microM).

Abstract Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury 1–4 . These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries 5 . Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.