Genomics Research Center, Academia Sinica

Worldwide, some 240 million people have chronic hepatitis B virus (HBV), with the highest rates of infection in Africa and Asia. Our understanding of the natural history of HBV infection and the potential for therapy of the resultant disease is continuously improving. New data have become available since the previous APASL guidelines for management of HBV infection were published in 2012. The objective of this manuscript is to update the recommendations for the optimal management of chronic HBV infection. The 2015 guidelines were developed by a panel of Asian experts chosen by the APASL. The clinical practice guidelines are based on evidence from existing publications or, if evidence was unavailable, on the experts' personal experience and opinion after deliberations. Manuscripts and abstracts of important meetings published through January 2015 have been evaluated. This guideline covers the full spectrum of care of patients infected with hepatitis B, including new terminology, natural history, screening, vaccination, counseling, diagnosis, assessment of the stage of liver disease, the indications, timing, choice and duration of single or combination of antiviral drugs, screening for HCC, management in special situations like childhood, pregnancy, coinfections, renal impairment and pre- and post-liver transplant, and policy guidelines. However, areas of uncertainty still exist, and clinicians, patients, and public health authorities must therefore continue to make choices on the basis of the evolving evidence. The final clinical practice guidelines and recommendations are presented here, along with the relevant background information.

BACKGROUND: Preclinical and preliminary clinical data indicate that ch14.18, a monoclonal antibody against the tumor-associated disialoganglioside GD2, has activity against neuroblastoma and that such activity is enhanced when ch14.18 is combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2. We conducted a study to determine whether adding ch14.18, GM-CSF, and interleukin-2 to standard isotretinoin therapy after intensive multimodal therapy would improve outcomes in high-risk neuroblastoma. METHODS: Patients with high-risk neuroblastoma who had a response to induction therapy and stem-cell transplantation were randomly assigned, in a 1:1 ratio, to receive standard therapy (six cycles of isotretinoin) or immunotherapy (six cycles of isotretinoin and five concomitant cycles of ch14.18 in combination with alternating GM-CSF and interleukin-2). Event-free survival and overall survival were compared between the immunotherapy group and the standard-therapy group, on an intention-to-treat basis. RESULTS: A total of 226 eligible patients were randomly assigned to a treatment group. In the immunotherapy group, a total of 52% of patients had pain of grade 3, 4, or 5, and 23% and 25% of patients had capillary leak syndrome and hypersensitivity reactions, respectively. With 61% of the number of expected events observed, the study met the criteria for early stopping owing to efficacy. The median duration of follow-up was 2.1 years. Immunotherapy was superior to standard therapy with regard to rates of event-free survival (66±5% vs. 46±5% at 2 years, P=0.01) and overall survival (86±4% vs. 75±5% at 2 years, P=0.02 without adjustment for interim analyses). CONCLUSIONS: Immunotherapy with ch14.18, GM-CSF, and interleukin-2 was associated with a significantly improved outcome as compared with standard therapy in patients with high-risk neuroblastoma. (Funded by the National Institutes of Health and the Food and Drug Administration; ClinicalTrials.gov number, NCT00026312.)

Type Ib diamonds emit bright fluorescence at 550-800 nm from nitrogen-vacancy point defects, (N-V)(0) and (N-V)(-), produced by high-energy ion beam irradiation and subsequent thermal annealing. The emission, together with noncytotoxicity and easiness of surface functionalization, makes nano-sized diamonds a promising fluorescent probe for single-particle tracking in heterogeneous environments. We present the result of our characterization and application of single fluorescent nanodiamonds as cellular biomarkers. We found that, under the same excitation conditions, the fluorescence of a single 35-nm diamond is significantly brighter than that of a single dye molecule such as Alexa Fluor 546. The latter photobleached in the range of 10 s at a laser power density of 10(4) W/cm(2), whereas the nanodiamond particle showed no sign of photobleaching even after 5 min of continuous excitation. Furthermore, no fluorescence blinking was detected within a time resolution of 1 ms. The photophysical properties of the particles do not deteriorate even after surface functionalization with carboxyl groups, which form covalent bonding with polyL-lysines that interact with DNA molecules through electrostatic forces. The feasibility of using surface-functionalized fluorescent nanodiamonds as single-particle biomarkers is demonstrated with both fixed and live HeLa cells.

MicroRNA-122 (miR-122), which accounts for 70% of the liver's total miRNAs, plays a pivotal role in the liver. However, its intrinsic physiological roles remain largely undetermined. We demonstrated that mice lacking the gene encoding miR-122a (Mir122a) are viable but develop temporally controlled steatohepatitis, fibrosis, and hepatocellular carcinoma (HCC). These mice exhibited a striking disparity in HCC incidence based on sex, with a male-to-female ratio of 3.9:1, which recapitulates the disease incidence in humans. Impaired expression of microsomal triglyceride transfer protein (MTTP) contributed to steatosis, which was reversed by in vivo restoration of Mttp expression. We found that hepatic fibrosis onset can be partially attributed to the action of a miR-122a target, the Klf6 transcript. In addition, Mir122a(-/-) livers exhibited disruptions in a range of pathways, many of which closely resemble the disruptions found in human HCC. Importantly, the reexpression of miR-122a reduced disease manifestation and tumor incidence in Mir122a(-/-) mice. This study demonstrates that mice with a targeted deletion of the Mir122a gene possess several key phenotypes of human liver diseases, which provides a rationale for the development of a unique therapy for the treatment of chronic liver disease and HCC.

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.

The sudden outbreak of 2019 novel coronavirus (2019-nCoV, later named SARS-CoV-2) in Wuhan, China, which rapidly grew into a global pandemic, marked the third introduction of a virulent coronavirus into the human society, affecting not only the healthcare system, but also the global economy. Although our understanding of coronaviruses has undergone a huge leap after two precedents, the effective approaches to treatment and epidemiological control are still lacking. In this article, we present a succinct overview of the epidemiology, clinical features, and molecular characteristics of SARS-CoV-2. We summarize the current epidemiological and clinical data from the initial Wuhan studies, and emphasize several features of SARS-CoV-2, which differentiate it from SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), such as high variability of disease presentation. We systematize the current clinical trials that have been rapidly initiated after the outbreak of COVID-19 pandemic. Whereas the trials on SARS-CoV-2 genome-based specific vaccines and therapeutic antibodies are currently being tested, this solution is more long-term, as they require thorough testing of their safety. On the other hand, the repurposing of the existing therapeutic agents previously designed for other virus infections and pathologies happens to be the only practical approach as a rapid response measure to the emergent pandemic, as most of these agents have already been tested for their safety. These agents can be divided into two broad categories, those that can directly target the virus replication cycle, and those based on immunotherapy approaches either aimed to boost innate antiviral immune responses or alleviate damage induced by dysregulated inflammatory responses. The initial clinical studies revealed the promising therapeutic potential of several of such drugs, including favipiravir, a broad-spectrum antiviral drug that interferes with the viral replication, and hydroxychloroquine, the repurposed antimalarial drug that interferes with the virus endosomal entry pathway. We speculate that the current pandemic emergency will be a trigger for more systematic drug repurposing design approaches based on big data analysis.

The anticonvulsant carbamazepine (CBZ) frequently causes cutaneous adverse drug reactions (cADRs), including maculopapular eruption (MPE), hypersensitivity syndrome (HSS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We reported that SJS/TEN caused by CBZ is strongly associated with the HLA-B*1502 gene in Han Chinese. Here, we extended our genetic study to different types of CBZ-cADRs (91 patients, including 60 patients with SJS/TEN, 13 patients with hypersensitivity syndrome and 18 with maculopapular exanthema versus 144 tolerant controls). We used MALDI-TOF mass spectrometry to screen the genetic association of 278 single nucleotide polymorphisms (SNPs), which cover the major histocompatibility complex (MHC) region, tumor necrosis factor-alpha, heat shock protein and CBZ-metabolic enzymes, including CYP3A4, 2B6, 2C8, 2C9, 1A2 and epoxide hydrolase 1. In addition, we genotyped 20 microsatellites in the MHC region and performed HLA-typing to construct the recombinant map. We narrowed the susceptibility locus for CBZ-SJS/TEN to within 86 kb flanking the HLA-B gene on the extended B*1502 haplotype, and confirmed the association of B*1502 with SJS/TEN [Pc=1.6x10, odds ratio (OR)=1357; 95% confidence interval (CI)=193.4-8838.3]. By contrast to CBZ-SJS/TEN, HLA-B*1502 association was not observed in the MPE or HSS groups: MPE was associated with SNPs in the HLA-E region and a nearby allele, HLA-A*3101 (Pc=2.2x10, OR=17.5; 95% CI=4.6-66.5), and HSS with SNPs in the motilin gene (Pc=0.0064, OR=7.11; 95% CI=3.1-16.5) located terminal to the MHC class II genes. No SNPs in genes involved in CBZ metabolism were associated with CBZ-induced cADRs. Our data suggest that HLA-B*1502 could contribute to the pathogenesis of CBZ-SJS/TEN, and that genetic susceptibility to CBZ-induced cADRs is phenotype-specific.

BACKGROUND: Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma. This population-based study aimed to investigate whether prevention of hepatocellular carcinoma by the universal Taiwanese HBV vaccine program, launched in July 1984, has extended beyond childhood and to identify the predictors of hepatocellular carcinoma for vaccinated birth cohorts. METHODS: Data on 1958 patients with hepatocellular carcinoma who were aged 6-29 years at diagnosis in Taiwan between 1983 and 2004 were collected from two national hepatocellular carcinoma registries. Age- and sex-specific incidence among vaccinated and unvaccinated birth cohorts were analyzed by using Poisson regression models. All statistical tests were two-sided. Records of 64 hepatocellular carcinoma patients and 5 524 435 HBV vaccinees who were born after the initiation of the vaccination program were compared for HBV immunization characteristics during infancy and prenatal maternal hepatitis B surface antigen (HBsAg) and e antigen (HBeAg) serostatus. RESULTS: Hepatocellular carcinoma incidence was statistically significantly lower among children aged 6-19 years in vaccinated compared with unvaccinated birth cohorts (64 hepatocellular cancers among vaccinees in 37 709 304 person-years vs 444 cancers in unvaccinated subjects in 78 496 406 person-years, showing an age- and sex-adjusted relative risk of 0.31, P < .001, for persons vaccinated at birth). The risk of developing hepatocellular carcinoma for vaccinated cohorts was statistically significantly associated with incomplete HBV vaccination (for those who received fewer than three doses of HBV vaccine, odds ratio [OR] = 4.32, 95% confidence interval [CI] = 2.34 to 7.91); with prenatal maternal HBsAg seropositivity (OR = 29.50, 95% CI = 13.98 to 62.60); with prenatal maternal HBeAg seropositivity (with administration of hepatitis B immunoglobulin at birth, OR = 5.13, 95% CI = 2.24 to 11.71; and without it, OR = 9.43, 95% CI = 3.54 to 25.11). CONCLUSION: The prevention of hepatocellular carcinoma by this HBV vaccine extends from childhood to early adulthood. Failure to prevent hepatocellular carcinoma results mostly from unsuccessful control of HBV infection by highly infectious mothers.

UNLABELLED: MicroRNAs (miRNAs), which are inhibitors of gene expression, participate in diverse biological functions and in carcinogenesis. In this study, we show that liver-specific microRNA-122 (miR-122) is significantly down-regulated in liver cancers with intrahepatic metastasis and negatively regulates tumorigenesis. Restoration of miR-122 in metastatic Mahlavu and SK-HEP-1 cells significantly reduced in vitro migration, invasion, and anchorage-independent growth as well as in vivo tumorigenesis, angiogenesis, and intrahepatic metastasis in an orthotopic liver cancer model. Because an inverse expression pattern is often present between an miRNA and its target genes, we used a computational approach and identified multiple miR-122 candidate target genes from two independent expression microarray datasets. Thirty-two target genes were empirically verified, and this group of genes was enriched with genes regulating cell movement, cell morphology, cell-cell signaling, and transcription. We further showed that one of the miR-122 targets, ADAM17 (a disintegrin and metalloprotease 17) is involved in metastasis. Silencing of ADAM17 resulted in a dramatic reduction of in vitro migration, invasion, in vivo tumorigenesis, angiogenesis, and local invasion in the livers of nude mice, which is similar to that which occurs with the restoration of miR-122. CONCLUSION: Our study suggests that miR-122, a tumor suppressor microRNA affecting hepatocellular carcinoma intrahepatic metastasis by angiogenesis suppression, exerts some of its action via regulation of ADAM17. Restoration of miR-122 has a far-reaching effect on the cell. Using the concomitant down-regulation of its targets, including ADAM17, a rational therapeutic strategy based on miR-122 may prove to be beneficial for patients with hepatocellular carcinoma.

BACKGROUND: The risk of hepatocellular carcinoma (HCC) increases with increasing level of hepatitis B virus (HBV) in serum (viral load). However, it is unclear whether genetic characteristics of HBV, including HBV genotype and specific genetic mutations, contribute to the risk of HCC. We examined the HCC risk associated with HBV genotypes and common variants in the precore and basal core promoter (BCP) regions. METHODS: From January 5, 1991, to December 21, 1992, baseline blood samples were collected from 2762 Taiwanese men and women who were seropositive for HBV surface antigen but had not been diagnosed with HCC; the samples were tested for HBV viral load by real-time polymerase chain reaction and genotyped by melting curve analysis. Participants who had a baseline serum HBV DNA level greater than 10(4) copies/mL (n = 1526) were tested for the precore G1896A and BCP A1762T/G1764A mutants by direct sequencing. Incident cases of HCC were ascertained through follow-up examinations and computerized linkage to the National Cancer Registry and death certification profiles. A Cox proportional hazards model was used to estimate the risk of HCC associated with HBV genotype and precore and BCP mutants after adjustment for other risk factors. All statistical tests were two-sided. RESULTS: A total of 153 HCC cases occurred during 33 847 person-years of follow-up. The HCC incidence rates per 100 000 person-years for participants infected with HBV genotype B or C were 305.6 (95% confidence interval [CI] = 236.9 to 388.1) and 785.8 (95% CI = 626.8 to 972.9), respectively. Among participants with a baseline HBV DNA level of at least 10(4) copies/mL, HCC incidence per 100 000 person-years was higher for those with the precore G1896 (wild-type) variant than for those with the G1896A variant (955.5 [95% CI = 749.0 to 1201.4] vs 269.4 [95% CI = 172.6 to 400.9]) and for those with the BCP A1762T/G1764A double mutant than for those with BCP A1762/G1764 (wild-type) variant (1149.2 [95% CI = 872.6 to 1485.6] vs 358.7 [95% CI = 255.1 to 490.4]). The multivariable-adjusted hazard ratio of developing HCC was 1.76 (95% CI = 1.19 to 2.61) for genotype C vs genotype B, 0.34 (95% CI = 0.21 to 0.57) for precore G1896A vs wild type, and 1.73 (95% CI = 1.13 to 2.67) for BCP A1762T/G1764A vs wild type. Risk was highest among participants infected with genotype C HBV and wild type for the precore 1896 variant and mutant for the BCP 1762/1764 variant (adjusted hazard ratio = 2.99, 95% CI = 1.57 to 5.70, P < .001). CONCLUSIONS: HBV genotype C and specific alleles of BCP and precore were associated with risk of HCC. These associations were independent of serum HBV DNA level.

BACKGROUND: The study aimed to evaluate the risk of hepatitis C virus (HCV) infection on hepatic and extrahepatic deaths. METHODS: A cohort of 23 820 adults aged 30-65 years old were enrolled during 1991-1992. The seromarkers hepatitis B surface antigen (HBsAg), anti-HCV, and serum HCV RNA levels at study entry were tested. The vital status was ascertained through computerized linkage with national death certification profiles from 1991 to 2008. RESULTS: There were 19,636 HBsAg-seronegatives, including 18,541 anti-HCV seronegatives and 1095 anti-HCV seropositives. Among anti-HCV seropositives, 69.4% had detectable serum HCV RNA levels. There were 2394 deaths that occurred during an average follow-up period of 16.2 years. Compared with anti-HCV seronegatives, anti-HCV seropositives had higher mortality from both hepatic and extrahepatic diseases, showing multivariate-adjusted hazard ratio (95% confidence interval) of 1.89 (1.66-2.15) for all causes of death; 12.48 (9.34-16.66) for hepatic diseases; 1.35 (1.15-1.57) for extrahepatic diseases; 1.50 (1.10-2.03) for circulatory diseases; 2.77 (1.49-5.15) for nephritis, nephrotic syndrome, and nephrosis; 4.08 (1.38-12.08) for esophageal cancer; 4.19 (1.18-14.94) for prostate cancer; and 8.22 (1.36-49.66) for thyroid cancer. Anti-HCV seropositives with detectable HCV RNA levels had significantly higher mortality from hepatic and extrahepatic diseases than anti-HCV seropositives with undetectable HCV RNA. CONCLUSIONS: Monitoring HCV RNA in anti-HCV seropositives is essential for the prediction of mortality associated with hepatitis C.

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. 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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. 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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. 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The Asia-Pacific region is home to more than half of the global population and accounted for 62·6% of global deaths due to liver diseases in 2015. 54·3% of global deaths due to cirrhosis, 72·7% of global deaths due to hepatocellular carcinoma, and more than two-thirds of the global burden of acute viral hepatitis occurred in this region in 2015. Chronic hepatitis B virus (HBV) infection caused more than half of the deaths due to cirrhosis in the region, followed by alcohol consumption (20·8%), non-alcoholic fatty liver disease (NAFLD; 12·1%), and chronic infection with hepatitis C virus (HCV; 15·7%). In 2015, HBV accounted for about half the cases of hepatocellular carcinoma in the region. Preventive strategies for viral hepatitis-related liver disease include increasing access to clean drinking water and sanitation. HBV vaccination programmes for neonates have been implemented by all countries, although birth-dose coverage is extremely suboptimal in some. Availability of screening tests for blood and tissue, donor recall policies, and harm reduction strategies are in their initial stages in most countries. Many governments have put HBV and HCV drugs on their essential medicines lists and the availability of generic versions of these drugs has reduced costs. Efforts to eliminate viral hepatitis as a public health threat, together with the rapid increase in per-capita alcohol consumption in countries and the epidemic of obesity, are expected to change the spectrum of liver diseases in the Asia-Pacific region in the near future. The increasing burden of alcohol-related liver diseases can be contained through government policies to limit consumption and promote less harmful patterns of alcohol use, which are in place in some countries but need to be enforced more strictly. Steps are needed to control obesity and NAFLD, including policies to promote healthy lifestyles and regulate the food industry. Inadequate infrastructure and insufficient health-care personnel trained in liver diseases are issues that also need to be addressed in the Asia-Pacific region. The policy response of most governments to liver diseases has thus far been inadequate and poorly funded. There must be a renewed focus on prevention, early detection, timely referral, and research into the best means to introduce and improve health interventions to reduce the burden of liver diseases in the Asia-Pacific region.

Knowledge of the precise rigidity dependence of the helium flux is important in understanding the origin, acceleration, and propagation of cosmic rays. A precise measurement of the helium flux in primary cosmic rays with rigidity (momentum/charge) from 1.9 GV to 3 TV based on 50 million events is presented and compared to the proton flux. The detailed variation with rigidity of the helium flux spectral index is presented for the first time. The spectral index progressively hardens at rigidities larger than 100 GV. The rigidity dependence of the helium flux spectral index is similar to that of the proton spectral index though the magnitudes are different. Remarkably, the spectral index of the proton to helium flux ratio increases with rigidity up to 45 GV and then becomes constant; the flux ratio above 45 GV is well described by a single power law.

BACKGROUND: Tumor mutational burden (TMB), defined as the number of somatic mutations per megabase of interrogated genomic sequence, demonstrates predictive biomarker potential for the identification of patients with cancer most likely to respond to immune checkpoint inhibitors. TMB is optimally calculated by whole exome sequencing (WES), but next-generation sequencing targeted panels provide TMB estimates in a time-effective and cost-effective manner. However, differences in panel size and gene coverage, in addition to the underlying bioinformatics pipelines, are known drivers of variability in TMB estimates across laboratories. By directly comparing panel-based TMB estimates from participating laboratories, this study aims to characterize the theoretical variability of panel-based TMB estimates, and provides guidelines on TMB reporting, analytic validation requirements and reference standard alignment in order to maintain consistency of TMB estimation across platforms. METHODS: Eleven laboratories used WES data from The Cancer Genome Atlas Multi-Center Mutation calling in Multiple Cancers (MC3) samples and calculated TMB from the subset of the exome restricted to the genes covered by their targeted panel using their own bioinformatics pipeline (panel TMB). A reference TMB value was calculated from the entire exome using a uniform bioinformatics pipeline all members agreed on (WES TMB). Linear regression analyses were performed to investigate the relationship between WES and panel TMB for all 32 cancer types combined and separately. Variability in panel TMB values at various WES TMB values was also quantified using 95% prediction limits. RESULTS: Study results demonstrated that variability within and between panel TMB values increases as the WES TMB values increase. For each panel, prediction limits based on linear regression analyses that modeled panel TMB as a function of WES TMB were calculated and found to approximately capture the intended 95% of observed panel TMB values. Certain cancer types, such as uterine, bladder and colon cancers exhibited greater variability in panel TMB values, compared with lung and head and neck cancers. CONCLUSIONS: Increasing uptake of TMB as a predictive biomarker in the clinic creates an urgent need to bring stakeholders together to agree on the harmonization of key aspects of panel-based TMB estimation, such as the standardization of TMB reporting, standardization of analytical validation studies and the alignment of panel-based TMB values with a reference standard. These harmonization efforts should improve consistency and reliability of panel TMB estimates and aid in clinical decision-making.

Circular RNAs (circRNAs) are closed long non-coding RNAs, in which the 5' and 3' termini are covalently linked by back-splicing of exons from a single pre-mRNA. Emerging evidence indicates that circRNAs are broadly expressed in mammalian cells and show cell type- or tissue-specific expression patterns. Importantly, circRNAs have been shown to participate in regulating various biological processes. Functionally, circRNAs can influence cellular physiology through various molecular mechanisms, such as serving as a decoy for microRNAs or RNA-binding proteins to modulate gene expression or translation of regulatory proteins. The biogenesis of circRNAs is known to be tightly regulated by cis- (intronic complementary sequences) and/or trans-factors (splicing factors) that constitute a cell- and context-dependent regulatory layer in the control of gene expression. However, our understanding of the regulation and function of circRNAs is still limited. In this review, we summarize the current progress in elucidating the functional roles, mechanisms and biogenesis of circRNAs. We also discuss the relationship between regulation and formation of circRNAs.

A precision measurement by AMS of the antiproton flux and the antiproton-to-proton flux ratio in primary cosmic rays in the absolute rigidity range from 1 to 450 GV is presented based on $3.49\ifmmode\times\else\texttimes\fi{}1{0}^{5}$ antiproton events and $2.42\ifmmode\times\else\texttimes\fi{}1{0}^{9}$ proton events. The fluxes and flux ratios of charged elementary particles in cosmic rays are also presented. In the absolute rigidity range $\ensuremath{\sim}60$ to $\ensuremath{\sim}500\text{ }\text{ }\mathrm{GV}$, the antiproton $\overline{p}$, proton $p$, and positron ${e}^{+}$ fluxes are found to have nearly identical rigidity dependence and the electron ${e}^{\ensuremath{-}}$ flux exhibits a different rigidity dependence. Below 60 GV, the ($\overline{p}/p$), ($\overline{p}/{e}^{+}$), and ($p/{e}^{+}$) flux ratios each reaches a maximum. From $\ensuremath{\sim}60$ to $\ensuremath{\sim}500\text{ }\text{ }\mathrm{GV}$, the ($\overline{p}/p$), ($\overline{p}/{e}^{+}$), and ($p/{e}^{+}$) flux ratios show no rigidity dependence. These are new observations of the properties of elementary particles in the cosmos.

Circular RNAs (circRNAs) arise during post-transcriptional processes, in which a single-stranded RNA molecule forms a circle through covalent binding. Previously, circRNA products were often regarded to be splicing intermediates, by-products, or products of aberrant splicing. But recently, rapid advances in high-throughput RNA sequencing (RNA-seq) for global investigation of nonco-linear (NCL) RNAs, which comprised sequence segments that are topologically inconsistent with the reference genome, leads to renewed interest in this type of NCL RNA (i.e., circRNA), especially exonic circRNAs (ecircRNAs). Although the biogenesis and function of ecircRNAs are mostly unknown, some ecircRNAs are abundant, highly expressed, or evolutionarily conserved. Some ecircRNAs have been shown to affect microRNA regulation, and probably play roles in regulating parental gene transcription, cell proliferation, and RNA-binding proteins, indicating their functional potential for development as diagnostic tools. To date, thousands of ecircRNAs have been identified in multiple tissues/cell types from diverse species, through analyses of RNA-seq data. However, the detection of ecircRNA candidates involves several major challenges, including discrimination between ecircRNAs and other types of NCL RNAs (e.g., trans-spliced RNAs and genetic rearrangements); removal of sequencing errors, alignment errors, and in vitro artifacts; and the reconciliation of heterogeneous results arising from the use of different bioinformatics methods or sequencing data generated under different treatments. Such challenges may severely hamper the understanding of ecircRNAs. Herein, we review the biogenesis, identification, properties, and function of ecircRNAs, and discuss some unanswered questions regarding ecircRNAs. We also evaluate the accuracy (in terms of sensitivity and precision) of some well-known circRNA-detecting methods.

Protein glycosylation is an important posttranslational process, which regulates protein folding and functional expression. Studies have shown that abnormal glycosylation in tumor cells affects cancer progression and malignancy. In the current study, we have identified sialylated proteins using an alkynyl sugar probe in two different lung cancer cell lines, CL1-0 and CL1-5 with distinct invasiveness derived from the same parental cell line. Among the identified sialylated proteins, epidermal growth factor receptor (EGFR) was chosen to understand the effect of sialylation on its function. We have determined the differences in glycan sequences of EGFR in both cells and observed higher sialylation and fucosylation of EGFR in CL1-5 than in CL1-0. Further study suggested that overexpression of sialyltransferases in CL1-5 and α1,3-fucosyltransferases (FUT4 or FUT6) in CL1-5 and A549 cells would suppress EGFR dimerization and phosphorylation upon EGF treatment, as compared to the control and CL1-0 cells. Such modulating effects on EGFR dimerization were further confirmed by sialidase or fucosidase treatment. Thus, increasing sialylation and fucosylation could attenuate EGFR-mediated invasion of lung cancer cells. However, incorporation of the core fucose by α1,6-fucosylatransferase (FUT8) would promote EGFR dimerization and phosphorylation.

Glycomics is emerging as a new field for the biology of complex glycoproteins and glycoconjugates. The lack of versatile glycan-labeling methods has presented a major obstacle to visualizing at the cellular level and studying glycoconjugates. To address this issue, we developed a fluorescent labeling technique based on the Cu(I)-catalyzed [3 + 2] cycloaddition, or click chemistry, which allows rapid, versatile, and specific covalent labeling of cellular glycans bearing azide groups. The method entails generating a fluorescent probe from a nonfluorescent precursor, 4-ethynyl-N-ethyl-1,8-naphthalimide, by clicking the fluorescent trigger, the alkyne at the 4 position, with an azido-modified sugar. Using this click-activated fluorescent probe, we demonstrate incorporation of an azido-containing fucose analog into glycoproteins via the fucose salvage pathway. Distinct fluorescent signals were observed by flow cytometry when cells treated with 6-azidofucose were labeled with the click-activated fluorogenic probe or biotinylated alkyne. The intracellular localization of fucosylated glycoconjugates was visualized by using fluorescence microscopy. This technique will allow dynamic imaging of cellular fucosylation and facilitate studies of fucosylated glycoproteins and glycolipids.