Hepatocellular carcinoma (HCC) is a major cause of cancer death in Taiwan, and in the past 30-40 years, Taiwan has been committed to its prevention and treatment. We aimed to investigate the secular trends of characteristics and the survival of HCC in recent decades after making increased efforts. Between 2011 and 2019, a total of 73,817 cases were enrolled from the TCR database. The overall male-to-female ratio was 7/3. The overall, male and female mean ages increased from 63.8 to 66.1 years, 62.0 to 64.3 years and 68.3 to 70.4 years, respectively. After dividing by viral etiologies and gender, the mean age showed increasing trends in all subgroups. The proportions of HBV-HCC, HCV-HCC, HBV+HCV-HCC and Non-HBV+non-HCV-HCC were 48.3%, 25.2%, 5.3% and 21.3% in males, compared with 25.5%, 48.6%, 5.3% and 20.5% in females, respectively. The 5-year survival rates of BCLC stages 0, A, B, C and D were 70%, 58%, 34%, 11% and 4%, respectively. The proportion of BCLC stage 0 increased from 6.2% to 11.3%. Multivariate analysis showed that being female, older age, diagnostic year, BCLC stages, hospital level, body mass index, smoking, alcohol consumption, AFP, Child-Pugh classification and HBV/HCV status were independent predictors for survival. In recent decades, the overall survival of HCC in Taiwan has been improving and might be partly associated with increased BCLC 0 and Child-Pugh A patients, while with the consequent age of patients increasing over time. The proportion of viral-related HCC is decreasing, while nonviral-related HCC is increasing.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-aged women. Women with PCOS frequently have metabolic complications including insulin resistance (IR), early diabetes, hypertension and dyslipidemia. Recent studies have demonstrated an association between PCOS and another metabolic complication: nonalcoholic fatty liver disease (NAFLD). NAFLD occurs as a result of abnormal lipid handling by the liver, which sensitizes the liver to injury and inflammation. It can progress to nonalcoholic steatohepatitis (NASH), which is characterized by hepatocyte injury and apoptosis. With time and further inflammation, NASH can progress to cirrhosis. Thus, given the young age at which NAFLD may occur in PCOS, these women may be at significant risk for progressive hepatic injury over the course of their lives. Many potential links between PCOS and NAFLD have been proposed, most notably IR and hyperandrogenemia. Further studies are needed to clarify the association between PCOS and NAFLD. In the interim, clinicians should be aware of this connection and consider screening for NAFLD in PCOS patients who have other metabolic risk factors. The optimal method of screening is unknown. However, measuring alanine aminotransferase and/or obtaining ultrasound on high-risk patients can be considered. First line treatment consists of lifestyle interventions and weight loss, with possible pharmacologic interventions in some cases.

To investigate the impact of menarche on the natural course of chronic hepatitis B virus (HBV) infection in women.

Young women who are positive for hepatitis B e antigen (HBeAg; n = 101) chronically infected with genotypes B and C HBV were recruited at a mean age of 4.57 ± 3.08 years, and a mean follow-up duration of 23.98 ± 3.77 years. Clinical data, including age at menarche, HBV genotypes, serum HBV viral loads, hepatitis B surface antigen (HBsAg) titers, and serial liver functional profiles were analyzed.

Women with earlier onset of menarche had earlier spontaneous HBeAg seroconversion than others (hazard ratio, 2.0; P = .02) adjusting for HBV genotype and peak alanine aminotransferase levels before HBeAg seroconversion. The annual decrease in HBsAg titer from 15 to 20 years of age also was greater in the early menarche group compared with the late menarche group (0.11 ± 0.11 vs 0.05 ± 0.11 log10 IU/mL, P = .04). The baseline HBV viral load was also borderline low in female subjects with earlier menarche as compared with others (P = .06). Earlier menarche onset was associated with higher spontaneous HBeAg seroconversion, HBsAg seroclearance, and HBsAg seroconversion rate before 15 years of age in females with chronic HBV infection.

Earlier puberty-onset, indicated by menarche-onset, was associated with earlier spontaneous HBeAg seroconversion and greater rate of HBV clearance before 15 years of age in female subjects with chronic HBV infection.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. It is more prevalent in men than women. Related to this, recent genetic studies have revealed a causal role for androgen receptor (AR) in hepatocarcinogenesis, but the underlying molecular mechanism remains unclear. Here, we used genome-wide location and functional analyses to identify a critical mediator of AR signaling - cell cycle-related kinase (CCRK) - that drives hepatocarcinogenesis via a signaling pathway dependent on β-catenin and T cell factor (TCF). Ligand-bound AR activated CCRK transcription and protein expression via direct binding to the androgen-responsive element of the CCRK promoter in human HCC cell lines. In vitro analyses showed that CCRK was critical in human cell lines for AR-induced cell cycle progression, hepatocellular proliferation, and malignant transformation. Ectopic expression of CCRK in immortalized human liver cells activated β-catenin/TCF signaling to stimulate cell cycle progression and to induce tumor formation, as shown in both xenograft and orthotopic models. Conversely, knockdown of CCRK decreased HCC cell growth, and this could be rescued by constitutively active β-catenin or TCF. In primary human HCC tissue samples, AR, CCRK, and β-catenin were concordantly overexpressed in the tumor cells. Furthermore, CCRK overexpression correlated with the tumor staging and poor overall survival of patients. Our results reveal a direct AR transcriptional target, CCRK, that promotes hepatocarcinogenesis through the upregulation of β-catenin/TCF signaling.

Hepatitis B virus (HBV) infection is an important disease globally. Chronic HBV infection may result in serious complications. Its transmission may be either perinatal or horizontal. Perinatal transmission is particularly important after the implementation of a universal vaccination program. Through either route, chronic carrier status is usually established in early childhood. The course of the disease course is determined by the host-virus interaction. The host's immune system initially tolerates the virus, and then gradually attempts to clear it. The virus, on the other hand, tries to avoid host immune system attack by a strategy involving targeted epitope mutations. By generating mutants, the virus can survive attacks from the host's immune system, enabling the infection to persist. Different individuals have different responses to HBV infection; genetic polymorphisms in cytokines, hormones, and other immune modulators may affect the final outcome of chronic HBV infection. Due to the implementation of a universal infant HBV vaccination program, HBV infection is now under control. Unfortunately, there still are some cases of vaccination failure. Very high maternal viremia, in utero infection, or escape mutants are possible reasons for vaccination failure. Immunocompromised hosts also risk vaccination failure. Blood or organ donors with occult HBV infection are possible sources for immunocompromised hosts. These victims of vaccination failure may exhibit a different disease course due to chronic HBV infection from those who acquired the infection before the universal vaccination era. The achievement of our ultimate goal of HBV elimination depends on a globally effective universal vaccination program, as well as the application of some novel successful medications to control those who are already infected.

Women with polycystic ovary syndrome (PCOS) have been implicated to have higher levels of alanine aminotransferase (ALT) because of the high prevalence of obesity.

Our aim was to investigate the relationship between elevated ALT and aspartate aminotransferase (AST) activity and characteristic hyperandrogenism in women with PCOS.

We conducted a cross-sectional case-control study in a reproductive endocrinology clinic and voluntary annual medical health check-up program of the health management center in a tertiary medical center.

A total of 279 women with PCOS and 279 age-frequency-matched healthy women were studied.

There were no interventions.

All subjects underwent anthropometric measurement, clinical history recorded by questionnaires, and biochemical tests after an overnight fast.

The prevalence of elevated ALT and AST levels was significantly higher in women with PCOS than healthy control subjects. Multivariate regression analysis for women revealed that the presence of PCOS was significantly associated with elevated ALT but not AST after adjustment for age, obesity, and dyslipidemia. The level of androgenicity represented by free androgen index in women with PCOS was significantly related to elevated ALT and AST levels in multivariate regression models. Women with PCOS who had the highest quartile of free androgen index level had the highest risk of elevated ALT level after adjustment for age, obesity, insulin resistance, and dyslipidemia.

The risk of elevated ALT level is significantly higher in women with PCOS than those without, independent of obesity. The elevated ALT levels in women with PCOS were associated with the increased androgen levels, independent of obesity, insulin resistance, and dyslipidemia.

Male predominance is a remarkable phenomenon in hepatitis B virus (HBV)-related liver disease. This study elucidated the effects of puberty on spontaneous hepatitis B virus e antigen (HBeAg) seroconversion in boys.

One-hundred HBeAg-positive chronic HBV-infected males recruited at younger than 10 years of age who had been followed for >10 years were selected randomly from our long-term followed cohort into this study. Serum testosterone levels, androgen receptor exon-1 CAG repeat number and steroid 5alpha reductase type II (SRD5A2, valine vs leucine alleles) polymorphism were determined. Serial clinical data, HBV genotype, and spontaneous HBeAg seroconversion age were also analyzed.

Seventy-two subjects had spontaneous HBeAg seroconversion during the follow-up period. Subjects with serum testosterone levels > or =2.5 ng/mL at 15 years old (earlier-onset puberty, n = 87) had earlier HBeAg seroconversion (median age, 13.2 vs 22.5 years; hazard ratio = 2.95; P = .005), higher peak alanine aminotransferase levels when HBeAg positive (305.7 +/- 372.7 vs 154.8 +/- 126.0 IU/L; P = .006), and a greater HBV viral load reduction from 10 to 20 years of age (1.6 +/- 2.4 vs 0.2 +/- 1.4 log10 copies/mL; P = .009) than those with serum testosterone levels <2.5 ng/mL (later-onset puberty, n = 13). Valine allele carrier at the SRD5A2 V89L polymorphism was also associated with earlier spontaneous HBeAg seroconversion (median age, 11.7 vs 18.7 years; hazard ratio = 1.88; P = .028).

Earlier-onset puberty and increased SRD5A2 enzyme activity are associated with earlier HBeAg seroconversion, higher serum alanine aminotransferase levels, and a greater HBV viral load decrement in chronic HBV infected males.

Androgen receptors (ARs) act as transcription factors. An increased AR activity could be due either to mutations or to an increased expression of the receptor. AR mutations involving the hormone binding domain could increase AR function and promote carcinogenesis, as suggested for prostate cancer.

Herein, we evaluated qualitative (point mutations involving the hormone binding domain) and quantitative AR alterations and their possible correlation with cell proliferation and tumour grading.

Carcinomatous and non-cancerous surrounding liver tissue was collected from 14 Caucasian patients with hepatocarcinoma. They were all affected by cirrhosis with different aetiologies.

AR missense mutations, AR mRNA and protein levels, AR distribution in the liver, liver cell proliferation, and tumour staging were evaluated by DNA sequencing, quantitative real-time PCR, Western blot analysis, immunofluorescence, PCNA immunostaining, and conventional histological techniques, respectively.

AR gene regions encoding the hormone binding domain did not contain any missense mutation. AR mRNA and protein levels were increased in hepatocarcinoma compared to non-cancerous surrounding tissue. Cell proliferation was significantly increased in the tumour compared to non-cancerous surrounding tissue.

Mutations of the AR regions studied were not involved in hepatocarcinogenesis. Elevated AR levels in transformed cells could have a tumour promoting effect by stimulating cell growth.

Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) occurs predominantly in men. By enhancing the transcriptional activity of the androgen receptor (AR) gene in a ligand-dependent manner, the HBV X protein (HBx) might contribute to this disparity between sexes. To dissect the mechanisms underlying HBx-enhanced AR transactivation, we investigated the effect of HBx on two critical steps in the regulation of ligand-stimulated AR activities. One step is the dimerization of AR (through the interaction of its N-termini and C-termini), and the other step is the activation of the AR N-terminal transactivation domain (NTD). HBx increased the NTD activation of the AR through c-Src kinase. HBx also enhanced AR dimerization by inhibiting glycogen synthase kinase-3beta (GSK-3beta) activity, which acts as a negative regulator of the interaction between AR and the N-termini and C-termini. The HBx-enhanced AR transactivation was abolished by blocking c-Src and activating GSK-3beta kinases simultaneously, suggesting that these two kinases act as major switches in the activation process. The regulatory function of both kinases has been further verified in primary hepatocytes isolated from the livers of HBx transgenic male mice.

Our study thus identified two key kinases through which HBx enhances the AR transcriptional activity. These kinases might be potential candidates for future prevention or therapy for HBV-related HCC in men.

Androgen effects on hepatocellular carcinoma (HCC) remain controversial and androgen ablation therapy to treat HCC also leads to inconsistent results. Here we examine androgen receptor (AR) roles in hepatocarcinogenesis using mice lacking AR in hepatocytes.

By using the Cre-Lox conditional knockout mice model injected with carcinogen, we examined the AR roles in hepatocarcinogenesis. We also tested the possible roles of AR in cellular oxidative stress and DNA damage sensing/repairing systems. By using AR degrading compound, ASC-J9, or AR-small interference RNA, we also examined the therapeutic potentials of targeting AR in HCC.

We found AR expression was increased in human HCC compared with normal livers. We also found mice lacking hepatic AR developed later and less HCC than their wild-type littermates with comparable serum testosterone in both male and female mice. Addition of functional AR in human HCC cells also resulted in the promotion of cell growth in the absence or presence of 5alpha-dihydrotestosterone. Mechanistic dissection suggests that AR may promote hepatocarcinogenesis via increased cellular oxidative stress and DNA damage, as well as suppression of p53-mediated DNA damage sensing/repairing system and cell apoptosis. Targeting AR directly via either AR-small interference RNA or ASC-J9 resulted in suppression of HCC in both ex vivo cell lines and in vivo mice models.

Our data point to AR, but not androgens, as a potential new and better therapeutic target for the battle of HCC.

To investigate contraction of CAG repeats within the androgen receptor gene (AR) as shorter CAG repeats have been implicated as a possible risk factor in prostate cancer (PCa). AR CAG repeat lengths were analyzed in DNA from microdissected diseased prostates, leukocytes from matched peripheral blood, and control non-diseased prostates. Consistently, all prostatic tissues, whether from benign or cancerous areas of diseased prostates, or from control prostates, showed multiple AR CAG repeat contractions. Germline DNA from blood leukocytes had single CAG repeat lengths in the normal range. AR CAG repeat length contraction may be involved in prostate carcinogenesis and may precede the pathological process.