Urinary transforming growth factor α and serum α-fetoprotein as tumor markers of hepatocellular carcinoma.

This case-control study aimed to evaluate the diagnostic application of urinary transforming growth factor (TGF) α and serum α-fetoprotein (AFP) in hepatocellular carcinoma (HCC). TGFα and AFP were determined in 90 pairs of age- and gender-matched patients with cirrhotic HCC and patients with cirrhosis alone and 60 healthy controls. The results indicated that TGFα and AFP levels in patients with HCC were higher than in those with cirrhosis alone or healthy controls (each P = 0.0001). Multivariate analysis indicated that TGFα (odds ratio (OR) 1.03, 95% confidence interval (CI) 1.05-1.16) and AFP (OR 1.03, 95% CI 1.01-1.06) were closely associated, in a dose-related fashion, with the development of HCC. The optimal cutoff values, determined with the receiver operating characteristic (ROC) curves, were 29 µg/g creatinine for TGFα and 100 ng/ml for AFP, respectively. The areas under ROC curve (AUC) were 0.74 for TGFα and 0.78 for AFP, respectively. Both biomarkers showed the same sensitivity (52.2%), high specificity, high positive predictive value, and moderate positive likelihood ratio. Determination of both markers in parallel significantly increased the AUC (0.91) and diagnostic accuracy (92.2%), with a high sensitivity (86.7 %), specificity (97.8%), positive predictive value (PPV; 97.5%), and moderate positive likelihood ratio (PLR; 39.4). Among 31 cirrhotic HCC with AFP ≤ 20 ng/ml, the calculated AUC for TGFα was 0.79, with a sensitivity of 64.5%, specificity of 96.7%, PPV of 87.0%, and PLR of 19.5. In conclusion, urinary TGFα and serum AFP are complementary tumor markers for detection of HCC with low AFP production.

Is it good to hold more cash before the pandemic? A case of Taiwanese firms.

The Covid-19 pandemic poses a great damage to firm performance worldwide. It raises the empirical question that if any factor can help firm perform better during the pandemic. In this study, we hypothesize that firms holding more cash before the pandemic can perform better during the pandemic year in 2020. We collect all listed firms from Taiwan Stock Exchange and test this hypothesis. Adopting a panel-data regression models with fixed effects, we find supportive evidence that pre-saved cash is valuable and can help firms perform better during the pandemic. Cash-rich firms will have a higher return on equity and return on assets. The economic significance is also non-trivial. Our study thus contributes to our understanding of how the pandemic can affect firm business and which lesson we can learn from this pandemic.

Medium-term surgical outcomes and health-related quality of life after laparoscopic vs open colorectal cancer resection: SF-36 health survey questionnaire.

BACKGROUND: Previous studies that compared the postoperative health-related quality of life (HRQoL) outcomes after receiving laparoscopic resection (LR) or open resection (OR) in patients with colorectal cancer (CRC) have different conclusions. AIM: To explore the medium-term effect of postoperative HRQoL in such patients. METHODS: This study randomized 567 patients undergoing non-metastatic CRC surgery managed by one surgeon to the LR or OR groups. HRQoL was assessed during the preoperative period and 3, 6, and 12 mo postoperative using a modified version of the 36-Item Short Form (SF-36) Health Survey questionnaire, emphasizing eight specific items. RESULTS: This cohort randomly assigned 541 patients to receive LR (n = 296) or OR (n = 245) surgical procedures. More episodes of postoperative urinary tract infection (P < 0.001), wound infection (P < 0.001), and pneumonia (P = 0.048) were encountered in the OR group. The results demonstrated that the LR group subjectively gained mildly better general health (P = 0.045), moderately better physical activity (P = 0.006), and significantly better social function recovery (P = 0.0001) 3 mo postoperatively. Only the aspect of social function recovery was claimed at 6 mo, with a significant advantage in the LR group (P = 0.001). No clinical difference was found in HRQoL during the 12 mo. CONCLUSION: Our results demonstrated that LR resulted in better outcomes, including intra-operative blood loss, surgery-related complications, course of recovery, and especially some health domains of HRQoL at least within 6 mo postoperatively. Patients should undergo LR if there is no contraindication.

Solving Patient Allocation Problem during an Epidemic Dengue Fever Outbreak by Mathematical Modelling.

Dengue fever is a mosquito-borne disease that has rapidly spread throughout the last few decades. Most preventive mechanisms to deal with the disease focus on the eradication of the vector mosquito and vaccination campaigns. However, appropriate mechanisms of response are indispensable to face the consequent events when an outbreak takes place. This study applied single and multiple objective linear programming models to optimize the allocation of patients and additional resources during an epidemic dengue fever outbreak, minimizing the summation of the distance travelled by all patients. An empirical study was set in Ciudad del Este, Paraguay. Data provided by a privately run health insurance cooperative was used to verify the applicability of the models in this study. The results can be used by analysts and decision makers to solve patient allocation problems for providing essential medical care during an epidemic dengue fever outbreak.

An Optimized Fractional Grey Prediction Model for Carbon Dioxide Emissions Forecasting.

Because grey prediction does not demand that the collected data have to be in line with any statistical distribution, it is pertinent to set up grey prediction models for real-world problems. GM(1,1) has been a widely used grey prediction model, but relevant parameters, including the control variable and developing coefficient, rely on background values that are not easily determined. Furthermore, one-order accumulation is usually incorporated into grey prediction models, which assigns equal weights to each sample, to recognize regularities embedded in data sequences. Therefore, to optimize grey prediction models, this study employed a genetic algorithm to determine the relevant parameters and assigned appropriate weights to the sample data using fractional-order accumulation. Experimental results on the carbon dioxide emission data reported by the International Energy Agency demonstrated that the proposed grey prediction model was significantly superior to the other considered prediction models.

Arecoline-induced phosphorylated p53 and p21(WAF1) protein expression is dependent on ATM/ATR and phosphatidylinositol-3-kinase in clone-9 cells.

Betel-quid use is associated with liver cancer whereas its constituent arecoline is cytotoxic, genotoxic, and induces p53-dependent p21(WAF1) protein expression in Clone-9 cells (rat hepatocytes). The ataxia telangiectasia mutated (ATM)/rad3-related (ATR)-p53-p21(WAF1) and the phosphatidylinositol-3-kinase (PI3K)-mammalian target of rapamycin (mTOR) pathways are involved in the DNA damage response and the pathogenesis of cancers. Thus, we studied the role of ATM/ATR and PI3K in arecoline-induced p53 and p21(WAF1) protein expression in Clone-9 cells. We found that arecoline (0.5 mM) activated the ATM/ATR kinase at 30 min. The arecoline-activated ATM/ATR substrate contained p-p53Ser15. Moreover, arecoline only increased the levels of the p-p53Ser6, p-p53Ser15, and p-p53Ser392 phosphorylated p53 isoforms among the known isoforms. ATM shRNA attenuated arecoline-induced p-p53Ser15 and p21(WAF1) at 24 h. Arecoline (0.5 mM) increased phosphorylation levels of p-AktSer473 and p-mTORSer2448 at 30-60 min. Dominant-negative PI3K plasmids attenuated arecoline-induced p21(WAF1), but not p-p53Ser15, at 24 h. Rapamycin attenuated arecoline-induced phosphrylated p-p53Ser15, but not p21(WAF1), at 24 h. ATM shRNA, but not dominant-negative PI3K plasmids, attenuated arecoline-induced p21(WAF1) gene transcription. We conclude that arecoline activates the ATM/ATR-p53-p21(WAF1) and the PI3K/Akt-mTOR-p53 pathways in Clone-9 cells. Arecoline-induced phosphorylated p-p53Ser15 expression is dependent on ATM whereas arecoline-induced p21(WAF1) protein expression is dependent on ATM and PI3K. Moreover, p21(WAF1) gene is transcriptionally induced by arecoline-activated ATM.

Heat shock protein A1B 1267 polymorphism is highly associated with risk and prognosis of hepatocellular carcinoma: a case-control study.

We conducted a case-control study to elucidate the role of heat shock protein A1B (HSPA1B) 1267 single nucleotide polymorphism (SNP) on the risk and prognosis of hepatocellular carcinoma (HCC). Subjects enrolled included 150 pairs of sex- and age-matched HCC patients and unrelated controls. Genomic DNA was typed for HSPA1B1267 SNP using polymerase chain reaction with restriction fragment length polymorphism. The frequencies of the HSPA1B P2/P2 genotype and the HSPA1B P2 allele in HCC patients were higher than in unrelated controls (each p = 0.0001). Multivariate analysis identified the following independent risk factors for HCC: HSPA1B P1/P2 genotype (odds ratio [OR], 2.34; 95% confidence interval [CI], 1.07-5.11), HSPA1B P2/P2 genotype (OR, 12.06; 95% CI, 4.43-32.79), hepatitis B surface antigen (HBsAg) (OR, 25.95; 95% CI, 11.88-56.68), and antibodies to hepatitis C virus (anti-HCV) (OR, 70.43; 95% CI, 21.89-226.64). There was an additive interaction between HSPA1B P2 allele carriers and the presence of either HBsAg (synergy index = 2.48) or anti-HCV (synergy index = 1.52). However, as HSPA1B1267 SNP is a silent mutation, it is a surrogate genetic marker for increasing risk of HCC. Our findings indicate that patients with chronic hepatitis B/hepatitis C virus infection who harbor this SNP represent a high-risk group for HCC. They should receive more intensive surveillance for early detection of HCC. Moreover, patients with the HSPA1B P2 allele had significantly longer survival (p = 0.002).The limitations of this study include the unknown functional significance of the HSPA1B1267 polymorphism, the relatively small sample size, the fact that this was not a prospective study of cases and controls, and the questionable generalizability of the findings given the specific ethnic composition of the population studied.

Arecoline-induced growth arrest and p21WAF1 expression are dependent on p53 in rat hepatocytes.

Betel-quid use is associated with the risk of liver cirrhosis and hepatocellular carcinoma and arecoline, the major alkaloid of betel-quid, is hepatotoxic in mice. Therefore, we studied the cytotoxic and genotoxic effects of arecoline in normal rat hepatocytes (Clone-9 cells). Arecoline dose-dependently (0.1-1mM) decreased cell cycle-dependent proliferation while inducing DNA damage at 24h. Moreover, arecoline (1mM)-induced apoptosis and necrosis at 24h. Arecoline dose-dependently (0.1-0.5mM) increased transforming growth factor-beta (TGF-beta) mRNA, gene transcription and bioactivity and neutralizing TGF-beta antibody attenuated arecoline (0.5mM)-inhibited cell proliferation at 24h. Arecoline (0.5mM) also increased p21(WAF1) protein expression and p21(WAF1) gene transcription. Moreover, arecoline (0.5mM) time-dependently (8-24h) increased p53 serine 15 phosphorylation. Pifithrin-alpha (p53 inhibitor) and the loss of the two p53-binding elements in the p21(WAF1) gene promoter attenuated arecoline-induced p21(WAF1) gene transcription at 24h. Pifithrin-alpha also attenuated arecoline (0.5mM)-inhibited cell proliferation at 24h. We concluded that arecoline induces cytotoxicity, DNA damage, G(0)/G(1) cell cycle arrest, TGF-beta1, p21(WAF1) and activates p53 in Clone-9 cells. Moreover, arecoline-induced p21(WAF1) is dependent on p53 while arecoline-inhibited growth is dependent on both TGF-beta and p53.

Betel-quid use is associated with heart disease in women.

BACKGROUND: Betel quid (Areca catechu) is used by approximately 10% of the world population. Betel-quid use is associated with the metabolic syndrome--a risk factor for heart disease. OBJECTIVE: The objective was to test whether betel-quid use is associated with heart disease in adults. DESIGN: Nonpregnant adults aged 20-64 y (n=1932, 52% women) from the nationally representative Nutrition and Health Survey in Taiwan (1993-1996) were studied for independent associations between betel-quid use and heart disease after adjustment for lifestyle factors, age, obesity, diabetes mellitus, hypertension, and concentrations of serum total cholesterol and HDL cholesterol. RESULTS: The prevalence of betel-quid use was higher in men than in women (31% compared with 2.4%; P<0.001). The prevalence of heart disease was not significantly different between men and women (3.3% compared with 2.3%; P=0.12). The prevalence of betel-quid use decreased, whereas the prevalence of heart disease increased, with age. Betel-quid users were younger, drank more, had a lower dietary fruit intake, had a higher Framingham risk score, and had higher serum triacylglycerol concentrations than did the nonusers. At a mean consumption rate of 10 times/d (the third quartile of betel-quid consumption in betel-quid users), betel-quid use was independently associated with the Framingham risk score in subjects without heart disease only if obesity was not included as an adjustment factor (P=0.007). Moreover, the daily rate of betel-quid use was independently associated with prevalent heart disease; the odds ratio associated with a betel-quid consumption rate of 10 times/d was 1.37 (95% CI: 1.1, 1.6; P=0.003) in women. CONCLUSION: Betel-quid use is independently associated with heart disease in women.

Herbal therapy is associated with the risk of CKD in adults not using analgesics in Taiwan.

BACKGROUND: Taiwan has the greatest incidence rate of end-stage renal disease in the world. Several cases of Chinese herb nephropathy were reported in Taiwan. Therefore, we studied the association between herbal therapy and chronic kidney disease (CKD) in Taiwan. STUDY DESIGN: Cross-sectional survey. SETTING & PARTICIPANTS: 1,740 adults in the Nutrition and Health Survey in Taiwan (1993 to 1996). PREDICTOR: Herbal and analgesic therapy. OUTCOMES & MEASUREMENTS: CKD after adjustment for potential confounding variables. RESULTS: Among medication users, prevalences of herbal therapy and analgesic use were 21.6% and 13.2%, respectively. The prevalence of CKD was 9.9%. Participants with CKD were older and had more analgesic use, diabetes, hypertension, and cardiovascular disease. Analgesic use was associated independently and positively with CKD (odds ratio, 2.2; 95% confidence interval, 1.4 to 3.5; P = 0.003) and CKD stage (odds ratio, 2.3; 95% confidence interval, 1.4 to 3.6; P = 0.003). Conversely, herbal therapy was associated independently and positively with CKD (odds ratio, 1.39; 95% confidence interval, 1.2 to 1.7; P = 0.002) and CKD stage (odds ratio, 1.38; 95% confidence interval, 1.1 to 1.7; P = 0.004) only in participants who did not use analgesics. LIMITATIONS: Because this was a cross-sectional study, cause and effect could not be ascertained. CONCLUSIONS: Herbal therapy was associated with CKD in adults in Taiwan who did not use analgesics.

Independent and additive interaction between polymorphisms of tumor necrosis factor α-308 and lymphotoxin α+252 on risk of hepatocellular carcinoma related to hepatitis B.

This case-control study was aimed to assess the effect of genetic variants of tumor necrosis factor (TNF) α-308 and lymphotoxin (LT) α+252 on development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Their gene-gene interaction was also investigated. We enrolled 200 pairs of age- and sex-matched patients with cirrhotic HBV-HCC and unrelated patients with HBV-cirrhosis alone. Polymorphisms of TNFα-308 and LTα+252 were genotyped. Synergy index was used to calculate interaction between the variant genotypes. The results indicated that the frequency distribution of the variant genotypes (TNFα-308 G/A and LTα+252 G/G) in patients with HCC were significantly higher than those in patients with cirrhosis alone. Multivariate analysis indicated that TNFα-308 G/A (odds ratio [OR], 2.34) and LTα+252 G/G (OR, 2.04) were independent risk factors for HCC. By the clinical characteristics of study population, multivariate analysis demonstrated that independent factors associated with harboring the variant genotypes included cirrhosis with Child-Pugh C (OR = 6.47 in cases and OR = 11.56 in controls) and thrombocytopenia (OR = 8.86 in cases and OR = 7.74 in controls). Calculation of synergy index (SI) indicated that there are additive interaction between TNFα-308 G/A and LTα+252 G/G on risk of HCC (SI = 1.29). IN CONCLUSION: There are independent and additive interactions between TNFα-308 G/A and LTα+252 G/G on risk for HBV-HCC. They correlated with advanced hepatic fibrosis and severe liver damage, which might contribute to a higher risk for HCC.

Interactive effects between Lymphotoxin α +252 polymorphism and habits of substance use on risk of hepatocellular carcinoma.

This case-control study aimed to assess the interactive effect between polymorphisms of lymphotoxin (LT) α +252 and habitual substance use on risk of hepatocellular carcinoma (HCC). We enrolled 150 pairs of sex- and age-matched HCC patients and unrelated healthy controls. LTα genotypes were detected with polymerase-chain reaction and restrictive fragment length polymorphisms. Information about habits of substance use was obtained through personal interview. Multivariate analysis indicated that LTα +252 G/G genotypes [odds ratio (OR) = 3.36], Hepatitis B surface antigen (OR = 16.68), antibodies to hepatitis C virus (OR = 34.88) and having at least two habits of substance use (OR = 2.50) were independent risk factors for HCC. There were additive interactions among LTα +252 G/G genotype, chronic viral hepatitis, and habit of each substance use. IN CONCLUSION: There are independent and additive interactions between LTα +252 G/G genotype, chronic viral hepatitis, and habits of substance use on risk of HCC.

Prevalence and clinical significance of HGV/GBV-C infection in patients with chronic hepatitis B or C.

Hepatitis G virus/GB virus-C (HGV/GBV-C) is a newly identified Flavivirus. Its clinical significance in chronic hepatitis B and C remains controversial. Infection with HGV/GBV-C was surveyed in 500 blood donors, 130 patients with chronic hepatitis B and 173 with hepatitis C, with chronic liver disease, cirrhosis, and/or hepatocellular carcinoma (HCC). HGV/GBV-C RNA was detected by reverse transcription-polymerase chain reaction. An antibody to HGV/GBV-C's second envelope protein (anti-E2 Ab) was detected using an enzyme immunoassay. The prevalence of HGV/GBV-C RNA was 3.4% and the exposure rate 10.2% in blood donors. The prevalence of HGV/GBV-C RNA in patients with chronic hepatitis B and hepatitis C was 7.7 and 17.3%, respectively (P = 0.002). The prevalence of the HGV/GBV-C infection in hepatitis B carriers increased with the severity of chronic liver disease and risk of HCC. The age and duration of hepatitis B virus infection were the more important contributing factors. Clinical and virological characteristics were comparable between those with and without coinfection of HGV/GBV-C and hepatitis C. The seroconversion rate was high. Coinfection of HGV/GBV-C with hepatitis B or C does not affect disease severity, but accelerates the progression of chronic liver disease and the development of HCC.

High versus standard doses interferon-alpha in the treatment of naïve chronic hepatitis C patients in Taiwan: a 10-year cohort study.

BACKGROUND: Interferon-alpha monotherapy is effective in less than one-third patients with chronic hepatitis C. The dose-effect, tolerability and durability of interferon-alpha treatment and its long-term effect on the prevention of cirrhosis and hepatocellular carcinoma in naive Taiwanese patients with chronic hepatitis C have not been well investigated. We conducted the present cohort study treated with high and standard interferon-alpha to illustrate the issues. METHODS: We performed a long-term virologic and histological follow-up of 214 chronic hepatitis C patients treated with interferon-alpha, 3 million units (3-MU, n = 80) or 6-MU (n = 134) thrice weekly for 24 weeks, in Taiwan between 1992 and 2001. RESULTS: There was no difference in the incidence of discontinuation between 3-MU and 6-MU groups (4/80, 5.0% versus 10/134. 7.5%). The 6-MU group had similar incidence of adverse events with the 3-MU group, except that 6-MU group had significantly higher incidence of psychological manifestations, mainly presented as irritability. The rates of sustained virological response (SVR) were significantly higher in 6-MU regimen (37.1%) than in 3-MU regimen (23.7%, p < 0.05) in per protocol analysis. Based on multivariate analysis, baseline viral load was strongly associated with SVR, followed by hepatitis C virus genotype, interferon-alpha regimen, and liver fibrosis. A histological improvement in necroinflammatory activity, but not in fibrosis was observed in the follow-up biopsy performed 0.5-5.5 years (mean: 1.9 years, n = 51) after end-of-treatment. Among patients without SVR, there was more activity improvement in 6-MU group. The durability of SVR was 100% (18/18) and 97.8% (45/46) for 3-MU and 6-MU group, respectively, in a mean follow-up period of 6.81 years (5.25-9.18 years). For 163 baseline non-cirrhotic patients, 9 of 84 (10.7%) non-responders and 3 of 79 (3.8%) sustained responders progressed to cirrhosis during a mean follow-up period of 5.52 and 5.74 years, respectively (p = 0.067, Kaplan-Meier survival analysis, log-rank test). For all 200 patients, hepatocellular carcinoma was detected in 12 of 113 (10.6%) non-responders and one of 87 (1.1%) sustained responders during a mean follow-up period of 5.67 and 5.73 years, respectively (p < 0.01, Kaplan-Meier survival analysis, log-rank test). CONCLUSION: We confirm the dose effect of interferon-alpha in chronic hepatitis C. Six-MU regimen had better efficacy than 3-MU regimen in virologic and histological responses. Both regimens had good tolerability and durability in Taiwan. Sustained response could reduce the incidence of cirrhotic change and hepatocarcinogenesis.

Safety of fine-needle aspiration in patients with small hepatocellular carcinoma.

OBJECTIVE.: This study was to clarify the safety of fine-needle aspiration of small hepatocellular carcinoma (HCC). METHODS.: Ninety consecutive patients with small hepatocellular carcinoma (46 with single nodule, 44 with multiple nodules, all

Habitual betel quid chewing and risk for hepatocellular carcinoma complicating cirrhosis.

This case-control study aimed to assess the independent and interactive role of habitual betel quid chewing and known risk factors for hepatocellular carcinoma (HCC). Subjects enrolled included 210 pairs of sex- and age-matched cirrhotic patients with HCC, patients with cirrhosis alone, and healthy controls. Information on risk factors was obtained through serologic examination of hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (anti-HCV), and a standardized personal interview with a structured questionnaire. Multivariate analysis indicated that betel quid chewing (odds ratio [OR], 5.81; 95% confidence interval [CI], 2.26-14.94); HBsAg (OR, 37.98; 95% CI, 19.65-73.42); and anti-HCV (OR, 47.23; 95% CI, 18.86-118.25) were independent risk factors for HCC when HCC patients were compared with healthy controls. Using patients with cirrhosis alone as a reference group, multivariate analysis indicated that only betel quid chewing (OR, 1.69; 95% CI, 1.04-2.76) and HBsAg (OR, 1.54; 95% CI, l.01-2.37) were independent risk factors for HCC. There was an additive interaction between betel quid chewing and the presence of either HBsAg (synergy index, 5.22) or anti-HCV (synergy index, 1.35). Moreover, a higher risk of HCC was associated with a longer duration of betel quid chewing and a larger amount of betel quid consumed (each p(for trend) < 0.0001). In conclusion, betel quid chewing is an independent risk factor for cirrhotic HCC. There is an additive interaction between betel quid chewing and chronic hepatitis B and/or hepatitis C virus infection.