Discovery of an Orally Efficacious MYC Inhibitor for Liver Cancer Using a GNMT-Based High-Throughput Screening System and Structure-Activity Relationship Analysis.

Glycine-N-methyl transferase (GNMT) downregulation results in spontaneous hepatocellular carcinoma (HCC). Overexpression of GNMT inhibits the proliferation of liver cancer cell lines and prevents carcinogen-induced HCC, suggesting that GNMT induction is a potential approach for anti-HCC therapy. Herein, we used Huh7 GNMT promoter-driven screening to identify a GNMT inducer. Compound K78 was identified and validated for its induction of GNMT and inhibition of Huh7 cell growth. Subsequently, we employed structure-activity relationship analysis and found a potent GNMT inducer, K117. K117 inhibited Huh7 cell growth in vitro and xenograft in vivo. Oral administration of a dosage of K117 at 10 mpk (milligrams per kilogram) can inhibit Huh7 xenograft in a manner equivalent to the effect of sorafenib at a dosage of 25 mpk. A mechanistic study revealed that K117 is an MYC inhibitor. Ectopic expression of MYC using CMV promoter blocked K117-mediated MYC inhibition and GNMT induction. Overall, K117 is a potential lead compound for HCC- and MYC-dependent cancers.

Analysis of risk factors of bladder neck contracture following transurethral surgery of prostate.

BACKGROUNDS: The aim of the present study was to investigate the perioperative parameters associated with bladder neck contracture (BNC) after transurethral surgery of the prostate and to compare the incidence of BNC after transurethral resection of the prostate (TURP) or Thulium vaporesection (resection group) versus Thulium vapoenucleation or enucleation of the prostate (enucleation group). METHODS: Between March 2008 and March 2020, 2363 patients received TURP and 1656 patients received transurethral surgery of the prostate with Thulium laser (ThuP) at Mackay Memorial Hospital. A total of 62 patients developed BNC. These BNC patients were age-and operation-matched to 124 randomly sampled TURP/ThuP controls without BNC. A 1:1 propensity score matching model was used to evaluate the difference in incidence of BNC. RESULTS: Our study demonstrated that a greater proportion of BNC patients had history of cerebrovascular accidents (11/62 vs. 7/124, p = 0.009), coronary artery disease (14/48 vs. 16/108, p = 0.03), chronic kidney disease (14/62 vs. 11/124, p = 0.01), and two or more comorbidities (29/62 vs. 27/124, p = 0.001) compared with NBNC patients. Multivariate analysis showed that smaller prostate volume (OR 0.96 (0.94-0.99), p = 0.008) and recatherization (OR 5.6 (1.02-30.6), p = 0.047) were significantly associated with BNC. A ROC curve predicted that a prostate volume < 42.9 cm3 was associated with a notably higher rate of BNC. The propensity score matching model reported there was no difference in incidence between resection and enucleation groups. CONCLUSION: This study demonstrated that incidence of BNC was the same in different surgical techniques and that low prostate volume, recatherization and ≥ 2 comorbidities were positively correlated with the development of BNC after TURP or ThuP.

Preoperative treatment with 5α-reductase inhibitors and the risk of hemorrhagic events in patients undergoing transurethral resection of the prostate - A population-based cohort study.

OBJECTIVES: To assess the associations between preoperative treatment with 5-alpha reductase inhibitors and the risks of blood transfusion during transurethral resection of the prostate and blood clot evacuation or emergency department visits for hematuria within 1 month after surgery. METHODS: We used data from the Taiwan National Health Insurance Research Database in this population-based cohort study. A total of 3,126 patients who underwent first-time transurethral resection of the prostate from 2004 to 2013 were identified. Adjusted odds ratios estimated by multiple logistic regression models were used to assess the independent effects of the preoperative use of 5-alpha reductase inhibitors on the risks of perioperative hemorrhagic events after adjustment for potential confounders. RESULTS: Two hundred and ninety-seven (9.4%) patients were treated with 5-alpha reductase inhibitors for <3 months, and 65 (2.1%) patients were treated for ≥3 months prior to undergoing transurethral resection of the prostate. The blood transfusion rates for patients who were not treated with 5-alpha reductase inhibitors (controls), patients who were treated with 5-alpha reductase inhibitors for <3 months, and patients who were treated with 5-alpha reductase inhibitors ≥3 months were 9.5%, 8.8%, and 3.1%, respectively. 5-alpha reductase inhibitors tended to decrease the risk of blood transfusion; however, this association was not statistically significant (adjusted odds ratio=0.14, 95% confidence interval: 0.02-1.01). Age ≥80 years, coagulopathy, and a resected prostate tissue weight >50 g were associated with significantly higher risks of blood transfusion than other parameters. CONCLUSIONS: This nationwide study did not show that significant associations exist between 5-alpha reductase inhibitor use before transurethral resection of the prostate and the risks of blood transfusion and blood clot evacuation or emergency visits for hematuria.

Gynura divaricata attenuates tumor growth and tumor relapse after cisplatin therapy in HCC xenograft model through suppression of cancer stem cell growth and Wnt/ß-catenin signalling.

ETHNOPHARMACOLOGICAL RELEVANCE: Gynura divaricata subsp. formosana is a widely used traditional herbal medicine for treating liver disorders such as hepatitis and liver cancer in Taiwan. AIM OF THE STUDY: This study was aimed to evaluate the anti-cancer and cancer stabilization effect of water extract of the aerial part of G. divaricata (GD extract) both in vitro and in vivo. MATERIALS AND METHODS: Cytotoxicity and anti-proliferative effects of GD extract alone and in combination with cisplatin were determined by alamarBlue and clonogenic assay. Cancer stem cell (CSC) inhibition and the expression of CSC markers were revealed by sphere formation assay and real-time PCR (qPCR). The in vivo anti-cancer effect of GD extract was evaluated in Huh7 xenograft mice model and Ki-67 expression were also measured. The activity of Wnt signalling and the expression level of Wnt target genes and ß-catenin were determined by luciferase reporter assay, qPCR, immunoblotting and IHC. RESULTS: Moderate cytotoxicity of GD extract in liver cancer cells was observed. GD extract sensitized Huh7 cells to cisplatin treatment. Interestingly, GD extract inhibited cancer sphere formation and reduced the expression of CSC markers. Importantly, GD extract suppressed Huh7 tumor growth, Ki-67 expression and prolonged the anti-liver cancer effect of cisplatin in vivo. Treatment of GD extract resulted in reductions of Wnt reporter activity and the expression of Wnt target genes. Moreover, suppression of ß-catenin were observed in both GD extract treated Huh7 spheres and xenograft tumors. CONCLUSION: Accordingly, our findings suggest that G. divaricata may target liver CSC by suppressing the Wnt pathway and the combination of G. divaricata and cisplatin could be a candidate regimen for treating HCC.

Zerumbone Regulates DNA Repair Responding to Ionizing Radiation and Enhances Radiosensitivity of Human Prostatic Cancer Cells.

INTRODUCTION: Radiation therapy using ionizing radiation is widely used for the treatment of prostate cancer. The intrinsic radiation sensitivity of cancer cells could be enhanced by modulating multiple factors including the capacity to repair DNA damage, especially double-strand breaks (DSBs). We aimed to examine the effect of zerumbone on radiation sensitivity and its protective effects against ionizing radiation-induced DSB in human prostate cancer cells. MATERIALS AND METHODS: The human prostate cancer PC3 and DU145 cell lines were used. A colony formation assay was performed to analyze the radiation survival of cells. DNA histogram and generation of reactive oxygen species (ROS) were examined using flow cytometry. Western blotting was used to examine the expression of regulatory molecules related to DNA damage repair. RESULTS: Pretreatment with zerumbone enhanced the radiation effect on prostate cancer cells. Zerumbone delayed the abrogation of radiation-induced expression of γ-H2AX, an indicator of DNA DSB. Zerumbone pretreatment markedly reduced ionizing radiation-induced upregulated expression of phosphorylated ATM (ataxia telangiectasia-mutated), which was partially reversed by the ATM agonist methyl methanesulfonate. Ionizing radiation augmented and zerumbone pretreatment reduced the expression of Jak2 and Stat3, which are involved in DNA damage repair signaling. No significant effect on the generation of ROS and expression of ATR was noted after zerumbone treatment. CONCLUSION: Zerumbone sensitized DU145 and PC3 prostatic cancer cells to ionizing radiation by modulating radiation-induced ATM activation during repair of DNA DSBs.

Preoperative treatment with 5α-reductase inhibitors and the risk of hemorrhagic events in patients undergoing transurethral resection of the prostate - A population-based cohort study

OBJECTIVES: To assess the associations between preoperative treatment with 5-alpha reductase inhibitors and the risks of blood transfusion during transurethral resection of the prostate and blood clot evacuation or emergency department visits for hematuria within 1 month after surgery. METHODS: We used data from the Taiwan National Health Insurance Research Database in this population-based cohort study. A total of 3,126 patients who underwent first-time transurethral resection of the prostate from 2004 to 2013 were identified. Adjusted odds ratios estimated by multiple logistic regression models were used to assess the independent effects of the preoperative use of 5-alpha reductase inhibitors on the risks of perioperative hemorrhagic events after adjustment for potential confounders. RESULTS: Two hundred and ninety-seven (9.4%) patients were treated with 5-alpha reductase inhibitors for <3 months, and 65 (2.1%) patients were treated for ≥3 months prior to undergoing transurethral resection of the prostate. The blood transfusion rates for patients who were not treated with 5-alpha reductase inhibitors (controls), patients who were treated with 5-alpha reductase inhibitors for <3 months, and patients who were treated with 5-alpha reductase inhibitors ≥3 months were 9.5%, 8.8%, and 3.1%, respectively. 5-alpha reductase inhibitors tended to decrease the risk of blood transfusion; however, this association was not statistically significant (adjusted odds ratio=0.14, 95% confidence interval: 0.02-1.01). Age ≥80 years, coagulopathy, and a resected prostate tissue weight >50 g were associated with significantly higher risks of blood transfusion than other parameters. CONCLUSIONS: This nationwide study did not show that significant associations exist between 5-alpha reductase inhibitor use before transurethral resection of the prostate and the risks of blood transfusion and blood clot evacuation or emergency visits for hematuria.

Concomitant transrectal ultrasound-guided biopsy and transurethral resection of prostate in patients with urinary retention and elevated serum prostate-specific antigen levels.

BACKGROUND: There was no consensus about the management of patients with urinary retention and elevated serum prostate-specific antigen (PSA) levels. This study aimed to determine whether concomitant transrectal ultrasound (TRUS)-guided biopsy and transurethral resection of prostate (TURP) is practical in patients with urinary retention and elevated serum PSA levels. METHODS: From March 2007 to May 2015, a total of 34 patients with urinary retention and elevated PSA (≥ 4 ng/mL) underwent concomitant TRUS-guided biopsy and TURP. The medical records were evaluated retrospectively, and data including PSA, prostate volume, TURP results, TRUS-guided biopsy results, length of hospitalization, and complications were collected. These patients were then compared with 40 patients with urinary retention who underwent TURP alone. RESULTS: The mean age of the patients was 71.6 years. The mean PSA levels were 16.9 ng/mL. Prostate cancer was detected in eight cases (23.5%): one case by TRUS-guided biopsy alone, two cases by TURP alone, and five cases by both TRUS-guided biopsy and TURP. Complications included fever in five patients (14.7%), recatheterization for urine retention in two patients (5.9%), urinary tract infection in two patients (5.9%), and de novo urge incontinence in seven patients (20.6%). The complication rate was not significantly increased compared with that of the patients who underwent TURP alone. CONCLUSION: This study showed that concomitant TRUS-guided biopsy and TURP was safe and of possible clinical significance in urinary retention patients with elevated serum PSA.

Risk factors for HIV-1 seroconversion among Taiwanese men visiting gay saunas who have sex with men.

BACKGROUND: Men having sex with men (MSM) accounts for 33.6% of all reported cases of HIV-1 infection in Taiwan. The aim of this study was to investigate the epidemiology of HIV-1 infection among MSM in gay saunas in Taiwan. METHODS: Patrons of 5 gay saunas were recruited for a weekly volunteer counseling and testing program from 2001 to 2005. Questionnaires were collected for a risk factor analysis. HIV-1 subtypes were determined using DNA sequencing and phylogenetic analyses. RESULTS: HIV-1 prevalence rates among MSM in gay saunas in 2001 through 2005 were 3.4%, 5.1%, 8.9%, 8.5%, and 8.3%, respectively. In total, 81 of 1, 093 (7.4%) MSM had HIV-1 infection. Fifty-two HIV-1 strains were genotyped, and all of them were subtype B. HIV-seropositive men were significantly younger than the seronegatives. Only 37.1% used condoms every time during sexual intercourse. A multivariate logistic regression analysis showed that the risk factors for HIV-1 were being uncircumcised (odds ratio (OR) = 2.19; 95% confidence interval (CI), 1.08~4.45); having sexual intercourse with at least 2 partners during each sauna visit (≥ 2 vs. ≤ 1, OR = 1.71; 95% CI, 1.02~2.89); and the role played during anal intercourse (versatile vs. an exclusively insertive role, OR = 2.76; 95% CI, 1.42~5.36). CONCLUSIONS: Overall, 7.4% Taiwanese MSM participating in this study had HIV-1 subtype B infection. Uncircumcised, being versatile role during anal intercourse, and having sex with more than one person during each sauna visit were main risk factors for HIV-1 infection.

Gyrus plasmasect: is it better than monopolar transurethral resection of prostate?

INTRODUCTION: This randomized prospective study was conducted to compare the efficacy and safety of the Gyrus Plasmasect loop bipolar transurethral resection of prostate (TURP) and conventional monopolar TURP in the treatment of benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: A total of 117 men were enrolled in this study. Fifty-eight patients underwent Gyrus Plasmasect TURP and 59 patients underwent monopolar TURP. They were followed up for 3 months after surgery. RESULTS: Significant improvements were seen postoperatively in both the Gyrus and monopolar groups in terms of prostatic volume, International Prostate Symptom Score, quality of life score, peak flow rate, and post-void residual urine volume. However, the degree of improvement was not statistically different between the 2 groups. Significantly less blood loss, shorter postoperative catheterization time and length of hospital stay were seen in the Gyrus group. CONCLUSIONS: Gyrus Plasmasect TURP yielded comparable results to monopolar TURP; however, this is only a preliminary study and follow-up is necessary to assess its long-term efficacy.