Un-methylation of NUDT21 represses docosahexaenoic acid biosynthesis contributing to enzalutamide resistance in prostate cancer.

AIMS: The recent approval of enzalutamide for metastatic castration-sensitive prostate cancer underscores its growing clinical significance, raising concerns about emerging resistance and limited treatment options. While the reactivation of the androgen receptor (AR) and other genes plays a role in enzalutamide resistance, identifications of novel underlying mechanism with therapeutic potential in enzalutamide-resistant (EnzaR) cells remain largely elusive. METHODS: Drug-resistant prostate cancer cell lines, animal models, and organoids were utilized to examine NUDT21 function by transcriptomic and metabolomic analyses through loss-of-function and gain-of-function assays. Notably, a mono-methylation monoclonal antibody and conditional-knockin transgenic mouse model of NUDT21 were generated for evaluating its function. RESULTS: NUDT21 overexpression acts as a crucial alternative polyadenylation (APA) mediator, supported by its oncogenic role in prostate cancer. PRMT7-mediated mono-methylation of NUDT21 induces a shift in 3'UTR usage, reducing oncogenicity. In contrast, its un-methylation promotes cancer growth and cuproptosis insensitivity in EnzaR cells by exporting toxic copper and suppressing docosahexaenoic acid (DHA) biosynthesis. Crucially, NUDT21 inhibition or DHA supplementation with copper ionophore holds therapeutic promise for EnzaR cells. CONCLUSIONS: The un-methylation of NUDT21-mediated 3'UTR shortening unveils a novel mechanism for enzalutamide resistance, and our findings offer innovative strategies for advancing the treatment of prostate cancer patients experiencing enzalutamide resistance.

Association between chronic prostatitis and the subsequent benign prostatic hyperplasia: a population-based national cohort study.

PURPOSE: To explore the association between chronic prostatitis (CP) and the subsequent development of benign prostatic hyperplasia (BPH). METHODS: Data analyzed were medical claims of Taiwan's National Health Insurance program. From 2010 to 2017, 3571 patients ≧20 years with CP diagnosed by certified urologists were enrolled. Patients with past BPH diagnosis and diagnosis of prostate cancer, inguinal hernia, interstitial cystitis, and urethritis in the past and within one year after the first CP diagnosis were excluded. Age-matched controls were randomly selected from all non-CP individuals of the same exclusion criteria in the study period with a CP/non-CP ratio of 1:4. The follow-up was made from the first CP diagnosis to death or the end of 2018. The endpoint was the newly diagnosed BPH. Cox proportional hazard regression model was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of BPH in association with CP. RESULTS: Over a maximum of 8 years of follow-up, 287 (8.03%) and 258 (0.43%) BPH events were noted for the CP and non-CP group, respectively, representing a covariate adjusted HR (aHR) of 4.30 (95% CI, 3.61-5.13). Younger patients tended to suffer from higher aHRs, especially those aged 20-39 years (aHR: 11.45, 95% CI, 5.12-25.64). CONCLUSION: The Taiwan national health database indicated that CP patients had a significantly higher risk of developing BPH later than non-CP patients. Interestingly, the younger the CP is diagnosed (under 40), the greater the risk.

Therapeutic efficacy of 180-W GreenLight laser photoselective vaporization of the prostate for storage symptoms concomitant with benign prostatic obstruction and a search for outcome predictors.

PURPOSE: Benign prostatic obstruction (BPO) is the most common cause of lower urinary tract symptoms among men. GreenLight photoselective vaporization of the prostate (GL-PVP) using a 180-W Xcelerated performance system (XPS) laser is a well-established method for treating BPO-induced voiding symptoms. However, its therapeutic effects on storage symptoms remain unclear. This study aimed to analyze the storage outcomes in patients who underwent 180-W XPS GL-PVP for BPO and to identify outcome predictors. MATERIALS AND METHODS: Patients who underwent 180-W XPS GL-PVP for BPO between May 2018 and May 2021 were retrospectively reviewed. Data on clinical characteristics, prostate volume, preoperative and postoperative International Prostate Symptom Scores (IPSS), and preoperative urodynamic parameters were collected. A favorable storage outcome was defined as ≥50% reduction in the IPSS storage subscore. RESULTS: Ninety-nine male patients were included, with a mean age of 69.4 ± 9.6 years and a baseline prostatic volume of 75.9 ± 33.1 mL. The IPSS total, storage, and voiding subscores significantly decreased after GL-PVP (all p < 0.001). Seventy-two patients achieved favorable storage outcome at 6 months. Multivariate analysis revealed that detrusor underactivity was predictive of unfavorable storage outcomes (p = 0.022), while IPSS voiding-to-storage subscore ratio >1.25 and the presence of detrusor overactivity were predictive of favorable storage outcomes (p = 0.008 and 0.033, respectively). CONCLUSION: 180-W XPS GL-PVP provided excellent outcomes in both voiding and storage lower urinary tract symptoms concomitant with BPO. Preoperative IPSS and multichannel urodynamic parameters including detrusor overactivity and underactivity are valuable predictors of postoperative storage outcomes.

lncRNA TMEM161B-AS1 screened the onset of oral squamous cell carcinoma in HPV-infected patients, predicted poor prognosis, and regulated cell progression via modulating the miR-651-5p/BDNF axis.

Oral squamous cell carcinoma (OSCC) has become the most common HPV-related cancer with high invasion and metastasis. Exploring biomarkers for the screening and monitoring of OSCC, especially for the HPV-OSCC, would benefit patients' diagnosis and prognosis. This study evaluated the significance and mechanism of TMEM161B-AS1 and miR-651-5p in HPV-OSCC aiming to provide novel insight into the mechanism of HPV-OSCC development. Expression of TMEM161B-AS1 and miR-561-5p was analyzed in healthy individuals, HPV-infected non-OSCC patients, and HPV-OSCC patients using PCR. Their significance in HPV-OSCC occurrence and prognosis was evaluated by logistic regression, ROC, Kaplan-Meier, and Cox regression analysis. In OSCC cells, CCK8 and Transwell assays were employed for assessing cell growth and metastasis. The luciferase reporter assay and cell transfection were performed to evaluate the regulatory association between TMEM161B-AS1, miR-561-5p, and BDNF. Significant upregulation of TMEM161B-AS1 and downregulation of miR-561-5p were observed in oral HPV-infected patients. Both TMEM161B-AS1 and miR-651-5p served as risk factors for the occurrence of OSCC in oral HPV-infected patients and could distinguish HPV-OSCC patients from HPV-infected non-OSCC patients. Increased TMEM161B-AS1 and reduced miR-561-5p indicated severe development and adverse prognosis of HPV-OSCC patients. In OSCC cells, silencing TMEM161-AS1 suppressed cell proliferation and motility via negatively modulating miR-561-5p. miR-561-5p negatively regulated BDNF, which was considered the underlying mechanism of TMEM161B-AS1. Increasing TMEM161B-AS expression and decreasing miR-561-5p showed the occurrence of OSCC in HPV-infected patients and predicted malignant development and adverse prognosis. TMEME161B-AS1 served as a tumor promoter via regulating the miR-561-5p/BDNF axis.

The sufficient multidisciplinary specialists under a government-led health care system associated with the downward mortality trend of Fournier's gangrene in Taiwan.

OBJECTIVES: To explore the trends in Fournier's gangrene (FG) incidence and mortality rate in Taiwan and to investigate the contributing factors to such changes. METHODS: Between 2002 and 2016, hospitalized FG patients who underwent subsequent surgical intervention were included in this retrospective study. Incidence, outcomes, age-adjusted Charlson Comorbidity Index (ACCI), hospitalization cost, surgical timing, and the number of multidisciplinary specialists involved in the first-line management of FG in each year were collected. Simple linear regression and Pearson correlation coefficient (r) were used for the subsequent analysis. RESULTS: The national cohort enrolled 2183 FG patients from 2002 to 2016 in Taiwan. The age-standardized incidence rate of FG was between 0.4 and 0.8 per 100 000 population, and overall mortality was 7.8% in these 15 years. We illustrated the downward trendline of FG mortality with a 0.62 coefficient of determination. The mortality of FG patients who underwent surgery within 24 h and after 24 h were found to be 8.3 ± 3.9% and 14.6 ± 25.2%, respectively (p = 0.02). The numbers of urologists, anesthesiologists, emergency doctors, and physicians per 100 000 population had a strong negative linear correlation with FG mortality (r = 0.8, p < 0.001). ACCI score had a moderate linear relationship with FG mortality (r = 0.57, p = 0.027). The hospitalization cost showed a weak linear correlation with FG mortality (r = -0.03, p = 0.92). CONCLUSIONS: We demonstrated the downward trend of the FG mortality rate in Taiwan from 2002 to 2016. Besides underlying comorbidities and surgical timing, sufficient multidisciplinary specialists are essential for the survival benefit of FG patients in Taiwan experience.

Influence of inflammation on bleeding and wound healing following surgical extraction of impacted lower third molars.

OBJECTIVE: This study aimed to investigate the effect of inflammatory states following impacted lower third molar (ILTM) surgery regarding postoperative bleeding and wound healing. METHODS: The study included patients who underwent extraction of ILTMs associated with or without inflammatory conditions. Post-extraction bleeding and wound healing were assessed. In addition, mean grey values (MGVs) of alveolar bone and bone height using an orthopantomography radiograph were analyzed. RESULTS: A total of 376 patients were enrolled; 171 pericoronitis, 51 pulpitis, 44 chronic periapical periodontitis, 36 chronic periodontitis, and 74 control. The bleeding score in the control group was significantly lower than in the periapical periodontitis and periodontitis groups. Excellent wound healing for control, pericoronitis, pulpitis, periapical periodontitis, and periodontitis groups was (78.38%, 35.67%, 70.59%, 70.45%, and 33.33%, respectively). Patients with pericoronitis and periodontitis had significantly poorer wound healing (P < 0.01). The MGV in periapical periodontitis and periodontitis was considerably lower than in the control group. CONCLUSIONS: The inflammatory conditions associated with ILTMs increase the risk of bleeding. So suturing with the placement of local hemostatic agents over a pressure pack alone is recommended. The poorest wound healing was in localized gingival inflammation. Furthermore, MGV was affected by age and was lower with periapical periodontitis.

Circadian clock gene Clock-Bmal1 regulates cellular senescence in Chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disease. COPD is associated with accelerated lung aging. Circadian clock is believed to play important roles in COPD. Although the circadian molecular clock regulates cellular senescence, there is no information available regarding the impact of COPD. The aim of this study is to investigate the role of the circadian clock protein BMAL1 and CLOCK in cellular senescence in order to understand the cellular mechanisms of accelerated aging of COPD. Bmal1 and Clock levels were assessed in the plasma samples of non-smokers, smokers, and patients with COPD. The regulation of ciracadian clock expression and cell senescence by cigarette smoke extract (CSE) was studied in vitro, and small interfering RNA (siRNA) and overexpression of Bmal1 or Clock were employed to investigate the role of circadian clock on cell senescence. Herein, patients with COPD showed lower Bmal1 and Clock expression in the plasma. Interestingly, CSE exposure contributed to the increased cell senescence, decreased Clock and Bmal1 in human bronchial epithelial cells (Beas-2B cells). We found that knockdown of Clock or Bmal1 lead to upregulation of cell senescence in Beas-2B cells, while overexpression of Clock or Bmal1 inhibited cell senescence in Beas-2B cells, which is through the MAPK pathways. Therefore, our findings indicated that Bmal1 or Clock deficiency may be a significant factor to increase cellular senescence of the lung to develop COPD.

Incorporating sperm DNA fragmentation index with computer-assisted semen morphokinematic parameters as a better window to male fertility.

This study aimed to assess (1) the reproducibility of three sperm chromatin dispersion (SCD) assays for sperm DNA fragmentation, i.e., LensHooke R10® (R10), Halosperm G2® (G2), and BASO® (BA); (2) the correlation between computer-assisted semen analyzer (CASA) morphokinematic parameters and sperm DNA fragmentation index (DFI), and (3) the diagnostic value for male reproduction by combining semen morphokinematic parameters and DFI. Total 50 male participants were recruited, and all collected semen samples underwent semen analyses and SCD assays. Intra- and inter-observer variability of DFI data from different SCD measures was tested. In addition, the predictive ability of CASA parameters and DFI (with different cutoffs, i.e., 15% and 20%) for infertility was assessed using receiver operating characteristic curve analysis. We found that the G2 and R10 produced satisfactory variance coefficients (5.53%, 5.67%) compared to BA (14.8%). The DFI data from the R10 had lower intra-observer variability, in terms of higher intra-class coefficient (0.9615), than that of the G2 (0.8847) or BA (0.8824). Inter-observer variability of three SCD kits in scoring the DFI was comparable and satisfactory (concordance correlation coefficients ranging 0.9895-0.9630). The CASA parameters (i.e., total motility [r = -0.57], progression motility [r = -0.55], and rapidly progressive motility [r = -0.55]) were significantly correlated with DFI (P < 0.001). The predictive ability of the 15%-cutoff DFI data was better than that of the 20%-cutoff or continuous DFI data. The model comprising the CASA parameters, 15%-cutoff DFI, and 4%-cutoff normal morphology had the highest area under curve (0.8125) for infertility. For SCD assay, the R10 was the most reliable SCD assay to detect sperm DNA fragmentation. Combining the sperm DFI with CASA parameters might be a better diagnostic tool for male reproduction.

Glucagon-like peptide-1 (GLP-1) mediates the protective effects of dipeptidyl peptidase IV inhibition on pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a progressive disease leading to death ultimately. Our recently published data demonstrated that inhibiting dipeptidyl peptidase IV (DPP-4) alleviated pulmonary vascular remodeling in experimental PH. However, whether glucagon-like peptide-1 (GLP-1) mediated the protective effect of DPP-4 inhibition (DPP-4i) on PH is unclear. RESULTS: In the present study, GLP-1 receptor antagonist (exendin-3) abolished the protective effects of DPP-4 inhibitor (sitagliptin) on right ventricular systolic pressure (RVSP) and pulmonary vascular remodeling (PVR) in monocrotaline (MCT, 60 mg/kg)-induced PH in rat. Notably, activation of GLP-1 receptor by GLP-1 analogue liraglutide directly attenuated RVSP and PVR in MCT-induced PH, as well as bleomycin- and chronic hypoxia-induced PH. Moreover, liraglutide potently inhibited MCT-induced inflammation and suppressed MCT-induced down-regulation of vascular endothelial marker (VE-cadherin and vWF) in lung. In vitro studies showed liraglutide reversed TGF-ß1 (5 ng/ml) combining IL-1ß (5 ng/ml) induced endothelial-mesenchymal transition (EndMT) in human umbilical vein endothelial cells (HUVECs), which could be abolished by GLP-1 receptor antagonist (exendin-3). Furtermore, liraglutide suppressed TGF-ß1-IL-1ß-induced phosphorylation of both Smad3 and ERK1/2. CONCLUSIONS: Our data suggest that GLP-1 mediated the protective effects of DPP-4i on pulmonary vascular and RV remodeling in experimental PH, which may be attributed to the inhibitory effect on EndMT.

Fasudil dichloroacetate (FDCA), an orally available agent with potent therapeutic efficiency on monocrotaline-induced pulmonary arterial hypertension rats.

Given the therapeutic efficacy of fasudil hydrochloride (F) and dichloroacetate (DCA) on pulmonary arterial hypertension (PAH), a new salt fasudil dichloroacetate (FDCA) was designed, synthesized and biologically evaluated. FDCA exhibited comparable ROCK II inhibitory activity relative to fasudil hydrochloride, and suppressed the expression of TNF-α and IL-6 in both PDGF-BB and hypoxia-treated pulmonary arterial smooth muscle cells (PASMCs) and endothelial cells (PAECs). Significantly, FDCA lowered mean pulmonary artery pressure (mPAP) and right ventricular systolic pressure (RVSP), and decreased right ventricular hypertrophy (RVH) in monocrotaline (MCT)-induced PAH rats. Meanwhile, FDCA remarkably decreased pulmonary artery medial thickness (PAMT) and hyperplasia, restoring the elasticity of elastic fiber, reduced cardiac hypertrophy, and attenuated fibrosis of heart and lung. Collectively, FDCA exhibited triple activities of pulmonary vasodilation, vascular remodeling inhibition and RVH inhibition, suggesting that it may be a promising agent for PAH intervention.

Incorporating Simplified Fournier's Gangrene Severity Index with early surgical intervention can maximize survival in high-risk Fournier's gangrene patients.

OBJECTIVES: To determine the optimal surgical timing in high-risk patients with Fournier's gangrene by the Simplified Fournier's Gangrene Severity Index. METHODS: From 1989 to 2018, 118 male patients diagnosed with Fournier's gangrene with complete medical records were retrospectively reviewed. Patients' demographics, laboratory parameters at initial diagnosis, Fournier's Gangrene Severity Index and Simplified Fournier's Gangrene Severity Index, and the time interval from emergency room arrival to surgical intervention were collected. The Fournier's gangrene patients were categorized into low-risk (Simplified Fournier's Gangrene Severity Index ≤2) and high-risk groups (Simplified Fournier's Gangrene Severity Index >2). Differences between the variables within the two groups were analyzed. The optimal surgical timing was analyzed with the receiver operating characteristic curve in high-risk Fournier's gangrene patients. RESULTS: The overall mortality of 118 Fournier's gangrene patients was 14.4%. After risk stratification with the Simplified Fournier's Gangrene Severity Index scoring system, the mortality of low-risk and high-risk Fournier's gangrene patients was 1.3% and 41.0%, respectively. In the high-risk group, the time interval from emergency room arrival to surgical intervention was the only variable with a significant difference between survivors and non-survivors (P = 0.039). The optimal surgical timing was determined at 14.35 h, which allowed the highest sensitivity (0.688) and specificity (0.762) to affect mortality. The mortality was significantly lower in high-risk Fournier's gangrene patients with early surgical intervention compared with late intervention (23.8% vs 68.8%, P = 0.007). CONCLUSIONS: The Simplified Fournier's Gangrene Severity Index is a quick and reliable screening tool for first-line physicians to identify high-risk patients with Fournier's gangrene (Simplified Fournier's Gangrene Severity Index >2) who have poor survival outcomes. We recommended early surgical intervention within 14.35 h to maximize the survival of high-risk Fournier's gangrene patients.

The Prognostic Significance of NEK2 in Hepatocellular Carcinoma: Evidence from a Meta-Analysis and Retrospective Cohort Study.

BACKGROUND/AIMS: Numerous studies have shown that NIMA-related kinase 2 (NEK2) expression in hepatocellular carcinoma (HCC) tissue is associated with survival and clinicopathological features; however, the evidence remains inconclusive. Thus, we aimed to further explore the prognostic and clinicopathological significance of NEK2 expression in HCC using a two-part study consisting of a retrospective cohort study and a meta-analysis. METHODS: In the cohort study, NEK2 expression in 206 HCC samples and adjacent normal liver tissues was detected by immunohistochemistry (IHC). Patients were divided into a high NEK2 expression group and a low NEK2 expression group by the median value of the immunohistochemical scores. The Kaplan-Meier method with the log-rank test was used to analyze survival outcomes in the two groups, and multivariate analysis based on Cox proportional hazard regression models was applied to identify independent prognostic factors. In the meta-analysis, eligible studies were searched in PubMed, EMBASE, Web of Science, and CNKI databases. STATA version 12.0 (Stata Corporation, College Station, TX) was used for statistical analyses. RESULTS: The IHC results of our cohort study showed higher NEK2 expression in HCC tissues compared with adjacent normal liver tissues. Multivariate analysis revealed that high NEK2 expression was an independent risk factor for poor overall survival (OS) [hazard ratio (HR) = 1.763; 95% CI, 1.060-2.935; P = 0.029] and disease-free survival (DFS) [hazard ratio (HR) = 1.687; 95% CI, 1.102-2.584; P = 0.016] in HCC patients. A total of 11 studies with 1,698 patients were enrolled in the meta-analysis, consisting of 10 studies from the database search and our cohort study. The pooled results revealed that high NEK2 expression correlated closely with poor OS among HCC patients (HR = 1.47; 95% CI, 1.21-1.80; P < 0.01), and DFS/recurrence-free survival (RFS) (HR = 1.92; 95% CI, 1.41-2.63; P < 0.01). Additionally, our meta-analysis also showed that the proportion of HCC patients with high NEK2 expression was greater in the group with larger tumors (> 5 cm) than in the group with smaller tumors (≤ 5 cm) [odds ratio (OR) = 2.02; 95% CI, 1.13-3.64; P < 0.01). CONCLUSION: Our study demonstrated that high NEK2 expression is a risk factor for poor survival in HCC patients. More prospective, homogeneous, and multiethnic studies are required to validate our findings.

Inhibition of Shp2 ameliorates monocrotaline-induced pulmonary arterial hypertension in rats.

BACKGROUND: Src homology 2 containing protein tyrosine phosphatase (PTP) 2 (Shp2) is a typical tyrosine phosphatase interacting with receptor tyrosine kinase to regulate multiple signaling pathways in diverse pathological processes. Here, we will investigate the effect of Shp2 inhibition on pulmonary arterial hypertension (PAH) in a rat model and its potential cellular and molecular mechanisms underlying. METHODS: Monocrotaline (MCT)-induced PAH rat model was used in this study. Phps-1, a highly selective inhibitor for Shp2, was administered from 21 days to 35 days after MCT single-injection. Microcatheter method was applied to detected hemodynamic parameters. Histological methods were used to determine PVR changes in PAH rats. Moreover, cultured pulmonary artery smooth muscle cells (PASMCs) treated by platelet-derived growth factor (PDGF) with or without Phps-1 was used to investigate the potential cellular and molecular mechanisms underlying in vitro. RESULTS: Inhibition of Shp2 significantly attenuated MCT-induced increases of mean pulmonary arterial pressure (mPAP), right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) in rats. Shp2 inhibition effectively decreased thickening of pulmonary artery media and cardiomyocyte hypertrophy as well as perivascular and myocardial fibrosis in MCT-treated rats. Moreover, Shp2 inhibition ameliorated muscularization of pulmonary arterioles in MCT-induced PAH rats. Shp2 inhibition significantly reduced platelet-derived growth factor (PDGF)-triggered proliferation and migration of human pulmonary artery smooth muscle cells (PASMCs), which might be attributed to the inactivations of Akt and Stat3 pathways. CONCLUSIONS: Shp2 contributes to the development of PAH in rats, which might be a potential target for the treatment of PAH.

MAEL promoter hypermethylation is associated with de-repression of LINE-1 in human hypospermatogenesis.

STUDY QUESTION: Does the hypermethylation of the maelstrom spermatogenic transposon silencer (MAEL) promoter and subsequent de-repression of transposable elements represent one of the causes of spermatogenic failure in infertile men? SUMMARY ANSWER: Experimental hypermethylation of a specific region (-131 to +177) of the MAEL promoter leads to decreased expression of MAEL with increased expression of the transposable element LINE-1 (L1) and in infertile men methylation of the MAEL promoter is associated with the severity of spermatogenic failure. WHAT IS KNOWN ALREADY: MAEL induces transposon repression in the male germline and is required for mammalian meiotic progression and post-meiotic spermiogenesis. Patients with non-obstructive azoospermia (NOA), defined as no sperm in the ejaculate due to spermatogenic failure, and histopathologically proven hypospermatogenesis (HS) is not uncommon and its etiology is largely unknown. STUDY DESIGN, SIZE, DURATION: Luciferase reporter assay and a targeted DNA methylation model were used to explore the effects of hypermethylation of MAEL promoter on gene expression. Germ cell-enriched testicular cells from infertile patients were used to determine the methylation levels of MAEL and expressions of MAEL and L1. PARTICIPANTS/MATERIALS, SETTING, METHODS: Twenty-six patients with histopathologically proven NOA and HS and 12 patients with obstructive azoospermia and normal spermatogenesis (NS) were enrolled in this study. Demographic and clinical information were obtained. The severity of HS was determined by a spermatogenic scoring system. The methylation levels of 26 CpGs in the MAEL promoter was measured, and quantitative real-time RT-PCR was used to determine the expressional levels of MAEL and L1. MAIN RESULTS AND THE ROLE OF CHANCE: Targeted DNA methylation of MAEL promoter suppressed MAEL expression and de-repressed L1 activity in vitro. Patients with HS had significantly higher mean methylation levels of 26 consecutive CpGs in the MAEL promoter, compared to patients with NS. The MAEL methylation levels were negatively correlated with MAEL transcript levels and higher methylation level of MAEL was associated with severe spermatogenic defect. L1 transcript level was significantly higher in patients with HS. No differences in age, frequency of testicular insults and genetic anomalies was noted between patients with high or low MAEL methylation levels. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Because of the difficulty in the use of human germ cells for study, the in vitro targeted DNA methylation model was performed by using human NCI-H358 cells to explore the effects of MAEL methylation on transposable elements activity. Because the germ cell-enriched testicular cells isolated from a testicular sample were relatively few, the purity of cell populations was not determined. WIDER IMPLICATIONS OF THE FINDINGS: Measurement of the methylation level of MAEL gene may be feasible to predict the severity of spermatogenic failure or the outcome of testicular sperm retrieval. STUDY FUNDING/COMPETING INTERESTS: This work was supported through grants from the Ministry of Science and Technology of Taiwan (100-2314-B-006-017) and National Cheng Kung University Hospital, Tainan, Taiwan (NCKUH 20120266). The authors declare no conflicts of interest.

Laparoscopic versus open liver resection for colorectal liver metastases: a systematic review.

BACKGROUND: Laparoscopic liver resection (LLR) has been proposed as a safe and feasible treatment option for colorectal liver metastasis (CRLM). However, the short-term and oncologic outcomes of LLR versus open liver resection (OLR) for CRLM have not been adequately assessed. Thus, we herein provide an updated systematic review comparing short-term and oncologic outcomes of CRLM patients undergoing LLR versus OLR. METHODS: A systematic literature search was performed in the Pubmed, Embase, and Cochrane Library databases (until November 2, 2016) with a limitation to the publications in English. Quality assessment was performed based on the modification of the Newcastle-Ottawa Scale. Dichotomous data were calculated by odds ratio (OR), and continuous data were calculated by weighted mean difference (WMD) with 95% confidence intervals (CIs). RESULTS: A total of 28 studies enrolling 4591 patients with CRLM were included. With respect to short-term outcomes, patients in LLR group showed significantly reduced blood loss (WMD: -143.64; 95% CI: -180.56 to -106.73; I2 = 86%; P < 0.001), lower operative transfusion requirement (OR: 0.40; 95% CI: 0.30-0.53; I2 = 0%; P < 0.001), shorter hospital stay (WMD: -2.47; 95% CI: -2.99 to -1.94; I2 = 82%; P < 0.001), reduced overall postoperative morbidity (OR: 0.53; 95% CI: 0.42-0.66; I2 = 38%; P < 0.001) and reduced severe morbidity (OR: 0.44; 95% CI: 0.32-0.60; I2 = 35%; P < 0.001). Regarding oncologic outcomes, there were no significant differences between the two surgical procedures in recurrence and 1-, 3-, and 5-overall survival and disease-free survival except for slightly higher R0 resection rate in LLR group was slightly higher than that of OLR group (OR: 1.43; 95% CI: 1.03-1.97; I2 = 37%; P = 0.03). CONCLUSIONS: LLR should be the standard approach for selected patients with CRLM, and further research should focus on determining which patients would benefit most from LLR.

Klotho Regulates Cigarette Smoke-Induced Autophagy: Implication in Pathogenesis of COPD.

INTRODUCTION: Chronic obstructive pulmonary disease is a progressive lung disease characterized by abnormal cellular responses to cigarette smoke, resulting in tissue destruction and airflow limitation. Autophagy is a fundamental cellular process that eliminates long-lived proteins and damaged organelles through lysosomal degradation pathway, though its role in human diseases remains unclear. We hypothesized that an anti-aging protein, Klotho plays an important role in regulating autophagy in response to cigarette smoke (CS). METHODS: Autophagy was measured by detecting LC3-I and LC3-II expressions. The regulation of autophagy expression by cigarette smoke extract (CSE) was studied in vitro, and small-interfering RNA (siRNA) and recombinant Klotho were employed to investigate the role of Klotho on CSE-induced autophagy. Protein levels and phosphorylation were measured by Western blot assay. RESULTS: CS exposure resulted in induction of autophagy in alveolar macrophages. Pretreatment of cells with Klotho attenuated CS-induced autophagy whereas knockdown of Klotho augmented CS-induced autophagy. Klotho inhibited phosphorylation of ERK, Akt, and IGF-1 in CSE-stimulated cells. CONCLUSIONS: These data suggest that Klotho plays a critical role in the regulation of CS-induced autophagy and have important implications in understanding the mechanisms of CS-induced cell death and senescence.

A test data compression scheme based on irrational numbers stored coding.

Test question has already become an important factor to restrict the development of integrated circuit industry. A new test data compression scheme, namely irrational numbers stored (INS), is presented. To achieve the goal of compress test data efficiently, test data is converted into floating-point numbers, stored in the form of irrational numbers. The algorithm of converting floating-point number to irrational number precisely is given. Experimental results for some ISCAS 89 benchmarks show that the compression effect of proposed scheme is better than the coding methods such as FDR, AARLC, INDC, FAVLC, and VRL.

Soft-label recover based label-specific features learning.

Presently, multi-label classification algorithms are mainly based on positive and negative logical labels, which have achieved good results. However, logical labeling inevitably leads to the label misclassification problem. In addition, missing labels are common in multi-label datasets. Recovering missing labels and constructing soft labels that reflect the mapping relationship between instances and labels is a difficult task. Most existing algorithms can only solve one of these problems. Based on this, this paper proposes a soft-label recover based label-specific features learning (SLR-LSF) to solve the above problems simultaneously. Firstly, the information entropy is used to calculate the confidence matrix between labels, and the membership degree of soft labels is obtained by combining the label density information. Secondly, the membership degree and confidence matrix are combined to construct soft labels, and this process not only solves the problem of missing labels but also obtains soft labels with richer semantic information. Finally, in the process of learning specific label features for soft labels. The local smoothness of the labels learned through stream regularization is complemented by the global label correlation, thus improving the classification performance of the algorithm. To demonstrate the effectiveness of the proposed algorithm, we conduct comprehensive experiments on several datasets.

Surgical Outcomes and Predictive Factors in Patients With Detrusor Underactivity Undergoing Bladder Outlet Obstruction Surgery.

PURPOSE: This study was conducted to evaluate the efficacy of bladder outlet surgery in patients with detrusor underactivity (DU) and to identify factors associated with successful outcomes. METHODS: We conducted a retrospective review of men diagnosed with DU in urodynamic studies who underwent bladder outlet surgery for lower urinary tract symptoms between May 2018 and April 2023. The International Prostate Symptom Score (IPSS) questionnaire, uroflowmetry (UFM), and multichannel urodynamic studies were administered. Successful treatment outcomes were defined as either an IPSS improvement of at least 50% or the regaining of spontaneous voiding in patients urethral catheterization prior to surgery. RESULTS: The study included 93 male patients. Men diagnosed with significant or equivocal bladder outlet obstruction (BOO) experienced significant postoperative improvements in IPSS (from 20.6 to 6.0 and from 17.4 to 6.5, respectively), maximum urine flow rate (from 5.0 mL/sec to 14.4 mL/sec and from 8.8 mL/sec to 12.2 mL/sec, respectively) and voiding efficiency (from 48.8% to 86.0% and from 61.2% to 85.1%, respectively). However, in the group without obstruction, the improvements in IPSS and UFM results were not significant. The presence of detrusor overactivity (odds ratio [OR], 3.152; P=0.025) and preoperative urinary catheterization (OR, 2.756; P=0.040) were associated with favorable treatment outcomes. Conversely, an unobstructed bladder outlet was identified as a negative prognostic factor. CONCLUSION: In men with DU accompanied by equivocal or significant BOO, surgical intervention to alleviate the obstruction may enhance the IPSS, quality of life, and UFM results. However, those with DU and an unobstructed bladder outlet face a comparatively high risk of treatment failure. Preoperative detrusor overactivity and urinary catheterization are associated with more favorable surgical outcomes. Consequently, active deobstructive surgery should be considered for patients with DU who are experiencing urinary retention.

MicroRNA-320a enhances LRWD1 expression through the AGO2/FXR1-dependent pathway to affect cell behaviors and the oxidative stress response in human testicular embryonic carcinoma cells.

BACKGROUND: Testicular cancer is fairly rare but can affect fertility in adult males. Leucine-rich repeats- and WD repeat domain-containing protein 1 (LRWD1) is a sperm-specific marker that mainly affects sperm motility in reproduction. Our previous study demonstrated the impact of LRWD1 on testicular cancer development; however, the underlying mechanisms remain unclear. METHODS: In this study, various plasmids associated with LRWD1 and miR-320a manipulation were used to explore the roles and regulatory effects of these molecules in NT2D1 cellular processes. A Dual-Glo luciferin-luciferase system was used to investigate LRWD1 transcriptional activity, and qRT-PCR and western blotting were used to determine gene and protein expression. RESULTS: The results suggested that miR-320a positively regulated LRWD1 and positively correlated with NT2D1 cell proliferation but negatively correlated with cell migration and invasion ability. In addition, the miRNA-ribonucleoprotein complex AGO2/FXR1 was shown to be essential in the mechanism by which miR-320a regulates LRWD1 mRNA expression. As miR-320a was required to regulate LRWD1 expression through the AGO2 and FXR1 complex, eEF2 and eLF4E were also found to be involved in miR-320a increasing LRWD1 expression. Furthermore, miR-320a and LRWD1 were responsive to oxidative stress, and NRF2 was affected by the presence of miR-320a in response to ROS stimulation. CONCLUSIONS: This is the first study showing the role of miR-320a in upregulating the testicular cancer-specific regulator LRWD1 and the importance of the AGO2/FXR1 complex in miR-320a-mediated upregulation of LRWD1 during testicular cancer progression.