The causal effect of metabolic syndrome and its components on benign prostatic hyperplasia: A univariable and multivariable Mendelian randomization study.

BACKGROUND: Previous observational studies have indicated that metabolic abnormalities are associated with benign prostatic hyperplasia (BPH). The limitations of the research methodology of observational studies do not allow causal inference to be drawn; however, Mendelian randomization (MR) can clarify this. METHODS: Using summary-level data from genome-wide association studies, we conducted a two-sample MR study to examine the causality of the metabolic syndrome (MetS) and its components on BPH (26,358 BPH cases and 110,070 controls). The random-effects inverse-variance weighted was employed as the primary method for MR analyses. RESULTS: We observed that genetically predicted waist circumference (WC) (odds ratio [OR] = 1.236, 95% confidence interval [CI]: 1.034-1.478, p = 0.020) and diastolic blood pressure (DBP) (OR = 1.011, 95% CI: 1.002-1.020, p = 0.020) were significantly positively associated with BPH risk. We did not identify a causal effect of MetS (OR = 0.975, 95% CI: 0.922-1.031, p = 0.375), systolic blood pressure (OR = 1.004, 95% CI: 0.999-1.008, p = 0.115), triglycerides (OR = 1.016, 95% CI: 0.932-1.109, p = 0.712), high-density lipoprotein (OR = 1.005, 95% CI: 0.930-1.086, p = 0.907), and fasting blood glucose (OR = 1.037, 95% CI: 0.874-1.322, p = 0.678) on BPH. In the multivariable MR analysis, we observed that the risk effect of DBP (OR = 1.013, 95% CI: 1.000-1.026, p = 0.047) on BPH persisted after conditioning with WC (OR = 1.132, 95% CI: 0.946-1.356, p = 0.177). CONCLUSIONS: Our study provides genetic evidence supporting the causal effect of DBP on BPH, although the effect of WC needs to be further validated.

FGF13A interacts with NPM1 and UBF and inhibits the invasion of bladder cancer cells.

Bladder cancer (BC) invasion is a critical factor that impacts the prognosis and quality of life of patients. However, the underlying mechanisms of BC invasion is far from clear. Fibroblast growth factor 13 (FGF13), a non-secretory FGF, has been found to be ectopically expressed in various tumors and implicated in tumor development, but its potential association to BC has not been investigated. Here, we reported that the expression of FGF13A, one nucleolar isoform of FGF13, was downregulated in BC patients and negatively associated with tumor invasion. Additionally, we demonstrated that overexpression of FGF13A could inhibit the migration and invasion of BC 5637 and T24 cells. We also confirmed the localization of FGF13A in the nucleolus and its interaction with nucleoproteins NPM1 and UBP. Subsequently, we identified that the N-terminal region of FGF13A was essential for its nucleolus location and interaction with NPM1. Furthermore, we found that FGF13A inhibited the generation of nascent ribosomal RNA and suppressed the migration and invasion of BC cells through its N-terminal region. Our research establishes, for the first time, a correlation between the expression of FGF13A and the onset and progression of BC. This provides novel insights into the role of FGF13A in the development of BC.

Leukocyte Telomere Length and the Risk of Prostate Cancer and Benign Prostatic Hyperplasia: Insights From UK Biobank and Mendelian Randomization Study.

BACKGROUND: Previous observational studies have been controversial regarding the association of leukocyte telomere length (LTL) with prostate cancer (PCa) and benign prostatic hyperplasia (BPH). METHODS: First, we conducted an observational study utilizing UK Biobank data. The correlation between LTL and the risk of PCa and BPH was evaluated via multivariate-adjusted logistic regression. Then, we conducted a 2-sample Mendelian randomization to examine causal links between LTL (472 174 individuals) and PCa as well as BPH. To verify the reliability of the primary analysis, we conducted a second analysis and sensitivity analyses. RESULTS: In the UK Biobank study, individuals in the longer quartiles of LTL were observed to have a higher risk of PCa (1.155-fold to 1.349-fold, all p < .001) and BPH (1.119-fold to 1.212-fold, all p < .001) compared to those in the lowest quartile in multivariate-adjusted logistic regression. We observed that genetically predicted longer LTL resulted in a 1.427-fold risk of PCa (odds ratio [OR] = 1.427, 95% confidence interval [CI] = 1.197-1.702, p < .001) and 1.539-fold risk of BPH (OR = 1.539, 95% CI = 1.387-1.707, p < .001) in the primary analysis. In the second analysis, the results also indicated that longer LTL increased the genetic liability to both PCa (OR = 1.338, 95% CI = 1.189-1.507, p < .001) and BPH (OR = 1.006, 95% CI = 1.003-1.008, p < .001). Sensitivity analyses also supported the reliability of the results. CONCLUSIONS: Our study provides convincing evidence supporting that longer LTL increases the risk of PCa and BPH in European individuals. Large-scale studies are needed to elucidate the potential mechanisms of LTL in PCa and BPH occurrence.

Waiting-List and early posttransplant prognosis among ethnoracial groups: Data from the organ procurement and transplantation network.

Background: Racial/ethnic disparity in waiting-list mortality among candidates listed for kidney transplantation (KT) in the United States remains unclear. We aimed to assess racial/ethnic disparity in waiting-list prognosis among patients listed for KT in the United States in the current era. Methods: We compared waiting-list and early posttransplant in-hospital mortality or primary nonfunction (PNF) among adult (age ≥18 years) white, black, Hispanic, and Asian patients listed for only KT in the United States between July 1, 2004 and March 31, 2020. Results: Of the 516,451 participants, 45.6%, 29.8%, 17.5%, and 7.1% were white, black, Hispanic, and Asian, respectively. Mortality on the 3-year waiting list (including patients who were removed for deterioration) was 23.2%, 16.6%, 16.2%, and 13.8% in white, black, Hispanic, and Asian patients, respectively. The cumulative incidence of posttransplant in-hospital death or PNF after KT was 3.3%, 2.5%, 2.4%, and 2.2% in black, white, Hispanic, and Asian patients,respectively. White candidates had the highest mortality risk on the waiting list or of becoming too sick for a transplant, while black (adjusted hazard ratio, [95% confidence interval, CI], 0.67 [0.66-0.68]), Hispanic (0.59 [0.58-0.60]), and Asian (0.54 [0.52-0.55]) candidates had a lower risk. Black KT recipients (odds ratio, [95% CI] 1.29 [1.21-1.38]) had a higher risk of PNF or death before discharge than white patients. After controlling confounders, black recipients (0.99 [0.92-1.07]) had a similar higher risk of posttransplant in-hospital mortality or PNF as white patients than Hispanic and Asian counterparts. Conclusions: Despite having a better socioeconomic status and being allocated better kidneys, white patients had the worst prognosis during the waiting periods. Black recipients and white recipients have higher posttransplant in-hospital mortality or PNF.

Effects of recipient education disparity on living donor kidney transplant outcomes across different ethnic groups: a retrospective study in the United States.

Background: Previous studies have shown that education level is associated with the prognosis of cadaveric kidney transplant recipients. However, it is unclear whether education affects the prognosis of living kidney transplant (LDKT) recipients. In addition, it remains to be determined whether the uneven distribution of educational levels consistently affects the prognosis of LDKT recipients across ethnic groups (White, Black, Hispanic and Asian). Methods: After establishing inclusion and exclusion criteria, we conducted a retrospective study of LDKT recipients who received their first single LDKT between 2005 and 2020. The LDKT recipients were divided into lower- and higher-education groups according to categorize the educational level of recipients, and transplant outcomes, including graft survival, patient survival, and death-censored graft survival (DCGS), were analyzed and compared. Results: Graft survival, DCGS and patient mortality were significantly better in the higher-education group compared with those in the lower-education group (P<0.001), with the risk of graft failure, death censored graft failure (DCGF) and patient mortality increasing by 11%, 15% and 7% in the lower-education group, respectively. Furthermore, compared with the higher-education group, the risk of graft failure in Black recipients increased by 18% [adjusted hazard ratio (aHR), 1.18; 95% confidence interval (CI): 1.07 to 1.30], and the risk of patient mortality among White recipients decreased by 7% (aHR, 0.93; 95% CI: 0.87 to 0.99). However, there were no significant differences in graft failure and patient mortality among Hispanic and Asian recipients, respectively. Conclusions: This study revealed that LDKT recipients with a higher education level had better transplant outcomes. However, these transplant outcome differences were mainly found in White and Black recipients. These data confirm the significant effect of different levels of education on the prognosis of LDKT recipients.

Simpson's paradox and the impact of donor-recipient race-matching on outcomes post living or deceased donor kidney transplantation in the United States.

Background: Race is a prognostic indicator in kidney transplant (KT). However, the effect of donor-recipient race-matching on survival after KT remains unclear. Methods: Using the United Network for Organ Sharing (UNOS) database, a retrospective study was conducted on 244,037 adults who received first-time, kidney-alone transplantation between 2000 and 2019. All patients were categorized into two groups according to donor-recipient race-matching, and the living and deceased donor KT (LDKT and DDKT) were analyzed in subgroups. Results: Of the 244,037 patients, 149,600 (61%) were race-matched, including 107,351 (87%) Caucasian, 20,741 (31%) African Americans, 17,927 (47%) Hispanics, and 3,581 (25%) Asians. Compared with race-unmatching, race-matching showed a reduced risk of overall mortality and graft loss (unadjusted hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.84-0.87; and unadjusted HR 0.79, 95% CI: 0.78-0.80, respectively). After propensity score-matching, donor-recipient race-matching was associated with a decreased risk of overall graft loss (P < 0.001) but not mortality. In subgroup analysis, race-matching was associated with higher crude mortality (HR 1.12, 95% CI: 1.06-1.20 in LDKT and HR 1.11, 95% CI: 1.09-1.14 in DDKT). However, race-matching was associated with a decreased risk of graft loss in DDKT (unadjusted HR 0.97, 95% CI: 0.96-0.99), but not in LDKT. After propensity score-matching, race-matching had better outcomes for LDKT (patient survival, P = 0.047; graft survival, P < 0.001; and death-censored graft survival, P < 0.001) and DDKT (death-censored graft survival, P = 0.018). Nonetheless, race-matching was associated with an increased adjusted mortality rate in the DDKT group (P < 0.001). Conclusion: Race-matching provided modest survival advantages after KT but was not enough to influence organ offers. Cofounding factors at baseline led to a contorted crude conclusion in subgroups, which was reversed again to normal trends in the combined analysis due to Simpson's paradox caused by the LDKT/DDKT ratio.

Age and metabolic syndrome are associated with unsatisfactory improvement in nocturia after holmium laser enucleation of the prostate.

Objective: To investigate the association between age, metabolic syndrome (MetS) and improvement in nocturia in patients with benign prostate hyperplasia (BPH) receiving holmium laser enucleation of the prostate (HoLEP). Methods: The retrospective study was conducted on patients treated for BPH using HoLEP between January 2021 and May 2022. Lower urinary tract symptoms (LUTS) were measured before surgery and at 3 months postoperatively using the International Prostate Symptom Score (IPSS). The criteria of the Adult Treatment Panel III (ATP III) were adopted to diagnose the MetS. Unsatisfactory improvement in nocturia was defined as <50% reduction in nocturia from baseline on the IPSS. Results: One hundred and seventy-five patients were eventually enrolled, with a median age of 69 years (IQR: 63/73). Unsatisfactory improvement in nocturia was reported in 95 patients (54%) after HoLEP. These patients were older (73; IQR: 67/79 vs. 66; IQR: 60/71, P < 0.001) and more likely to present with higher postoperative total (6; IQR: 4/9 vs. 3; IQR:2/5, P < 0.001), voiding (1; IQR: 0/3 vs. 1; IQR: 0/2, P = 0.017), and storage (4; IQR: 3/6 vs. 2; IQR: 1/4, P < 0.001) IPSS when compared to patients with satisfactory improvement in nocturia. Overall, 63 of 175 (36%) patients were diagnosed with MetS and of these, 44 (70%) reported unsatisfactory improvement in nocturia (P = 0.002) after HoLEP. Multivariate analysis revealed that age (OR = 1.117, 95% CI: 1.068-1.169, P < 0.001) and MetS (OR = 3.613, 95% CI: 1.727-7.562, P = 0.001) were independent risk factors for unsatisfactory improvement in nocturia after HoLEP. Conclusion: Our findings suggest that increased age and MetS were associated with unsatisfactory improvement in nocturia in patients with BPH after HoLEP. Lifestyle management, including weight loss, may be of great importance in the improvement of nocturia.

Transplant or dialysis: What's the better choice for RCC-induced ESRD patients? A 20-year analysis of OPTN/UNOS data.

Purpose: The incidence of end-stage renal disease (ESRD) caused by renal cell carcinoma (RCC) is increasing with the high prevalence of RCC as well as those with treatment-related renal function impairment. Worries about tumor recurrence after transplant-related immunosuppression hinder the recommendation of kidney transplantation for RCC-induced ESRD patients. However, no direct analysis has been performed to identify whether kidney transplantation can offer better survival than maintaining dialysis. Materials and methods: This retrospective population-based cohort study was based on Organ Procurement and Transplantation Network data released in March 2021. Characteristics and outcomes were compared, including the patient and graft survival of candidates and recipients with RCC-induced ESRD etiology as well as other primary diseases. Results: Patients with RCC-induced ESRD were older; more likely to be male, White, and obese; and more likely to have a history of diabetes and dialysis. They also had higher creatinine levels, more delayed graft function, more primary non-function, and higher Kidney Donor Profile Index score donors, compared with the glomerulonephritis (GN) group. While waiting, RCC candidates suffered the worst outcomes of all groups, a 44% (adjusted hazard ratio [aHR], 1.44 [1.27-1.62]) higher risk of removal than GN patients. After transplantation, RCC recipients demonstrated comparable patient survival and better graft survival (p=0.21 and p=0.13, respectively). Compared with still-waiting RCC patients, the RCC recipients who received kidney transplants had significantly better outcomes (13.6 [9.3-17.8] vs. 61 [52-68.4] %), decreasing the death or deteriorating risk by 84% (aHR, 0.16 [0.13-0.20]). Conclusions: Patients with RCC-induced ESRD can dramatically benefit from kidney transplantation. Hence, these patients should not be limited to transplantation by strict strategies or a delayed waiting time out of their malignancy history.

Skin cancer outcomes and risk factors in renal transplant recipients: Analysis of organ procurement and transplantation network data from 2000 to 2021.

Purpose: Posttransplant skin cancer is the most common malignancy after patients have undergone renal transplantation. Through comprehensive observation with a large sample size nationwide, understanding the risk factors and outcome of posttransplant skin cancer will help to develop appropriate patient surveillance and disease prevention strategies. Materials and methods: This retrospective population-based cohort study was based on Organ Procurement and Transplantation Network data released in March 2021. Characteristics and outcomes, including patient survival and graft survival of recipients, were compared. Risk factors for posttransplant skin cancer, cancer onset momentum, and mortality were determined. Results: A total of 199,564 renal transplant recipients were included. After renal transplantation, 7,334 (3.68%), 6,093 (3.05%), and 936 (0.47%) were diagnosed with squamous cell carcinoma, basal cell carcinoma, and melanoma, respectively. Skin cancer was the major cause of death (squamous cell carcinoma: 23.8%, basal cell carcinoma: 18%, and melanoma: 41.6%). Five-year survival rates ranked from best to worst were as follows: basal cell carcinoma (96.7 [95% confidence interval: 96.3-97.2]%), squamous cell carcinoma (94.1 [93.5-94.6]%), melanoma (89.7 [87.7-91.6]%), and cancer-free (87.4 [87.2-87.5]%) (p < 0.001 for all except melanoma vs. cancer-free, p = 0.534). Regarding graft survival, death-censored graft survival, posttransplant skin cancer, and melanoma were significantly better than the cancer-free group (p < 0.001). Independent risk factors for developing posttransplant skin cancer included older age, male sex, Caucasian race, pretransplant malignancy, polycystic kidney disease-induced end-stage renal disease (ESRD), retransplantation, private health insurance, T-cell depletion induction, and tacrolimus/mycophenolic acid use. Caucasian race and pretransplant malignancy were independent risk factors for posttransplant skin cancer onset momentum. Male sex, Caucasian race, pretransplant malignancy, hypertension- or diabetes-induced ESRD, retransplantation, diabetes history, deceased donor, cyclosporin, and mTOR inhibitor use were independent risk factors for posttransplant skin cancer mortality. Conclusion: Although posttransplant skin cancer is a major cause of recipient death, information regarding its impact on patient and graft survival is limited. Given the differences regarding risk factors for posttransplant skin cancer incidence, onset momentum, and mortality, personalized approaches to screening may be appropriate to address the complex issues encountered by kidney transplant recipients.

Comparison of Digestive Enzyme Activities and Expression of Small Intestinal Transporter Genes in Jinhua and Landrace Pigs.

Digestive enzyme activity is involved in the regulation of growth performance because digestive enzymes function to improve the feed efficiency by digestion and in turn to modulate the process of nutrient metabolism. The objective of this study was to investigate the differences of the digestive enzyme activities and expression of nutrient transporters in the intestinal tract between Jinhua and Landrace pigs and to explore the potential breed-specificity in digestion and absorption. The pancreas segments and the digesta and mucosa of the duodenum, jejunum, and ileum were collected from 10 Jinhua pigs and Landrace pigs, respectively. The activities of trypsin, chymotrypsin, amylase, maltase, sucrase, and lipase were measured and the expression levels of PepT1, GLUT2, SGLT1, FABP1, FABP2, and FABP4 were examined. Results showed that the trypsin activity in the pancreas of Jinhua pigs was higher than that in Landrace pigs, but was lower in the small intestine, except for in the jejunal mucosa. The chymotrypsin activity in the small intestine of Jinhua pigs was higher than that in Landrace pigs, except for in jejunal mucosa and contents. Compared with Landrace pigs, the amylase and maltase activity in the small intestine of Jinhua pigs was lower, except for in ileal mucosa. The sucrase activity in the small intestine of Jinhua pigs was also lower than Landrace pigs, except for in jejunal mucosa. Furthermore, the lipase activity in the small intestine of Jinhua pigs was higher than that in Landrace pigs. The mRNA levels of PepT1 and GLUT2 in duodenal, jejunal and ileal mucosa showed no difference between Jinhua and Landrace pigs, whereas SGLT1 in ileal mucosa was lower in Jinhua pigs. The mRNA levels of FABP1, FABP2 and FABP4 in the small intestinal mucosa of Jinhua pigs were higher than in Landrace pigs. These findings indicate that there is a certain difference in the digestibility and absorption of nutrients in small intestine of Jinhua and Landrace pigs, partially resulting in their differences in growth development and fat deposition.

Analgesic effect of the main components of Corydalis yanhusuo (yanhusuo in Chinese) is caused by inhibition of voltage gated sodium channels.

ETHNOPHARMACOLOGY RELEVANCE: Pain often causes a series of abnormal changes in physiology and psychology, which can lead to disease and even death. Drug therapy is the most basic and commonly used method for pain relief and management. Interestingly, at present, hundreds of traditional Chinese medicines have been reported to be used for pain relief, most of which are monomer preparations, which have been developed into new painkillers. Corydalis yanhusuo is a representative of one of these medicines and is available for pain relief. AIM OF THE STUDY: This study aims to determine the analgesic effect and the potential targets of the monomers derived from Corydalis yanhusuo, and to explore any possible associated cardiac risk factors. MATERIALS AND METHODS: In this study, four monomers derived from Corydalis yanhusuo (tetrahydropalmatine, corydaline, protopine, dehydrocorydaline) were tested in vivo, using the formalin-induced pain model to determine their analgesic properties. Their potential targets were also determined using whole cell patch clamp recordings and myocardial enzyme assays. RESULTS: The results showed that all monomers showed analgesic activity and inhibited the peak currents, promoted the activation and inactivation phases of Nav1.7, which indicating that Nav1.7 might be involved in the analgesic mechanism of Corydalis yanhusuo. Protopine increased the level of creatine kinase-MB (CK-MB) and inhibited the peak currents, promoted the activation and inactivation phases of Nav1.5, indicating that Nav1.5 might be involved in the cardiac risk associated with protopine treatment. CONCLUSION: These data showed that tetrahydropalmatine produced the best analgesic effect and the lowest cardiac risk. Thus, voltage gated sodium channels (VGSCs) might be the main targets associated with Corydalis yanhusuo. This study, therefore, provides valuable information for future studies and use of traditional Chines medicines for the alleviation of pain.

Novel bivalent BET inhibitor N2817 exhibits potent anticancer activity and inhibits TAF1.

Bromodomain and extra-terminal domain (BET) family proteins are promising anticancer targets. Most BET inhibitors in clinical trials are monovalent. They competitively bind to one of the bromodomains (BD1 and BD2) in BET proteins and exhibit relatively weak anticancer activity, poor pharmacokinetics, and low metabolic stability. Here, we evaluated the anticancer activity of a novel bivalent BET inhibitor, N2817, which consists of two molecules of the monovalent BET inhibitor 8124-053 connected by a common piperazine ring, rendering a long linker unnecessary. Compared with ABBV-075, one of the potent monovalent BET inhibitors reported to date, N2817 showed greater potency in inhibiting proliferation, arresting cell-cycle, inducing apoptosis, and suppressing the growth of tumor xenografts. Moreover, N2817 showed high metabolic stability, a relatively long half-life, and no brain penetration after oral administration. Additionally, N2817 directly bound and inhibited another BD-containing protein, TAF1 (BD2), as evidenced by a reduction in mRNA and protein levels. TAF1 inhibition contributed to the anticancer effect of N2817. Therefore, this study offers a new paradigm for designing bivalent BET inhibitors and introduces a novel potent bivalent BET inhibitor and a new anticancer mechanism.

Rational Design and Evaluation of 6-(Pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1H)-ones as Polypharmacological Inhibitors of BET and Kinases.

Cancer exhibits diverse heterogeneity with a complicated molecular basis that usually harbors genetic and epigenetic abnormality, which poses a big challenge for single-target agents. In the current work, we proposed a hybrid strategy by incorporating pharmacophores that bind to the acetylated lysine binding pocket of BET proteins with a typical kinase hinge binder to generate novel polypharmacological inhibitors of BET and kinases. Through elaborating the core structure of 6-(pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1H)-one, we demonstrated that this rational design can produce high potent inhibitors of CDK9 and BET proteins. In this series, compound 40 was identified as the potential lead compound with balanced activities of BRD4 (IC50 = 12.7 nM) and CDK9 (IC50 = 22.4 nM), as well as good antiproliferative activities on a small cancer cell panel. Together, the current study provided a new method for the discovery of bromodomain and kinase dual inhibitors rather than only being discovered by serendipity.

Structure-Based Discovery and Development of a Series of Potent and Selective Bromodomain and Extra-Terminal Protein Inhibitors.

BRD4 has recently emerged as a promising drug target. Therefore, identifying novel inhibitors with distinct properties could enrich their use in anticancer treatment. Guided by the cocrystal structure of hit compound 4 harboring a five-membered-ring linker motif, we quickly identified lead compound 7, which exhibited good antitumor effects in an MM.1S xenograft model by oral administration. Encouraged by its high potency and interesting scaffold, we performed further lead optimization to generate a novel potent series of bromodomain and extra-terminal (BET) inhibitors with a (1,2,4-triazol-5-yl)-3,4-dihydroquinoxalin-2(1H)-one structure. Among them, compound 19 was found to have the best balance of activity, stability, and antitumor efficacy. After confirming its low brain penetration, we conducted comprehensive preclinical studies, including a multiple-species pharmacokinetics profile, extensive cellular mechanism studies, hERG assay, and in vivo antitumor growth effect testing, and we found that compound 19 is a potential BET protein drug candidate for the treatment of cancer.

A facile method to fabricate functionally integrated devices for oil/water separation.

In this paper, we present a facile method for the fabrication of a functionally integrated device, which has the multi-functions of the oil-containment boom, oil-sorption material, and water/oil-separating film, through a single immersion step in an ethanol solution of stearic acid. During the simple immersion process, the two dominant factors of superhydrophobicity, surface roughness and low-surface-energy coatings, could be accomplished simultaneously. The as-prepared functionally integrated device with superhydrophobicity/superoleophilicity displayed a lower density than that of water, such that it could float on water and act as an oil-containment boom; an efficient oil-absorbing property, which was attributed to the capillary effect caused by micrometer-sized pore structures and could be used as oil-sorption materials; a high oil/water separating efficiency which was suitable for water/oil-separating film. In this way, the functions of oil collection, absorption, and water/oil separation are integrated into a single device, and these functions could work independently, reducing the cost in terms of energy consumption and being versatile for a wide range of applications.