D-mannose facilitates immunotherapy and radiotherapy of triple-negative breast cancer via degradation of PD-L1.

Breast cancer is the most frequent malignancy in women worldwide, and triple-negative breast cancer (TNBC) patients have the worst prognosis and highest risk of recurrence. The therapeutic strategies for TNBC are limited. It is urgent to develop new methods to enhance the efficacy of TNBC treatment. Previous studies demonstrated that D-mannose, a hexose, can enhance chemotherapy in cancer and suppress the immunopathology of autoimmune diseases. Here, we show that D-mannose can significantly facilitate TNBC treatment via degradation of PD-L1. Specifically, D-mannose can activate AMP-activated protein kinase (AMPK) to phosphorylate PD-L1 at S195, which leads to abnormal glycosylation and proteasomal degradation of PD-L1. D-mannose-mediated PD-L1 degradation promotes T cell activation and T cell killing of tumor cells. The combination of D-mannose and PD-1 blockade therapy dramatically inhibits TNBC growth and extends the lifespan of tumor-bearing mice. Moreover, D-mannose-induced PD-L1 degradation also results in messenger RNA destabilization of DNA damage repair-related genes, thereby sensitizing breast cancer cells to ionizing radiation (IR) treatment and facilitating radiotherapy of TNBC in mice. Of note, the effective level of D-mannose can be easily achieved by oral administration in mice. Our study unveils a mechanism by which D-mannose targets PD-L1 for degradation and provides methods to facilitate immunotherapy and radiotherapy in TNBC. This function of D-mannose may be useful for clinical treatment of TNBC.

Kikuchi disease in acute leukaemia: a distinct clinical syndrome with HLA association.

AIMS: To report the clinicopathological features of Kikuchi disease in patients with acute leukaemia, emphasising similarities among cases. METHODS AND RESULTS: In a cohort of 454 Kikuchi disease patients, we identified three cases of concurrent acute leukaemia. These patients shared similar clinical traits, with Kikuchi disease emerging approximately a month after induction chemotherapy onset, featuring neck-region lymphadenopathy. Notably, two patients were middle-aged, deviating from the typical age distribution of Kikuchi disease. Histologically, these cases aligned with typical Kikuchi disease. Negative immunohistochemical stains (CD34, CD117, ERG, TdT) indicated the absence of extramedullary leukaemic infiltration. Herpes simplex virus immunohistochemical staining was also negative. Significantly, a human leucocyte antigen (HLA) association was observed in these three cases. HLA-B*15:01, C*04:01, and DRB1*04:06 were more prevalent in these patients compared to the general population (compared with three independent control cohorts: Taiwanese Han Chinese (n = 504), Tzu Chi Taiwanese bone marrow donors (n = 364) and Hong Kong Chinese (n = 5266)). CONCLUSIONS: Our study underscores the unique link between Kikuchi disease and acute leukaemia, characterised by specific features and HLA associations. This underlines Kikuchi disease as a possible differential diagnosis in pertinent clinical scenarios. Furthermore, this syndrome offers insights into postchemotherapy immunology in acute leukaemia, enhancing comprehension.

Relationship between the weight-adjusted-waist index and kidney stone: a population-based study.

BACKGROUND: At present, a growing number of studies have shown a positive association between obesity and kidney stone, while traditional anthropometric measures, such as body mass index (BMI) and Waist circumference (WC), have limited ability to assess the risk of kidney stone. Therefore, this study aimed to investigate the association between the weight-adjusted-waist index (WWI) and the risk of kidney stone. METHOD: Data from the National Health and Nutrition Examination Survey (NHANES) between 2009 and 2016 were used. A total of 17,292 participants from NHANES were included in the study. Multivariate logistic regression and restricted cubic splines (RCS) were used to investigate the relationship between WWI and kidney stone. Interaction analysis was performed for subgroups to verify the results. Meanwhile, the receiver operating characteristic curve (ROC) was used to analyze the efficacy of different anthropometric indices in predicting the risk of kidney stone. RESULTS: After adjusting for potential confounding factors, we found a positive and independent association between kidney stone and WWI. After adjusting for all covariates, a one-unit increase in WWI was associated with a 36% increase in the risk of kidney stones. Dose-response curve analysis showed that WWI was non-linear correlated with the prevalence of kidney stone. In ROC analysis, WWI showed better discrimination for kidney stone (area under the curve: 0.612; 95% CI: 0.599-0.626; optimal cutoff value: 11.063) compared with other indices. CONCLUSION: In this study, increased WWI was strongly associated with the risk of kidney stone.

A novel ferroptosis-related 12-gene signature predicts clinical prognosis and reveals immune relevancy in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is still highly aggressive and lethal even with various therapeutic approaches. As the kidney is an iron metabolism-related organ, exploring and assessing the clinical value of ferroptosis, an iron-dependent regulated cell death, is practical and important. METHODS: Prognostic ferroptosis-related differentially expressed genes (DEGs) were identified from the KIRC cohort in the cancer genome atlas (TCGA) database, from which a prognostic signature was established using Lasso-penalized Cox regression analysis. Each patient in the KIRC cohort and the E-MTAB-1980 cohort (from the ArrayExpress database) was assigned a calculated signature-correlated risk score and categorized to be either in the high- or low-risk group divided by the median risk score in the KIRC cohort. Then, the independent prognostic value of the signature was further assessed by Kaplan-Meier (K-M) survival, time-dependent receiver operating characteristic (ROC) and Cox regression analyses based on overall survival (OS) in both cohorts. Finally, risk-related DEGs were identified in both cohorts and subjected to enrichment analyses for Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and immune infiltration. RESULTS: Among 60 ferroptosis-related genes, 32 prognostic DEGs were identified, from which we constructed a prognostic 12-gene signature with CARS1, HMGCR, CHAC1, GOT1, CD44, STEAP3, AKR1C1, CBS, DPP4, FANCD2, SLC1A5 and NCOA4. Patients in both cohorts were divided into high- and low-risk groups, which were visually distributed in two sets and had positive-risk-related mortality. The K-M survival and the ROC curves validated that the signature has prognostic value with P < 0.05 and area under the curve > 0.7 in both cohorts, respectively. Multivariate Cox regression further confirmed the risk score as an independent prognostic predictor for OS. Commonly enriched terms in GO and KEGG not only showed a high iron correlation but also, interestingly, immune relevance of 3 immune cells (macrophages, mast cells and regulatory T cells) and 1 immune-related function (antigen processing cell co-stimulation). CONCLUSION: We established a novel 12 ferroptosis-related-gene signature that was proven to be an independent prognostic predictor for OS and inferred to be related to tumour immunity in ccRCC; however, the underlying mechanism is still poorly characterized and needs further exploration.

In silico analysis of the immune microenvironment in bladder cancer.

BACKGROUND: Infiltrating immune and stromal cells are vital components of the bladder cancer (BC) microenvironment, which can significantly affect BC progression and outcome. However, the contribution of each subset of tumour-infiltrating immune cells is unclear. The objective of this study was to perform cell phenotyping and transcriptional profiling of the tumour immune microenvironment and analyse the association of distinct cell subsets and genes with BC prognosis. METHODS: Clinical data of 412 patients with BC and 433 transcription files for normal and cancer tissues were downloaded from The Cancer Genome Atlas. The CIBERSORT algorithm was used to determine the relative abundance of 22 immune cell types in each sample and the ESTIMATE algorithm was used to identify differentially expressed genes within the tumour microenvironment of BC, which were subjected to functional enrichment and protein-protein interaction (PPI) analyses. The association of cell subsets and differentially expressed genes with patient survival and clinical parameters was examined by Cox regression analysis and the Kaplan-Meier method. RESULTS: Resting natural killer cells and activated memory CD4+ and CD8+ T cells were associated with favourable patient outcome, whereas resting memory CD4+ T cells were associated with poor outcome. Differential expression analysis revealed 1334 genes influencing both immune and stromal cell scores; of them, 97 were predictive of overall survival in patients with BC. Among the top 10 statistically significant hub genes in the PPI network, CXCL12, FN1, LCK, and CXCR4 were found to be associated with BC prognosis. CONCLUSION: Tumour-infiltrating immune cells and cancer microenvironment-related genes can affect the outcomes of patients and are likely to be important determinants of both prognosis and response to immunotherapy in BC.

Associations between nephrolithiasis and diabetes mellitus, hypertension and gallstones: A meta-analysis of cohort studies.

AIM: To review and clarify the strengths and directions of associations between nephrolithiasis and hypertension (HTN), diabetes mellitus (DM) and gallstones (GS) given the inconsistent results reported in cohort studies. METHODS: Relevant literature was searched in PubMed and EMBASE from inception to July 2019, for cohort studies that examined the relationships between kidney stones and these three diseases among adults. Pooled relative risks (RRs) were calculated by maximally adjusted risk estimates using a random effect model. Subgroup analysis, meta-regression and sensitivity analysis were conducted whenever appropriate. RESULTS: Of 3537 papers, 21 articles with each including 1 to 3 cohorts were identified. In this meta-analysis, nephrolithiasis was reciprocally linked to HTN, DM and GS. Kidney stones were significantly associated with 31%, 33% and 46% higher risks of incident HTN, DM and GS whereas GS was associated with a significantly higher risk of nephrolithiasis (RR: 1.49; 95% CI, 1.28-1.73), followed by HTN (RR: 1.30; 95% CI, 1.11-1.52) and DM (RR: 1.18; 95% CI, 1.07-1.29). Also, females with DM (RR: 1.29; 95% CI, 1.08-1.55) were more likely to develop kidney stones than diabetic male patients (RR: 0.91; 95% CI, 0.75-1.10). CONCLUSION: Although additional studies are needed to confirm these findings and elucidate the mechanisms, this study revealed possible bidirectional associations between nephrolithiasis and HTN, diabetes and GS, which reinforced the notion of nephrolithiasis as a systemic disease that requires comprehensive investigations.

Dietary and lifestyle factors for primary prevention of nephrolithiasis: a systematic review and meta-analysis.

BACKGROUND: Dietary and lifestyle factors may play an important role in the increasing prevalence of nephrolithiasis. We aimed to review and quantify the associations between lifestyle factors and incident nephrolithiasis and suggest lifestyle changes for the primary prevention of nephrolithiasis. METHODS: PubMed, EMBASE, and Cochrane Library were searched up to May 2019, for observational studies and randomized controlled trials (RCTs) that assessed modifiable lifestyle factors and risk of nephrolithiasis in adults. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were computed using a random effects model. The I2 statistic was employed to evaluate heterogeneity. Subgroup analysis, sensitivity analysis and meta-regression were also conducted whenever possible. RESULTS: Fifty relevant articles with 1,322,133 participants and 21,030 cases in total were identified. Prominent risk factors for incident stones were body mass index (1.39,1.27-1.52), dietary sodium (1.38, 1.21-1.56), fructose, meat, animal protein, and soda. In contrast, protective factors included fluid intake (0.55, 0.51-0.60), a Dietary Approaches to Stop Hypertension (DASH) style diet (0.69, 0.64-0.75), alcohol (0.69, 0.56-0.85), water, coffee, tea, vegetables, fruits, dietary fiber, dietary calcium (0.83, 0.76-0.90), and potassium. Vitamin D (1.22, 1.01-1.49) and calcium (1.16, 1.00-1.35) supplementation alone increased the risk of stones in meta-analyses of observational studies, but not in RCTs, where the cosupplementation conferred significant risk. CONCLUSIONS: Several modifiable factors, notably fluid intake, dietary patterns, and obesity, were significantly associated with nephrolithiasis. Long-term RCTs are required to investigate the cost-effectiveness of dietary patterns for stone prevention. The independent and combined effects of vitamin D and calcium supplementation on nephrolithiasis need further elucidation.

Bladder preservation approach versus radical cystectomy for high-grade non-muscle-invasive bladder cancer: a meta-analysis of cohort studies.

BACKGROUND: High-grade non-muscle-invasive bladder cancer is superficial; nonetheless, it is an aggressive cancer. Proper management strategy selection following transurethral resection between bladder preservation (BP) and radical cystectomy (RC) could result in delayed or excessive treatment. Hence, selecting the optimal treatment modality remains controversial to date. METHODS: We searched MEDLINE, The Cochrane Library, EMBASE, China National Knowledge Infrastructure, and Wanfang database through 12 April 2018. Quality and publication bias were assessed using the Newcastle-Ottawa Scale and Begg's/Egger's test. We collected 2-year, 5-year, 10-year, and 15-year survival rate and hazard ratio (HR) for overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS). Using the Review Manager 5.2 software, we used the odds ratio (OR) of specific years and HR for meta-analysis. Subgroup analysis was performed by the original tumor state, radical cystectomy timing, bladder preservation modality, and age. RESULTS: In total, 11 cohorts with 1735 patients were selected for the meta-analysis. All OR of OS supported BP as a better treatment option; however, all OR of PFS had no significant differences. As for CSS, only the 15-year OR reflected a statistical significance preferring RC. Subgroup analysis showed that BP is more appropriate for patients older than 65 and G3 tumor. Limited data demonstrated that late RC (> 3 months) is more effective compared to early RC (< 3 months) and intravesical Bacillus Calmette-Guerin was not statistically different from that of RC. The mixed BP modalities were significantly better compared to RC in OS and worse in CSS, with both having a very low evidence strength. CONCLUSIONS: BP is a superior treatment modality compare to RC, especially for older patients and T1G3 or lower grade tumors. However, the superior BP modality was unclear. Conversely, RC could be a better option for younger patients. More specifically, late RC may be more beneficial but had a very-low-level of evidence. Quality of life should be considered equal to survival outcome; hence, post-treatment follow-up needs to be performed. Prospective randomized studies should be performed to overcome the limitations of this meta-analysis study. REGISTRATION: Registration ID is CRD42018093491 .

Unexplained association between cystitis glandularis and interstitial cystitis in females: a retrospective study.

INTRODUCTION AND HYPOTHESIS: An increasing number of female patients have received comorbid diagnoses of cystitis glandularis (CG) and interstitial cystitis (IC) at our institution. In addition, most of these patients suffer from coexisting obstructive lower urinary tract diseases (OLUTDs). In this study, we aimed to present evidence of the possible association between CG and IC and analyze the clinical features of this association. METHODS: We retrospectively reviewed the charts of 395 female patients diagnosed with CG and/or IC. The patients were divided into three groups: group A (CG only), group B (IC only), and group C (CG+IC). Chi-squared tests were applied to compare the prevalence rates of CG in patients with IC and in the general population, the prevalence rates of IC in patients with CG and in the general population, and the prevalence rates of OLUTD in the three patient groups. RESULTS: The prevalence rate of IC in patients with CG was significantly higher than that in the general population, while the prevalence rate of CG in patients with IC was also significantly higher than that in the general population. For groups A, B, and C, 93 (39.2 %), 30 (44.1 %), and 58 (64.4 %) cases respectively presented with OLUTDs, and the prevalence rate of OLUTDs varied significantly among the three groups. CONCLUSIONS: This retrospective study found a possible association between CG and IC, and coexisting OLUTDs influenced this association.

Novel anthropometric measures are positively associated with erectile dysfunction: a cross-sectional study.

BACKGROUND: Currently, a growing number of research studies have shown a positive association between obesity and erectile dysfunction, while traditional anthropometric measures, such as BMI, have limited ability to assess the risk of erectile dysfunction. Therefore, this study aimed to investigate the association between the new anthropometric index and erectile dysfunction. METHODS: A study involving 3594 participants from the National Health and Nutrition Examination Survey was conducted. The study calculated various anthropometric indices such as waist circumference (WC), waist-to-height ratio (WtHR), body mass index (BMI), a body shape index (ABSI), conicity index (CI), and body roundness index (BRI). The relationship between anthropometric indices and erectile dysfunction (ED) was investigated using multivariate logistic regression and restricted cubic splines (RCS). Interaction analysis was conducted on subgroups to confirm the findings. Additionally, the efficacy of various anthropometric indicators in predicting the risk of erectile dysfunction was assessed using the receiver operating characteristic curve (ROC). RESULTS: After adjusting for potential confounding factors, we identified a positive and independent correlation between erectile dysfunction (ED) and all other anthropometric measures except for BMI. Additionally, the risk of ED increased by 49% and 42% for each standard deviation increment in ABSI and CI, respectively. Dose-response curve analysis demonstrated that WC, BMI, WtHR, and CI displayed a non-linear correlation with the risk of ED. The subgroup analysis revealed that individuals classified as White, who had higher levels of WC, ABSI, and CI, were more susceptible to erectile dysfunction compared to people from other races. ROC analysis showed that ABSI was superior in detecting erectile dysfunction (area under the curve: 0.750; 95% CI 0.732-0.768; optimal cutoff value: 0.083) as compared to other indices. The combination of obesity defined by BMI and other anthropometric measures showed that higher ABSI and CI levels were positively associated with the prevalence of erectile dysfunction, independent of BMI (P < .001). CONCLUSION: In this study, anthropometric indicators including ABSI, BRI, WtHR, CI, and WC were positively associated with erectile dysfunction. To improve the prevention and treatment of this condition, it is recommended that new anthropometric indicators receive greater consideration.

Liposome-coated nanoparticle triggers prostate cancer ferroptosis through synergetic chemodynamic-gas therapy.

Ferroptosis has attracted much attention for tumor treatment. It has been recently identified that castration-resistant prostate cancer (CRPC) is vulnerable to ferroptosis inducers. Notably, chemodynamic therapy (CDT), triggered by metal ions, could easily induce ferroptosis via a Fenton/Fenton-like reaction, but its efficiency was highly dependent on the intracellular H2O2 concentration, posing significant changes for its clinical translation. Herein, we attached glucose oxidase (GOx) onto the surface of manganese sulfide (MnS) and developed therapeutic nanocomposites (Lpo@MnS-GOx) after encapsulating with liposome. Upon internalization by cancer cells, the released GOx could transform glucose into gluconic acid (GA) and H2O2. Notably, the generated GA stimulates the degradation of MnS, followed by the promotion of the release of H2S and Mn2+, whereas the produced H2O2 can amplify the Fenton-like response initiated by Mn2+. The enhanced CDT combined with the gas therapy effect could simultaneously promote the accumulation of reactive oxygen species and finally induce ferroptosis and exhibit an excellent anti-tumor effect. Consequently, these Lpo@MnS-GOx NPs with enhanced ferroptosis-induced effect will find great potential for CRPC cancer treatment.

GABA/baclofen stabilizes PD-L1 and enhances immunotherapy of breast cancer.

The programmed death-ligand 1 (PD-L1) on the surface of tumor cells binds to the receptor programmed cell death protein 1 (PD-1) on effector T cells, thereby inhibiting the anti-tumor immune response. Immune checkpoint blockade (ICB) therapy targeting PD-1/PD-L1 has been approved for the treatment of human cancers with lasting clinical benefit. However, many cancer patients did not respond to anti-PD-1/PD-L1 antibody blocking therapy or drugs targeting PD-1/PD-L1. Recent studies have shown that the response to PD-1/PD-L1 blockade may be related to the PD-L1 abundance of tumor cells. Therefore, it is of crucial significance to find drugs to regulate the expression of PD-L1, which can provide new strategies to improve the response rate and efficacy of PD-1/PD-L1 blocking in cancer treatment. Here, we found that GABA and baclofen, upregulates the protein level of PD-L1 by reducing the mRNA and protein levels of STUB1, a E3 ubiquitin ligase, thereby decreasing the interaction between STUB1 and PD-L1, and ultimately stabilizing PD-L1. Notably, GABA and baclofen did not affect cell proliferation in vitro, while in the treatment of breast cancer in mice, the therapeutic effect of baclofen combined with anti-PD-L1 antibody is significantly better than that of using anti-PD-L1 antibody alone by stimulating tumor infiltration of CD8+ T cells and antitumor immunity. Taken together, we unveiled a previously unappreciated role of GABA/baclofen in stabilizing PD-L1 and enhancing the immunotherapy of breast cancer.

Relationship between dietary niacin intake and erectile dysfunction: a population-based study.

Existing research on the precise link between dietary niacin intake and erectile dysfunction (ED) is scarce. Thus, this study aimed to investigate the potential association between dietary niacin intake and the risk of ED. Multivariate logistic regression and restricted cubic splines (RCSs) were used to examine the relationship between dietary niacin intake and ED. Subgroup interaction analysis was performed to assess the impact of different subgroups on the study outcomes. In addition, 1:1 propensity score matching (PSM) was employed to adjust for potential confounding factors, ensuring the reliability of the results. The analyzed data were collected from the 2001-2004 National Health and Nutrition Examination Survey (NHANES) in the USA. The study encompassed 3184 adults, among whom 863 participants were identified as having ED. Following adjustments for potential confounders, the findings revealed that higher niacin intake, specifically in the highest tertile, was associated with a decreased risk of ED compared to that in the lowest tertile, showing an odds ratio (OR) of 0.56 (95% confidence interval [CI]: 0.37-0.85). Analysis of dose-response curves illustrated a negative correlation between dietary niacin intake and the risk of ED. Subgroup and interaction analyses fortified the consistency of these results. Furthermore, PSM corroborated the validity of the findings. This study suggests an inverse association between dietary niacin intake and the risk of ED. However, establishing a cause-and-effect relationship remains elusive, and defining the safe threshold of niacin intake to prevent ED requires further investigation.

d-mannose targets PD-1 to lysosomal degradation and enhances T cell-mediated anti-tumor immunity.

High expression of programmed cell death protein 1 (PD-1), a typical immune checkpoint, results in dysfunction of T cells in tumor microenvironment. Antibodies and inhibitors against PD-1 or its ligand (PD-L1) have been widely used in various malignant tumors. However, the mechanisms by which PD-1 is regulated are not fully understood. Here, we report a mechanism of PD-1 degradation triggered by d-mannose and the universality of this mechanism in anti-tumor immunity. We show that d-mannose inactivates GSK3ß via promoting phosphorylation of GSK3ß at Ser9, thereby leading to TFE3 translocation to nucleus and subsequent PD-1 proteolysis induced by enhanced lysosome biogenesis. Notably, combination of d-mannose and PD-1 blockade exhibits remarkable tumor growth suppression attributed to elevated cytotoxicity activity of T cells in vivo. Furthermore, d-mannose treatment dramatically improves the therapeutic efficacy of MEK inhibitor (MEKi) trametinib in vivo. Our findings unveil a universally unrecognized anti-tumor mechanism of d-mannose by destabilizing PD-1 and provide strategies to enhance the efficacy of both immune checkpoint blockade (ICB) and MEKi -based therapies.

Expression and functional role of Cdx2 in intestinal metaplasia of cystitis glandularis.

PURPOSE: Cdx2 is an essential transcription factor in intestinal epithelial cell differentiation and proliferation. However, to our knowledge the expression and role of Cdx2 in the development of intestinal cystitis glandularis, a metaplastic lesion induced by chronic inflammation, remained to be explored. MATERIALS AND METHODS: Real-time polymerase chain reaction was used to examine Cdx2, LI-cadherin and villin expression in typical and intestinal cystitis glandularis, and normal bladder tissue. Cdx2 cDNA was subcloned to the retroviral vector pLNCX2 for subsequent transfection into human bladder urothelium cells and rat bladder urothelium. Cdx2 mRNA and protein levels, and cell morphology and proliferation were assessed after transfection using real-time polymerase chain reaction, phase contrast microscopy, transmission electron microscopy and MTT assay, respectively. RESULTS: Higher mRNA levels of Cdx2, villin and LI-cadherin were detected in intestinal cystitis glandularis compared to normal bladder and typical cystitis glandularis. Only Cdx2 groups attained statistical significance (p <0.001). Retroviral over expression of Cdx2 resulted in increased mRNA and protein expression of Cdx2 as well as villin and LI-cadherin levels, and increased cell proliferation. A distinct change in cellular morphology, in which cells resembled intestinal-like cells, was also observed in vitro and in vivo. CONCLUSIONS: Cdx2 may have a critical role in regulating intestinal metaplasia in cystitis glandularis. Further studies are planned to assess the potential of using Cdx2 as a marker and therapeutic target for cystitis glandularis.

Interleukin-6 levels in female rats with protamine sulfate-induced chronic cystitis treated with hyaluronic acid.

OBJECTIVES: To measure interleukin-6 levels in a protamine sulfate-induced chronic cystitis rat model treated with hyaluronic acid, and to study the correlation among interleukin-6, bladder inflammatory degree and voiding frequency. METHODS: A chronic cystitis model was created in female rats by using long-term intermittent intravesical protamine sulfate (0.5 mL, 30 mg/mL). Then, hyaluronic acid (0.5 mL, 0.8 mg/mL) was also instilled intravesically in the rats. Interleukin-6 levels were analyzed with immunohistochemistry, real-time reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. Hematoxylin-eosin staining was carried out to examine bladder inflammatory degree based on a four-point scoring system (from 0 - none to 3 - severe). Voiding patterns were investigated by cystometrography. RESULTS: According to cystometrography, protamine sulfate-induced rats had significantly shorter intercontraction intervals and less bladder capacity (P < 0.001). The bladder tissue of the rats showed severe chronic inflammation. Immunohistochemistry, reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay showed significantly higher expression of interleukin-6 (P < 0.001). After intravesical administration of hyaluronic acid, both intercontraction intervals and bladder capacity increased significantly (P < 0.001), whereas both bladder inflammatory degree and interleukin-6 levels decreased significantly (P < 0.001). Furthermore, there was a strong correlation between interleukin-6 levels and inflammatory degree (r = 0.727, P < 0.001), and also between interleukin-6 levels and voiding frequency (r = -0.761, P < 0.001). CONCLUSIONS: Intravesical administration of hyaluronic acid decreases interleukin-6 levels, as well as the severity of bladder inflammation and voiding frequency in a rat model of chronic cystitis. Interleukin-6 levels closely correlate with the inflammatory degree and voiding frequency. Thus, they can be regarded as an assessment measure of therapeutic impact.

New insights and options into the mechanisms and effects of combined targeted therapy and immunotherapy in prostate cancer.

Chronic inflammation is believed to drive prostate carcinogenesis by producing reactive oxygen species or reactive nitrogen species to induce DNA damage. This effect might subsequently cause epigenetic and genomic alterations, leading to malignant transformation. Although established therapeutic advances have extended overall survival, tumors in patients with advanced prostate cancer are prone to metastasis, transformation into metastatic castration-resistant prostate cancer, and therapeutic resistance. The tumor microenvironment (TME) of prostate cancer is involved in carcinogenesis, invasion and drug resistance. A plethora of preclinical studies have focused on immune-based therapies. Understanding the intricate TME system in prostate cancer may hold much promise for developing novel therapies, designing combinational therapeutic strategies, and further overcoming resistance to established treatments to improve the lives of prostate cancer patients. In this review, we discuss nonimmune components and various immune cells within the TME and their putative roles during prostate cancer initiation, progression, and metastasis. We also outline the updated fundamental research focusing on therapeutic advances of targeted therapy as well as combinational options for prostate cancer.

Relationship Between Systemic Inflammatory Response Index and Erectile Dysfunction: A Cross-sectional Study.

OBJECTIVE: To explore the association between systemic inflammation response index (SIRI) and erectile dysfunction (ED) in American men. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) between 2001 and 2004 were used. Multivariate logistic regression and restricted cubic spline were used to evaluate the relationship between SIRI and ED. Interaction analysis was performed for subgroups to verify the results. Meanwhile, 1:1 propensity score matching was performed to adjust for potential confounding factors for data reanalysis to confirm the reliability of the results. RESULTS: A total of 3543 US adults aged 20years or older were included in the study, of whom 955 participants were considered to have ED. After adjusting for potential confounding factors, we found that compared with the lowest tertiles, the highest tertiles of SIRI showed a positive association with ED, which odd ratio was 1.70 (95%CI: 1.16-2.50). Dose-response curve analysis showed a positive linear correlation between SIRI and ED prevalence. And in the subgroup analysis, the interaction analysis showed that the results were consistent. Meanwhile, the matching of propensity scores further confirmed the validity of the results. CONCLUSION: In conclusion, in this cross-sectional study, we found a positive relationship between SIRI and the prevalence of ED. Further experimental studies are needed to explore the underlying mechanism in the future.

Associations between exposure to organophosphate esters and overactive bladder in U.S. adults: a cross-sectional study.

Background: The relationship between exposure to organophosphate esters (OPEs) and the risk of developing overactive bladder (OAB) is uncertain. The purpose of this study is to examine the potential link between urinary metabolites of organophosphate esters and OAB. Method: Data from the National Health and Nutrition Examination Survey (NHANES) database of the 2011-2016 cycles were utilized. Four urinary metabolites of organophosphate esters: diphenyl phosphate (DPHP), bis (1,3-dichloro-2-propyl) phosphate (BDCPP), bis (2-chloroethyl) phosphate (BCEP), and dibutyl phosphate (DBUP) were included in the study. Multivariate logistic regression and restricted cubic spline (RCS) were used to evaluate the relationship between urinary OPEs metabolites and OAB. Interaction analysis was conducted on subgroups to confirm the findings. Results: A total of 3,443 United States (US) adults aged 20 years or older were included in the study, of whom 597 participants were considered to have OAB. After adjusting for potential confounding factors, we found a positive association between DPHP and the risk of overactive bladder. The risk of overactive bladder increased with increasing DPHP concentrations compared with quartile 1 (quartile 2, OR = 1.19, 95% CI, 0.82-1.73, P = 0.34; quartile 3, OR = 1.67, 95% CI, 1.10-2.53, P = 0.02; Q4, OR = 1.75, 95% CI, 1.26-2.43, P = 0.002). However, after dividing the participants by gender, only the female group retained consistent results. Additionally, restricted cubic spline analysis revealed a nonlinear dose-response correlation between DPHP and OAB in female participants. In the subgroup analysis based on age, race, body mass index (BMI), recreational activity, smoking status, drinking status, hypertension, diabetes, and stroke, the interaction analysis revealed that the findings were uniform. Conclusion: Our findings indicate that exposure to DPHP could elevate the risk of OAB in US adult females. Further experimental studies are needed to explore the underlying mechanism in the future.

Targeting fibrinogen-like protein 1 enhances immunotherapy in hepatocellular carcinoma.

How cancer cells evade the therapeutic effects of immune checkpoint blockade is largely unknown. Here, we report that fibrinogen-like protein 1 (FGL1), a newly identified immune checkpoint ligand, was modified by acetylation at Lys 98 in hepatocellular carcinoma (HCC), which targeted it for proteasomal degradation. Sirtuin 2 (SIRT2) deacetylated and stabilized FGL1, thus promoting immune evasion. Notably, the SIRT2 inhibitor 2-Cyano-3-[5-(2,5-dichlorophenyl)-2-furanyl]-N-5-quinolinyl-2-propenamide (AGK2) enhanced acetylation of FGL1 and reduced FGL1 protein levels in vitro. The combination of AGK2 and programmed death ligand 1 (PD-L1) blockade effectively suppressed tumor growth and improved overall survival of mice. Furthermore, aspirin, an old drug, could directly acetylate FGL1 at Lys 98 and promote its degradation in vitro. Aspirin enhanced the immunotherapeutic efficacy, induced tumor regression, and extended the lifespan of tumor-bearing mice. Furthermore, the SIRT2/FGL1 axis was expressed in HCC specimens. Collectively, these findings unveil an acetylation-mediated regulation of FGL1, identify a potential target for HCC immunotherapy, and provide therapeutic strategies for the clinical treatment of HCC.