FSH Is Responsible for Androgen Deprivation Therapy-Associated Atherosclerosis in Mice by Exaggerating Endothelial Inflammation and Monocyte Adhesion.

BACKGROUND: Androgen deprivation therapy (ADT) is the mainstay treatment for advanced prostate cancer. But ADTs with orchiectomy and gonadotropin-releasing hormone (GnRH) agonist are associated with increased risk of cardiovascular diseases, which appears less significant with GnRH antagonist. The difference of follicle-stimulating hormone (FSH) in ADT modalities is hypothesized to be responsible for ADT-associated cardiovascular diseases. METHODS: We administered orchiectomy, GnRH agonist, or GnRH antagonist in male ApoE-/- mice fed with Western diet and manipulated FSH levels by testosterone and FSH supplementation or FSH antibody to investigate the role of FSH elevation on atherosclerosis. By combining lipidomics, in vitro study, and intraluminal FSHR (FSH receptor) inhibition, we delineated the effects of FSH on endothelium and monocytes and the underlying mechanisms. RESULTS: Orchiectomy and GnRH agonist, but not GnRH antagonist, induced long- or short-term FSH elevation and significantly accelerated atherogenesis. In orchiectomized and testosterone-supplemented mice, FSH exposure increased atherosclerosis. In GnRH agonist-treated mice, blocking of short FSH surge by anti-FSHß antibody greatly alleviated endothelial inflammation and delayed atherogenesis. In GnRH antagonist-treated mice, FSH supplementation aggravated atherogenesis. Mechanistically, FSH, synergizing with TNF-α (tumor necrosis factor alpha), exacerbated endothelial inflammation by elevating VCAM-1 (vascular cell adhesion protein 1) expression through the cAMP/PKA (protein kinase A)/CREB (cAMP response element-binding protein)/c-Jun and PI3K (phosphatidylinositol 3 kinase)/AKT (protein kinase B)/GSK-3ß (glycogen synthase kinase 3 beta)/GATA-6 (GATA-binding protein 6) pathways. In monocytes, FSH upregulated CD29 (cluster of differentiation 29) expression via the PI3K/AKT/GSK-3ß/SP1 (specificity protein 1) pathway and promoted monocyte-endothelial adhesion both in vitro and in vivo. Importantly, FSHR knockdown by shRNA in endothelium of carotid arteries markedly reduced GnRH agonist-induced endothelial inflammation and atherosclerosis in mice. CONCLUSIONS: FSH is responsible for ADT-associated atherosclerosis by exaggerating endothelial inflammation and promoting monocyte-endothelial adhesion.

Effect of FGFR alteration on prognosis in 1963 urothelial carcinoma patients with immune checkpoint inhibitors: Implying combination of FGFR inhibitor and immunotherapy for FGFR-altered urothelial carcinoma.

Immune checkpoint inhibitors (ICIs) are essential for urothelial carcinoma (UC) treatment. Fibroblast growth factor receptor (FGFR) alterations, as common oncogenic drivers in UC, have been reported to drive T cell depletion of UC immune microenvironment via up-regulating FGFR signaling, which indicated FGFR alterations potentially result in reduced response to ICIs. In addition, the selective pan-FGFR inhibitor showed better clinical benefit in clinical trials, indicating FGFR has emerged as critical therapeutic target via inhibiting FGFR signaling. The present study aims to evaluate prognosis and response to ICIs between FGFR-altered UC patients and FGFR-wildtype UC patients via 1963 UC patients and offers new insights into personalized precision therapy and combination therapy for UC.

Follicle-Stimulating Hormone Provokes Macrophages to Secrete IL-1ß Contributing to Atherosclerosis Progression.

Abnormally high follicle-stimulating hormone (FSH) has been reported to associate with cardiovascular diseases in prostate cancer patients with specific androgen deprivation therapy and in menopausal women. All of the cardiovascular diseases were involved in atherosclerosis. However, the pathogenic mechanism of FSH-associated atherosclerosis remains uncertain. Apolipoprotein E-deficient mice were chosen to develop atherosclerosis, of which the plaques were analyzed with administration of short- and long-term FSH imitating androgen deprivation therapy-induced and menopausal FSH elevation. The study showed that short- and long-term exposure of FSH significantly accelerated atherosclerosis progression in apolipoprotein E-deficient mice, manifested as strikingly increased plaques in the aorta and its roots, increased macrophage content, reduced fibrin, and an enlarged necrotic core, suggesting a decrease in plaque stability. Furthermore, expression profiles from the Gene Expression Omnibus GSE21545 dataset revealed that macrophage inflammation was tightly associated with FSH-induced atherosclerotic progression. The human monocyte cell line THP-1 was induced by PMA and worked as a macrophage model to detect inflammatory factors and cellular functions. FSH remarkably promoted the expression of IL-1ß in macrophages and strikingly increased the chemotactic migratory capacity of macrophages toward MCP-1, but the promigratory capacity of FSH was attenuated in foam cells. Overall, we revealed that FSH significantly promoted the inflammatory response and migration of macrophages, thereby provoking atherosclerosis development.

Follicle-Stimulating Hormone Provokes Macrophages to Secrete IL-1ß Contributing to Atherosclerosis Progression.

Abnormally high follicle-stimulating hormone (FSH) has been reported to associate with cardiovascular diseases in prostate cancer patients with specific androgen deprivation therapy and in menopausal women. All of the cardiovascular diseases were involved in atherosclerosis. However, the pathogenic mechanism of FSH-associated atherosclerosis remains uncertain. Apolipoprotein E-deficient mice were chosen to develop atherosclerosis, of which the plaques were analyzed with administration of short- and long-term FSH imitating androgen deprivation therapy-induced and menopausal FSH elevation. The study showed that short- and long-term exposure of FSH significantly accelerated atherosclerosis progression in apolipoprotein E-deficient mice, manifested as strikingly increased plaques in the aorta and its roots, increased macrophage content, reduced fibrin, and an enlarged necrotic core, suggesting a decrease in plaque stability. Furthermore, expression profiles from the Gene Expression Omnibus GSE21545 dataset revealed that macrophage inflammation was tightly associated with FSH-induced atherosclerotic progression. The human monocyte cell line THP-1 was induced by PMA and worked as a macrophage model to detect inflammatory factors and cellular functions. FSH remarkably promoted the expression of IL-1ß in macrophages and strikingly increased the chemotactic migratory capacity of macrophages toward MCP-1, but the promigratory capacity of FSH was attenuated in foam cells. Overall, we revealed that FSH significantly promoted the inflammatory response and migration of macrophages, thereby provoking atherosclerosis development.

Effect of regional versus general anesthesia on recurrence of non-muscle invasive bladder cancer: a systematic review and meta-analysis of eight retrospective cohort studies.

BACKGROUND: Regional anesthesia appears to reduce cancer recurrence, but the optimal anesthesia modality for non-muscle invasive bladder cancer (NMIBC) were still under debate. Therefore, we sought to assess the effect of regional and GA only upon the recurrence and long-term prognosis of NMIBC through this meta-analysis. METHODS: We performed an extensive literature search of PubMed, Embase, Web of Science, the Cochrane Library and China National Knowledge Infrastructure (up to October 30, 2022) to identify eligible articles on the possible impact of different anesthetic modalities for the recurrence rate of NMIBC. RESULTS: Eight studies comprising 3764 participants, including 2117 subjects with RA and 1647 with GA, were finally enrolled. Cancer recurrence rate was significantly lower in subjects with RA than those with GA (RR 0.84, 95%CI 0.72-0.98, P = 0.03). We didn't detect the differences between GA and RA in the time of recurrence (SMD 2.07, 95% CI -0.49-4.63, P = 0.11) and cancer progression (RR 1.14, 95%CI 0.71-1.84, P = 0.59). Results from subgroup analysis demonstrated that spinal anesthesia could significantly decrease the incidence of cancer recurrence in comparison with general anesthesia (RR 0.80, 95%CI 0.72-0.88, P < 0.001) and high-risk NMIBC patients who received RA tended to have less recurrence (HR 0.55, 95%CI 0.39-0.79, P = 0.001) than those receiving GA. CONCLUSIONS: RA, especially spinal anesthesia, may be effective in reducing the recurrence rate after transurethral resection of NMIBC. More prospective experimental and clinical studies are needed to validate our findings. TRIAL REGISTRATION: INPLASY registration INPLASY2022110097.

Intratumoral fibrosis and patterns of immune infiltration in clear cell renal cell carcinoma.

BACKGROUND: Intratumoral fibrosis was positively correlated with histological grade of renal clear cell carcinoma (ccRCC) and intratumoral inflammation. However, the association of intratumoral fibrosis with the immune infiltration of ccRCC was few evaluated. METHODS: We used the second harmonic generation (SHG)-based imaging technology and evaluated the intratumoral fibrosis in ccRCC, and then divided the patients into the high fibrosis group (HF) and the low fibrosis group (LF). Meanwhile, the Kaplan-Meier survival curve analysis was performed to analyze the relationship between intratumoral fibrosis and the disease-free survival rate. Antibody arrays were used for seeking difference in cytokines and immune infiltration between the HF group (N = 11) and LF group (N = 11). The selected immune infiltration marker was then verified by immunohistochemistry (IHC) staining in 45 ccRCC samples. RESULTS: Out of 640 cytokines and immune infiltration markers, we identified 115 proteins that were significantly different in quantity between ccRCC and adjacent normal tissues. In addition, the Venn diagram indicated that six proteins, including Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4), were significantly associated with intratumoral fibrosis (p < 0.05). The GO/KEGG enrichment analysis indicated that the proteins associated with intratumoral fibrosis were involved in the immunity and tumor-infiltrating lymphocytes. The expression of the CTLA4 was negatively correlated with collagen level, confirmed by IHC staining of CTLA4 (p < 0.05). CONCLUSIONS: The study indicated that the intratumoral fibrosis level was negatively correlated with the expression of CTLA4 in the tumor immune microenvironment of the ccRCC, which posed the potential value of targeting the stroma of the tumor, a supplement to immunotherapy. However, the specific mechanism of this association is still unclear and needs further investigation.

Predicting ureteral status below the ureteral calculi in patients undergoing ureteroscopic lithotomy.

BACKGROUND: During ureteroscopy, severe ureter straightness or contortion may occur before the stone is passed. PURPOSE: To identify clinical factors associated with distal ureteral status below the ureteral calculi in patients before surgery. MATERIAL AND METHODS: From October 2016 to March 2017, 101 patients with ureteral calculi who underwent ureteroscopic lithotripsy were reviewed. Patients who lacked clinical data and underwent preoperative indwelling ureteral stent placement were excluded. Univariate and multivariate analyses were performed to determine the clinical factors associated with intraoperative findings. RESULTS: A total of 101 patients were enrolled in the study (mean age = 54 years; mean stone size = 7.9 ± 4.5 mm). Overall, 25 of the 101 patients (24.7%) were diagnosed with poor distal ureteral status defined as intraoperative ureterostenosis or contortion resulting in a ureteroscope being unable to pass during the initial attempt. Univariate analysis showed significant differences in renal parenchyma thickness, ureteral wall thickening on imaging, and stone location (all, P < 0.05) with and without poor distal ureteral status. On multivariable analysis, renal parenchyma thickness (adjusted odds ratio [aOR] 0.288; 95% confidence interval [CI] 0.099-0.838; P = 0.022) and ureteral wall thickening on imaging (aOR 6.114; 95% CI 2.015-18.548; P = 0.001) independently predicted poor distal ureteral status. However, only renal parenchyma thickness was associated with severe ureter straightness or tortuosity that resulted in conversion. CONCLUSION: In conclusion, renal parenchyma thickness and ureteral wall thickening on imaging were associated with poor distal ureteral status. Therefore, patients with these predictive factors should undergo more intensive preparation before surgery.

Multivariate analysis of factors for failed continuous bladder irrigation in hemorrhagic cystitis patients after hematopoietic stem cell transplantation.

BACKGROUND: Continuous bladder irrigation (CBI) and proper adjustment of saline irrigation speed are important to avoid CBI failure in hemorrhagic cystitis (HC) patients after allogeneic hematopoietic stem cell transplantation (HSCT). Nevertheless, too fast irrigation speed could take away the patient's much heat, contribute to blood coagulopathy, and increase the nursing workload. Evaluation of risk for CBI failure remains an unmet clinical need. METHODS: The general information, clinical characteristics, and consultation records of HC patients in 1380 patients with hematopoietic stem cell transplantation in our center from 2017 to 2019 were analyzed retrospectively. The receiver operating characteristic (ROC) curve was used to calculate the cutoff point of the continuous variable, and multivariate logistic regression was used to analyze the risk factors affecting CBI failure in HC patients. RESULTS: The incidence of HC after HSCT was 23%. A total of 227 patients with HC above grade 2 were included. Univariate analysis showed that CRP, age, platelet counts, onset time after transplantation, albumin, and hemoglobin were associated with CBI failure in the short-term (P < 0.05). ROC curve and multivariate logistic regression analysis showed that CRP > 8.89 ng/ml (RR = 7.828, 95% CI 2.885-21.244), age < 14.5 years (RR = 9.940, 95% CI 3.219-30.697), and onset time of HC > 37d after transplantation (RR = 7.021, 95% CI 2.204-22.364), were independent risk factors for failure of CBI (P < 0.05). CONCLUSIONS: The study identified CRP > 8.89 ng/ml, age < 14.5 years, and onset time of HC after HSCT > 37d are independent factors for failure of CBI, which could be combined to allow stratification of HC after HSCT patients into low-, intermediate- and high-risk subgroups of CBI failure.

The Clinical Effects of Utilizing Allogeneic Acellular Dermal Matrix in the Surgical Therapy of Anterior Urethral Stricture.

OBJECTIVE: The aim of this study was to estimate the clinical effects of allogeneic acellular dermal matrix (ADM) in the surgical therapy of anterior urethral stricture (AUS). METHODS: We retrospectively collected the clinical data of 49 patients with AUS who underwent urethral repair surgery with ADM in the Department of Urology of the Peking University People's Hospital, and in the First Affiliated Hospital of the People's Liberation Army, from September 2015 to January 2019. The changes in urine flow rate and conditions of urethral mucosal coverage were observed as well as complications and outcomes, and statistical analysis was performed. RESULTS: The average maximum urine flow rates at the 1st, 6th, and 12th month post-surgery were 16.3 ± 1.5, 15.0 ± 1.9, and 14.6 ± 2.1 mL/s, respectively. These values were significantly higher than the preoperative maximum urine flow rate, 1.3 ± 0.5 mL/s (p < 0.05). Cystoscopy was performed in 11 patients 12 months after surgery, with microscopic assessment revealing good urethral epithelial mucosal coverage. Only 2 patients developed infection 2-4 weeks after surgery, while 7 patients developed noninfective urethral restricture 6-10 months after surgery and 1 patient developed urinary fistula 5 months after surgery. All of these statuses improved after receiving appropriate treatment. CONCLUSIONS: Use of ADM represents a new option for the surgical management of AUS repair and reconstruction, with positive clinical effects. In addition, it has the advantages of convenient for operation procedures and access, with no need for additional sampling surgery.

Addition of intrarectal local analgesia to periprostatic nerve block improves pain control for transrectal ultrasonography-guided prostate biopsy: a systematic review and meta-analysis.

OBJECTIVES: To evaluate the efficacy and safety of combined intrarectal local analgesia and periprostatic nerve block versus periprostatic nerve block alone for pain control during transrectal ultrasound-guided prostate biopsy. METHODS: We comprehensively searched PubMed, Embase and the Cochrane Library trials. Studies comparing the two techniques were identified and pooled for cumulative analysis. The outcome measurements included visual pain scales of three consecutive procedures of transrectal ultrasound-guided prostate biopsy, as well as short-term postoperative complication rates. RESULTS: There were 18 studies that were finally eligible for the quantitative analysis involving 2076 participants. Combined modalities significantly reduced the pain associated with probe manipulation (weighted mean difference -2.06, 95% confidence interval -2.77 to -1.35, P < 0.001), anesthesia infiltration (weighted mean difference -1.45, 95% confidence interval -2.20 to -0.70, P < 0.001) and needle biopsy (weighted mean difference -0.55, 95% confidence interval -0.76 to -0.34, P < 0.001). Subgroup analyses assessing different local analgesics showed that local anesthetics are generally more effective than myorelaxant and non-steroidal anti-inflammatory drugs. Lidocaine-prilocaine cream proved the most effective in pain control regardless of the origin of pain. No significant difference of short-term postoperative complications (fever, dysuria, acute urinary retention, hematuria, hematospermia and rectal bleeding) was found between the two techniques. The only side-effect associated with local analgesics was headache reported in studies using glyceryl trinitrate ointment. CONCLUSIONS: Combined modalities show better analgesic efficacy than periprostatic nerve block alone for transrectal ultrasound-guided prostate biopsy without increased morbidities. Among the various local analgesics, lidocaine-prilocaine cream seems to offer the best overall efficacy.

[Improved synthesis process of diethyl N-[4-[(2,4-diaminopyrido[3,2-d]pyrimidin-6-yl)methylamino]benzoyl]-L-glutamate].

OBJECTIVE: To establish a new approach to synthesis of diethyl N-[4-[(2,4-diaminopyrido[3,2-d]pyrimidin-6-yl)methylamino]benzoyl]-L-glutamate. METHODS: Target compound (5) was synthesized by the use of (2,4-dioxo-tetrahydropyridopyrimidin-6-yl)methyl acetate (1) as starting material via hydrolysis, chlorination, condensation with diethyl (p-aminobenzoyl)glutamate and aminolysis. RESULTS: A new approach to synthesis of diethyl N-[4-[(2,4-diaminopyrido[3,2-d]pyrimidin-6-yl)methylamino]benzoyl]-L-glutamate was established. This synthetic route has hydrolysis reaction, chlorination, diethyl N-(p-aminobenzoyl)-L-glutamate condensation reaction and ammonolysis reaction. The total yield is 36.7%.The structures of those compounds have identified by 1H nuclear magnetic resonance, 13C nuclear magnetic resonance and mass spectrometry. This synthetic route avoid the unstable brominated reaction product and improves the harsh condition of ammonolysis reaction. CONCLUSION: The new synthetic route has improved the reaction condition and the stability of the intermediate, and increased the extent of the derivative compounds, which has great significance to anti-folic acid of anti-tumor inhibitor synthesis.

[Clinical characteristics of IgG4 related retroperitoneal fibrosis: a report of 5 cases and literature review].

OBJECTIVE: To explore the clinical characteristics, treatment and prognosis of IgG4-related retroperitoneal fibrosis (RPF). METHODS: All the patients diagnosed as RPF in Peking University People's Hospital between February 2008 and October 2014 were included. Among them, 5 patients were identified as IgG4 related RPF. We analyzed their medical records and summarized the clinical, laboratory, and imaging features of IgG4 related RPF, which had taken the recent literature into account. RESULTS: All the 5 patients were male, with the average age 62.2 years (55-67 years). They mainly complained of abdominal pain, flank pain and weight loss, two of whom had concurrent antoimmune pancreatitis. Renal insufficiency was present in 3 patients (3/5). Four patients (4/4) showed increased erythrocyte sedimentation rate (ESR), while 3 patients (3/4) had higher serum C-reactive protein (CRP) and IgG. In addition, 4 patients (4/4) had significantly elevated serum IgG4 level. On computed tomography (CT) imaging, 5 patients showed retroperitoneal mass which surrounded the abdominal aorta and the iliac arteries, and even enveloped the ureters and the inferior vena cava. Only one patient received tissue pathological examination, which indicated the numbers of IgG4-positive plasma cells per high power field>10 and a ratio of IgG4-positive cells to all IgG-bearing cells>40%. One patient received simple surgical intervention, and 1 patient received medical treatment alone, while the remaining 3 patients received combined treatment of surgery and medications. follow-up was available for the 4 patients, all of whom had good prognosis. CONCLUSION: Part of RPF was actually IgG4-related, which was also nominated as IgG4 related RPF. It was a rare disease with unknown etiology, characterized by the elevated serum IgG4 concentration (≥1.35 g/L), with marked tissue infiltration by lymphocytes and IgG4-positive plasma cells with fibrosis, in addition to the presence of retroperitoneal mass. Glucocorticoids were the first-line therapy and IgG4 related RPF had a favourable prognosis.

Comparative analysis of adverse events among intravesical drugs in bladder cancer: a real-world study on FAERS database.

BACKGROUND: Intravesical therapy is a commonly utilized treatment for non-muscle invasive bladder cancer (NMIBC). This study focuses on summarizing the signals of all intravesical drugs and aims to highlight the comprehensive differences in adverse events (AEs) between these drugs. RESEARCH DESIGN AND METHODS: We conducted pharmacovigilance data analysis based on the real-world big data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. RESULTS: We elucidated all signals compared with the overall FAERS database or other administration routes for Bacillus Calmette-Guerin (BCG), mitomycin, gemcitabine, valrubicin, and epirubicin. Notably, the distribution of reported AEs associated with intravesical therapy exhibited a noticeable inclination toward male patients. Furthermore, all five drugs demonstrated a disproportionate distribution in local AEs, particularly in renal and urinary disorders. Additionally, specific signals and findings were summarized for each individual drug. Finally, we highlighted the AEs that resulted in serious outcomes for each drug. CONCLUSION: We have compiled an overview of the AEs tied to intravesical drugs whilst considering their individual distinctions. These insightful findings serve to enrich our comprehension of the safety profiles and potential risks linked to intravesical therapy.

New flavonoid and their anti-A549 cell activity from the bi-directional solid fermentation products of Astragalus membranaceus and Cordyceps kyushuensis.

Astragalus membranaceus and Cordyceps kyushuensis were used to obtain Astragalus membranaceus-Cordyceps kyushuensis bi-directional solid fermentation products using the bi-directional solid fermentation technique. The fermentation products were isolated and purified to obtain 20 individual compounds, of which compound 1 was a novel isoflavane, and compounds 2, 3, and 4 were novel isoflavones, along with 16 known compounds. In vitro experiments demonstrated that compounds 4, 5, 8, 10, and 20 exhibited significant inhibitory activity against A549 lung cancer cells. Specifically, the IC50 value of the novel compound 4 was 53.4 µM, while the IC50 value of cordycepin was 9.0 µM.