Influence of COVID-19 pandemic on timing and outcomes of treatment for acute testicular torsion in adults: a single institution experience.

INTRODUCTION: The worldwide spread of SARS-COV2 had led to a delay in treatment of numerous urological pathologies, even in emergency conditions. We therefore sought to determine whether the timing of diagnosis and treatment and the postoperative outcome of patients with testicular torsion had been changed during the COVID pandemic. MATERIALS AND METHODS: We considered all patients evaluated in the emergency department (ED) for testicular torsion from February 2018 to August 2019 (pre-COVID period) and from February 2020 to August 2021 (during COVID pandemic). All patients underwent clinical and ultrasound evaluation and subsequently scrotal exploration. Primary outcomes were the time differences from pain onset to ED presentation and from ED presentation to surgical treatment. We also investigated whether the number or orchiectomies required changed during the pandemic. RESULTS: A total of 54 patients were divided in two groups: 40 patients in pre-COVID-19 group and 14 in the COVID-19 cohort. Mean time from symptoms onset to ED access was longer during the pandemic (4.2 ± 5.7 versus 39.6 ± 37.3 hours, p = 0.009). Mean time from ED access to surgery was similar (2.9 ± 1.1 versus 4.2 ± 2.3, p = 0.355). In addition, the number of orchiectomies was higher in COVID-19 group (2.5% versus 28.6%, p < 0.01), compared to a lower number of detorsions (97.5% versus 71.4%, p < 0.01). Elapsed time from pain onset to surgery was directly correlated with the increased white blood cell (WBC) count after surgery (r = 0.399, p = 0.002). DISCUSSION AND CONCLUSIONS: The current study identifies a significant delay in presentation of testicular torsion which resulted in a significant increase in orchiectomies with the expected decreased in detorsion/orchiopexy. In addition, there was an increase in the WBC at presentation associated with delayed presentation.

The association of impaired semen quality and pregnancy rates in assisted reproduction technology cycles: Systematic review and meta-analysis.

Some studies suggest a relationship between semen quality and pregnancy rates of assisted reproduction technologies (ART). Others have questioned the utility of semen quality as proxy for fertility in couples attempting to conceive with or without assistance. We aimed to investigate the current body of evidence which correlates semen parameters and clinical pregnancy among couples utilizing ART (i.e. in vitro fertilization [IVF], intracytoplasmic sperm injection [ICSI]) through a systematic review and meta-analysis of cross-sectional and retrospective cohort studies. Pooled Odd Ratio (OR) for oligo-, astheno- and teratospermic compared to normospermic number of ART cycles were calculated among. Meta-regression and sub-group analysis were implemented to model the contribution of clinical/demographic and laboratory standards differences among the studies. Overall, 17 studies were analysed representing 17,348 cycles were analysed. Pooled OR for impaired sperm concentration, motility and morphology was 1 (95%Confidence Interval [CI]: 0.97-1.03), 0.88 (95%CI: 0.73-1.03) and 0.88 (95%CI: 0.75-1) respectively. Further analysis on sperm morphology showed no differences with regard of IVF versus ICSI (p = 0.14) nor a significant correlation with rising reference thresholds (Coeff: -0.02, p = 0.38). A temporal trend towards a null association between semen parameters and clinical pregnancy was observed over the 20-year observation period (Coeff: 0.01, p = 0.014). The current analysis found no association between semen quality (as measured by concentration, motility or morphology) and clinical pregnancy rates utilizing ART. Future investigations are necessary to explore the association between semen parameters and other ART outcomes (e.g. fertilization, implantation, birth and perinatal health).

Neuropathic pain-alleviating activity of novel 5-HT6 receptor inverse agonists derived from 2-aryl-1H-pyrrole-3-carboxamide.

The diverse signaling pathways engaged by serotonin type 6 receptor (5-HT6R) together with its high constitutive activity suggests different types of pharmacological interventions for the treatment of CNS disorders. Non-physiological activation of mTOR kinase by constitutively active 5-HT6R under neuropathic pain conditions focused our attention on the possible repurposing of 5-HT6R inverse agonists as a strategy to treat painful symptoms associated with neuropathies of different etiologies. Herein, we report the identification of compound 33 derived from the library of 2-aryl-1H-pyrrole-3-carboxamides as a potential analgesic agent. Compound 33 behaves as a potent 5-HT6R inverse agonist at Gs, Cdk5, and mTOR signaling. Preliminary ADME/Tox studies revealed preferential distribution of 33 to the CNS and placed it in the low-risk safety space. Finally, compound 33 dose-dependently reduced tactile allodynia in spinal nerve ligation (SNL)-induced neuropathic rats.

A biofeedback-guided programme or pelvic floor muscle electric stimulation can improve early recovery of urinary continence after radical prostatectomy: A meta-analysis and systematic review.

PURPOSE: Urinary incontinence (UI) after radical prostatectomy (RP) is an early side effect after catheter removal. This systematic review and meta-analysis were conducted to compare different forms of non-invasive treatments for post-RP UI and to analyse whether the addition of biofeedback (BF) and/or pelvic floor muscle electric stimulation (PFES) to PF muscle exercise (PFME) alone can improve results in terms of continence recovery rate. MATERIALS AND METHODS: A literature search was performed following the PRISMA guidelines. We performed a cumulative meta-analysis to explore the trend in the effect sizes across subgroups during a 12-months follow-up. RESULTS: Twenty-six articles were selected. At baseline after RP and catheter removal, mean pad weight varied extremely. At 1- and 3-months intervals, mean difference in pad weight recovery from baseline was significantly higher using guided programs (BF, PFES or both) than using PFME alone (3-months: PFME 111.09 g (95%CI 77.59-144.59), BF 213.81 g (95%CI -80.51-508-13), PFES 306.88 g (95%CI 158.11-455.66), BF + PFES 266.31 g (95%CI 22.69-302.93); P < .01), while at 6- and 12-months differences were similar (P > .04). At 1- and 3-months intervals, event rate (ER) of continence recovery was significantly higher using guided programs than using PFME alone (3-months: PFME 0.40 (95%CI 0.30-0.49), BF 0.49 (95%CI 0.31-0.67), PFES 0.57 (95%CI 0.46-0.69), BF + PFES 0.75 (95%CI 0.60-0.91); P < .01), while at 6- and 12-months ERs were similar. CONCLUSIONS: Regarding non-invasive treatment of UI secondary to RP, the addition of guided programs using BF or/and PFES demonstrated to improve continence recovery rate, particularly in the first 3-month interval, when compared with the use of PFME alone.

Novel mutual prodrug of 5-fluorouracil and heme oxygenase-1 inhibitor (5-FU/HO-1 hybrid): design and preliminary in vitro evaluation.

In this work, the first mutual prodrug of 5-fluorouracil and heme oxygenase1 inhibitor (5-FU/HO-1 hybrid) has been designed, synthesised, and evaluated for its in vitro chemical and enzymatic hydrolysis stability. Predicted in silico physicochemical properties of the newly synthesised hybrid (3) demonstrated a drug-like profile with suitable Absorption, Distribution, Metabolism, and Excretion (ADME) properties and low toxic liabilities. Preliminary cytotoxicity evaluation towards human prostate (DU145) and lung (A549) cancer cell lines demonstrated that 3 exerted a similar effect on cell viability to that produced by the reference drug 5-FU. Among the two tested cancer cell lines, the A549 cells were more susceptible for 3. Of note, hybrid 3 also had a significantly lower cytotoxic effect on healthy human lung epithelial cells (BEAS-2B) than 5-FU. Altogether our results served as an initial proof-of-concept to develop 5-FU/HO-1 mutual prodrugs as potential novel anticancer agents.

Design, Sustainable Synthesis and Biological Evaluation of a Novel Dual α2A/5-HT7 Receptor Antagonist with Antidepressant-Like Properties.

The complex pathophysiology of depression, together with the limits of currently available antidepressants, has resulted in the continuous quest for alternative therapeutic strategies. Numerous findings suggest that pharmacological blockade of α2-adrenoceptor might be beneficial for the treatment of depressive symptoms by increasing both norepinephrine and serotonin levels in certain brain areas. Moreover, the antidepressant properties of 5-HT7 receptor antagonists have been widely demonstrated in a large set of animal models. Considering the potential therapeutic advantages in targeting both α2-adrenoceptors and 5-HT7 receptors, we designed a small series of arylsulfonamide derivatives of (dihydrobenzofuranoxy)ethyl piperidines as dually active ligands. Following green chemistry principles, the designed compounds were synthesized entirely using a sustainable mechanochemical approach. The identified compound 8 behaved as a potent α2A/5-HT7 receptor antagonist and displayed moderate-to-high selectivity over α1-adrenoceptor subtypes and selected serotonin and dopaminergic receptors. Finally, compound 8 improved performance of mice in the forced swim test, displaying similar potency to the reference drug mirtazapine.

Sustainable Synthesis of a Potent and Selective 5-HT7 Receptor Antagonist Using a Mechanochemical Approach.

A mechanochemical procedure was developed to obtain PZ-1361, a potent and selective 5-HT7 receptor antagonist, with antidepressant properties in rodents. The elaborated protocol offered several advantages over classical batch synthesis, including improvement of the overall yield (from 34% to 64%), reduction of reaction time (from 60 to 5.5 h), limitation of the use of toxic solvents, and the formation of byproducts. This approach represents a rare example of the synthesis of biologically active compounds exclusively performed using mechanochemical reactions.

Biotransformation of 4-fluoro-N-(1-{2-[(propan-2-yl)phenoxy]ethyl}-8-azabicyclo[3.2.1]octan-3-yl)-benzenesulfonamide, a novel potent 5-HT7 receptor antagonist with antidepressant-like and anxiolytic properties: In vitro and in silico approach.

The aim of the study was to investigate the metabolism of 4-fluoro-N-(1-{2-[(propan-2-yl)phenoxy]ethyl}-8-azabicyclo[3.2.1]octan-3-yl)-benzenesulfonamide (PZ-1150), a novel 5-HT7 receptor antagonist with antidepressant-like and anxiolytic properties, by the following three ways: in vitro with microsomes; in vitro employing Cunninghamella echinulata, and in silico using MetaSite. Biotransformation of PZ-1150 with microsomes resulted in five metabolites, while transformation with C. echinulata afforded two metabolites. In both models, the predominant metabolite occurred due to hydroxylation of benzene ring. In silico data coincide with in vitro experiments, as three MetaSite metabolites matched compounds identified in microsomal samples. In human liver microsomes PZ-1150 exhibited in vitro half-life of 64 min, with microsomal intrinsic clearance of 54.1 µL/min/mg and intrinsic clearance of 48.7 mL/min/kg. Therefore, PZ-1150 is predicted to be a high-clearance agent. The study demonstrated the applicability of using microsomal model coupled with microbial model to elucidate the metabolic pathways of compounds and comparison with in silico metabolite predictions.

Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α1A/α1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile.

Benign prostatic hyperplasia (BPH) is the most common male clinical problem impacting the quality of life of older men. Clinical studies have indicated that the inhibition of α1A-/α1D adrenoceptors might offer effective therapy in lower urinary tract symptoms. Herein, a limited series of arylsulfonamide derivatives of (aryloxy)ethyl alicyclic amines was designed, synthesized, and biologically evaluated as potent α1-adrenoceptor antagonists with uroselective profile. Among them, compound 9 (3-chloro-2-fluoro-N-([1-(2-(2-(2,2,2-trifluoroethoxy)phenoxy]ethyl)piperidin-4-yl)methyl)benzenesulfonamide) behaved as an α1A-/α1D-adrenoceptor antagonist (Ki(α1) = 50 nM, EC50(α1A) = 0.8 nM, EC50(α1D) = 1.1 nM), displayed selectivity over α2-adrenoceptors (Ki(α2) = 858 nM), and a 5-fold functional preference over the α1B subtype. Compound 9 showed adequate metabolic stability in rat-liver microsome assay similar to the reference drug tamsulosin (Clint = 67 and 41 µL/min/mg, respectively). Compound 9 did not decrease systolic and diastolic blood pressure in normotensive anesthetized rats in the dose of 2 mg/kg, i.v. These data support development of uroselective agents in the group of arylsulfonamides of alicyclic amines with potential efficacy in the treatment of lower urinary tract symptoms associated to benign prostatic hyperplasia.

The impact of the halogen bonding on D2 and 5-HT1A/5-HT7 receptor activity of azinesulfonamides of 4-[(2-ethyl)piperidinyl-1-yl]phenylpiperazines with antipsychotic and antidepressant properties.

A series of azinesulfonamides of long-chain arylpiperazine derivatives with semi-rigid alkylene spacer was designed, synthesized, and biologically evaluated using in vitro methods for their affinity for dopaminergic D2 and serotoninergic 5-HT1A, 5-HT2A, 5-HT6 and 5-HT7 receptors. Docking to homology models revealed a possible halogen bond formation in complexes of the most potent ligands and the target receptors. The study allowed for the identification of compound 5-({4-(2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl)piperidin-1-yl}sulfonyl)quinoline (21), which behaved as D2, 5-HT1A and 5-HT7 receptor antagonist. In preliminary in vivo studies, compound 21 displayed distinct antipsychotic properties in the MK-801-evoked hyperactivity test in mice at a dose of 10mg/kg, and exerted antidepressant-like effect in a forced swim test in mice (MED=0.625mg/kg, i.p.).

Novel 5-HT7R antagonists, arylsulfonamide derivatives of (aryloxy)propyl piperidines: Add-on effect to the antidepressant activity of SSRI and DRI, and pro-cognitive profile.

A novel series of arylsulfonamide derivatives of (aryloxy)propyl piperidines was designed to obtain potent 5-HT7R antagonists. Among the compounds evaluated herein, 3-chloro-N-{1-[3-(1,1-biphenyl-2-yloxy)2-hydroxypropyl]piperidin-4-yl}benzenesulfonamide (25) exhibited antagonistic properties at 5-HT7R and showed selectivity over selected serotoninergic and dopaminergic receptors, as well as over serotonin, noradrenaline and dopamine transporters. Compound 25 demonstrated significant antidepressant-like activity in the forced swim test (0.625-2.5mg/kg, i.p.) and in the tail suspension test (1.25mg/kg, i.p.), augmented the antidepressant effect of inactive doses of escitalopram (selective serotonin reuptake inhibitor) and bupropion (dopamine reuptake inhibitor) in the FST in mice, and similarly to SB-269970, exerted pro-cognitive properties in the novel object recognition task in cognitively unimpaired conditions in rats (0.3mg/kg, i.p.). Such an extended pharmacological profile, especially the augmentation effect of the identified 5-HT7R antagonist on SSRI activity, seems promising regarding the complexity of affective disorders and potentially improved outcomes, including mnemonic performance.

Arylsulfonamide derivatives of (aryloxy)ethyl pyrrolidines and piperidines as α1-adrenergic receptor antagonist with uro-selective activity.

A series of arylsulfonamide derivatives of (aryloxy)ethyl pyrrolidines and piperidines was synthesized to develop new α1-adrenoceptor antagonists with uroselective profile. Biological evaluation for α1- and α2-adrenorecepor showed that tested compounds 13-37 displayed high-to-moderate affinity for the α1-adrenoceptor (Ki=34-348nM) and moderate selectivity over α2-receptor subtype. Compounds with highest affinity and selectivity for α1-adrenoceptor were evaluated in vitro for their intrinsic activity toward α1A- and α1B-adrenoceptor subtypes. All compounds behaved as antagonists at both α1-adrenoceptor subtypes, displaying 2- to 6-fold functional preference to α1A-subtype. Among them, N-{1-[2-(2-methoxyphenoxy)ethyl]piperidin-4-yl}isoquinoline-4-sulfonamide (25) and 3-chloro-2-fluoro-N-{[1-(2-(2-isopropoxyphenoxy)ethyl)piperidin-4-yl]methyl}benzene sulfonamide (34) displayed the highest preference to α1A-adrenoceptor. Finally, compounds 25 and 34 (2-5mg/kg, iv), in contrast to tamsulosin (1-2mg/kg, iv), did not significantly decrease systolic and diastolic blood pressure in normotensive anesthetized rats to determine their influence on blood pressure.

N-Alkylated arylsulfonamides of (aryloxy)ethyl piperidines: 5-HT(7) receptor selectivity versus multireceptor profile.

The N-alkylation of the sulfonamide moiety, in a group of arylsulfonamide derivatives of (aryloxy)ethyl piperidines, may be considered as a strategy for the design of selective 5-HT7 receptor ligands or multifunctional agents to extend a polypharmacological approach to the treatment of complex diseases. The study allowed for the identification of 31 (1-methyl-N-{1-[2-(2-(t-butyl)phenoxy)ethyl]piperidin-4-yl}-N-cyclopropylmethyl-1H-pyrazole-4-sulfonamide), a potent and selective 5-HT7 receptor antagonist and 33 (1-methyl-N-{1-[2-(biphenyl-2-yloxy)ethyl]piperidin-4-yl}-N-cyclopropylmethyl-1H-pyrazole-4-sulfonamide), as multimodal 5-HT/dopamine receptor ligand, as 5-HT2A/5-HT7/D2 receptor antagonists. Both selected compounds were evaluated in vivo in a forced swim test (FST) in mice and in a novel object recognition (NOR) task in rats, demonstrating distinct antidepressant-like and pro-cognitive properties (MED=1.25 mg/kg and 1 mg/kg, ip, respectively). These findings warrant further studies to explore the therapeutic potential of N-alkylated arylsulfonamides for the treatment of CNS disorders.

Qualitative and quantitative characteristics of CEUS for renal cell carcinoma and angiomyolipoma: a narrative review.

Incidental findings of renal masses are increasing. However, a substantial portion of surgically treated renal masses turn out to be benign on histopathological examination. Thus, there is a clear need for improved pre-surgical assessment to minimize unnecessary invasive procedures. The challenge intensifies when distinguishing between renal cell carcinoma (RCC) and angiomyolipoma (AML) in renal lesions smaller than 4 cm with minimal adipose tissue. In such cases, contrast-enhanced ultrasound (CEUS) has emerged as a valuable diagnostic tool, by utilizing both qualitative and quantitative parameters. Quantitative measures offer objectivity, reliability, and reproducibility compared to qualitative parameters, enabling the characterization of RCC subtypes and differentiation from AML. Qualitative features as enhancement pattern, degree, and peak were less helpful in distinguishing triphasic minimal fat AML (TAML) from epithelioid AML (EAML), with the pseudocapsule sign potentially being the only distinguishing qualitative feature. The pseudocapsule sign was more frequently observed in ccRCCs (38.0%) than in AMLs (15.6%). Moreover, it was detected in 40.0% of EAMLs and 34.5% of ccRCCs but not in TAMLs due to similar growth patterns between EAMLs and low-grade ccRCCs. Quantitative measures such as the time-to-peak (TTP) ratio can further enhance diagnostic accuracy and also TOC ratio should be considered, as it was higher in clear cell RCCs (ccRCCs) and in EAMLs compared to TAMLs, indicating behavior similar to ccRCCs. However, CEUS remains an operator-dependent exam.

Improving Activity of New Arylurea Agents against Multidrug-Resistant and Biofilm-Producing Staphylococcus epidermidis.

Multidrug-resistant (MDR) strains of Staphylococcus epidermidis (S. epidermidis), prevalent in hospital environments, contribute to increased morbidity and mortality, especially among newborns, posing a critical concern for neonatal sepsis. In response to the pressing demand for novel antibacterial therapies, we present findings from synthetic chemistry and structure-activity relationship studies focused on arylsulfonamide/arylurea derivatives of aryloxy[1-(thien-2-yl)propyl]piperidines. Through bioisosteric replacement of the sulfonamide fragment with a urea moiety, compound 25 was identified, demonstrating potent bacteriostatic activity against clinical multidrug-resistant S. epidermidis strains (MIC50 and MIC90 = 1.6 and 3.125 µg/mL). Importantly, it showed activity against linezolid-resistant strains and exhibited selectivity over mammalian cells. Compound 25 displayed antibiofilm-forming properties against clinical S. epidermidis strains and demonstrated the capacity to eliminate existing biofilm layers. Additionally, it induced complete depolarization of the bacterial membrane in clinical S. epidermidis strains. In light of these findings, targeting bacterial cell membranes with compound 25 emerges as a promising strategy in the fight against multidrug-resistant S. epidermidis strains.

Diagnostic Accuracy of Contrast-Enhanced Ultrasound (CEUS) in the Detection of Muscle-Invasive Bladder Cancer: A Systematic Review and Diagnostic Meta-Analysis.

BACKGROUND: Contrast-enhanced ultrasound (CEUS) is a diagnostic tool that is gaining popularity for its ability to improve overall diagnostic accuracy in bladder cancer (BC) staging. Our aim is to determine the cumulative diagnostic performance of CEUS in predicting preoperative muscle invasiveness using a comprehensive systematic review and pooled meta-analysis. METHODS: A systematic review until October 2023 was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Patients with BC suspicion were offered CEUS before the transurethral resection of the bladder tumor (TURBT). The diagnostic performance of CEUS was evaluated based on non-muscle-invasive bladder cancer (NMIBC) vs. muscle-invasive bladder cancer (MIBC) confirmed at the final histopathological examination after TURBT. The outcomes were determined through pooled sensitivity, specificity, pooled positive likelihood ratio (PLR+), negative likelihood ratio (PLR-), and area under the summary receiver operating characteristic (SROC) along with their respective 95% confidence intervals (CI). RESULTS: Overall, five studies were included. In these studies, a total of 362 patients underwent CEUS prior to TURBT. The pooled sensitivity and specificity were 0.88 (95% CI: 0.81-0.93) and 0.88 (95% CI: 0.82-0.92), respectively. SROC curve depicted a diagnostic accuracy of 0.94 (95% CI: 0.81-0.98). The pooled PLR+ and PLR- were 7.3 (95% CI: 4.8-11.2) and 0.14 (95% CI: 0.08-0.23), respectively. CONCLUSIONS: Our meta-analysis indicates that CEUS is highly accurate in the diagnosis and staging for BC. Beyond its accuracy, CEUS offers the advantage of being a cost-effective, safe, and versatile imaging tool.

Systematic review and meta-analysis of serum total testosterone and luteinizing hormone variations across hospitalized Covid-19 patients.

A growing body of evidence suggests the role of male hypogonadism as a possible harbinger for poor clinical outcomes across hospitalized Covid-19 patients. Accordingly, we sought to investigate the impact of dysregulated hypothalamic-pituitary-gonadal axis on the severity of the clinical manifestations for hospitalized Covid-19 patients matched with healthy controls through a systematic review and meta-analysis. Databases were searched from inception to March 2022. A standardized mean difference (SMD) meta-analysis focused on hospitalized Covid-19 patients and healthy controls was developed for studies who reported total testosterone (TT) and luteinizing hormone (LH) levels at hospital admission. Overall, n = 18 series with n = 1575 patients between 2020 and 2022 were reviewed. A significant decrease in SMD of TT levels in Covid-19 patients compared to paired controls was observed (- 3.25 nmol/L, 95%CI - 0.57 and - 5.93). This reduction was even more consistent when matching severe Covid-19 patients with controls (- 5.04 nmol/L, 95%CI - 1.26 and - 8.82) but similar for Covid-19 survivors and non-survivors (- 3.04 nmol/L, 95%CI - 2.04 and - 4.05). No significant variation was observed for serum LH levels across studies. Patient related comorbidities, year of the pandemic, and total lymphocyte count were associated with the observed estimates. TT levels may be a useful serum marker of poor outcomes among Covid-19 patients. These findings may support the development of ad-hoc clinical trials in the Covid-19 risk-group classification and subsequent disease monitoring. The interplay between TT and immune response should be evaluated in future researches.

5-HT6 receptor neutral antagonists protect astrocytes: A lesson from 2-phenylpyrrole derivatives.

The serotonin type 6 receptor (5-HT6R) displays a strong constitutive activity, suggesting it participates largely in the physiological and pathological processes controlled by the receptor. The active states of 5-HT6R engage particular signal transduction pathways that lead to different biological responses. In this study, we present the development of 5-HT6R neutral antagonists at Gs signaling built upon the 2-phenylpyrrole scaffold. Using molecular dynamics simulations, we outline the relationship between the exposure of the basic center of the molecules and their ability to target the agonist-activated state of the receptor. Our study identifies compound 30 as a potent and selective neutral antagonist at 5-HT6R-operated Gs signaling. Furthermore, we demonstrate the cytoprotective effects of 30 and structurally diverse 5-HT6R neutral antagonists at Gs signaling in C8-D1A cells and human astrocytes exposed to rotenone. This effect is not observed for 5-HT6R agonists or inverse agonists. In light of these findings, we propose compound 30 as a valuable molecular probe to study the biological effects associated with the agonist-activated state of 5-HT6R and provide insight into the glioprotective properties of 5-HT6R neutral antagonists at Gs signaling.

Quinolinesulfonamides of aryloxy-/arylthio-ethyl piperidines: influence of an arylether fragment on 5-HT1A/5-HT7 receptor selectivity.

The solid-phase synthesis of a new series of 19 biomimetics of long-chain arylpiperazines, namely flexible quinoline sulfonamides of aryl(heteroaryl)oxy-/heteroarylthio-ethyl 4-aminomethylpiperidines, is reported. Various structural modifications applied followed by biological evaluation for 5-HT1A, 5-HT6, and 5-HT7 receptors gave further support of a possible replacement of arylpiperazine with aryloxy-/arylthio-ethyl derivatives of alicyclic amines and control of receptor selectivity upon diversification in the aryl(heteroaryl)oxy-/heteroarylthio-ethyl fragment.

The Impact of Ethnicity and Age on Distribution of Metastases in Patients with Upper Tract Urothelial Carcinoma: Analysis of SEER Data.

Upper tract urothelial carcinoma (UTUC) constitutes a rare and aggressive entity accounting for 5% to 10% of all urothelial tumors. The importance of stratification and disparities according to ethnicity and age has never been tested in a sufficiently large sample of patients with metastatic UTUC (mUTUC). We conducted this study to address this void, and we hypothesized that the distribution of metastases may vary according to age and ethnicity. Within the Surveillance, Epidemiology, and End Results (SEER) database (2004-2016), we identified 1115 patients with mUTUC. The chi-square and t-test tests were used to examine statistical significance in terms of proportions and mean differences. A total of 925 (83.0%) patients were Caucasians, while 190 (17.0%) were African Americans. Among both ethnicities, lungs were the most common metastatic site (39.1% vs. 48.9%). Brain metastases were infrequent among both ethnicities (1.2 vs. 2.6%; p = 0.13). The trends in the lung metastases decreased with age from 42.3% to 36.6% (p = 0.010) among Caucasians, whereas they increased among African Americans from 34.0% to 51.7% (p = 0.04). Overall, 32.8% of Caucasians and 40.5% of African Americans exhibited more than one metastatic site. Among Caucasians, increasing age was associated with lower rates of having multiple metastatic sites (from 34.3% to 30.2%) (p = 0.004). According to our multivariable analyses, younger age was associated with an increased risk of lung (OR: 1.29, 95% CI 1.04-1.71; p = 0.045) and bone metastases (OR: 1.34, 95% CI 1.07-1.79; p = 0.046). Racial differences exist in the distribution of mUTUC metastasis and vary according to age. Our findings may also be considered in the design of randomized trials.