Design, synthesis and functional evaluation of a novel series of phosphonate-functionalized 1,2,3-triazoles as positive allosteric modulators of α7 nicotinic acetylcholine receptors

The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel widely distributed in the central nervous system, mainly in hippocampus and cortex. The enhancement of its activity by positive allosteric modulators (PAMs) is a promising therapeutic strategy for cognitive deficits and neurodegenerative disorders. With the aim of developing novel scaffolds with PAM activity, we designed and synthesized a series of phosphonate-functionalized 1,4-disubstituted 1,2,3-triazoles using supported copper nanoparticles as cycloaddition reaction catalyst, and evaluated their activity on α7 receptors by single-channel and whole-cell recordings. We identified several triazole derivatives that displayed PAM activity, the compound functionalized with the methyl phosphonate group being the most efficacious one. At the macroscopic level, α7 potentiation was evidenced as an increase of the maximal currents elicited by acetylcholine with minimal effects on desensitization, recapitulating the actions of type I PAMs. At the single-channel level, the active compounds did not affect channel amplitude, but significantly increased the duration of channel openings and activation episodes. By using chimeric and mutant α7 receptors, we demonstrated that the new α7 PAMs share transmembrane structural determinants of potentiation with other chemically non-related PAMs. To gain further insight into the chemical basis of potentiation, we applied structure-activity relationship strategies involving modification of the chain length, inversion of substituent positions in the triazole ring and changes in the aromatic nucleus. Our findings revealed that the phosphonate-functionalized 1,4-disubstituted 1,2,3-triazole is a novel pharmacophore for the development of therapeutic agents for neurological and neurodegenerative disorders associated to cholinergic dysfunction.Fil: Nielsen, Beatriz Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Stabile, Santiago Armando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Vitale, Cristian Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentin

Factors Influencing Variability in the Performance of Multiparametric Magnetic Resonance Imaging in Detecting Clinically Significant Prostate Cancer: A Systematic Literature Review

CONTEXT: There is a lack of comprehensive data regarding the factors that influence the diagnostic accuracy of multiparametric magnetic resonance imaging (mpMRI) to detect and localize clinically significant prostate cancer (csPCa). OBJECTIVE: To systematically review the current literature assessing the factors influencing the variability of mpMRI performance in csPCa diagnosis. EVIDENCE ACQUISITION: A computerized bibliographic search of Medline/PubMed database was performed for all studies assessing magnetic field strength, use of an endorectal coil, assessment system used by radiologists and inter-reader variability, experience of radiologists and urologists, use of a contrast agent, and use of computer-aided diagnosis (CAD) tools in relation to mpMRI diagnostic accuracy. EVIDENCE SYNTHESIS: A total of 77 articles were included. Both radiologists' reading experience and urologists'/radiologists' biopsy experience were the main factors that influenced diagnostic accuracy. Therefore, it is mandatory to indicate the experience of the interpreting radiologists and biopsy-performing urologists to support the reliability of the findings. The most recent Prostate Imaging Reporting and Data System (PI-RADS) guidelines are recommended for use as the main assessment system for csPCa, given the simplified and standardized approach as well as its particular added value for less experienced radiologists. Biparametric MRI had similar accuracy to mpMRI; however, biparametric MRI performed better with experienced readers. The limited data available suggest that the combination of CAD and radiologist readings may influence diagnostic accuracy positively. CONCLUSIONS: Multiple factors affect the accuracy of mpMRI and MRI-targeted biopsy to detect and localize csPCa. The high heterogeneity across the studies underlines the need to define the experience of radiologists and urologists, implement quality control, and adhere to the most recent PI-RADS assessment guidelines. Further research is needed to clarify which factors impact the accuracy of the MRI pathway and how. PATIENT SUMMARY: We systematically reported the factors influencing the accuracy of multiparametric magnetic resonance imaging (mpMRI) in detecting clinically significant prostate cancer (csPCa). These factors are significantly related to each other, with the experience of the radiologists being the dominating factor. In order to deliver the benefits of mpMRI to diagnose csPCa, it is necessary to develop expertise for both radiologists and urologists, implement quality control, and adhere to the most recent Prostate Imaging Reporting and Data System assessment guidelines

Multiparametric magnetic resonance imaging and clinical variables: Which is the best combination to predict reclassification in active surveillance patients?

n/

Exigencias que deberá enfrentar el contador en el ejercicio de su profesión ante el contexto económico globalizado en América

Los nuevos requerimientos en la demanda de servicios profesionales del Contador, implican fundamentalmente la adaptación a los cambios producidos en las economías, tomando en cuenta mercados altamente competitivos y globalizados. La Internacionalización de la producción y las finanzas, la apertura de nuevos mercados y la formación de bloques político - económicos, están dando lugar a un mundo substancialmente distinto.Fil: Pasqualino, Roberto Emilio. Universidad Nacional de La Matanza; Argentina.Fil: Imwinkelried, Ángel Mario. Universidad Nacional de La Matanza; Argentina.Fil: Varela, Silvia Isolina. Universidad Nacional de La Matanza; Argentina.Fil: Peleteiro, Ernesto Hugo. Universidad Nacional de La Matanza; Argentina.Fil: Tomas de Richmond, Leticia Isabel. Universidad Nacional de La Matanza; Argentina.Fil: Rosario Stabile, Luis Alberto. Universidad Nacional de La Matanza; Argentina.Fil: Cersósimo, Pablo Armando. Universidad Nacional de La Matanza; Argentina

Open Versus Robotic Cystectomy: A Propensity Score Matched Analysis Comparing Survival Outcomes

Background: To assess the differential effect of robotic assisted radical cystectomy (RARC) versus open radical cystectomy (ORC) on survival outcomes in matched analyses performed on a large multicentric cohort. Methods: The study included 9757 patients with urothelial bladder cancer (BCa) treated in a consecutive manner at each of 25 institutions. All patients underwent radical cystectomy with bilateral pelvic lymphadenectomy. To adjust for potential selection bias, propensity score matching 2:1 was performed with two ORC patients matched to one RARC patient. The propensity-matched cohort included 1374 patients. Multivariable competing risk analyses accounting for death of other causes, tested association of surgical technique with recurrence and cancer specific mortality (CSM), before and after propensity score matching. Results: Overall, 767 (7.8%) patients underwent RARC and 8990 (92.2%) ORC. The median follow-up before and after propensity matching was 81 and 102 months, respectively. In the overall population, the 3-year recurrence rates and CSM were 37% vs. 26% and 34% vs. 24% for ORC vs. RARC (all p values > 0.1), respectively. On multivariable Cox regression analyses, RARC and ORC had similar recurrence and CSM rates before and after matching (all p values > 0.1). Conclusions: Patients treated with RARC and ORC have similar survival outcomes. This data is helpful in consulting patients until long term survival outcomes of level one evidence is available

Molecular biomarkers in the context of focal therapy for prostate cancer: Recommendations of a delphi consensus from the focal therapy society

BACKGROUND: Focal therapy (FT) for prostate cancer (PCa) is promising. However, long-term oncological results are awaited and there is no consensus on follow-up strategies. Molecular biomarkers (MB) may be useful in selecting, treating and following up men undergoing FT, though there is limited evidence in this field to guide practice. We aimed to conduct a consensus meeting, endorsed by the Focal Therapy Society, amongst a large group of experts, to understand the potential utility of MB in FT for localized PCa. METHODS: A 38-item questionnaire was built following a literature search. The authors then performed three rounds of a Delphi Consensus using DelphiManager, using the GRADE grid scoring system, followed by a face-to-face expert meeting. Three areas of interest were identified and covered concerning MB for FT, 1) the current/present role; 2) the potential/future role; 3) the recommended features for future studies. Consensus was defined using a 70% agreement threshold. RESULTS: Of 95 invited experts, 42 (44.2%) completed the three Delphi rounds. Twenty-four items reached a consensus and they were then approved at the meeting involving (N.=15) experts. Fourteen items reached a consensus on uncertainty, or they did not reach a consensus. They were re-discussed, resulting in a consensus (N.=3), a consensus on a partial agreement (N.=1), and a consensus on uncertainty (N.=10). A final list of statements were derived from the approved and discussed items, with the addition of three generated statements, to provide guidance regarding MB in the context of FT for localized PCa. Research efforts in this field should be considered a priority. CONCLUSIONS: The present study detailed an initial consensus on the use of MB in FT for PCa. This is until evidence becomes available on the subject

The Mount Sinai Prebiopsy Risk Calculator for Predicting any Prostate Cancer and Clinically Significant Prostate Cancer: Development of a Risk Predictive Tool and Validation with Advanced Neural Networking, Prostate Magnetic Resonance Imaging Outcome Database, and European Randomized Study of Screening for Prostate Cancer Risk Calculator

Background: The European Association of Urology guidelines recommend the use of imaging, biomarkers, and risk calculators in men at risk of prostate cancer. Risk predictive calculators that combine multiparametric magnetic resonance imaging with prebiopsy variables aid as an individualized decision-making tool for patients at risk of prostate cancer, and advanced neural networking increases reliability of these tools.Objective: To develop a comprehensive risk predictive online web-based tool using magnetic resonance imaging (MRI) and clinical data, to predict the risk of any prostate cancer (PCa) and clinically significant PCa (csPCa) applicable to biopsy-naive men, men with a prior negative biopsy, men with prior positive low-grade cancer, and men with negative MRI.Design, setting, and participants: Institutional review board-approved prospective data of 1902 men undergoing biopsy from October 2013 to September 2021 at Mount Sinai were collected.Outcome measurements and statistical analysis: Univariable and multivariable analyses were used to evaluate clinical variables such as age, race, digital rectal examination, family history, prostate-specific antigen (PSA), biopsy status, Prostate Imaging Reporting and Data System score, and prostate volume, which emerged as predictors for any PCa and csPCa. Binary logistic regression was performed to study the probability. Validation was performed with advanced neural networking (ANN), multi-institutional European cohort (Prostate MRI Outcome Database [PROMOD]), and European Randomized Study of Screening for Prostate Cancer Risk Calculator (ERSPC RC) 3/4.Results and limitations: Overall, 2363 biopsies had complete clinical information, with 57.98% any cancer and 31.40% csPCa. The prediction model was significantly associated with both any PCa and csPCa having an area under the curve (AUC) of 81.9% including clinical data. The AUC for external validation was calculated in PROMOD, ERSPC RC, and ANN for any PCa (0.82 vs 0.70 vs 0.90) and csPCa (0.82 vs 0.78 vs 0.92), respectively. This study is limited by its retrospective design and over-estimation of csPCa in the PROMOD cohort.Conclusions: The Mount Sinai Prebiopsy Risk Calculator combines PSA, imaging and clinical data to predict the risk of any PCa and csPCa for all patient settings. With accurate validation results in a large European cohort, ERSPC RC, and ANN, it exhibits its efficiency and applicability in a more generalized population. This calculator is available online in the form of a free web-based tool that can aid clinicians in better patients counseling and treatment decision-making.Patient summary: We developed the Mount Sinai Prebiopsy Risk Calculator (MSP-RC) to assess the likelihood of any prostate cancer and clinically significant disease based on a combination of clinical and imaging characteristics. MSP-RC is applicable to all patient settings and accessible online. Crown Copyright (C) 2022 Published by Elsevier B.V. on behalf of European Association of Urology.</p