Insight into Recent Advances in Degrading Androgen Receptor for Castration-Resistant Prostate Cancer.

Induced protein degradation has emerged as an innovative drug discovery approach, complementary to the classical method of suppressing protein function. The androgen receptor signaling pathway has been identified as the primary driving force in the development and progression of lethal castration-resistant prostate cancer. Since androgen receptor degraders function differently from androgen receptor antagonists, they hold the promise to overcome the drug resistance challenges faced by current therapeutics. Proteolysis-targeting chimeras (PROTACs), monomeric degraders, hydrophobic tagging, molecular glues, and autophagic degradation have demonstrated their capability in downregulating intracellular androgen receptor concentrations. The potential of these androgen receptor degraders to treat castration-resistant prostate cancer is substantiated by the advancement of six PROTACs and two monomeric androgen receptor degraders into phase I or II clinical trials. Although the chemical structures, in vitro and in vivo data, and degradation mechanisms of androgen receptor degraders have been reviewed, it is crucial to stay updated on recent advances in this field as novel androgen receptor degraders and new strategies continue to emerge. This review thus provides insight into recent advancements in this paradigm, offering an overview of the progress made since 2020.

Synthesis and biological evaluation of niclosamide PROTACs.

Roughly 268,000 new cases of prostate cancer and 34,000 deaths from prostate cancer are projected by the American Cancer Society to occur in the United States in 2022. Androgen receptor is a key protein in the proliferation and survival of prostate cancer cells and has been revealed to be overexpressed in 30% to 50% of castration-resistant prostate cancer patients. One promising approach to reducing the level of this protein is Proteolysis Targeting Chimeras (PROTACs) that is an emerging drug discovery technology. PROTACs are hetero-bifunctional molecules where one end binds to a protein of interest and the other to an E3 ligase ligand, initiating the Ubiquitin-Proteasome Pathway for protein degradation. Two PROTACs with niclosamide as androgen receptor ligand and VHL-032 as the E3 ligase ligand have been designed and synthesized for suppressing proliferation of androgen receptor-positive prostate cancer cells via degrading androgen receptor. The in vitro antiproliferative assessment suggested that they can selectively suppress PC-3, LNCaP, and 22Rv1 prostate cancer cell proliferation, but cannot inhibit DU145 cell proliferation. However, the mechanism of both compounds in suppressing prostate cancer cell proliferation is not through the AR PROTAC mechanism because they did not degrade AR in our Western Blotting assay up to 1 µM.

The influence of cognitive factors in relation to the patients' treatment adherence for non-specific chronic low-back pain. A case series.

INTRODUCTION: The positive effects of exercise programs in relation to chronic low-back pain have been long established and patient adherence has a fundamental role in the impact of the resulting benefits. On the other hand, cognitive factors have shown to be the predictors of poor outcomes in patient suffering from this condition to the point of possibly affecting adherence. OBJECTIVE: To determine the influence of cognitive factors on the adherence to a home exercise program, the patient's pain intensity and their level of disability at a two-month follow-up, specifically regarding patients with non-specific chronic low-back pain (NSCLBP). METHOD: ology: Ten patients with NSLBP underwent a home exercise program. This study was undertaken to assess their adherence rate after two months. The assessment tools included the Visual Analogue Scale (VAS), the Oswestry Disability Index pre-follow-up and post-follow-up (ODI1 and ODI2), the Tampa Kinesiophobia Scale (TSK-11), the Pain Catastrophism Scale (PCS), the Fear-Avoidance Beliefs Questionnaire (FABQ) and the General Self-efficacy Scale (GSS) respectively. RESULTS: There were no significant associations found between adherence and the selected cognitive factors. There was an association between GSS and VAS (R = 0.68, p = 0.031). A clinically relevant improvement of 6.8 points in the mean of ODI2 in relation to ODI1 was observed. CONCLUSION: The influence of cognitive factors on adherence has not been ruled out because the study had a low sample size. Future studies should replicate the evaluation protocol in a larger population.

The Evolving Concept of Damage Control in Neurotrauma: Application of Military Protocols in Civilian Settings with Limited Resources.

OBJECTIVE: The aim of the present review was to describe the evolution of the damage control concept in neurotrauma, including the surgical technique and medical postoperative care, from the lessons learned from civilian and military neurosurgeons who have applied the concept regularly in practice at military hospitals and civilian institutions in areas with limited resources. METHODS: The present narrative review was based on the experience of a group of neurosurgeons who participated in the development of the concept from their practice working in military theaters and low-resources settings with an important burden of blunt and penetrating cranial neurotrauma. RESULTS: Damage control surgery in neurotrauma has been described as a sequential therapeutic strategy that supports physiological restoration before anatomical repair in patients with critical injuries. The application of the concept has evolved since the early definitions in 1998. Current strategies have been supported by military neurosurgery experience, and the concept has been applied in civilian settings with limited resources. CONCLUSION: Damage control in neurotrauma is a therapeutic option for severe traumatic brain injury management in austere environments. To apply the concept while using an appropriate approach, lessons must be learned from experienced neurosurgeons who use this technique regularly.

Determinants of perceived insufficient milk among new mothers in León, Nicaragua.

Breastfeeding has been shown to improve maternal and child health. In Nicaragua, the primary risk of death and disability-adjusted life years among children under 5 years of age is suboptimal breastfeeding. Although the Nicaraguan Ministry of Health promotes exclusive breastfeeding from within the first half hour through the first 6 months of life, less than a third of children in the country under 6 months of age are exclusively breastfed. As part of a larger, mixed-methods study, 21 semi-structured, in-depth interviews were conducted with new mothers recruited from three primary health centers between June and August 2015 in order to identify the social, cultural, and structural factors that contribute to infant feeding practices and the discrepancy between recommendations and practices among mothers who delivered at an urban public hospital in León, Nicaragua. Audio recordings were transcribed verbatim, and interview transcripts were coded and analyzed by a three-member team using a grounded theory approach. Findings highlight a widespread perception of insufficient milk among mothers that influenced early cessation of exclusive breastfeeding and other infant feeding practices. This perception stemmed from anxiety about meeting infant nutritional needs and infant satiety, anxiety about maternal nutrition, advice from and role modeling of family members about mixed feeding, and perceived infant feeding norms. Results suggest that support modeled after the 10 steps of the Baby-friendly Hospital Initiative as well as strengthened policy-level support are needed. Community interventions that address cultural and structural barriers to improve breastfeeding practices may also help to increase breastfeeding rates.

Valoración del tratamiento de la incotinencia urinaria en el Hospital Escuela "Oscar Danilo Rosales Argüello / Treatment appraisal of urinary incontinence in the Hospital Escuela \"Oscar Danilo Rosales Argüello

Se valoro la evolución de las pacientes trtadas por incontinencia urinaria y el reultado durante los 12 meses posteriores. Se realizó un estudio descriptivo de serie de casos del 1º de enero de 1997 al 31 de diciembre de 2000 en el servicio de Urología Ginecológica del Hospital Escuela Oscar Danilo Rosales Arguello, incluyéndose 75 expedientes de las pacientes con diagnóstico de incontinencia urinaria. Se evaluó edad, paridad, inicio del padecimiento, sintomatología, antecedentes médicos y quirúrgicos, hallazgos al examen físico, tipo de incotinencia urinaria, tratamiento recibido y seguimiento a 12 meses. El diagnóstico más frecuente correspondió a la incontinencia urinaria mixta (66.7 porciento)seguida de la de esfuerzo (25.3 porciento) y la de urgencia (8 porciento). El 48 porciento de las pacientes recibieron tratamiento combinado (médico quirúrgico), 31 porciento se les brindo tratamiento médico solamente y 21 porciento se les realizó cirugía solamente. Se realizaron 37 operaciones de Pereyra (70 porciento) y 16 operaciones de Burch (30 porciento), 67 porciento recibieron imipramina. El tratamiento de la incotinencia urinaria en el Servicio de Uroginecología del HEODRA presenta limitaciones para una valoración más objetiva debido al número de pacientes que abandonaron al momento de realizarse los controles. La frecuencia de complicaciones es similar a lo reportado en la literatura. Las dos técnicas quirúrgicas empleadas, Pereira y Burch, mostrarón efectividad semejante, o apenas levemente a favor de la primera que además resultó ser la más indicada para el grado de trastorno de la estática pélvica observado en las pacientes atendidas en el período del estudio en este Hospital...