Dual-target inhibitors of bromodomain-containing protein 4 (BRD4) in cancer therapy: Current situation and future directions

Bromodomain-containing protein 4 (BRD4) is emerging as a therapeutic target that acts synergistically with other targets of small-molecule drugs in cancer. Therefore, the discovery of potential new dual-target inhibitors of BRD4 may be a promising strategy for cancer therapy. In this review, we highlight a series of strategies to design therapeutic dual-target inhibitors of BRD4 that focus on the synergistic functions of this protein. Drug combinations that exploit synthetic lethality, protein–protein interactions, functional complementarity, and blocking of resistance mechanisms could ultimately overcome the barriers inherent to the development of BRD4 inhibitors as future cancer drugs.     

Short-Term Left Ventricular Reverse Remodeling after Transcatheter Aortic Valve Replacement in Children

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Características y resultados oncológicos del carcinoma epidermoide de ano: análisis comparativo entre los pacientes inmunocompetentes y los inmunodeprimidos

ObjectiveMost evidence, including recent randomized controlled trials, analysing anal squamous cell carcinoma (SCC) do not consider immunocompromise patient population. The aim of this study was to compare clinical and oncological outcomes among immunocompetent and immunocompromised patients with anal squamous cell carcinoma.MethodMulticentric retrospective comparative study including 2 cohorts of consecutive patients, immunocompetent and immunocompromised, diagnosed with anal SCC. This study evaluated clinical characteristics, clinical response to radical chemoradiotherapy (CRT) and long-term oncological results including both local and distant recurrence, overall survival (OS) and disease-free survival (DFS).ResultsA total of 84 patients, 47 (55.6%) female, diagnosed with anal SCC from January 2012 to December 2017 were included, 22 (26%) and 62 (74%) patients in immunocompromised and immunocompetent groups respectively. Patients in immunocompromised group were significantly younger (53 vs. 61 years; P=0.001), with smaller tumoral size (P=0.044) and reported higher rates of substance abuse.including tobacco use (P=0.034) and parenteral drug consumption (P=0.001). No differences were found in administered therapies (P=301) neither in clinical response to chemoradiotherapy (83 vs. 100%). Moreover, similar 5-year OS (60 vs. 64%; P=0.756) and DFS (65 vs. 68%; P=0.338) were observed.ConclusionThe present study shows no significant differences in long-term oncological results among immunocompetent and immunocompromised patients diagnosed with anal SCC, with a similar oncologic treatment. This evidence might be explained due to the close monitoring and adequate therapeutic control of HIV positive patients.     

Residual limb strength and functional performance measures in individuals with unilateral transtibial amputation

BackgroundIndividuals with lower limb amputation exhibit lower residual limb strength compared to their sound limb. Deficits in residual limb knee flexion and extension strength may impact functional performance during tasks relevant to daily living.Research questionDoes knee flexor and extensor strength in the residual limb impact functional outcome measures, such as walking energetics and performance metrics, in individuals with unilateral transtibial amputation?MethodsFourteen individuals with traumatic unilateral transtibial amputation were recruited for this observational study. Participants completed metabolic testing at three standardized speeds based on leg length, as well maximum isokinetic knee flexion and extension strength for both residual and sound limbs. Participants also completed a series of functional outcome tests, including a two-minute walk test, timed stair ascent test, and four-square step test. Walking energetics (metabolic cost, heart rate, and rating of perceived exertion) and performance metrics were compared to percent deficit of residual limb to sound limb knee flexion and extension muscle strength. A linear regression assessed significant relationships (p < 0.05).ResultsA significant relationship was observed between percent deficit of knee extension strength and heart rate (p = 0.024) at a fast walking speed. Additionally, percent deficit knee flexion strength related to rating of perceived exertion at slow and moderate walking speeds (p = 0.038, p = 0.024). Percent deficit knee extension strength related to two-minute walk time performance (p = 0.035) and percent deficit knee flexion strength related to timed stair ascent time (p = 0.025).SignificanceThese findings suggest the importance of strength retention of the residual limb knee flexion and extension musculature to improve certain functional outcomes in individuals with unilateral transtibial amputation.