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IntroductionDNA double-strand breaks (DSBs) are believed to be the most critical lesions induced by many cancer therapies, including chemotherapy and ionizing radiation (IR). Homology-directed repair (HDR), or homologous recombination repair, [...], After the initial responsiveness of triple-negative breast cancers (TNBCs) to chemotherapy, they often recur as chemotherapyresistant tumors, and this has been associated with upregulated homology-directed repair (HDR). Thus, inhibitors of HDR could be a useful adjunct to chemotherapy treatment of these cancers. We performed a high-throughput chemical screen for inhibitors of HDR from which we obtained a number of hits that disrupted microtubule dynamics. We postulated that high levels of the target molecules of our screen in tumors would correlate with poor chemotherapy response. We found that inhibition or knockdown of dynamin 2 (DNM2), known for its role in endocytic cell trafficking and microtubule dynamics, impaired HDR and improved response to chemotherapy of cells and of tumors in mice. In a retrospective analysis, levels of DNM2 at the time of treatment strongly predicted chemotherapy outcome for estrogen receptor-negative and especially for TNBC patients. We propose that DNM2-associated DNA repair enzyme trafficking is important for HDR efficiency and is a powerful predictor of sensitivity to breast cancer chemotherapy and an important target for therapy.

Background: Discordant practice patterns may be a consequence of evidence-practice gaps or deficiencies in knowledge translation. We examined the current strategies used by hepato-pancreatico-biliary (HPB) surgeons in Canada for the [...]

Background: Socioeconomic factors are known to affect outcomes for both medical and surgical conditions. The purpose of this systematic review was to assess the current evidence regarding the effect of socioeconomic factors such as income, geographic location, educational level, and occupation on clinical outcomes after distal radius fractures. Methods: A systematic search strategy was performed to identify studies commenting on the effect of socioeconomic factors on clinical outcomes following open or closed distal radius fracture repair. Abstract and full-text screening was performed by 2 independent reviewers, and articles were evaluated by Structured Effectiveness Quality Evaluation Scale (SEQES). Treatment outcomes of interest included, but were not limited to, pain, function, range of motion, and grip strength. Results: There were 1745 studies that met our inclusion and exclusion criteria for abstract screening. Of these, 48 studies met our inclusion criteria for full-text screening and 20 studies met our criteria for quality analysis with the SEQES score. There were 3 studies of high quality, 16 of moderate quality, and 1 of low quality. Meta-analyses were not possible due to the variability in outcomes of interest across papers. Conclusions: Patient factors indicative of socioeconomic status are relevant predictors of functional outcome after distal radius fractures. There is currently limited evidence in this area of research, and further examination should be considered to improve outcomes from a patient and system standpoint. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, which involves the progressive degeneration of motor neurons. ALS has long been considered a disease of the grey matter; however, pathological alterations of the white matter (WM), including axonal loss, axonal demyelination and oligodendrocyte death, have been reported in patients with ALS. The present review examined motor neuron death as the primary cause of ALS and evaluated the associated WM damage that is guided by neuronal‑glial interactions. Previous studies have suggested that WM damage may occur prior to the death of motor neurons, and thus may be considered an early indicator for the diagnosis and prognosis of ALS. However, the exact molecular mechanisms underlying early‑onset WM damage in ALS have yet to be elucidated. The present review explored the detailed anatomy of WM and identified several pathological mechanisms that may be implicated in WM damage in ALS. In addition, it associated the pathophysiological alterations of WM, which may contribute to motor neuron death in ALS, with similar mechanisms of WM damage that are involved in multiple sclerosis (MS). Furthermore, the early detection of WM damage in ALS, using neuroimaging techniques, may lead to earlier therapeutic intervention, using immunomodulatory treatment strategies similar to those used in relapsing‑remitting MS, aimed at delaying WM damage in ALS. Early therapeutic approaches may have the potential to delay motor neuron damage and thus prolong the survival of patients with ALS. The therapeutic interventions that are currently available for ALS are only marginally effective. However, early intervention with immunomodulatory drugs may slow the progression of WM damage in the early stages of ALS, thus delaying motor neuron death and increasing the life expectancy of patients with ALS. [ABSTRACT FROM AUTHOR]