Sustained proliferation in cancer: mechanisms and novel therapeutic targets

Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Initial and Long-term Retention of Robotic Technical Skills in an Otolaryngology Residency Program.

Objectives/hypothesisTo objectively assess the initial and long-term retention of robotic surgical skills of otolaryngology residents.Study designThis study was performed in an academic otolaryngology residency training program. Between October 2015 and November 2016, residents were invited to complete a prospective, multiphase robotic surgical skills training course: 1) online da Vinci Surgical System Assessment and didactic, 2) faculty-supervised robotic simulator training, 3) robotic docking and draping training, 4) robotic dry-lab exercises. To optimize surgical skill retention, the training laboratory was repeated 2 weeks after the initial training session.MethodsTwenty otolaryngology residents were included. Primary outcome was measured as robotic skill assessment scores on three tasks: camera targeting, peg board, and needle targeting. Skill assessments were completed prior to training, between the two training sessions, and at 1 month and 6 months after training. Residents were also asked to complete a self-assessment questionnaire.ResultsCamera targeting scores were improved at midtraining (P < .001) and 1-month posttraining (P = .010). Peg board scores were improved at 1 month training (P = .043). Needle targeting scores were improved at midtraining (P = .002), 1 month (P = .002), and 6 months posttraining (P < .001). Resident self-assessment scores demonstrating comfort with using the robotic console (P < .01) and docking/draping (P < .01) improved significantly following the training.ConclusionsFollowing a multiphase robotic training program, otolaryngology residents demonstrated significant, objective skill acquisition and retention at 1 month and 6 months follow-up. Although the proposed training strategy may be considered an important step in otolaryngology residency training, additional innovations are being designed toward a formal robotic training curriculum.Level of evidenceNA Laryngoscope, 129:1380-1385, 2019

Initial and Long-term Retention of Robotic Technical Skills in an Otolaryngology Residency Program.

Objectives/hypothesisTo objectively assess the initial and long-term retention of robotic surgical skills of otolaryngology residents.Study designThis study was performed in an academic otolaryngology residency training program. Between October 2015 and November 2016, residents were invited to complete a prospective, multiphase robotic surgical skills training course: 1) online da Vinci Surgical System Assessment and didactic, 2) faculty-supervised robotic simulator training, 3) robotic docking and draping training, 4) robotic dry-lab exercises. To optimize surgical skill retention, the training laboratory was repeated 2 weeks after the initial training session.MethodsTwenty otolaryngology residents were included. Primary outcome was measured as robotic skill assessment scores on three tasks: camera targeting, peg board, and needle targeting. Skill assessments were completed prior to training, between the two training sessions, and at 1 month and 6 months after training. Residents were also asked to complete a self-assessment questionnaire.ResultsCamera targeting scores were improved at midtraining (P < .001) and 1-month posttraining (P = .010). Peg board scores were improved at 1 month training (P = .043). Needle targeting scores were improved at midtraining (P = .002), 1 month (P = .002), and 6 months posttraining (P < .001). Resident self-assessment scores demonstrating comfort with using the robotic console (P < .01) and docking/draping (P < .01) improved significantly following the training.ConclusionsFollowing a multiphase robotic training program, otolaryngology residents demonstrated significant, objective skill acquisition and retention at 1 month and 6 months follow-up. Although the proposed training strategy may be considered an important step in otolaryngology residency training, additional innovations are being designed toward a formal robotic training curriculum.Level of evidenceNA Laryngoscope, 129:1380-1385, 2019

Affected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: delineating diagnostic clues.

X-linked myotubular myopathy (XLMTM), a severe congenital myopathy, is caused by mutations in the MTM1 gene located on the X chromosome. A majority of affected males die in the early postnatal period, whereas female carriers are believed to be usually asymptomatic. Nevertheless, several affected females have been reported. To assess the phenotypic and pathological spectra of carrier females and to delineate diagnostic clues, we characterized 17 new unrelated affected females and performed a detailed comparison with previously reported cases at the clinical, muscle imaging, histological, ultrastructural and molecular levels. Taken together, the analysis of this large cohort of 43 cases highlights a wide spectrum of clinical severity ranging from severe neonatal and generalized weakness, similar to XLMTM male, to milder adult forms. Several females show a decline in respiratory function. Asymmetric weakness is a noteworthy frequent specific feature potentially correlated to an increased prevalence of highly skewed X inactivation. Asymmetry of growth was also noted. Other diagnostic clues include facial weakness, ptosis and ophthalmoplegia, skeletal and joint abnormalities, and histopathological signs that are hallmarks of centronuclear myopathy such as centralized nuclei and necklace fibers. The histopathological findings also demonstrate a general disorganization of muscle structure in addition to these specific hallmarks. Thus, MTM1 mutations in carrier females define a specific myopathy, which may be independent of the presence of an XLMTM male in the family. As several of the reported affected females carry large heterozygous MTM1 deletions not detectable by Sanger sequencing, and as milder phenotypes present as adult-onset limb-girdle myopathy, the prevalence of this myopathy is likely to be greatly underestimated. This report should aid diagnosis and thus the clinical management and genetic counseling of MTM1 carrier females. Furthermore, the clinical and pathological history of this cohort may be useful for therapeutic projects in males with XLMTM, as it illustrates the spectrum of possible evolution of the disease in patients surviving long term