Advances in the treatment of metastatic melanoma have improved responses and survival. However, many patients continue to experience resistance or toxicity to treatment, highlighting a crucial need ...to identify biomarkers and understand mechanisms of response and toxicity. Neoadjuvant therapy for regional metastases might improve operability and clinical outcomes over upfront surgery and adjuvant therapy, and has become an established role for drug development and biomarker discovery in other cancers (including locally advanced breast cancer, head and neck squamous cell carcinomas, gastroesophageal cancer, and anal cancer). Patients with clinically detectable stage III melanoma are ideal candidates for neoadjuvant therapy, because they represent a high-risk patient population with poor outcomes when treated with upfront surgery alone. Neoadjuvant therapy is now an active area of research for melanoma with numerous completed and ongoing trials (since 2014) with disparate designs, endpoints, and analyses under investigation. We have, therefore, established the International Neoadjuvant Melanoma Consortium with experts in medical oncology, surgical oncology, pathology, radiation oncology, radiology, and translational research to develop recommendations for investigating neoadjuvant therapy in melanoma to align future trial designs and correlative analyses. Alignment and consistency of neoadjuvant trials will facilitate optimal data organisation for future regulatory review and strengthen translational research across the melanoma disease continuum.
Thromboembolic event (TE) risk stratification is performed by using CHA2DS2VASc score. It has been suggested that left atrial appendage (LAA) morphology independently influences TE risk in patients ...with nonvalvular atrial fibrillation. LAA morphology has been classified into 4 types: chicken wing, cauliflower, windsock, and cactus.
The purpose of this study was to determine TE risk for each LAA morphology in patients with atrial fibrillation with low to intermediate TE risk.
A systematic review of MEDLINE, Cochrane Library, and Embase for studies that used computed tomography, tridimensional transesophageal echocardiography, and cardiac magnetic resonance imaging to categorize the LAA morphologies with assessment of TE prevalence. Odds ratio (OR) and 95% confidence intervals (CIs) were measured using the Mantel-Haenszel method. The fixed effects model was used, and if heterogeneity (I2) was >25%, effects were analyzed using a random model.
Eight studies with 2596 patients were included. Eighty-four percent (n=1872) of patients had a CHADS2 score of <2. TE risk was lower in chicken wing morphology than in non-chicken wing morphology (OR 0.46; 95% CI 0.36-0.58). Likewise, chicken wing morphology had lower TE risk than did other morphologies (chicken wing vs cauliflower: OR 0.38; 95% CI 0.26-0.56; chicken wing vs windsock: OR 0.48; 95% CI 0.31-0.73; chicken wing vs cactus: OR 0.49; 95% CI 0.36-0.66).
Patients with chicken wing LAA morphology are less likely to develop TE than patients with non-chicken wing morphology. LAA morphology may be a valuable criterion in predicting TE and could affect the stratification and anticoagulation management of patients with low to intermediate TE risk.
Appropriate instruction is a key component of quality physical education, which aligns student learning activities with grade-level learning outcomes. Historically, in the 1980s and late 1990s, an ...abundance of research was conducted to empirically link teacher effectiveness to student learning outcomes. In recent years, however, limited research has been published. Purpose: The purpose of this study was to: (a) identify research studies examining appropriate instructional practice in K-12 physical education since 2000, (b) describe the study characteristics and summarize the findings, (c) compare research to the SHAPE America's guidelines for appropriate instruction, and (d) make recommendations for future research. Methods: This study was conducted using the Preferred Reporting Items for Systematic Reviews (PRISMA) standards of quality for reporting meta-analyses. A systematic search of five electronic databases was conducted. Two reviewers retrieved articles, assessed risk of bias, and performed data extraction. The findings were synthesized using a descriptive analysis. Results: A total of 37 articles met the inclusion criteria. A thematic analysis was conducted to reduce the included articles into four themes that influenced student outcomes: (1) student engagement and participation, (2) motivation, (3) student learning, and (4) physical activity and fitness. Conclusions: This review of the literature provides evidence of the benefits of effective teaching practices and suggests that future studies in instruction should focus on teacher effectiveness and its relation to student learning outcomes. Recommendations and future directions are discussed.
The combination of daunorubicin (dnr) and cytarabine (Ara-C) is a cornerstone of treatment for acute myelogenous leukemia (AML); resistance to these drugs is a major cause of treatment failure. ...Ceramide, a sphingolipid (SL), plays a critical role in cancer cell apoptosis in response to chemotherapy. Here, we investigated the effects of chemotherapy selection pressure with Ara-C and dnr on SL composition and enzyme activity in the AML cell line HL-60. Resistant cells, those selected for growth in Ara-C- and dnr-containing medium (HL-60/Ara-C and HL-60/dnr, respectively), demonstrated upregulated expression and activity of glucosylceramide synthase, acid ceramidase (AC), and sphingosine kinase 1 (SPHK1); were more resistant to ceramide than parental cells; and displayed sensitivity to inhibitors of SL metabolism. Lipidomic analysis revealed a general ceramide deficit and a profound upswing in levels of sphingosine 1-phosphate (S1P) and ceramide 1-phosphate (C1P) in HL-60/dnr cells versus parental and HL-60/Ara-C cells. Both chemotherapy-selected cells also exhibited comprehensive upregulations in mitochondrial biogenesis consistent with heightened reliance on oxidative phosphorylation, a property that was partially reversed by exposure to AC and SPHK1 inhibitors and that supports a role for the phosphorylation system in resistance. In summary, dnr and Ara-C selection pressure induces acute reductions in ceramide levels and large increases in S1P and C1P, concomitant with cell resilience bolstered by enhanced mitochondrial remodeling. Thus, strategic control of ceramide metabolism and further research to define mitochondrial perturbations that accompany the drug-resistant phenotype offer new opportunities for developing therapies that regulate cancer growth.
Abstract A total of 208 patients were enrolled in a multicenter, prospective randomized, institutional review board–approved study that compared preoperative surgical plan to postoperative ...2-dimensional radiographic alignment measured by a blinded reviewer for primary total knee arthroplasty (TKA) implanted using computer-assisted surgery (CAS) compared with conventional TKA instrumentation. The results demonstrated a statistically significant improvement in the coronal tibial component alignment ( P < .03) and failed to demonstrate a statistically significant improvement in the mechanical axis, femoral coronal/sagittal, and tibial sagittal alignment. Knee Society Score knee and function scores and 6-minute walk test were equivalent between the 2 treatment groups at all postoperative intervals. There was a statistically significant increase in the skin-skin time ( P < .0001) and the time until first bone cut ( P < .0001) for the CAS knees compared with those implanted with conventional instrumentation. The use of CAS in this randomized clinical trial conducted at high-volume centers did not offer a clinically meaningful improvement in postoperative alignment, clinical, functional, or safety outcomes compared with conventional TKA.
Abstract Lower socioeconomic status (SES) is associated with a higher risk of cardiovascular disease. However, the association between SES and mortality in patients with atrial fibrillation (AF) is ...not clear. We examined whether SES predicts all-cause mortality in patients hospitalized with AF. This is a retrospective study of patients aged >18 years, admitted with a primary diagnosis of AF to Montefiore Medical Center between 2000 and 2010. Multivariable logistic regression models were used to determine predictors of survival adjusted for age, gender, heart failure, diabetes mellitus, chronic kidney disease, prior myocardial infraction, chronic obstructive pulmonary disease, hypertension, peripheral vascular disease, and SES. SES was determined using the New York City Department of Health Standardized Score (a log composite score of household income, value of housing units, net rental income, household occupations, and educational level). The cohort was divided into quartiles based on SES-score, with Q4 the highest and Q1 the lowest SES score. There were 4,503 patients identified with a mean follow up of 4.5 years in the following SES quartiles: Q1 (n= 1,132), Q2 (n= 1,119), Q3 (n= 1,126), and Q4 (n= 1,126). The unadjusted mortality varied across quartiles (Q1-Q4), 54%, 58%, 56%, and 59%, respectively (p= 0.004). After controlling for other variables in the multivariable analysis, patients with the lowest SES (Q1) had a significantly higher mortality than patients in the quartile with the highest (Q4) SES, (OR 1.3, CI: 1.1-1.5). In conclusion, patients admitted to the hospital with AF have varying mortality based on their socioeconomic status. After controlling for comorbidities, patients with AF and lower SES scores had higher mortality. Further research studies are warranted to study this risk of increased mortality in AF population.
Modifications in sphingolipid (SL) metabolism and mitochondrial bioenergetics are key factors implicated in cancer cell response to chemotherapy, including chemotherapy resistance. In the present ...work, we utilized acute myeloid leukemia (AML) cell lines, selected to be refractory to various chemotherapeutics, to explore the interplay between SL metabolism and mitochondrial biology supportive of multidrug resistance (MDR). In agreement with previous findings in cytarabine or daunorubicin resistant AML cells, relative to chemosensitive wildtype controls, HL‐60 cells refractory to vincristine (HL60/VCR) presented with alterations in SL enzyme expression and lipidome composition. Such changes were typified by upregulated expression of various ceramide detoxifying enzymes, as well as corresponding shifts in ceramide, glucosylceramide, and sphingomyelin (SM) molecular species. With respect to mitochondria, despite consistent increases in both basal respiration and maximal respiratory capacity, direct interrogation of the oxidative phosphorylation (OXPHOS) system revealed intrinsic deficiencies in HL60/VCR, as well as across multiple MDR model systems. Based on the apparent requirement for augmented SL and mitochondrial flux to support the MDR phenotype, we explored a combinatorial therapeutic paradigm designed to target each pathway. Remarkably, despite minimal cytotoxicity in peripheral blood mononuclear cells (PBMC), co‐targeting SL metabolism, and respiratory complex I (CI) induced synergistic cytotoxicity consistently across multiple MDR leukemia models. Together, these data underscore the intimate connection between cellular sphingolipids and mitochondrial metabolism and suggest that pharmacological intervention across both pathways may represent a novel treatment strategy against MDR.
Measures of cerebrovascular reactivity (CVR) are used to judge the health of the brain vasculature. In this study, we report the use of several different analyses of blood oxygen dependent (BOLD) ...fMRI responses to CO
to provide a number of metrics of CVR based on the sigmoidal resistance response to CO
. To assess possible differences in these metrics with age, we compiled atlases reflecting voxel-wise means and standard deviations for four different age ranges and for a group of patients with mild cognitive impairment (MCI) and compared them. Sixty-seven subjects were recruited for this study and scanned at 3T field strength. Of those, 51 healthy control volunteers between the ages of 18-83 were recruited, and 16 (MCI) subjects between the ages of 61-83 were recruited. Testing was carried out using an automated computer-controlled gas blender to induce hypercapnia in a step and ramp paradigm while monitoring end-tidal partial pressures of CO
. Surprisingly, some resistance sigmoid parameters in the oldest control group were increased compared to the youngest control group. Resistance amplitude maps showed increases in clusters within the temporal cortex, thalamus, corpus callosum and brainstem, and resistance reserve maps showed increases in clusters within the cingulate cortex, frontal gyrus, and corpus callosum. These findings suggest that some aspects of vascular reactivity in parts of the brain are initially maintained with age but then may increase in later years. We found significant reductions in all resistance sigmoid parameters (amplitude, reserve, sensitivity, midpoint, and range) when comparing MCI patients to controls. Additionally, in controls and in MCI patients, amplitude, range, reserve, and sensitivity in white matter (WM) was significantly reduced compared to gray matter (GM). WM midpoints were significantly above those of GM. Our general conclusion is that vascular regulation in terms of cerebral blood flow (CBF) responsiveness to CO
is not significantly affected by age, but is reduced in MCI. These changes in cerebrovascular regulation demonstrate the value of resistance metrics for mapping areas of dysregulated blood flow in individuals with MCI. They may also be of value in the investigation of patients with vascular risk factors at risk for developing vascular dementia.
Dentate gyrus (DG) development requires specification of granule cell (GC) progenitors in the hippocampal neuroepithelium, as well as their proliferation and migration into the primordial DG. We ...identify the Plexin family members Plxna2 and Plxna4 as important regulators of DG development. Distribution of immature GCs is regulated by Sema5A signaling through PlxnA2 and requires a functional PlxnA2 GTPase-activating protein (GAP) domain and Rap1 small GTPases. In adult Plxna2−/− but not Plxna2-GAP-deficient mice, the dentate GC layer is severely malformed, neurogenesis is compromised, and mossy fibers form aberrant synaptic boutons within CA3. Behavioral studies with Plxna2−/− mice revealed deficits in associative learning, sociability, and sensorimotor gating—traits commonly observed in neuropsychiatric disorder. Remarkably, while morphological defects are minimal in Plxna2-GAP-deficient brains, defects in fear memory and sensorimotor gating persist. Since allelic variants of human PLXNA2 and RAP1 associate with schizophrenia, our studies identify a biochemical pathway important for brain development and mental health.
Display omitted
•Sema5A-PlexinA2 signaling regulates dentate granule cell progenitor migration•PlexinA2 GAP activity and Rap1 small GTPases direct progenitor migration•Plxna2 function is required for the formation of the DG neurogenic niche•Plxna2-GAP deficiency disrupts contextual fear memory and sensorimotor gating
Zhao et al. find that Sema5A-PlexinA2 forward signaling through Rap1 GTPases is required for progenitor distribution in the developing mouse dentate gyrus. Adult Plxna2−/−, but not Plxna2-GAP-deficient, mice show defects in dentate morphology, neurogenesis, and mossy fiber connectivity. Plxna2−/− and Plxna2-GAP mice exhibit behavioral defects suggestive of neuropsychiatric illness.
PDF
