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Results from phase II studies in patients with stage IIIA non-small-cell lung cancer with ipsilateral mediastinal nodal metastases (N2) have shown the feasibility of resection after concurrent chemotherapy and radiotherapy with promising rates of survival. We therefore did this phase III trial to compare concurrent chemotherapy and radiotherapy followed by resection with standard concurrent chemotherapy and definitive radiotherapy without resection. Patients with stage T1-3pN2M0 non-small-cell lung cancer were randomly assigned in a 1:1 ratio to concurrent induction chemotherapy (two cycles of cisplatin [50 mg/m 2 on days 1, 8, 29, and 36] and etoposide [50 mg/m 2 on days 1–5 and 29–33]) plus radiotherapy (45 Gy) in multiple academic and community hospitals. If no progression, patients in group 1 underwent resection and those in group 2 continued radiotherapy uninterrupted up to 61 Gy. Two additional cycles of cisplatin and etoposide were given in both groups. The primary endpoint was overall survival (OS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00002550. 202 patients (median age 59 years, range 31–77) were assigned to group 1 and 194 (61 years, 32–78) to group 2. Median OS was 23·6 months (IQR 9·0–not reached) in group 1 versus 22·2 months (9·4–52·7) in group 2 (hazard ratio [HR] 0·87 [0·70–1·10]; p=0·24). Number of patients alive at 5 years was 37 (point estimate 27%) in group 1 and 24 (point estimate 20%) in group 2 (odds ratio 0·63 [0·36–1·10]; p=0·10). With N0 status at thoracotomy, the median OS was 34·4 months (IQR 15·7–not reached; 19 [point estimate 41%] patients alive at 5 years). Progression-free survival (PFS) was better in group 1 than in group 2, median 12·8 months (5·3–42·2) vs 10·5 months (4·8–20·6), HR 0·77 [0·62–0·96]; p=0·017); the number of patients without disease progression at 5 years was 32 (point estimate 22%) versus 13 (point estimate 11%), respectively. Neutropenia and oesophagitis were the main grade 3 or 4 toxicities associated with chemotherapy plus radiotherapy in group 1 (77 [38%] and 20 [10%], respectively) and group 2 (80 [41%] and 44 [23%], respectively). In group 1, 16 (8%) deaths were treatment related versus four (2%) in group 2. In an exploratory analysis, OS was improved for patients who underwent lobectomy, but not pneumonectomy, versus chemotherapy plus radiotherapy. Chemotherapy plus radiotherapy with or without resection (preferably lobectomy) are options for patients with stage IIIA(N2) non-small-cell lung cancer. National Cancer Institute, Canadian Cancer Society, and National Cancer Institute of Canada.

Activation of the insulin-like growth factor 1 receptor may underlie clinical resistance to inhibition of the anaplastic lymphoma receptor kinase in lung cancer. Crizotinib, a selective tyrosine kinase inhibitor (TKI), shows marked activity in patients whose lung cancers harbor fusions in the gene encoding anaplastic lymphoma receptor tyrosine kinase (ALK), but its efficacy is limited by variable primary responses and acquired resistance. In work arising from the clinical observation of a patient with ALK fusion–positive lung cancer who had an exceptional response to an insulin-like growth factor 1 receptor (IGF-1R)-specific antibody, we define a therapeutic synergism between ALK and IGF-1R inhibitors. Similar to IGF-1R, ALK fusion proteins bind to the adaptor insulin receptor substrate 1 (IRS-1), and IRS-1 knockdown enhances the antitumor effects of ALK inhibitors. In models of ALK TKI resistance, the IGF-1R pathway is activated, and combined ALK and IGF-1R inhibition improves therapeutic efficacy. Consistent with this finding, the levels of IGF-1R and IRS-1 are increased in biopsy samples from patients progressing on crizotinib monotherapy. Collectively these data support a role for the IGF-1R–IRS-1 pathway in both ALK TKI–sensitive and ALK TKI–resistant states and provide a biological rationale for further clinical development of dual ALK and IGF-1R inhibitors.

Four combinations of chemotherapy were compared in patients with advanced non–small-cell lung cancer. No one regimen appeared to be superior to the others. The overall survival rate at one year was 33 percent. The regimen of carboplatin plus paclitaxel was less toxic than the other regimens. The regimen of carboplatin plus paclitaxel was less toxic than the other regimens. Approximately one third of all cancer-related deaths are due to lung cancer, which accounts for more deaths each year than breast, prostate, and colon cancer combined. The median survival of patients with untreated metastatic non–small-cell lung cancer is only four to five months, with a survival rate at one year of only 10 percent. 1 Chemotherapy for advanced non–small-cell lung cancer is often considered ineffective or excessively toxic. However, meta-analyses have demonstrated that, as compared with supportive care, chemotherapy results in a small improvement in survival in patients with advanced non–small-cell lung cancer. 2 – 4 In addition, randomized studies comparing chemotherapy with . . .

α-Synuclein (αSyn), an intrinsically disordered protein implicated in Parkinson’s disease, is thought to initiate aggregation by binding to cellular membranes. Previous studies suggest that anionic lipids are necessary for this binding. However, these studies largely focused on unmodified αSyn, while physiological αSyn is N-terminally acetylated (NTA). Our work challenges the long-standing paradigm that anionic lipids are necessary for αSyn binding by demonstrating that NTA diminishes αSyn’s reliance on anionic membranes, revealing that membrane packing defects (i.e., interfacial hydrophobicity) alone can drive membrane binding. Using fluorescence microscopy and circular dichroism spectroscopy, we monitored the binding of NTA-αSyn to membrane vesicles with different lipid compositions. Phosphatidylcholine and phosphatidylserine concentrations were varied to control surface charge, while phospholipid tail unsaturation and methylation were varied to modulate lipid packing. We also formulated cholesterol-containing membranes that mimicked the lipid composition of synaptic vesicles. In these membranes, all-atom molecular dynamics simulations were used to visualize and quantify membrane packing defects. Our results demonstrate that membrane packing defects are necessary for NTA-αSyn binding and that defect-rich membranes are sufficient for NTA-αSyn binding regardless of membrane charge. These findings provide a molecular mechanism by which lipid structural properties, such as poly-unsaturation, can regulate αSyn binding to physiological membranes. Mechanistic analysis of α-synuclein binding clarifies the roles of lipid packing defects and charge in regulating membrane interactions.

Background Core landbirds undergo adaptive radiation with different ecological niches, but the genomic bases that underlie their ecological diversification remain unclear. Results Here we used the genome-wide target enrichment sequencing of the genes related to vision, hearing, language, temperature sensation, beak shape, taste transduction, and carbohydrate, protein and fat digestion and absorption to examine the genomic bases underlying their ecological diversification. Our comparative molecular phyloecological analyses show that different core landbirds present adaptive enhancement in different aspects, and two general patterns emerge. First, all three raptorial birds (Accipitriformes, Strigiformes, and Falconiformes) show a convergent adaptive enhancement for fat digestion and absorption, while non-raptorial birds tend to exhibit a promoted capability for protein and carbohydrate digestion and absorption. Using this as a molecular marker, our results show relatively strong support for the raptorial lifestyle of the common ancestor of core landbirds, consequently suggesting a single origin of raptors, followed by two secondary losses of raptorial lifestyle within core landbirds. In addition to the dietary niche, we find at temporal niche that diurnal birds tend to exhibit an adaptive enhancement in bright-light vision, while nocturnal birds show an increased adaption in dim-light vision, in line with previous findings. Conclusions Our molecular phyloecological study reveals the genome-wide adaptive differentiations underlying the ecological diversification of core landbirds.

Leptin dysregulation has been postulated to affect cancer risk through its effects on obesity and inflammation. Epidemiological data evaluating this relationship are conflicting and studies in non-white cohorts is lacking. Therefore, we examined the association of leptin with the risk of incident cancer in the multiethnic Dallas Heart Study (DHS). Participants enrolled in the DHS without prevalent cancer and with baseline leptin measurements were included. Incident cancer cases were identified through a systematic linkage of the DHS and the Texas Cancer Registry. Leptin was evaluated both as a continuous variable and in sex-specific quartiles. Multivariable Cox proportional hazards modeling was performed to examine the association between leptin levels with incident cancer after adjusting for age, sex, race, smoking status, alcohol use, family history of malignancy, body mass index (BMI), diabetes mellitus and C-reactive protein. Among 2,919 participants (median age 44 years; 54% women; 70% nonwhite; median BMI 29.4 kg/m2), 190 (6.5%) developed cancer after median follow- up of 12 years. Median leptin levels were 12.9 (interquartile range [IQR] 5.8-29.5) ng/ml in the incident cancer group vs. 12.3 (IQR 5.4-26.4) ng/ml those without an incident cancer (p = 0.34). Leptin was not associated with cancer incidence in multivariable analysis (unit standard deviation increase in log-transformed leptin, hazard ratio 0.95; 95% confidence interval, 0.77-1.16; p = 0.60). No association was observed in analyses stratified by sex, race/ethnicity, diabetes, or obesity status. In this study of a predominantly minority population, no association between premorbid leptin levels and cancer incidence was demonstrated. Despite preclinical rationale and positive findings in other studies, this association may not replicate across all racial/ethnic populations.

Background Though the proportion of female Internal Medicine (IM) residents and faculty has increased, there is minimal large scale modern data comparing resident performance by gender. This study sought to examine the effects of resident and faculty gender on resident evaluations. Methods Retrospective observational study over 5 years in a single IM program. IM certifying examination pass rates were obtained from the American Board of IM. Results Four hundred eighty-eight residents (195 women, 293 men), evaluated by 430 attending physicians (163 women, 270 men) were included. Twelve thousand six hundred eighty-one evaluations between 2007 and 2012 were analyzed. Female residents scored higher in two domains (Medical Interviewing, and Interpersonal and Communication Skills) ( p  < 0.01 for each), with no significant difference between genders for the other domains (Medical Knowledge, Overall Patient Care, Physical Examination, Procedural Skills, Professionalism, Practice Based Learning and Improvement, System Based Practices and Overall score). There were no differences in scoring between female and male attending physicians. There were no differences in certifying examination scores between women and men among graduating residents. National pass rates for women were not statistically different to pass rates for men from 1987 to 2015. Conclusions Data from one large academic medical center demonstrate higher ratings for female residents on performance domains reflecting bedside care and interpersonal skills, with similar scores for medical knowledge and remaining domains. No significant difference was seen locally in certifying examination scores, nor in recent national pass rates, an objective measure of medical knowledge. Despite imbalanced female representation in areas of medicine, our data suggest that gender-based disparities in Internal Medicine resident medical knowledge and physician competency are no longer present.

Importance: Nomogram prognostic models can facilitate cancer patient treatment plans and patient enrollment in clinical trials. Objective: The primary objective is to provide an updated and accurate prognostic model for predicting the survival of advanced non-small-cell lung cancer (NSCLC) patients, and the secondary objective is to validate a published nomogram prognostic model for NSCLC using an independent patient cohort. Design: 1817 patients with advanced NSCLC from the control arms of 4 Phase III randomized clinical trials were included in this study. Data from 524 NSCLC patients from one of these trials were used to validate a previously published nomogram and then used to develop an updated nomogram. Patients from the other 3 trials were used as independent validation cohorts of the new nomogram. The prognostic performances were comprehensively evaluated using hazard ratios, integrated area under the curve (AUC), concordance index, and calibration plots. Setting: General community. Main outcome: A nomogram model was developed to predict overall survival in NSCLC patients. Results: We demonstrated the prognostic power of the previously published model in an independent cohort. The updated prognostic model contains the following variables: sex, histology, performance status, liver metastasis, hemoglobin level, white blood cell counts, peritoneal metastasis, skin metastasis, and lymphocyte percentage. This model was validated using various evaluation criteria on the 3 independent cohorts with heterogeneous NSCLC populations. In the SUN1087 patient cohort, the continuous risk score output by the nomogram achieved an integrated area under the receiver operating characteristics (ROC) curve of 0.83, a log-rank P-value of 3.87e−11, and a concordance index of 0.717. In the SAVEONCO patient cohort, the integrated area under the ROC curve was 0.755, the log-rank P-value was 4.94e−6 and the concordance index was 0.678. In the VITAL patient cohort, the integrated area under the ROC curve was 0.723, the log-rank P-value was 1.36e−11, and the concordance index was 0.654. We implemented the proposed nomogram and several previously published prognostic models on an online Web server for easy user access. Conclusions: This nomogram model based on basic clinical features and routine lab testing predicts individual survival probabilities for advanced NSCLC and exhibits cross-study robustness.