Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Effects of mometasone furoate/formoterol fumarate fixed-dose combination formulation on chronic obstructive pulmonary disease (COPD): results from a 52-week Phase III trial in subjects with moderate-to-very severe COPD

RATIONALE: The purpose of this study was to investigate the clinical efficacy and safety of a fixed-dose combination of mometasone furoate/formoterol fumarate (MF/F) administered via a metered-dose inhaler in subjects with moderate-to-very severe chronic obstructive pulmonary disease (COPD). METHODS: This multicenter, double-blind, placebo-controlled trial had a 26-week treatment period and a 26-week safety extension. Subjects (n = 1196), at least 40 years old, were current or ex-smokers randomized to twice-daily inhaled MF/F 400/10 μg, MF/F 200/10 μg, MF 400 μg, F 10 μg, or placebo. The trial\u27s co-primary endpoints were mean changes from baseline, as area under the curve (AUC), in forced expiratory volume (FEV1) over 0-12 hours (AUC0-12 h FEV1) with MF/F versus MF, and in morning (AM) pre-dose (trough) FEV1 with MF/F versus F after 13 weeks of treatment. Key secondary endpoints were the effects of MF/F on respiratory health status using the Saint George\u27s Respiratory Questionnaire (SGRQ), symptom-free nights, partly stable COPD at 26 weeks, and time to first COPD exacerbation. RESULTS: The largest improvements in AUC0-12 h FEV1 were observed with MF/F 400/10 μg and MF/F 200/10 μg. Serial spirometry results demonstrated that bronchodilator effects with MF/F occurred rapidly (within 5 minutes), persisted for 12 hours after dosing, and were sustained over the 26-week treatment period. Similar findings were observed for AM pre-dose FEV1, for which effects were further investigated, excluding subjects whose AM FEV1 data were incorrectly collected after 2 days from the last dose of study treatment. Improvements in SGRQ scores surpassed the minimum clinically important difference of more than four units with both MF/F treatments. At 26 weeks, no notable between-treatment differences in the occurrence and nature of adverse events (AEs) were reported. No unexpected AEs were observed. Overall, 90 subjects reported AEs considered to be treatment-related, the most common of which were lenticular opacities, dysphonia, and oral candidiasis. DISCUSSION: In conclusion, MF/F treatments improved lung function and respiratory health status, reduced exacerbations, and were well tolerated in subjects with moderate-to-very severe COPD

Efficacy and safety characteristics of mometasone furoate/formoterol fumarate fixed-dose combination in subjects with moderate to very severe COPD: findings from pooled analysis of two randomized, 52-week placebo-controlled trials

Background: The clinical efficacy and safety of a mometasone furoate/formoterol fumarate (MF/F) fixed-dose combination formulation administered via a metered-dose inhaler was investigated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). Methods: Two 52-week, multicenter, double-blind, placebo-controlled trials with identical study designs were conducted in current or ex-smokers (aged =40 years), and pooled study results are presented herein. Subjects (n = 2251) were randomized to 26 weeks of twice-daily treatment with MF/F 400/10 µg, MF/F 200/10 µg, MF 400 µg, F 10 µg, or placebo. After the 26-week treatment period, placebo subjects completed the trial and 75% of subjects on active treatment entered a 26-week safety extension. Coprimary efficacy variables were mean changes in forced expiratory volume in one second (FEV1), area under the curve from 0 to 12 hours postdose (AUC0–12 h), and morning predose/trough FEV1 from baseline to the week 13 endpoint. Key secondary efficacy variables were St George’s Respiratory Questionnaire scores, symptom-free nights, time-to-first exacerbation, and partly stable COPD at the week 26 endpoint. Results: In the 26-week treatment period, significantly greater increases in FEV1 AUC0–12 h occurred with MF/F 400/10 versus MF 400 and placebo at the week 13 and week 26 endpoints (P = 0.032). These increases were over three-fold greater with MF/F 400/10 than with MF 400. Also, significantly greater increases in morning predose/trough FEV1 occurred with MF/F 400/10 versus F 10 and placebo at the week 13 endpoint (P \u3c 0.05). The increase was four-fold greater with MF/F 400/10 than with F 10. All active treatment groups achieved minimum clinically important differences from baseline (\u3e4 units) in St George’s Respiratory Questionnaire scores at week 26. Symptom-free nights increased by =14% in the MF/F 400/10, MF 400, and F 10 groups (P= 0.033 versus placebo). The incidence of exacerbations was lower in the MF/F groups (=33.3%) than it was in the MF, formoterol, and placebo groups (=33.8%) over the 26-week treatment period. The incidence of adverse events was similar in the active-treated and placebo-treated subjects across 26 weeks of treatment. Over the 1-year study period, there were no notable differences in the incidence or types of adverse events between the MF/F 400/10 and MF/F 200/10 groups compared with the MF or formoterol groups. Differences in rates of individual treatment-emergent adverse events were Conclusion: Patients treated with MF/F demonstrated significant improvements in lung function, health status, and exacerbation rates. Although significant improvements were seen with both doses, a trend showing a dose-response effect was observed in the lung function measurements

Model International Mobility Convention

While people are as mobile as they ever were in our globalized world, the movement of people across borders lacks global regulation. This leaves many refugees in protracted displacement and many migrants unprotected in irregular and dire situations. Meanwhile, some states have become concerned that their borders have become irrelevant. International mobility—the movement of individuals across borders for any length of time as visitors, students, tourists, labor migrants, entrepreneurs, long-term residents, asylum seekers, or refugees—has no common definition or legal framework. To address this key gap in international law, and the growing gaps in protection and responsibility that are leaving people vulnerable, the "Model International Mobility Convention" proposes a framework for mobility with the goals of reaffirming the existing rights afforded to mobile people (and the corresponding rights and responsibilities of states) as well as expanding those basic rights where warranted. In 213 articles divided over eight chapters, the Convention establishes both the minimum rights afforded to all people who cross state borders as visitors, and the special rights afforded to tourists, students, migrant workers, investors and residents, forced migrants, refugees, migrant victims of trafficking and migrants caught in countries in crisis. Some of these categories are covered by existing international legal regimes. However, in this Convention these groups are for the first time brought together under a single framework. An essential feature of the Convention is that it is cumulative. This means, for the most part, that the chapters build on and add rights to the set of rights afforded to categories of migrants covered by earlier chapters. The Convention contains not only provisions that afford rights to migrants and, to a lesser extent, States (such as the right to decide who can enter and remain in their territory). It also articulates the responsibilities of migrants vis-à-vis States and the rights and responsibilities of different institutions that do not directly respond to a right held by migrants

Computational Thermochemistry and Benchmarking of Reliable Methods

During the first and second years of the Computational Thermochemistry and Benchmarking of Reliable Methods project, we completed several studies using the parallel computing capabilities of the NWChem software and Molecular Science Computing Facility (MSCF), including large-scale density functional theory (DFT), second-order Moeller-Plesset (MP2) perturbation theory, and CCSD(T) calculations. During the third year, we continued to pursue the computational thermodynamic and benchmarking studies outlined in our proposal. With the issues affecting the robustness of the coupled cluster part of NWChem resolved, we pursued studies of the heats-of-formation of compounds containing 5 to 7 first- and/or second-row elements and approximately 10 to 14 hydrogens. The size of these systems, when combined with the large basis sets (cc-pVQZ and aug-cc-pVQZ) that are necessary for extrapolating to the complete basis set limit, creates a formidable computational challenge, for which NWChem on NWMPP1 is well suited