The Joint Program Dilemma: Analyzing the Pervasive Role That Social Dilemmas Play in Undermining Acquisition Success

Tenth Annual Acquisition Research Symposium Acquisition ManagementExcerpt from the Proceedings of the Tenth Annual Acquisition Research Symposium Acquisition ManagementNaval Postgraduate School Acquisition Research ProgramPrepared for the Naval Postgraduate School, Monterey, CANaval Postgraduate School Acquisition Research ProgramApproved for public release; distribution is unlimited

HDAC1 interacts with the p50 NF-κB subunit via its nuclear localization sequence to constrain inflammatory gene expression

The NF-κB p50 subunit is an important regulator of inflammation, with recent experimental evidence to support it also having a tumor suppressor role. Classically, p50 functions in heterodimeric form with the RelA (p65) NF-κB subunit to activate inflammatory genes. However, p50 also forms homodimers which actively repress NF-κB-dependent inflammatory gene expression and exert an important brake on the inflammatory process. This repressive activity of p50:p50 is thought to be in part mediated by an interaction with the epigenetic repressor protein Histone Deacetylase 1 (HDAC1). However, neither the interaction of p50 with HDAC1 nor the requirement of HDAC1 for the repressive activities of p50 has been well defined. Here we employed in silico prediction with in vitro assays to map sites of interaction of HDAC1 on the p50 protein. Directed mutagenesis of one such region resulted in almost complete loss of HDAC1 binding to p50. Transfected mutant p50 protein lacking the putative HDAC1 docking motif resulted in enhanced cytokine and chemokine expression when compared with cells expressing a transfected wild type p50. In addition, expression of this mutant p50 was associated with enhanced chemoattraction of neutrophils and acetylation of known inflammatory genes demonstrating the likely importance of the p50:HDAC1 interaction for controlling inflammation. These new insights provide an advance on current knowledge of the mechanisms by which NF-κB-dependent gene transcription are regulated and highlight the potential for manipulation of p50:HDAC1 interactions to bring about experimental modulation of chronic inflammation and pathologies associated with dysregulated neutrophil accumulation and activation

Treating triple negative breast cancer cells with erlotinib plus a select antioxidant overcomes drug resistance by targeting cancer cell heterogeneity

Among breast cancer patients, those diagnosed with the triple-negative breast cancer (TNBC) subtype have the worst prog-nosis. TNBC does not express estrogen receptor-alpha, progesterone receptor, or the HER2 oncogene; therefore, TNBC lacks targets for molecularly-guided therapies. The concept that EGFR oncogene inhibitor drugs could be used as targeted treatment against TNBC has been put forth based on estimates that 30-60% of TNBC express high levels of EGFR. However, results from clinical trials testing EGFR inhibitors, alone or in combination with cytotoxic chemotherapy, did not improve patient outcomes. Results herein offer an explanation as to why EGFR inhibitors failed TNBC patients and support how combining a select antioxidant and an EGFR-specific small molecule kinase inhibitor (SMKI) could be an effective, novel therapeutic strategy. Treatment with CAT-SKL-a re-engineered protein form of the antioxidant enzyme catalase-inhibited cancer stem-like cells (CSCs), and treatment with the EGFR-specific SMKI erlotinib inhibited non-CSCs. Thus, combining the antioxidant CAT-SKL with erlotinib targeted both CSCs and bulk cancer cells in cultures of EGFR-expressing TNBC-derived cells. We also report evidence that the mechanism for CAT-SKL inhibition of CSCs may depend on antioxidant-induced downregulation of a short alternative mRNA splicing variant of the methyl-CpG binding domain 2 gene, isoform MBD2c

Safety Monitoring in Group A Meningococcal Conjugate Vaccine Trials: Description, Challenges, and Lessons

Background. The determination of the safety profile of any vaccine is critical to its widespread use in any population. In addition, the application of international guidelines to fit local context could be a challenging but important step toward obtaining quality safety data. Methods. In clinical studies of PsA-TT (MenAfriVac), safety was monitored immediately after vaccination, at 4-7 days for postimmunization local and systemic reactions, within 28 days for adverse events, and throughout the duration of study for serious adverse events. Initial and ongoing training of sites' staff were undertaken during the studies, and a data and safety monitoring board reviewed all the data during and after the studies. Results. The safety of PsA-TT was evaluated according to international standards despite obvious challenges in remote areas where these studies were conducted. These challenges included the need for uniformity of methods, timely reporting in the context of frequent communication problems, occurrence of seasonal diseases such as malaria and rotavirus diarrhea, and healthcare systems that required improvement. Conclusions. The trials of PsA-TT highlighted the value of a robust vaccine development plan and design so that lessons learned in initial studies were incorporated into the subsequent ones, initial training and periodic retraining, strict monitoring of all procedures, and continuous channel of communication with all stakeholders that enabled the application of international requirements to local settings, with high quality of dat

The liver receptor homolog-1 (LRH-1) is expressed in human islets and protects β-cells against stress-induced apoptosis

Liver receptor homolog (LRH-1) is an orphan nuclear receptor (NR5A2) that regulates cholesterol homeostasis and cell plasticity in endodermal-derived tissues. Estrogen increases LRH-1 expression conveying cell protection and proliferation. Independently, estrogen also protects isolated human islets against cytokine-induced apoptosis. Herein, we demonstrate that LRH-1 is expressed in islets, including β-cells, and that transcript levels are modulated by 17β-estradiol through the estrogen receptor (ER)α but not ERβ signaling pathway. Repression of LRH-1 by siRNA abrogated the protective effect conveyed by estrogen on rat islets against cytokines. Adenoviral-mediated overexpression of LRH-1 in human islets did not alter proliferation but conferred protection against cytokines and streptozotocin-induced apoptosis. Expression levels of the cell cycle genes cyclin D1 and cyclin E1 as well as the antiapoptotic gene bcl-xl were unaltered in LRH-1 expressing islets. In contrast, the steroidogenic enzymes CYP11A1 and CYP11B1 involved in glucocorticoid biosynthesis were both stimulated in transduced islets. In parallel, graded overexpression of LRH-1 dose-dependently impaired glucose-induced insulin secretion. Our results demonstrate the crucial role of the estrogen target gene nr5a2 in protecting human islets against-stressed-induced apoptosis. We postulate that this effect is mediated through increased glucocorticoid production that blunts the pro-inflammatory response of islet

Detailed modelling of a large sample of Herschel sources in the Lockman Hole: identification of cold dust and of lensing candidates through their anomalous SEDs

We have studied in detail a sample of 967 SPIRE sources with 5σ detections at 350 and 500 μm and associations with Spitzer-SWIRE 24 μm galaxies in the HerMES-Lockman survey area, fitting theirmid- and far-infrared, and submillimetre, spectral energy distributions (SEDs) in an automatic search with a set of six infrared templates. For almost 300 galaxies,we havemodelled their SEDs individually to ensure the physicality of the fits. We confirm the need for the new cool and cold cirrus templates, and also of the young starburst template, introduced in earlier work. We also identify 109 lensing candidates via their anomalous SEDs and provide a set of colour–redshift constraints which allow lensing candidates to be identified from combined Herschel and Spitzer data. The picture that emerges of the submillimetre galaxy population is complex, comprising ultraluminous and hyperluminous starbursts, lower luminosity galaxies dominated by interstellar dust emission, lensed galaxies and galaxies with surprisingly cold (10–13 K) dust. 11 per cent of 500 μm selected sources are lensing candidates. 70 per cent of the unlensed sources are ultraluminous infrared galaxies and 26 per cent are hyperluminous. 34 per cent are dominated by optically thin interstellar dust (‘cirrus’) emission, but most of these are due to cooler dust than is characteristic of our Galaxy. At the highest infrared luminosities we see SEDs dominated by M82, Arp 220 and young starburst types, in roughly equal proportions

Effect of Food on the Pharmacokinetics of the Oral Docetaxel Tablet Formulation ModraDoc006 Combined with Ritonavir (ModraDoc006/r) in Patients with Advanced Solid Tumours

Introduction: ModraDoc006 is a novel docetaxel tablet formulation that is co-administrated with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir (r): ModraDoc006/r. Objectives: This study evaluated the effect of food consumed prior to administration of ModraDoc006/r on the pharmacokinetics of docetaxel and ritonavir. Methods: Patients with advanced solid tumours were enrolled in this randomized crossover study to receive ModraDoc006/r in a fasted state in week 1 and after a standardized high-fat meal in week 2 and vice versa. Pharmacokinetic sampling was conducted until 48 h after both study drug administrations. Docetaxel and ritonavir plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. Safety was evaluated with the Common Terminology Criteria for Adverse Events, version 4.03. Results: In total, 16 patients completed the food-effect study. The geometric mean ratio (GMR) for the docetaxel area under the plasma concentration–time curve (AUC)0–48, AUC0–inf and maximum concentration (Cmax) were 1.11 (90% confidence interval [CI] 0.93–1.33), 1.19 (90% CI 1.00–1.41) and 1.07 (90% CI 0.81–1.42) in fed versus fasted conditions, respectively. For the ritonavir Cmax, the GMR was 0.79 (90% CI 0.69–0.90), whereas the AUC0–48 and AUC0–inf were bioequivalent. The most frequent treatment-related toxicities were grade ≤ 2 diarrhoea and fatigue. Hypokalaemia was the only observed treatment-related grade 3 toxicity. Conclusions: The docetaxel and ritonavir exposure were not bioequivalent, as consumption of a high-fat meal prior to administration of ModraDoc006/r resulted in a slightly higher docetaxel exposure and lower ritonavir Cmax. Since docetaxel exposure is the only clinically relevant parameter in our patient population, the overall conclusion is that combined ModraDoc006 and ritonavir treatment may be slightly affected by concomitant intake of a high-fat meal. In view of the small effect, it is most likely that the intake of a light meal will not affect the systemic exposure to docetaxel. ClinicalTrials.gov Identifier: NCT03147378, date of registration: May 10 2017

Liquid-Diet with Alcohol Alters Maternal, Fetal and Placental Weights and the Expression of Molecules Involved in Integrin Signaling in the Fetal Cerebral Cortex

Maternal alcohol consumption during pregnancy causes wide range of behavioral and structural deficits in children, commonly known as Fetal Alcohol Syndrome (FAS). Children with FAS may suffer behavioral deficits in the absence of obvious malformations. In rodents, the exposure to alcohol during gestation changes brain structures and weights of offspring. The mechanism of FAS is not completely understood. In the present study, an established rat (Long-Evans) model of FAS was used. The litter size and the weights of mothers, fetuses and placentas were examined on gestation days 18 or 20. On gestation day 18, the effects of chronic alcohol on the expression levels of integrin receptor subunits, phospholipase-Cγ and N-cadherin were examined in the fetal cerebral cortices. Presence of alcohol in the liquid-diet reduced the consumption and decreased weights of mothers and fetuses but increased the placental weights. Expression levels of β1 and α3 integrin subunits and phospholipase-Cγ2 were significantly altered in the fetal cerebral cortices of mothers on alcohol containing diet. Results show that alcohol consumption during pregnancy even with protein, mineral and vitamin enriched diet may affect maternal and fetal health, and alter integrin receptor signaling pathways in the fetal cerebral cortex disturbing the development of fetal brains