Current state of vaccine therapies in non-small-cell lung cancer.

A large variety of cancer vaccines have undergone extensive testing in early-phase clinical trials. A limited number have also been tested in randomized phase II clinical trials. Encouraging trends toward increased survival in the vaccine arms have been recently observed for 2 vaccine candidates in patients with non-small-cell lung cancer. These have provided the impetus for the initiation of phase III trials in large groups of patients with lung cancer. These vaccines target 2 antigens widely expressed in lung carcinomas: melanoma-associated antigen 3, a cancer testis antigen; and mucin 1, an antigen overexpressed in a largely deglycosylated form in advanced tumors. Therapeutic cancer vaccines aim at inducing strong CD8 and CD4 T-cell responses. The majority of vaccines recently tested in phase I clinical trials show efficacy in terms of induction of specific tumor antigen immunity. However, clinical efficacy remains to be determined but appears limited. Efforts are thus aimed at understanding the basis for this apparent lack of effect on tumors. Two major factors are involved. On one hand, current vaccines are suboptimal. Strong adjuvant agents and appropriate tumor antigens are needed. Moreover, dose, route, and schedule also need optimization. On the other hand, it is now clear that large tumors often present a tolerogenic microenvironment that hampers effective antitumor immunity. The partial understanding of the molecular pathways leading to functional inactivation of T cells at tumor sites has provided new targets for intervention. In this regard, blockade of cytotoxic T-lymphocyte antigen-4 and programmed death-1 with humanized monoclonal antibodies has reached the clinical testing stage. In the future, more potent cancer vaccines will benefit from intense research in antigen discovery and adjuvant agents. Furthermore, it is likely that vaccines need to be combined with compounds that reverse major tolerogenic pathways that are constitutively active at the tumor site. Developing these combined approaches to vaccination in cancer promises new, exciting findings and, at the same time, poses important challenges to academic research institutions and the pharmaceutical industry.

Crystal engineering studies: polymorphs and co-crystals

We review the key topics of one of the areas with the biggest impact of the last years in the chemical and pharmaceutical industry that is Crystal Engineering. The relevance of polymorphs and co-crystals from different points of view is been highlighted and broadly illustrated by means of several recent examples of studies carried out in this field. In addition, the most suitableinstrumental techniques and the intellectual property implications are reviewed.

Detection of an asymptomatic right-ventricle cardiac metastasis from a small-cell lung cancer by F-18-FDG PET/CT.

A right heart metastasis of a small-cell lung cancer was found on the whole-body F-fluoro-deoxy-glucose positron emission tomography/computed tomography (F-FDG-PET/CT) of a 69-year-old smoker investigated for a right pulmonary mass discovered on chest radiography after a fracture of the right humerus. The PET scan showed an increased FDG uptake by the mass in the right lung and an intense, atypical focal activity of the right ventricle strongly suggestive of a neoplastic process. CT-guided lung biopsy revealed a small-cell lung cancer and myocardial biopsy confirmed the presence of a cardiac metastasis. The patient was treated with six cycles of chemotherapy followed by radiation therapy, which included the heart lesion. At follow-up PET/CT 2 months after the end of treatment, the abnormal cardiac uptake had disappeared, whereas increased FDG uptake persisted in the pulmonary residual mass.

Overfishing of small pelagic fishes increases trophic overlap between immature and mature striped dolphins in the Mediterranean Sea

The interactions among diet, ecology, physiology, and biochemistry affect N and C stable isotope signatures in animal tissues. Here, we examined if ecological segregation among animals in relation to sex and age existed by analyzing the signatures of delta15N and delta13C in the muscle of Western Mediterranean striped dolphins. Moreover, we used a Bayesian mixing model to study diet composition and investigated potential dietary changes over the last two decades in this population. For this, we compared isotope signatures in samples of stranded dolphins obtained during two epizootic events occurring in 1990 and 2007-2008. Mean delta13C values for females and males were not significantly different, but age-related variation indicated delta13C enrichment in both sexes, suggesting that females and males most likely fed in the same general areas, increasing their consumption of benthic prey with age. Enrichment of delta15N was only observed in females, suggesting a preference for larger or higher trophic level prey than males, which could reflect different nutritional requirements. delta13C values showed no temporal variation, although the mean delta15N signature decreased from 1990 to 2007-2008, which could indicate a dietary shift in the striped dolphin over the last two decades. The results of SIAR indicated that in 1990, hake and sardine together contributed to 60% on the diet of immature striped dolphins, and close to 90% for mature striped dolphins. Conversely, the diet of both groups in 2007-2008 was more diverse, as hake and sardine contributed to less than 40% of the entire diet. These results suggest a dietary change that was possibly related to changes in food availability, which is consistent with the depletion of sardine stocks by fishing.

Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells.

Deregulation of the ubiquitin/proteasome system has been implicated in the pathogenesis of many human diseases, including cancer. Ubiquitin-specific proteases (USP) are cysteine proteases involved in the deubiquitination of protein substrates. Functional connections between USP7 and essential viral proteins and oncogenic pathways, such as the p53/Mdm2 and phosphatidylinositol 3-kinase/protein kinase B networks, strongly suggest that the targeting of USP7 with small-molecule inhibitors may be useful for the treatment of cancers and viral diseases. Using high-throughput screening, we have discovered HBX 41,108, a small-molecule compound that inhibits USP7 deubiquitinating activity with an IC(50) in the submicromolar range. Kinetics data indicate an uncompetitive reversible inhibition mechanism. HBX 41,108 was shown to affect USP7-mediated p53 deubiquitination in vitro and in cells. As RNA interference-mediated USP7 silencing in cancer cells, HBX 41,108 treatment stabilized p53, activated the transcription of a p53 target gene without inducing genotoxic stress, and inhibited cancer cell growth. Finally, HBX 41,108 induced p53-dependent apoptosis as shown in p53 wild-type and null isogenic cancer cell lines. We thus report the identification of the first lead-like inhibitor against USP7, providing a structural basis for the development of new anticancer drugs.

Owl pellets as a source of DNA for genetic studies of small mammals.

Owl pellets contain a good skeletal record of the small mammals consumed, and correspond to the undigested portions of prey which are regurgitated. These pellets are easy to find at the roosting site of owls. As it has been demonstrated that amplifiable DNA can be isolated from ancient bone remains, the possibility of using owl pellets as a source of DNA for small mammal genetics studies via the polymerase chain reaction has been investigated. The main uncertainties when isolating DNA from such a material are firstly the possibility that the extracted DNA would be too degraded during the digestion in the stomach of the owl, and secondly that extensive cross-contaminations could occur among the different prey consumed. The results obtained clearly demonstrate that cross-contamination does not occur, and that mitochondrial and nuclear DNA can be amplified using skulls of small mammals found in owl pellets as a source of DNA. The relative efficiency of two methods of DNA extraction is estimated and discussed. Thus, owl pellets represent a non-invasive sampling technique which provides a valuable source of DNA for studying population genetics of small mammals.

2014 Small Businesses and Disadvantaged Business Enterprises report

Pursuant to H.F. 2460, passed during the 2010 session of the 83rd Iowa General Assembly, attached are recommendations regarding methods to track and assess the participation of small businesses and disadvantaged business enterprises (DBE) in receiving nonfederal highway funding.

Effect of a small dose of alcohol on the endurance performance of trained cyclists.

AIM: The aim of this study was to investigate the effect of an acute small ethanol (EtOH) dose (0.5 ml EtOH/kg fat-free mass, combined with carbohydrate) in a drink on endurance performance of trained cyclists. METHODS: Thirteen well-trained male cyclists took part in this study. A 60-min cycling endurance performance test (time trial) was performed in a calorimetric chamber after drinking an EtOH (30 +/- 1.8 ml) or a non-EtOH control (C) drink. RESULTS: Overall, EtOH induced a significant decrease in the average cycling power output (PO) (EtOH: 233 +/- 23 W versus C: 243 +/- 24 W, P < 0.01). The time course of mechanical PO showed an early decrease during the EtOH trial as compared to C (P < 0.01). Due to the lower PO, oxygen consumption, carbon dioxide production and glucose oxidation were significantly lower (P < 0.05) as compared to C. Relative to PO, heart rate response and ratings of perceived exertion (RPE) were increased by EtOH as compared to C (P < 0.05). In contrast, EtOH did not influence gross work efficiency, glycaemia and blood lactate concentration. CONCLUSIONS: These results show that the acute low dose of EtOH decreased endurance performance. An increase of cardio-vascular strain and psychobiological mechanisms may explain this decrease of endurance performance.

Review of targeted small business procurement activities for the year ended June 30, 2014

Review of targeted small business procurement activities for the year ended June 30, 2014

Small GTPase RhoE/Rnd3 is a critical regulator of Notch1 signaling.

Aberrations of Notch signaling have been implicated in a variety of human cancers. Oncogenic mutations in NOTCH1 are common in human T-cell leukemia and lymphomas. However, loss-of-function somatic mutations in NOTCH1 arising in solid tumors imply a tumor suppressor function, which highlights the need to understand Notch signaling more completely. Here, we describe the small GTPase RhoE/Rnd3 as a downstream mediator of Notch signaling in squamous cell carcinomas (SCC) that arise in skin epithelia. RhoE is a transcriptional target of activated Notch1, which is attenuated broadly in SCC cells. RhoE depletion suppresses Notch1-mediated signaling in vitro, rendering primary keratinocytes resistant to Notch1-mediated differentiation and thereby favoring a proliferative cell fate. Mechanistic investigations indicated that RhoE controls a key step in Notch1 signaling by mediating nuclear translocation of the activated portion of Notch1 (N1IC) through interaction with importins. Our results define RhoE as a Notch1 target that is essential for recruitment of N1IC to the promoters of Notch1 target genes, establishing a regulatory feedback loop in Notch1 signaling. This molecular circuitry may inform distinct cell fate decisions to Notch1 in epithelial tissues, where carcinomas such as SCC arise. Cancer Res; 74(7); 2082-93. ©2014 AACR.

Objectives and motivations of small-scale forest owners : theoretical modelling and qualitative assessment

Abstract

A pathogenic mechanism in Huntington"s disease involves small CAG-repeated RNAs with neurotoxic activity

Huntington's disease (HD) is an autosomal dominantly inherited disorder caused by the expansion of CAG repeats in the Huntingtin (HTT) gene. The abnormally extended polyglutamine in the HTT protein encoded by the CAG repeats has toxic effects. Here, we provide evidence to support that the mutant HTT CAG repeats interfere with cell viability at the RNA level. In human neuronal cells, expanded HTT exon-1 mRNA with CAG repeat lengths above the threshold for complete penetrance (40 or greater) induced cell death and increased levels of small CAG-repeated RNAs (sCAGs), of ≈21 nucleotides in a Dicer-dependent manner. The severity of the toxic effect of HTT mRNA and sCAG generation correlated with CAG expansion length. Small RNAs obtained from cells expressing mutant HTT and from HD human brains significantly decreased neuronal viability, in an Ago2-dependent mechanism. In both cases, the use of anti-miRs specific for sCAGs efficiently blocked the toxic effect, supporting a key role of sCAGs in HTT-mediated toxicity. Luciferase-reporter assays showed that expanded HTT silences the expression of CTG-containing genes that are down-regulated in HD. These results suggest a possible link between HD and sCAG expression with an aberrant activation of the siRNA/miRNA gene silencing machinery, which may trigger a detrimental response. The identification of the specific cellular processes affected by sCAGs may provide insights into the pathogenic mechanisms underlying HD, offering opportunities to develop new therapeutic approaches

A realistic Computed Tomography simulator for small motion analysis of cerebral aneurysms.

This paper describes a realistic simulator for the Computed Tomography (CT) scan process for motion analysis. In fact, we are currently developing a new framework to find small motion from the CT scan. In order to prove the fidelity of this framework, or potentially any other algorithm, we present in this paper a simulator to simulate the whole CT acquisition process with a priori known parameters. In other words, it is a digital phantom for the motion analysis that can be used to compare the results of any related algorithm with the ground-truth realistic analytical model. Such a simulator can be used by the community to test different algorithms in the biomedical imaging domain. The most important features of this simulator are its different considerations to simulate the best the real acquisition process and its generality.