Identification and characterization of novel classes of macrophage migration inhibitory factor (MIF) inhibitors with distinct mechanisms of action.

Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, is considered an attractive therapeutic target in multiple inflammatory and autoimmune disorders. In addition to its known biologic activities, MIF can also function as a tautomerase. Several small molecules have been reported to be effective inhibitors of MIF tautomerase activity in vitro. Herein we employed a robust activity-based assay to identify different classes of novel inhibitors of the catalytic and biological activities of MIF. Several novel chemical classes of inhibitors of the catalytic activity of MIF with IC(50) values in the range of 0.2-15.5 microm were identified and validated. The interaction site and mechanism of action of these inhibitors were defined using structure-activity studies and a battery of biochemical and biophysical methods. MIF inhibitors emerging from these studies could be divided into three categories based on their mechanism of action: 1) molecules that covalently modify the catalytic site at the N-terminal proline residue, Pro(1); 2) a novel class of catalytic site inhibitors; and finally 3) molecules that disrupt the trimeric structure of MIF. Importantly, all inhibitors demonstrated total inhibition of MIF-mediated glucocorticoid overriding and AKT phosphorylation, whereas ebselen, a trimer-disrupting inhibitor, additionally acted as a potent hyperagonist in MIF-mediated chemotactic migration. The identification of biologically active compounds with known toxicity, pharmacokinetic properties, and biological activities in vivo should accelerate the development of clinically relevant MIF inhibitors. Furthermore, the diversity of chemical structures and mechanisms of action of our inhibitors makes them ideal mechanistic probes for elucidating the structure-function relationships of MIF and to further determine the role of the oligomerization state and catalytic activity of MIF in regulating the function(s) of MIF in health and disease.

Reproductive bribing and policing as evolutionary mechanisms for the suppression of within-group selfishness.

We show that a new, simple, and robust general mechanism for the social suppression of within-group selfishness follows from Hamilton's rule applied in a multilevel selection approach to asymmetrical, two-person groups: If it pays a group member to behave selfishly (i.e., increase its share of the group's reproduction, at the expense of group productivity), then its partner will virtually always be favored to provide a reproductive "bribe" sufficient to remove the incentive for the selfish behavior. The magnitude of the bribe will vary directly with the number of offspring (or other close kin) potentially gained by the selfish individual and inversely with both the relatedness r between the interactants and the loss in group productivity because of selfishness. This bribe principle greatly extends the scope for cooperation within groups. Reproductive bribing is more likely to be favored over social policing for dominants rather than subordinates and as intragroup relatedness increases. Finally, analysis of the difference between the group optimum for an individual's behavior and the individual's inclusive fitness optimum reveals a paradoxical feedback loop by which bribing and policing, while nullifying particular selfish acts, automatically widen the separation of individual and group optima for other behaviors (i.e., resolution of one conflict intensifies others).

Occupational exposure to solar ultraviolet radiation of outdoor workers in France

Question: Outdoor occupational exposure could be associated with important cumulative and intense exposure to ultraviolet (UV) solar radiation. Such exposure would increase risk of skin cancer. However, little information exists on jobs associated with intense UV exposure. The objective of this study was to characterise occupational UV exposure in a representative sample in France. Methods: A population-based survey was conducted in May-June 2012 through computer-assisted telephonic interviews in population 25 to 69 years of age. Individual UV irradiation was computed with declared time and place of residence matched to UV records from satellite measurement (Eurosun project). We analysed factors influencing exposure to UV (annual average and seasonal peak). Results: A total of 1442 individuals declared having an occupational exposure to UV which represents 18% of population aged 25 to 69 years. Outdoor workers were more frequently men (58%), aged 40-54 (43%), with a phototype III or IV (69%). Occupations associated with highest UV exposure were: construction workers (annual daily average 62.8 Joules/m2), gardeners (62.6), farmers (52.8), culture/art/social sciences workers (52.0) and transport workers/mail carriers (49.5). The maximum of UVA exposure was found for occupation with a strong seasonality of exposure: culture, art or social sciences works (98.1 Joules/m2), construction works (97.2), gardening (96.7) and farming (95.0). Significant factors associated with high occupational UV exposure were gender (men vs. women: 53.6 vs. 42.6), phototype (IV vs. I: 51.9 vs. 45.5) and taking lunch outdoors (always vs. never: 59.8 vs. 48.6). Conclusion: Our study showed that some occupations were associated with particularly intense UV exposure such as farmers, gardeners, construction workers. Other unexpected occupations were also associated with high UV exposure such as transport workers, mail carriers and culture/art/social sciences workers.

Molecular Mechanisms of Acute Brain Injury and Ensuing Neurodegeneration

Injury to the central nervous system (CNS), including stroke, traumatic brain injury andspinal cord injury, cause devastating and irreversible damage and loss of function. Forexample, stroke affects very large patient populations, results in major suffering for the patients and their relatives, and involves a significant cost to society. CNS damage implies disruption of the intricate internal circuits involved in cognition, the sensory-motor functions, and other important functions. There are currently no treatments available to properly restore such lost functions. New therapeutic proposals will emerge from an understanding of the interdependence of molecular and cellular responses to CNS injury, in particular the inhibitory mechanisms that block regeneration and those that enhanceneuronal plasticity...

Allergic reactions following contrast material administration: nomenclature, classification, and mechanisms

In forensic pathology routine, fatal cases of contrast agent exposure can be occasionally encountered. In such situations, beyond the difficulties inherent in establishing the cause of death due to nonspecific or absent autopsy and histology findings as well as limited laboratory investigations, pathologists may face other problems in formulating exhaustive, complete reports, and conclusions that are scientifically accurate. Indeed, terminology concerning adverse drug reactions and allergy nomenclature is confusing. Some terms, still utilized in forensic and radiological reports, are outdated and should be avoided. Additionally, not all forensic pathologists master contrast material classification and pathogenesis of contrast agent reactions. We present a review of the literature covering allergic reactions to contrast material exposure in order to update used terminology, explain the pathophysiology, and list currently available laboratory investigations for diagnosis in the forensic setting.

Radiation protection education and training in several ionising radiation applications

Ionising radiation (IR) applications are quiet common among several areas of knowledge, medicine or industry. Medical X-rays, Nuclear Medicine, Xrays used in non-destructive testing or applications in research are a few examples. These radiations originate from radioactive materials or radiation emitting devices. Radiation Protection education and training (E&T) is of paramount importance to work safely in areas that imply the use of IR. TheTechnical Unit for Radiation Protection at the University of Barcelona has anextensive expertise in basic, initial and refresher training, in general or specificareas, as well as in courses validated by the Spanish Nuclear Safety Council orto satisfy specific needs with bespoke courses. These specific customer needsare evaluated and on-site courses can also be carried out.

X-Ray systems: radiation protection program in basic research applications

Although the radiation doses involved in basic research radiology are relatively small, the increasing number of radiological procedures makes risks becoming increasingly high. Quality control techniques in radiological practice have to ensure an adequate system of protection for people exposed to radiation. These techniques belong to a quality assurance program for X-ray machines and are designed to correct problems related to equipment and radiological practices, to obtain radiological images of high quality and to reduce the unnecessary exposures.

Chemoradiotherapy in malignant glioma: standard of care and future directions.

Glioma has been considered resistant to chemotherapy and radiation. Recently, concomitant and adjuvant chemoradiotherapy with temozolomide has become the standard treatment for newly diagnosed glioblastoma. Conversely (neo-)adjuvant PCV (procarbazine, lomustine, vincristine) failed to improve survival in the more chemoresponsive tumor entities of anaplastic oligoastrocytoma and oligodendroglioma. Preclinical investigations suggest synergism or additivity of radiotherapy and temozolomide in glioma cell lines. Although the relative contribution of the concomitant and the adjuvant chemotherapy, respectively, cannot be assessed, the early introduction of chemotherapy and the simultaneous administration with radiotherapy appear to be key for the improvement of outcome. Epigenetic inactivation of the DNA repair enzyme methylguanine methyltransferase (MGMT) seems to be the strongest predictive marker for outcome in patients treated with alkylating agent chemotherapy. Patients whose tumors do not have MGMT promoter methylation are less likely to benefit from the addition of temozolomide chemotherapy and require alternative treatment strategies. The predictive value of MGMT gene promoter methylation is being validated in ongoing trials aiming at overcoming this resistance by a dose-dense continuous temozolomide administration or in combination with MGMT inhibitors. Understanding of molecular mechanisms allows for rational targeting of specific pathways of repair, signaling, and angiogenesis. The addition of tyrosine kinase inhibitors vatalanib (PTK787) and vandetinib (ZD6474), the integrin inhibitor cilengitide, the monoclonal antibodies bevacizumab and cetuximab, the mammalian target of rapamycin inhibitors temsirolimus and everolimus, and the protein kinase C inhibitor enzastaurin, among other agents, are in clinical investigation, building on the established chemoradiotherapy regimen for newly diagnosed glioblastoma.

Mechanisms of cross-modal plasticity in early-blind subjects.

A variety of studies have demonstrated enhanced blood oxygenation level dependent responses to auditory and tactile stimuli within occipital cortex as a result of early blindness. However, little is known about the organizational principles that drive this cross-modal plasticity. We compared BOLD responses to a wide variety of auditory and tactile tasks (vs. rest) in early-blind and sighted subjects. As expected, cross-modal responses were larger in blind than in sighted subjects in occipital cortex for all tasks (cross-modal plasticity). Within both blind and sighted subject groups, we found patterns of cross-modal activity that were remarkably similar across tasks: a large proportion of cross-modal responses within occipital cortex are neither task nor stimulus specific. We next examined the mechanisms underlying enhanced BOLD responses within early-blind subjects. We found that the enhancement of cross-modal responses due to early blindness was best described as an additive shift, suggesting that cross-modal plasticity within blind subjects does not originate from either a scaling or unmasking of cross-modal responsivities found in sighted subjects.

Cellular source and mechanisms of high transcriptome complexity in the Mammalian testis.

Understanding the extent of genomic transcription and its functional relevance is a central goal in genomics research. However, detailed genome-wide investigations of transcriptome complexity in major mammalian organs have been scarce. Here, using extensive RNA-seq data, we show that transcription of the genome is substantially more widespread in the testis than in other organs across representative mammals. Furthermore, we reveal that meiotic spermatocytes and especially postmeiotic round spermatids have remarkably diverse transcriptomes, which explains the high transcriptome complexity of the testis as a whole. The widespread transcriptional activity in spermatocytes and spermatids encompasses protein-coding and long noncoding RNA genes but also poorly conserves intergenic sequences, suggesting that it may not be of immediate functional relevance. Rather, our analyses of genome-wide epigenetic data suggest that this prevalent transcription, which most likely promoted the birth of new genes during evolution, is facilitated by an overall permissive chromatin in these germ cells that results from extensive chromatin remodeling.

Feasibility and efficacy of accelerated weekly concomitant boost postoperative radiation therapy combined with concomitant chemotherapy in patients with locally advanced head and neck cancer.

BACKGROUND: The aim of this study was to assess feasibility and efficacy of weekly concomitant boost accelerated postoperative radiation therapy (PORT) with concomitant chemotherapy (CT) in patients with locally advanced head and neck cancer (LAHNC). METHODS AND MATERIALS: Conformal or intensity-modulated 66-Gy RT was performed in 5.5 weeks in 40 patients. Cisplatin was given at days 1, 22, and 43. Median follow-up was 36 months. RESULTS AND DISCUSSION: Grade 3 mucositis, dysphagia, and erythema was observed in ten (25%), nine (23%), and six (13%) patients, respectively. Grade 3 or more anemia was observed in two (6%) patients, and leukopenia in five (13%) patients. No grade 3 or 4 thrombocytopenia was observed. Grade 3 nephrotoxicity was observed in one patient (3%). No treatment-related mortality was observed. Grade 2 or more xerostomia and edema were observed in ten (25%) and one (3%) patient, respectively. Locoregional relapse occurred in eight patients, and seven patients developed distant metastases. Median time to locoregional relapse was 6 months. Three-year overall, disease-free survival, and locoregional control rates were 63%, 62%, and 81%, respectively. Multivariate analysis revealed that the only prognostic factor was nodal status. CONCLUSION: Reducing overall treatment time using accelerated PORT/CT by weekly concomitant boost (six fractions per week) combined with concomitant cisplatin CT is easily feasible with acceptable morbidity.

Worlds of working poverty : Cross-national variation in the mechanisms that lead to poverty among workers

The objective of this paper is to distinguish between different types of working poverty, on the basis of the mechanisms that produce it. Whereas the poverty literature identifies a myriad of risk factors and of categories of disadvantaged workers, we focus on three immediate causes of working poverty, namely low wage rate, weak labour force attachment, and high needs, the latter mainly due to the presence of children (and sometimes to the increase in needs caused by a divorce). These three mechanisms are the channels through which macroeconomic, demographic and policy factors have a direct bearing on working households. The main assumption tested here is that welfare regimes strongly influence the relative weight of these three mechanisms in producing working poverty, and, hence, the composition of the working-poor population. Our figures confirm this hypothesis and show that low-wage employment is a key factor, but, by far, not the only one and that family policies broadly understood play a decisive role, as well as patterns of labour market participation and integration.

Experimental cutaneous Leishmaniasis: a powerful model to study in vivo the mechanisms underlying genetic differences in Th subset differentiation.

The murine model of infection with Leishmania major has allowed the demonstration in vivo of the importance CD4+ T cell subsets, distinguishable by the pattern of cytokines they produce, on the outcome of infectious diseases. Genetically determined resistance and susceptibility to infection with this parasite are the result of the development of Th1 and Th2 response, respectively. In this short paper, we present some results obtained in our group pertaining to the analysis of the mechanisms, operational during the early phase of this infection, responsible for the maturation of these functionally distinct CD4+ responses.