Epithelial damage and tissue γδ T cells promote a unique tumor-protective IgE response

IgE is an ancient and conserved immunoglobulin isotype with potent immunological function. Nevertheless, the regulation of IgE responses remains an enigma, and evidence of a role for IgE in host defense is limited. Here we report that topical exposure to a common environmental DNA-damaging xenobiotic initiated stress surveillance by γδTCR+ intraepithelial lymphocytes that resulted in class switching to IgE in B cells and the accumulation of autoreactive IgE. High-throughput antibody sequencing revealed that γδ T cells shaped the IgE repertoire by supporting specific variable-diversity-joining (VDJ) rearrangements with unique characteristics of the complementarity-determining region CDRH3. This endogenous IgE response, via the IgE receptor FcεRI, provided protection against epithelial carcinogenesis, and expression of the gene encoding FcεRI in human squamous-cell carcinoma correlated with good disease prognosis. These data indicate a joint role for immunosurveillance by T cells and by B cells in epithelial tissues and suggest that IgE is part of the host defense against epithelial damage and tumor development

Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies

Targeting Signal Transduction Pathways in Metastatic Breast Cancer: A Comprehensive Review

This review summarizes some of the key signaling pathways involved in tumor progression and some of the novel therapies that are in development for the treatment of metastatic breast cancer patients

Regulatory RNAs and chromatin modification in dosage compensation: A continuous path from flies to humans?

Chromosomal sex determination is a widely distributed strategy in nature. In the most classic scenario, one sex is characterized by a homologue pair of sex chromosomes, while the other includes two morphologically and functionally distinct gonosomes. In mammalian diploid cells, the female is characterized by the presence of two identical X chromosomes, while the male features an XY pair, with the Y bearing the major genetic determinant of sex, i.e. the SRY gene. In other species, such as the fruitfly, sex is determined by the ratio of autosomes to X chromosomes. Regardless of the exact mechanism, however, all these animals would exhibit a sex-specific gene expression inequality, due to the different number of X chromosomes, a phenomenon inhibited by a series of genetic and epigenetic regulatory events described as "dosage compensation". Since adequate available data is currently restricted to worms, flies and mammals, while for other groups of animals, such as reptiles, fish and birds it is very limited, it is not yet clear whether this is an evolutionary conserved mechanism. However certain striking similarities have already been observed among evolutionary distant species, such as Drosophila melanogaster and Mus musculus. These mainly refer to a) the need for a counting mechanism, to determine the chromosomal content of the cell, i.e. the ratio of autosomes to gonosomes (a process well understood in flies, but still hypothesized in mammals), b) the implication of non-translated, sex-specific, regulatory RNAs (roX and Xist, respectively) as key elements in this process and the location of similar mediators in the Z chromosome of chicken c) the inclusion of a chromatin modification epigenetic final step, which ensures that gene expression remains stably regulated throughout the affected area of the gonosome. This review summarizes these points and proposes a possible role for comparative genetics, as they seem to constitute proof of maintained cell economy (by using the same basic regulatory elements in various different scenarios) throughout numerous centuries of evolutionary history

Molecular targeted therapies for breast cancer treatment

Targeting the oestrogen receptor, HER2 (human epidermal growth factor receptor 2) and vascular endothelial growth factor has markedly improved breast cancer therapy. New targeted therapeutic approaches to induction of apoptosis or inhibition of anti-apoptosis, cell cycle progression, signal transduction and angiogenesis are described. The molecular pathways and their inhibitory or repair mechanisms are discussed in the preclinical and clinical settings

Present and future evolution of advanced breast cancer therapy

Although the introduction of novel therapies and drug combinations has improved the prognosis of metastatic breast cancer, the disease remains incurable. Increased knowledge of the biology and the molecular alterations in breast cancer has facilitated the design of targeted therapies. These agents include receptor and nonreceptor tyrosine kinase inhibitors (epidermal growth factor receptor family), intracellular signaling pathways (phosphatidylinositol-3-kinase, AKT, mammalian target of rapamycin) angiogenesis inhibitors and agents that interfere with DNA repair (poly(ADP-ribose) polymerase inhibitors). In the present review, we present the most promising studies of these new targeted therapies and novel combinations of targeted therapies with cytotoxic agents

Perfil do cirurgião de coluna brasileiro

OBJECTIVE: To conduct cross-sectional study identifying the profile of the Brazilian spinal surgeon. METHODS: Data were collected through a questionnaire with multiple alternatives during two major events for spine surgery at national level in 2011, the Congresso da Sociedade Brasileira de Coluna (Congress of the Brazilian Spine Society) and Simpósio Internacional de Coluna (International Spine Symposium, SINCOL). The data were submitted to statistical analysis comparing and stratifying the information obtained according to the profile. RESULTS: We obtained 182 questionnaires answered by orthopedists and neurosurgeons with peculiarities and similarities on their medical management. CONCLUSIONS: The data obtained in this study may be important for the development of health policies in the spine surgery in Brazil.OBJETIVO: Llevar a cabo estudio transversal para identificar el perfil del cirujano de columna en Brasil. MÉTODOS: Los datos fueron recolectados por medio de cuestionarios con opciones múltiples, en dos eventos de relevancia para la cirugía de columna vertebral, a nivel nacional en 2011, Congreso Brasileño de la Sociedad Brasileña de Columna (SBC) y el Simposio Internacional de Columna (SINCOL). Los datos fueron sometidos a análisis estadístico, comparándose y estratificándose las informaciones obtenidas, de acuerdo con el perfil encontrado. RESULTADOS: Se obtuvieron cuestionarios respondidos por 182 ortopedistas y neurocirujanos, con particularidades y similitudes en sus actividades médicas. CONCLUSIONES: Los datos obtenidos en este estudio pueden ser importantes para el desarrollo de políticas de salud en el área de la cirugía de columna en Brasil.OBJETIVO: Realizar estudo transversal identificando o perfil do cirurgião de coluna no Brasil. MÉTODOS: Foram coletados dados por meio de questionários com múltiplas alternativas, em dois eventos de relevância para a cirurgia de coluna no âmbito nacional em 2011, o Congresso da Sociedade Brasileira de Coluna (SBC) e o Simpósio Internacional de Coluna (SINCOL). Os dados foram submetidos a análise estatística comparando e estratificando as informações obtidas conforme o perfil encontrado. RESULTADOS: Obtivemos 182 questionários respondidos por ortopedistas e neurocirurgiões com particularidades e semelhanças em suas condutas médicas. CONCLUSÕES: Os dados obtidos nessa pesquisa podem ser importantes para o desenvolvimento de políticas de saúde na área de cirurgia de coluna no Brasil.Universidade Federal de São Paulo (UNIFESP) Departamento de Ortopedia e TraumatologiaUNIFESP, Depto. de Ortopedia e TraumatologiaSciEL

Exposure and connectedness to natural environments: An examination of the measurement invariance of the Nature Exposure Scale (NES) and Connectedness to Nature Scale (CNS) across 65 nations, 40 languages, gender identities, and age groups

Detachment from nature is contributing to the environmental crisis and reversing this trend requires detailed monitoring and targeted interventions to reconnect people to nature. Most tools measuring nature exposure and attachment were developed in high-income countries and little is known about their robustness across national and linguistic groups. Therefore, we used data from the Body Image in Nature Survey to assess measurement invariance of the Nature Exposure Scale (NES) and the Connectedness to Nature Scale (CNS) across 65 nations, 40 languages, gender identities, and age groups (N = 56,968). While multi-group confirmatory factor analysis (MG-CFA) of the NES supported full scalar invariance across gender identities and age groups, only partial scalar invariance was supported across national and linguistic groups. MG-CFA of the CNS also supported full scalar invariance across gender identities and age groups, but only partial scalar invariance of a 7-item version of the CNS across national and linguistic groups. Nation-level associations between NES and CNS scores were negligible, likely reflecting a lack of conceptual clarity over what the NES is measuring. Individual-level associations between both measures and sociodemographic variables were weak. Findings suggest that the CNS-7 may be a useful tool to measure nature connectedness globally, but measures other than the NES may be needed to capture nature exposure cross-culturally