Molecular profiling, including TERT promoter mutations, of acral lentiginous melanomas

Acral lentiginous melanoma (ALM) is the less common subtype with singular characterization. TERT (human telomerase reverse transcriptase) promoter mutations have being described as recurrent in melanomas and infrequent in ALM, but their real incidence and clinical relevance is unclear. The objectives of this study were to describe the prevalence of TERT promoter mutations in ALM, and correlate with the molecular profile of other drive genes and clinical features. Sixty-one samples from 48 patients with ALM were analyzed. After DNA isolation, the mutation profiles of the hotspot region of BRAF, NRAS, KIT, PDGFRA, and TERT genes were determined by PCR amplification followed by direct Sanger sequencing. KIT, PDGFRA, and VEGFR2 gene amplification was performed by quantitative PCR. Clinical information such as survival, clinical stage, and Breslow tumor classification were obtained from medical records. TERT promoter mutations were found in 9.3% of the cases, BRAF in 10.3%, NRAS in 7.5%, KIT in 20.7%, and PDGFRA in 14.8% of ALM. None of the cases showed KIT, PDGFRA, or VEGFR2 gene amplification. We found an association between KIT mutations and advanced Clark level (IV and V, P=0.043) and TERT promoter mutations with low mitotic index. No other significant associations were observed between mutation profile and patients' clinical features nor survival rates. Oncogenic TERT promoter mutations are present in a fraction of ALMs. No relevant associations were found between TERT mutation status and clinical/molecular features nor survival. Mutations of KIT and PDGFRA are the most common genetic alterations, and they can be therapeutic targets for these patients.This project was supported by FAPESP - Brazil (2012/4194-1) to Vinicius de Lima Vazquez.info:eu-repo/semantics/publishedVersio

MODELAGEM HÍBRIDA EM TRÊS ESCALAS PARA O CRESCIMENTO TUMORAL

O crescimento tumoral é resultado de uma série de complexos fenômenos que ocorrem em múltiplas escalas de tempo e espaço. Neste trabalho, desenvolvemos um modelo híbrido que representa fenômenos do crescimento tumoral avascular que ocorrem nas escalas tecidual, celular e sub-celular. A dispersão de nutrientes e de fatores de crescimento ocorrem na escala do tecido. Na escala da célula, destacam-se as interações mecânicas entre células e entre os componentes do microambiente. Na escala sub-celular ocorre uma variedade de cascatas de reações moleculares que regulam as atividades celulares. Eventos que ocorrem em distintas escalas se inter-relacionam, de modo que o entendimento destes mecanismos é fundamental para a compreensão da doença e para o desenvolvimento de terapias. Experimentos computacionais são realizados para demonstrar o potencial uso da metodologia desenvolvida

Cataclysmic Variables in the First Year of the Zwicky Transient Facility

Using selection criteria based on amplitude, time, and color, we have identified 329 objects as known or candidate cataclysmic variables (CVs) during the first year of testing and operation of the Zwicky Transient Facility. Of these, 90 are previously confirmed CVs, 218 are strong candidates based on the shape and color of their light curves obtained during 3–562 days of observation, and the remaining 21 are possible CVs but with too few data points to be listed as good candidates. Almost half of the strong candidates are within 10 deg of the galactic plane, in contrast to most other large surveys that have avoided crowded fields. The available Gaia parallaxes are consistent with sampling the low mass transfer CVs, as predicted by population models. Our follow-up spectra have confirmed Balmer/helium emission lines in 27 objects, with four showing high-excitation He ii emission, including candidates for an AM CVn, a polar, and an intermediate polar. Our results demonstrate that a complete survey of the Galactic plane is needed to accomplish an accurate determination of the number of CVs existing in the Milky Way

Recurrent Pregnancy Loss: Investigations and Interventions

Recurrent pregnancy loss (RPL) affects 0.8–1.4% of couples, and this prevalence increases with aging. However, etiology is commonly unknown, and most therapies are not supported by strong evidence. There are many examinations that investigate causes of RPL: hormonal status, spermatozoa morphology and DNA fragmentation, immunologic status, uterine assessment, thrombophilia, and others. Recently different types of treatment have emerged, most lacking good evidence. As for example, we may mention the use of anticoagulants, aspirin, corticosteroids, progesterone, and antioxidants and psychological support. It is argued that some procedures such as preimplantation genetic testing for aneuploidy and intracytoplasmic morphologically selected sperm injection would impact on the outcomes and help RPL management. This chapter will discuss the current evidence concerning examinations and treatments that would improve the outcomes in patients with RPL, with recommended practice

Early and Middle Holocene Hunter-Gatherer Occupations in Western Amazonia: The Hidden Shell Middens

We report on previously unknown early archaeological sites in the Bolivian lowlands, demonstrating for the first time early and middle Holocene human presence in western Amazonia. Multidisciplinary research in forest islands situated in seasonally-inundated savannahs has revealed stratified shell middens produced by human foragers as early as 10,000 years ago, making them the oldest archaeological sites in the region. The absence of stone resources and partial burial by recent alluvial sediments has meant that these kinds of deposits have, until now, remained unidentified. We conducted core sampling, archaeological excavations and an interdisciplinary study of the stratigraphy and recovered materials from three shell midden mounds. Based on multiple lines of evidence, including radiocarbon dating, sedimentary proxies (elements, steroids and black carbon), micromorphology and faunal analysis, we demonstrate the anthropogenic origin and antiquity of these sites. In a tropical and geomorphologically active landscape often considered challenging both for early human occupation and for the preservation of hunter-gatherer sites, the newly discovered shell middens provide evidence for early to middle Holocene occupation and illustrate the potential for identifying and interpreting early open-air archaeological sites in western Amazonia. The existence of early hunter-gatherer sites in the Bolivian lowlands sheds new light on the region's past and offers a new context within which the late Holocene "Earthmovers" of the Llanos de Moxos could have emerged. © 2013 Lombardo et al

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Особливості формування самостійної пізнавальної діяльності майбутніх учителів математики

(uk) У статті зроблено спробу розкрити особливості самостійної пізнавальної діяльності майбутніх вчителів; досліджуються різні підходи до цього поняття; розкриваються такі його складові, як самостійність, пізнавальна самостійність, пізнавальна діяльність.(ru) В статье сделана попытка раскрыть особенности самостоятельной познавательной деятельности будущих учителей; исследуются различные подходы к этому понятию; раскрываются такие его составляющие, как самостоятельность, познавательная самостоятельность, познавательная деятельность