Replication stress and chromatin context link ATM activation to a role in DNA replication

ATM-mediated signaling in response to DNA damage is a barrier to tumorigenesis. Here we asked whether replication stress could also contribute to ATM signaling. We demonstrate that, in the absence of DNA damage, ATM responds to replication stress in a hypoxia-induced heterochromatin-like context. In certain hypoxic conditions, replication stress occurs in the absence of detectable DNA damage. Hypoxia also induces H3K9me3, a histone modification associated with gene repression and heterochromatin. Hypoxia-induced replication stress together with increased H3K9me3 leads to ATM activation. Importantly, ATM prevents the accumulation of DNA damage in hypoxia. Most significantly, we describe a stress-specific role for ATM in maintaining DNA replication rates in a background of increased H3K9me3. Furthermore, the ATM-mediated response to oncogene-induced replication stress is enhanced in hypoxic conditions. Together, these data indicate that hypoxia plays a critical role in the activation of the DNA damage response, therefore contributing to this barrier to tumorigenesis

HIF-1 alpha-independent hypoxia-induced rapid PTK6 stabilization is associated with increased motility and invasion

© 2014 Landes Bioscience. PTK6/Brk is a non-receptor tyrosine kinase overexpressed in cancer. Here we demonstrate that cytosolic PTK6 is rapidly and robustly induced in response to hypoxic conditions in a HIF-1-independent manner. Furthermore, a proportion of hypoxic PTK6 subsequently re-localized to the cell membrane. We observed that the rapid stabilization of PTK6 is associated with a decrease in PTK6 ubiquitylation and we have identified c-Cbl as a putative PTK6 E3 ligase in normoxia. The consequences of hypoxia-induced PTK6 stabilization and subcellular re-localization to the plasma membrane include increased cell motility and invasion, suggesting PTK6 targeting as a therapeutic approach to reduce hypoxia-regulated metastatic potential. This could have particular significance for breast cancer patients with triple negative disease

The impact of social risk in a paediatric department

Introdução: Os maus tratos a crianças correspondem a qualquer acção ou omissão não acidental, que ameace a sua segurança, dignidade e correcto desenvolvimento biopsicossocial. Pretendeu-se avaliar o seu impacto no internamento de Pediatria. Metodologia: Estudo retrospectivo dos doentes internados no Serviço de Pediatria de um hospital terciário entre 1/10/10 e 30/09/11, sinalizados ao Núcleo Hospitalar de Apoio a Crianças e Jovens em Risco (NHACJR). Foi considerada alta clínica o momento em que o doente já não apresentava critérios clínicos para o internamento. Na avaliação do impacto económico foi considerado o valor do custo diário de assistência hospitalar (85,00€) referido no DR 1ªsérie, de Janeiro de 2009. Resultados: Num total de 1052 internamentos, foi solicitada avaliação ao NHACJR em 4,1% (43) dos episódios. Os lactentes representaram 53,5% das sinalizações. O desemprego verificou-se em 66% dos pais e 37,2% destes tinham completadoo 3º ciclo de ensino básico. O modelo de família nuclear foi identificado em 37,2% dos casos. A presença de indicadores de risco social sem evidência aparente de maus tratos ocorreu em 48,8%. A negligência foi identificada em 39,5% das crianças, seguida dos maus tratos físicos com 6,9%. Quatro internamentos foram por motivos exclusivamente sociais, com um tempo médio de internamento de 10,5 dias. Dez crianças com critérios clínicos de internamento vieram a ter adiamento da alta hospitalar por motivos sociais, com um prolongamento médio do tempo de internamento de 33,2 dias. Neste grupo de catorze casos ocorreram seis infecções nosocomiais, um traumatismo crânio-encefálico e o custo adicional estimado de assistência hospitalar foi de 31.790,00€. Comentários: O impacto das razões sociais no internamento em Pediatria não é negligenciável quer do ponto de vista clínico quer económico. Uma reflexão multidisciplinar sobre a necessidade de maior apoio social na comunidade revela-se necessária, tendo por base os direitos da criança hospitalizada e o contexto socioeconómico actual

Solos ferruginosos em áreas de canga, sinclinal do gandarela, quadrilátero ferrífero (MG).

O presente trabalho visa contribuir na caracterização de solos relacionados a áreas de canga (ferricrete, ironstone) no Quadrilátero Ferrífero (Minas Gerais, Brasil), para melhor entendimento sobre seus processos de gênese e da dinâmica ambiental desses ecossistemas. A Sinclinal do Gandarela abriga as maiores extensões de canga e ecossistemas relacionados preservados em Minas Gerais, e constitui importante local de recarga dos mananciais que abastecem a Região Metropolitana de Belo Horizonte. Foram descritos, coletados e analisados 6 perfis de solo, sob diferentes fitofisionomias, ocorrendo numa sequência de topos da serra do Gandarela, sobre a mesma litologia (itabiritos da Fm. Cauê - Gr. Itabira). Em laboratório foi separada a fração terra fina (< 2 mm) e quantificados a composição granulométrica, pH em água, complexo sortivo, carbono orgânico, e óxidos de ferro, alumínio e silício pelo ataque sulfúrico. Todos os solos estudados são argilosos, de cores vermelhas, com teores muito elevados de óxidos de ferro indicados pelo ataque sulfúrico, distróficos ou álicos, com altos teores de carbono orgânico, e ocorrência expressiva de concreções ferruginosas na fração grosseira, em geral em proporção superior a 50% em volume. A matéria orgânica constitui elemento chave na manutenção e ciclagem de nutrientes nos ecossistemas relacionados aos solos estudados. Todos os solos estudados são classificados como Oxisols pela Soil Taxonomy, mas de acordo com o Sistema Brasileiro de Classificação de Solos, alguns enquadram-se como Latossolos e outros como Plintossolos. O enquadramento taxonômico segundo critérios atuais do SiBCS restringe sua utilização como estraficador ambiental na realidade estudada

Produção de frutos de pedra-ume-caá em função de condições meteorológicas em Manaus-AM.

O objetivo do presente trabalho foi avaliar o comportamento da produção de frutos de pedra-ume-caá, espécie medicinal amazônica, em função das variações das condições meteorológicas em Manaus-AM

Putative biomarkers for cervical cancer: SNVs, methylation and expression profiles

Cervical cancer is primarily caused by Human papillomavirus (HPV) infection, but other factors such as smoking habits, co-infections and genetic background, can also contribute to its development. Although this cancer is avoidable, it is the fourth most frequent type of cancer in females worldwide and can only be treated with chemotherapy and radical surgery. There is a need for biomarkers that will enable early diagnosis and targeted therapy for this type of cancer. Therefore, a systems biology pipeline was applied in order to identify potential biomarkers for cervical cancer, which show significant reports in three molecular aspects: DNA sequence variants, DNA methylation pattern and alterations in mRNA/protein expression levels. CDH1, CDKN2A, RB1 and TP53 genes were selected as putative biomarkers, being involved in metastasis, cell cycle regulation and tumour suppression. The other ten genes (CDH13, FHIT, PTEN, MLH1, TP73, CDKN1A, CACNA2D2, TERT, WIF1, APC) seemed to play a role in cervical cancer, but the lack of studies prevented their inclusion as possible biomarkers. Our results highlight the importance of these genes. However, further studies should be performed to elucidate the impact of DNA sequence variants and/or epigenetic deregulation and altered expression of these genes in cervical carcinogenesis and their potential as biomarkers for cervical cancer diagnosis and prognosis.This work was funded by the Foundation for Science and Technology of the state of Pernambuco (FACEPE). The authors are grateful to Vinicius Albertin Tigre da Costa for his contributions to the construction of the figures.info:eu-repo/semantics/publishedVersio

Impact of prevalence ratios of chondroitin sulfate (CS)- 4 and -6 isomers derived from marine sources in cell proliferation and chondrogenic differentiation processes

[Abstract] Osteoarthritis is the most prevalent rheumatic disease. During disease progression, differences have been described in the prevalence of chondroitin sulfate (CS) isomers. Marine derived-CS present a higher proportion of the 6S isomer, offering therapeutic potential. Accordingly, we evaluated the effect of exogenous supplementation of CS, derived from the small spotted catshark (Scyliorhinus canicula), blue shark (Prionace glauca), thornback skate (Raja clavata) and bovine CS (reference), on the proliferation of osteochondral cell lines (MG-63 and T/C-28a2) and the chondrogenic differentiation of mesenchymal stromal cells (MSCs). MG-G3 proliferation was comparable between R. clavata (CS-6 intermediate ratio) and bovine CS (CS-4 enrichment), for concentrations below 0.5 mg/mL, defined as a toxicity threshold. T/C-28a2 proliferation was significantly improved by intermediate ratios of CS-6 and -4 isomers (S. canicula and R. clavata). A dose-dependent response was observed for S. canicula (200 µg/mL vs 50 and 10 µg/mL) and bovine CS (200 and 100 µg/mL vs 10 µg/mL). CS sulfation patterns discretely affected MSCs chondrogenesis; even though S. canicula and R. clavata CS up-regulated chondrogenic markers expression (aggrecan and collagen type II) these were not statistically significant. We demonstrate that intermediate values of CS-4 and -6 isomers improve cell proliferation and offer potential for chondrogenic promotion, although more studies are needed to elucidate its mechanism of action.Xunta de Galicia; IN607A 2017/11Xunta de Galicia; IN607B 2018/19European Commission; 0245_IBEROS_1_

Experimental characterization and test-beam results of MACACO III Compton camera

The IRIS group at IFIC-Valencia is developing a Compton camera prototype with the aim of applying it in hadron therapy treatment monitoring. Recently, a third version of the prototype MACACO (Medical Applications CompAct COmpton camera) has been built. The system is composed of three Lanthanum (III) bromide scintillator crystals coupled to silicon photomultipliers. To improve its performance for the final application, several detectors are tested, two different silicon photomultipliers (25 and 50 um) have been chosen as possible candidates. The 25 up photodetector provided better performance in therms of dynamic range, energy resolution (5.2/ FWHM at 511 keV) and stability with temperature variations. MACACO III has also been tested in the CNA cyclotron (Seville) with 18 MeV proton beam to produce 4.439 MeV gamma rays. Data have been acquired with a graphite target in five different positions at 2.5 nA nominal beam intensity. Images with 4.439 MeV photons have been reconstructed, demonstrating the system capability to reconstruct images at energies relevant for hadron therapy. Moreover, the system has been able to distinguish 1mm displacements in the target position

Gamma-ray sources imaging and test-beam results with MACACO III Compton camera

Hadron therapy is a radiotherapy modality which offers a precise energy deposition to the tumors and a dose reduction to healthy tissue as compared to conventional methods. However, methods for real-time monitoring are required to ensure that the radiation dose is deposited on the target. The IRIS group of IFIC-Valencia developed a Compton camera prototype for this purpose, intending to image the Prompt Gammas emitted by the tissue during irradiation. The system detectors are composed of Lanthanum (III) bromide scintillator crystals coupled to silicon photomultipliers. After an initial characterization in the laboratory, in order to assess the system capabilities for future experiments in proton therapy centers, different tests were carried out in two facilities: PARTREC (Groningen, The Netherlands) and the CNA cyclotron (Sevilla, Spain). Characterization studies performed at PARTREC indicated that the detectors linearity was improved with respect to the previous version and an energy resolution of 5.2 % FWHM at 511 keV was achieved. Moreover, the imaging capabilities of the system were evaluated with a line source of 68Ge and a point-like source of 241Am-9Be. Images at 4.439 MeV were obtained from irradiation of a graphite target with an 18 MeV proton beam at CNA, to perform a study of the system potential to detect shifts at different intensities. In this sense, the system was able to distinguish 1 mm variations in the target position at different beam current intensities for measurement times of 1800 and 600 s.</p

Gamma-ray sources imaging and test-beam results with MACACO III Compton camera

Hadron therapy is a radiotherapy modality which offers a precise energy deposition to the tumors and a dose reduction to healthy tissue as compared to conventional methods. However, methods for real-time monitoring are required to ensure that the radiation dose is deposited on the target. The IRIS group of IFIC-Valencia developed a Compton camera prototype for this purpose, intending to image the Prompt Gammas emitted by the tissue during irradiation. The system detectors are composed of Lanthanum (III) bromide scintillator crystals coupled to silicon photomultipliers. After an initial characterization in the laboratory, in order to assess the system capabilities for future experiments in proton therapy centers, different tests were carried out in two facilities: PARTREC (Groningen, The Netherlands) and the CNA cyclotron (Sevilla, Spain). Characterization studies performed at PARTREC indicated that the detectors linearity was improved with respect to the previous version and an energy resolution of 5.2 % FWHM at 511 keV was achieved. Moreover, the imaging capabilities of the system were evaluated with a line source of 68Ge and a point-like source of 241Am-9Be. Images at 4.439 MeV were obtained from irradiation of a graphite target with an 18 MeV proton beam at CNA, to perform a study of the system potential to detect shifts at different intensities. In this sense, the system was able to distinguish 1 mm variations in the target position at different beam current intensities for measurement times of 1800 and 600 s.</p