Simultaneous inhibition of pan-phosphatidylinositol-3-kinases and MEK as a potential therapeutic strategy in peripheral T-cell lymphomas

Obtained from Haematologica/the Hematology Journal website http://www.haematologica.orgPeripheral T-cell lymphomas are very aggressive hematologic malignancies for which there is no targeted therapy. New, rational approaches are necessary to improve the very poor outcome in these patients. Phosphatidylinositol- 3-kinase is one of the most important pathways in cell survival and proliferation. We hypothesized that phosphatidylinositol- 3-kinase inhibitors could be rationally selected drugs for treating peripheral T-cell lymphomas. Several phosphatidylinositol-3-kinase isoforms were inhibited genetically (using small interfering RNA) and pharmacologically (with CAL-101 and GDC-0941 compounds) in a panel of six peripheral and cutaneous T-cell lymphoma cell lines. Cell viability was measured by intracellular ATP content; apoptosis and cell cycle changes were checked by flow cytometry. Pharmacodynamic biomarkers were assessed by western blot. The PIK3CD gene, which encodes the δ isoform of phosphatidylinositol-3-kinase, was overexpressed in cell lines and primary samples, and correlated with survival pathways. However, neither genetic nor specific pharmacological inhibition of phosphatidylinositol-3-kinase δ affected cell survival. In contrast, the pan-phosphatidylinositol-3-kinase inhibitor GDC-0941 arrested all T-cell lymphoma cell lines in the G1 phase and induced apoptosis in a subset of them. We identified phospho-GSK3b and phospho-p70S6K as potential biomarkers of phosphatidylinositol-3-kinase inhibitors. Interestingly, an increase in ERK phosphorylation was observed in some GDC-0941-treated T-cell lymphoma cell lines, suggesting the presence of a combination of phosphatidylinositol-3-kinase and MEK inhibitors. A highly synergistic effect was found between the two inhibitors, with the combination enhancing cell cycle arrest at G0/G1 in all T-cell lymphoma cell lines, and reducing cell viability in primary tumor T cells ex vivo. These results suggest that the combined treatment of pan-phosphatidylinositol-3-kinase + MEK inhibitors could be more effective than single phosphatidylinositol-3-kinase inhibitor treatment, and therefore, that this combination could be of therapeutic value for treating peripheral and cutaneous T-cell lymphomas.This work was supported by grants from the Asociación Española Contra el Cáncer, Fondo de Investigaciones Sanitarias (PI051623, PI052800 and PI080856), RTICC (RD06/0020/0107) and Ministerio de Ciencia e Innovación (SAF2008-0387-1). EMS is supported by a grant from the Department of Education, Universities and Research of the Basque Government (BFI08.207). MSB is supported by a Contract Miguel Servet from Fondo de Investigaciones Sanitarias (CP11/00018

Chronic lymphocytic leukemia cells in lymph nodes show frequent NOTCH1 activation

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world. Pathogenic mechanisms involve multiple external events (such as microenvironmental and antigenic stimuli) and internal events (genetic and epigenetic alterations) that are associated with the transformation, progression and evolution of CLL. CLL is characterized by an accumulation of mature B cells in peripheral blood, bone marrow and lymphoid tissues. Extracellular stimuli play an important role in the development and maintenance of neoplastic cells. B-CLL cells proliferate and activate pathogenic signaling pathways in anatomical structures known as proliferation centers, which are usually more conspicuous in involved lymph nodes.1 Its clinical course is quite heterogeneous, whereby some patients progress rapidly and have short survival, whereas others have a more stable clinical course that may not need treatment for years.This work was supported by grants from the Ministerio de Economía y Competitividad (MINECO) (SAF2013-47416-R) Instituto de Salud Carlos III (ISCIII)- FEDER – MINECO- AES (CP11/00018, PI10/00621, RD012/0036/0060), and Asociación Española contra el Cancer (AECC). MS-B is supported by a Miguel Servet contract from ISCIII-FEDER (CP11/00018). Salary support to SG is provided by CP11/00018, from ISCIII-FEDER. JG-R is supported by a predoctoral grant from the Fundación Investigación Puerta de Hierro.S

Peripheral T-cell lymphoma: Molecular profiling recognizes subclasses and identifies prognostic markers

Peripheral T-cell lymphoma (PTCL) is a clinically aggressive disease, with a poor response to therapy and a low overall survival rate of approximately 30% after 5 years. We have analyzed a series of 105 cases with a diagnosis of PTCL using a customized NanoString platform (NanoString Technologies, Seattle, WA) that includes 208 genes associated with T-cell differentiation, oncogenes and tumor suppressor genes, deregulated pathways, and stromal cell subpopulations. A comparative analysis of the various histological types of PTCL (angioimmunoblastic T-cell lymphoma [AITL]; PTCL with T follicular helper [TFH] phenotype; PTCL not otherwise specified [NOS]) showed that specific sets of genes were associated with each of the diagnoses. These included TFH markers, cytotoxic markers, and genes whose expression was a surrogate for specific cellular subpopulations, including follicular dendritic cells, mast cells, and genes belonging to precise survival (NF-κB) and other pathways. Furthermore, the mutational profile was analyzed using a custom panel that targeted 62 genes in 76 cases distributed in AITL, PTCL-TFH, and PTCL-NOS. The main differences among the 3 nodal PTCL classes involved the RHOAG17V mutations (P < .0001), which were approximately twice as frequent in AITL (34.09%) as in PTCL-TFH (16.66%) cases but were not detected in PTCL-NOS. A multivariate analysis identified gene sets that allowed the series of cases to be stratified into different risk groups. This study supports and validates the current division of PTCL into these 3 categories, identifies sets of markers that can be used for a more precise diagnosis, and recognizes the expression of B-cell genes as an IPI-independent prognostic factor for AITL

Global respiratory syncytial virus-associated mortality in young children (RSV GOLD): a retrospective case series

Background Respiratory syncytial virus (RSV) infection is an important cause of pneumonia mortality in young children. However, clinical data for fatal RSV infection are scarce. We aimed to identify clinical and socioeconomic characteristics of children aged younger than 5 years with RSV-related mortality using individual patient data. Methods In this retrospective case series, we developed an online questionnaire to obtain individual patient data for clinical and socioeconomic characteristics of children aged younger than 5 years who died with community-acquired RSV infection between Jan 1, 1995, and Oct 31, 2015, through leading research groups for child pneumonia identified through a comprehensive literature search and existing research networks. For the literature search, we searched PubMed for articles published up to Feb 3, 2015, using the key terms “RSV”, “respiratory syncytial virus”, or “respiratory syncytial viral” combined with “mortality”, “fatality”, “death”, “died”, “deaths”, or “CFR” for articles published in English. We invited researchers and clinicians identified to participate between Nov 1, 2014, and Oct 31, 2015. We calculated descriptive statistics for all variables. Findings We studied 358 children with RSV-related in-hospital death from 23 countries across the world, with data contributed from 31 research groups. 117 (33%) children were from low-income or lower middle-income countries, 77 (22%) were from upper middle-income countries, and 164 (46%) were from high-income countries. 190 (53%) were male. Data for comorbidities were missing for some children in low-income and middle-income countries. Available data showed that comorbidities were present in at least 33 (28%) children from low-income or lower middle-income countries, 36 (47%) from upper middle-income countries, and 114 (70%) from high-income countries. Median age for RSV-related deaths was 5·0 months (IQR 2·3–11·0) in low-income or lower middle-income countries, 4·0 years (2·0–10·0) in upper middle-income countries, and 7·0 years (3·6–16·8) in high-income countries. Interpretation This study is the first large case series of children who died with community-acquired RSV infection. A substantial proportion of children with RSV-related death had comorbidities. Our results show that perinatal immunisation strategies for children aged younger than 6 months could have a substantial impact on RSV-related child mortality in low-income and middle-income countries

Study of pallial neurogenesis in shark embryos and the evolutionary origin of the subventricular zone

The dorsal part of the developing telencephalon is one of the brain areas that has suffered most drastic changes throughout vertebrate evolution. Its evolutionary increase in complexity was thought to be partly achieved by the appearance of a new neurogenic niche in the embryonic subventricular zone (SVZ). Here, a new kind of amplifying progenitors (basal progenitors) expressing Tbr2, undergo a second round of divisions, which is believed to have contributed to the expansion of the neocortex. Accordingly, the existence of a pallial SVZ has been classically considered exclusive of mammals. However, the lack of studies in ancient vertebrates precludes any clear conclusion about the evolutionary origin of the SVZ and the neurogenic mechanisms that rule pallial development. In this work, we explore pallial neurogenesis in a basal vertebrate, the shark Scyliorhinus canicula, through the study of the expression patterns of several neurogenic markers. We found that apical progenitors and radial migration are present in sharks, and therefore, their presence must be highly conserved throughout evolution. Surprisingly, we detected a subventricular band of ScTbr2-expressing cells, some of which also expressed mitotic markers, indicating that the existence of basal progenitors should be considered an ancestral condition rather than a novelty of mammals or amniotes. Finally, we report that the transcriptional program for the specification of glutamatergic pallial cells (Pax6, Tbr2, NeuroD, Tbr1) is also present in sharks. However, the segregation of these markers into different cell types is not clear yet, which may be linked to the lack of layering in anamniotesThis work was supported by the Spanish Ministerio de Economía y Competitividad-FEDER (BFU2014-5863-1P)S

Variação espacial de cátions, ânions e variáveis físico-químicas no rio Solimões-Amazonas entre Manaus e Jutaí, bacia amazônica

C&#225;tions e &#226;nions majorit&#225;rios s&#227;o esp&#233;cies qu&#237;micas de grande import&#226;ncia nos diversos compartimentos aqu&#225;ticos, por&#233;m, pouco abordados de forma exclusiva na bacia amaz&#244;nica. Neste sentido, o objetivo deste estudo foi avaliar a din&#226;mica espacial de Na+, Ca2+, K+, Mg2+, Cl- e SO4 2- em um trecho do rio Solim&#245;es-Amazonas, levando-se em considera&#231;&#227;o a alcalinidade, potencial hidrogeni&#244;nico (pH), condutividade el&#233;trica (CE), s&#243;lidos totais em suspens&#227;o (STS) e carbono org&#226;nico total (COT). As coletas foram realizadas em maio, julho e setembro de 2012 em sete pontos na calha principal do rio Solim&#245;es-Amazonas e na foz de alguns dos principais tribut&#225;rios: rios Juta&#237;, Juru&#225;, Japur&#225; e Purus. Os c&#225;tions e &#226;nions foram analisados por cromatografia de &#237;ons, STS por gravimetria, pH por potenciometria, alcalinidade por titula&#231;&#227;o potenciom&#233;trica, CE por condutimetria e o COT por oxida&#231;&#227;o catal&#237;tica por combust&#227;o. As concentra&#231;&#245;es m&#233;dias dos c&#225;tions seguiram esta ordem Ca2+>Na+>Mg2+>K+ e dos &#226;nions SO4 2->Cl-. De montante &#224; jusante a tend&#234;ncia foi diminui&#231;&#227;o nas concentra&#231;&#245;es de c&#225;tions e &#226;nions, das vari&#225;veis pH, CE, STS e alcalinidade, al&#233;m do aumento das concentra&#231;&#245;es de COT. O presente estudo evidenciou mudan&#231;as nas caracter&#237;sticas qu&#237;micas sofridas pelo rio Solim&#245;es em seu curso. O aporte dos tribut&#225;rios pode ser apontado como um dos fatores respons&#225;veis por essas modifica&#231;&#245;es

Global respiratory syncytial virus–related infant community deaths

Background Respiratory syncytial virus (RSV) is a leading cause of pediatric death, with >99% of mortality occurring in low- and lower middle-income countries. At least half of RSV-related deaths are estimated to occur in the community, but clinical characteristics of this group of children remain poorly characterized. Methods The RSV Global Online Mortality Database (RSV GOLD), a global registry of under-5 children who have died with RSV-related illness, describes clinical characteristics of children dying of RSV through global data sharing. RSV GOLD acts as a collaborative platform for global deaths, including community mortality studies described in this supplement. We aimed to compare the age distribution of infant deaths <6 months occurring in the community with in-hospital. Results We studied 829 RSV-related deaths <1 year of age from 38 developing countries, including 166 community deaths from 12 countries. There were 629 deaths that occurred <6 months, of which 156 (25%) occurred in the community. Among infants who died before 6 months of age, median age at death in the community (1.5 months; IQR: 0.8−3.3) was lower than in-hospital (2.4 months; IQR: 1.5−4.0; P < .0001). The proportion of neonatal deaths was higher in the community (29%, 46/156) than in-hospital (12%, 57/473, P < 0.0001). Conclusions We observed that children in the community die at a younger age. We expect that maternal vaccination or immunoprophylaxis against RSV will have a larger impact on RSV-related mortality in the community than in-hospital. This case series of RSV-related community deaths, made possible through global data sharing, allowed us to assess the potential impact of future RSV vaccines

Debut sexual y conocimientos sobre el uso de anticonceptivos en una población adolescente. Programa Forma Joven

Es labor importante dentro de la cartera de Atención Primaria la promoción y protección de la salud, especialmente en los sectores de población más vulnerables. Entre este colectivo se encuentran los jóvenes adolescentes en la fase educativa ESO y Bachillerato. El Programa Forma Joven pone en marcha herramientas que, a través de las enfermeras de Atención Primaria, contribuye a proteger la salud y potenciar los hábitos saludables. Gracias a este programa las enfermeras tenemos ocasión de contactar con la población juvenil y pulsar sus inquietudes y tendencias, analizando situaciones que nos pueden ayudar en nuestra práctica asistencial. Recogemos en este trabajo una serie de elementos que nos ponen en antecedentes sobre el comportamiento sexual de un grupo de jóvenes y sobre los conocimientos que tienen de los anticonceptivos habituales y de urgencia (píldora poscoital). Estos datos tienen una repercusión directa sobre nuestro trabajo en el Programa ya que nos ayudan a aportar conocimientos donde existen lagunas o a enderezar situaciones que detectamos están desviadas por desconocimiento o información erróneaIn primary care it is an important task to promote and protect health, especially among those population who are more vulnerable. In this group, there are young teens en the educative period of secondary education. Young shape program provides tools that, through nurses of primary care, helps to protect health and to promote healthy habits. Thanks to that program, nurses have the chance to establish contact with young population and deal with their worries and tendencies, analyzing actions that can help in our clinical practice. We compile in this study different elements that inform us about sexual behabiours of a group of teens and about the information that they have about usual/urgency contraceptives (morning-after pill). These data has direct impact about our work in the Program as they help us to know where there are gaps or to improve situations that are risky because of ignorance or mistaken information

Influence of Environmental Factors on Forest Understorey Species in Northern Mexico

Background: Understorey plants are key to maintaining forest structure and functioning. They protect the soil, improve its structure and fertility, reduce water run-off and sustain the below-ground biota, amongst other ecological services. However, little is known about the environmental conditions that regulate the occurrence of these plants. This study focuses on determining how canopy cover influences the occurrence of understorey species and identifying the most important soil properties that affect these species. The study area was a pine-oak forest in the Sierra Madre Occidental, an important source of ecological services for northwestern Mexico. Methods: To assess the conditions influencing the presence of herbaceous and shrub species, 25 soil variables were examined in relation to the species occurring in forest gaps and under the canopy. Sampling was conducted in five plots, each of 100 × 100 m. In each plot, 4 subplots, each of 20 × 20 m, were each subdivided in a grid of 2 × 2 m units, in which the presence-absence of herbaceous and shrub species was recorded (2000 units in total). Soil samples were extracted for analysis from the central point in each subplot. Data were analyzed using a Binomial Logistic Model (BLM) and Random Forest (RF) classification. Results: Understorey species were more strongly affected by soil variables than by their location in gaps or below canopy. The concentrations of Ca, P, K, Fe, Na, C, Zn, Mn, nitrates, organic matter, sand, silt, and percentage water saturation were statistically significantly associated with the presence of some plant species, whilst no significant differences were found in regard to preference for gaps or canopy, although several species were more frequent in open areas. Conclusions: Given the importance of the understorey cover in forest system functioning, we propose that understorey should be considered in integrated management and conservation practices for the temperate forests of northern Mexico

Cultivo de Bivalvos marinos del caribe colombiano

El cultivo de bilvavos marinos es una buena alternativa de desarrollo para Colombia pues ofrece importantes beneficios al tiempo que se hace un aprovechamiento sostenible de los recursos biológicos. Los autores de este artículo presentan el resultado del estudio y cultivo experimental de varias especies, particularmente las ostras perlíferas (familia Pteriidae) y los ostiones (familia Pectinidae), con el fin de ser utilizados en cultivos piloto y comerciales en la región Caribe colombiana