JAK, an Oncokinase in Hematological Cancer

Janus kinases (JAKs) play an essential role in the regulation of cytokine signaling. They control cell survival, proliferation, differentiation, immune response, and hematopoiesis. Deregulation of JAK signaling has been associated to the pathogenesis of numerous immune-inflammatory diseases, hematological malignancies, and solid tumors. Thus, JAK proteins have emerged as attractive therapeutic targets in the last decade. The discovery of the gain-of-function JAK2 mutation (JAK2 V617F) as the main cause of polycythemia vera—a chronic myeloproliferative syndrome—led to the development of the JAK inhibitor ruxolitinib. This key finding opened the door to the search for new therapeutic agents able to suppress the constitutive activation of JAK signaling in hematological cancers and other tumors. However, given the conserved nature of the kinase domain among JAK family members, and the interrelated roles of JAK kinases in many physiological processes, including hematopoiesis and immunity, the broad usage of JAK inhibitors in hematology is challenged by their narrow therapeutic window. Novel therapies are, therefore, needed. This chapter focuses on the understanding of the complex signaling of JAK proteins in cancerous cells, the various JAK aberrations implicated in myeloproliferative neoplasms, leukemia, and lymphoma, and the clinically available JAK inhibitors in cancer therapy

Qualitative methodology for a palliative care resources and services questionnaire validation

Objetivo: Establecer la validez de composición, contenido y criterios de un cuestionario de recursos para la provisión de servicios en Cuidados Paliativos (CP) a través de una metodología cualitativa, mediante grupos focales con profesionales de CP; en el marco de un proyecto de validación y evaluación de los resultados de un cuestionario de recursos para la provisión de servicios en (CP) en la Comunidad de Madrid (CM). Método: Se lleva a cabo un abordaje cualitativo para la validación del cuestionario de recursos. Se selecciona el grupo de discusión como técnica de elección para obtener un discurso en base a la experiencia personal de los profesionales implicados en el ámbito de los CP. Los grupos se componen de médicos, enfermeras, psicólogos, trabajadores sociales y agente de pastoral. Resultado: Los temas de discusión en los grupos fueron: dispersión geográfica de los recursos humanos, motivación laboral y personal, “ayuda psico-emocional” para profesionales, valoración integral y holística del paciente, equidad de los equipos, presupuesto social, apoyo al cuidador, ayuda entre equipos, sobrecarga laboral y humana, relación con la gerencia, futuro de los equipos: “estar quemados”, trabajo en equipo, formación en CP, labor enfermería en CP, protocolo de acogida en CP y aclaraciones terminológicas o conceptuales. Conclusiones: Este trabajo pretende ser el punto de partida para la elaboración y validación de un cuestionario en la provisión de servicios en CP, y así evaluar los recursos humanos y técnicos de nuestra red asistencial sanitaria paliativa.Objective: To establish the composition, content and criteria validity of a questionnaire of resources for services provision in Palliative Care (PC) through a qualitative methodology using focus groups with PC professionals. This is a part of a validation and evaluation research project for the provision of services (CP) in the Community of Madrid (CM). Methods: We performed a qualitative approach to the resource questionnaire validation. It was selected the focus group technique based on the personal experience of the professionals involved in PC. The groups were made up of physicians, nurses, psychologists, social workers and pastoral agent. Results: Discussion items in the groups were: human resources, geographical dispersion, work and personal motivation, “psycho-emotional” help for professionals, comprehensive and holistic patient approach, equipment equity, social budget, caregiver support , support between teams, overburden and human relationship with CEOs, future of teams: “be burned”, team-working, teaching in PC, PC nursing work, PC welcome protocol and terminological and conceptual clarifications. Conclusions: This study tries to be the starting point for the development questionnaire. It will be useful to assess the human and technical resources of our palliative health care network

Involvement of EupR, a response regulator of the NarL/FixJ family, in the control of the uptake of the compatible solutes ectoines by the halophilic bacterium Chromohalobacter salexigens

de Lucena DK, Pühler A, Weidner S. The role of sigma factor RpoH1 in the pH stress response of Sinorhizobium meliloti. BMC Microbiology. 2010;10(1): 256.Background: Environmental pH stress constitutes a limiting factor for S. meliloti survival and development. The response to acidic pH stress in S. meliloti is versatile and characterized by the differential expression of genes associated with various cellular functions. The purpose of this study was to gain detailed insight into the participation of sigma factors in the complex stress response system of S. meliloti 1021 using pH stress as an effector. Results: In vitro assessment of S meliloti wild type and sigma factor mutants provided first evidence that the sigma factor RpoH1 plays a major role in the pH stress response. Differential expression of genes related to rhizobactin biosynthesis was observed in microarray analyses performed with the rpoH1 mutant at pH 7.0. The involvement of the sigma factor RpoH1 in the regulation of S. meliloti genes upon pH stress was analyzed by comparing timecourse experiments of the wild type and the rpoH1 mutant. Three classes of S. meliloti genes could be identified, which were transcriptionally regulated in an RpoH1-independent, an RpoH1-dependent or in a complex manner. The first class of S. meliloti genes, regulated in an RpoH1-independent manner, comprises the group of the exopolysaccharide I biosynthesis genes and also the group of genes involved in motility and flagellar biosynthesis. The second class of S. meliloti genes, regulated in an RpoH1-dependent manner, is composed of genes known from heat shock studies, like ibpA, grpE and groEL5, as well as genes involved in translation like tufA and rplC. Finally, the third class of S. meliloti genes was regulated in a complex manner, which indicates that besides sigma factor RpoH1, further regulation takes place. This was found to be the case for the genes dctA, ndvA and smc01505. Conclusions: Clustering of time-course microarray data of S. meliloti wild type and sigma factor rpoH1 mutant allowed for the identification of gene clusters, each with a unique time-dependent expression pattern, as well as for the classification of genes according to their dependence on RpoH1 expression and regulation. This study provided clear evidence that the sigma factor RpoH1 plays a major role in pH stress response

Extender osmolality, glycerol and egg yolk on the cryopreservation of epididymal spermatozoa for gamete banking of the Cantabric Chamois (Rupicapra pyrenaica parva)

P. 109-114Germplasm banking is a key technology enabling the ex-situ conservation of wild species. However, cryopreservation protocols must be tested to assure the applicability of the banked material. The objective of this study was defining a range of parameters for the composition of a semen extender for Cantabrian chamois epididymal spermatozoa (post-mortem collection). The freezing extender was based in a TES-Tris-fructose buffer, modifying its composition in three experiments: Osmolality of the buffer (320, 380 or 430 mOsm/kg, 8% glycerol, 15% egg yolk), glycerol (4 or 8%, 430 mOsm/kg, 15% egg yolk), egg yolk (10 or 15%, 430 mOsm/kg, 4% glycerol). Sperm was extended at 100 mill. spermatozoa/ml, cooled at 5 °C and frozen at −20 °C/min. Sperm quality was assessed pre and post-thawing (CASA, HOS test, abnormal forms, cytoplasmic droplets, and viability and acrosomal damage by flow cytometry). Freezability was good overall, with total motility of 65.5% ± 2.4 initial and 55.8% ± 2.4 post-thawing. The extenders affected the post-thaw sperm quality marginally. Whereas osmolalities and glycerol concentrations seemed not to differ, 430 mOsm/kg and 4% glycerol might be preferred. Egg yolk concentrations only differed on sperm velocity (VCL: 84.0 ± 6.7 μm/s in 10% vs. 70.7 ± 6.2 μm/s in 15%, P < 0.05). Our results suggest a good cryotolerance of chamois epididymal spermatozoa, with a preferred extender composition of hyperosmotic buffer, glycerol in the 4% range and lower egg yolk (10% range) than other ruminants.S

Effect of length of time post-mortem on quality and freezing capacity of Cantabric chamois (Rupicapra pyrenaica parva) epididymal spermatozoa

P. 184-192Genome Resource Banks are keystones in the ex-situ conservation of wild species. Post-mortem (PM) collection of epididymal spermatozoa is an opportunistic and valuable source of germplasm, the time from the death of the animal limits its use. Seeking to improve germplasm preservation strategies for the chamois (Rupicapra sp.), the effect of PM time on epididymal sperm quality and freezability was studied using the Cantabrian chamois. Samples were classified according to PM collection time, up to 216 h (refrigerated), and cryopreserved (Tris-citric acid-fructose, 430 mOsm/kg, 15% egg yolk, 8% glycerol; freezing at −20 °C/min). Sperm quality was assessed after recovery and post-thawing (motility by CASA, HOS test, abnormal forms, cytoplasmic droplets, and viability and acrosomal damage by flow cytometry). The sperm mass pH and osmolality showed a positive correlation with time. Total sperm motility dropped after 2 days PM, with progressivity and sperm velocities remained similar up to 3 days PM. Sperm freezability was acceptable, with the post-thawing HOST, motility, progressivity, VAP, VCL, VSL and BCF negatively correlating with PM time. Overall, chamois epidydimal samples were not adequate for preservation after 6 days PM. Freezability capacity could make these spermatozoa suitable for specific ART even if kept refrigerated for several days PM.S

Valoración de la producción de las agencias españolas de evaluación de tecnologías sanitarias: Análisis bibliográfico de sus informes y artículos científicos

Ponencias de la Segunda Conferencia internacional sobre brecha digital e inclusión social, celebrada del 28 al 30 de octubre de 2009 en la Universidad Carlos III de MadridEl objetivo de este trabajo es evaluar el impacto en términos de citas bibliográficas de los informes y artículos producidos por las agencias y unidades de evaluación de tecnologías sanitarias españolas (Agencias de ETS). Metodología: se analizó la producción de las Agencias de ETS, tanto documentos como artículos publicados entre los años 2000 y 2006 y se estudiaron las características de los mismos: idioma de publicación, año de publicación, tipo de revista, posición del primer autor de la agencia, factor de impacto, financiación, indización en las bases de datos básicas (INAHTA, Medline, DARE, Cochrane Iberoamericana, IME, IBECS,…) y el número de citas recibidas en las bases de datos referenciales (Scopus, ISI WoK y Google Scholar). Posteriormente se analizaron las características de los documentos que citaban: idioma de publicación, tipo de documento, año de edición, idioma de publicación, factor de impacto, indización en bases de datos (INAHTA, Medline, DARE, Cochrane Iberoamericana, IME, IBECS,…) y bases de datos de origen de las citas (Scopus, ISI WoK y Google Scholar). Resultados: se analizaron un total de 576 documentos producidos por las agencias españolas, dichos documentos produjeron un total de 1.811 citas bibliográficas. Del análisis de los documentos propios se pudo comprobar que fundamentalmente las agencias publican informes o monografías (52,1%), en castellano y no indizadas en las bases de datos tradicionales. El nivel medio de autocita fue bajo (menor de 1) y la posición que ocupaba el primer autor perteneciente a la agencia era predominante (media < 2). De los artículos se pudo comprobar que estaban publicados en revistas con impacto medio-alto 1,85 y que estaban publicados fundamentalmente en inglés. En cuanto a las citaciones provenían de 47 países de todo el mundo, principalmente provenientes de España, pero también del Reino Unido (8,2%) y de EEUU (6,8%). La mayor parte de las citas eran artículos, publicados en inglés, en revistas internacionales e indizados en las bases de datos internacionales más habituales. Discusión: los estudios bibliométricos son una herramienta ampliamente utilizada para el análisis de la calidad de la difusión y el impacto que la misma tiene sobre los agentes diana. Sin embargo, no es una herramienta habitual en ETS. Nuestro estudio aporta información sobre el impacto que procuran las agencias de ETS españolas a la vez que muestra fallas en el proceso que pudieran ser subsanadas. El análisis de nuestra producción ha expuesto que las agencias tienen una amplia presencia internacional pese a que su producción es fundamentalmente en castellano. Igualmente la no indización de los documentos en bases de datos genéricas habituales reducen claramente el impacto de los documentos y fundamentalmente en el nivel micro de decisión (profesionales sanitarios). Sería de interés continuar comprobando la evolución tras la implantación de medidas correctoras y la influencia de nuevas fuentes de financiación que han incrementado la producción científica de las agencias de ETS españolas.Este trabajo se ha realizado en el marco de colaboración previsto en el Plan de Calidad para el Sistema Nacional de Salud, al amparo del convenio de colaboración suscrito por el Instituto de Salud Carlos III, organismo autónomo del Ministerio de Ciencia e Innovación, y la Agència d’Avaluació de Tecnologia i Recerca Mèdiques de Cataluña

Season effect on genitalia and epididymal sperm from Iberian red deer, roe deer and Cantabrian chamois

P. 1857-1875Seasonality deeply affects the physiology and behavior of many species, and must be taken into account when biological resource banks (BRBs) are established. We have studied the effect of seasonality on many reproductive parameters of free-ranging Iberian red deer, roe deer and Cantabrian chamois, living in Spain. Testicles from hunted animals were collected and sent to our laboratory at different times during the year. We recorded the weight and volume of testis, the weight of the epididymis and its separate parts (caput, corpus, and cauda), the weight of the sperm sample collected from the cauda epididymis, and several sperm parameters (sperm concentration, spermatozoa recovered, motility, HOS test reactivity, acrosomal status, and viability). We studied the data according to several periods, defined accordingly to each species. For red deer, we defined rut (mid-September to mid-October), post-rut (mid-October to mid-December), and non-breeding season (February). For roe deer, they were pre-rut (June), rut (July), post-rut (first fortnight of August), and non-breeding season (September). For chamois: non-breeding season (June to mid-September) and breeding season (October–November). The rut/breeding season yielded significantly higher numbers for almost all parameters. However, in the case of red deer, sperm quality was higher in the post-rut. For roe deer, testicular weight was similar in the pre-rut and in the rut, and sperm quality did not differ significantly between these two periods, although we noticed higher values in the rut. In the case of chamois, sperm quality did not differ significantly from the breeding season, but data distribution suggested that in the non-breeding season there are less males with sperm of good quality. On the whole, we find these results of interest for BRB planning. The best season to collect sperm in this species would be the breeding season. However, post-rut in red deer, pre-rut in roe deer, and non-breeding season in chamois could be used too, because of the acceptable sperm quality, despite the lower quantity salvaged. More in-depth research needs to be carried out on the quality of sperm salvaged at different times of the year in order to confirm these findings.S

The effect of smoking on clinical parameters and structural damage in patients with axial spondyloarthritis: a systematic literature review.

Objectives: To evaluate the association between smoking and clinical parameters and structural damage in axial spondyloarthritis (axSpA). Methods: We systematically searched MEDLINE, EMBASE and Cochrane Library up to November 2015. We selected articles that analysed the smoking impact on disease activity, functional status, structural damage, physical mobility and life quality. Independent extraction of articles by 2 authors using predefined data fields was performed. Studies quality was graded according to the Oxford Level of Evidence scale. Results: A total of 17 articles were selected for inclusion: 2 case-control, 11 cross sectional and 4 prospective cohort studies, which analysed 4,694 patients. Weak evidence suggested a smoking effect on pain, overall assessment of health, disease activity, physical mobility and life quality in ankylosing spondylitis (AS). Moderate-good evidence revealed higher HAQ-AS among smokers (0.025 units/yr, 95%CI: 0.0071-0.0429, p=0.007). Every additional unit of ASDAS resulted in an increase of 1.9 vs. 0.4 mSASSS units/2 yr in AS smokers vs. non-smokers. Good evidence revealed that cigarette smoking and smoking intensity was associated with spinal radiographic progression in axSpA [mSASSS ≥2 units/2 yr: OR=2.75, 95%CI: 1.25-6.05, p=0.012; mSASSS progression in heavy smokers (> 10 cigarettes/day): OR=3.57, 95%IC: 1.33-9.60, p=0.012]. Conclusions: Published data indicate that smoking has a dose-dependent impact on structural damage progression in axSpA. There is worse HAQ among AS smokers compared to non-smokers. Respect to pain, overall assessment of health, disease activity, physical mobility and life quality, although the evidence level is poor, all evidence points in the same direction: smoking AS patients are worse than non-smoking.pre-print260 K

Seminal plasma improves cryopreservation of Iberian red deer epididymal sperm

P. 1847-1856We tested the protective action of seminal plasma on epididymal spermatozoa from Iberian red deer, especially considering cryopreservation, as a means for germplasm banking improvement. We obtained seminal plasma by centrifuging electroejaculated semen, and part of it was thermically inactivated (denatured plasma; 55 °C 30 min). Epididymal samples (always at 5 °C) were obtained from genitalia harvested after regulated hunting, and pooled for each assay (five in total). We tested three seminal plasma treatments (mixing seminal plasma with samples 2:1): no plasma, untreated plasma and denatured plasma; and four incubation treatments: 32 °C 15 min, 5 °C 15 min, 5 °C 2 h and 5 °C 6 h. After each incubation, samples were diluted 1:1 with extender: Tes-Tris-Fructose, 10% egg yolk, 4% glycerol; equilibrated for 2 h at 5 °C, extended down to 108 spz./mL and frozen. Sperm quality was evaluated before 1:1 dilution, before freezing and after thawing the samples, assessing motility (CASA) and viability (percentage of viable and acrosome-intact spermatozoa; PI/PNA-FITC and fluorescent microscopy). Plasma treatment, both untreated and denatured, rendered higher viability before freezing and higher results for most parameters after thawing. The improvement was irrespective of incubation treatment, except for viability, which rendered slightly different results for untreated and denatured plasma. This may be due to the presence of thermolabile components. We still have to determine the underlying mechanisms involved in this protection. These results might help to improve the design of cryopreservation extenders for red deer epididymal sperm.S

Efecto larvicida y adulticida de extractos etanólicos de ayote (cucurbita argyrosperma), chipilín (crotalaria longirostrata) y chile cobanero (capsicum annuum) contra mosquitos aedes sp

Mosquitoes of the genus Aedes are the main vectors of important zoonotic viral diseases such as dengue, chikungunya and Zika. Controlling the populations and preventing the expansion of these mosquito species is a difficult challenge for health institutions worldwide. Resistance to synthetic insecticides represents a challenge to find viable alternatives for the control and eradication of these vectors. In response to the above described, the objective of the present study was to evaluate the larvicidal and adulticidal effect of three ethanolic extracts of native plants of Guatemala against Aedes mosquitoes. The treatments were: (1) ayote extract (Cucurbita argyrosperma), (2) chipilín extract (Crotalaria longirostrata), and (3) cobanero pepper extract (Capsicum annuum var annuum). Bioassays were carried out following the methodology of the World Health Organization and recording mortality at 24 hours. The extracts of the three plants showed larvicidal and adulticidal effect against Aedes mosquitoes under laboratory conditions. The extract of Crotalaria longirostrata exhibited the highest larvicidal activity with the lowest lethal concentration 50 (LC50=775 mg/L), followed by Capsicum annuum (LC50=1330 mg/L) and Cucurbita argyrosperma (LC50=1525 mg/L). The evaluated extracts can become natural, ecological, and safe alternatives to synthetic mosquito control products.Los mosquitos del género Aedes son los principales vectores de importantes enfermedades virales zoonóticas tales como dengue, chikungunya y zika. Controlar las poblaciones y evitar la expansión de estas especies de mosquitos constituye un difícil reto para las instituciones sanitarias a nivel mundial. La resistencia a los insecticidas sintéticos representa un desafío para encontrar alternativas viables para el control y la erradicación de estos vectores. El objetivo del presente estudio fue evaluar el efecto larvicida y adulticida de tres extractos etanólicos de plantas nativas de Guatemala contra mosquitos Aedes. Los tratamientos fueron: (1) extracto de ayote (Cucurbita argyrosperma), (2) extracto de chipilín (Crotalaria longirostrata), y (3) extracto de chile cobanero (Capsicum annuum var annuum). Los bioensayos se realizaron siguiendo la metodología de la Organización Mundial de la Salud y registrando la mortalidad a las 24 horas. Los extractos de las tres plantas mostraron efecto larvicida y adulticida contra los mosquitos Aedes en condiciones de laboratorio. El extracto de Crotalaria longirostrata exhibió mayor actividad larvicida con la menor concentración letal50 (CL50=775 mg/L), seguido por Capsicum annuum (CL50=1330 mg/L) y Cucurbita argyrosperma (CL50=1525 mg/L). Los extractos evaluados pueden ser alternativas para el control de mosquitos, siendo productos naturales, amigables con el medio ambiente, y menos perjudiciales para el equilibrio ecológico y la salud humana.&nbsp