GARP promotes the proliferation and therapeutic resistance of bone sarcoma cancer cells through the activation of TGF-β

Sarcomas are mesenchymal cancers with poor prognosis, representing about 20% of all solid malignancies in children, adolescents, and young adults. Radio- and chemoresistance are common features of sarcomas warranting the search for novel prognostic and predictive markers. GARP/LRRC32 is a TGF-β-activating protein that promotes immune escape and dissemination in various cancers. However, if GARP affects the tumorigenicity and treatment resistance of sarcomas is not known. We show that GARP is expressed by human osteo-, chondro-, and undifferentiated pleomorphic sarcomas and is associated with a significantly worse clinical prognosis. Silencing of GARP in bone sarcoma cell lines blocked their proliferation and induced apoptosis. In contrast, overexpression of GARP promoted their growth in vitro and in vivo and increased their resistance to DNA damage and cell death induced by etoposide, doxorubicin, and irradiation. Our data suggest that GARP could serve as a marker with therapeutic, prognostic, and predictive value in sarcoma. We propose that targeting GARP in bone sarcomas could reduce tumour burden while simultaneously improving the efficacy of chemo- and radiotherapy.Instituto de Salud Carlos IIIEuropean Union (EU) PI15/00794 PI18/00826 CPII15/00032 PI15/02015Junta de Andalucía C-0013-2018Spanish Government PEJ-2014-A-46314Agencia Estatal de Investigación (AEI) [MICINN/Fondo Europeo de Desarrollo Regional (FEDER)] SAF-2016-75286-RISCIII/FEDER [Miguel Servet Program] CPII16/00049ISCIII/FEDER [Sara Borrell Program] CD16/00103Servicio de Salud del Principado de Asturias, Instituto de Salud Carlos III PT17/0015/0023Fundación Bancaria Cajastur PT17/0015/0023ISCIII/FEDER [Consorcio CIBERONC] CB16/12/0039

Identification of Methylated Genes Associated with Aggressive Clinicopathological Features in Mantle Cell Lymphoma

Background: Mantle cell lymphoma (MCL) is genetically characterized by the t(11;14)(q13;q32) translocation and a high number of secondary chromosomal alterations. The contribution of DNA methylation to MCL lymphomagenesis is not well known. We sought to identify epigenetically silenced genes in these tumours that might have clinical relevance. Methodology/Principal Findings: To identify potential methylated genes in MCL we initially investigated seven MCL cell lines treated with epigenetic drugs and gene expression microarray profiling. The methylation status of selected candidate genes was validated by a quantitative assay and subsequently analyzed in a series of primary MCL (n=38). After pharmacological reversion we identified 252 potentially methylated genes. The methylation analysis of a subset of these genes (n=25) in the MCL cell lines and normal B lymphocytes confirmed that 80% of them were methylated in the cell lines but not in normal lymphocytes. The subsequent analysis in primary MCL identified five genes (SOX9,HOXA9,AHR,NR2F2 ,and ROBO1) frequently methylated in these tumours. The gene methylation events tended to occur in the same primary neoplasms and correlated with higher proliferation, increased number of chromosomal abnormalities, and shorter survival of the patients. Conclusions: We have identified a set of genes whose methylation degree and gene expression levels correlate with aggressive clinicopathological features of MCL. Our findings also suggest that a subset of MCL might show a CpG island methylator phenotype (CIMP) that may influence the behaviour of the tumours

Evolution of the use of corticosteroids for the treatment of hospitalised COVID-19 patients in Spain between March and November 2020: SEMI-COVID national registry

Objectives: Since the results of the RECOVERY trial, WHO recommendations about the use of corticosteroids (CTs) in COVID-19 have changed. The aim of the study is to analyse the evolutive use of CTs in Spain during the pandemic to assess the potential influence of new recommendations. Material and methods: A retrospective, descriptive, and observational study was conducted on adults hospitalised due to COVID-19 in Spain who were included in the SEMI-COVID- 19 Registry from March to November 2020. Results: CTs were used in 6053 (36.21%) of the included patients. The patients were older (mean (SD)) (69.6 (14.6) vs. 66.0 (16.8) years; p < 0.001), with hypertension (57.0% vs. 47.7%; p < 0.001), obesity (26.4% vs. 19.3%; p < 0.0001), and multimorbidity prevalence (20.6% vs. 16.1%; p < 0.001). These patients had higher values (mean (95% CI)) of C-reactive protein (CRP) (86 (32.7-160) vs. 49.3 (16-109) mg/dL; p < 0.001), ferritin (791 (393-1534) vs. 470 (236- 996) µg/dL; p < 0.001), D dimer (750 (430-1400) vs. 617 (345-1180) µg/dL; p < 0.001), and lower Sp02/Fi02 (266 (91.1) vs. 301 (101); p < 0.001). Since June 2020, there was an increment in the use of CTs (March vs. September; p < 0.001). Overall, 20% did not receive steroids, and 40% received less than 200 mg accumulated prednisone equivalent dose (APED). Severe patients are treated with higher doses. The mortality benefit was observed in patients with oxygen saturation </=90%. Conclusions: Patients with greater comorbidity, severity, and inflammatory markers were those treated with CTs. In severe patients, there is a trend towards the use of higher doses. The mortality benefit was observed in patients with oxygen saturation </=90%

Epidemiological trends of HIV/HCV coinfection in Spain, 2015-2019

Altres ajuts: Spanish AIDS Research Network; European Funding for Regional Development (FEDER).Objectives: We assessed the prevalence of anti-hepatitis C virus (HCV) antibodies and active HCV infection (HCV-RNA-positive) in people living with HIV (PLWH) in Spain in 2019 and compared the results with those of four similar studies performed during 2015-2018. Methods: The study was performed in 41 centres. Sample size was estimated for an accuracy of 1%. Patients were selected by random sampling with proportional allocation. Results: The reference population comprised 41 973 PLWH, and the sample size was 1325. HCV serostatus was known in 1316 PLWH (99.3%), of whom 376 (28.6%) were HCV antibody (Ab)-positive (78.7% were prior injection drug users); 29 were HCV-RNA-positive (2.2%). Of the 29 HCV-RNA-positive PLWH, infection was chronic in 24, it was acute/recent in one, and it was of unknown duration in four. Cirrhosis was present in 71 (5.4%) PLWH overall, three (10.3%) HCV-RNA-positive patients and 68 (23.4%) of those who cleared HCV after anti-HCV therapy (p = 0.04). The prevalence of anti-HCV antibodies decreased steadily from 37.7% in 2015 to 28.6% in 2019 (p < 0.001); the prevalence of active HCV infection decreased from 22.1% in 2015 to 2.2% in 2019 (p < 0.001). Uptake of anti-HCV treatment increased from 53.9% in 2015 to 95.0% in 2019 (p < 0.001). Conclusions: In Spain, the prevalence of active HCV infection among PLWH at the end of 2019 was 2.2%, i.e. 90.0% lower than in 2015. Increased exposure to DAAs was probably the main reason for this sharp reduction. Despite the high coverage of treatment with direct-acting antiviral agents, HCV-related cirrhosis remains significant in this population

Ocratoxin A and fumonisin B1 natural interaction in pigs. Clinical and pathological study

Se realizó un estudio en 12 cerdos de 13 a 18 semanas de edad, los lechones mestizos de Yorkshire, de ambos sexos procedían de 2 granjas porcinas de estados centrales de Venezuela (Aragua y Carabobo), los cuales sufrieron de muerte súbita, sin mostrar signos clínicos previos, al momento de ser estudiados. El examen postmortem fue efectuado, con estudios macroscópicos e histopatológicos. Se practicó el estudio toxicológico, el cual fue particularmente orientado para detección de micotoxinas en el alimento: Aflatoxina B1 (AFB1), Fumonisina B1 (FB1) y Ocratoxina A (OA), siguiendo la técnica sugerida por la AOAC para HPLC. El aspecto macroscópico mostró: edema agudo pulmonar con grado variable de hidrotórax, moderada congestión en hígados y quistes renales; los otros órganos no mostraron lesiones. El estudio histopatológico mostró, Pulmones: edema agudo pulmonar y marcada congestión vascular; Hígado: congestión sinusoidal y microfocos de necrosis unicelular; Riñones: quistes, ectasia tubular y glomérulo esclerosis. El estudio toxicológico de alimentos reveló: 10-40 ppm de FB1 y 20-39 ppm de OA. La causa de muerte en todos los lechones estudiados fue edema agudo pulmonar, no asociado con cardiopatía. Este evento patológico agudo se atribuye a la acción de FB1, demostrada en los análisis toxicológicos. El edema pulmonar se debió al daño vascular ocasionado por esta micotoxina, mientras que las alteraciones hepáticas eran causadas por la inhibición de la ceramida sintetasa, incrementándose la biosíntesis de esfingolípidos, coincidiendo con lo demostrado en los valores toxicológicos, los cuales, aunque con niveles eventuales bajos, aparentemente son potenciados o interactúan con los niveles de OA detectados, estos últimos, responsables de las mencionadas lesiones renales. En vista de que no fueron detectados otros agentes tóxicos, se pudo asumir que tales daños Tisulares eran causados por la interacción entre FB1 y OA. Este es el primer reporte en Venezuela demostrando la interacción entre FB1 y OA, lo que permite recomendar el monitoreo periódico de las mencionadas micotoxinas.314 - 321BimestralDetermination of several mycotoxins was carried out in twelve 13 to 18 week old, Yorkshire piglets. The animals were obtained from two farms Aragua and Carabobo states, Venezuela, which suffered sudden death with no previous clinical signs. Postmortem examination was performed for gross and histopathological study. Presence of two mycotoxins was assessed: Fumonisin B1 (FB1) and Ochratoxin A (OA) from feedstuff samples, according to the HPLC technique. Gross examination showed: acute pulmonary oedema with several degrees of hydrotorax. Mild congestion in liver and cysts in kidneys were observed. No lesions were detected in other organs. Histopathological evaluation showed the following results, Lungs: Acute oedema and marked vascular congestion. Liver: Sinusoidal congestion, and unicellular necrosis microfocuses, Kidneys: cysts, tubular ectasia and glomerulosclerosis. Feedstuff toxicological study showed: 10-40ppm FB1, and 20-39 ppm of OA. The cause of sudden death in all studied piglets was acute pulmonary oedema not associated with cardiopathy. This acute pathological event is attributed to Fumonisin 131 action shown through toxicological analyses. Pulmonary oedema is due to vascular damage caused by this mycotoxin, whereas liver alterations caused by inhibition of ceramide synthetase, increasing sphyngolipids biosynthesis, which coincide with the demonstrated toxicological values, that eventhough show low levels of Ochratoxin, responsible for the mentioned kidneys lesions. Since other etiological agents were not detected it can be assumed that such tissue damage is caused by FB1 and OA interaction. This is the first report demonstrating FB1 and OA interaction in Venezuela, which suggest that periodical monitoring on these mycotoxins should be performed

Histologycal characterization of the reproductive tract as puberty and sexual maturity indicator in gilts

Se realizó un estudio en 12 cerdas mestizas (F1) Landrace York, durante el período de un año en el área de patología porcina de la Facultad de Ciencias Veterinarias, Universidad Central de Venezuela. Los animales fueron organizados en cuatro grupos de tres cerdas cada uno: 1. Prepuberal. 2. Primer estro, 3 Segundo estro, 4. Tercer estro. Se practicó la eutanasia el séptimo día después del estro (fase progestacional temprana), con excepción de las cerdas prepuberales, las cuales fueron sacrificadas sin evidenciar celo, se realizó la necropsia y los órganos reproductivos removidos y medidos, muestras de ellos se fiaron en formol al 10% y luego enviadas para procesamiento histopatológico, donde se realizó un estudio comparativo de los tres primeros ciclos estrales de las cerdas maduras, así mismo entre las maduras y las cerdas prepuberales. El estudio histológico permitió señalar diferencias en el aspecto ovárico, particularmente evidentes en el cuerpo lúteo obtenido de los tres primeros ciclos, donde el correspondiente al del tercer ciclo mostraba el mayor desarrollo, con células luteales cuantitativamente y cualitativamente diferentes a la de los estros primero y segundo. El endometrio también presentaba en el tercer estro mayor rapacidad secretoria, con elevada densidad glandular, a diferencia del de los estros primero y segundo, que presentaban paja vascularización y estroma laxo, con escasa capacidad de producir tejido histiotrofo. Estos aspectos histológicos del desarrollo del endometrio en los tres primeros ciclos astrales evidencian un desarrollo gradual dependiente de las hormonas ováricas, determinando una óptima expresión de la capacidad reproductiva de la cerda en el tercer estro219 - 229BimestralA study with twelve crossbred (F1) Landrace-Yorkshire gilts were performed during one year in the Swinat Pathology unit, Veterinary Science Faculty, Universidad Central de Venezuela. Gilts were arranged in four groups of three animals each: 1. Prepubertal, 2.First estrus, 3. Second estrus, 4.Third estrus. Gilts were slaughtered on the seventh day after estrus onset (early progestational stage), with the exception of the prepubertal gilts. The necropsies were performed and the reproductive organs were removed and measured. The organ samples were fixed in 10% formalin and processed for histologic study. Comparisons of the first three estrus cycles histologic findings among mature gilts were stablished. Histological studies finding showed differences in ovaries aspects, comparing corpus luteum (early progestational stage) obtained at the first three estrus cycles. The third cycle corpus luteum showed the greatest structural development due to cualitativa and cuantitativa differences in luteal cells. Endometrial histological findings showed a marked difference as far as cualitativa and cuantitative characteristics of uterus secreting components, with greater glandular density in third cycle gilts, while first and second cycles gilts showed a low vascularized and laxed stroma and little capacity to produce histiotrophic tissue. These histological features of endometrium development the first three estrus cycles evidence a gradual development which depends on ovarian hormones which determine an optimal expression of gilt reproductive capacity in ther third estrus cycle

Management and outcomes in chronic thromboembolic pulmonary hypertension: From expert centers to a nationwide perspective.

The Spanish "Registry of Pulmonary Arterial Hypertension" (REHAP), started in 2007, includes chronic thromboembolic hypertension (CTEPH) patients. Based on data provided by this registry and retrospective data from patients diagnosed during 2006 (≤ 12 months since the registry was created), clinical management and long-term outcomes of CTEPH patients are analyzed nationwide for the first time in a scenario of a decentralized organization model of CTEPH management. A total of 391 patients (median [Q1:Q3] age 63.7 [48.0;73.3] years, 58% females) with CTEPH included during the period January 1, 2006-December 31, 2013 in the REHAP registry were analyzed. Rate of pulmonary endarterectomy (PEA) was 31.2%, and highly asymmetric among centers: rate was 47.9% at two centers designated as CTEPH expert centers, while it was 4.6% in other centers. Among patients not undergoing PEA, 82% were treated with therapies licensed for pulmonary arterial hypertension (PAH). Five-year survival rate was 86.3% for PEA patients, and 64.9% for non-PEA patients. Among non-PEA patients, presenting proximal lesions (42% of non-referred patients) was associated with a 3-fold increase in mortality. PEA patients achieved significantly better hemodynamic and clinical outcomes at one-year follow-up compared to non-PEA patients. Patients not being referred for PEA assessment were older and had a worse functional capacity. Older age was the most deterrent factor for non-operability. Despite the increase in diagnosis and expertise in PEA-specialized centers, an important percentage of patients do not benefit of PEA in a decentralized organization model of CTEPH management