Estudio observacional con certolizumab pegol de 12 semanas de duración en pacientes con artritis reumatoide con y sin exposición previa a anti-TNF: resultados ecográficos, clínicos y reportados por los pacientes

[Abstract] Objectives: To assess the effectiveness and safety of certolizumab pegol (CZP) in Spanish patients with RA. Materials and methods: SONAR (NCT01526434), a 12-week, open-label, prospective, observational, multicenter study. Patients with active RA for ≥3 months, according to ACR criteria, were treated with CZP (400mg at Weeks 0, 2 and 4, then 200mg every 2 weeks). The primary effectiveness endpoint was change from baseline (CFB) in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 12. Other assessments included DAS28(ESR), patient's assessment of arthritis pain (PtAAP-VAS) and Short Form 36-item Health Survey (SF-36) physical component summary (PCS) and mental component summary (MCS). Joint inflammation was investigated using Power Doppler (PD) ultrasound (US), to detect effusion, synovial hypertrophy and synovial PD signal. PDUS outcomes assessed CFB to Week 12 in synovial hypertrophy, effusion and PD signal indices. Results: A total of 77/80 enrolled patients received ≥1 dose of CZP. The 12-week mean reduction from baseline (SD) was -0.6 (0.6) for HAQ-DI and -2.2 (1.5) for DAS28(ESR). PtAAP-VAS was reduced from baseline (mean [SD]: -36.8 [26.8]) and improvements in SF-36 PCS and SF-36 MCS were reported. Synovial hypertrophy, effusion and PD signal indices were reduced from baseline to Week 12. One death was reported during the study. Conclusions: Spanish patients with RA demonstrated improvements in clinical, PDUS and patient-reported outcomes over 12 weeks of CZP treatment. No new safety signals were identified, and the safety profile was in line with previous CZP studies. These results support previous clinical trial findings investigating CZP treatment for active RA.[Resumen] Objetivos: Evaluar la eficacia y la seguridad de certolizumab pegol (CZP) en pacientes españoles con artritis reumatoide (AR). Materiales y métodos: SONAR (NCT01526434), un estudio multicéntrico, observacional, prospectivo, abierto de 12 semanas. Pacientes con AR activa ≥3 meses, según criterios ACR, recibieron CZP (400 mg en las semanas 0, 2 y 4, seguido de 200 mg cada 2 semanas). La variable principal de eficacia fue el cambio desde el inicio (CDI) en el HAQ en la semana 12. Otras evaluaciones incluían el DAS28-VSG, la valoración del dolor (PtAAP-VAS) y el componente físico (PCS) y mental (MCS) del SF-36. La inflamación articular se estudió utilizando ecografía con Power Doppler (PDUS) midiendo derrame, hipertrofia sinovial y señal PD sinovial. Los resultados de PDUS evaluaron el CDI hasta la semana 12 en índices de hipertrofia sinovial, derrame y PD. Resultados: Un total de 77/80 pacientes recibieron ≥una dosis de CZP. La reducción media en 12 semanas desde el inicio (DE) fue de −0,6 (0,6) para HAQ y de −2,2 (1,5) para DAS28-VSG. La PtAAP-VAS disminuyó desde el inicio (media [DE]: −36,8 [26,8]) y hubo mejorías en los componentes PCS y MCS del SF-36. Los índices de señales de hipertrofia sinovial, derrame y PD disminuyeron desde el inicio hasta la semana 12. Se notificó una muerte durante el estudio. Conclusiones: Los pacientes españoles con AR mostraron mejoras en resultados clínicos, PDUS y notificados por el paciente durante 12 semanas de tratamiento con CZP. No hubo nuevas señales de seguridad, y el perfil de seguridad estaba en línea con estudios previos. Estos resultados respaldan los hallazgos de ensayos clínicos previos de CZP en AR

Unveiling the molecular environment of the ring nebula RCW 78

We present a study of the ionized, neutral atomic, and molecular gas associated with the ring nebula RCW 78 around the WR star HD 117688 (= WR 55). We based our study on CO observations carried out with the SEST and NANTEN telescopes. We report the detection of molecular gas with velocities in the range -56 to -33 km/s. The CO emission is mainly connected to the western section, with a total molecular mass of 1.3 x 10^5 solar masses. The analysis of the HI gas distribution reveals the HI envelope of the molecular cloud, while the radio continuum emission shows a ring-like structure, which is the radio counterpart of the optical nebula. The gas distribution is compatible with the western section of RCW 78 having originated in the photodissociation and ionization of the molecular gas by HD 117688, and with the action of the stellar winds of the WR star. A number of infrared point sources classified as YSO candidates showed that stellar formation activity is present in the molecular gas linked to the nebula. The fact that the expansion of the bubble have triggered star formation in this region can not be discarded.Comment: 15 pages, 11 Postscript figures, to be published in A&

Newcastle Disease Virus (NDV) Oncolytic Activity in Human Glioma Tumors Is Dependent on CDKN2A-Type I IFN Gene Cluster Codeletion.

Glioblastoma (GBM) is the most aggressive and frequent primary brain tumor in adults with a median overall survival of 15 months. Tumor recurrence and poor prognosis are related to cancer stem cells (CSCs), which drive resistance to therapies. A common characteristic in GBM is CDKN2A gene loss, located close to the cluster of type I IFN genes at Ch9p21. Newcastle disease virus (NDV) is an avian paramyxovirus with oncolytic and immunostimulatory properties that has been proposed for the treatment of GBM. We have analyzed the CDKN2A-IFN I gene cluster in 1018 glioma tumors and evaluated the NDV oncolytic e ect in six GBM CSCs ex vivo and in a mouse model. Our results indicate that more than 50% of GBM patients have some IFN deletion. Moreover, GBM susceptibility to NDV is dependent on the loss of the type I IFN. Infection of GBM with an NDV-expressing influenza virus NS1 protein can overcome the resistance to oncolysis by NDV of type I-competent cells. These results highlight the potential of using NDV vectors in antitumor therapies.post-print3309 K

Antecedentes y perspectivas de algunas enfermedades prioritarias que afectan a la ganadería bovina en México

The review focused on concisely presenting the contributions that INIFAP researchers have developed, directly or in collaboration with researchers from other institutions, on different aspects of the diseases that affect cattle farming in Mexico. It describes the research on viral diseases such as rabies and bovine viral diarrhea; bacterial diseases such as anaplasmosis, brucellosis, tuberculosis, paratuberculosis, leptospirosis and bovine respiratory disease, and among parasitic diseases, tick infestation and babesiosis. It identifies potential lines of research that can help mitigate the impact of diseases on production. It considers contributions on the development or adaptation of serological and molecular diagnostic techniques and the diagnosis of resistance to ixodicides. In addition, it indicates epidemiological parameters of the diseases and makes reference to the biologics generated, which include vaccines against rabies, anaplasmosis and babesiosis; bacterin against leptospirosis, and a bacterin-toxoid against pneumonia. It also discusses the evaluations of the use of BCG against tuberculosis and a new generation vaccine against brucellosis. The review concludes that the research of INIFAP in animal health must necessarily have the omic sciences as a perspective. This is the only way to complement the understanding of disease mechanisms, the development of new diagnostic techniques and the design of effective and safe vaccines. Therefore, the great challenge will be the involvement of the animal health area in the concept of "One Health".La revisión se enfocó en presentar de manera concisa las aportaciones que investigadores del INIFAP, han desarrollado directamente o en colaboración con investigadores de otras instituciones sobre diferentes aspectos de las enfermedades que afectan a la ganadería bovina en México. Se describen investigaciones sobre enfermedades virales como la rabia y la diarrea viral bovina; bacterianas como la anaplasmosis, brucelosis, tuberculosis, paratuberculosis, leptospirosis y enfermedad respiratoria bovina; de las enfermedades parasitarias se incluye a la infestación por garrapatas y a la babesiosis. Se identifican posibles líneas de investigación que pueden coadyuvar a mitigar el impacto de las enfermedades en la producción. Se señalan aportes sobre el desarrollo o adaptación de técnicas diagnósticas de tipo serológico y molecular y se considera el diagnóstico de resistencia a los ixodicidas. Además, se indican parámetros epidemiológicos de las enfermedades y se refieren los biológicos generados que comprenden vacuna contra rabia, anaplasmosis y babesiosis; bacterina contra leptospirosis y una bacterina-toxoide contra neumonías. Asimismo, se comentan las evaluaciones del uso de BCG contra tuberculosis y una vacuna de nueva generación contra la brucelosis. En la revisión se concluye que la investigación del INIFAP en salud animal debe forzosamente tener como perspectiva las ciencias ómicas. Solo así se complementará el entendimiento de los mecanismos de las enfermedades, el desarrollo de nuevas técnicas diagnósticas y el diseño de vacunas efectivas y seguras. De modo que el gran reto será el involucramiento del área de salud animal al concepto de "Una Salud"

DNA sequences within glioma-derived extracellular vesicles can cross the intact blood-brain barrier and be detected in peripheral blood of patients

Tumor-cell-secreted extracellular vesicles (EVs) can cross the disrupted bloodbrain barrier (BBB) into the bloodstream. However, in certain gliomas, the BBB remains intact, which might limit EVs release. To evaluate the ability of tumor-derived EVs to cross the BBB, we used an orthotopic xenotransplant mouse model of human glioma-cancer stem cells featuring an intact BBB. We demonstrated that all types of tumor cells-derived EVs−apoptotic bodies, shedding microvesicles and exosomes− cross the intact BBB and can be detected in the peripheral blood, which provides a minimally invasive method for their detection compared to liquid biopsies obtained from cerebrospinal fluid (CSF). Furthermore, these EVs can be readily distinguished from total murine EVs, since they carry human-specific DNA sequences relevant for GBM biology. In a small cohort of glioma patients, we finally demonstrated that peripheral blood EVs cargo can be successfully used to detect the presence of IDH1G395A, an essential biomarker in the current management of human gliomaWe are grateful for the financial support from the ‘Fondo de Investigaciones Sanitarias’ (FIS) (PI10/01069 and PI14/00077) and the ‘Miguel Servet Program’ (CP11/00147) from the ‘Instituto de Salud Carlos III’ (AAS), RTC-2015-3846-1 from Ministerio de Economía y Competitividad and FEDER fund

Cancer stem cells from human glioblastoma resemble but do not mimic original tumors after in vitro passaging in serum-free media

Human gliomas harbour cancer stem cells (CSCs) that evolve along the course of the disease, forming highly heterogeneous subpopulations within the tumour mass. These cells possess self-renewal properties and appear to contribute to tumour initiation, metastasis and resistance to therapy. CSC cultures isolated from surgical samples are considered the best preclinical in vitro model for primary human gliomas. However, it is not yet well characterized to which extent their biological and functional properties change during in vitro passaging in the serum-free culture conditions. Here, we demonstrate that our CSC-enriched cultures harboured from one to several CSC clones from the human glioma sample. When xenotransplanted into mouse brain, these cells generated tumours that reproduced at least three different dissemination patterns found in original tumours. Along the passages in culture, CSCs displayed increased expression of stem cell markers, different ratios of chromosomal instability events, and a varied response to drug treatment. Our findings highlight the need for better characterization of CSC-enriched cultures in the context of their evolution in vitro, in order to uncover their full potential as preclinical models in the studies aimed at identifying molecular biomarkers and developing new therapeutic approaches of human gliomas.Peer reviewe

Bevacizumab dose adjustment to improve clinical outcomes of glioblastoma.

Background Glioblastoma (GBM) is one of the most aggressive and vascularized brain tumors in adults, with a median survival of 20.9 months. In newly diagnosed and recurrent GBM, bevacizumab demonstrated an increase in progression-free survival, but not in overall survival. Methods We conducted an in silico analysis of VEGF expression, in a cohort of 1082 glioma patients. Then, to determine whether appropriate bevacizumab dose adjustment could increase the anti-angiogenic response, we used in vitro and in vivo GBM models. Additionally, we analyzed VEGFA expression in tissue, serum, and plasma in a cohort of GBM patients before and during bevacizumab treatment. Results We identified that 20% of primary GBM did not express VEGFA suggesting that these patients would probably not respond to bevacizumab therapy as we proved in vitro and in vivo. We found that a specific dose of bevacizumab calculated based on VEGFA expression levels increases the response to treatment in cell culture and serum samples from mice bearing GBM tumors. Additionally, in a cohort of GBM patients, we observed a correlation of VEGFA levels in serum, but not in plasma, with bevacizumab treatment performance. Conclusions Our data suggest that bevacizumab dose adjustment could improve clinical outcomes in Glioblastoma treatment.post-print1360 K

Association of HLA-B*41:02 with Henoch-Schönlein Purpura (IgA Vasculitis) in Spanish individuals irrespective of the HLA-DRB1 status

INTRODUCTION: To determine whether the human leukocyte antigen (HLA) B alleles are implicated in the susceptibility to Henoch-Schönlein purpura (HSP) in the largest series of Caucasian HSP patients ever assessed for genetic studies. METHODS: The study population was composed of 349 Spanish patients diagnosed with HSP fulfilling the American College of Rheumatology and the Michel et al. classification criteria, and 335 sex and ethnically matched controls. HLA-B phenotypes were determined by sequencing-based typing (SBT) and analyzed by chi-square or Fisher exact test. RESULTS: A statistically significant increase of HLA-B*41:02 allele in HSP patients when compared with controls was found (8.3% versus 1.5% respectively; p = 0.0001; OR (odds ratio) =5.76 [2.15-19.3]). These results remained statistically significant after adjusting for Bonferroni correction (p = 0.0028). An internal validation also confirmed the susceptibility effect on HSP associated with HLA-B*41:02 (OR = 5.70 [1.98-16.44]). Since a former study described an association between HLA-DRB1*01:03 and HSP susceptibility, we also evaluated the implication of HLA-B*41:02 independently of HLA-DRB1*01:03. Interestingly, the association remained statistically significant (p = 0.0004, OR = 4.97 [1.8-16.9]). No HLA-B association with specific HSP clinical features was found. CONCLUSIONS: Our study indicates that HLA-B*41:02 is associated with the susceptibility to HSP in Spanish patients irrespective of HLA-DRB1 status