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In the past two decades, high-amplitude electromagnetic outbursts have been detected from dormant galaxies and often attributed to the tidal disruption of a star by the central black hole1,2. X-ray emission from the Seyfert 2 galaxy GSN 069 (2MASX J01190869-3411305) at a redshift of z = 0.018 was first detected in July 2010 and implies an X-ray brightening by a factor of more than 240 over ROSAT observations performed 16 years earlier3,4. The emission has smoothly decayed over time since 2010, possibly indicating a long-lived tidal disruption event5. The X-ray spectrum is ultra-soft and can be described by accretion disk emission with luminosity proportional to the fourth power of the disk temperature during long-term evolution. Here we report observations of quasi-periodic X-ray eruptions from the nucleus of GSN 069 over the course of 54 days, from December 2018 onwards. During these eruptions, the X-ray count rate increases by up to two orders of magnitude with an event duration of just over an hour and a recurrence time of about nine hours. These eruptions are associated with fast spectral transitions between a cold and a warm phase in the accretion flow around a low-mass black hole (of approximately 4 × 105 solar masses) with peak X-ray luminosity of about 5 × 1042 erg per second. The warm phase has kT (where T is the temperature and k is the Boltzmann constant) of about 120 electronvolts, reminiscent of the typical soft-X-ray excess, an almost universal thermal-like feature in the X-ray spectra of luminous active nuclei6-8. If the observed properties are not unique to GSN 069, and assuming standard scaling of timescales with black hole mass and accretion properties, typical active galactic nuclei with higher-mass black holes can be expected to exhibit high-amplitude optical to X-ray variability on timescales as short as months or years9.
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Allergic contact dermatitis induced by the use of ophthalmic topical drugs is one of the most common causes of eyelid dermatitis. The introduction of new formulations, both of active ingredients and excipients, and the lack of marketing in some of them, makes patch testing in patients whose source of contact are topical ophthalmic drugs truly challenging. Across this manuscript, most, if not all, topical ophthalmic drugs used in our national health system have been collected, including information on the allergens available, and the concentration and vehicle advised for those that still remain unavailable.
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Alérgenos , Dermatite Alérgica de Contato , Soluções Oftálmicas , Dermatite Alérgica de Contato/etiologia , Humanos , Espanha , Alérgenos/efeitos adversos , Soluções Oftálmicas/efeitos adversos , Testes do EmplastroRESUMO
Prenatal alcohol exposure (PAE) is a major cause of nongenetic mental retardation and can lead to fetal alcohol syndrome (FAS), the most severe manifestation of fetal alcohol spectrum disorder (FASD). FASD infants present behavioral disabilities resulting from neurodevelopmental defects. Both grey and white matter lesions have been characterized and are associated with apoptotic death and/or ectopic migration profiles. In the last decade, it was shown that PAE impairs brain angiogenesis, and the radial organization of cortical microvessels is lost. Concurrently, several studies have reported that tangential migration of oligodendrocyte precursors (OPCs) originating from ganglionic eminences is vascular associated. Because numerous migrating oligodendrocytes enter the developing neocortex, the present study aimed to determine whether migrating OPCs interacted with radial cortical microvessels and whether alcohol-induced vascular impairments were associated with altered positioning and differentiation of cortical oligodendrocytes. Using a 3D morphometric analysis, the results revealed that in both human and mouse cortices, 15 to 40% of Olig2-positive cells were in close association with radial cortical microvessels, respectively. Despite perinatal vascular disorganization, PAE did not modify the vessel association of Olig2-positive cells but impaired their positioning between deep and superficial cortical layers. At the molecular level, PAE markedly but transiently reduced the expression of CNPase and MBP, two differentiation markers of immature and mature oligodendrocytes. In particular, PAE inverted their distribution profiles in cortical layers V and VI and reduced the thickness of the myelin sheath of efferent axons. These perinatal oligo-vascular defects were associated with motor disabilities that persisted in adults. Altogether, the present study provides the first evidence that Olig2-positive cells entering the neocortex are associated with radial microvessels. PAE disorganized the cortical microvasculature and delayed the positioning and differentiation of oligodendrocytes. Although most of these oligovascular defects occurred in perinatal life, the offspring developed long-term motor troubles. Altogether, these data suggest that alcohol-induced oligo-vascular impairments contribute to the neurodevelopmental issues described in FASD.
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Transtornos do Espectro Alcoólico Fetal , Neocórtex , Efeitos Tardios da Exposição Pré-Natal , Animais , Etanol , Feminino , Transtornos do Espectro Alcoólico Fetal/patologia , Humanos , Camundongos , Neocórtex/metabolismo , Oligodendroglia/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismoRESUMO
Spotted fever group (SFG) rickettsiae are obligatory intracellular bacteria that cause disease in humans and other animals. Ixodid ticks are the principal vectors of SFG rickettsiae. The present study aimed to determine the prevalence and species identity of SFG rickettsiae in ticks and horses from urban and rural areas of western Cuba using PCR assays. Tick samples, collected from 79 horses, consisted of 14 Amblyomma mixtum adults, 111 Dermacentor nitens adults and 19 pools of D. nitens nymphs (2-5 individuals/pool). The PCR results revealed the presence of Rickettsia spp. in 64% of the A. mixtum adults, 16% of the D. nitens adults, and 11% of the pooled samples of D. nitens nymphs. In contrast, Rickettsia spp. was not detected in any of the 200 horse blood samples included in this study. DNA sequence data of the rickettsial 17 kDa antigen gene showed that Rickettsia amblyommatis was present in A. mixtum; and Rickettsia felis in D. nitens. This is the first report of R. felis in D. nitens in Cuba. The present study extends our knowledge of the potential vector spectrum and distribution of SFG rickettsiae pathogens in western Cuba.
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Cavalos , Ixodidae/microbiologia , Rickettsia , Rickettsiose do Grupo da Febre Maculosa/veterinária , Amblyomma/microbiologia , Animais , Vetores Aracnídeos/microbiologia , Cuba/epidemiologia , DNA Bacteriano/genética , Dermacentor/microbiologia , Doenças dos Cavalos/microbiologia , Cavalos/microbiologia , Cavalos/parasitologia , Ninfa/microbiologia , Patologia Molecular , Reação em Cadeia da Polimerase/veterinária , Rickettsia/genética , Rickettsia/isolamento & purificação , Rickettsiose do Grupo da Febre Maculosa/epidemiologia , Rickettsiose do Grupo da Febre Maculosa/microbiologia , Infestações por Carrapato/veterináriaRESUMO
BACKGROUND: The overall mortality of patients with COVID-19 admitted to intensive care units is approximately 40%. AIM: To describe the characteristics of a cohort of patients with COVID-19 who required invasive mechanical ventilation due to severe hypoxemic acute respiratory failure at a general hospital in Santiago, Chile. MATERIAL AND METHODS: Review of medical records and follow up for 28 days of patients with COVID-19 confirmed by polymerase chain reaction who required invasive mechanical ventilation and who were admitted to the intensive care unit from March 24 to June 7, 2020. RESULTS: Data from 152 patients aged 58 (interquartile range (IQR) 47-65 years (66% men) was analyzed. As of July 5, 36 (24%) had died, 75 (49%) were discharged, 10 (7%) were still on invasive mechanical ventilation, 11 (7%) remained with tracheostomy but without invasive mechanical ventilation, and 20 (13%) were hospitalized in a basic unit. The median time on invasive mechanical ventilation among extubated patients was 14 days (IQR 10-21) and 121 (80%) were in the prone position. Patients who died were older, had a higher frequency of diabetes mellitus and a higher driving pressure at 7 days than those discharged alive from the intensive care unit. CONCLUSIONS: In this study mortality was lower than that reported in the first international studies, probably due to the selection of younger patients and greater knowledge of the disease.
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COVID-19 , COVID-19/terapia , Feminino , Hospitalização , Humanos , Unidades de Terapia Intensiva , Masculino , Respiração Artificial , Estudos Retrospectivos , SARS-CoV-2RESUMO
There is no standard treatment for relapsed follicular lymphoma (FL). Although platinum-based combinations are one of the most used treatments, few data have been reported in this setting. Our aim was to analyse R-ESHAP efficacy in relapsed FL patients. We retrospectively analysed 80 FL patients treated with R-ESHAP in the first or successive relapses. Responding patients received a stem cell transplantation following R-ESHAP. Seventeen histologically transformed patients were included. Median age was 50 years. At R-ESHAP initiation, 85% of the patients were in an advanced stage, 28% had a bulky disease and 40% had increased LDH. There were no statistically significant differences between POD24 and non-POD24 patients in terms of response to R-ESHAP (ORR 72% vs. 93%, p = 0.109). When analyzing R-ESHAP efficacy according to the response to the immediately previous line, patients achieving CR or PR had better CR rates to R-ESHAP than those who did not respond (CR of 57% vs. 15%, respectively, p = 0.009), as well as differences in OS (7.2 vs. 1.4 years, p < 0.0001) and in PFS (2.1 vs. 0.3 years, p < 0.0001). R-ESHAP is an effective treatment in relapsed FL patients who respond to the previous line and has to be considered as an adequate alternative for some patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/patologia , Rituximab/administração & dosagem , Terapia de Salvação/métodos , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Linfoma Folicular/mortalidade , Masculino , Metilprednisolona/administração & dosagem , Metilprednisolona/efeitos adversos , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva , Estudos Retrospectivos , Rituximab/efeitos adversos , Espanha/epidemiologia , Análise de Sobrevida , Falha de Tratamento , Resultado do Tratamento , Adulto JovemRESUMO
Objective: The aim of this study was to estimate the prevalence of ankylosing spondylitis (AS) in Spain.Method: This is a cross-sectional, population-based study of people aged 20 years or older in Spain. Randomly selected individuals were contacted by telephone and rheumatic disease screening was performed. If the first screening was positive, medical records were then reviewed and/or a telephone questionnaire was conducted by a rheumatologist, followed by an appointment if necessary. Cases had to fulfil the modified New York (mNY) criteria.Results: In total, 4916 individuals were included, of whom 355 had a positive screening result for AS. Of these, 11 were classified as AS. An additional individual who reported a prior diagnosis of rheumatoid arthritis had a diagnosis of AS confirmed on review of the medical records. Estimated prevalence was 0.26% (95% CI 0.14-0.49).Conclusion: EPISER2016 is the first population-based study to estimate the prevalence of AS in Spain, which has been estimated as being similar to that in other European countries.
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Espondilite Anquilosante/epidemiologia , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Sobrepeso/epidemiologia , Prevalência , Fumar/epidemiologia , Espanha/epidemiologia , Adulto JovemRESUMO
INTRODUCTION: Nivolumab is a fully human programmed death control immune point 1 immune checkpoint inhibitor antibody which promotes antitumor immunity. Cutaneous toxicity associated with nivolumab, immune system related, could be linked to a more durable response in patients with squamous cell lung cancer. CASE REPORT: We present the case of a 62-year-old male diagnosed with metastatic squamous cell lung cancer, who was treated with nivolumab after cytotoxic chemotherapy. After treatment discontinuation, due to grade 2 cutaneous toxicity, the patient is maintaining with durable partial response for more than one year with close follow-up. MANAGEMENT AND OUTCOME: Cumulative doses of nivolumab could cause immunological toxicities that may prolong survival of these patients even after discontinuation of treatment. DISCUSSION: Nivolumab was approved by European Medicines Agency (EMA), as second-line therapeutic, for the treatment of squamous cell lung cancer, showing a median of 9.23 months of overall survival. The development of immune-related skin toxicities has been associated with greater clinical benefit in patients with lung cancer. When cutaneous toxicity forces to nivolumab suspension, in certain cases, the option of not starting again and closely following up the patient may appear reasonable, even though there are no survival data in this context. Suspension of treatment with close monitoring of these patients until progression may be an alternative, since immune-related skin toxicities could be related to a greater clinical benefit and a durable response to nivolumab.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/administração & dosagem , Carcinoma de Células Escamosas/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversosRESUMO
INTRODUCTION: The Multidimensional Weight Locus of Control Scale (MWLCS) measures a person's beliefs regarding the locus of control or lack of locus of control over his/her body weight. PURPOSE: We aim to evaluate the factorial structure and psychometric properties of the MWLCS with Spanish normal weight, overweight and obese samples. METHODS: The research was carried out in two different studies. The first included a sample of 140 normal weight participants, selected out of a 274 sample recruited with an online survey. Study 2 was carried out in a sample of 633 participants recruited from the PREDIMED-Plus study. Out of them, 558 participants fulfilled the weight criteria and were categorized into: overweight (BMI 25 - < 29.99; N = 170), obese class I (BMI 30 - < 34.99; N = 266), and obese class II (BMI 35 - < 39.99; N = 122). Exploratory (EFA) and confirmatory (CFA) factor analyses were used to evaluate the factor structure of the MWLCS, and reliabilities and Spearman's correlations were estimated. Invariance measurement was tested across the three subgroups of weight in Study 2. RESULTS: A three-factor structure indicating weight locus of control factors (internal, chance, and powerful others) was supported, both via EFA in the normal weight sample and CFA in the overweight and obese samples. In the normal weight sample, the powerful others dimension was positively related to BMI and the dimensions of the Dutch Eating Behaviors Questionnaire. Additionally, the scale showed evidence of scalar invariance across the groups with different weight conditions. CONCLUSIONS: This scale seems to be a psychometrically appropriate instrument and its use is highly recommended when designing interventions for overweight or obese individuals. LEVEL OF EVIDENCE: Level V, descriptive study.
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Controle Interno-Externo , Estado Nutricional , Peso Corporal , Feminino , Humanos , Masculino , Psicometria , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
BACKGROUND: In this work, we assessed the efficacy and safety of brentuximab vedotin (BV) plus ESHAP (BRESHAP) as second-line therapy for Relapsed/Refractory Hodgkin lymphoma (RRHL) to improve the results before autologous stem-cell transplantation (ASCT). PATIENTS AND METHODS: This was a multicenter, open-label, phase I-II trial of patients with RRHL after first-line chemotherapy. Treatment had three 21-day cycles of etoposide, solumedrol, high-dose AraC, and cisplatin. BV was administered at three dose levels (0.9, 1.2, and 1.8 mg/kg) intravenous on day â1 to 3 + 3 cohorts of patients. Final BV dose was 1.8 mg/kg. Responding patients proceeded to ASCT, followed by three BV courses (1.8 mg/kg, every 21 days). Main end points for evaluation were maximum tolerable dose and overall and complete response (CR) before ASCT. RESULTS: A total of 66 patients were recruited (median age 36 years; range 18-66): 40 were primary refractory, 16 early relapse and 10 late relapse. There were 39 severe adverse events were reported in 22 patients, most frequently fever (n = 25, 35% neutropenic), including 3 deaths. Grade 3-4 hematological toxicity presented in 28 cases: neutropenia (n = 21), thrombocytopenia (n = 14), and anemia (n = 7). Grade ≥3-4 extrahematological adverse events (≥5%) were non-neutropenic fever (n = 13) and hypomagnesaemia (n = 3). Sixty-four patients underwent stem-cell mobilization; all collected >2×10e6/kg CD34+ cells (median 5.75; range 2.12-33.4). Overall response before transplant was 91% (CI 84% to 98%), including 70% (CRs 95% CI 59% to 81%). 60 patients were transplanted with no failure engraftments. Post-transplant response was CR in 49 patients (82% CI 73% to 91%) and partial responses in six (10% CI 5% to 15%). After a mean follow-up of 27 months, the 30-month time to treatment to failure was 74% (95% CI 68% to 80%), progression-free survival 71% (95% CI 65% to 77%), and overall survival 91% (CI 84% to 98%). CONCLUSION: BRESHAP looks a safe and effective pre-transplant induction regimen, does not jeopardize transplant and allows long-term remissions and survival.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Brentuximab Vedotin/administração & dosagem , Neutropenia Febril Induzida por Quimioterapia/epidemiologia , Doença de Hodgkin/terapia , Recidiva Local de Neoplasia/terapia , Terapia de Salvação/métodos , Administração Intravenosa , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Brentuximab Vedotin/efeitos adversos , Neutropenia Febril Induzida por Quimioterapia/etiologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/mortalidade , Doença de Hodgkin/patologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Intervalo Livre de Progressão , Terapia de Salvação/efeitos adversos , Transplante Autólogo , Adulto JovemRESUMO
An electronic health record (eHR) review of Veterans with a spinal cord injury and disorder (SCI/D) was conducted to understand the extent to which Veterans Affairs (VA) providers pursue workups for secondary causes of osteoporosis in this population. Laboratory tests for secondary causes were ordered in only one-third of Veterans, with secondary causes identified in two-thirds of those tested, most frequently, hypogonadism and hypovitaminosis D. PURPOSE: To identify workups for secondary causes of osteoporosis in SCI/D and the extent to which subspecialty consultations are sought. METHODS: A total of 3018 prescriptions for an osteoporosis medication (bisphosphonate, calcitonin, denosumab, raloxifene, teriparatide) among 2675 Veterans were identified in fiscal years 2005-2015 from VA administrative databases. Approximately 10% of these prescriptions were selected for eHR review. RESULTS: eHR records of 187 Veterans with a SCI/D who had received pharmacological treatment for osteoporosis were reviewed. Workups for secondary causes of osteoporosis were performed in 31.5% of Veterans (n = 59) with approximately 64.4% of those tested (n = 38) having at least one abnormality. Hypogonadism (52.0% of those tested) and hypovitaminosis D (50.0% of those tested) were the most common secondary causes of osteoporosis identified in this population. Approximately 10% of primary care and SCI providers consulted subspecialists for further evaluation and treatment of osteoporosis. Endocrinologists more frequently performed a workup for secondary causes of osteoporosis compared to other provider specialties. CONCLUSIONS: Screening for secondary causes of osteoporosis, particularly for hypogonadism and hypovitaminosis D, should be considered in patients with a SCI/D.
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Osteoporose/diagnóstico , Osteoporose/etiologia , Doenças da Medula Espinal/complicações , Traumatismos da Medula Espinal/complicações , Veteranos , Absorciometria de Fóton , Adulto , Idoso , Conservadores da Densidade Óssea/uso terapêutico , Técnicas de Laboratório Clínico , Registros Eletrônicos de Saúde , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/tratamento farmacológico , Encaminhamento e Consulta , Estados Unidos , United States Department of Veterans AffairsRESUMO
AIMS: Human Sapoviruses (HSaVs) are etiological agents of sporadic cases and outbreaks of acute gastroenteritis in humans of all ages. Evidence of worldwide distribution of HSaV has been documented; however, little is known about HSaV circulation in Italy. To study their occurrence and genetic diversity a nation-wide environmental surveillance was undertaken. METHODS AND RESULTS: One hundred and sixty-six raw sewage samples, collected from 16 wastewater treatment plants throughout Italy, were processed and analysed by a RT-nested PCR targeting the capsid region, followed by amplicon sequencing. HSaV was detected in 56 of 166 (33·7%) samples, characterized as genotypes GI.1 (n = 30 samples), GI.2 (n = 3), GI.3 (n = 2) and GII.1 (n = 1). Mixed electropherograms were detected in 20 samples. Next-generation sequencing (NGS)-based amplicon sequencing was performed on pools of PCR amplicons to detect viruses in mixed samples and less prevalent genotypes undetectable by conventional Sanger sequencing. NGS revealed three additional genotypes (GI.6, GII.6 and GV.1) beyond the four detected by Sanger sequencing. CONCLUSIONS: Our results show a significant circulation of HSaV in Italy with three genogroups (GI, GII and GV) and seven genotypes detected. The high detection rate in sewage samples suggests that HSaV infection in Italy could be underestimated or associated with asymptomatic or mild cases. SIGNIFICANCE AND IMPACT OF THE STUDY: The study detected HSaV in a relevant proportion of raw sewage samples, reflecting a considerable circulation of these viruses in the Italian population, pointing to the usefulness of including HSaV in testing patients with gastroenteritis. Furthermore, our results confirm that wastewater surveillance coupled with NGS is a powerful tool to study the molecular epidemiology of enteric viruses.
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Sapovirus/genética , Esgotos/virologia , Proteínas do Capsídeo/genética , Sequenciamento de Nucleotídeos em Larga Escala , Itália , RNA Viral/genéticaRESUMO
Background: We hypothesized that the abundance of PD1 mRNA in tumor samples might explain the differences in overall response rates (ORR) observed following anti-PD1 monotherapy across cancer types. Patients and methods: RNASeqv2 data from 10 078 tumor samples representing 34 different cancer types was analyzed from TCGA. Eighteen immune-related gene signatures and 547 immune-related genes, including PD1, were explored. Correlations between each gene/signature and ORRs reported in the literature following anti-PD1 monotherapy were calculated. To translate the in silico findings to the clinical setting, we analyzed the expression of PD1 mRNA using the nCounter platform in 773 formalin-fixed paraffin embedded (FFPE) tumor samples across 17 cancer types. To test the direct relationship between PD1 mRNA, PDL1 immunohistochemistry (IHC), stromal tumor-infiltrating lymphocytes (sTILs) and ORR, we evaluated an independent FFPE-based dataset of 117 patients with advanced disease treated with anti-PD1 monotherapy. Results: In pan-cancer TCGA, PD1 mRNA expression was found strongly correlated (r > 0.80) with CD8 T-cell genes and signatures and the proportion of PD1 mRNA-high tumors (80th percentile) within a given cancer type was variable (0%-84%). Strikingly, the PD1-high proportions across cancer types were found strongly correlated (r = 0.91) with the ORR following anti-PD1 monotherapy reported in the literature. Lower correlations were found with other immune-related genes/signatures, including PDL1. Using the same population-based cutoff (80th percentile), similar proportions of PD1-high disease in a given cancer type were identified in our in-house 773 tumor dataset as compared with TCGA. Finally, the pre-established PD1 mRNA FFPE-based cutoff was found significantly associated with anti-PD1 response in 117 patients with advanced disease (PD1-high 51.5%, PD1-intermediate 26.6% and PD1-low 15.0%; odds ratio between PD1-high and PD1-intermediate/low = 8.31; P < 0.001). In this same dataset, PDL1 tumor expression by IHC or percentage of sTILs was not found associated with response. Conclusions: Our study provides a clinically applicable assay that links PD1 mRNA abundance, activated CD8 T-cells and anti-PD1 efficacy.
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Antineoplásicos Imunológicos/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Neoplasias/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , RNA Mensageiro/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linfócitos T CD8-Positivos/imunologia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , RNA Mensageiro/genética , Taxa de SobrevidaRESUMO
Sleep loss induces a low-grade inflammatory status characterized by a subtle but sustained increase of pro-inflammatory mediators, which are key regulators of blood-brain barrier function. To investigate the influence of inflammatory status on blood-brain barrier dysfunction induced by sleep restriction we performed an experiment using two strains of mice with different immunological backgrounds, C57BL/6 mice that have a predominant pro-inflammatory response and BALB/c mice that have a predominant anti-inflammatory response. Mice were sleep-restricted during 10â¯days using the flowerpot technique during 20â¯h per day with 4â¯h of daily sleep opportunity. The systemic inflammatory status, blood-brain barrier permeability, and the hippocampal expression of neuroinflammatory markers were characterized at the 10thâ¯day. Serum levels of TNF and IFN-γ increased in sleep-restricted C57BL/6 but not in BALB/c mice; no changes in other cytokines were found. Sleep restriction increased blood-brain barrier permeability in C57BL/6 strain but not in BALB/c. The hippocampus of sleep-restricted C57BL/6 mice exhibited an increase in the expression of the neuroinflammatory markers Iba-1, A2A adenosine receptor, and MMP-9; meanwhile in sleep-restricted BALB/c mice the expression of this markers was lesser than the control group. These data suggest that cytokines may be playing a key role in modulating blood-brain barrier function during sleep restriction, and probably the effects are related to Iba-1, MMP-9 and A2A adenosine receptor overexpression.
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Barreira Hematoencefálica/metabolismo , Hipocampo/metabolismo , Inflamação/metabolismo , Privação do Sono/metabolismo , Sono/fisiologia , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Mediadores da Inflamação/metabolismo , Interferon gama/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Permeabilidade , Receptor A2A de Adenosina/metabolismo , Fator de Necrose Tumoral alfa/sangueRESUMO
Burkitt's monomorphic posttransplant lymphoproliferative disorder (B-PTLD) is an uncommon subtype of PTLD. Owing to the paucity of this complication, clinical characteristics and outcome has not been fully described. Clinical characteristics and outcomes of 20 patients diagnosed with B-PTLD from 10 transplant centers belonging to the GEL/TAMO group were reviewed. Median time from transplant to B-PTLD was 7.2 years. All the cases fulfill the morphologic and genetic criteria of B-PTLD, whereas Epstein-Barr virus (EBV) was detected in 70% of cases. Patients were treated with different chemotherapy combinations, and three patients received upfront rituximab monotherapy. The great majority of patients receiving CHOP-like regimens attained a complete response (CR) (73%), similar to that obtained with dose-intensive chemotherapy (83% CR). In contrast, patients receiving upfront rituximab monotherapy required subsequent chemotherapy. Two patients (10%) died during treatment due to infection. The median progression-free survival and overall survival (OS) were 16 months and 139 months, respectively. When analyzing variables predicting for OS, we found that patients with bone marrow involvement had an adverse prognosis, with a median OS of 6 months (p = 0.008). In conclusion, B-PTLD is an uncommon complication usually associated with EBV infection and with an aggressive clinical course, particularly in patients with bone marrow involvement. High-dose chemoimmunotherapy obtained similar responses to R-CHOP, suggesting that R-CHOP could be an adequate alternative for these patients. In contrast, rituximab monotherapy does not seem to be effective enough to control the disease.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma de Burkitt , Transplante de Células-Tronco Hematopoéticas , Transplante de Órgãos , Adulto , Idoso , Aloenxertos , Anticorpos Monoclonais Murinos/administração & dosagem , Linfoma de Burkitt/sangue , Linfoma de Burkitt/tratamento farmacológico , Linfoma de Burkitt/etiologia , Linfoma de Burkitt/mortalidade , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Herpesvirus Humano 4 , Humanos , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Rituximab , Taxa de Sobrevida , Vincristina/administração & dosagemRESUMO
Ehlers Danlos Syndrome comprises a heterogeneous group of genetic disorders of the connective tissue, due to defects in collagen or its modifying enzymes. We report a 21 years old male presenting with translucent skin revealing the subcutaneous venous pattern. He had a thin face, large-appearing eyes, thin lips, thin nose, joint hypermotility and history of hip dysplasia. A vascular Ehlers Danlos Syndrome was suspected. However, the genetic study to confirm the diagnosis was not done.
Assuntos
Síndrome de Ehlers-Danlos/diagnóstico , Adulto , Doenças do Tecido Conjuntivo/diagnóstico por imagem , Doenças do Tecido Conjuntivo/genética , Síndrome de Ehlers-Danlos/genética , Heterogeneidade Genética , Humanos , Masculino , Técnicas de Diagnóstico Molecular , Adulto JovemRESUMO
Children and adolescents with rheumatologic diseases require specialized and comprehensive care, but pediatric rheumatologists and immunologists are concentrated in hospitals with specific, high-cost and modern technology. Considering that some patients with juvenile idiopathic arthritis (JIA) live in rural, remote and limited accessibility areas, the use of Telemedicine (TM) can optimize diag nosis, follow-up and prognosis. OBJECTIVE: Reporting 10 years of experience of a mixed care model: face-to-face and distance, using basic TM; the institutional impact, advantages, disadvantages and acceptance informed by parents and patients. PATIENTS AND METHOD: Exploratory, descriptive, and re trospective study with qualitative component. After the authorization of a scientific-ethics committee of the Reloncaví Health Service and the application of informed consent, a review of medical records was carried out and a qualitative survey was applied to parents and children over 14 years of age with JIA, seen between 2005-2015 in the pediatric ambulatory rheumatology polyclinic of Puerto Montt Hospital. RESULTS: The were 27/35 participating patients with JIA attended by a trained pediatrician and assisted by distance (1,000 km) by an immunologist. The 8/35 patients did not answer by choice or change of address. The 70% of parents and patients accepted the model of care and 4% would pre fer sporadic care only by specialists for diagnosis and follow-up. The number of patients transferred annually decreased from 10 to 1. The advantages of the care model outweighed the disadvantages perceived by parents and JIA patients. CONCLUSION: The use of TM tools in JIA decreased transfers, improved follow-up and were considered advantageous by patients and their parents.
Assuntos
Artrite Juvenil/terapia , Acessibilidade aos Serviços de Saúde/organização & administração , Serviços de Saúde Rural/organização & administração , Telemedicina , Adolescente , Criança , Pré-Escolar , Chile , Feminino , Pesquisas sobre Atenção à Saúde , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Hospitais , Humanos , Masculino , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Pesquisa Qualitativa , Estudos Retrospectivos , Serviços de Saúde Rural/estatística & dados numéricos , Telemedicina/métodos , Telemedicina/organização & administração , Telemedicina/estatística & dados numéricosRESUMO
BACKGROUND: The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation. METHODS: We analyzed the DNA of an index patient with early-onset systemic inflammation, cutaneous vasculopathy, and pulmonary inflammation. We sequenced a candidate gene, TMEM173, encoding the stimulator of interferon genes (STING), in this patient and in five unrelated children with similar clinical phenotypes. Four children were evaluated clinically and immunologically. With the STING ligand cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), we stimulated peripheral-blood mononuclear cells and fibroblasts from patients and controls, as well as commercially obtained endothelial cells, and then assayed transcription of IFNB1, the gene encoding interferon-ß, in the stimulated cells. We analyzed IFNB1 reporter levels in HEK293T cells cotransfected with mutant or nonmutant STING constructs. Mutant STING leads to increased phosphorylation of signal transducer and activator of transcription 1 (STAT1), so we tested the effect of Janus kinase (JAK) inhibitors on STAT1 phosphorylation in lymphocytes from the affected children and controls. RESULTS: We identified three mutations in exon 5 of TMEM173 in the six patients. Elevated transcription of IFNB1 and other gene targets of STING in peripheral-blood mononuclear cells from the patients indicated constitutive activation of the pathway that cannot be further up-regulated with stimulation. On stimulation with cGAMP, fibroblasts from the patients showed increased transcription of IFNB1 but not of the genes encoding interleukin-1 (IL1), interleukin-6 (IL6), or tumor necrosis factor (TNF). HEK293T cells transfected with mutant constructs show elevated IFNB1 reporter levels. STING is expressed in endothelial cells, and exposure of these cells to cGAMP resulted in endothelial activation and apoptosis. Constitutive up-regulation of phosphorylated STAT1 in patients' lymphocytes was reduced by JAK inhibitors. CONCLUSIONS: STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease caused by gain-of-function mutations in TMEM173. (Funded by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases; ClinicalTrials.gov number, NCT00059748.).
Assuntos
Inflamação/genética , Proteínas de Membrana/genética , Mutação , Dermatopatias Vasculares/genética , Idade de Início , Citocinas/genética , Citocinas/metabolismo , Feminino , Fibroblastos/metabolismo , Genes Dominantes , Humanos , Lactente , Recém-Nascido , Inflamação/metabolismo , Interferon gama/genética , Interferon gama/metabolismo , Janus Quinases/antagonistas & inibidores , Pneumopatias/genética , Masculino , Linhagem , Fosforilação , Fator de Transcrição STAT1/metabolismo , Análise de Sequência de DNA , Dermatopatias Vasculares/metabolismo , Síndrome , Transcrição Gênica , Regulação para CimaRESUMO
Chronic sleep loss in the rat increases blood-brain barrier permeability to Evans blue and FITC-dextrans in almost the whole brain and sleep recovery during short periods restores normal blood-brain barrier permeability. Sleep loss increases vesicle density in hippocampal endothelial cells and decreases tight junction protein expression. However, at the ultrastructural level the effect of chronic sleep loss on interendothelial junctions is unknown. In this study we characterised the ultrastructure of interendothelial junctions in the hippocampus, the expression of tight junction proteins, and quantified blood-brain barrier permeability to fluorescein-sodium after chronic sleep restriction. Male Wistar rats were sleep restricted using the modified multiple platform method during 10 days, with a daily schedule of 20-h sleep deprivation plus 4-h sleep recovery at their home-cages. At the 10th day hippocampal samples were obtained immediately at the end of the 20-h sleep deprivation period, and after 40 and 120 min of sleep recovery. Samples were processed for transmission electron microscopy and western blot. Chronic sleep restriction increased blood-brain barrier permeability to fluorescein-sodium, and decreased interendothelial junction complexity by increasing the frequency of less mature end-to-end and simply overlap junctions, even after sleep recovery, as compared to intact controls. Chronic sleep loss also induced the formation of clefts between narrow zones of adjacent endothelial cell membranes in the hippocampus. The expression of claudin-5 and actin decreased after chronic sleep loss as compared to intact animals. Therefore, it seems that chronic sleep loss disrupts interendothelial junctions that leads to blood-brain barrier hyperpermeability in the hippocampus.