Identifying clinical clusters with distinct trajectories in first-episode psychosis through an unsupervised machine learning technique

The extreme variability in symptom presentation reveals that individuals diagnosed with a first-episode psychosis (FEP) may encompass different sub-populations with potentially different illness courses and, hence, different treatment needs. Previous studies have shown that sociodemographic and family environment factors are associated with more unfavorable symptom trajectories. The aim of this study was to examine the dimensional structure of symptoms and to identify individuals’ trajectories at early stage of illness and potential risk factors associated with poor outcomes at follow-up in non-affective FEP. One hundred and forty-four non-affective FEP patients were assessed at baseline and at 2-year follow-up. A Principal component analysis has been conducted to identify dimensions, then an unsupervised machine learning technique (fuzzy clustering) was performed to identify clinical subgroups of patients. Six symptom factors were extracted (positive, negative, depressive, anxiety, disorganization and somatic/cognitive). Three distinct clinical clusters were determined at baseline: mild; negative and moderate; and positive and severe symptoms, and five at follow-up: minimal; mild; moderate; negative and depressive; and severe symptoms. Receiving a low-dose antipsychotic, having a more severe depressive symptomatology and a positive family history for psychiatric disorders were risk factors for poor recovery, whilst having a high cognitive reserve and better premorbid adjustment may confer a better prognosis. The current study provided a better understanding of the heterogeneous profile of FEP. Early identification of patients who could likely present poor outcomes may be an initial step for the development of targeted interventions to improve illness trajectories and preserve psychosocial functioning

The African swine fever virus dynein-binding protein p54 induces infected cell apoptosis

AbstractA specific interaction of ASFV p54 protein with 8 kDa light chain cytoplasmic dynein (DLC8) has been previously characterized and this interaction is critical during virus internalization and transport to factory sites. During early phases of infection, the virus induces the initiation of apoptosis triggering activation of caspase-9 and -3. To analyze the role of the structural protein p54 in apoptosis, transient expression experiments of p54 in Vero cells were carried out which resulted in effector caspase-3 activation and apoptosis. Interestingly, p54 mutants, lacking the 13 aa dynein-binding motif lose caspase activation ability and pro-death function of p54. This is the first reported ASFV protein which induces apoptosis

Gene expression analyses determine two different subpopulations in KIT-negative GIST-like (KNGL) patients

Introduction: there are limited findings available on KIT-negative GIST-like (KNGL) population. Also, KIT expression may be post-transcriptionally regulated by miRNA221 and miRNA222. Hence, the aim of this study is to characterize KNGL population, by differential gene expression, and to analyze miRNA221/222 expression and their prognostic value in KNGL patients. Methods: KIT, PDGFRA, DOG1, IGF1R, MIR221 and MIR222 expression levels were determined by qRT-PCR. We also analyzed KIT and PDGFRA mutations, DOG1 expression, by immunohistochemistry, along with clinical and pathological data. Disease-free survival (DFS) and overall survival (OS) differences were calculated using Log-rank test. Results: hierarchical cluster analyses from gene expression data identified two groups: group I had KIT, DOG1 and PDGFRA overexpression and IGF1R underexpression and group II had overexpression of IGF1R and low expression of KIT, DOG1 and PDGFRA. Group II had a significant worse OS (p = 0.013) in all the series, and showed a tendency for worse OS (p = 0.11), when analyzed only the localized cases. MiRNA222 expression was significantly lower in a control subset of KIT-positive GIST (p < 0.001). OS was significantly worse in KNGL cases with higher expression of MIR221 (p = 0.028) or MIR222 (p = 0.014). Conclusions: we identified two distinct KNGL subsets, with a different prognostic value. Increased levels of miRNA221/222, which are associated with worse OS, could explain the absence of KIT protein expression of most KNGL tumors

Foxa1 Reduces Lipid Accumulation in Human Hepatocytes and Is Down-Regulated in Nonalcoholic Fatty Liver

Triglyceride accumulation in nonalcoholic fatty liver (NAFL) results from unbalanced lipid metabolism which, in the liver, is controlled by several transcription factors. The Foxa subfamily of winged helix/forkhead box (Fox) transcription factors comprises three members which play important roles in controlling both metabolism and homeostasis through the regulation of multiple target genes in the liver, pancreas and adipose tissue. In the mouse liver, Foxa2 is repressed by insulin and mediates fasting responses. Unlike Foxa2 however, the role of Foxa1 in the liver has not yet been investigated in detail. In this study, we evaluate the role of Foxa1 in two human liver cell models, primary cultured hepatocytes and HepG2 cells, by adenoviral infection. Moreover, human and rat livers were analyzed to determine Foxa1 regulation in NAFL. Results demonstrate that Foxa1 is a potent inhibitor of hepatic triglyceride synthesis, accumulation and secretion by repressing the expression of multiple target genes of these pathways (e.g., GPAM, DGAT2, MTP, APOB). Moreover, Foxa1 represses the fatty acid transporter protein FATP2 and lowers fatty acid uptake. Foxa1 also increases the breakdown of fatty acids by inducing peroxisomal fatty acid β-oxidation and ketone body synthesis. Finally, Foxa1 is able to largely up-regulate UCP1, thereby dissipating energy and consistently decreasing the mitochondria membrane potential. We also report that human and rat NAFL have a reduced Foxa1 expression, possibly through a protein kinase C-dependent pathway. We conclude that Foxa1 is an antisteatotic factor that coordinately tunes several lipid metabolic pathways to block triglyceride accumulation in hepatocytes. However, Foxa1 is down-regulated in human and rat NAFL and, therefore, increasing Foxa1 levels could protect from steatosis. Altogether, we suggest that Foxa1 could be a novel therapeutic target for NAFL disease and insulin resistance

Negative Supercoiling Creates Single-Stranded Patches of DNA That Are Substrates for AID–Mediated Mutagenesis

Antibody diversification necessitates targeted mutation of regions within the immunoglobulin locus by activation-induced cytidine deaminase (AID). While AID is known to act on single-stranded DNA (ssDNA), the source, structure, and distribution of these substrates in vivo remain unclear. Using the technique of in situ bisulfite treatment, we characterized these substrates—which we found to be unique to actively transcribed genes—as short ssDNA regions, that are equally distributed on both DNA strands. We found that the frequencies of these ssDNA patches act as accurate predictors of AID activity at reporter genes in hypermutating and class switching B cells as well as in Escherichia coli. Importantly, these ssDNA patches rely on transcription, and we report that transcription-induced negative supercoiling enhances both ssDNA tract formation and AID mutagenesis. In addition, RNaseH1 expression does not impact the formation of these ssDNA tracts indicating that these structures are distinct from R-loops. These data emphasize the notion that these transcription-generated ssDNA tracts are one of many in vivo substrates for AID

Assessment of a New ROS1 Immunohistochemistry Clone (SP384) for the Identification of ROS1 Rearrangements in Patients with Non–Small Cell Lung Carcinoma: the ROSING Study

Introduction: The ROS1 gene rearrangement has become an important biomarker in NSCLC. The College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology testing guidelines support the use of ROS1 immunohistochemistry (IHC) as a screening test, followed by confirmation with fluorescence in situ hybridization (FISH) or a molecular test in all positive results. We have evaluated a novel anti-ROS1 IHC antibody (SP384) in a large multicenter series to obtain real-world data. Methods: A total of 43 ROS1 FISH-positive and 193 ROS1 FISH-negative NSCLC samples were studied. All specimens were screened by using two antibodies (clone D4D6 from Cell Signaling Technology and clone SP384 from Ventana Medical Systems), and the different interpretation criteria were compared with break-apart FISH (Vysis). FISH-positive samples were also analyzed with next-generation sequencing (Oncomine Dx Target Test Panel, Thermo Fisher Scientific). Results: An H-score of 150 or higher or the presence of at least 70% of tumor cells with an intensity of staining of 2+ or higher by the SP384 clone was the optimal cutoff value (both with 93% sensitivity and 100% specificity). The D4D6 clone showed similar results, with an H-score of at least 100 (91% sensitivity and 100% specificity). ROS1 expression in normal lung was more frequent with use of the SP384 clone (p < 0.0001). The ezrin gene (EZR)-ROS1 variant was associated with membranous staining and an isolated green signal FISH pattern (p = 0.001 and p = 0.017, respectively). Conclusions: The new SP384 ROS1 IHC clone showed excellent sensitivity without compromising specificity, so it is another excellent analytical option for the proposed testing algorithm

Estudio comparativo del desarrollo de aleros en diferentes regiones climáticas y contextos geológicos de la Argentina: hacia una caracterización de patrones y procesos

Este estudio forma parte de un proyecto interdisciplinario en etapa de gestión cuyo objetivo consiste en realizar un análisis geoarqueológico comparativo de aleros ubicados en diferentes contextos geológicos y climáticos de Argentina, a fin de evaluar patrones recurrentes y peculiaridades en el desarrollo de sus morfologías y estratigrafías. El origen, evolución temporal, los tipos de rellenos y el eventual colapso de los aleros responde a factores de control cuyo análisis resulta clave para entender el uso humano de estos espacios en el pasado, su potencial cronológico, los procesos de sedimentación, las discontinuidades estratigráficas y las condiciones de preservación de materiales arqueológicos y tafonómicos. Entre aquellos factores que controlan el desarrollo de un alero pueden destacarse su litología y estructura (tipo de roca, composición mineralógica, textura, fracturas), las condiciones climático-ambientales (precipitación, temperatura, vientos, insolación), la biota (tipo de vegetación, fauna local), el marco tectónico (actividad sísmica) y el tiempo. Estos factores intervienen en los procesos de meteorización y erosión que inician y van modelando el crecimiento de un espacio u oquedad en la roca, que en determinada etapa de su evolución puede llegar a formar un refugio o reparo útil para ser ocupado por los seres humanos, transformándose en un abrigo rocoso o alero. Esta oquedad funciona como una trampa sedimentaria que no sólo contendrá los clastos derivados de la roca de caja, sino también los aportes sedimentarios clásticos (partículas) y químicos (sales, óxidos) acarreados hasta allí por el viento, el agua y/o una pendiente cercana. A este relleno se suman los materiales (clásticos, químicos y biológicos) que puedan generar la fauna y los seres humanos a partir del uso del reparo, produciéndose una suma de aportes autóctonos y alóctonos que van a configurar la estratigrafía del sitio que constituirá una evidencia, al menos parcial, de su historia de formación y ocupación. Finalmente, el alero puede degradarse o colapsar, perdiendo su relleno o quedando oculto. Este proyecto busca profundizar el conocimiento de estos aspectos a través de un abordaje comparativo intra e inter-regional, en función de determinadas preguntas básicas y metodologías analíticas similares aplicadas a estudios de casos en el sur, centro y norte de Argentina. Bajo esta perspectiva se evaluará la utilización y la modificación de estos loci puntuales por parte de los seres humanos y de la fauna que los ha ocupado en forma recurrente. Todo ello a fin de maximizar la contribución de los aleros a las investigaciones arqueológicas y paleoecológicas en las regiones donde éstos se desarrollan.Fil: Favier Dubois, Cristian Mario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Investigaciones Arqueológicas y Paleontológicas del Cuaternario Pampeano. Universidad Nacional del Centro de la Provincia de Buenos Aires. Investigaciones Arqueológicas y Paleontológicas del Cuaternario Pampeano; ArgentinaFil: Mosquera, Bruno Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo; ArgentinaFil: Ambrústulo, Pablo. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo; ArgentinaFil: Herrera Villegas, Dalila Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Investigaciones Arqueológicas y Paleontológicas del Cuaternario Pampeano. Universidad Nacional del Centro de la Provincia de Buenos Aires. Investigaciones Arqueológicas y Paleontológicas del Cuaternario Pampeano; ArgentinaFil: Scartascini, F.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigaciones en Diversidad Cultural y Procesos de Cambio. Universidad Nacional de Río Negro. Instituto de Investigaciones en Diversidad Cultural y Procesos de Cambio; ArgentinaFil: Barberena, Ramiro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Interdisciplinario de Ciencias Básicas. - Universidad Nacional de Cuyo. Instituto Interdisciplinario de Ciencias Básicas; ArgentinaFil: Zárate, M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Confluencia; ArgentinaFil: Martínez, G. A.. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Geología de Costas y del Cuaternario. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto de Geología de Costas y del Cuaternario; ArgentinaFil: Massigoge, Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Investigaciones Arqueológicas y Paleontológicas del Cuaternario Pampeano. Universidad Nacional del Centro de la Provincia de Buenos Aires. Investigaciones Arqueológicas y Paleontológicas del Cuaternario Pampeano; ArgentinaFil: Durán, V.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Interdisciplinario de Ciencias Básicas. - Universidad Nacional de Cuyo. Instituto Interdisciplinario de Ciencias Básicas; ArgentinaFil: Storchi Lobos, Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Investigaciones Arqueológicas y Paleontológicas del Cuaternario Pampeano. Universidad Nacional del Centro de la Provincia de Buenos Aires. Investigaciones Arqueológicas y Paleontológicas del Cuaternario Pampeano; ArgentinaFil: Carrera Aizpitarte, Manuel Pedro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Filosofía y Letras. Museo Etnográfico "Juan B. Ambrosetti"; ArgentinaFil: Rivero, Diego Eduardo. Centro de Estudios Historicos "prof. Carlos S.a. Segreti". Instituto de Estudios Historicos. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Cordoba. Instituto de Estudios Historicos.; ArgentinaFil: Carbonelli, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Filosofía y Letras. Museo Etnográfico "Juan B. Ambrosetti"; ArgentinaFil: Kligmann, Debora Myriam. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Filosofía y Letras. Instituto de Arqueología; ArgentinaFil: Hocsman, Salomón. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Estudios Sociales. Universidad Nacional de Tucumán. Instituto Superior de Estudios Sociales; ArgentinaFil: Babot, Maria del Pilar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Estudios Sociales. Universidad Nacional de Tucumán. Instituto Superior de Estudios Sociales; ArgentinaFil: Gomez Augier, Julian Patricio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo. Instituto de Geociencias y Medio Ambiente; ArgentinaFil: Tchilinguirian, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Secretaría de Cultura de la Nación. Dirección Nacional de Cultura y Museos. Instituto Nacional de Antropología y Pensamiento Latinoamericano; ArgentinaVII Taller del Grupo de Estudios Geoarqueológicos de América Latina: Encuentro Latinoamericano de GeoarqueologíaLimaPerúPontificia Universidad Católica del Per

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update

Recent insights in rheumatoid arthritis (RA) necessitated updating the European League Against Rheumatism (EULAR) RA management recommendations. A large international Task Force based decisions on evidence from 3 systematic literature reviews, developing 4 overarching principles and 12 recommendations (vs 3 and 14, respectively, in 2013). The recommendations address conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GC); biological (b) DMARDs (tumour necrosis factor (TNF)-inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, clazakizumab, sarilumab and sirukumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (Janus kinase (Jak) inhibitors tofacitinib, baricitinib). Monotherapy, combination therapy, treatment strategies (treat-to-target) and the targets of sustained clinical remission (as defined by the American College of Rheumatology-(ACR)-EULAR Boolean or index criteria) or low disease activity are discussed. Cost aspects were taken into consideration. As first strategy, the Task Force recommends MTX (rapid escalation to 25 mg/week) plus short-term GC, aiming at >50% improvement within 3 and target attainment within 6 months. If this fails stratification is recommended. Without unfavourable prognostic markers, switching to—or adding—another csDMARDs (plus short-term GC) is suggested. In the presence of unfavourable prognostic markers (autoantibodies, high disease activity, early erosions, failure of 2 csDMARDs), any bDMARD (current practice) or Jak-inhibitor should be added to the csDMARD. If this fails, any other bDMARD or tsDMARD is recommended. If a patient is in sustained remission, bDMARDs can be tapered. For each recommendation, levels of evidence and Task Force agreement are provided, both mostly very high. These recommendations intend informing rheumatologists, patients, national rheumatology societies, hospital officials, social security agencies and regulators about EULAR's most recent consensus on the management of RA, aimed at attaining best outcomes with current therapies

A View from the Past Into our Collective Future: The Oncofertility Consortium Vision Statement

Today, male and female adult and pediatric cancer patients, individuals transitioning between gender identities, and other individuals facing health extending but fertility limiting treatments can look forward to a fertile future. This is, in part, due to the work of members associated with the Oncofertility Consortium. The Oncofertility Consortium is an international, interdisciplinary initiative originally designed to explore the urgent unmet need associated with the reproductive future of cancer survivors. As the strategies for fertility management were invented, developed or applied, the individuals for who the program offered hope, similarly expanded. As a community of practice, Consortium participants share information in an open and rapid manner to addresses the complex health care and quality-of-life issues of cancer, transgender and other patients. To ensure that the organization remains contemporary to the needs of the community, the field designed a fully inclusive mechanism for strategic planning and here present the findings of this process. This interprofessional network of medical specialists, scientists, and scholars in the law, medical ethics, religious studies and other disciplines associated with human interventions, explore the relationships between health, disease, survivorship, treatment, gender and reproductive longevity. The goals are to continually integrate the best science in the service of the needs of patients and build a community of care that is ready for the challenges of the field in the future