Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation.

RAF kinases are RAS-activated enzymes that initiate signaling through the MAPK cascade to control cellular proliferation, differentiation, and survival. Here, we describe the structure of the full-length RAF1 protein in complex with HSP90 and CDC37 obtained by cryoelectron microscopy. The reconstruction reveals a RAF1 kinase with an unfolded N-lobe separated from its C-lobe. The hydrophobic core of the N-lobe is trapped in the HSP90 dimer, while CDC37 wraps around the chaperone and interacts with the N- and C-lobes of the kinase. The structure indicates how CDC37 can discriminate between the different members of the RAF family. Our structural analysis also reveals that the folded RAF1 assembles with 14-3-3 dimers, suggesting that after folding RAF1 follows a similar activation as B-RAF. Finally, disruption of the interaction between CDC37 and the DFG segment of RAF1 unveils potential vulnerabilities in attempting the pharmacological degradation of RAF1 for therapeutic purposes.

Innate IRE1α-XBP1 activation by viral single-stranded RNA and its influence on lung cytokine production during SARS-CoV-2 pneumonia.

The utilization of host-cell machinery during SARS-CoV-2 infection can overwhelm the protein-folding capacity of the endoplasmic reticulum and activate the unfolded protein response (UPR). The IRE1α-XBP1 arm of the UPR could also be activated by viral RNA via Toll-like receptors. Based on these premises, a study to gain insight into the pathogenesis of COVID-19 disease was conducted using nasopharyngeal exudates and bronchioloalveolar aspirates. The presence of the mRNA of spliced XBP1 and a high expression of cytokine mRNAs were observed during active infection. TLR8 mRNA showed an overwhelming expression in comparison with TLR7 mRNA in bronchioloalveolar aspirates of COVID-19 patients, thus suggesting the presence of monocytes and monocyte-derived dendritic cells (MDDCs). In vitro experiments in MDDCs activated with ssRNA40, a synthetic mimic of SARS-CoV-2 RNA, showed induction of XBP1 splicing and the expression of proinflammatory cytokines. These responses were blunted by the IRE1α inhibitor MKC8866, the TLR8 antagonist CU-CPT9a, and knockdown of TLR8 receptor. In contrast, the IRE1α-XBP1 activator IXA4 enhanced these responses. Based on these findings, the TLR8/IRE1α system seems to play a significant role in the induction of the proinflammatory cytokines associated with severe COVID-19 disease and might be a druggable target to control cytokine storm.

Fungal Patterns Induce Cytokine Expression through Fluxes of Metabolic Intermediates That Support Glycolysis and Oxidative Phosphorylation.

Cytokine expression is fine-tuned by metabolic intermediates, which makes research on immunometabolism suitable to yield drugs with a wider prospect of application than the biological therapies that block proinflammatory cytokines. Switch from oxidative phosphorylation (OXPHOS) to glycolysis has been considered a characteristic feature of activated immune cells. However, some stimuli might enhance both routes concomitantly. The connection between the tricarboxylic acid cycle and cytokine expression was scrutinized in human monocyte-derived dendritic cells stimulated with the fungal surrogate zymosan. Results showed that nucleocytosolic citrate and ATP-citrate lyase activity drove IL1B, IL10, and IL23A expression by yielding acetyl-CoA and oxaloacetate, with the latter one supporting glycolysis and OXPHOS by maintaining cytosolic NAD+ and mitochondrial NADH levels through mitochondrial shuttles. Succinate dehydrogenase showed a subunit-specific ability to modulate IL23A and IL10 expression. Succinate dehydrogenase A subunit activity supported cytokine expression through the control of the 2-oxoglutarate/succinate ratio, whereas C and D subunits underpinned cytokine expression by conveying electron flux from complex II to complex III of the electron transport chain. Fatty acids may also fuel the tricarboxylic acid cycle and influence cytokine expression. Overall, these results show that fungal patterns support cytokine expression through a strong boost of glycolysis and OXPHOS supported by the use of pyruvate, citrate, and succinate, along with the compartmentalized NAD(H) redox state maintained by mitochondrial shuttles.

Efficacy and safety of biological treatment for inflammatory bowel disease in elderly patients: Results from a GETECCU cohort.

INTRODUCTION: Biological therapies used for the treatment of inflammatory bowel disease (IBD) have shown to be effective and safe, although these results were obtained from studies involving mostly a young population, who are generally included in clinical trials. The aim of our study was to determine the efficacy and safety of the different biological treatments in the elderly population. METHODS: Multicenter study was carried out in the GETECCU group. Patients diagnosed with IBD and aged over 65 years at the time of initiating biological therapy (infliximab, adalimumab, golimumab, ustekinumab or vedolizumab) were retrospectively included. Among the patients included, clinical response was assessed after drug induction (12 weeks of treatment) and at 52 weeks. Patients' colonoscopy data in week 52 were assessment, where available. Regarding complications, development of oncological events during follow-up and infectious processes occurring during biological treatment were collected (excluding bowel infection by cytomegalovirus). RESULTS: A total of 1090 patients were included. After induction, at approximately 12-14 weeks of treatment, 419 patients (39.6%) were in clinical remission, 502 patients (47.4%) had responded without remission and 137 patients (12.9%) had no response. At 52 weeks of treatment 442 patients (57.1%) had achieved clinical remission, 249 patients had responded without remission (32.2%) and 53 patients had no response to the treatment (6.8%). Before 52 weeks, 129 patients (14.8%) had discontinued treatment due to inefficacy, this being significantly higher (p<0.0001) for Golimumab - 9 patients (37.5%) - compared to the other biological treatments analyzed. With respect to tumor development, an oncological event was observed in 74 patients (6.9%): 30 patients (8%) on infliximab, 23 (7.14%) on adalimumab, 3 (11.1%) on golimumab, 10 (6.4%) on ustekinumab, and 8 (3.8%) on vedolizumab. The incidence was significantly lower (p=0.04) for the vedolizumab group compared to other treatments. As regards infections, these occurred in 160 patients during treatment (14.9%), with no differences between the different biologicals used (p=0.61): 61 patients (19.4%) on infliximab, 39 (12.5%) on adalimumab, 5 (17.8%) on golimumab, 22 (14.1%) on ustekinumab, and 34 (16.5%) on vedolizumab. CONCLUSIONS: Biological drug therapies have response rates in elderly patients similar to those described in the general population, Golimumab was the drug that was discontinued most frequently due to inefficacy. In our experience, tumor development was more frequent in patients who used anti-TNF therapies compared to other targets, although its incidence was generally low and that this is in line with younger patients based on previous literature.

Temporary immobilization methods for closed low-energy ankle fracture-dislocations: comparative analysis of a retrospective cohort.

PURPOSE: Ankle fracture-dislocations (AFD) often necessitate staged management involving temporary external fixation (EF) due to mechanical instability or blistering. However, limited literature exists on the optimal temporary immobilization method for low-energy closed AFD. This study compared baseline patient and fracture characteristics, along with clinical and radiological outcomes between AFD initially immobilized with EF versus splinting. METHODS: A retrospective cohort study was conducted involving patients with AFD temporarily immobilized using EF or splinting, followed by definitive open reduction and internal fixation. Quality of reduction (QOR) was assessed for each patient post-initial immobilization and after the definitive surgery. RESULTS: The study encompassed 194 patients: 138 treated with a splint (71.1%) and 56 (28.9%) with EF. Secondary loss of reduction had occurred in three patients who were splinted (2.2%). The mean ages in the EF and splint groups were 63.2 and 56.1 years, respectively (p = 0.01). Posterior malleolus fracture (PMF) and blisters were more prevalent in EF patients (69.6% vs. 43.5% for PMF and 76.8% vs. 20.3% for blisters, respectively; p = 0.05 and p < 0.01). Postoperative complication rates were 8.9% for EF versus 10.9% for splinting (p = 0.69). Satisfactory final QOR was attained in 79.8% of patients treated with a splint versus 64.3% with EF (p = 0.02). CONCLUSION: Patients immobilized by EF presented with poorer baseline characteristics and had more unstable injuries. Nevertheless, postoperative complication rates were comparable. Thus, EF appears to be a valuable tool for standardizing outcomes in AFD patients with a less favorable prognosis.

An increase in neural stem cells and olfactory bulb adult neurogenesis improves discrimination of highly similar odorants.

Adult neurogenesis is involved in cognitive performance but studies that manipulated this process to improve brain function are scarce. Here, we characterized a genetic mouse model in which neural stem cells (NSC) of the subventricular zone (SVZ) were temporarily expanded by conditional expression of the cell cycle regulators Cdk4/cyclinD1, thus increasing neurogenesis. We found that supernumerary neurons matured and integrated in the olfactory bulb similarly to physiologically generated newborn neurons displaying a correct expression of molecular markers, morphology and electrophysiological activity. Olfactory performance upon increased neurogenesis was unchanged when mice were tested on relatively easy tasks using distinct odor stimuli. In contrast, intriguingly, increasing neurogenesis improved the discrimination ability of mice when challenged with a difficult task using mixtures of highly similar odorants. Together, our study provides a mammalian model to control the expansion of somatic stem cells that can in principle be applied to any tissue for basic research and models of therapy. By applying this to NSC of the SVZ, we highlighted the importance of adult neurogenesis to specifically improve performance in a challenging olfactory task.

Mapping the genetic features of T-ALL cases through simplified NGS approach.

BACKGROUND: Despite the irruption of massive sequencing technologies in clinical routine, the genetic diagnosis of T-cell acute lymphoblastic leukemia (T-ALL) continues to be based on traditional techniques. The integration of old and new technologies with diagnostic and prognostic purposes represents a major challenge. METHODS: A High-Throughput Sequencing (HTS) approach was applied to analyze the genetic landscape of two patients diagnosed with T-ALL and one early T cell precursor acute leukemia. Orthogonal standard techniques were used to confirm the findings of NGS analysis. RESULTS: By using a single test, a complete genetic map including 2 previously unreported missense mutations in BCL11B gene are reported. Cooperating oncogenic lesions including CDKN2A/B deletions, SIL-TAL1 rearrangement and FLT3 amplification were also captured by using a single test. CONCLUSIONS: HTS is a useful approach that allows simultaneously analyzing mutations, CNVs and the clonal repertoire in T-ALL patients. This approach may simplify the genetic assessment of ALL.

The UPPS model of impulsivity in the abuse of Information and Communication Technologies (ICT). / El modelo UPPS de impulsividad en el abuso de las Tecnologías de la Información y la Comunicación (TIC).

The UPPS model of impulsivity has recently been proposed, has been widely applied to substance abuse and is one of those recommended in the context of Research Domain Criteria, RDoC. However, its application to the abuse of information and communication technologies (ICTs) has been very limited. In the present work, a sample of n = 748 (67% females) was recruited through the Internet, and the reduced version of the UPPS-P was administered, in addition to the MULTICAGE-TIC and the Prefrontal Symptoms Inventory (PSI-20). The psychometric properties of UPPS-P were satisfactory in terms of internal consistency (0.87 > ω > 0.75) and structural validity. Impulsivity measured by UPPS-P correlated with all MULTICAGE-TIC scales, although with a very small effect size, and with greater magnitude with prefrontal dysfunction symptoms. The impulsivity dimension most related to ICT abuse was Urgency (0.3 > r > 0.2). A structural analysis of all the variables was carried out, with impulsivity appearing as a product of the prefrontal malfunction that predicted, through Positive Urgency, the abuse of ICTs. Impulsivity does not seem to be the central nucleus of ICT abuse, but rather failures in the superior control of behavior, of which impulsivity would be a consequence, but not the most important. This makes it advisable to design cognitive rehabilitation interventions that improve the functioning of superior behavior control mechanisms in the prevention and treatment of ICT abuse.

El modelo UPPS de impulsividad se ha propuesto recientemente, ha sido ampliamente aplicado al abuso de sustancias y es uno de los recomendados en el contexto de investigación Research Domain Criteria, RDoC. Sin embargo, su aplicación al abuso de tecnologías de la información y la comunicación (TIC) ha sido muy limitado. En el presente trabajo se reclutó a través de Internet una muestra de n = 748 (67% mujeres) y se administró la versión reducida de la UPPS-P, además del MULTICAGE-TIC y el Inventario de Síntomas Prefrontales (ISP-20). Las propiedades psicométricas de la UPPS-P resultaron satisfactorias en consistencia interna (0,87 > ω >0,75) y validez estructural. La impulsividad medida por la UPPS-P correlacionó con todas las escalas del MULTICAGE-TIC, aunque con un tamaño del efecto muy pequeño, y con mayor magnitud con las de síntomas de mal funcionamiento prefrontal. Las dimensiones de impulsividad más relacionadas con el abuso de las TIC fueron las de Urgencia (0,3 > r > 0,2). Se realizó un análisis estructural de todas las variables apareciendo la impulsividad como un producto del mal funcionamiento prefrontal que predecía, a través de la Urgencia Positiva, el abuso de las TIC. La impulsividad no parece ser el núcleo central del abuso de las TIC, sino los fallos en el control superior de la conducta, de los que la impulsividad sería una consecuencia, pero no la más importante. Ello hace recomendable el diseño de intervenciones de rehabilitación cognitiva que mejoren el funcionamiento de los mecanismos de control superior de la conducta en la prevención y tratamiento del abuso de las TIC.

Functional connectivity patterns predict naturalistic viewing versus rest across development.

Cognitive states, such as rest and task engagement, share an 'intrinsic' functional network organization that is subject to minimal variation over time and yields stable signatures within an individual. Importantly, there are also transient state-specific functional connectivity (FC) patterns that vary across neural states. Here, we examine functional brain organization differences that underlie distinct states in a cross-sectional developmental sample. We compare FC fMRI data acquired during naturalistic viewing (i.e., movie-watching) and resting-state paradigms in a large cohort of 157 children and young adults aged 6-20. Naturalistic paradigms are commonly implemented in pediatric research because they maintain the child's attention and contribute to reduced head motion. It remains unknown, however, to what extent the brain-wide functional network organization is comparable during movie-watching and rest across development. Here, we identify a widespread FC pattern that predicts whether individuals are watching a movie or resting. Specifically, we develop a model for prediction of multilevel neural effects (termed PrimeNet), which can with high reliability distinguish between movie-watching and rest irrespective of age and that generalizes across movies. In turn, we characterize FC patterns in the most predictive functional networks for movie-watching versus rest and show that these patterns can indeed vary as a function of development. Collectively, these effects highlight a 'core' FC pattern that is robustly associated with naturalistic viewing, which also exhibits change across age. These results, focused here on naturalistic viewing, provide a roadmap for quantifying state-specific functional neural organization across development, which may reveal key variation in neurodevelopmental trajectories associated with behavioral phenotypes.

Exosomes in the Healthy and Malignant Bone Marrow Microenvironment.

The bone marrow (BM) is a complex organ that sustains hematopoiesis via mechanisms involving the microenvironment. The microenvironment includes several cell types, neurotransmitters from innervated fibers, growth factors, extracellular matrix proteins, and extracellular vesicles. The main function of the BM is to regulate hematopoietic function to sustain the production of blood and immune cells. However, the BM microenvironment can also accommodate the survival of malignant cells. A major mechanism by which the cancer cells communicate with cells of the BM microenvironment is through the exchange of exosomes, a subset of extracellular vesicles that deliver molecular signals bidirectionally between malignant and healthy cells. The field of exosomes is an active area of investigation since an understanding of how the exosomal packaging, cargo, and production can be leveraged therapeutically to deter cancer progression and sensitize malignant cells to other therapies. Altogether, this chapter discusses the crucial role of exosomes in the development and progression of BM-associated cancers, such as hematologic malignancies and marrow-metastatic breast cancer. Exosome-based therapeutic strategies and their limitations are also considered.

Treatment with proton pump inhibitors as a cofactor in adverse reactions of patients undergoing oral food immunotherapy.

BACKGROUND AND OBJECTIVES: Based on previous studies revealing acid-suppression medication as a risk factor for food allergy tolerance induction, we aimed to establish the importance of those findings in patients undergoing oral immunotherapy (OIT). MATERIALS AND METHODS, RESULTS: We describe a case series of four patients who underwent milk OIT with a concomitant use of proton pump inhibitor (PPI) medication and who developed anaphylaxis after a known, previously tolerated dose of milk. CONCLUSIONS: PPIs may act as a cofactor in patients undergoing OIT, triggering adverse reactions, irrespective of the PPI used or the dosage. It would be necessary to separate the administration of drug from food intake.Since OIT is a new form of treatment, long-term adverse events arising from PPI treatment and other possible triggers are still uncertain. Consequently, monitoring of patient must be prolonged over time. Additional investigations on the influence of different drugs in OIT maintenance phase are required.

Reliability and Validity of the Spanish Version of the Executive Function Performance Test (EFPT) in Assessing People in Treatment for Substance Addiction.

IMPORTANCE: Assessing people's executive function (EF) during addiction treatment makes it possible to design individualized occupational goals. OBJECTIVE: To determine the reliability and validity of the Spanish version of the Executive Function Performance Test (EFPT) in the occupational assessment of people being treated for substance addiction. DESIGN: Cross-sectional, observational study to determine the EFPT's internal consistency as well as its convergent and discriminant validity with complementary tests. SETTING: A public, free addiction treatment center operated by Madrid Salud (Madrid City Council, Spain). PARTICIPANTS: Fifty-two people referred to an occupational therapy department for evaluation and intervention. Inclusion was based on Diagnostic and Statistical Manual of Mental Disorders (4th ed., text revision) criteria for substance abuse or dependence; the exclusion criterion consisted of any circumstances that made it difficult for a person to understand or perform the test. OUTCOMES AND MEASURES: The EFPT, other occupational tests (Allen Cognitive Level Screen-5, Lowenstein Occupational Therapy Cognitive Assessment), and a battery of neuropsychological EF tests. RESULTS: The EFPT had an unequivocal unifactorial structure and showed strong correlations between its components and adequate consistency with the scales and the complete test. As expected, the EFPT correlated with the neuropsychological tests with a considerable effect size (-.40 < r < -.60). CONCLUSIONS AND RELEVANCE: The EFPT's psychometric properties are adequate to assess the EF of people being treated for substance addiction from an occupational perspective using real activities of daily living (ADLs). WHAT THIS ARTICLE ADDS: The results show that the EFPT can be used to assess performance of ADLs without needing to use tests from disciplines other than occupational therapy. Further studies in different sociocultural settings are needed to generalize the results.

Obsession and compulsion in mobile phone use/abuse: OCDUS-ICT. / Obsesión y compulsión en el uso/abuso del móvil: el OCDUS-TIC.

Compulsiveness has been considered one of the core characteristics of addictive behaviours. One of the abusive behaviours that has acquired importance in recent times involves the use of mobile phones. The aim of this study is to obtain a version of the Obsessive-Compulsive Drug-Use Scale (OCDUS) to study the compulsivity associated with mobile phone abuse, its basic psychometric properties and the results of its application. The OCDUS-ICT was created and administered over the Internet, through instant messaging programs, social networks and e-mail, and anonymous and voluntary participation was requested. Additionally, MULTICAGE-ICT and the Inventory of Prefrontal Symptoms were administered. A sample of n=748 subjects, 33% males and 94% born and resident in Spain was obtained. The test obtained adequate values of internal consistency, applying different estimators. Confirmatory factor analysis of the theoretical scales yielded adequate fit indices. Obsessive-compulsive components were observed to become stronger as mobile phone use increased and approached abuse levels. OCDUS-ICT scales showed large correlations with prefrontal malfunction symptoms, especially Thoughts-Interference (r>0.80). In conclusion, OCDUS-ICT explores with psychometric accuracy the obsessive-compulsive components of mobile use/abuse, which are closely related to malfunctions in daily life attributable to the prefrontal cortex. If impulsivity has so far been the focus in the study of mobile phone abuse, the data from the present study suggest that greater attention should be paid to compulsivity as a factor in maintaining abuse.

La compulsividad ha sido considerada una de las características nucleares de las conductas adictivas. Uno de los comportamientos abusivos que ha adquirido importancia en tiempos recientes es el uso del teléfono móvil. El objetivo del presente trabajo es obtener una versión de la Escala de Uso Obsesivo-Compulsivo de Drogas (OCDUS) para estudiar la compulsividad asociada al abuso del móvil, conocer sus propiedades psicométricas básicas y resultados de su aplicación. Se creó y administró el OCDUS-TIC por Internet, mediante mensajería instantánea, redes sociales y correo electrónico, solicitándose la participación anónima y voluntaria. Adicionalmente se administraron el MULTICAGE-TIC y el Inventario de Síntomas Prefrontales (ISP). Se obtuvo una muestra de n=748 sujetos, 33% varones y 94% nacidos y residentes en España. El test obtuvo adecuados valores de consistencia interna, aplicando diferentes estimadores. Se realizó un análisis factorial confirmatorio sobre las escalas teóricas, alcanzando adecuados estimadores de ajuste. Se observó que los componentes obsesivo-compulsivos son de mayor magnitud a medida que se incrementa la implicación en el uso y su progresión al abuso del móvil. Las escalas del OCDUS-TIC mostraron correlaciones de gran magnitud con los síntomas de mal funcionamiento prefrontal, especialmente la de Pensamiento-Interferencia (r>0,80). En conclusión, el OCDUS-TIC explora con garantías psicométricas los componentes obsesivo-compulsivos del uso/abuso del móvil, que se relacionan estrechamente con fallos cotidianos de origen prefrontal. Si la impulsividad ha centrado el interés en el estudio del abuso del móvil, los datos del presente estudio aconsejan prestar mayor atención a la compulsividad como factor de mantenimiento del abuso.

Opiate drug use in the city of Madrid: Associated health and sociodemographic factors. / Consumo de fármacos opiáceos en la ciudad de Madrid: Factores sanitarios y sociodemográficos asociados.

The use of opiate analgesics has led to a health and social emergency in the United States. In Spain, according to official data, the prescription of these drugs has risen dramatically in the last decade. This study explores the prevalence of the use of these drugs and the health and socio-demographic characteristics of their consumers in the city of Madrid. A telephone survey was carried on a stratified, randomised sample, asking about the use of these drugs and whether or not they were medically prescribed. The sample consisted of n=8,845 subjects aged between 15 and 98 years. Sixteen percent stated that they had used these drugs in the last year and 9.1% had taken them in the last two weeks. Consumption was more frequent among women, lower social class and lower level of education. Among the youngest group (15-29 years old) 12.5% had already used it. Those who use opioids report worse perceived health, lower quality of life, more mental health problems, more loneliness, more use of other psychoactive drugs, more frequent daily use of tobacco and less problematic consumption of alcohol. Ten percent of those who use them do so without a doctor's prescription. Combining these data with the prescription data offered by the Ministry of Health, it is necessary to pay attention to a problem that may become apparent in the coming years, and the adoption of urgent measures to tackle it before it brings the Spanish situation closer to that already well known in countries of our socio-political environment is advised.

El consumo de analgésicos opiáceos ha provocado una situación de emergencia sanitaria y social en Estados Unidos. En España, según datos oficiales, la prescripción de estos fármacos ha experimentado un espectacular ascenso en la última década. Este estudio explora la prevalencia del uso de estos fármacos y las características sanitarias y sociodemográficas de sus consumidores en la ciudad de Madrid. Se realizó una encuesta telefónica aplicando un muestreo estratificado y aleatorizado, en la que se preguntó por el uso de estos fármacos y si fueron médicamente prescritos o no. La muestra estuvo compuesta por n= 8.845 sujetos de edades entre 15 y 98 años. Un 16,0% declara haber usado estos fármacos en el último año y un 9,1 los toma en las dos últimas semanas. El consumo es más frecuente en mujeres, clase social baja y menor nivel de estudios. El grupo más joven (15-29 años) ya lo usa en el 12,5%. Quienes usan opioides refieren peor salud percibida, menor calidad de vida, más problemas de salud mental, más soledad no deseada, más uso de otros psicofármacos, más frecuente uso diario de tabaco y menos consumo problemático de alcohol. Un 10% de quienes los usan lo hacen sin prescripción médica. Combinando estos datos con los de prescripción ofrecidos por el Ministerio de Sanidad, resulta necesario prestar atención a un problema que puede hacerse patente en los próximos años, aconsejando la adopción de medidas urgentes para atajarlo antes de que aproxime la situación española a la ya bien conocida en otros países.

Chronic lymphocytic leukemia patients with IGH translocations are characterized by a distinct genetic landscape with prognostic implications.

Chromosome 14q32 rearrangements/translocations involving the immunoglobulin heavy chain (IGH) are rarely detected in chronic lymphocytic leukemia (CLL). The prognostic significance of the IGH translocation is controversial and its mutational profile remains unknown. Here, we present for the first time a comprehensive next-generation sequencing (NGS) analysis of 46 CLL patients with IGH rearrangement (IGHR-CLLs) and we demonstrate that IGHR-CLLs have a distinct mutational profile with recurrent mutations in NOTCH1, IGLL5, POT1, BCL2, FBXW7, ZMYM3, MGA, BRAF and HIST1H1E genes. Interestingly, BCL2 and FBXW7 mutations were significantly associated with this subgroup and almost half of BCL2, IGLL5 and HISTH1E mutations reported were previously identified in non-Hodgkin lymphomas. Notably, IGH/BCL2 rearrangements were associated with a lower mutation frequency and carried BCL2 and IGLL5 mutations, while the other IGHR-CLLs had mutations in genes related to poor prognosis (NOTCH1, SF3B1 and TP53) and shorter time to first treatment (TFT). Moreover, IGHR-CLLs patients showed a shorter TFT than CLL patients carrying 13q-, normal fluorescence in situ hybridization (FISH) and +12 CLL, being this prognosis particularly poor when NOTCH1, SF3B1, TP53, BIRC3 and BRAF were also mutated. The presence of these mutations not only was an independent risk factor within IGHR-CLLs, but also refined the prognosis of low-risk cytogenetic patients (13q-/normal FISH). Hence, our study demonstrates that IGHR-CLLs have a distinct mutational profile from the majority of CLLs and highlights the relevance of incorporating NGS and the status of IGH by FISH analysis to refine the risk-stratification CLL model.

Disease Activity in Psoriatic Arthritis Index and Psoriatic Arthritis Impact of Disease Questionnaire: correlation and sensitivity to change in a real clinical setting.

OBJECTIVES: The performance of many outcome measures for psoriatic arthritis (PsA) is almost unknown in real clinical practice. Our objective was to study the correlation and sensitivity to change of the Disease Activity in Psoriatic Arthritis (DAPSA) index and the Psoriatic Arthritis Impact of Disease (PsAID) questionnaire in a real practice setting. METHODS: This was a prospective, open, non-controlled study that included 60 consecutive patients with PsA treated with ustekinumab. Most had been previously treated with one or more biologic therapeutic agents. The correlation (Spearman's rho coefficient) and the sensitivity to change [Standardized Mean Response (SMR)] of DAPSA and PsAID were studied. Effect size values of 0.20, 0.50 and 0.80 corresponded to low, moderate and high sensitivity to change, respectively. RESULTS: More than 70% of patients achieved therapeutic goals (21.7% were in remission and 50% in low disease activity according to DAPSA categories). Two out of three patients reached an acceptable symptomatic state (PsAID <4). The correlation between final values of both instruments was substantial (Spearman's rho: 0.62, p<0.0001). The SMR for the PsAID was 1.08 (0.95-1.21) and for DAPSA was 1.5 (1.37-1.63), both values corresponding to instruments with a high sensitivity to change (>0.80). The best PsAID cut-off value for identifying DAPSA remission was 3.32 with an area under the ROC curve of 0.82. CONCLUSIONS: DAPSA and PsAID seem to be useful instruments for a more comprehensive assessment of PsA in daily practice. Our results can help to disseminate the use of these instruments in the clinical practice of many rheumatologists.

Endoscopic mucosal resection for cap poliposis treatment.

Cap-polyposis is a rare benign condition characterized by inflammatory colorectal polyps covered by a "cap" of fibrinopurulent exudate. Mucous diarrhea and rectal bleeding are frequent symtoms. It can be difficult to diagnose and it is necessary to make a differential diagnosis from other entities. Its pathogenesis is unknown and it has a variable clinical course. The optimal treatment has not been established.

Tox: a multifunctional transcription factor and novel regulator of mammalian corticogenesis.

Major efforts are invested to characterize the factors controlling the proliferation of neural stem cells. During mammalian corticogenesis, our group has identified a small pool of genes that are transiently downregulated in the switch of neural stem cells to neurogenic division and reinduced in newborn neurons. Among these switch genes, we found Tox, a transcription factor with hitherto uncharacterized roles in the nervous system. Here, we investigated the role of Tox in corticogenesis by characterizing its expression at the tissue, cellular and temporal level. We found that Tox is regulated by calcineurin/Nfat signalling. Moreover, we combined DNA adenine methyltransferase identification (DamID) with deep sequencing to characterize the chromatin binding properties of Tox including its motif and downstream transcriptional targets including Sox2, Tbr2, Prox1 and other key factors. Finally, we manipulated Tox in the developing brain and validated its multiple roles in promoting neural stem cell proliferation and neurite outgrowth of newborn neurons. Our data provide a valuable resource to study the role of Tox in other tissues and highlight a novel key player in brain development.

Polymorphisms in Receptors Involved in Opsonic and Nonopsonic Phagocytosis, and Correlation with Risk of Infection in Oncohematology Patients.

High-risk hematological malignancies are a privileged setting for infection by opportunistic microbes, with invasive mycosis being one of the most serious complications. Recently, genetic background has emerged as an unanticipated risk factor. For this reason, polymorphisms for genes encoding archetypal receptors involved in the opsonic and nonopsonic clearance of microbes, pentraxin-3 (PTX3) and Dectin-1, respectively, were studied and correlated with the risk of infection. Fungal, bacterial, and viral infections were registered for a group of 198 patients with high-risk hematological malignancies. Polymorphisms for the pentraxin-3 gene (PTX3) showed a significant association with the risk of fungal infection by Candida spp. and, especially, by Aspergillus spp. This link remained even for patients undergoing antifungal prophylaxis, thus demonstrating the clinical relevance of PTX3 in the defense against fungi. CLEC7A polymorphisms did not show any definite correlation with the risk of invasive mycosis, nor did they influence the expression of Dectin-1 isoforms generated by alternative splicing. The PTX3 mRNA expression level was significantly lower in samples from healthy volunteers who showed these polymorphisms, although no differences were observed in the extents of induction elicited by bacterial lipopolysaccharide and heat-killed Candidaalbicans, thus suggesting that the expression of PTX3 at the start of infection may influence the clinical outcome. PTX3 mRNA expression can be a good biomarker to establish proper antifungal prophylaxis in immunodepressed patients.