Mycosis Fungoides and Sézary Syndrome: An Integrative Review of the Pathophysiology, Molecular Drivers, and Targeted Therapy

Primary cutaneous T-cell lymphomas (CTCLs) constitute a heterogeneous group of diseases that affect the skin. Mycosis fungoides (MF) and Sézary syndrome (SS) account for the majority of these lesions and have recently been the focus of extensive translational research. This review describes and discusses the main pathobiological manifestations of MF/SS, the molecular and clinical features currently used for diagnosis and staging, and the different therapies already approved or under development. Furthermore, we highlight and discuss the main findings illuminating key molecular mechanisms that can act as drivers for the development and progression of MF/SS. These seem to make up an orchestrated constellation of genomic and environmental alterations generated around deregulated T-cell receptor (TCR)/phospholipase C, gamma 1, (PLCG1) and Janus kinase/ signal transducer and activator of transcription (JAK/STAT) activities that do indeed provide us with novel opportunities for diagnosis and therapy.This work was funded by grants from Instituto de Salud Carlos III (ISCIII), co-financed by FEDER: PI16/00156 and PI19/00204 to JPV, PI17/0957 to P.L.O.-R., J.P.V. and M.Á.P. also received private funding from the Asociación Luchamos Por La Vida (LPLV) and the Asociación Española Contra El Cancer (AECC), respectively. N.G.-D. was supported by a pre-doctoral contract from UC-IDIVAL

Deletion Syndrome 22q11.2: A Systematic Review

DiGeorge syndrome; Congenital anomalies; Velocardiofacial syndromeSíndrome de DiGeorge; Anomalías congénitas; Síndrome velocardiofacialSíndrome de DiGeorge; Anomalies congènites; Síndrome velocardiofacial22q11.2 deletion syndrome (DS 22q11.2) is a rare disease of genetic origin, caused by the loss of the q11.2 region of chromosome 22. It affects one in 4000 live newborns, and among the clinical manifestations that can occur in this syndrome are abnormalities in the parathyroid glands (producing calcium deficits), the palate, the heart and the thymus. It is also known as DiGeorge syndrome or velocardiofacial syndrome, among other names, depending on the clinical presentation of each individual. The main objective of the review was to update information on DS 22q11.2 from publications in the scientific literature. The daily activities of these patients are seriously impaired, due to the impact of the clinical manifestations. Interventions can be performed to improve their social, cognitive and emotional skills, thus increasing their ability to perform different daily activities

Quantum simulation of conductivity plateaux and fractional quantum Hall effect using ultracold atoms

We analyze the role of impurities in the fractional quantum Hall effect using a highly controllable system of ultracold atoms. We investigate the mechanism responsible for the formation of plateaux in the resistivity/conductivity as a function of the applied magnetic field in the lowest Landau level regime. To this aim, we consider an impurity immersed in a small cloud of an ultracold quantum Bose gas subjected to an artificial magnetic field. We consider scenarios corresponding to experimentally realistic systems with gauge fields induced by rotation of the trapping parabolic potential. Systems of this kind are adequate to simulate quantum Hall effects in ultracold atom setups. We use exact diagonalization for few atoms and to emulate transport equations, we analyze the time evolution of the system under a periodic perturbation. We provide a theoretical proposal to detect the up-to-now elusive presence of strongly correlated states related to fractional filling factors in the context of ultracold atoms. We analyze the conditions under which these strongly correlated states are associated with the presence of the resistivity/conductivity plateaux. Our main result is the presence of a plateau in a region, where the transfer between localized and non-localized particles takes place, as a necessary condition to maintain a constant value of the resistivity/conductivity as the magnetic field increases

Prognostic models for mortality after cardiac surgery in patients with infective endocarditis: a systematic review and aggregation of prediction models.

Background There are several prognostic models to estimate the risk of mortality after surgery for active infective endocarditis (IE). However, these models incorporate different predictors and their performance is uncertain. Objective We systematically reviewed and critically appraised all available prediction models of postoperative mortality in patients undergoing surgery for IE, and aggregated them into a meta-model. Data sources We searched Medline and EMBASE databases from inception to June 2020. Study eligibility criteria We included studies that developed or updated a prognostic model of postoperative mortality in patient with IE. Methods We assessed the risk of bias of the models using PROBAST (Prediction model Risk Of Bias ASsessment Tool) and we aggregated them into an aggregate meta-model based on stacked regressions and optimized it for a nationwide registry of IE patients. The meta-model performance was assessed using bootstrap validation methods and adjusted for optimism. Results We identified 11 prognostic models for postoperative mortality. Eight models had a high risk of bias. The meta-model included weighted predictors from the remaining three models (EndoSCORE, specific ES-I and specific ES-II), which were not rated as high risk of bias and provided full model equations. Additionally, two variables (age and infectious agent) that had been modelled differently across studies, were estimated based on the nationwide registry. The performance of the meta-model was better than the original three models, with the corresponding performance measures: C-statistics 0.79 (95% CI 0.76–0.82), calibration slope 0.98 (95% CI 0.86–1.13) and calibration-in-the-large –0.05 (95% CI –0.20 to 0.11). Conclusions The meta-model outperformed published models and showed a robust predictive capacity for predicting the individualized risk of postoperative mortality in patients with IE. Protocol registration PROSPERO (registration number CRD42020192602).pre-print270 K

Primary care randomized clinical trial: manual therapy effectiveness in comparison with TENS in patients with neck pain

This study investigated effectiveness of manual therapy (MT) with transcutaneous electrical nerve stimulation (TENS) to reduce pain intensity in patients with mechanical neck disorder (MND). A randomized multi-centered controlled clinical trial was performed in 12 Primary Care Physiotherapy Units in Madrid Region. Ninety patients were included with diagnoses of subacute or chronic MND without neurological damage, 47 patients received MT and 43 TENS. The primary outcome was pain intensity measured in millimeters using the Visual Analogue Scale (VAS). Also disability, quality of life, adverse effects and sociodemographic and prognosis variables were measured. Three evaluations were performed (before, when the procedure ?nished and six months after). Seventy-one patients (79%) completed the follow-up measurement at six months. In more than half of the treated patients the procedure had a clinically relevant ?short term? result after having ended the intervention, when either MT or TENS was used. The success rate decreased to one-third of the patients 6 months after the intervention. No differences can be found in the reduction of pain, in the decrease of disability nor in the quality of life between both therapies. Both analyzed physiotherapy techniques produce a short-term pain reduction that is clinically relevant.Ministerio de SanidadInstituto de Salud Carlos II

Applied diagnostics in liver cancer. Efficient combinations of sorafenib with targeted inhibitors blocking AKT/mTOR

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. There is increasing interest in developing specific markers to serve as predictors of response to sorafenib and to guide targeted therapy. Using a sequencing platform designed to study somatic mutations in a selection of 112 genes (HepatoExome), we aimed to characterize lesions from HCC patients and cell lines, and to use the data to study the biological and mechanistic effects of case-specific targeted therapies used alone or in combination with sorafenib. We characterized 331 HCC cases in silico and 32 paired samples obtained prospectively from primary tumors of HCC patients. Each case was analyzed in a time compatible with the requirements of the clinic (within 15 days). In 53% of the discovery cohort cases, we detected unique mutational signatures, with up to 34% of them carrying mutated genes with the potential to guide therapy. In a panel of HCC cell lines, each characterized by a specific mutational signature, sorafenib elicited heterogeneous mechanistic and biological responses, whereas targeted therapy provoked the robust inhibition of cell proliferation and DNA synthesis along with the blockage of AKT/mTOR signaling. The combination of sorafenib with targeted therapies exhibited synergistic anti-HCC biological activity concomitantly with highly effective inhibition of MAPK and AKT/mTOR signaling. Thus, somatic mutations may lead to identify case-specific mechanisms of disease in HCC lesions arising from multiple etiologies. Moreover, targeted therapies guided by molecular characterization, used alone or in combination with sorafenib, can effectively block important HCC disease mechanisms.FUNDING: Grants from ISCIII, co-financed by the European Union (FEDER) (PI16/00156), Ramón and Cajal research program from MINECO (RYC-2013-14097) and FUNDACIÓN LUCHAMOS POR LA VIDA to JPV. Grants from ISCIII (RD06/0020/0107-RD012/0036/0060) to MAP. Grant from ISCIII (Ref. PIE15/00079) to JC & JPV. NGD is a recipient of a UC-IDIVAL pre-doctoral fellow. I.V. was also supported by the Ramón and Cajal research program

Dystrophinopathy Phenotypes and Modifying Factors in Exon 45-55 Deletion

Duchenne muscular dystrophy (DMD) exon 45-55 deletion (del45-55) has been postulated as a model that could treat up to 60% of DMD patients, but the associated clinical variability and complications require clarification. We aimed to understand the phenotypes and potential modifying factors of this dystrophinopathy subset. This cross-sectional, multicenter cohort study applied clinical and functional evaluation. Next generation sequencing was employed to identify intronic breakpoints and their impact on the Dp140 promotor, intronic long noncoding RNA, and regulatory splicing sequences. DMD modifiers (SPP1, LTBP4, ACTN3) and concomitant mutations were also assessed. Haplotypes were built using DMD single nucleotide polymorphisms. Dystrophin expression was evaluated via immunostaining, Western blotting, reverse transcription polymerase chain reaction (PCR), and droplet digital PCR in 9 muscle biopsies. The series comprised 57 subjects (23 index) expressing Becker phenotype (28%), isolated cardiopathy (19%), and asymptomatic features (53%). Cognitive impairment occurred in 90% of children. Patients were classified according to 10 distinct index-case breakpoints; 4 of them were recurrent due to founder events. A specific breakpoint (D5) was associated with severity, but no significant effect was appreciated due to the changes in intronic sequences. All biopsies showed dystrophin expression of >67% and traces of alternative del45-57 transcript that were not deemed pathogenically relevant. Only the LTBP4 haplotype appeared associated the presence of cardiopathy among the explored extragenic factors. We confirmed that del45-55 segregates a high proportion of benign phenotypes, severe cases, and isolated cardiac and cognitive presentations. Although some influence of the intronic breakpoint position and the LTBP4 modifier may exist, the pathomechanisms responsible for the phenotypic variability remain largely unresolved. ANN NEUROL 2022;92:793-80

Proteomic approach to endometrial carcinoma invasion front

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Morbid liver manifestations are intrinsically bound to metabolic syndrome and nutrient intake based on a machine-learning cluster analysis

Metabolic syndrome (MetS) is one of the most important medical problems around the world. Identification of patient ' s singular characteristic could help to reduce the clinical impact and facilitate individualized management. This study aimed to categorize MetS patients using phenotypical and clinical variables habitually collected during health check-ups of individuals considered to have high cardiovascular risk. The selected markers to categorize MetS participants included anthropometric variables as well as clinical data, biochemical parameters and prescribed pharmacological treatment. An exploratory factor analysis was carried out with a subsequent hierarchical cluster analysis using the z-scores from factor analysis. The first step identified three different factors. The first was determined by hypercholesterolemia and associated treatments, the second factor exhibited glycemic disorders and accompanying treatments and the third factor was characterized by hepatic enzymes. Subsequently four clusters of patients were identified, where cluster 1 was characterized by glucose disorders and treatments, cluster 2 presented mild MetS, cluster 3 presented exacerbated levels of hepatic enzymes and cluster 4 highlighted cholesterol and its associated treatments Interestingly, the liver status related cluster was characterized by higher protein consumption and cluster 4 with low polyunsaturated fatty acid intake. This research emphasized the potential clinical relevance of hepatic impairments in addition to MetS traditional characterization for precision and personalized management of MetS patients

Genomics improves risk stratifi cation of adults with T-cell acute lymphoblastic leukemia enrolled in measurable residual disease-oriented trials

Genetic information has been crucial to understand the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) at diagnosis and at relapse, but still nowadays has a limited value in a clinical context. Few genetic markers are associated with the outcome of T-ALL patients, independently of measurable residual disease (MRD) status after therapy. In addition, the prognostic relevance of genetic features may be modulated by the specific treatment used. We analyzed the genetic profile of 145 T-ALL patients by targeted deep sequencing. Genomic information was integrated with the clinical -biological and survival data of a subset of 116 adult patients enrolled in two consecutive MRD-oriented trials of the Spanish PETHEMA (Programa Espanol de Tratamientos en Hematologia) group. Genetic analysis revealed a mutational profile defined by DNMT3A/ N/KRAS/ MSH2/ U2AF1 gene mutations that identified refractory/resistant patients. Mutations in the DMNT3A gene were also found in the non-leukemic cell fraction of patients with T-ALL, revealing a possible mutational-driven clonal hematopoiesis event to prime T-ALL in elderly. The prognostic impact of this adverse genetic profile was independent of MRD status on day +35 of induction therapy. The combined worse-outcome genetic signature and MRD on day +35 allowed risk stratification of T-ALL into standard or high-risk groups with significantly different 5 -year overall survival (OS) of 52% (95% confidence interval: 37-67) and 17% (95% confidence interval: 1-33), respectively. These results confirm the relevance of the tumor genetic profile in predicting patient outcome in adult T-ALL and highlight the need for novel gene-targeted chemotherapeutic schedules to improve the OS of poor-prognosis T-ALL patients