Prevalence of p.G87V and p.Gln298=Variations in LIPA Gene Within Middle Eastern Population Living Around Los Angeles.

Background: The LIPA gene encodes for lysosomal acid lipase (LAL), which catalyzes the hydrolysis of cholesterol esters and triglycerides. Variations in the LIPA gene impair LAL activity, predisposing patients to a rare metabolic disorder called LAL deficiency (LAL-D). The lack of functioning LAL promotes lipid accumulation and subsequent dyslipidemia, which can increase the likelihood of complications in both infants and adults. Although the worldwide prevalence is 1:500,000 births, the frequency in Mizrahi Jewish populations is projected to be as high as 1 in every 4200 births (Valles-Ayoub et al.) based on the LIPA p.G87V variant frequency among 162 individuals. Materials and Methods: This study was conducted to validate the previously reported prevalence of LAL-D in the Mizrahi Jewish population based on the pathogenic LIPA missense variants in exon 4 (c.260G>T; p.G87V) and exon 8 (c.894G>A; p.Gln298=) using a larger cohort of those with Middle Eastern ancestry living around Los Angeles. Among the 1184 individual samples sequenced, 660 self-reported as Mizrahi Jewish, while the remaining 524 came from other Middle Eastern groups labeled as "non-Jewish." Results: Of the 1184 samples, 22 alleles of the exon 4 variant were identified (1.85%), and 2 alleles of the exon 8 variant were identified (0.16%). For the exon 4 variant, 20 of 22 (90.9%) heterozygotes were Mizrahi Jewish, while 2 of 22 (9.09%) heterozygotes were "non-Jewish." For the exon 8 variant, 2 of 2 (100%) heterozygotes were Mizrahi Jewish. This suggests that the prevalence of LAL-D in this population is 1 in 900, which suggests that LAL-D may be 4.6% higher in the Mizrahi Jewish population in previous reports. Conclusion: These findings show increased prevalence of LIPA gene exon 4 variation p.G87V in the Middle East population when compared to the general population, indicating the need for prenatal screening in those of Mizrahi Jewish ancestry.

Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy.

Anti-CD19 chimeric antigen receptor (CAR) T cell therapy has led to unprecedented responses in patients with high-risk hematologic malignancies. However, up to 60% of patients still experience disease relapse and up to 80% of patients experience CAR-mediated toxicities, such as cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. We investigated the role of the intestinal microbiome on these outcomes in a multicenter study of patients with B cell lymphoma and leukemia. We found in a retrospective cohort (n = 228) that exposure to antibiotics, in particular piperacillin/tazobactam, meropenem and imipenem/cilastatin (P-I-M), in the 4 weeks before therapy was associated with worse survival and increased neurotoxicity. In stool samples from a prospective cohort of CAR T cell recipients (n = 48), the fecal microbiome was altered at baseline compared to healthy controls. Stool sample profiling by 16S ribosomal RNA and metagenomic shotgun sequencing revealed that clinical outcomes were associated with differences in specific bacterial taxa and metabolic pathways. Through both untargeted and hypothesis-driven analysis of 16S sequencing data, we identified species within the class Clostridia that were associated with day 100 complete response. We concluded that changes in the intestinal microbiome are associated with clinical outcomes after anti-CD19 CAR T cell therapy in patients with B cell malignancies.

Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen.

The majority of tumor-infiltrating T cells exhibit a terminally exhausted phenotype, marked by a loss of self-renewal capacity. How repetitive antigenic stimulation impairs T cell self-renewal remains poorly defined. Here, we show that persistent antigenic stimulation impaired ADP-coupled oxidative phosphorylation. The resultant bioenergetic compromise blocked proliferation by limiting nucleotide triphosphate synthesis. Inhibition of mitochondrial oxidative phosphorylation in activated T cells was sufficient to suppress proliferation and upregulate genes linked to T cell exhaustion. Conversely, prevention of mitochondrial oxidative stress during chronic T cell stimulation allowed sustained T cell proliferation and induced genes associated with stem-like progenitor T cells. As a result, antioxidant treatment enhanced the anti-tumor efficacy of chronically stimulated T cells. These data reveal that loss of ATP production through oxidative phosphorylation limits T cell proliferation and effector function during chronic antigenic stimulation. Furthermore, treatments that maintain redox balance promote T cell self-renewal and enhance anti-tumor immunity.

Amelioration of Neurosensory Structure and Function in Animal and Cellular Models of a Congenital Blindness.

Most genetically distinct inherited retinal degenerations are primary photoreceptor degenerations. We selected a severe early onset form of Leber congenital amaurosis (LCA), caused by mutations in the gene LCA5, in order to test the efficacy of gene augmentation therapy for a ciliopathy. The LCA5-encoded protein, Lebercilin, is essential for the trafficking of proteins and vesicles to the photoreceptor outer segment. Using the AAV serotype AAV7m8 to deliver a human LCA5 cDNA into an Lca5 null mouse model of LCA5, we show partial rescue of retinal structure and visual function. Specifically, we observed restoration of rod-and-cone-driven electroretinograms in about 25% of injected eyes, restoration of pupillary light responses in the majority of treated eyes, an ∼20-fold decrease in target luminance necessary for visually guided behavior, and improved retinal architecture following gene transfer. Using LCA5 patient-derived iPSC-RPEs, we show that delivery of the LCA5 cDNA restores lebercilin protein and rescues cilia quantity. The results presented in this study support a path forward aiming to develop safety and efficacy trials for gene augmentation therapy in human subjects with LCA5 mutations. They also provide the framework for measuring the effects of intervention in ciliopathies and other severe, early-onset blinding conditions.

Use of induced pluripotent stem cell models to probe the pathogenesis of Choroideremia and to develop a potential treatment.

Choroideremia (CHM) is a rare monogenic, X-linked recessive inherited retinal degeneration resulting from mutations in the Rab Escort Protein-1 (REP1) encoding CHM gene. The primary retinal cell type leading to CHM is unknown. In this study, we explored the utility of induced pluripotent stem cell-derived models of retinal pigmented epithelium (iPSC-RPE) to study disease pathogenesis and a potential gene-based intervention in four different genetically distinct forms of CHM. A number of abnormal cell biologic, biochemical, and physiologic functions were identified in the CHM mutant cells. We then identified a recombinant adeno-associated virus (AAV) serotype, AAV7m8, that is optimal for both delivering transgenes to iPSC-RPEs as well as to appropriate target cells (RPE cells and rod photoreceptors) in the primate retina. To establish the proof of concept of AAV7m8 mediated CHM gene therapy, we developed AAV7m8.hCHM, which delivers the human CHM cDNA under control of CMV-enhanced chicken ß-actin promoter (CßA). Delivery of AAV7m8.hCHM to CHM iPSC-RPEs restored protein prenylation, trafficking and phagocytosis. The results confirm that AAV-mediated delivery of the REP1-encoding gene can rescue defects in CHM iPSC-RPE regardless of the type of disease-causing mutation. The results also extend our understanding of mechanisms involved in the pathophysiology of choroideremia.

[Not Available]. / Efectos de la suplementación de omega-3 y entrenamiento de intervalos de alta intensidad en el rendimiento físico, presión arterial y composición corporal en individuos sedentarios con sobrepeso.

Introducción: el entrenamiento de intervalos de alta intensidad (HIIT) y el consumo de ácidos grasos omega-3 (O3) ha demostrado cada uno por separado aumentar la capacidad aeróbica, metabolismo oxidativo y función cardiovascular.Objetivo: examinar el efecto combinado de HIIT más suplementación de O3 en el rendimiento físico, presión arterial y composición corporal en jóvenes sedentarios.Método: 28 jóvenes sedentarios con sobrepeso (Edad=22 ± 4 años; IMC=25.8 ± 2.4 kg·m-2) fueron distribuidos aleatoriamente en cuatro grupos: grupo O3/HIIT (n=7) realizó un protocolo de HIIT, tres veces por semana durante seis semanas y consumió 2 g·día-1 de O3; grupo HIIT (n=7) realizó solo el HIIT; grupo O3 (n=7) solo consumió O3; y grupo CONTROL (n=7) que no realizó ninguna intervención. Consumo de oxígeno peak (VO2peak), velocidad máxima (Vmax), presión arterial sistólica y diastólica (PAS y PAD), y porcentaje de grasa fueron medidos antes y después de la intervención.Resultados: el consumo de oxígeno peak aumentó más en el grupo O3/HIIT (+10.9%) en comparación con HIIT, O3 y CONTROL. Velocidad máxima aumentó en O3/HIIT (+7.1%) y HIIT (+11.9%). La presión arterial sistólica disminuyó más en O3 (-6.8%) en comparación con O3/HIIT, HIIT y CONTROL. Por último, O3/HIIT (-19.2%), HIIT (-20.2%), y O3 (-15.2%) presentaron mayores disminuciones del porcentaje de masa grasa en relación al CONTROL.Conclusión: nuestros resultados sugieren un efecto potenciador de la capacidad aeróbica máxima producto de la combinación de HIIT y suplementación de O3. Además, se observó una disminución de masa grasa en todos los grupos intervenidos.

Evaluación de un modelo de intervención para fomentar estilos de vida saludables en preescolares / Evaluation of an intervention model to stimulate healthy life habits in preeschool children

El propósito del estudio fué probar un modelo de intervención orientado a fomentar estilos de vida saludables en preescolares con énfasis en hábitos alimentarios y actividad física. La muestra estuvo constituida por 100 preescolares (50 intervenidos y 50 controles) de 4 centros INTEGRA de la Región Metropolitana. El modelo consideró educación alimentaria y fomento de la actividad física, desarrollada por el personal institucional previamente capacitado y en una modificación de la alimentación institucional. Para validar la metodología de evaluación de impacto se determinó estado nutricional, ingesta alimentaria, desarrollo motor, conocimientos alimentarios maternos y hábitos alimentarios del niño en el hogar. Para la evaluación del proceso se realizaron visitas de observación y entrevistas. El 35 por ciento de los niños estudiados presentaba exceso de peso. Se observó un bajo consumo de verduras, frutas, pescados, calcio y fibra y alto consumo de golosinas. Las madres mostraron un buen nivel de información. Las modificaciones a la alimentación no produjeron problemas ni de aceptación ni adminstrativos. La promoción de alimentación y actividad física saludable se incorporó a la rutina diaria. Se demostró la necesidad de capacitación y asesoría en terreno. Se concluye que el modelo es factible de aplicar con los esquemas de funcionamiento y recursos institucionales y solo se deben modificar algunos instrumentos de evaluación por su baja sensibilidad para medir impacto

Carcinoma epidermoide de cavidad bucal; revision de 3622 casos entre 1985-1990 / Epidermoid carcinoma of buccal cavity

El proposito de este trabajo es demostrar la prevalencia del cancer de boca en nuestro medio. Para lo cual se tomaron en cuenta los siguientes parametros: edad, sexo, ubicacion de la lesion, diagnostico histopatologico, grado de diferenciacion, formas macroscopicas, estadio clinico, factores de riesgo, estatus socioeconomico y cuadro clinico. Se revisaron retrospectivamente 3266 informes histopatologicos del departamento de patologia del Hospital Clinico "Viedma" y las historias clinicas de la Fac. de odontologia de la UMSS de Cochabamba, en el periodo comprendido entre enero de 1985 a diciembre de 1990. Se informa de 20 casos (6.5

de los 20 casos de cancer de boca corresponden a carcinoma epidermoide. Presentandose el tipo histopatologico mas frecuente como carcinoma epidermoide moderadamente diferenciado, la mayoria de las lesiones provienen de mucosa bucal, el grupo etareo mas afectado corresponde entre la cuarta a septima decada de la vida. El carcinoma epidermoide bucal afecto con mayor frecuencia al sexo femenino 2:1. Los pacientes acudieron a la consulta por la presencia de ulceras y tumor vegetante. Siendo en este estudio el carcinoma epidermoide el mas frecuente en nuestra casuistica, como en la literatura nacional e internacional.

) de cancer bucal de 310 casos que corresponden a 9.5

de la totalidad de casos revisados. El 60