Therapeutic Potential of EWSR1-FLI1 Inactivation by CRISPR/Cas9 in Ewing Sarcoma.

Ewing sarcoma is an aggressive bone cancer affecting children and young adults. The main molecular hallmark of Ewing sarcoma are chromosomal translocations that produce chimeric oncogenic transcription factors, the most frequent of which is the aberrant transcription factor EWSR1-FLI1. Because this is the principal oncogenic driver of Ewing sarcoma, its inactivation should be the best therapeutic strategy to block tumor growth. In this study, we genetically inactivated EWSR1-FLI1 using CRISPR-Cas9 technology in order to cause permanent gene inactivation. We found that gene editing at the exon 9 of FLI1 was able to block cell proliferation drastically and induce senescence massively in the well-studied Ewing sarcoma cell line A673. In comparison with an extensively used cellular model of EWSR1-FLI1 knockdown (A673/TR/shEF), genetic inactivation was more effective, particularly in its capability to block cell proliferation. In summary, genetic inactivation of EWSR1-FLI1 in A673 Ewing sarcoma cells blocks cell proliferation and induces a senescence phenotype that could be exploited therapeutically. Although efficient and specific in vivo CRISPR-Cas9 editing still presents many challenges today, our data suggest that complete inactivation of EWSR1-FLI1 at the cell level should be considered a therapeutic approach to develop in the future.This research was funded by the Instituto de Salud Carlos III, grant numbers PI20CIII/00020, DTS18CIII/00005, PI16CIII/00026; Asociación Pablo Ugarte, grant numbers TRPV205/18, TPI-M 1149/13; Asociación Candela Riera, Asociación Todos Somos Iván & Fundación Sonrisa de Alex, grant numbers TVP333-19, TVP-1324/15; ASION, grant number TVP141/17, and by the Spanish Center for Biomedical Network Research on Rare Diseases (CIBERER, ER19P5AC728/2021, grant to M.M.), and by the Regional Government of Madrid (CAM, B2017/BMD3721, grant to M.A.M.-P.). R.M.M-F.d.M. was supported by a grant from the Spanish Center for Biomedical Network Research on Rare Diseases (CIBERER).S

Efficacy of chemotherapy for malignant pleural mesothelioma according to histology in a real-world cohort

Cancer therapy; MesotheliomaTerapia del cáncer; MesoteliomaTeràpia del càncer; MesoteliomaCheckMate 743 trial demonstrated survival benefit of immunotherapy in first line in MPM with some differences in the efficacy of chemotherapy according to histology. The objective of this study is to characterize the impact of chemotherapy according to histology in patients diagnosed with MPM at our institution. Clinical records of all MPM patients diagnosed at Vall d’Hebron University Hospital between November 2002 and April 2020 were reviewed. Associations between clinical variables and outcomes were assessed with Cox regression models. Survival data were calculated by the Kaplan–Meier method. 189 patients were included with 76% of tumors classified as epithelioid subtype. First line chemotherapy was offered to 85% of patients. Median survival in overall population was 21.3 months (95% CI 17.2–24.3). We found that patients with epithelioid tumors had better overall survival (OS) and progression free survival (PFS). Median OS of epithelioid patients treated with first line chemotherapy was 26.7 months versus 15.0 months in non-epithelioid patients (HR 2.25 CI 95% 1.4–3.4; p < 0.001). Median PFS for patients with epithelioid tumors treated with chemotherapy was 4.8 months versus 3.6 months in non-epithelioid (HR 1.5 CI 95% 1.0–2.3; p = 0.03). The improvement of outcomes in patients with epithelioid histology was detected in patients treated with cisplatin or carboplatin. Histology was not a predictive factor for the platinum agent sensitivity (p of interaction PFS = 0.09, p of interaction OS = 0.65). In our series, patients with non-epithelioid tumors presented worse prognosis. Although epithelioid tumors exposed to cisplatin had higher PFS, histology was not a clear predictor of chemotherapy efficacy

Descripción de los resultados y costes de una intervención preventiva a nivel respiratorio en el anciano institucionalizado: estudio controlado aleatorizado

Introducción. En el anciano institucionalizado con limitación funcional se evidencia una mayor reducción de la funcionalidad de la musculatura respiratoria (MR). Los objetivos de este estudio son evaluar los resultados y costes de una intervención de entrenamiento de la MR mediante Pranayama en población anciana institucionalizada con limitación funcional. Material y métodos. Ensayo controlado aleatorizado desarrollado en ancianos institucionalizados con limitación para la deambulación (n=54). La intervención consistió en el entrenamiento de la MR mediante Pranayama, durante 6 semanas (5 sesiones/semana). Los resultados se midieron en relación a la función de la MR mediante las presiones respiratorias máximas (PImáx y PEmáx) y la ventilación máxima voluntaria (MVV), en 4 tiempos. También se valoró la satisfacción percibida por el grupo experimental (GE) a través de un cuestionario ad hoc. Se estimaron los costes directos e indirectos de la intervención desde la perspectiva social. Resultados. El GE reveló una mejora significativa de la fuerza (PImáx y PEmáx) y de la resistencia (MVV) de la MR. Además, un 92% del GE refirió una satisfacción alta. Los costes sociales totales, directos e indirectos, ascendieron a 21678¿. Conclusiones. Esta evaluación revela que los resultados en términos de la función de la MR son significativos, que la intervención es bien tolerada y valorada por el residente, y los costes de la intervención son moderados

Nonmotor Symptoms in LRRK2 G2019S Associated Parkinson's Disease

BACKGROUND: Idiopathic Parkinson's disease (IPD) and LRRK2-associated PD (LRRK2-PD) might be expected to differ clinically since the neuropathological substrate of LRRK2-PD is heterogeneous. The range and severity of extra-nigral nonmotor features associated with LRRK2 mutations is also not well-defined. OBJECTIVE: To evaluate the prevalence and time of onset of nonmotor symptoms (NMS) in LRRK2-PD patients. METHODS: The presence of hyposmia and of neuropsychiatric, dysautonomic and sleep disturbances was assessed in 33 LRRK2-G2019S-PD patients by standardized questionnaires and validated scales. Thirty-three IPD patients, matched for age, gender, duration of parkinsonism and disease severity and 33 healthy subjects were also evaluated. RESULTS: University of Pennsylvania Smell Identification Test (UPSIT) scores in LRRK2-G2019S-PD were higher than those in IPD (23.5±6.8 vs 18.4±6.0; p = 0.002), and hyposmia was less frequent in G2019S carriers than in IPD (39.4% vs 75.8%; p = 0.01). UPSIT scores were significantly higher in females than in males in LRRK2-PD patients (26.9±4.7 vs 19.4±6.8; p<0.01). The frequency of sleep and neuropsychiatric disturbances and of dysautonomic symptoms in LRRK2-G2019S-PD was not significantly different from that in IPD. Hyposmia, depression, constipation and excessive daytime sleepiness, were reported to occur before the onset of classical motor symptoms in more than 40% of LRRK2-PD patients in whom these symptoms were present at the time of examination. CONCLUSION: Neuropsychiatric, dysautonomic and sleep disturbances occur as frequently in patients with LRRK2-G2019S-PD as in IPD but smell loss was less frequent in LRRK2-PD. Like in IPD, disturbances such as hyposmia, depression, constipation and excessive daytime sleepiness may antedate the onset of classical motor symptoms in LRRK2-G2019S-PD

A facility and community-based assessment of scabies in rural Malawi.

Background Scabies is a neglected tropical disease of the skin, causing severe itching, stigmatizing skin lesions and systemic complications. Since 2015, the DerMalawi project provide an integrated skin diseases clinics and Tele-dermatology care in Malawi. Clinic based data suggested a progressive increase in scabies cases observed. To better identify and treat individuals with scabies in the region, we shifted from a clinic-based model to a community based outreach programme. Methodology/principal findings From May 2015, DerMalawi project provide integrated skin diseases and Tele-dermatological care in the Nkhotakota and Salima health districts in Malawi. Demographic and clinical data of all patients personally attended are recorded. Due to a progressive increase in the number of cases of scabies the project shifted to a community-based outreach programme. For the community outreach activities, we conducted three visits between 2018 to 2019 and undertook screening in schools and villages of Alinafe Hospital catchment area. Treatment was offered for all the cases and school or household contacts. Scabies increased from 2.9% to 39.2% of all cases seen by the DerMalawi project at clinics between 2015 to 2018. During the community-based activities approximately 50% of the population was assessed in each of three visits. The prevalence of scabies was similar in the first two rounds, 15.4% (2392) at the first visit and 17.2% at the second visit. The prevalence of scabies appeared to be lower (2.4%) at the third visit. The prevalence of impetigo appeared unchanged and was 6.7% at the first visit and 5.2% at the final visit. Conclusions/significance Prevalence of scabies in our setting was very high suggesting that scabies is a major public health problem in parts of Malawi. Further work is required to more accurately assess the burden of disease and develop appropriate public health strategies for its control

Innovation for Children

[EN] Design4Children is the most ambitious European project carried out in relation to the design of products for children. It is coordinated by the Spanish Association of products for children (ASEPRI) and involves 12 entities the first year of the project, just ended, the IBV has played a fundamental role generating knowledge, inexistent to date, to satisfy the comfort and safety needs of children from 0 to 12 years. This knowledge includes the perception that parents have about children¿s product in the market and specific design criteria for children¿s products to ensure the health of children and the comfort and usability of parents. In addition, it has been defined the specifications of a set of innovative tools, that will be developed over the next two years, and will support designers allowing to introduce scientific knowledge regarding products comfort and usability into the design process to ensure the comfort and welfare of children throughout the process of developing new products, advising parents to buy and retailers to select the best products for sale. (R&D centers, associations and companies). With a budget of 1.5M Euros, it covers 3 years. During[ES] Design4Children es el proyecto europeo más ambicioso que se ha llevado a cabo en relación con el diseño de productos para la infancia. Está coordinado por la Asociación Española de Productos para la Infancia (ASEPRI) y participan 12 entidades (centros de I+D, asociaciones y empresas). Con un presupuesto de 1.5 millones de Euros, tiene una duración de 3 años. Durante el primer año del proyecto, que acaba de finalizar, el Instituto de Biomecánica (IBV) ha desarrollado un papel fundamental en la generación de conocimiento, inexistente hasta ahora, relativo a las necesidades en materia de confort y seguridad de la población infantil de 0 a 12 años, así como sobre la percepción que los padres tienen del producto infantil actualmente en el mercado, se han generado criterios de diseño específicos para productos infantiles que aseguren la salud de niños y el confort y usabilidad para los padres. Además, se han definido las especificaciones de un set de herramientas informáticas innovadoras que serán desarrolladas a lo largo de los dos próximos años, y que darán apoyo a los diseñadores. Estas herramientas permitirán a éstos introducir conocimiento científico para asegurar el confort y el bienestar de los niños a lo largo del proceso de desarrollo de nuevos productos, a los padres les aconsejará en la compra y a los minoristas les ayudará en la selección de los productos óptimos para la venta.También queremos dar las gracias a la Comisión Europea por el apoyo financiero brindado en la realización del proyecto dentro de la convocatoria del 7º programa marco "Research for SME associations"Olaso Melis, J.; Ballester Fernández, A.; Hernández Alonso, A.; Gil Garcia, M.; Gonzalez Garcia, JC.; Gil Mora, S.; Iranzo Martínez, L.... (2011). Innovación para los más pequeños. Revista de biomecánica. (57):35-40. http://hdl.handle.net/10251/38459S35405

An algorithm based on immunotherapy discontinuation and liver biopsy spares corticosteroids in two thirds of cases of severe checkpoint inhibitor-induced liver injury

Altres ajuts: acords transformatius de la UABBackground: There are few data on corticosteroids (CS)-sparing strategies for checkpoint inhibitor (ICI)-induced liver injury (ChILI). Aim: We aimed to assess the performance of a 2-step algorithm for severe ChILI, based on ICI temporary discontinuation (step-1) and, if lack of biochemical improvement, CS based on the degree of necroinflammation at biopsy (step-2). Methods: Prospective study that included all subjects with grade 3/4 ChILI. Peripheral extended immunophenotyping was performed. Indication for CS: severe necroinflammation; mild or moderate necroinflammation with later biochemical worsening. Results: From 111 subjects with increased transaminases (January 2020 to August 2023), 44 were diagnosed with grade 3 (N = 35) or grade 4 (N = 9) ChILI. Main reason for exclusion was alternative diagnosis. Lung cancer (13) and melanoma (12) were the most common malignancies. ICI: 23(52.3%) anti-PD1, 8(18.2%) anti-PD-L1, 3(6.8%) anti-CTLA-4, 10(22.7%) combined ICI. Liver injury pattern: hepatocellular (23,52.3%) mixed (12,27.3%) and cholestatic (9,20.5%). 14(32%) presented bilirubin >1.2 mg/dL. Overall, 30(68.2%) patients did not require CS: 22(50.0%) due to ICI discontinuation (step-1) and 8/22 (36.4%) based on the degree of necroinflammation (step-2). Biopsy mainly impacted on grade 3 ChILI, sparing CS in 8 out of 15 (53.3%) non-improvement patients after ICI discontinuation. CD8 HLA-DR expression (p = 0.028), central memory (p = 0.046) were lower in CS-free managed subjects, but effector-memory cells (p = 0.002) were higher. Time to transaminases normalisation was shorter in those CS-free managed (overall: p < 0.001, grade 3: p < 0.001). Considering our results, a strategy based on ICI discontinuation and biopsy for grade 3 ChILI is proposed. Conclusions: An algorithm based on temporary immunotherapy discontinuation and biopsy allows CS avoidance in two thirds of cases of severe ChILI

Patients attended: Scabies, Impetigo and demographic data

A dataset that contains information on patients who received a facility or community-based assessment of Scabies . It contains six variables – age, gender, scabies assessment status, impetigo assessment status, site location, and treatment round number. Data was collected by the DerMalawi project through integrated skin diseases clinics and Tele-dermatology care that they established in 2015 in the Nkhotakota and Salima health districts in Malawi