Selective activation of striatal indirect pathway suppresses levodopa induced-dyskinesias

Levodopa (L-DOPA) administration remains the gold standard therapy for Parkinson's disease (PD). Despite several pharmacological advances in the use of L-DOPA, a high proportion of chronically treated patients continues to suffer disabling involuntary movements, namely, L-DOPA-induced dyskinesias (LIDs). As part of the effort to stop these unwanted side effects, the present study used a rodent model to identify and manipulate the striatal outflow circuitry responsible for LIDs. To do so, optogenetic technology was used to activate separately the striatal direct (D1R- expressing) and indirect (D2R- expressing) pathways in a mouse model of PD. Firstly, D1-cre or A2a-cre animals received unilateral injections of neurotoxin 6-hydroxydopamine (6-OHDA) to simulate the loss of dopamine observed in PD patients. The effects of independently stimulating each pathway were tested to see if experimental dyskinesias could be induced. Secondly, dopamine depleted A2a-cre animals received systemic L-DOPA to evoke dyskinetic movements. The ability of indirect pathway optogenetic stimulation to suppress pre-established LIDs was then tested. Selective manipulation of direct pathway evoked optodyskinesias both in dopamine depleted and intact animals, but optical inhibition of these neurons failed to suppress LIDs. On the other hand, selective activation of indirect striatal projection neurons produced an immediate and reliable suppression of LIDs. Thus, a functional dissociation has been found here whereby activation of D1R- and D2R-expressing projection neurons evokes and inhibits LIDs respectively, supporting the notion of tight interaction between the two striatal efferent systems in both normal and pathological conditions. This points to the importance of maintaining an equilibrium in the activity of both striatal pathways to produce normal movement. Finally, the ability of selective indirect pathway optogenetic activation to block the expression of LIDs in an animal model of PD sheds light on intrinsic mechanisms responsible for striatal-based dyskinesias and identifies a potential therapeutic target for suppressing LIDs in PD patients.This work was supported by: Marie Slodowksa-Curie Fellowship, H2020-MSCA-IF-2014_RI:660964-ROSNPD (LFH); and by grants from the Spanish Government: SAF2015–67239-P (JAO), BES-2016-077493 (ICM); CIBERNED (JAO, LFH). Fundación Gangoiti (YVW). Funding agencies: Marie Slodowksa-Curie Fellowship, H2020-MSCA-IF-2014_RI:660964-ROSNPD (LFH); and by grants from the Spanish Government: SAF2015–67239-P (JAO), BES-2016-077493 (ICM); CIBERNED (JAO, LFH). Fundación Gangoiti (YVW) and by grants PID2019-111693RB-100 funded by MICIN /AEI/http://dx.doi.org/10.13039/501100011033, by European Union's Horizon 2020 research and innovation program, AND-PD (grant agreement no. 84800), and by NextGenerationEU/PRTR (MICIN/CSIC/PTI+ NeuroAging) to R.M

Immediate effects of dasatinib on the migration and redistribution of naïve and memory lymphocytes associated with lymphocytosis in chronic myeloid leukemia patients

Introduction: Dasatinib is a dual SRC/ABL tyrosine kinase inhibitor used to treat chronic myeloid leukemia (CML) that is known to have unique immunomodulatory effects. In particular, dasatinib intake typically causes lymphocytosis, which has been linked to better clinical response. Since the underlying mechanisms are unknown and SRC family kinases are involved in many cell motility processes, we hypothesized that the movement and migration of lymphocytes is modulated by dasatinib. Patients, Materials and Methods: Peripheral blood samples from CML patients treated with second-line dasatinib were collected before and 2 h after the first dasatinib intake, and follow-up samples from the same patients 3 and 6 months after the start of therapy. The migratory capacity and phenotype of lymphocytes and differential blood counts before and after drug intake were compared for all study time-points. Results: We report here for the first time that dasatinib intake is associated with inhibition of peripheral blood T-cell migration toward the homeostatic chemokines CCL19 and CCL21, which control the trafficking toward secondary lymphoid organs, mainly the lymph nodes. Accordingly, the proportion of lymphocytes in blood expressing CCR7, the chemokine receptor for both CCL19 and CCL21, decreased after the intake including both naïve CD45RA+ and central memory CD45RO+ T-cells. Similarly, naïve B-cells diminished with dasatinib. Finally, such changes in the migratory patterns did not occur in those patients whose lymphocyte counts remained unchanged after taking the drug. Discussion: We, therefore, conclude that lymphocytosis induced by dasatinib reflects a pronounced redistribution of naïve and memory populations of all lymphocyte subsets including CD4+ and CD8+ T-cells and B-cells

Multiple myeloma and SARS-CoV-2 infection : clinical characteristics and prognostic factors of inpatient mortality

There is limited information on the characteristics, prognostic factors, and outcomes of patients with multiple myeloma (MM) hospitalized with COVID-19. This retrospective case series investigated 167 patients reported from 73 hospitals within the Spanish Myeloma Collaborative Group network in March and April, 2020. Outcomes were compared with 167 randomly selected, contemporary, age-/sex-matched noncancer patients with COVID-19 admitted at six participating hospitals. Among MM and noncancer patients, median age was 71 years, and 57% of patients were male; 75 and 77% of patients, respectively, had at least one comorbidity. COVID-19 clinical severity was moderate-severe in 77 and 89% of patients and critical in 8 and 4%, respectively. Supplemental oxygen was required by 47 and 55% of MM and noncancer patients, respectively, and 21%/9% vs 8%/6% required noninvasive/invasive ventilation. Inpatient mortality was 34 and 23% in MM and noncancer patients, respectively. Among MM patients, inpatient mortality was 41% in males, 42% in patients aged >65 years, 49% in patients with active/progressive MM at hospitalization, and 59% in patients with comorbid renal disease at hospitalization, which were independent prognostic factors on adjusted multivariate analysis. This case series demonstrates the increased risk and identifies predictors of inpatient mortality among MM patients hospitalized with COVID-19

Results of an early access treatment protocol of daratumumab monotherapy in spanish patients with relapsed or refractory multiple myeloma

Daratumumab is a human CD38-targeted monoclonal antibody approved as monotherapy for heavily pretreated relapsed and refractory multiple myeloma. We report findings for the Spanish cohort of an open-label treatment protocol that provided early access to daratumumab monotherapy and collected safety and patient-reported outcomes data for patients with relapsed or refractory multiple myeloma. At 15 centers across Spain, intravenous daratumumab (16mg/kg) was administered to 73 patients who had ≥3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or who were double refractory to both. The median duration of daratumumab treatment was 3.3 (range: 0.03–13.17) months, with a median number of 12 (range: 1–25) infusions. Grade 3/4 treatment-emergent adverse events were reported in 74% of patients and included lymphopenia (28.8%), thrombocytopenia (27.4%), neutropenia (21.9%), leukopenia (19.2%), and anemia (15.1%). Common (>5%) serious treatmentemergent adverse events included respiratory tract infection (9.6%), general physical health deterioration (6.8%), and back pain (5.5%). Infusion-related reactions occurred in 45% of patients. The median change from baseline in all domains of the EQ-5D-5L and EORTC QLQ-C30 was mostly 0. A total of 18 (24.7%) patients achieved a partial response or better, with 10 (13.7%) patients achieving a very good partial response or better. Median progression-free survival was 3.98 months. The results of this early access treatment protocol are consistent with previously reported trials of daratumumab monotherapy and confirm its safety and antitumoral efficacy in Spanish patients with heavily treated relapsed or refractory multiple myeloma

Analisis de las respuestas moleculares profundas alcanzadas por las multiples secuencias de tratamientos con ITKS en LMC. Estudio de largo seguimiento del registro español de LMC

Poster [PC-231] Introducción: Cinco inhibidores de tirosina cinasa (ITKs) están disponibles para el tratamiento de pacientes con leucemia mieloide crónica en fase crónica (LMC-FC). Analizamos las diferentes secuencias de ITKs utilizadas como terapia para la LMC-FC en un análisis a largo plazo en vida real. Métodos: En un análisis retrospectivo de cohortes, se incluyeron pacientes con LMC-FC tratados en la práctica clínica con diferentes ITKs en el Registro Español de LMC (RELMC) (17 hospitales de todo el país) entre 2000 y 2014. El objetivo principal del estudio fue describir la secuencia del tratamiento con ITKs en la práctica de la vida real y la última respuesta molecular profunda (DMR) (MR4, MR4.5 o transcrito indetectable) para cada esquema. Resultados: Nuestro análisis incluyó 862 pacientes con LMC en 1º FC tratados con ITKs en 1ª línea o después de interferón alfa. Datos demográficos demográficos: 517 H, 345 M, mediana de edad: 52 años (14-94a). Distribución del Índice Sokal (bajo 49% Inter 38% Alto 13%), Índice EURO (bajo 50% Inter 45% Alto 5%), Índice EUTOS (bajo 93% Alto 7%), Índice LT-EUTOS (bajo 68 % Inter 25% Alto 7%). Esquemas de tratamiento: la Tabla 1 resume todos los esquemas utilizados y la última respuesta molecular. Los pacientes se dividieron en 4 grupos según el tratamiento con ITKs. Grupo 1: solo tratados con Imatinib 394 p (45, 7%) Grupo 2: Imatinib y luego 2ºGITKs debido a intolerancia o fallo 170 p (19, 7%) (12 esquemas de tratamiento secuenciales diferentes con ITKs) Grupo 3: 2ºGITKs en 1ª línea 91 p (13 esquemas secuenciales) (10, 5%) Grupo 4: Interferón alfa y luego ITKs 207 p (24%) (9 esquemas secuenciales). La Figura 1 resume la evolución de diferentes tratamientos alrededor de los 14 años. Última respuesta molecular profunda: con una mediana de seguimiento de 82 meses (1-351 m) desde el diagnóstico, 77 m (1-311 m) desde el primer tratamiento y 70 m (1-191 m) desde el primer tratamiento con ITK. Las tasas de respuesta molecular profunda para cada grupo fueron (G1: DMR 65% MMR 13% No MMR 15%, G2: DMR 46% MMR 24% No MMR 17%, G3: DMR 62% MMR 13% No MMR 12%, G4: DMR 53% MMR 17% No MMR 18%). Supervivencia a largo plazo (SLP o SG): no se encontraron diferencias estadísticas entre los grupos de tratamiento, ya sea desde el diagnóstico, el primer tratamiento o el primer ITK. Alcanzar una respuesta profunda garantiza mejores resultados. Variables predictivas de respuesta: los índices SOKAL, EUTOS, EURO y LT-EUTOS continúan siendo útiles para predecir el resultado a largo plazo. Conclusiones: En el contexto de un registro multicéntrico basado en hospitales, el tratamiento con ITKs es muy variable, con un gran número de secuencias diferentes de ITKs. Con una mediana de seguimiento de 7 años la tasa de respuesta molecular profunda es aproximadamente del 60% en pacientes tratados con imatinib y que no necesitan cambio de ITKs, y en aquellos tratados en 1º línea con 2ºGITKs(a pesar de su corto seguimiento), pero parece menor en pacientes tratados con imatinib que necesitan cambiar a 2ºGITKs. Los resultados de supervivencia fueron similares para todos los grupos

Search for the glueball candidates f0(1500) and fJ(1710) in gamma gamma collisions

Data taken with the ALEPH detector at LEP1 have been used to search for gamma gamma production of the glueball candidates f0(1500) and fJ(1710) via their decay to pi+pi-. No signal is observed and upper limits to the product of gamma gamma width and pi+pi- branching ratio of the f0(1500) and the fJ(1710) have been measured to be Gamma_(gamma gamma -> f0(1500)). BR(f0(1500)->pi+pi-) < 0.31 keV and Gamma_(gamma gamma -> fJ(1710)). BR(fJ(1710)->pi+pi-) < 0.55 keV at 95% confidence level.Comment: 10 pages, 3 figure

Search for supersymmetry with a dominant R-parity violating LQDbar couplings in e+e- collisions at centre-of-mass energies of 130GeV to 172 GeV

A search for pair-production of supersymmetric particles under the assumption that R-parity is violated via a dominant LQDbar coupling has been performed using the data collected by ALEPH at centre-of-mass energies of 130-172 GeV. The observed candidate events in the data are in agreement with the Standard Model expectation. This result is translated into lower limits on the masses of charginos, neutralinos, sleptons, sneutrinos and squarks. For instance, for m_0=500 GeV/c^2 and tan(beta)=sqrt(2) charginos with masses smaller than 81 GeV/c^2 and neutralinos with masses smaller than 29 GeV/c^2 are excluded at the 95% confidence level for any generation structure of the LQDbar coupling.Comment: 32 pages, 30 figure

Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s = 7 TeV pp collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb−1 of proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results

Jet size dependence of single jet suppression in lead-lead collisions at sqrt(s(NN)) = 2.76 TeV with the ATLAS detector at the LHC

Measurements of inclusive jet suppression in heavy ion collisions at the LHC provide direct sensitivity to the physics of jet quenching. In a sample of lead-lead collisions at sqrt(s) = 2.76 TeV corresponding to an integrated luminosity of approximately 7 inverse microbarns, ATLAS has measured jets with a calorimeter over the pseudorapidity interval |eta| < 2.1 and over the transverse momentum range 38 < pT < 210 GeV. Jets were reconstructed using the anti-kt algorithm with values for the distance parameter that determines the nominal jet radius of R = 0.2, 0.3, 0.4 and 0.5. The centrality dependence of the jet yield is characterized by the jet "central-to-peripheral ratio," Rcp. Jet production is found to be suppressed by approximately a factor of two in the 10% most central collisions relative to peripheral collisions. Rcp varies smoothly with centrality as characterized by the number of participating nucleons. The observed suppression is only weakly dependent on jet radius and transverse momentum. These results provide the first direct measurement of inclusive jet suppression in heavy ion collisions and complement previous measurements of dijet transverse energy imbalance at the LHC.Comment: 15 pages plus author list (30 pages total), 8 figures, 2 tables, submitted to Physics Letters B. All figures including auxiliary figures are available at http://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/HION-2011-02

Suspensión del tratamiento con inhibidores de BCR-ABL en los pacientes con leucemia mieloide crónica en respuesta molecular profunda dentro de la práctica clínica asistencial: Experiencia española en un total de 236 casos

Oral Presentation [CO-092] Introducción: La mitad de los pacientes con leucemia mieloide crónica (LMC) en respuesta molecular profunda no pierde la respuesta molecular mayor (RMM) tras la suspensión del tratamiento con inhibidores de BCR-ABL (ITC). Esta estrategia ha demostrado ser segura en ensayos clínicos pero hay poca información acerca de su aplicabilidad en la práctica clínica asistencial. El objetivo del estudio fue analizar la experiencia con la suspensión del tratamiento fuera de ensayo clínico en España. Métodos: Se analizan los resultados de 236 pacientes con LMC en fase crónica que suspendieron el tratamiento fuera de ensayo clínico en 33 hospitales. Criterios de inclusión: a) tratamiento con ITC >3 años, b) respuesta molecular grado 4.5 durante >2 años (se permitió una única determinación de RM4 durante ese período). Se excluyeron los pacientes trasplantados. Resultados: Las características de la serie se muestran en la tabla 1. Los motivos principales para suspender el tratamiento fueron los efectos secundarios (n=66), lograr la remisión libre de tratamiento (n=166) y el embarazo (n=4). La mediana de seguimiento tras la suspensión fue de 21, 5 meses y 5 pacientes fallecieron por causas no relacionadas con la LMC. Durante este periodo, 67 pacientes reiniciaron el tratamiento por recaída molecular (pérdida de RMM: n=52, aumento de tránscritos >1 log en dos controles sucesivos sin pérdida de RMM: n=12), decisión del paciente (n=2) o síndrome de discontinuación (n=1). Un paciente perdió la RMM a los 20 meses y decidió no tratarse, recuperando la RMM espontáneamente. Cuarenta y nueve recaídas (75% del total) ocurrieron en los primeros 6 meses, 8 entre los meses 7-12, y 8 tras los 12 meses, produciéndose la pérdida de RMM más tardía a los 30 meses. La supervivencia libre de reinicio del tratamiento (figura 1) y de recaída molecular fue del 66, 8% y del 67, 5% a los 3 años, respectivamente. Los factores asociados a mayor supervivencia libre de recaída fueron la duración del tratamiento con ITC >5 años (p=0.01) y la RM4.5 >4 años antes de la suspensión (p=0.017). Un total de 51 pacientes (22%) desarrollaron dolor osteomuscular tras la suspensión. No se registró ningún caso de progresión a fases avanzadas. El valor mediano de la carga de BCR-ABL al reinicio del tratamiento fue del 0, 3% (>5% en 7 casos). La mediana de seguimiento tras reinicio del tratamiento fue de 20 meses; 46 de 52 casos (88%) recuperaron la RMM tras una mediana de tiempo de 3 meses; 50 de 64 recuperaron la RM4 (mediana 3, 5 meses) y 47 de 64 recuperaron la MR4.5 (mediana 5 meses). En el último control, el estado de la respuesta fue: RM4.5 (n=195), RM4 (n=15), RMM (n=14), respuesta citogenética completa (n=10), otros (n=2). Conclusiones: los resultados confirman que la suspensión del tratamiento es factible en la práctica clínica asistencial en España. La duración del tratamiento y de la respuesta molecular profunda se asociaron con la supervivencia libre de recaída. Esta información puede ser útil para establecer recomendaciones generales acerca de la discontinuación del tratamiento de la LMC en nuestro medio