NAP1L1-MLLT10 is a rare recurrent translocation that is associated with HOXA activation and poor treatment response in T-cell acute lymphoblastic leukaemia

International audienceno abstrac

Trayecto terapéutico de receptores de trasplante de células madre hematopoyéticas: una perspectiva de farmacéuticos hospitalarios

Introduction: Patients undergoing allogeneic and autologous hematopoietic stem cell transplantation (Allo-HSCT and Auto-HSCT) are at risk of pharmacotherapy-related problems. Objective: To describe in Allo-HSCT and Auto-HSCT patients from admission to hospital discharge, their therapeutic profile, and the time-course of biomarkers of renal and liver dysfunction, and of inflammation to display a more specific overview of drug therapy in HSCT patients. Method: Data were retrospectively extracted from the charts of 20 Allo-HSCT and 20 Auto-HSCT patients. The therapeutic pathway was described by the turn-over of drug treatments, the potentially inappropriate medications by using the GO-PIM scale, and the anticholinergic burden. Patho-physiological variations affecting clearance organs were characterized by the C-Reactive Protein (CRP) levels, and the hepatic and renal impairment evaluation tools (Model for End-stage Liver Disease score: MELD score, and glomerular filtration rate: GFR). Results: Compared to Auto-HSCT patients, Allo-HSCT patients had a higher number of drugs initiated during hospital stay leading to hyper-polypharmacy during the stay and at discharge. Around 35 % of drugs used were metabolized by CYP3A4 in HSCT patients. Anticholinergic burden increased at discharge in HSCT patients. Auto-HSCT patients ≥ 65 years were taking at least one PIM. High CRP levels were reported in HSCT recipients. MELD score increased and GFR decreased in Allo-HSCT patients while GFR slightly increased in Auto-HSCT patients. Conclusion: Clinical pharmacist should target polypharmacy, PIM and anticholinergic burden, and evaluate inflammation and both renal and hepatic functions in order to thoughtfully assess the clearance potential of patients and to suggest individualized dosing.Introducción: Pacientes de trasplante de células madre hematopoyéticas autólogo y alogénico (Alo-TCMH y Auto-TCMH) enfrentan riesgos farmacoterapéuticos. Objetivo: Detallar el perfil terapéutico y la evolución de biomarcadores de disfunción renal, hepática e inflamatoria en pacientes de Alo- y Auto-TCMH desde su ingreso hasta el alta hospitalaria, ofreciendo una perspectiva detallada del manejo farmacológico. Método: Se extrajeron datos retrospectivos de las historias clínicas de 20 pacientes de Alo-TCMH y 20 de Auto-TCMH. Se describió el trayecto terapéutico mediante el cambio de tratamientos farmacológicos, los medicamentos potencialmente inapropiados utilizando la escala GO-PIM, y la carga anticolinérgica (CA). Se evaluaron las variaciones fisiopatológicas afectando órganos de eliminación, mediante niveles de proteína C reactiva (PCR), puntuación para la enfermedad hepática en etapa terminal (puntuación MELD) y filtración glomerular (FG). Resultados: Alo-TCMH pacientes tuvieron un mayor número de fármacos iniciados durante la estancia hospitalaria, lo que llevó a una hiperpolifarmacia durante la estancia y al alta. Un 35% de los medicamentos usados eran metabolizados por CYP3A4. CA aumentó al alta en pacientes de HSCT. Los pacientes de Auto-TCMH ≥ 65 años tomaban al menos un PIM. Se informaron niveles altos de CRP en los receptores de TCMH. Puntuación MELD aumentó y la GFR disminuyó en pacientes de Alo-TCMH mientras que la FG aumentó ligeramente en pacientes de Auto-TCMH. Conclusión: El farmacéutico clínico debe enfocarse en la polifarmacia, PIM y CA, y evaluar la inflamación y las funciones renales y hepáticas para evaluar de manera reflexiva el potencial de depuración de los pacientes y sugerir dosificaciones individualizadas

Toll-like receptor signaling adapter proteins govern spread of neuropathic pain and recovery following nerve injury in male mice.

BackgroundSpinal Toll-like receptors (TLRs) and signaling intermediaries have been implicated in persistent pain states. We examined the roles of two major TLR signaling pathways and selected TLRs in a mononeuropathic allodynia.MethodsL5 spinal nerve ligation (SNL) was performed in wild type (WT, C57BL/6) male and female mice and in male Tlr2-/-Tlr3-/-, Tlr4-/-, Tlr5-/-, Myd88-/-, Triflps2, Myd88/Triflps2, Tnf-/-, and Ifnar1-/- mice. We also examined L5 ligation in Tlr4-/- female mice. We examined tactile allodynia using von Frey hairs. Iba-1 (microglia) and GFAP (astrocytes) were assessed in spinal cords by immunostaining. Tactile thresholds were analyzed by 1- and 2-way ANOVA and the Bonferroni post hoc test was used.ResultsIn WT male and female mice, SNL lesions resulted in a persistent and robust ipsilateral, tactile allodynia. In males with TLR2, 3, 4, or 5 deficiencies, tactile allodynia was significantly, but incompletely, reversed (approximately 50%) as compared to WT. This effect was not seen in female Tlr4-/- mice. Increases in ipsilateral lumbar Iba-1 and GFAP were seen in mutant and WT mice. Mice deficient in MyD88, or MyD88 and TRIF, showed an approximately 50% reduction in withdrawal thresholds and reduced ipsilateral Iba-1. In contrast, TRIF and interferon receptor null mice developed a profound ipsilateral and contralateral tactile allodynia. In lumbar sections of the spinal cords, we observed a greater increase in Iba-1 immunoreactivity in the TRIF-signaling deficient mice as compared to WT, but no significant increase in GFAP. Removing MyD88 abrogated the contralateral allodynia in the TRIF signaling-deficient mice. Conversely, IFNβ, released downstream to TRIF signaling, administered intrathecally, temporarily reversed the tactile allodynia.ConclusionsThese observations suggest a critical role for the MyD88 pathway in initiating neuropathic pain, but a distinct role for the TRIF pathway and interferon in regulating neuropathic pain phenotypes in male mice

Trayecto terapéutico de receptores de trasplante de células madre hematopoyéticas: una perspectiva de farmacéuticos hospitalarios

Introduction: Patients undergoing allogeneic and autologous hematopoietic stem cell transplantation (Allo-HSCT and Auto-HSCT) are at risk of pharmacotherapy-related problems. Objective: To describe in Allo-HSCT and Auto-HSCT patients from admission to hospital discharge, their therapeutic profile, and the time-course of biomarkers of renal and liver dysfunction, and of inflammation to display a more specific overview of drug therapy in HSCT patients. Method: Data were retrospectively extracted from the charts of 20 Allo-HSCT and 20 Auto-HSCT patients. The therapeutic pathway was described by the turn-over of drug treatments, the potentially inappropriate medications by using the GO-PIM scale, and the anticholinergic burden. Patho-physiological variations affecting clearance organs were characterized by the C-Reactive Protein (CRP) levels, and the hepatic and renal impairment evaluation tools (Model for End-stage Liver Disease score: MELD score, and glomerular filtration rate: GFR). Results: Compared to Auto-HSCT patients, Allo-HSCT patients had a higher number of drugs initiated during hospital stay leading to hyper-polypharmacy during the stay and at discharge. Around 35 % of drugs used were metabolized by CYP3A4 in HSCT patients. Anticholinergic burden increased at discharge in HSCT patients. Auto-HSCT patients ≥ 65 years were taking at least one PIM. High CRP levels were reported in HSCT recipients. MELD score increased and GFR decreased in Allo-HSCT patients while GFR slightly increased in Auto-HSCT patients. Conclusion: Clinical pharmacist should target polypharmacy, PIM and anticholinergic burden, and evaluate inflammation and both renal and hepatic functions in order to thoughtfully assess the clearance potential of patients and to suggest individualized dosing.Introducción: Pacientes de trasplante de células madre hematopoyéticas autólogo y alogénico (Alo-TCMH y Auto-TCMH) enfrentan riesgos farmacoterapéuticos. Objetivo: Detallar el perfil terapéutico y la evolución de biomarcadores de disfunción renal, hepática e inflamatoria en pacientes de Alo- y Auto-TCMH desde su ingreso hasta el alta hospitalaria, ofreciendo una perspectiva detallada del manejo farmacológico. Método: Se extrajeron datos retrospectivos de las historias clínicas de 20 pacientes de Alo-TCMH y 20 de Auto-TCMH. Se describió el trayecto terapéutico mediante el cambio de tratamientos farmacológicos, los medicamentos potencialmente inapropiados utilizando la escala GO-PIM, y la carga anticolinérgica (CA). Se evaluaron las variaciones fisiopatológicas afectando órganos de eliminación, mediante niveles de proteína C reactiva (PCR), puntuación para la enfermedad hepática en etapa terminal (puntuación MELD) y filtración glomerular (FG). Resultados: Alo-TCMH pacientes tuvieron un mayor número de fármacos iniciados durante la estancia hospitalaria, lo que llevó a una hiperpolifarmacia durante la estancia y al alta. Un 35% de los medicamentos usados eran metabolizados por CYP3A4. CA aumentó al alta en pacientes de HSCT. Los pacientes de Auto-TCMH ≥ 65 años tomaban al menos un PIM. Se informaron niveles altos de CRP en los receptores de TCMH. Puntuación MELD aumentó y la GFR disminuyó en pacientes de Alo-TCMH mientras que la FG aumentó ligeramente en pacientes de Auto-TCMH. Conclusión: El farmacéutico clínico debe enfocarse en la polifarmacia, PIM y CA, y evaluar la inflamación y las funciones renales y hepáticas para evaluar de manera reflexiva el potencial de depuración de los pacientes y sugerir dosificaciones individualizadas

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Allogeneic stem cell transplant in patients with acute myeloid leukemia and karnofsky performance status score less than or equal to 80% : A study from the acute leukemia working party of the European Society for Blood and Marrow Transplantation (EBMT)

Limited data are currently available on the outcome of patients with acute myeloid leukemia (AML) undergoing allogeneic stem cell transplantation (allo-SCT) with a reduced performance status. We herein present the results of a registry study on 2,936 AML patients undergoing allo-SCT in first remission (CR1) with a Karnofsky Performance Status (KPS) score less than or equal to 80%. Two-year leukemia-free survival (LFS), overall survival (OS) and graft-versus-host disease (GVHD)-free, and relapse-free survival (GRFS) rates were 54%, 59%, and 41%, respectively. In multivariable analysis, patients with a KPS score = 80% had lower non-relapse mortality (NRM) and superior OS in comparison to patients with a KPS scorePeer reviewe

Impact of Individual Level Uncertainty of Lung Cancer Polygenic Risk Score (Prs) on Risk Stratification

BACKGROUND: Although polygenic risk score (PRS) has emerged as a promising tool for predicting cancer risk from genome-wide association studies (GWAS), the individual-level accuracy of lung cancer PRS and the extent to which its impact on subsequent clinical applications remains largely unexplored. METHODS: Lung cancer PRSs and confidence/credible interval (CI) were constructed using two statistical approaches for each individual: (1) the weighted sum of 16 GWAS-derived significant SNP loci and the CI through the bootstrapping method (PRS-16-CV) and (2) LDpred2 and the CI through posteriors sampling (PRS-Bayes), among 17,166 lung cancer cases and 12,894 controls with European ancestry from the International Lung Cancer Consortium. Individuals were classified into different genetic risk subgroups based on the relationship between their own PRS mean/PRS CI and the population level threshold. RESULTS: Considerable variances in PRS point estimates at the individual level were observed for both methods, with an average standard deviation (s.d.) of 0.12 for PRS-16-CV and a much larger s.d. of 0.88 for PRS-Bayes. Using PRS-16-CV, only 25.0% of individuals with PRS point estimates in the lowest decile of PRS and 16.8% in the highest decile have their entire 95% CI fully contained in the lowest and highest decile, respectively, while PRS-Bayes was unable to find any eligible individuals. Only 19% of the individuals were concordantly identified as having high genetic risk (\u3e 90th percentile) using the two PRS estimators. An increased relative risk of lung cancer comparing the highest PRS percentile to the lowest was observed when taking the CI into account (OR = 2.73, 95% CI: 2.12-3.50, P-value = 4.13 × 10 CONCLUSIONS: Lung cancer PRS estimates using different methods have modest correlations at the individual level, highlighting the importance of considering individual-level uncertainty when evaluating the practical utility of PRS

Impact of individual level uncertainty of lung cancer polygenic risk score (PRS) on risk stratification

Abstract Background Although polygenic risk score (PRS) has emerged as a promising tool for predicting cancer risk from genome-wide association studies (GWAS), the individual-level accuracy of lung cancer PRS and the extent to which its impact on subsequent clinical applications remains largely unexplored. Methods Lung cancer PRSs and confidence/credible interval (CI) were constructed using two statistical approaches for each individual: (1) the weighted sum of 16 GWAS-derived significant SNP loci and the CI through the bootstrapping method (PRS-16-CV) and (2) LDpred2 and the CI through posteriors sampling (PRS-Bayes), among 17,166 lung cancer cases and 12,894 controls with European ancestry from the International Lung Cancer Consortium. Individuals were classified into different genetic risk subgroups based on the relationship between their own PRS mean/PRS CI and the population level threshold. Results Considerable variances in PRS point estimates at the individual level were observed for both methods, with an average standard deviation (s.d.) of 0.12 for PRS-16-CV and a much larger s.d. of 0.88 for PRS-Bayes. Using PRS-16-CV, only 25.0% of individuals with PRS point estimates in the lowest decile of PRS and 16.8% in the highest decile have their entire 95% CI fully contained in the lowest and highest decile, respectively, while PRS-Bayes was unable to find any eligible individuals. Only 19% of the individuals were concordantly identified as having high genetic risk (&gt; 90th percentile) using the two PRS estimators. An increased relative risk of lung cancer comparing the highest PRS percentile to the lowest was observed when taking the CI into account (OR = 2.73, 95% CI: 2.12–3.50, P-value = 4.13 × 10−15) compared to using PRS-16-CV mean (OR = 2.23, 95% CI: 1.99–2.49, P-value = 5.70 × 10−46). Improved risk prediction performance with higher AUC was consistently observed in individuals identified by PRS-16-CV CI, and the best performance was achieved by incorporating age, gender, and detailed smoking pack-years (AUC: 0.73, 95% CI = 0.72–0.74). Conclusions Lung cancer PRS estimates using different methods have modest correlations at the individual level, highlighting the importance of considering individual-level uncertainty when evaluating the practical utility of PRS. </jats:sec