RESUMO

The members of the evolutionary conserved actin-binding Ezrin, Radixin and Moesin (ERM) protein family are involved in numerous key cellular processes in the cytoplasm. In the last decades, ERM proteins, like actin and other cytoskeletal components, have also been shown to be functional components of the nucleus; however, the molecular mechanism behind their nuclear activities remained unclear. Therefore, our primary aim was to identify the nuclear protein interactome of the single Drosophila ERM protein, Moesin. We demonstrate that Moesin directly interacts with the Mediator complex through direct binding to its Med15 subunit, and the presence of Moesin at the regulatory regions of the Hsp70Ab heat shock gene was found to be Med15-dependent. Both Moesin and Med15 bind to heat shock factor (Hsf), and they are required for proper Hsp gene expression under physiological conditions. Moreover, we confirmed that Moesin, Med15 and Hsf are able to bind the monomeric form of actin and together they form a complex in the nucleus. These results elucidate a mechanism by which ERMs function within the nucleus. Finally, we present the direct interaction of the human orthologues of Drosophila Moesin and Med15, which highlights the evolutionary significance of our finding.

Assuntos

Núcleo Celular , Proteínas de Drosophila , Resposta ao Choque Térmico , Proteínas dos Microfilamentos , Ligação Proteica , Animais , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Núcleo Celular/metabolismo , Humanos , Proteínas dos Microfilamentos/metabolismo , Proteínas dos Microfilamentos/genética , Complexo Mediador/metabolismo , Complexo Mediador/genética , Drosophila melanogaster/metabolismo , Drosophila melanogaster/genética , Actinas/metabolismo , Regulação da Expressão Gênica , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas de Membrana

Assuntos

Anticorpos Biespecíficos , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , Anticorpos Biespecíficos/uso terapêutico , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Indução de Remissão , Antineoplásicos Imunológicos/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Resultado do Tratamento

RESUMO

INTRODUCTION: After mild traumatic brain injury (mTBI), the brain is labile for weeks and months and vulnerable to repeated concussions. During this time, patients are exposed to everyday circumstances that, in themselves, affect brain metabolism and blood flow and neural processing. How commonplace activities interact with the injured brain is unknown. The present study in an animal model investigated the extent to which three commonly experienced exposures-daily caffeine usage, chronic sleep loss, and chronic sleep aid medication-affect the injured brain in the chronic phase. METHODS: Subclinical trauma by repeated mTBIs was produced by our head rotational acceleration injury model, which causes brain injury consistent with the mechanism of concussion in humans. Forty-eight hours after a third mTBI, chronic administrations of caffeine, sleep restriction, or zolpidem (sedative hypnotic) began and were continued for 70 days. On Days 30 and 60 post injury, resting state functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) were performed. RESULTS: Chronic caffeine, sleep restriction, and zolpidem each changed the subclinical brain characteristics of mTBI at both 30 and 60 days post injury, detected by different MRI modalities. Each treatment caused microstructural alterations in DTI metrics in the insular cortex and retrosplenial cortex compared with mTBI, but also uniquely affected other gray and white matter regions. Zolpidem administration affected the largest number of individual structures in mTBI at both 30 and 60 days, and not necessarily toward normalization (sham treatment). Chronic sleep restriction changed local functional connectivity at 30 days in diametrical opposition to chronic caffeine ingestion, and both treatment outcomes were different from sham, mTBI-only and zolpidem comparisons. The results indicate that commonly encountered exposures modify subclinical brain activity and structure long after healing is expected to be complete. CONCLUSIONS: Changes in activity and structure detected by fMRI are widely understood to reflect changes in the functions of the affected region which conceivably underlie mTBI neuropathology and symptomatology in the chronic phase after injury.

Assuntos

Concussão Encefálica , Cafeína , Imageamento por Ressonância Magnética , Zolpidem , Cafeína/farmacologia , Masculino , Concussão Encefálica/diagnóstico por imagem , Concussão Encefálica/patologia , Animais , Privação do Sono , Encéfalo/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Imagem de Tensor de Difusão , Ratos , Medicamentos Indutores do Sono , Estimulantes do Sistema Nervoso Central/toxicidade , Ratos Sprague-Dawley

RESUMO

The Glasgow prognostic score (GPS) and CAR-HEMATOTOX (CAR-HT) score identify multiple myeloma (MM) patients at high risk for immune-mediated toxicity and early mortality with cellular immunotherapy. However, their association with outcomes in patients receiving T-cell redirecting bispecific antibodies (bsAb) is unclear. This multi-centre retrospective study examines the association of baseline GPS and CAR-HT scores with outcomes in 126 MM patients treated with bsAb. Overall, 19% were identified as GPS high risk but did not experience increased toxicity or mortality. Conversely, high-risk CAR-HT patients had a higher incidence of infections and inferior survival, suggesting a need for aggressive infection mitigation strategies.

RESUMO

Leukemias with ambiguous lineage comprise several loosely defined entities, often without a clear mechanistic basis. Here, we extensively profile the epigenome and transcriptome of a subgroup of such leukemias with CpG Island Methylator Phenotype. These leukemias exhibit comparable hybrid myeloid/lymphoid epigenetic landscapes, yet heterogeneous genetic alterations, suggesting they are defined by their shared epigenetic profile rather than common genetic lesions. Gene expression enrichment reveals similarity with early T-cell precursor acute lymphoblastic leukemia and a lymphoid progenitor cell of origin. In line with this, integration of differential DNA methylation and gene expression shows widespread silencing of myeloid transcription factors. Moreover, binding sites for hematopoietic transcription factors, including CEBPA, SPI1 and LEF1, are uniquely inaccessible in these leukemias. Hypermethylation also results in loss of CTCF binding, accompanied by changes in chromatin interactions involving key transcription factors. In conclusion, epigenetic dysregulation, and not genetic lesions, explains the mixed phenotype of this group of leukemias with ambiguous lineage. The data collected here constitute a useful and comprehensive epigenomic reference for subsequent studies of acute myeloid leukemias, T-cell acute lymphoblastic leukemias and mixed-phenotype leukemias.

Assuntos

Ilhas de CpG , Metilação de DNA , Epigênese Genética , Redes Reguladoras de Genes , Humanos , Metilação de DNA/genética , Ilhas de CpG/genética , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Fator 1 de Ligação ao Facilitador Linfoide/genética , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Fator de Ligação a CCCTC/metabolismo , Fator de Ligação a CCCTC/genética , Regulação Leucêmica da Expressão Gênica , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Cromatina/metabolismo , Cromatina/genética , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Feminino , Hematopoese/genética , Criança , Transcriptoma , Proteínas Proto-Oncogênicas , Transativadores

RESUMO

Objective: To assess the perception of medical students at Alfaisal University College of Medicine (AUCOM) of their learning environment at a referral-based tertiary hospital in Riyadh, Saudi Arabia. Methods: The validated Dundee Ready Educational Environment Measure (DREEM) questionnaire was administered to all year 4 and year 5 students during the academic year 2020-2021. Scores were analyzed using the descriptors provided by the questionnaire developers and compared across different students' cohorts using SPSS. Results: The overall DREEM score was 120.45/200, which can be described as a "more positive than negative environment", indicating a positive perception with a potential for improvement. All domain scores were on the positive side except the "students' social self-perception" which had a score indicating a problematic area. Female students had a statistically significant more positive score in the domain "students' perception of learning" than male students. Scores for individual questions were persistently on the positive side except for eight questions that pointed to problematic areas in the curriculum. When compared between student cohorts, five questions had statistically significant difference in scores between students in both academic years, but only two of those had scores indicating concerning areas. Conclusion: Referral-based tertiary hospitals can be perceived positively by students as a learning environment in undergraduate medical education. We identified some areas of concern in our curriculum to be targeted by future research.

Assuntos

Amiloidose de Cadeia Leve de Imunoglobulina , Satisfação do Paciente , Telemedicina , Humanos , Masculino , Feminino , Amiloidose de Cadeia Leve de Imunoglobulina/terapia , Amiloidose de Cadeia Leve de Imunoglobulina/diagnóstico , Pessoa de Meia-Idade , Idoso

Assuntos

Neoplasias do Sistema Nervoso Central , Imunoterapia Adotiva , Linfoma de Célula do Manto , Humanos , Linfoma de Célula do Manto/terapia , Linfoma de Célula do Manto/patologia , Imunoterapia Adotiva/métodos , Neoplasias do Sistema Nervoso Central/terapia , Masculino , Pessoa de Meia-Idade , Idoso , Feminino , Receptores de Antígenos Quiméricos , Resultado do Tratamento

RESUMO

Cytokine release syndrome (CRS) occurs frequently after haplo-identical allogeneic stem cell transplantation (alloSCT) with post-transplant cyclophosphamide (PTCy), increasing nonrelapse mortality (NRM) and decreasing survival. Data on CRS in HLA-matched alloSCT are limited and effects of specific HLA-mismatches on CRS development unknown. We hypothesized that in HLA-matched alloSCT increasing degrees of HLA-mismatching influence CRS incidence, NRM and survival. Retrospective analysis of 126 HLA-matched PTCy-alloSCT patients showed that higher degrees of HLA-mismatching significantly increased CRS incidence (26%, 75% and 90% CRS with 12/12, 10/10 and 9/10 matched donors, respectively). Maximum temperature during CRS increased with higher HLA-mismatch. Specific associations between HLA-mismatches and CRS could be determined. Grade 2 CRS and CRS-induced grade 3 fever were associated with significantly increased NRM (p < 0.001 and p = 0.003, respectively) and inferior survival (p < 0.001 and p = 0.005, respectively). NRM was mainly caused by disease conditions that may be considered CRS-induced inflammatory responses (encephalopathy, cryptogenic organizing pneumonia and multi-organ failure).

Assuntos

Ciclofosfamida , Síndrome da Liberação de Citocina , Antígenos HLA , Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Transplante Homólogo , Humanos , Masculino , Feminino , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/mortalidade , Pessoa de Meia-Idade , Ciclofosfamida/uso terapêutico , Adulto , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Incidência , Antígenos HLA/imunologia , Antígenos HLA/genética , Transplante Homólogo/efeitos adversos , Estudos Retrospectivos , Idoso , Adulto Jovem , Adolescente , Histocompatibilidade , Doença Enxerto-Hospedeiro/etiologia , Condicionamento Pré-Transplante/métodos , Imunossupressores/uso terapêutico

RESUMO

Background: KRAS wild-type (WT) pancreatic ductal adenocarcinoma (PDAC) represents a distinct entity with unique biology. The therapeutic impact of matched targeted therapy in these patients in a real-world setting, to date, is less established. Objectives: The aim of our study was to review our institutional database to identify the prevalence of actionable genomic alterations in patients with KRAS-WT tumors and to evaluate the therapeutic impact of matched targeted therapy in these patients. Design: We reviewed electronic medical records of patients with KRAS-WT PDAC and advanced disease (n = 14) who underwent clinical-grade tissue ± liquid next-generation sequencing (315-648 genes for tissue) between years 2015 and 2021. Methods: Demographic and disease characteristics were summarized using descriptive parameters. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results: Of 236 PDAC patients, 14 had advanced/metastatic disease with KRAS-WT tumors. Median age at diagnosis was 66 years. There was a high frequency of potentially actionable genomic alterations, including three (21%) with BRAF alterations, two (14%) with fusions [RET-PCM1 and FGFR2-POC1B (N = 1 each)]; and one with a druggable EGFR (EGFR E746_A755delISERD) variant; two other patients had an STK11 and a MUTYH alteration. Five patients were treated with matched targeted therapy, with three having durable benefit: (i) erlotinib for EGFR-altered tumor, followed by osimertinib/capmatinib when MET amplification emerged (first-line therapy); (ii) pralsetinib for RET fusion (fifth line); and (iii) dabrafenib/trametinib for BRAF N486_P490del (third line). Duration of time on chemotherapy-free matched targeted therapy for these patients was 17+, 11, and 18+ months, respectively. Conclusion: Sustained therapeutic benefit can be achieved in a real-world setting in a subset of patients with advanced/metastatic KRAS-WT PDAC treated with chemotherapy-free matched targeted agents. Prospective studies are warranted.

RESUMO

BACKGROUND: Retained hemothorax (rHTX) requiring intervention occurs in up to 20% of patients who undergo chest tube (TT) placement for a hemothorax (HTX). Thoracic irrigation at the time of TT placement decreases the need for secondary intervention in this patient group but those findings are limited because of the single center design. A multi-center study was conducted to evaluate the effectiveness of thoracic irrigation. METHODS: A multi-center, prospective, observational study was conducted between June 2018 and July 2023. Eleven sites contributed patients. Patients were included if they had a TT placed for a HTX and were excluded if: age < 18 years, TT for pneumothorax, thoracotomy or VATS performed within 6 hours of TT, TT >24 hours after injury, TT removed <24 hours, or death within 48 hours. Thoracic irrigation was performed at the discretion of the attending. Each hemithorax was considered separately if bilateral HTX. The primary outcome was secondary intervention for HTX-related complications (rHTX, effusion, or empyema). Secondary intervention was defined as: TT placement, instillation of thrombolytics, VATS, or thoracotomy. Irrigated and non-irrigated hemithoraces were compared using a propensity weighted analysis with age, sex, mechanism of injury, Abbreviated Injury Scale (AIS) chest and TT size as predictors. RESULTS: 493 patients with 462 treated hemothoraces were included, 123 (25%) had thoracic irrigation at TT placement. There were no significant demographic differences between the cohorts. Fifty-seven secondary interventions were performed, 10 (8%) and 47 (13%) in the irrigated and non-irrigated groups, respectively (p = 0.015). Propensity weighted analysis demonstrated a reduction in secondary interventions in the irrigated cohort (Odds Ratio 0.56 (0.34-0.85); p = 0.005). CONCLUSION: This Western Trauma Association multi-center study demonstrates a benefit of thoracic irrigation at the time of TT placement for a HTX. Thoracic irrigation reduces the odds of a secondary intervention for rHTX-related complications by 44%. LEVEL OF EVIDENCE: Therapeutic Study, Level II.

RESUMO

It is well-established that most patients with systemic light chain (AL) amyloidosis have multi-organ involvement and are often diagnosed after a lag period of increasing symptoms. We leverage electronic health record (EHR) data from the TriNetX research network to describe the incidence, timing, and co-occurrence of precursor conditions of interests in a cohort of AL amyloidosis patients identified between October 2015-December 2020. Nineteen precursor diagnoses of interest representing features of AL amyloidosis were identified using ICD codes up to 36 months prior to AL amyloidosis diagnosis. Among 1,401 patients with at least 36 months of EHR data prior to AL amyloidosis diagnosis, 46% were females, 16% were non-Hispanic Black, and 6% were Hispanic. The median age was 71 (range, 21-91) years. The median number of precursor diagnoses was 5 with dyspnea and fatigue being the most prevalent. The time from the first occurrence of a precursor to AL diagnosis ranged from 3.2 to 21.4 months. Analyses of pairwise co-occurrence of specific diagnoses indicated a high association (Cole's coefficient >0.6) among the examined precursor diagnoses. These findings provide novel information about the timing and co-occurrence of key precursor conditions and could be used to develop algorithms for early identification of AL amyloidosis.

Assuntos

Amiloidose de Cadeia Leve de Imunoglobulina , Humanos , Feminino , Masculino , Idoso , Amiloidose de Cadeia Leve de Imunoglobulina/diagnóstico , Amiloidose de Cadeia Leve de Imunoglobulina/epidemiologia , Pessoa de Meia-Idade , Adulto , Idoso de 80 Anos ou mais , Adulto Jovem , Fatores de Tempo , Registros Eletrônicos de Saúde

RESUMO

BACKGROUND: Neck pain in a concussion population is an emerging area of study that has been shown to have a negative influence on recovery. This effect has not yet been studied in collegiate athletes. HYPOTHESIS: New or worsened neck pain is common after a concussion (>30%), negatively influences recovery, and is associated with patient sex and level of contact in sport. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Varsity-level athletes from 29 National Collegiate Athletic Association member institutions as well as nonvarsity sport athletes at military service academies were eligible for enrollment. Participants completed a preseason baseline assessment and follow-up assessments at 6 and 24 to 48 hours after a concussion, when they were symptom-free, and when they returned to unrestricted play. Data collection occurred between January 2014 and September 2018. RESULTS: A total of 2163 injuries were studied. New or worsened neck pain was reported with 47.0% of injuries. New or worsened neck pain was associated with patient sex (higher in female athletes), an altered mental status after the injury, the mechanism of injury, and what the athlete collided with. The presence of new/worsened neck pain was associated with delayed recovery. Those with new or worsened neck pain had 11.1 days of symptoms versus 8.8 days in those without (P < .001). They were also less likely to have a resolution of self-reported symptoms in ≤7 days (P < .001). However, the mean duration of the return-to-play protocol was not significantly different for those with new or worsened neck pain (7.5 ± 7.7 days) than those without (7.4 ± 8.3 days) (P = .592). CONCLUSION: This novel study shows that neck pain was common in collegiate athletes sustaining a concussion, was influenced by many factors, and negatively affected recovery.

Assuntos

Traumatismos em Atletas , Concussão Encefálica , Cervicalgia , Humanos , Masculino , Feminino , Cervicalgia/etiologia , Cervicalgia/epidemiologia , Concussão Encefálica/complicações , Concussão Encefálica/epidemiologia , Traumatismos em Atletas/epidemiologia , Adulto Jovem , Prevalência , Atletas/estatística & dados numéricos , Universidades , Adolescente , Volta ao Esporte , Estudos de Coortes , Fatores Sexuais

RESUMO

Background: Tiered trauma team activation (TTA) allows systems to optimally allocate resources to an injured patient. Target undertriage and overtriage rates of <5% and <35% are difficult for centers to achieve, and performance variability exists. The objective of this study was to optimize and externally validate a previously developed hospital trauma triage prediction model to predict the need for emergent intervention in 6 hours (NEI-6), an indicator of need for a full TTA. Methods: The model was previously developed and internally validated using data from 31 US trauma centers. Data were collected prospectively at five sites using a mobile application which hosted the NEI-6 model. A weighted multiple logistic regression model was used to retrain and optimize the model using the original data set and a portion of data from one of the prospective sites. The remaining data from the five sites were designated for external validation. The area under the receiver operating characteristic curve (AUROC) and the area under the precision-recall curve (AUPRC) were used to assess the validation cohort. Subanalyses were performed for age, race, and mechanism of injury. Results: 14 421 patients were included in the training data set and 2476 patients in the external validation data set across five sites. On validation, the model had an overall undertriage rate of 9.1% and overtriage rate of 53.7%, with an AUROC of 0.80 and an AUPRC of 0.63. Blunt injury had an undertriage rate of 8.8%, whereas penetrating injury had 31.2%. For those aged ≥65, the undertriage rate was 8.4%, and for Black or African American patients the undertriage rate was 7.7%. Conclusion: The optimized and externally validated NEI-6 model approaches the recommended undertriage and overtriage rates while significantly reducing variability of TTA across centers for blunt trauma patients. The model performs well for populations that traditionally have high rates of undertriage. Level of evidence: 2.

Assuntos

Neoplasias do Sistema Nervoso Central , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Humanos , Neoplasias do Sistema Nervoso Central/terapia , Masculino , Feminino , Receptores de Antígenos Quiméricos/uso terapêutico , Pessoa de Meia-Idade , Idoso , Adulto , Linfoma/terapia

RESUMO

Azacitidine/venetoclax is an active regimen in patients with newly diagnosed acute myeloid leukemia (AML). However, primary or secondary resistance to azacitidine/venetoclax is an area of unmet need and overexpression of MCL1 is suggested to be a potential resistance mechanism. Pevonedistat inhibits MCL1 through activation of NOXA, and pevonedistat/azacitidine has previously shown activity in AML. To assess the tolerability and efficacy of adding pevonedistat to azacitidine/ venetoclax in relapsed/refractory AML, we conducted a phase I, multicenter, open-label study in 16 adults with relapsed/ refractory AML. Patients were treated with azacitidine, venetoclax along with pevonedistat intravenously on days 1, 3 and 5 of each 28-day cycle at doses of 10, 15 or 20 mg/m2 in successive cohorts in the dose escalation phase. The impact of treatment on protein neddylation as well as expression of pro-apoptotic BCL2 family members was assessed. The recommended phase II dose of pevonedistat was 20 mg/m2. Grade 3 or higher adverse events included neutropenia (31%), thrombocytopenia (13%), febrile neutropenia (19%), anemia (19%), hypertension (19%) and sepsis (19%). The overall response rate was 46.7% for the whole cohort including complete remission in five of seven (71.4%) patients who had not previously been treated with the hypomethylating agent/venetoclax. No measurable residual disease was detected in 80.0% of the patients who achieved complete remission. The median time to best response was 50 (range, 23-77) days. Four patients were bridged to allogeneic stem cell transplantation. The combination of azacitidine, venetoclax and pevonedistat is safe and shows encouraging preliminary activity in patients with relapsed/refractory AML. (NCT04172844).

Assuntos

Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina , Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Pirimidinas , Sulfonamidas , Humanos , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Azacitidina/administração & dosagem , Azacitidina/uso terapêutico , Azacitidina/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adulto , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversos , Naftiridinas/uso terapêutico , Naftiridinas/administração & dosagem , Recidiva , Resultado do Tratamento , Resistencia a Medicamentos Antineoplásicos , Idoso de 80 Anos ou mais , Ciclopentanos

RESUMO

Neuroinflammation is a recognized complication of immunotherapeutic approaches such as immune checkpoint inhibitor treatment, chimeric antigen receptor therapy, and graft versus host disease (GVHD) occurring after allogeneic hematopoietic stem cell transplantation. While T cells and inflammatory cytokines play a role in this process, the precise interplay between the adaptive and innate arms of the immune system that propagates inflammation in the central nervous system remains incompletely understood. Using a murine model of GVHD, we demonstrate that type 2 cannabinoid receptor (CB2R) signaling plays a critical role in the pathophysiology of neuroinflammation. In these studies, we identify that CB2R expression on microglial cells induces an activated inflammatory phenotype that potentiates the accumulation of donor-derived proinflammatory T cells, regulates chemokine gene regulatory networks, and promotes neuronal cell death. Pharmacological targeting of this receptor with a brain penetrant CB2R inverse agonist/antagonist selectively reduces neuroinflammation without deleteriously affecting systemic GVHD severity. Thus, these findings delineate a therapeutically targetable neuroinflammatory pathway and have implications for the attenuation of neurotoxicity after GVHD and potentially other T cell-based immunotherapeutic approaches.

Assuntos

Doença Enxerto-Hospedeiro , Microglia , Doenças Neuroinflamatórias , Receptor CB2 de Canabinoide , Animais , Camundongos , Aloenxertos , Modelos Animais de Doenças , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Camundongos Knockout , Microglia/metabolismo , Microglia/imunologia , Microglia/patologia , Doenças Neuroinflamatórias/imunologia , Doenças Neuroinflamatórias/patologia , Doenças Neuroinflamatórias/metabolismo , Receptor CB2 de Canabinoide/genética , Receptor CB2 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Masculino

RESUMO

The objective of our study was to report real-world data on the safety and efficacy of standard-of-care teclistamab in patients with relapsed/refractory multiple myeloma (MM). This is a multi-institutional retrospective cohort study and included all consecutive patients that received at least one dose of teclistamab up until August 2023. One hundred and ten patients were included, of whom, 86% had triple-class refractory disease, 76% penta-refractory disease, and 35% had prior exposure to B-cell maturation antigen (BCMA)-targeting therapies. The overall response rate (ORR) in our cohort was 62%, with a ≥ very good partial remission (VGPR) rate of 51%. The ORR in patients with and without prior BCMA-targeted therapies was 54% vs 67%, respectively (p = 0.23). At a median follow-up of 3.5 months (range, 0.39-10.92), the estimated 3 month and 6 month progression free survival (PFS) was 57% (95% CI, 48%, 68%) and 52% (95% CI, 42%, 64%) respectively. The incidence of cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) was 56% and 11% respectively, with grade ≥3 CRS and ICANS noted in 3.5% and 4.6% of patients respectively. 78 unique infections were diagnosed in 44 patients, with the incidence of all-grade and grade ≥3 infections being 40% vs 26% respectively. Primary prophylaxis with intravenous immunoglobulin (IVIG) was associated with a significantly lower infection risk on multivariate analysis (Hazard ratio [HR] 0.33; 95% CI 0.17, 0.64; p = 0.001).

Assuntos

Anticorpos Biespecíficos , Antineoplásicos , Mieloma Múltiplo , Neoplasias de Plasmócitos , Tetranitrato de Pentaeritritol , Humanos , Mieloma Múltiplo/tratamento farmacológico , Antígeno de Maturação de Linfócitos B , Estudos Retrospectivos

RESUMO

In the last decade, novel agents such as BTK and BCL-2 inhibitors have revolutionized treatment of CLL/SLL, with clinical trials showing improved overall survival compared to chemotherapeutic agents. However, studies examining whether they have improved overall survival at the population level are lacking. We evaluated this by conducting a retrospective analysis of CLL/SLL patients registered in the National Cancer Institute's surveillance epidemiology and end results (SEER) database, analyzing overall survival (OS) in periods pre- and post-availability of novel agents, along with demographic information. Our results showed that median OS significantly improved over time [7.8 years (2000-2005), 9.1 years (2006-2013), and not reached (2014-2018) (p < 0.001)]. Compared to diagnosis in 2014-2018, diagnosis in earlier periods was associated with higher mortality risk (2000-2005-HR 1.32, 95 % CI 1.28-1.37, p < 0.001: 2006-2013-HR 1.09, 95 % CI 1.06-1.13, p < 0.001). Lower mortality risk was seen in patients age < 85 years whereas median household income of <$75000 was associated with higher mortality. Our study provides real-world data suggesting a possible multifactorial contribution to improvement in survival, including availability of novel agents, better monitoring, and supportive care. They also show discrepancies in overall survival for CLL/SLL patients due to socioeconomic status and demographic factors.

Assuntos

Leucemia Linfocítica Crônica de Células B , Programa de SEER , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/epidemiologia , Leucemia Linfocítica Crônica de Células B/terapia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso de 80 Anos ou mais , Adulto , Sistema de Registros , Taxa de Sobrevida , Estados Unidos/epidemiologia , Resultado do Tratamento

RESUMO

The ERM protein family, which consists of three closely related proteins in vertebrates, ezrin, radixin, and moesin (ERM), is an ancient and important group of cytoplasmic actin-binding and organizing proteins. With their FERM domain, ERMs bind various transmembrane proteins and anchor them to the actin cortex through their C-terminal F-actin binding domain, thus they are major regulators of actin dynamics in the cell. ERMs participate in many fundamental cellular processes, such as phagocytosis, microvilli formation, T-cell activation and tumor metastasis. We have previously shown that, besides its cytoplasmic activities, the single ERM protein of Drosophila melanogaster, moesin, is also present in the cell nucleus, where it participates in gene expression and mRNA export. Here we study the mechanism by which moesin enters the nucleus. We show that the nuclear import of moesin is an NLS-mediated, active process. The nuclear localization sequence of the moesin protein is an evolutionarily highly conserved, conventional bipartite motif located on the surface of the FERM domain. Our experiments also reveal that the nuclear import of moesin does not require PIP2 binding or protein activation, and occurs in monomeric form. We propose, that the balance between the phosphorylated and non-phosphorylated protein pools determines the degree of nuclear import of moesin.