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ABSTRACT: Lisocabtagene maraleucel (liso-cel) demonstrated significant efficacy with a manageable safety profile as third-line or later treatment for patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) in the TRANSCEND NHL 001 study. Primary end points were adverse events (AEs), dose-limiting toxicities, and objective response rate (ORR) per independent review committee. Key secondary end points were complete response (CR) rate, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). After 2-year follow-up, patients could enroll in a separate study assessing long-term (≤15 years) safety and OS. Liso-cel-treated patients (N = 270) had a median age of 63 years (range, 18-86 years) and a median of 3 prior lines (range, 1-8) of systemic therapy, and 181 of them (67%) had chemotherapy-refractory LBCL. Median follow-up was 19.9 months. In efficacy-evaluable patients (N = 257), the ORR was 73% and CR rate was 53%. The median (95% confidence interval) DOR, PFS, and OS were 23.1 (8.6 to not reached), 6.8 (3.3-12.7), and 27.3 months (16.2-45.6), respectively. Estimated 2-year DOR, PFS, and OS rates were 49.5%, 40.6%, and 50.5%, respectively. In the 90-day treatment-emergent period (N = 270), grade 3 to 4 cytokine release syndrome and neurological events occurred in 2% and 10% of patients, respectively. The most common grade ≥3 AEs in treatment-emergent and posttreatment-emergent periods, respectively, were neutropenia (60% and 7%) and anemia (37% and 6%). Liso-cel demonstrated durable remissions and a manageable safety profile with no new safety signals during the 2-year follow-up in patients with R/R LBCL. These trials were registered at www.ClinicalTrials.gov as #NCT02631044 and #NCT03435796.
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Linfoma de Células B Grandes Difuso , Neutropenia , Humanos , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Estudios de Seguimiento , Recurrencia Local de Neoplasia/etiología , Linfoma de Células B Grandes Difuso/terapia , Neutropenia/etiología , Inmunoterapia Adoptiva/efectos adversosRESUMEN
The synthesis of 24 hybrid molecules, consisting of naturally occurring sclareol (SCL) and synthetic 1,2,4-triazolo[1,5-a]pyrimidines (TPs), is described. New compounds were designed with the aim of improving the cytotoxic properties, activity, and selectivity of the parent compounds. Six analogs (12a-f) contained 4-benzylpiperazine linkage, while 4-benzyldiamine linkage was present in eighteen derivatives (12g-r and 13a-f). Hybrids 13a-f consist of two TP units. After purification, all hybrids (12a-r and 13a-f), as well as their precursors (9a-e and 11a-c), were tested on human glioblastoma U87 cells. More than half of the tested synthesized molecules, 16 out of 31, caused a significant reduction of U87 cell viability (more than 75% reduction) at 30 µM. The concentration-dependent cytotoxicity of these 16 compounds was also examined on U87 cells, corresponding multidrug-resistant (MDR) U87-TxR cells with increased P-glycoprotein (P-gp) expression and activity, and normal lung fibroblasts MRC-5. Importantly, 12l and 12r were active in the nanomolar range, while seven compounds (11b, 11c, 12i, 12l, 12n, 12q, and 12r) were more selective towards glioblastoma cells than SCL. All compounds except 12r evaded MDR, showing even better cytotoxicity in U87-TxR cells. In particular, 11c, 12a, 12g, 12j, 12k, 12m, 12n, and SCL showed collateral sensitivity. Hybrid compounds 12l, 12q, and 12r decreased P-gp activity to the same extent as a well-known P-gp inhibitor - tariquidar (TQ). Hybrid compound 12l and its precursor 11c affected different cellular processes including the cell cycle, cell death, and mitochondrial membrane potential, and changed the levels of reactive oxygen and nitrogen species (ROS/RNS) in glioblastoma cells. Collateral sensitivity towards MDR glioblastoma cells was caused by the modulation of oxidative stress accompanied by inhibition of mitochondria.
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Antineoplásicos , Glioblastoma , Humanos , Línea Celular Tumoral , Sensibilidad Colateral al uso de Fármacos , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Glioblastoma/tratamiento farmacológico , Pirimidinas/farmacología , Pirimidinas/uso terapéuticoRESUMEN
Rationale: Sensitization to Fel d 1 (Felis domesticus allergen 1) contributes to persistent allergic rhinitis and asthma. Existing treatment options for cat allergy, including allergen immunotherapy, are only moderately effective, and allergen immunotherapy has limited use because of safety concerns. Objectives: To explore the relationship among the pharmacokinetic, clinical, and immunological effects of anti-Fel d 1 monoclonal antibodies (REGN1908-1909) in patients after treatment. Methods: Patients received REGN1908-1909 (n = 36) or a placebo (n = 37) in a phase 1b study. Fel d 1-induced basophil and IgE-facilitated allergen binding responses were evaluated at baseline and Days 8, 29, and 85. Cytokine and chemokine concentrations in nasal fluids were measured, and REGN1908-1909 inhibition of allergen-IgE binding in patient serum was evaluated. Measurements and Main Results: Peak serum drug concentrations were concordant with maximal observed clinical response. The anti-Fel d 1 IgE/cat dander IgE ratio in pretreatment serum correlated with Total Nasal Symptom Score improvement. The allergen-neutralizing capacity of REGN1908-1909 was observed in serum and nasal fluid and was detected in an inhibition assay. Type 2 cytokines (IL-4, IL-5, and IL-13) and chemokines (CCL17/TARC, CCL5/RANTES [regulated upon activation, normal T-cell expressed and secreted]) in nasal fluid were inhibited in REGN1908-1909-treated patients compared with placebo (P < 0.05 for all); IL-13 and IL-5 concentrations correlated with Total Nasal Symptom Score improvement. Ex vivo assays demonstrated that REGN1908 and REGN1909 combined were more potent than each alone for inhibiting FcεRI- and FcεRII (CD23)-mediated allergic responses and subsequent T-cell activation. Conclusions: A single, passive-dose administration of Fel d 1-neutralizing IgG antibodies improved nasal symptoms in cat-allergic patients and was underscored by suppression of FcεRI-, FcεRII-, and T-helper cell type 2-mediated allergic responses. Clinical trial registered with www.clinicaltrials.gov (NCT02127801).
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Alérgenos/efectos adversos , Antialérgicos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Gatos , Glicoproteínas/efectos adversos , Factores Inmunológicos/uso terapéutico , Rinitis Alérgica/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Animales , Antialérgicos/administración & dosificación , Anticuerpos Monoclonales/inmunología , Método Doble Ciego , Femenino , Humanos , Factores Inmunológicos/administración & dosificación , Inmunoterapia , Masculino , Persona de Mediana Edad , Efecto Placebo , Rinitis Alérgica/etiología , Rinitis Alérgica/inmunologíaRESUMEN
BACKGROUND: Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product. We aimed to assess the activity and safety of liso-cel in patients with relapsed or refractory large B-cell lymphomas. METHODS: We did a seamless design study at 14 cancer centres in the USA. We enrolled adult patients (aged ≥18 years) with relapsed or refractory large B-cell lymphomas. Eligible histological subgroups included diffuse large B-cell lymphoma, high-grade B-cell lymphoma with rearrangements of MYC and either BCL2, BCL6, or both (double-hit or triple-hit lymphoma), diffuse large B-cell lymphoma transformed from any indolent lymphoma, primary mediastinal B-cell lymphoma, and follicular lymphoma grade 3B. Patients were assigned to one of three target dose levels of liso-cel as they were sequentially tested in the trial (50â×â106 CAR+ T cells [one or two doses], 100â×â106 CAR+ T cells, and 150â×â106 CAR+ T cells), which were administered as a sequential infusion of two components (CD8+ and CD4+ CAR+ T cells) at equal target doses. Primary endpoints were adverse events, dose-limiting toxicities, and the objective response rate (assessed per Lugano criteria); endpoints were assessed by an independent review committee in the efficacy-evaluable set (comprising all patients who had confirmed PET-positive disease and received at least one dose of liso-cel). This trial is registered with ClinicalTrials.gov, NCT02631044. FINDINGS: Between Jan 11, 2016, and July 5, 2019, 344 patients underwent leukapheresis for manufacture of CAR+ T cells (liso-cel), of whom 269 patients received at least one dose of liso-cel. Patients had received a median of three (range 1-8) previous lines of systemic treatment, with 260 (97%) patients having had at least two lines. 112 (42%) patients were aged 65 years or older, 181 (67%) had chemotherapy-refractory disease, and seven (3%) had secondary CNS involvement. Median follow-up for overall survival for all 344 patients who had leukapheresis was 18·8 months (95% CI 15·0-19·3). Overall safety and activity of liso-cel did not differ by dose level. The recommended target dose was 100â×â106 CAR+ T cells (50â×â106 CD8+ and 50â×â106 CD4+ CAR+ T cells). Of 256 patients included in the efficacy-evaluable set, an objective response was achieved by 186 (73%, 95% CI 66·8-78·0) patients and a complete response by 136 (53%, 46·8-59·4). The most common grade 3 or worse adverse events were neutropenia in 161 (60%) patients, anaemia in 101 (37%), and thrombocytopenia in 72 (27%). Cytokine release syndrome and neurological events occurred in 113 (42%) and 80 (30%) patients, respectively; grade 3 or worse cytokine release syndrome and neurological events occurred in six (2%) and 27 (10%) patients, respectively. Nine (6%) patients had a dose-limiting toxicity, including one patient who died from diffuse alveolar damage following a dose of 50â×â106 CAR+ T cells. INTERPRETATION: Use of liso-cel resulted in a high objective response rate, with a low incidence of grade 3 or worse cytokine release syndrome and neurological events in patients with relapsed or refractory large B-cell lymphomas, including those with diverse histological subtypes and high-risk features. Liso-cel is under further evaluation at first relapse in large B-cell lymphomas and as a treatment for other relapsed or refractory B-cell malignancies. FUNDING: Juno Therapeutics, a Bristol-Myers Squibb Company.
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Antígenos CD19/uso terapéutico , Inmunoterapia Adoptiva/métodos , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/terapia , Anciano , Anciano de 80 o más Años , Anemia/epidemiología , Antígenos CD19/administración & dosificación , Antígenos CD19/efectos adversos , Productos Biológicos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/trasplante , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/trasplante , Síndrome de Liberación de Citoquinas/epidemiología , Femenino , Humanos , Inmunoterapia Adoptiva/efectos adversos , Infusiones Intravenosas , Leucaféresis/métodos , Linfoma de Células B Grandes Difuso/clasificación , Linfoma de Células B Grandes Difuso/inmunología , Masculino , Enfermedades del Sistema Nervioso/epidemiología , Neutropenia/epidemiología , Recurrencia , Seguridad , Análisis de Supervivencia , Trombocitopenia/epidemiología , Resultado del TratamientoRESUMEN
Background and objectives: For the last three decades, non-operative management (NOM) has been the standard in the treatment of clinically stable patients with blunt spleen injury, with a success rate of up to 95%. However, there are no prospective issues in the literature dealing with the incidence and type of splenic complications after NOM. Materials and methods: This study analyzed 76 pediatric patients, up to the age of 18, with blunt splenic injury who were treated non-operatively. All patients were included in a posttraumatic follow-up protocol with ultrasound examinations 4 and 12 weeks after injury. Results: The mean age of the children was 9.58 ± 3.97 years (range 1.98 to 17.75 years), with no statistically significant difference between the genders. The severity of the injury was determined according to the American Association for Surgery of Trauma (AAST) classification: 7 patients had grade I injuries (89.21%), 21 patients had grade II injuries (27.63%), 33 patients had grade III injuries (43.42%), and 15 patients had grade IV injuries (19.73%). The majority of the injuries were so-called high-energy ones, which were recorded in 45 patients (59.21%). According to a previously created posttraumatic follow-up protocol, complications were detected in 16 patients (21.05%). Hematomas had the highest incidence and were detected in 11 patients (14.47%), while pseudocysts were detected in 3 (3.94%), and a splenic abscess and pseudoaneurysm were detected in 1 patient (1.31%), respectively. The complications were in a direct correlation with injury grade: seven occurred in patients with grade IV injuries (9.21%), five occurred in children with grade III injuries (6.57%), three occurred in patients with grade II injuries (3.94%), and one occurred in a patient with a grade I injury (1.31%). Conclusion: Based on the severity of the spleen injury, it is difficult to predict the further course of developing complications, but complications are more common in high-grade injuries. The implementation of a follow-up ultrasound protocol is mandatory in all patients with NOM of spleen injuries for the early detection of potentially dangerous and fatal complications.
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Enfermedades del Bazo , Heridas no Penetrantes , Adolescente , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Puntaje de Gravedad del Traumatismo , Masculino , Estudios Retrospectivos , Enfermedades del Bazo/diagnóstico por imagen , Enfermedades del Bazo/epidemiología , Enfermedades del Bazo/etiología , Heridas no Penetrantes/complicaciones , Heridas no Penetrantes/diagnóstico por imagen , Heridas no Penetrantes/terapiaRESUMEN
AIMS: Glucagon receptor (GCGR) blockers are being investigated as potential therapeutics for type 1 and type 2 diabetes. Here we report the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of REGN1193, a fully human glucagon receptor blocking monoclonal antibody from a first-in-human healthy volunteer randomized double-blinded trial. METHODS: Healthy men and women received single ascending doses of REGN1193 ranging from 0.05 to 0.6 mg/kg (n = 42) or placebo (n = 14) intravenously. Safety, tolerability and PK were assessed over 106 days. The glucose-lowering effect of REGN1193 was assessed after induction of hyperglycaemia by serial glucagon challenges. RESULTS: REGN1193 was generally well tolerated. There were small (<3× the upper limit of normal) and transient dose-dependent increases in hepatic aminotransferases. No increase in LDL-C was observed. Hypoglycaemia, assessed as laboratory blood glucose ≤70 mg/dL, occurred in 6/14 (43%) subjects on placebo and 27/42 (57%) on REGN1193 across all dose groups. All episodes of hypoglycaemia were asymptomatic, >50 mg/dL, and did not require treatment or medical assistance. Concentration-time profiles suggest a 2-compartment disposition and marked nonlinearity, consistent with target-mediated clearance. REGN1193 inhibited the glucagon-stimulated glucose increase in a dose-dependent manner. The 0.6 mg/kg dose inhibited the glucagon-induced glucose area under the curve for 0 to 90 minutes (AUC0-90 minutes ) by 80% to 90% on days 3 and 15, while blunting the increase in C-peptide. REGN1193 dose-dependently increased total GLP-1, GLP-2 and glucagon, with plasma levels returning to baseline by day 29 in all dose groups. CONCLUSION: REGN1193, a GCGR-blocking monoclonal antibody, produced a safety, tolerability and PK/PD profile suitable for further clinical development. The occurrence of transient elevations in serum hepatic aminotransferases observed here and reported with several small molecule glucagon receptor antagonists suggests an on-target effect of glucagon receptor blockade. The underlying mechanism is unknown.
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Anticuerpos Monoclonales/farmacocinética , Hipoglucemiantes/farmacocinética , Receptores de Glucagón/antagonistas & inhibidores , Adulto , Anticuerpos Bloqueadores/administración & dosificación , Anticuerpos Bloqueadores/efectos adversos , Anticuerpos Bloqueadores/sangre , Anticuerpos Bloqueadores/farmacología , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Biomarcadores/sangre , Glucemia/análisis , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Estudios de Seguimiento , Semivida , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacología , Infusiones Intravenosas , Perdida de Seguimiento , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Pacientes Desistentes del Tratamiento , Receptores de Glucagón/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Severe atopic dermatitis (AD) has a high unmet need for effective and safe therapeutics. In early-phase trials, dupilumab, a fully human mAb targeting IL-4 receptor α, markedly improved disease activity, but the effect of IL-4/IL-13 blockade on AD at the molecular level has not been characterized. OBJECTIVES: We sought to evaluate dupilumab modulation of the AD molecular signature. METHODS: We performed transcriptomic analyses of pretreatment and posttreatment skin biopsy specimens from patients with moderate-to-severe AD treated weekly with 150 or 300 mg of dupilumab or placebo. RESULTS: Exacerbation of the AD transcriptome was observed in placebo-treated patients. Dupilumab improved the AD signature in a dose-dependent manner. Expression of genes upregulated in AD lesions decreased in patients treated with dupilumab by 26% (95% CI, 21% to 32%) and 65% (95% CI, 60% to 71%) for treatment with 150 and 300 mg, respectively. Genes downregulated in AD lesions increased by 21% (95% CI, 16% to 27%) and 32% (95% CI, 26% to 37%) with dupilumab (150 and 300 mg, respectively). The molecular changes paralleled improvements in clinical scores. A dupilumab treatment signature of 821 probes (>2-fold change, P < .05) significantly modulated in the 300-mg dupilumab group at week 4 compared with baseline was identified in this sample set. Significant (P < .05) decreases in mRNA expression of genes related to hyperplasia (K16 and MKI67), T cells, and dendritic cells (CD1b and CD1c) and potent inhibition of TH2-associated chemokines (CCL17, CCL18, CCL22, and CCL26) were noted without significant modulation of TH1-associated genes (IFNG). CONCLUSIONS: This is the first report showing rapid improvement of the AD molecular signature with targeted anti-IL-4 receptor α therapy. These data suggest that IL-4 and IL-13 drive a complex, TH2-centered inflammatory axis in patients with AD.
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Antialérgicos/farmacología , Antiasmáticos/farmacología , Anticuerpos Monoclonales/farmacología , Dermatitis Atópica/genética , Regulación de la Expresión Génica/efectos de los fármacos , Piel/efectos de los fármacos , Adulto , Anticuerpos Monoclonales Humanizados , Citocinas/antagonistas & inhibidores , Citocinas/genética , Dermatitis Atópica/inmunología , Método Doble Ciego , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/inmunología , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Piel/inmunología , Células Th2/inmunología , Adulto JovenRESUMEN
Activity-dependent neuroprotective protein (ADNP) syndrome is a rare neurodevelopmental disorder resulting in intellectual disability, developmental delay and autism spectrum disorder (ASD) and is due to mutations in the ADNP gene. Ketamine treatment has emerged as a promising therapeutic option for ADNP syndrome, showing safety and apparent behavioral improvements in a first open label study. However, the molecular perturbations induced by ketamine remain poorly understood. Here, we investigated the longitudinal effect of ketamine on the blood transcriptome of 10 individuals with ADNP syndrome. Transcriptomic profiling was performed before and at multiple time points after a single low-dose intravenous ketamine infusion (0.5 mg/kg). We show that ketamine triggers immediate and profound gene expression alterations, with specific enrichment of monocyte-related expression patterns. These acute alterations encompass diverse signaling pathways and co-expression networks, implicating upregulation of immune and inflammatory-related processes and down-regulation of RNA processing mechanisms and metabolism. Notably, these changes exhibit a transient nature, returning to baseline levels 24 hours to 1 week after treatment. These findings enhance our understanding of ketamine's molecular effects and lay the groundwork for further research elucidating its specific cellular and molecular targets. Moreover, they contribute to the development of therapeutic strategies for ADNP syndrome and potentially, ASD more broadly.
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Trastorno del Espectro Autista , Ketamina , Transcriptoma , Ketamina/farmacología , Ketamina/administración & dosificación , Ketamina/uso terapéutico , Humanos , Masculino , Transcriptoma/efectos de los fármacos , Niño , Femenino , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/sangre , Preescolar , Proteínas del Tejido Nervioso/genética , Discapacidad Intelectual/tratamiento farmacológico , Discapacidad Intelectual/genética , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/tratamiento farmacológico , Perfilación de la Expresión Génica , Adolescente , Proteínas de HomeodominioRESUMEN
Activity-dependent neuroprotective protein (ADNP) syndrome is a rare neurodevelopmental disorder resulting in intellectual disability, developmental delay and autism spectrum disorder (ASD) and is due to mutations in the ADNP gene. Ketamine treatment has emerged as a promising therapeutic option for ADNP syndrome, showing safety and apparent behavioral improvements in a first open label study. However, the molecular perturbations induced by ketamine remain poorly understood. Here, we investigated the longitudinal effect of ketamine on the blood transcriptome of 10 individuals with ADNP syndrome. Transcriptomic profiling was performed before and at multiple time points after a single low-dose intravenous ketamine infusion (0.5mg/kg). We show that ketamine triggers immediate and profound gene expression alterations, with specific enrichment of monocyte-related expression patterns. These acute alterations encompass diverse signaling pathways and co-expression networks, implicating up-regulation of immune and inflammatory-related processes and down-regulation of RNA processing mechanisms and metabolism. Notably, these changes exhibit a transient nature, returning to baseline levels 24 hours to 1 week after treatment. These findings enhance our understanding of ketamine's molecular effects and lay the groundwork for further research elucidating its specific cellular and molecular targets. Moreover, they contribute to the development of therapeutic strategies for ADNP syndrome and potentially, ASD more broadly.
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PURPOSE: To report the primary analysis results from the mantle cell lymphoma (MCL) cohort of the phase I seamless design TRANSCEND NHL 001 (ClinicalTrials.gov identifier: NCT02631044) study. METHODS: Patients with relapsed/refractory (R/R) MCL after ≥two lines of previous therapy, including a Bruton tyrosine kinase inhibitor (BTKi), an alkylating agent, and a CD20-targeted agent, received lisocabtagene maraleucel (liso-cel) at a target dose level (DL) of 50 × 106 (DL1) or 100 × 106 (DL2) chimeric antigen receptor-positive T cells. Primary end points were adverse events (AEs), dose-limiting toxicities, and objective response rate (ORR) by independent review committee per Lugano criteria. RESULTS: Of 104 leukapheresed patients, liso-cel was infused into 88. Median (range) number of previous lines of therapy was three (1-11) with 30% receiving ≥five previous lines of therapy, 73% of patients were age 65 years and older, 69% had refractory disease, 53% had BTKi refractory disease, 23% had TP53 mutation, and 8% had secondary CNS lymphoma. Median (range) on-study follow-up was 16.1 months (0.4-60.5). In the efficacy set (n = 83; DL1 + DL2), ORR was 83.1% (95% CI, 73.3 to 90.5) and complete response (CR) rate was 72.3% (95% CI, 61.4 to 81.6). Median duration of response was 15.7 months (95% CI, 6.2 to 24.0) and progression-free survival was 15.3 months (95% CI, 6.6 to 24.9). Most common grade ≥3 treatment-emergent AEs were neutropenia (56%), anemia (37.5%), and thrombocytopenia (25%). Cytokine release syndrome (CRS) was reported in 61% of patients (grade 3/4, 1%; grade 5, 0), neurologic events (NEs) in 31% (grade 3/4, 9%; grade 5, 0), grade ≥3 infections in 15%, and prolonged cytopenia in 40%. CONCLUSION: Liso-cel demonstrated high CR rate and deep, durable responses with low incidence of grade ≥3 CRS, NE, and infections in patients with heavily pretreated R/R MCL, including those with high-risk, aggressive disease.
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Antineoplásicos , Linfoma de Células B Grandes Difuso , Linfoma de Células del Manto , Neutropenia , Adulto , Anciano , Humanos , Antineoplásicos/efectos adversos , Inmunoterapia Adoptiva/efectos adversos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neutropenia/inducido químicamenteRESUMEN
Communication between glial cells has a profound impact on the pathophysiology of Alzheimer's disease (AD). We reveal here that reactive astrocytes control cell distancing in peri-plaque glial nets, which restricts microglial access to amyloid deposits. This process is governed by guidance receptor Plexin-B1 (PLXNB1), a network hub gene in individuals with late-onset AD that is upregulated in plaque-associated astrocytes. Plexin-B1 deletion in a mouse AD model led to reduced number of reactive astrocytes and microglia in peri-plaque glial nets, but higher coverage of plaques by glial processes, along with transcriptional changes signifying reduced neuroinflammation. Additionally, a reduced footprint of glial nets was associated with overall lower plaque burden, a shift toward dense-core-type plaques and reduced neuritic dystrophy. Altogether, our study demonstrates that Plexin-B1 regulates peri-plaque glial net activation in AD. Relaxing glial spacing by targeting guidance receptors may present an alternative strategy to increase plaque compaction and reduce neuroinflammation in AD.
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Enfermedad de Alzheimer , Proteínas del Tejido Nervioso , Neuroglía , Placa Amiloide , Animales , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Placa Amiloide/metabolismo , Placa Amiloide/patología , Ratones , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Neuroglía/metabolismo , Receptores de Superficie Celular/metabolismo , Receptores de Superficie Celular/genética , Humanos , Astrocitos/metabolismo , Ratones Transgénicos , Microglía/metabolismo , Péptidos beta-Amiloides/metabolismo , Masculino , Ratones Noqueados , FemeninoRESUMEN
Chronic abdominal pain is the most commonly seen condition in the pediatric population. Many causes can be successfully managed by conservative treatment; nevertheless, surgical intervention is sometimes inevitable. Among many surgical conditions, such as appendicitis as the most frequent cause, one is also to think about congenital abdominal bands. We report a case of a 10-year-old boy with chronic abdominal pain, who suddenly developed clinical and radiologic signs of intestinal obstruction. The cause of chronic abdominal pain as well as the intestinal obstruction was revealed during the operation: 2 congenital abdominal bands, trapping the gut convolutes. To our knowledge, this is the first report of 2 bands in a single patient.
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Dolor Abdominal/diagnóstico , Obstrucción Intestinal/diagnóstico , Dolor Abdominal/etiología , Niño , Diagnóstico Diferencial , Humanos , Obstrucción Intestinal/etiología , Obstrucción Intestinal/cirugía , MasculinoRESUMEN
Background: Phelan-McDermid syndrome is a genetic disorder caused by haploinsufficiency of the SHANK3 gene on chromosome 22q13.3 and is characterized by autism spectrum disorder, intellectual disability, speech and language abnormalities, hypotonia, and mild dysmorphic features. Early literature in Phelan-McDermid syndrome did not include gait abnormalities as part of the syndrome although recent prospective studies report that the prevalence of gait abnormalities ranges from 55% to 94%. We compared gait abnormalities in individuals with Phelan-McDermid syndrome, idiopathic autism spectrum disorder, and typically developing controls, and explored associations between gait abnormalities, autism spectrum disorder, and intellectual functioning. Method: The study cohort consists of 67 participants between the ages of 3 and 18 years, divided into 3 groups: Phelan-McDermid syndrome (n = 46), idiopathic autism spectrum disorder (n = 11), and typically developing controls (n = 10). Gait was recorded using a video camera and scored across 26 gait features using a "Gait Clinical Observations scale" designed specifically for this study. Results: Gait abnormalities were significantly higher in the Phelan-McDermid syndrome group as compared to idiopathic autism spectrum disorder or typically developing controls. The number of gait abnormalities across groups was also significantly correlated with Intellectual Quotient/Developmental Quotient (IQ/DQ). In analysis of covariance including IQ/DQ, the effect of group was not significant, but the effect of IQ/DQ was significant. Conclusions: Overall differences in gait abnormalities were determined by the degree of intellectual disability, which was significantly higher in Phelan-McDermid syndrome.
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Trastorno del Espectro Autista , Trastornos de los Cromosomas , Discapacidad Intelectual , Niño , Humanos , Preescolar , Adolescente , Trastorno del Espectro Autista/complicaciones , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/epidemiología , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/genética , Trastornos de los Cromosomas/complicaciones , Trastornos de los Cromosomas/genética , Deleción Cromosómica , Marcha , Cromosomas Humanos Par 22/genéticaRESUMEN
The issues of vertical viral transmission from mother to fetus and the potential complications caused by SARS-CoV-2 coagulopathy are still unclear. There are few literature data about the vertical transmission of SARS-CoV-2 and health outcomes in neonates born to mothers with symptomatic or asymptomatic coronavirus disease, with the existing data based on small sample sizes. This case series study consists of two newborn children (one pre-term and one term) who were born to SARS-CoV-2-positive mothers and admitted to the neonatal intensive care unit a few hours after birth. One child had cyanotic changes that affected the entire left leg and the left forearm, with multiple livid changes on the front of the chest and abdomen, the right upper arm, right thigh, neck, and face, and one child had an altered umbilical cord. The first child was treated conservatively, and the second child was treated surgically.
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Drug resistance presents a major obstacle to the successful treatment of glioblastoma. Autophagy plays a key role in drug resistance, particularly in relation to targeted therapy, which has prompted the use of autophagy inhibitors to increase the effectiveness of targeted therapeutics. The ability of two Src tyrosine kinase inhibitors, Si306 and its prodrug pro-Si306, to induce autophagy was evaluated in the human glioblastoma cell line U87 and its multidrug-resistant counterpart U87-TxR. Autophagy markers were assessed by flow cytometry, microscopy, and Western blot, and induction of autophagy by these compounds was demonstrated after 3 h as well as 48 h. The effects of Si306 and pro-Si306 on cell proliferation and cell death were examined in the presence or absence of autophagy inhibition by bafilomycin A1. Combined treatments of Si306 and pro-Si306 with bafilomycin A1 were synergistic in nature, and the inhibition of autophagy sensitized glioblastoma cells to Src tyrosine kinase inhibitors. Si306 and pro-Si306 more strongly inhibited cell proliferation and triggered necrosis in combination with bafilomycin A1. Our findings suggest that modulation of Si306- and pro-Si306-induced autophagy can be used to enhance the anticancer effects of these Src tyrosine kinase inhibitors and overcome the drug-resistant phenotype in glioblastoma cells.
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BACKGROUND: There are no head-to-head clinical studies comparing chimeric antigen receptor (CAR) T-cell therapies for the treatment of relapsed or refractory aggressive large B-cell lymphomas. Naive, indirect comparisons may be inappropriate, as the study designs and patient populations could differ substantially. Matching-adjusted indirect comparisons (MAIC) can reduce many biases associated with indirect comparisons between studies. To determine the comparative efficacy and safety of lisocabtagene maraleucel (liso-cel) to tisagenlecleucel, we describe an unanchored MAIC of the pivotal studies TRANSCEND NHL 001 (TRANSCEND; NCT02631044; liso-cel) and JULIET (NCT02445248; tisagenlecleucel). METHODS: Individual patient data (IPD) from TRANSCEND were available to the authors; for the JULIET pivotal study, summary-level data from the published study were used. To balance the populations between two studies, IPD from TRANSCEND were adjusted to match the marginal distribution (e.g., mean, variance) of clinical factors among patients from JULIET. RESULTS: Results from the primary MAIC showed liso-cel had statistically significant greater efficacy than tisagenlecleucel (objective response rate: odds ratio [OR] = 2.78, 95% confidence interval [CI]: 1.63â4.74; complete response rate: OR = 2.01, 95% CI: 1.22â3.30; progression-free survival: hazard ratio [HR] = 0.65, 95% CI: 0.47â0.91; overall survival: HR = 0.67, 95% CI: 0.47â0.95). MAIC of safety outcomes showed lower ORs for all-grade and grade ≥ 3 cytokine release syndrome, and grade ≥ 3 prolonged cytopenia for liso-cel when compared with tisagenlecleucel; there were no statistically significant differences detected for other safety outcomes. CONCLUSIONS: Overall, this MAIC of two CAR T-cell therapies indicates liso-cel had favorable efficacy and a comparable or better safety profile relative to tisagenlecleucel. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02631044 and NCT02445248.
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Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, chimeric antigen receptor T-cell product for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (LBCL) after 2 or more lines of systemic therapy. In vivo cellular expansion after single-dose administration of liso-cel has been characterized. In this article, in vivo liso-cel expansion in the pivotal study TRANSCEND NHL 001 (ClinicalTrials.gov identifier, NCT02631044) was further characterized to assess the relationship between in vivo cellular expansion after single-dose administration of liso-cel and efficacy or safety after adjusting for key baseline characteristics. Two bioanalytical methods, quantitative polymerase chain reaction and flow cytometry, were used for the assessment of cellular kinetics of liso-cel, which showed high concordance for in vivo cellular expansion. Multivariable logistic regression analyses demonstrated that higher in vivo cellular expansion of liso-cel was associated with a higher overall response and complete response rate, and a higher incidence of cytokine release syndrome and neurological events in patients with relapsed or refractory LBCL. Age and tumor burden (by sum of the product of perpendicular diameters) were likely to confound the relationship between in vivo cellular expansion and efficacy, where the association became stronger after controlling for these factors. Repeat dosing of liso-cel was tested in the study; however, in vivo cellular expansion of liso-cel was lower after repeat dosing than after the initial dose. These findings should enable a comprehensive understanding of the in vivo cellular kinetics of liso-cel and the association with outcomes in relapsed/refractory LBCL.
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Linfoma de Células B Grandes Difuso , Receptores Quiméricos de Antígenos , Adulto , Antígenos CD19 , Humanos , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfocitos TRESUMEN
Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental disorder. There are no drugs to treat the core symptoms. De novo mutations often play an important role in ASD and multiple high-risk loci have been identified in the last decade. These mutations range from copy number variants to small insertion/deletion and single nucleotide variants. Large-scale exome sequencing has identified over 100 risk genes that are associated with ASD. Both etiological heterogeneity and unavailability of human neurons remain major hurdles in understanding the pathophysiology of ASD and testing of new drug candidates. Hence, the most achievable and relevant model to screen for potential drugs is human neurons from inducible pluripotent stem cells (iPSCs), including those from individuals with genetic mutations. In this study, we tested stem cells from individuals carrying mutations in ADNP, FOXP1 or SHANK3. They were scaled and reprogrammed to glutamatergic neurons and assessed for the effects of their specific mutations on neurite outgrowth. High Content Analysis allowed us to observe phenotypic differences between ASD neurons compared to controls, in terms of neuron number, neurite number and neurite length per neuron. Further, neurons were derived from both patient derived and genetically modified iPSCs with DDX3X mutation which were tested against 5088 drug like compounds. We assessed individual compound effects on the induced neurons to determine if they elicited changes that would indicate neurite growth (neuroprotection) or, alternatively, reduce outgrowth and hence appear neurotoxic. This report includes all methods, phenotypic outcomes, and results for the largest ASD small molecule screening effort done to date.
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Trastorno del Espectro Autista , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/genética , Factores de Transcripción Forkhead/farmacología , Humanos , Neuritas , Neurogénesis , Proyección Neuronal/genética , Neuronas , Proteínas Represoras/farmacologíaRESUMEN
Activity-dependent neuroprotective protein (ADNP) syndrome is a rare genetic condition associated with intellectual disability and autism spectrum disorder. Preclinical evidence suggests that low-dose ketamine may induce expression of ADNP and that neuroprotective effects of ketamine may be mediated by ADNP. The goal of the proposed research was to evaluate the safety, tolerability, and behavioral outcomes of low-dose ketamine in children with ADNP syndrome. We also sought to explore the feasibility of using electrophysiological markers of auditory steady-state response and computerized eye tracking to assess biomarker sensitivity to treatment. This study utilized a single-dose (0.5 mg/kg), open-label design, with ketamine infused intravenously over 40 min. Ten children with ADNP syndrome ages 6 to 12 years were enrolled. Ketamine was generally well tolerated, and there were no serious adverse events. The most common adverse events were elation/silliness (50%), fatigue (40%), and increased aggression (40%). Using parent-report instruments to assess treatment effects, ketamine was associated with nominally significant improvement in a wide array of domains, including social behavior, attention deficit and hyperactivity, restricted and repetitive behaviors, and sensory sensitivities, a week after administration. Results derived from clinician-rated assessments aligned with findings from the parent reports. Overall, nominal improvement was evident based on the Clinical Global Impressions - Improvement scale, in addition to clinician-based scales reflecting key domains of social communication, attention deficit and hyperactivity, restricted and repetitive behaviors, speech, thinking, and learning, activities of daily living, and sensory sensitivities. Results also highlight the potential utility of electrophysiological measurement of auditory steady-state response and eye-tracking to index change with ketamine treatment. Findings are intended to be hypothesis generating and provide preliminary support for the safety and efficacy of ketamine in ADNP syndrome in addition to identifying useful endpoints for a ketamine clinical development program. However, results must be interpreted with caution given limitations of this study, most importantly the small sample size and absence of a placebo-control group.
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Autism spectrum disorder (ASD) is a clinically and etiologically diverse developmental condition characterized by diminished social interactions, impaired communication, and repetitive and/or restrictive behaviors. Recent advances in ASD genetics pave the way for implementation of precision medicine in clinical management of autism.