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1.
Blood ; 132(17): 1737-1749, 2018 10 25.
Artículo en Inglés | MEDLINE | ID: mdl-30154114

RESUMEN

The Primary Immune Deficiency Treatment Consortium (PIDTC) performed a retrospective analysis of 662 patients with severe combined immunodeficiency (SCID) who received a hematopoietic cell transplantation (HCT) as first-line treatment between 1982 and 2012 in 33 North American institutions. Overall survival was higher after HCT from matched-sibling donors (MSDs). Among recipients of non-MSD HCT, multivariate analysis showed that the SCID genotype strongly influenced survival and immune reconstitution. Overall survival was similar for patients with RAG, IL2RG, or JAK3 defects and was significantly better compared with patients with ADA or DCLRE1C mutations. Patients with RAG or DCLRE1C mutations had poorer immune reconstitution than other genotypes. Although survival did not correlate with the type of conditioning regimen, recipients of reduced-intensity or myeloablative conditioning had a lower incidence of treatment failure and better T- and B-cell reconstitution, but a higher risk for graft-versus-host disease, compared with those receiving no conditioning or immunosuppression only. Infection-free status and younger age at HCT were associated with improved survival. Typical SCID, leaky SCID, and Omenn syndrome had similar outcomes. Landmark analysis identified CD4+ and CD4+CD45RA+ cell counts at 6 and 12 months post-HCT as biomarkers predictive of overall survival and long-term T-cell reconstitution. Our data emphasize the need for patient-tailored treatment strategies depending upon the underlying SCID genotype. The prognostic significance of CD4+ cell counts as early as 6 months after HCT emphasizes the importance of close follow-up of immune reconstitution to identify patients who may need additional intervention to prevent poor long-term outcome.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Trasplante de Células Madre Hematopoyéticas , Reconstitución Inmune/inmunología , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/mortalidad , Inmunodeficiencia Combinada Grave/terapia , Genotipo , Humanos , Recuento de Linfocitos , Estudios Retrospectivos
2.
Haematologica ; 103(7): 1218-1228, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29622655

RESUMEN

The myeloma bone marrow microenvironment promotes proliferation of malignant plasma cells and resistance to therapy. Activation of JAK/STAT signaling is thought to be a central component of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor Food and Drug Administration (FDA) approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells. Herein, we validated in vitro, in stromal-responsive human myeloma cell lines, and in vivo, in orthotopic disseminated xenograft models of myeloma, that tofacitinib showed efficacy in myeloma models. Furthermore, tofacitinib strongly synergized with venetoclax in coculture with bone marrow stromal cells but not in monoculture. Surprisingly, we found that ruxolitinib, an FDA approved agent targeting JAK1 and JAK2, did not lead to the same anti-myeloma effects. Combination with a novel irreversible JAK3-selective inhibitor also did not enhance ruxolitinib effects. Transcriptome analysis and unbiased phosphoproteomics revealed that bone marrow stromal cells stimulate a JAK/STAT-mediated proliferative program in myeloma cells, and tofacitinib reversed the large majority of these pro-growth signals. Taken together, our results suggest that tofacitinib reverses the growth-promoting effects of the tumor microenvironment. As tofacitinib is already FDA approved, these results can be rapidly translated into potential clinical benefits for myeloma patients.


Asunto(s)
Médula Ósea/efectos de los fármacos , Médula Ósea/patología , Reposicionamiento de Medicamentos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Microambiente Tumoral/efectos de los fármacos , Animales , Comunicación Celular , Modelos Animales de Enfermedad , Humanos , Quinasas Janus/metabolismo , Células Madre Mesenquimatosas/metabolismo , Ratones , Mieloma Múltiple/metabolismo , Fosfoproteínas/metabolismo , Piperidinas/administración & dosificación , Células Plasmáticas/metabolismo , Células Plasmáticas/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteoma , Proteómica/métodos , Pirimidinas/administración & dosificación , Pirroles/administración & dosificación , Factores de Transcripción STAT/metabolismo , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Obstet Gynecol ; 141(4): 854-856, 2023 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-36897156

RESUMEN

Uterine rupture is a rare obstetric complication that is associated with maternal and neonatal morbidity and mortality. The aim of this study was to examine uterine rupture and its outcomes in the setting of the unscarred compared with the scarred uterus. A retrospective observational cohort study was performed examining all cases of uterine rupture in three tertiary care hospitals in Dublin, Ireland, over a 20-year period. The primary outcome was perinatal mortality rate with uterine rupture, which was 11.02% (95% CI 6.5-17.3). There was no significant difference in perinatal mortality between cases of scarred and unscarred uterine rupture. Unscarred uterine rupture was associated with higher maternal morbidity , defined as major obstetric hemorrhage or hysterectomy.


Asunto(s)
Muerte Perinatal , Rotura Uterina , Embarazo , Recién Nacido , Femenino , Humanos , Rotura Uterina/etiología , Rotura Uterina/cirugía , Resultado del Embarazo , Estudios Retrospectivos , Útero , Histerectomía/efectos adversos
4.
Clin Cancer Res ; 26(22): 6028-6038, 2020 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-32917735

RESUMEN

PURPOSE: New therapies have changed the outlook for patients with multiple myeloma, but novel agents are needed for patients who are refractory or relapsed on currently approved drug classes. Novel targets other than CD38 and BCMA are needed for new immunotherapy development, as resistance to daratumumab and emerging anti-BCMA approaches appears inevitable. One potential target of interest in myeloma is ICAM1. Naked anti-ICAM1 antibodies were active in preclinical models of myeloma and safe in patients, but showed limited clinical efficacy. Here, we sought to achieve improved targeting of multiple myeloma with an anti-ICAM1 antibody-drug conjugate (ADC). EXPERIMENTAL DESIGN: Our anti-ICAM1 human mAb was conjugated to an auristatin derivative, and tested against multiple myeloma cell lines in vitro, orthotopic xenografts in vivo, and patient samples ex vivo. The expression of ICAM1 was also measured by quantitative flow cytometry in patients spanning from diagnosis to the daratumumab-refractory state. RESULTS: The anti-ICAM1 ADC displayed potent anti-myeloma cytotoxicity in vitro and in vivo. In addition, we have verified that ICAM1 is highly expressed on myeloma cells and shown that its expression is further accentuated by the presence of bone marrow microenvironmental factors. In primary samples, ICAM1 is differentially overexpressed on multiple myeloma cells compared with normal cells, including daratumumab-refractory patients with decreased CD38. In addition, ICAM1-ADC showed selective cytotoxicity in multiple myeloma primary samples. CONCLUSIONS: We propose that anti-ICAM1 ADC should be further studied for toxicity, and if safe, tested for clinical efficacy in patients with relapsed or refractory multiple myeloma.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Inmunoconjugados/farmacología , Molécula 1 de Adhesión Intercelular/genética , Mieloma Múltiple/tratamiento farmacológico , ADP-Ribosil Ciclasa 1/antagonistas & inhibidores , ADP-Ribosil Ciclasa 1/inmunología , Adulto , Anciano , Animales , Anticuerpos Antiidiotipos/inmunología , Anticuerpos Antiidiotipos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Citometría de Flujo , Xenoinjertos , Humanos , Inmunoconjugados/inmunología , Molécula 1 de Adhesión Intercelular/inmunología , Masculino , Ratones , Persona de Mediana Edad , Mieloma Múltiple/genética , Mieloma Múltiple/inmunología , Mieloma Múltiple/patología
5.
Mol Cancer Ther ; 16(11): 2375-2386, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28878026

RESUMEN

Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system, and CB-5083, a first-in-class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematologic and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma cell lines and a number of in vivo multiple myeloma models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response, and apoptosis. CB-5083 decreases viability in multiple myeloma cell lines and patient-derived multiple myeloma cells, including those with background proteasome inhibitor (PI) resistance. CB-5083 has a unique mechanism of action that combines well with PIs, which is likely owing to the p97-dependent retro-translocation of the transcription factor, Nrf1, which transcribes proteasome subunit genes following exposure to a PI. In vivo studies using clinically relevant multiple myeloma models demonstrate that single-agent CB-5083 inhibits tumor growth and combines well with multiple myeloma standard-of-care agents. Our preclinical data demonstrate the efficacy of CB-5083 in several multiple myeloma disease models and provide the rationale for clinical evaluation as monotherapy and in combination in multiple myeloma. Mol Cancer Ther; 16(11); 2375-86. ©2017 AACR.


Asunto(s)
Adenosina Trifosfatasas/genética , Indoles/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Proteínas Nucleares/genética , Factor Nuclear 1 de Respiración/genética , Inhibidores de Proteasoma/administración & dosificación , Pirimidinas/administración & dosificación , Adenosina Trifosfatasas/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Proteínas Nucleares/antagonistas & inhibidores , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Ubiquitina/genética , Respuesta de Proteína Desplegada/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Mol Cancer Ther ; 14(3): 642-8, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25564440

RESUMEN

Hsp70 is a stress-inducible molecular chaperone that is required for cancer development at several steps. Targeting the active site of Hsp70 has proven relatively challenging, driving interest in alternative approaches. Hsp70 collaborates with the Bcl2-associated athanogene 3 (Bag3) to promote cell survival through multiple pathways, including FoxM1. Therefore, inhibitors of the Hsp70-Bag3 protein-protein interaction (PPI) may provide a noncanonical way to target this chaperone. We report that JG-98, an allosteric inhibitor of this PPI, indeed has antiproliferative activity (EC50 values between 0.3 and 4 µmol/L) across cancer cell lines from multiple origins. JG-98 destabilized FoxM1 and relieved suppression of downstream effectors, including p21 and p27. On the basis of these findings, JG-98 was evaluated in mice for pharmacokinetics, tolerability, and activity in two xenograft models. The results suggested that the Hsp70-Bag3 interaction may be a promising, new target for anticancer therapy.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Dominios y Motivos de Interacción de Proteínas/fisiología , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Proteína Forkhead Box M1 , Factores de Transcripción Forkhead/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HT29 , Células HeLa , Humanos , Células MCF-7 , Ratones , Antígeno Nuclear de Célula en Proliferación/metabolismo
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