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1.
Int J Mol Sci ; 23(22)2022 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-36430867

RESUMEN

Reliable preclinical models are needed for screening new cancer drugs. Thus, we developed an improved 3D tumor organoid model termed "organoid raft cultures" (ORCs). Development of ORCs involved culturing tumors ex vivo on collagen beds (boats) with grid supports to maintain their morphological structure. The ORCs were developed from patient-derived xenografts (PDXs) of colon cancers excised from immune-deficient mice (NOD/SCID/IL2Rgammanull). We utilized these new models to evaluate the efficacy of an investigational drug, Navitoclax (ABT-263). We tested the efficacy of ABT-263, an inhibitor of BCL-2 family proteins, in these ORCs derived from a PDX that showed high expression of antiapoptotic BCL2 family proteins (BCL-2, BCL-XL, and BCL-W). Hematoxylin and eosin staining evaluation of PDXs and corresponding ORCs indicated the retention of morphological and other histological integrity of ORCs. ORCs treated with ABT-263 showed decreased expression of antiapoptotic proteins (BCL2, BCL-XL and BCL-W) and increased proapoptotic proteins (BAX and PUMA), with concomitant activation of caspase 3. These studies support the usefulness of the ORCs, developed from PDXs, as an alternative to PDXs and as faster screening models.


Asunto(s)
Neoplasias , Organoides , Ratones , Humanos , Animales , Organoides/metabolismo , Ratones SCID , Ratones Endogámicos NOD , Navíos , Xenoinjertos , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteína bcl-X/metabolismo , Modelos Animales de Enfermedad , Neoplasias/patología , Proteínas Reguladoras de la Apoptosis
2.
Cancer Causes Control ; 27(1): 81-91, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26596855

RESUMEN

PURPOSE: Multiple myeloma (MM) is the most common hematologic malignancy affecting Blacks in the USA, with standardized incidence rates that are twofold to threefold higher than Whites. The rationale for the disparity is unclear. METHODS: Using participants enrolled in the Molecular And Genetic Epidemiology study of myeloma (259 MM cases; 461 controls), we examined the risk of MM associated with family history of cancer, differences by race and among cases, defining clinical features. Risk estimates were calculated using odds ratios and corresponding 95% confidence intervals from logistic regression adjusted for confounders. RESULTS: Overall, MM risk in cases with relatives affected with any hematologic malignancy was significantly elevated compared to controls (OR 1.89, 95% CI 1.25-2.86). Myeloma risk associated with a family history of MM was higher than the risk associated with any hematologic malignancy (OR 3.75, 95% CI 1.75-8.05), and the effect was greater for Blacks (OR 20.9, 95% CI 2.59-168) than Whites (OR 2.04, 95% 0.83-5.04), among cases with early onset (≤60 years; OR 4.58, 95% CI 1.21-17.3) and with increasing numbers of affected relatives (p trend = 0.001). Overall, frequencies of end organ damage differed in cases with relatives affected with any hematologic malignancy and significantly more cases exhibited κ light chain restriction (OR 3.23, 95% CI 1.13-9.26). CONCLUSIONS: The excess risk of MM observed in Blacks and the variation in clinical features observed in MM patients according to family history of hematologic malignancy may be attributed to a shared germline and environmental susceptibility.


Asunto(s)
Neoplasias Hematológicas/epidemiología , Mieloma Múltiple/epidemiología , Adulto , Anciano , Población Negra , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Neoplasias Hematológicas/genética , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Mieloma Múltiple/genética , Riesgo , Población Blanca
4.
Leuk Lymphoma ; 64(10): 1673-1680, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37493540

RESUMEN

Significant variations exist related to the end of induction practices in the management of Acute Promyelocytic Leukemia (APL). These variations include all-trans retinoic acid (ATRA)-arsenic trioxide (ATO) in fixed doses versus continuation until hematologic complete remission (CR) and performance versus omission of post-induction bone marrow biopsy to confirm morphological CR. A retrospective chart review was conducted of 61 patients (42 low/intermediate-risk and 19 high-risk) aged ≥ 18 years with newly diagnosed APL treated with fixed duration ATRA-ATO +/- cytoreduction at a tertiary medical center from December 2012 through March 2020. Of the 54 patients with post-induction bone marrow biopsy results, 52 (96%) demonstrated no morphologic evidence of APL while the remaining were equivocal. After 2.6 years median follow-up, no relapses occurred. The estimated 2-year overall survival rate of 95% suggests excellent outcomes with a fixed ATO induction regimen and safe omission of post-induction bone marrow biopsy irrespective of hematologic parameters.


Asunto(s)
Arsenicales , Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/etiología , Médula Ósea , Estudios Retrospectivos , Arsenicales/uso terapéutico , Óxidos/uso terapéutico , Resultado del Tratamiento , Trióxido de Arsénico/uso terapéutico , Tretinoina/uso terapéutico , Inducción de Remisión , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos
5.
Am J Clin Pathol ; 127(6): 962-76, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17509994

RESUMEN

The performance and interpretation of clinical hematology and hematopathology laboratory tests and diagnosis of benign or malignant hematolymphoid disorders present unique challenges to hematopathology fellow trainees. To assist hematopathology fellowship program directors in preparing trainees to meet these challenges, a task force of pathologists with expertise in hematopathology developed a suggested training curriculum that includes a comprehensive list of topics in the areas of analytic hematology, bone marrow pathology, lymph node pathology, splenic pathology, lymphoma diagnostics, cytogenetics, and molecular diagnostics. This report also includes recommendations for training experiences that will facilitate the transition of subspecialty residents to practicing consultants in hematopathology.


Asunto(s)
Curriculum , Becas , Directrices para la Planificación en Salud , Enfermedades Hematológicas/patología , Patología Clínica/educación , Humanos , Internado y Residencia
7.
Cancer Chemother Pharmacol ; 76(5): 949-55, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26395450

RESUMEN

PURPOSE: The sequence bendamustine (B) + Irinotecan (I) followed by etoposide (E) + carboplatin (C) was hypothesized to increase progression-free survival (PFS) and overall survival (OS) in untreated extensive-disease small cell lung cancer (EDSCLC) patients compared to historical controls by exploiting mitotic catastrophe. Absent expression of ERCC-1 and expression of topoisomerases were hypothesized to be predictive for PFS and OS. METHODS: This was a phase I/IIa trial in 30 patients to determine the maximum tolerated dose (MTD) of B + I and the PFS of B + I E + C with secondary end points including overall response rate (ORR) and OS. Biomarkers measured by immunohistochemistry (IHC) obtained from diagnostic specimens were correlated with outcome. RESULTS: The MTD of B + I was not reached. During treatment with B + I, there were two grade 5 toxicities from neutropenic sepsis and metabolic encephalopathy. Other toxicities included fatigue, nausea/vomiting, diarrhea, and weight loss. For the sequence, the PFS and OS were 6.0 months and 10 months, respectively. The ORR for B + I and the sequence were 82% and 83%, respectively. Topoisomerase-2 expression was predictive for TTP and OS, but absent ERCC-1 expression was not, contrary to our hypothesis. CONCLUSIONS: B + I is an active regimen in EDSCLC. Toxicities included two grade 5 events but were otherwise manageable. The novel sequence B + I E + C increased PFS and OS compared to historical controls. Correlative studies are conflicting regarding the mechanism of action of this novel sequence.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Clorhidrato de Bendamustina/administración & dosificación , Clorhidrato de Bendamustina/efectos adversos , Clorhidrato de Bendamustina/farmacología , Biomarcadores de Tumor/deficiencia , Biomarcadores de Tumor/genética , Encefalopatías Metabólicas/etiología , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/análogos & derivados , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Carcinoma de Células Pequeñas/genética , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Endonucleasas/deficiencia , Endonucleasas/genética , Etopósido/administración & dosificación , Etopósido/efectos adversos , Fatiga/inducido químicamente , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Hematológicas/inducido químicamente , Humanos , Irinotecán , Estimación de Kaplan-Meier , Neoplasias Pulmonares/genética , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Mitosis/efectos de los fármacos , Insuficiencia Multiorgánica/etiología , Neumonía/inducido químicamente , Resultado del Tratamiento , Pérdida de Peso/efectos de los fármacos
8.
Proc SPIE Int Soc Opt Eng ; 7559(75590G)2010 Jan 23.
Artículo en Inglés | MEDLINE | ID: mdl-21785531

RESUMEN

A rapid and cost-effective combination tapered fiber-optic biosensor (CTFOB) dip-probe was used for quantitative estimation of interleukin (IL)-6 in serum/plasma samples. Sandwich immunoassay was used as the detection technique. Probes could successfully detect presence of IL-6 in two serum samples, non-neoplastic autoimmune patient (lupus) sample and lymphoma patient sample. The estimated amount of IL-6 in lupus patient sample was 4.8 ± 0.9 pM and in lymphoma patient sample was 2 ± 1 pM. It is demonstrated that the developed CTFOB dip-probe is capable of quantitative estimation of proteins in serum/plasma samples with high specificity.

9.
J Biomed Opt ; 15(6): 067005, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-21198209

RESUMEN

A combination tapered fiber-optic biosensor (CTFOB) dip probe for rapid and cost-effective quantification of proteins in serum samples has been developed. This device relies on diode laser excitation and a charged-coupled device spectrometer and functions on a technique of sandwich immunoassay. As a proof of principle, this technique was applied in a quantitative estimation of interleukin IL-6. The probes detected IL-6 at picomolar levels in serum samples obtained from a patient with lupus, an autoimmune disease, and a patient with lymphoma. The estimated concentration of IL-6 in the lupus sample was 5.9 ± 0.6 pM, and in the lymphoma sample, it was below the detection limit. These concentrations were verified by a procedure involving bead-based xMAP technology. A similar trend in the concentrations was observed. The specificity of the CTFOB dip probes was assessed by analysis with receiver operating characteristics. This analysis suggests that the dip probes can detect 5-pM or higher concentration of IL-6 in these samples with specificities of 100%. The results provide information for guiding further studies in the utilization of these probes to quantify other analytes in body fluids with high specificity and sensitivity.


Asunto(s)
Técnicas Biosensibles/instrumentación , Tecnología de Fibra Óptica/instrumentación , Inmunoensayo/instrumentación , Interleucina-6/sangre , Refractometría/instrumentación , Transductores , Diseño de Equipo , Análisis de Falla de Equipo , Humanos
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