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1.
Mol Ther ; 32(10): 3522-3538, 2024 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-39086131

RESUMEN

Chimeric antigen receptor (CAR) T cells have shown significant efficacy in hematological diseases. However, CAR T therapy has demonstrated limited efficacy in solid tumors, including glioblastoma (GBM). One of the most important reasons is the immunosuppressive tumor microenvironment (TME), which promotes tumor growth and suppresses immune cells used to eliminate tumor cells. The human transforming growth factor ß (TGF-ß) plays a crucial role in forming the suppressive GBM TME and driving the suppression of the anti-GBM response. To mitigate TGF-ß-mediated suppressive activity, we combined a dominant-negative TGF-ß receptor II (dnTGFßRII) with our previous bicistronic CART-EGFR-IL13Rα2 construct, currently being evaluated in a clinical trial, to generate CART-EGFR-IL13Rα2-dnTGFßRII, a tri-modular construct we are developing for clinical application. We hypothesized that this approach would more effectively subvert resistance mechanisms observed with GBM. Our data suggest that CART-EGFR-IL13Rα2-dnTGFßRII significantly augments T cell proliferation, enhances functional responses, and improves the fitness of bystander cells, particularly by decreasing the TGF-ß concentration in a TGF-ß-rich TME. In addition, in vivo studies validate the safety and efficacy of the dnTGFßRII cooperating with CARs in targeting and eradicating GBM in an NSG mouse model.


Asunto(s)
Glioblastoma , Inmunoterapia Adoptiva , Receptor Tipo II de Factor de Crecimiento Transformador beta , Receptores Quiméricos de Antígenos , Microambiente Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Glioblastoma/terapia , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patología , Glioblastoma/inmunología , Humanos , Animales , Receptores Quiméricos de Antígenos/metabolismo , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/inmunología , Receptor Tipo II de Factor de Crecimiento Transformador beta/genética , Receptor Tipo II de Factor de Crecimiento Transformador beta/metabolismo , Ratones , Inmunoterapia Adoptiva/métodos , Línea Celular Tumoral , Microambiente Tumoral/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Receptores ErbB/metabolismo , Receptores ErbB/genética , Resistencia a Antineoplásicos/genética , Subunidad alfa2 del Receptor de Interleucina-13/metabolismo , Subunidad alfa2 del Receptor de Interleucina-13/genética , Modelos Animales de Enfermedad , Factor de Crecimiento Transformador beta/metabolismo
3.
Vet Comp Oncol ; 22(2): 245-254, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38622074

RESUMEN

Canine carcinomatosis (CC) and mesothelioma (CM) are rare but aggressive neoplasms that historically have been associated with poor prognoses. There is limited information regarding treatment for CC and CM. The purpose of this retrospective study was to evaluate the efficacy and tolerability of toceranib phosphate (Palladia) in dogs with CC and CM. Cases were solicited from the American College of Veterinary Internal Medicine (ACVIM) Oncology listserv and retrospectively reviewed. For eligibility, a cytologic and/or histopathologic diagnosis of CC or CM was required. A total of 23 cases were included (CC = 14, CM = 8, both = 1). Eighty-two percent (19/23) of dogs presented with effusion. The best overall response rate (BORR) was 30.4% (13% complete response [CR], 17.3% partial response [PR]). Stable disease (SD) was appreciated in 14 dogs (60.8%) including the four dogs without effusion. The most common toceranib-related adverse events were either Grade 1 and 2 diarrhea or hyporexia. The median progression-free survival (PFS) was 171 days (range, 7-519 days) and overall median survival time (MST) was 301 days (range, 49-875 days) for all dogs. When evaluating dogs solely with effusion, the median PFS and overall MST were 171 days (range, 7-519 days) and 285 days (range, 49-875 days), respectively. This report demonstrates that toceranib is both well tolerated and a potential treatment for CC and CM. A randomised, controlled, prospective study would be needed to objectively assess the survival benefit of toceranib in the management of CC and CM, with and without effusion.


Asunto(s)
Antineoplásicos , Enfermedades de los Perros , Indoles , Mesotelioma , Pirroles , Perros , Animales , Enfermedades de los Perros/tratamiento farmacológico , Estudios Retrospectivos , Indoles/uso terapéutico , Indoles/administración & dosificación , Masculino , Femenino , Pirroles/uso terapéutico , Pirroles/administración & dosificación , Antineoplásicos/uso terapéutico , Mesotelioma/tratamiento farmacológico , Mesotelioma/veterinaria , Mesotelioma/patología , Carcinoma/tratamiento farmacológico , Carcinoma/veterinaria , Resultado del Tratamiento
4.
J Am Anim Hosp Assoc ; 59(1): 36-39, 2023 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-36584319

RESUMEN

A 6 yr old male castrated American Staffordshire terrier was referred for a nonhealing wound at the site of a previously incompletely excised, high-grade soft tissue sarcoma. Physical examination revealed right popliteal lymphadenopathy and a fungating mass of the right pelvic limb at the level of the hock. Thoracic and abdominal computed tomography revealed mild lymphadenopathy of multiple iliac and inguinal lymph nodes. Right pelvic limb amputation and inguinal lymphadenectomy were performed. Histopathology was consistent of a high-grade soft tissue sarcoma with diffuse spread through the lymphatic vessels of the right pelvic limb up to the right inguinal lymph node but not affecting the lymph node itself. Doxorubicin chemotherapy was elected postoperatively as adjuvant therapy. Approximately 4 mo following initiation of chemotherapy, the patient developed a firm, tubular subcutaneous mass starting near the previous amputation site with tracking toward the thorax. Fine needle aspiration of the new mass was consistent with atypical spindle cell proliferation. Palliative care was elected, and the patient was euthanized 3 mo later because of progressive disease. In-transit metastasis is a rare behavior for soft tissue sarcomas across all species, and this is the first report of such a presentation for canine soft tissue sarcoma.


Asunto(s)
Enfermedades de los Perros , Linfadenopatía , Sarcoma , Perros , Masculino , Animales , Metástasis Linfática/patología , Enfermedades de los Perros/cirugía , Enfermedades de los Perros/patología , Sarcoma/cirugía , Sarcoma/veterinaria , Sarcoma/patología , Ganglios Linfáticos/patología , Linfadenopatía/patología , Linfadenopatía/veterinaria
6.
J Hand Ther ; 33(2): 164-169, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32423845

RESUMEN

STUDY DESIGN: This is a case report. INTRODUCTION: Persons with rheumatoid arthritis frequently use assistive devices as a compensatory strategy to enhance occupational performance when client factors such as hand weakness, pain, and/or limited range of motion interfere with activity performance. Computer-aided design software and 3D printers are increasingly being used to design and make assistive devices. PURPOSE OF THE STUDY: This case report describes a client-centered approach in the selection, three-dimensional (3D) printing, and evaluation of outcomes for three assistive devices to enhance occupational performance in a subject with rheumatoid arthritis. METHODS: Outcome measures used in this study included the Patient-Specific Functional Scale, Numeric Pain Rating Scale, and Quebec User Evaluation of Satisfaction with Assistive Technology V2.0. Activity analysis along with the subject input informed a client-centered approach in the selection, color, and design modifications of 3D printed assistive devices made for the study. RESULTS: The subject reported decreased pain, improved occupational performance, and satisfaction with use of 3D printed assistive devices to open plastic beverage bottles, unlock/lock doors, and write. DISCUSSION: 3D printing offers therapists a means to design and make assistive devices that can be cost-effective, customizable, and client-centered. CONCLUSION: Assistive devices made with 3D printing resulted in positive outcomes in a subject with rheumatoid arthritis.


Asunto(s)
Artritis Reumatoide/rehabilitación , Impresión Tridimensional , Dispositivos de Autoayuda , Adulto , Diseño de Equipo , Femenino , Humanos
7.
Glob Pediatr Health ; 6: 2333794X19875153, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31523703

RESUMEN

Background. McCune-Albright syndrome (MAS) is characterized by hyperpigmented macules, endocrinopathies, and fibrous dysplasia. Hyperthyroidism is the second most common endocrinopathy in MAS and its management is challenging, particularly among infants and toddlers. Traditionally, young infants have been treated with antithyroid medications, but remission is likely and these medications have severe side effects and affect the control of other endocrinopathies. Thus, it is reasonable to consider permanent treatment options at an earlier age. In this article, we performed a retrospective chart review and describe 3 children who underwent thyroidectomy at an early age due to complex presentation. Case Descriptions. Case 1 was a female patient who underwent bilateral adrenalectomy due to adrenal hyperplasia and subsequently underwent thyroidectomy at 5 months of age due to unremitting hyperthyroidism with fibrous dysplasia, multiple fractures, and ovarian cysts with vaginal bleeding. Case 2 was a 20-month-old female on methimazole who acquired influenza A, precipitating a thyroid storm, and subsequently developed central precocious puberty. Case 3 was a 4-year-old female who underwent thyroidectomy because of unremitting hyperthyroidism after methimazole cessation due to declining neutrophils. All 3 children experienced no complications from thyroidectomy. Conclusions. Early thyroidectomy by an experienced surgeon is an option for managing MAS-associated hyperthyroidism, even in very young patients, with excellent results.

8.
J Pediatr Endocrinol Metab ; 27(1-2): 135-8, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23959658

RESUMEN

Although KCNJ11 mutations of the KATP channel within the ß cell are known to prevent insulin secretion and cause permanent neonatal diabetes mellitus, the genotype-phenotype correlation continues to be of clinical interest. We report the clinical outcomes in monozygotic twins with neonatal diabetes due to heterozygous mutations in KCNJ11 at R201H. The twins demonstrated concordant clinical outcomes after transitioning from insulin to oral sulfonylurea therapy at 4 months of age. Both twins remained on sulfonylurea therapy while achieving similar growth, development, and metabolic goals. They exhibit marked sensitivity to sulfonylurea therapy with current dosing at 0.05 and 0.06 mg/kg per day at age 5 years which deviates from the approximate maintenance dose of 0.4 mg/kg per day at the time of transition and subsequent follow-up. Metabolic control provided by low-dose sulfonylurea therapy is likely due to early age at transition from insulin to sulfonylurea therapy and possible preservation of endogenous insulin secretion.


Asunto(s)
Diabetes Mellitus/diagnóstico , Gliburida/uso terapéutico , Hipoglucemiantes/uso terapéutico , Enfermedades del Recién Nacido/diagnóstico , Gemelos Monocigóticos , Diabetes Mellitus/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Femenino , Gliburida/administración & dosificación , Humanos , Hipoglucemiantes/administración & dosificación , Lactante , Recién Nacido , Enfermedades del Recién Nacido/tratamiento farmacológico
9.
Pediatrics ; 126(5): e1039-44, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20937651

RESUMEN

OBJECTIVE: The goal was to determine the prevalence of acute hepatitis A virus (HAV) infection and immunity among internationally adopted children. METHODS: Children seen at the International Adoption Center between September 25, 2006, and September 30, 2008, and were screened for HAV within 4 months after their arrival in the United States were eligible for the study. The age- and country-specific prevalence of acute HAV infection and immunity were determined. RESULTS: Overall, 288 children underwent HAV serological testing. Of the 279 with total HAV serological results, 29% had positive findings. Immunity varied according to region and country. The prevalence was lowest among children born in Asia/Pacific Rim region (17%) and highest among children born in Africa (72%). Only 13% of children <2 years of age were immune, compared with 80% of children 12 to 17 years of age (P = .002). Increasing age and birth region were associated independently with immunity. Positive HAV immunoglobulin M test results were found for 3 (1%) of 270 children; all were without symptoms. Their ages were 18, 27, and 41 months, and they were born in Kazakhstan, Russia, and the Latin America/Caribbean region, respectively. The father of 1 child developed HAV infection after arriving home. CONCLUSIONS: HAV immunity among internationally adopted children varied according to age and country of origin; 1% had acute infections. HAV screening is useful for determination of the need for HAV immunization and for prevention of transmission to family members and close contacts.


Asunto(s)
Adopción , Emigrantes e Inmigrantes/estadística & datos numéricos , Hepatitis A/epidemiología , Tamizaje Masivo/estadística & datos numéricos , Enfermedad Aguda , Adolescente , Factores de Edad , Niño , Preescolar , Comparación Transcultural , Estudios Transversales , Femenino , Hepatitis A/diagnóstico , Hepatitis A/inmunología , Hepatitis A/transmisión , Anticuerpos de Hepatitis A/sangre , Humanos , Inmunoglobulina M/sangre , Lactante , Masculino , Metilmetacrilatos , Oportunidad Relativa
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