No description available.

Acute Myeloid Leukemia (AML) is an aggressive hematopoietic neoplasm characterized by rapid clinical progression and universally fatal outcome if left untreated. The neoplastic cells are immature precursor cells that usually originate in the bone marrow and are often noted in the peripheral circulation. Myeloid sarcomas are rare abnormal collection of these cells in extramedullary sites and are now defined as a unique subset of AML as per the WHO classification. Here we describe a patient with AML presenting with a renal and testicular mass, which on biopsy revealed myeloid sarcoma in the absence of blood and bone marrow involvement. A 71 year old male was hospitalized with complaints of nausea, vomiting, confusion and jaundice associated with worsening pruritus in the absence of constitutional symptoms. Medical history notable for chronic kidney disease, Type 2 Diabetes Mellitus and history of localized prostate cancer treated with TURP. Family history of thyroid cancer in his mother. Clinical exam revealed small right testicular non tender mass. Labs revealed a total bilirubin of 11.5mg/dL, creatinine of 3.09 mg/dL, Hemoglobin 13.4g/dL, WBC 9.5k/uL and Platelet count of 283K/uL. Abdominal imaging studies demonstrated a biliary stricture, a 16mm right testicular lesion and a additional right renal mass measuring 4.0 x 3.9 x 2.4 cm. He underwent a right inguinal orchiectomy, which confirmed myeloid sarcoma. Histopathologically, numerous neoplastic cells with enlarged nuclei and mitotic figures were identified with immunohistochemical staining positive for CD45, MPO, CD117, CD68, CD71 and BCL2. A biopsy of the right renal mass also demonstrated myeloid sarcoma, with similar features. He had an ERCP with stent placement for his biliary stricture with negative cytology. Bone marrow biopsy was negative for AML. His challenging clinical presentation, advanced age, medical comorbidities, hyperbilirubinemia, and impaired kidney function, precluded aggressive treatment with standard acute myeloid leukemia induction chemotherapy regimens so a trial of hypomethylating agent (Azacitidine) was successfully initiated. AML is characterized by a rapid clonal proliferation of immature hematopoietic cells in the peripheral blood and bone marrow. It is a heterogeneous disease with regard to acquired genetic alterations, including cytogenetic aberrancies as well as gene mutations and changes in gene expression. The signs and symptoms of AML mostly reflect predominant cytopenias or cytoses and usually a short history (1 to 8 weeks) of constitutional complaints. Myeloid sarcomas are rare extramedullary solid tumors that have resulted in infiltration of organs such as gingiva, skin, lymph nodes and other organs with immature granulocytic precursor cells. The majority of cases are reported in association with coexisting acute myeloid leukemia and infrequently can present in isolation (a harbinger for future blood and marrow involvement). Treatment of myeloid sarcomas follows the AML paradigm. The overall survival of AML is dictated by cytogenetics/ molecular markers and age. Complete remission can be achieved in a group of patients. Relapses occur in the first two years. Leukemic infiltration of the kidney or testicle with myeloid sarcoma is extremely rare and the concurrent presentation is documented in isolated case reports only.

No description available.

No description available.

No description available.

No description available.

No description available.

El sarcoma de Kaposi es una patología tumoral angio-proliferativa cuyo agente etiológico asociado es el herpesvirus 8. El receptor viral acoplado a proteína G (vGPCR) es uno de los genes virales que induce la transformación oncogénica y la formación de lesiones angiogénicas asociadas al sarcoma de Kaposi a través de modificaciones paracrinas, por lo que su expresión es necesaria para el mantenimiento del tumor. El calcitriol o 1α,25(OH)2-vitamina D3 (1α,25(OH)2D3) es la forma hormonal activa de la vitamina D, no sólo es vital para la homeostasis mineral, sino que presenta efectos antineoplásicos en varios tipos de tumores. Nuestro grupo de investigación ha aportado evidencia sobre los efectos anti-proliferativos del 1α,25(OH)2D3 en un modelo celular murino de sarcoma de Kaposi. En esta Tesis Doctoral se investigó si la actividad anti-angiogénica y antiinflamatoria del 1α,25(OH)2D3 y su rol en el estrés oxidativo contribuyen a su mecanismo de acción antitumoral en un modelo celular murino de sarcoma de Kaposi. Se obtuvo evidencia de que 1α,25(OH)2D3 regula los factores pro-angiogénicos, se observó una disminución de la expresión de HIF-1α en forma dependiente del VDR, no así de VEGF, que aumentó independientemente de la disminución de HIF-1α y EGR-1, posiblemente por regulación directa del promotor de VEGF por parte del VDR. A su vez, la expresión del mensajero del factor anti-oncogénico JunB aumentó, mientras que el mensajero del factor pro-oncogénico c-Fos sólo disminuyó durante cortos periodos de tiempo. Además, se demostró que el 1α,25(OH)2D3 regula negativamente la vía Wnt/β-catenina por tres mecanismos diferentes relacionados y consecuentes en el tiempo. En primer lugar, se observó un aumento del inhibidor extracelular Dkk-1 el cual disminuyó inicialmente los niveles de β-catenina; en segundo lugar, una asociación de las proteínas β-catenina/VDR con la consecuente disminución de la actividad transcripcional de β-catenina en genes clave durante la proliferación celular como c-myc, Mmp-9 y ciclina D1 y finalmente, un aumento de VE-cadherina implicando la relocalización de β-catenina para participar de las uniones intercelulares. En cuanto a los efectos antiinflamatorios del 1α,25(OH)2D3, se demostró una modulación dual compuesta por la inhibición de la producción de PGE2 a través de la interacción entre las proteínas COX-2/VDR, la que disminuyó la actividad enzimática, y la supresión diferencial de los receptores EPs de PGE2. Finalmente, en cuanto al rol del 1α,25(OH)2D3 frente al estrés oxidativo, se determinó que los niveles de ROS se encontraron aumentados estimulando así el desencadenamiento del proceso apoptótico por medio del aumento de la expresión de factores pro-apoptóticos como BIM y Caspasa 3-clivada. Los resultados en este trabajo de Tesis Doctoral contribuyen al conocimiento sobre el mecanismo de acción anti-angiogénico y antinflamatorio, efecto frente al estrés oxidativo del 1α,25(OH)2D3 con la participación del VDR en un modelo celular murino de sarcoma de Kaposi. A su vez, sustenta las bases para dar continuación a otros estudios usando modelos in vivo y para evaluar el uso de análogos de 1α,25(OH)2D3 con menor efecto calcémico para el tratamiento de esta patología. / Kaposi's sarcoma is an angioproliferative tumor and herpesvirus 8 is the associated etiologic agent. The G protein-coupled viral receptor (vGPCR) is one of the viral genes that induces oncogenic transformation and the formation of angiogenic lesions associated with Kaposi's sarcoma through paracrine modifications, therefore its expression is necessary for tumor maintenance. Calcitriol or 1α,25(OH)2-vitamin D3 (1α,25(OH)2D3) is the active hormonal form of vitamin D, it is not only vital for mineral homeostasis, but it also has antineoplastic effects in various types of tumors. Our research group has provided evidence on the anti-proliferative effects of 1α,25(OH)2D3 in a murine cell model of Kaposi's sarcoma. This Doctoral Thesis investigated whether the anti-angiogenic and anti-inflammatory activity of 1α,25(OH)2D3 and its role in oxidative stress contribute to the antitumor action mechanism in a murine cell model of Kaposi's sarcoma. Evidence was obtained that 1α,25(OH)2D3 regulates pro-angiogenic factors. A decrease in the expression of HIF-1α was observed on a VDR dependent manner, but not on VEGF, which increased independently of the decrease in HIF-1α and EGR-1, possibly through direct regulation of the VEGF promoter by VDR. At the same time, the expression of the messenger of the anti-oncogenic factor JunB increased, while the messenger of the pro-oncogenic factor c-Fos only decreased for short periods of time. Furthermore, it was shown that 1α,25(OH)2D3 negatively regulates the Wnt/β-catenin pathway by three different related and consequent mechanisms over time. First, an increase in the extracellular inhibitor Dkk-1 was observed, which initially decreased the levels of β-catenin; second, an association of β-catenin/VDR proteins with the consequent decrease in the transcriptional activity of β-catenin upon key genes during cell proliferation such as c-myc, Mmp-9 and cyclin D1; and finally, an increase in VE-cadherin involving the relocation of β-catenin to participate in the intercellular junctions. Regarding to the anti-inflammatory effects of 1α,25(OH)2D3, a dual modulation was demonstrated, composed of PGE2 production inhibition through the interaction between the COX-2/VDR proteins, which decreased the enzymatic activity; and the differential suppression of EP receptors by PGE2. Finally, regarding the role of 1α,25(OH)2D3 against oxidative stress, it was determined that ROS levels were found increased, thus stimulating the apoptotic process by increasing the expression of pro-apoptotic factors such as BIM and Caspase-3 cleavage. The results of this Doctoral Thesis work contribute to the knowledge of the anti-angiogenic and anti-inflammatory mechanisms, the effect against oxidative stress of 1α,25(OH)2D3 with VDR participation in a murine cell model of Kaposi's sarcoma. It supports the basis for continuing other studies using in vivo models and evaluating the use of 1α,25(OH)2D3 analogues with less calcemic effect for the treatment of this pathology.

The drug, N,N bis (ethylene)-P (1-adamantyl) phosphonic diamide inhibits focus formation of Rous Sarcoma Virus in tissue culture. Transformation of chick cells was inhibited when the drug was added to chick cells prior to infection. The drug did not inhibit the transformation of Normal Rat Kidney Cells infected with RSV, when the cells were grown at non-permissive temperatures and shifted to permissive temperatures upon addition of the drug. Nor did the drug revert cells transformed at permissive temperatures. These studies indicated that the inhibition of RSV is in the early stage of viral growth, possible penetration or uncoating.

N^6,O^2' -Dibutyryl cyclic adenosine 3',5'-monophosphate (Bt_2cAMP) was investigated for its effects on various tissue culture cells infected with temperature-sensitive (ts) mutant, LA31 and Bratislava 77 (B77), a wild-type Rous sarcoma virus. Specifically, known parameters of transformation were investigated and a possible site of action has been tenably proposed. The drug Bt_2cAMP was found to have little effect on the transformation related properties of primary chick embryo fibroblasts (CEF) infected with either virus or normal rat kidney fibroblasts (NRK) infected with the wild-type B77-RSV. However, significant inhibition of the transforming properties in NRK infected with the ts mutant LA31 (LA31-NRK) were reported at the permissive temperature 33 degrees centigrade (33 C).