RESUMO
Several studies have shown that diverse components of the bone marrow (BM) microenvironment play a central role in the progression, pathophysiology, and drug resistance in multiple myeloma (MM). In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-κB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-κB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma. Considering that H929 cells were also directly susceptible to PKC and NF-κB inhibition, we showed that treatment of co-cultures with the HKPS peptide and BAY11-7082, followed by bortezomib, increased H929 cell death. Therefore, targeting simultaneously connected signalling elements of BM-MSC responsible for MM cells support with compounds that also have anti-MM activity can be an improved treatment strategy.
Assuntos
Células-Tronco Mesenquimais , Mieloma Múltiplo , Humanos , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Mieloma Múltiplo/metabolismo , NF-kappa B/metabolismo , Linhagem Celular Tumoral , Células-Tronco Mesenquimais/metabolismo , Microambiente TumoralRESUMO
Chagas disease is an endemic disease of the American continent caused by Trypanosoma cruzi and divided into six discrete typing units (TcI - TcVI). Nearly 10 million people harbour the infection representing a serious issue in public health. Epidemiological surveillance allowed us to detect a bat-related T. cruzi genotype (henceforth named TcBat) in a 5-year-old female living in a forest area in northwestern Colombia. Molecular tools determined a mixed infection of T. cruzi I and TcBat genotypes. This represents the first report of TcBat infection in humans; the epidemiological consequences of this finding are discussed herein.
Assuntos
Doença de Chagas/transmissão , Trypanosoma cruzi , Zoonoses/parasitologia , Animais , Doença de Chagas/sangue , Doença de Chagas/epidemiologia , Pré-Escolar , Quirópteros/parasitologia , Colômbia/epidemiologia , Ensaio de Imunoadsorção Enzimática , Feminino , Genótipo , Humanos , Vigilância da População , Trypanosoma cruzi/genética , Zoonoses/transmissãoRESUMO
UNLABELLED: Human parvovirus B19 (PVB19) is the etiologic agent of erythema infectiosum (fifth disease), a common childhood exanthema. Immunocompromised patients risk developing chronic infections leading to pure red blood cell aplasia. Herein we have reported our experience with two pediatric renal transplant recipients who had severe pure red cell aplasia in the early period after surgery, accompanying PVB19 infection. FIRST CASE: A 6-year-old boy underwent pro emptive living-related renal transplantation in September 2006. On day 4, he developed abdominal discomfort and diarrhea. After transplantation, he began an asymptomatic drop in hematocrit without reticulocytosis, which was unresponsive to recombinant erythropoietin. Diarrhea also persisted. Polymerase chain reaction (PCR) was positive for cytomegalovirus (CMV) in the gastrointestinal tract. PVB19 was confirmed by PCR on a bone marrow sample. He was transfused with packed red cells and treated with ganciclovir and intravenous immunoglobulin (IVIG). His hematocrit increased and diarrhea ended. Six months later anemia recurred requiring a second infusion of IVIG. Subsequently he has done well. SECOND CASE: A 15-year-old boy received a living-related renal transplant in October 2006, after 2 years on automated peritoneal dialysis. One month later he developed a progressive, nonregenerative anemia. A bone marrow aspirate confirmed a PVB19 infection by PCR. He received a blood transfusion and IVIG with a favorable response. CONCLUSIONS: The presence of persistent anemia in immunocompromised hosts with a low reticulocyte count suggests PVB19 infection. IVIG therapy is effective to treat chronic PVB19 infections.
Assuntos
Anemia/etiologia , Ganciclovir/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Transplante de Rim/efeitos adversos , Infecções por Parvoviridae/diagnóstico , Infecções por Parvoviridae/tratamento farmacológico , Parvovirus B19 Humano , Adolescente , Antivirais/uso terapêutico , Criança , Creatinina/sangue , Hematócrito , Humanos , Masculino , Parvovirus B19 Humano/genética , Parvovirus B19 Humano/isolamento & purificação , Reação em Cadeia da PolimeraseRESUMO
Between 1989 and 2002, 178 renal transplants were performed in 168 pediatric patients in Chile. The mean age was 10.9 +/- 3.7 years (range 1 to 17.9). End-state renal disease etiologies were: congenital renal hypoplasia/dysplasia, chronic glomerulonephritis, and reflux nephropathy. Seventy received a graft from a living donor (LD), and 108 from a cadaveric donor (CD). Only 9% received antibody induction. Acute rejection episodes were reported in 76 patients: 38% in LD recipients and 48% in CD recipients (P = NS). One-, 3-, and 5-year graft survivals were 88%, 84%, and 76%, respectively, for LD and 86%, 79%, and 68% for CD recipients. Actuarial graft survival was significantly better among those patients with serum creatinine < 1 mg/dL at 1 year posttransplant compared with those with creatinine > 1 mg/dL (P < .05). The graft survival rate has improved from the first period (1989 to 1996) to the second period (1997 to 2002); (P = .05). Patient survival rates at 1, 3, and 5 years were 98%, 98%, and 98%, respectively, for LD, and 95%, 94%, and 94% for CD. Global height/age Z-score decreased from -0.7 at birth to -1.5 when dialysis started, and to -2.4 at the time of transplantation. The Z-score height/age at 1, 3, and 5 years posttransplantation was -2.25, -2.24, and -2.5. No significant differences were observed in transplant outcomes comparing patients younger than 7 years with those older ones. In conclusion, pediatric renal transplant has been performed in Chile with acceptable morbidity. The patient and graft survivals are similar to the reported international experience. In the last period there was a significant improvement in graft survival.