Environmental risk factors of leishmaniasis in Bahia State, Brazil using NASA Earth observation satellites / Fatores de risco ambientais para leishmanioses no estado da Bahia, Brasil, utilizando satélites da NASA de observação da Terra

NASA’s Earth Observing Satellites (EOS) were used to calculate three vegetation indices, extract precipitation and elevation data, and then evaluate their applicability for assessing risk of visceral leishmaniasis (VL) and cutaneous leishmaniasis (CL) in Bahia State, Brazil. Regression models showed that either form of leishmaniasis can be predicted by NDVI, NDMI, NDWI data products and TRMM) precipitation data (R2 = 0.370; p<0.001). Elevation was not significantly associated with the distribution of either VL or CL. In areas of high annual precipitation, CL was 3.6 times more likely to occur than VL. For vegetative moisture (NDMI), CL was 2.11 times more likely to occur than VL. Odds of CL occurrence increased to 5.5 times when vegetation (NDVI) and 13.5 times when liquid water content of vegetation canopies (NDWI) was considered. Areas at risk of CL and VL were mapped based on the selected explanatory variables. Accuracy of models were assessed using area under the receiver operating characteristic curve (AUC=0.72). We propose that statewide scale risk models based on use of EOS products will be a useful tool at 1 km2 spatial resolution to enable health workers to identify and target high risk areas to prevent transmission of leishmaniasis.

Os satélites de observação da Terra (SOT) da NASA foram usados para calcular três índices de vegetação, extrair dados de precipitação e elevação e avaliar sua aplicabilidade para identificar o risco para leishmaniose visceral (LV) e leishmaniose tegumentar (LT) no Estado da Bahia, Brasil. Modelos de regressão mostraram que ambas as formas de leishmaniose podem ser preditas pelos NDVI, NDMI, NDWI e precipitação TRMM (R2 = 0,370; p<0,001). A elevação não foi significativamente associada à distribuição de LV ou LT. Em áreas de alta precipitação anual, a LT foi 3,6 vezes mais provável de ocorrer do que a LV. Para a umidade vegetativa (NDMI), a LT apresentou 2,11 maior probabilidade de ocorrer do que a LV. As chances de ocorrência de LT aumentaram para 5,5 vezes em relação com a vegetação (NDVI) e 13,5 vezes quando o conteúdo de água líquida dos dosséis da vegetação (NDWI) foi considerado. Áreas em risco de LT e LV foram mapeadas com base nas variáveis explicativas selecionadas. A precisão dos modelos foi avaliada usando a área sob curva característica de operação do receptor (Curva COR=0,72). Propusemos que os modelos de risco em escala estadual baseados no uso de produtos SOT são uma ferramenta útil na resolução espacial de 1 km2 por permitir que profissionais de saúde identifiquem e direcionem áreas de alto risco para evitar a transmissão da leishmaniose.

Environmental risk factors of leishmaniasis in Bahia State, Brazil using NASA Earth observation satellites / Fatores de risco ambientais para leishmanioses no estado da Bahia, Brasil, utilizando satélites da NASA de observação da Terra

NASA's Earth Observing Satellites (EOS) were used to calculate three vegetation indices, extract precipitation and elevation data, and then evaluate their applicability for assessing risk of visceral leishmaniasis (VL) and cutaneous leishmaniasis (CL) in Bahia State, Brazil. Regression models showed that either form of leishmaniasis can be predicted by NDVI, NDMI, NDWI data products and TRMM) precipitation data (R2= 0.370; p<0.001). Elevation was not significantly associated with the distribution of either VL or CL. In areas of high annual precipitation, CL was 3.6 times more likely to occur than VL. For vegetative moisture (NDMI), CL was 2.11 times more likely to occur than VL. Odds of CL occurrence increased to 5.5 times when vegetation (NDVI) and 13.5 times when liquid water content of vegetation canopies (NDWI) was considered. Areas at risk of CL and VL were mapped based on the selected explanatory variables. Accuracy of models were assessed using area under the receiver operating characteristic curve (AUC=0.72). We propose that statewide scale risk models based on use of EOS products will be a useful tool at 1 km2 spatial resolution to enable health workers to identify and target high risk areas to prevent transmission of leishmaniasis.(AU)

Os satélites de observação da Terra (SOT) da NASA foram usados para calcular três índices de vegetação, extrair dados de precipitação e elevação e avaliar sua aplicabilidade para identificar o risco para leishmaniose visceral (LV) e leishmaniose tegumentar (LT) no Estado da Bahia, Brasil. Modelos de regressão mostraram que ambas as formas de leishmaniose podem ser preditas pelos NDVI, NDMI, NDWI e precipitação TRMM (R2 = 0,370; p<0,001). A elevação não foi significativamente associada à distribuição de LV ou LT. Em áreas de alta precipitação anual, a LT foi 3,6 vezes mais provável de ocorrer do que a LV. Para a umidade vegetativa (NDMI), a LT apresentou 2,11 maior probabilidade de ocorrer do que a LV. As chances de ocorrência de LT aumentaram para 5,5 vezes em relação com a vegetação (NDVI) e 13,5 vezes quando o conteúdo de água líquida dos dosséis da vegetação (NDWI) foi considerado. Áreas em risco de LT e LV foram mapeadas com base nas variáveis explicativas selecionadas. A precisão dos modelos foi avaliada usando a área sob curva característica de operação do receptor (Curva COR=0,72). Propusemos que os modelos de risco em escala estadual baseados no uso de produtos SOT são uma ferramenta útil na resolução espacial de 1 km2 por permitir que profissionais de saúde identifiquem e direcionem áreas de alto risco para evitar a transmissão da leishmaniose. (AU)

Selective inhibition of Rab prenylation by a phosphonocarboxylate analogue of risedronate induces apoptosis, but not S-phase arrest, in human myeloma cells.

Bisphosphonates (BPs) are widely used in the treatment of osteolytic bone disease associated with multiple myeloma, and have been demonstrated to exert antitumor effects both in vitro and in vivo. However, the precise molecular mechanisms involved in the direct antitumor effects of BPs in vitro are not known. Nitrogen-containing BPs, such as risedronate (RIS), act by inhibiting protein prenylation. A phosphonocarboxylate analogue of RIS, 3-PEHPC, has previously been shown in osteoclasts and macrophages to specifically inhibit prenylation of Rab GTPases. The aim of this study was to identify the molecular targets of RIS and 3-PEHPC in human myeloma cells and to determine the cellular effects of selective inhibition of Rab prenylation by 3-PEHPC as compared to nonspecific inhibition of protein prenylation by RIS in human myeloma cells. RIS dose-dependently inhibited prenylation of both Rap1A and Rab6, whereas 3-PEHPC only inhibited Rab6 prenylation. Both RIS and 3-PEHPC dose-dependently increased apoptosis in human myeloma cells. RIS induced an accumulation of cells in the S-phase of the cell cycle, associated with inhibition of DNA replication. In contrast, 3-PEHPC did not cause cell-cycle arrest. Furthermore, geranylgeraniol could prevent inhibition of prenylation, induction of apoptosis, and cell-cycle arrest in response to RIS, but not inhibition of Rab prenylation and apoptosis induced by 3-PEHPC, consistent with specific inhibition of Rab geranylgeranyl transferase by 3-PEHPC. In conclusion, our studies demonstrate that selective inhibition of Rab prenylation induces apoptosis, but not S-phase arrest, thus identifying distinct molecular pathways that mediate the antimyeloma effect of nitrogen-containing BPs.

Role of osteoprotegerin (OPG) in cancer.

OPG (osteoprotegerin), a secreted member of the TNF (tumour necrosis factor) receptor superfamily, has a variety of biological functions which include the regulation of bone turnover. OPG is a potent inhibitor of osteoclastic bone resorption and has been investigated as a potential therapeutic for the treatment of both osteoporosis and tumour-induced bone disease. Indeed, in murine models of cancer-induced bone disease, inhibition of osteoclastic activity by OPG was also associated with a reduction in tumour burden. The discovery that OPG can bind to and inhibit the activity of TRAIL (TNF-related apoptosis-inducing ligand) triggered extensive research into the potential role of OPG in the regulation of tumour cell survival. A number of reports from studies using in vitro models have shown that OPG protects tumour cells from the effects of TRAIL, thereby possibly providing tumour cells that produce OPG with a survival advantage. However, the ability of OPG to act as a tumour cell survival factor remains to be verified using appropriate in vivo systems. A third area of interest has been the use of OPG as a prognostic marker in various cancer types, including myeloma, breast and prostate cancer. This review provides an overview of the role of OPG in cancer, both in cancer-induced bone disease and in tumour growth and survival.

Advances in the management of myeloma bone disease.

Multiple myeloma is the second most common adult haematological malignancy. One of the major clinical features is the development of a unique osteolytic bone disease, characterised by progressive and devastating bone destruction, bone pain, pathological fractures and hypercalcaemia. Bisphosphonates, inhibitors of osteoclastic bone resorption, are the standard therapy for myeloma-induced bone disease. However, as our understanding of the molecular mechanisms involved in the development of myeloma bone disease increases, new molecular targets have been identified for the treatment of this devastating bone disease.

Osteoprotegerin is a soluble decoy receptor for tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand and can function as a paracrine survival factor for human myeloma cells.

Myeloma cells grow only in the bone marrow closely associated with bone,suggesting that this microenvironment provides critical signals for their growth and survival. Osteoprotegerin (OPG) is a member of the tumor necrosis factor (TNF) receptor family, which binds to the ligand for receptor activator of nuclear factor kappa B and inhibits bone resorption. However, it is unclear whether OPG can also bind to other TNF family members, such as TNF-related apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo2L), and, by inhibiting their activity, function as a survival factor for myeloma cells. In the present study MG63 osteoblast-like cells and primary bone marrow stromal cells were both shown to produce OPG, whereas human myeloma cells did not produce OPG but down-regulated release of OPG from MG63 cells. TRAIL/Apo2L induced apoptosis in myeloma cells, and this could be prevented with the addition of recombinant OPG. Medium conditioned by MG63 cells was also shown to inhibit TRAIL/Apo2L-induced apoptosis, an effect that was reversed by the addition of soluble receptor activator of nuclear factor kappa B ligand. Medium conditioned by cocultures of MG63 cells with myeloma cells had a reduced effect on TRAIL/Apo2L-induced apoptosis, reflecting the decreased concentrations of OPG in cocultures of myeloma cells with bone cells. These observations suggest that OPG may function as a paracrine survival factor in the bone marrow microenvironment in multiple myeloma.

Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease: evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival.

Multiple myeloma is characterized by the growth of plasma cells in the bone marrow and the development of osteolytic bone disease. Myeloma cells are found closely associated with bone, and targeting this environment may therefore affect both the bone disease and the growth of myeloma cells. We have investigated the effect of the potent bisphosphonate, zoledronic acid, on the development of bone disease, tumor burden, and disease-free survival in the 5T2MM model of myeloma. 5T2MM murine myeloma cells were injected intravenously into C57BL/KaLwRij mice. After 8 weeks, all animals had a paraprotein. Animals were treated with zoledronic acid (120 microg/kg, subcutaneously, twice weekly) or vehicle, from the time of tumor cell injection or from paraprotein detection for 12 or 4 weeks, respectively. All animals injected with tumor cells developed osteolytic lesions, a decrease in cancellous bone volume, an increase in osteoclast perimeter, and a decrease in bone mineral density. Zoledronic acid prevented the formation of lesions, prevented cancellous bone loss and loss of bone mineral density, and reduced osteoclast perimeter. Zoledronic acid also decreased paraprotein concentration, decreased tumor burden, and reduced angiogenesis. In separate experiments, Kaplan-Meier analysis demonstrated a significant increase in survival after treatment with zoledronic acid when compared with control (47 vs. 35 days). A single dose of zoledronic acid was also shown to be effective in preventing the development of osteolytic bone disease. These data show that zoledronic acid is able to prevent the development of osteolytic bone disease, decrease tumor burden in bone, and increase survival in a model of established myeloma.

Recombinant osteoprotegerin decreases tumor burden and increases survival in a murine model of multiple myeloma.

The aim of the present study was to determine whether modifying the local bone environment with osteoprotegerin (OPG), the soluble decoy receptor for receptor activator of nuclear factor-kappaB (RANK) ligand, could affect tumor burden and survival in the 5T33MM murine model of multiple myeloma. Treatment of mice, injected with 5T33MM cells, with recombinant OPG (Fc-OPG) caused a significant decrease in serum paraprotein and tumor burden and a significant increase in time to morbidity. This was associated with a decrease in osteoclast number in vivo but had no effect on apoptosis and proliferation of 5T33MM cells in vitro. These data indicate that targeting the bone microenvironment by inhibiting the interaction between RANK ligand and RANK with Fc-OPG not only inhibits the development of myeloma bone disease but also decreases tumor growth and increases survival.

Bisphosphonates and osteoprotegerin as inhibitors of myeloma bone disease.

BACKGROUND: A major clinical feature in multiple myeloma is the development of osteolytic bone disease. The increase in bone destruction is due to uncontrolled osteoclastic bone resorption. Until recently the factors responsible for mediating the increase in osteoclast formation in myeloma have been unclear. However, recent studies have implicated a number of factors, including the ligand for receptor activator of NFkappaB (RANKL) and macrophage inflammatory protein-1alpha. The demonstration that increased osteoclastic activity plays a central role in this process and the identification of molecules that may play a critical role in the development of myeloma bone disease have resulted in studies aimed at identifying new approaches to treating this aspect of myeloma. METHODS: Studies have been performed to determine the ability of recombinant osteoprotegerin (Fc.OPG), a soluble decoy receptor for RANKL, and potent new bisphosphonates to inhibit the development of myeloma bone disease in the 5T2MM murine model of multiple myeloma. RESULTS: Fc.OPG was shown to prevent the development of osteolytic bone lesions in 5T2MM bearing animals. These changes were associated with a preservation of the cancellous bone loss induced by myeloma cells and an inhibition of osteoclast formation. Bisphosphonates, including ibandronate and zoledronic acid, were also shown to inhibit the development of osteolytic bone lesions in the 5T2MM model and alternative models of myeloma bone disease. CONCLUSIONS: Bisphosphonates and Fc.OPG are effective inhibitors of the development of osteolytic bone lesions in pre-clinical murine models of myeloma bone disease.