RESUMO
JAK proteins have been linked with survival and proliferation of multiple myeloma (MM) cells; therefore, JAK inhibition could be a therapeutic strategy for MM. We evaluated JAK1 and JAK2 expression in MM patients and the effects of JAK/STAT pathway inhibition on apoptosis, cell cycle, gene and protein expression in RPMI-8226 and U266 MM cell lines. 57% of patients presented overexpression of JAK2 and 27%, of JAK1. After treatment with ruxolitinib and bortezomib, RPMI-8226 and U266 presented 50% of cells in late apoptosis, reduction of anti-apoptotic genes expression and higher number of cells in SubG0 phase. Co-culture with stromal cells protected RPMI-8226 cells from apoptosis, which was reversed by lenalidomide addition. Combination of ruxolitinib, bortezomib and lenalidomide induced 72% of cell death, equivalent to bortezomib, lenalidomide and dexamethasone, combination used in clinical practice. Many JAK/STAT pathway genes, after treatment, had their expression reduced, mainly in RPMI-8226, with insignificant changes in U266. In this scenario, JAK/STAT pathway could pose as a new therapeutic target to be exploited, since it is constitutively active and contributes to survival of MM tumor cells.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Bortezomib/farmacologia , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Mieloma Múltiplo/tratamento farmacológico , Pirazóis/farmacologia , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos , Talidomida/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Relação Dose-Resposta a Droga , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Janus Quinase 1/genética , Janus Quinase 1/metabolismo , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Lenalidomida , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/enzimologia , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Nitrilas , Pirimidinas , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Células Estromais/patologia , Talidomida/farmacologia , Fatores de TempoRESUMO
Describing the distribution of aquatic habitats and the health of biological communities can be costly and time-consuming; therefore, simple, inexpensive methods to scale observations of aquatic biota to watersheds that lack data would be useful. In this study, we explored the potential of a simple "hydrogeomorphic" model to predict the effects of acid deposition on macroinvertebrate, fish, and diatom communities in 28 sub-watersheds of the 176-km2 Neversink River basin in the Catskill Mountains of New York State. The empirical model was originally developed to predict stream-water acid neutralizing capacity (ANC) using the watershed slope and drainage density. Because ANC is known to be strongly related to aquatic biological communities in the Neversink, we speculated that the model might correlate well with biotic indicators of ANC response. The hydrogeomorphic model was strongly correlated to several measures of macroinvertebrate and fish community richness and density, but less strongly correlated to diatom acid tolerance. The model was also strongly correlated to biological communities in 18 sub-watersheds independent of the model development, with the linear correlation capturing the strongly acidic nature of small upland watersheds (< 1 km2). Overall, we demonstrated the applicability of geospatial data sets and a simple hydrogeomorphic model for estimating aquatic biological communities in areas with stream-water acidification, allowing estimates where no direct field observations are available. Similar modeling approaches have the potential to complement or refine expensive and time-consuming measurements of aquatic biota populations and to aid in regional assessments of aquatic health.
Assuntos
Ecossistema , Água Doce , Fenômenos Geológicos , Animais , Concentração de Íons de Hidrogênio , Modelos Teóricos , New York , Dinâmica PopulacionalRESUMO
The aim of the present study was to determine whether there is an association between serum free light chains (sFLC) quantification and the development of post-transplant lymphoproliferative disorder (PTLD), using serum samples from a nested case-control cohort of patients with renal transplant. Ten new cases of PTLD and 46 controls were enrolled. Additional comparison groups consisted of five human immunodeficiency virus (HIV)-infected individuals, five with untreated Hodgkin lymphoma and six normal individuals. Serum κ and λ FLC concentrations were measured by nephelometry and compared with reference ranges (normal and renal ranges). κ and/or λ were above the normal range in 90% of cases and in 65% of matched controls. There was no statistically significant difference between all groups, except for λ FLC concentrations between cases of PTLD and normal individuals (p = 0.016). The κ/λ sFLC ratios of cases and controls were within the renal range and normal range. Our results suggest that sFLC are not useful to predict PTLD development in renal transplant recipients.
Assuntos
Cadeias Leves de Imunoglobulina/sangue , Transplante de Rim , Linfoma/sangue , Linfoma/etiologia , Adulto , Estudos de Casos e Controles , Infecções por Vírus Epstein-Barr/sangue , Infecções por Vírus Epstein-Barr/complicações , Feminino , Infecções por HIV/sangue , Infecções por HIV/complicações , Doença de Hodgkin/sangue , Doença de Hodgkin/etiologia , Humanos , Cadeias kappa de Imunoglobulina/sangue , Cadeias lambda de Imunoglobulina/sangue , Testes de Função Renal , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
The exact function of MAGE-C1/CT7 and MAGE-C2/CT10 is not yet understood in multiple myeloma (MM). However, the homologs MAGE-C1/CT7 and MAGE-C2/CT10 genes encode highly immunogeneic cancer/testis antigens (CTAs) and can be potential targets for T cell-based immunotherapy. MAGE-C1/CT7 and MAGE-C2/CT10 mRNA expression were investigated in MM patients, solitary plasmacytomas, monoclonal gammopathies of undetermined significance (MGUS) and bone marrow (BM) aspirates from healthy donors by RT-PCR. MAGE-C1/CT7 and MAGE-C1/CT10 were expressed in 67 and 59 % of the 46 MM analyzed patients. At least one of the genes was expressed in 76 % of MM cases. Solitary plasmacytoma also showed MAGE-C1/CT7 and MAGE-C2/CT10 expression. MAGE-C1/CT7 and MAGE-C2/CT10 were not expressed in normal BM samples, showing restricted expression of these CTA genes in MM, solitary plasmacytoma and MGUS. In the present study, we found high expression of the homologs MAGE-C1/CT7 and MAGE-C2/CT10 in monoclonal gammopathies and speculate whether these genes might represent a valuable therapeutic option for myeloma, in particular for combined immunotherapy.
Assuntos
Antígenos de Neoplasias/biossíntese , Regulação da Expressão Gênica , Imunoterapia , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/terapia , Proteínas de Neoplasias/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/análise , Biomarcadores/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Proteínas de Neoplasias/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , TranscriptomaRESUMO
The development of multiple myeloma (MM) involves a series of genetic alterations and changes in the bone marrow microenvironment, favoring the growth of the tumor and failure of local immune control. Quantitative and functional alterations in CD4(+) and CD8(+) T cells have been described in MM. The balance between T regulatory cells (Treg) and T helper (Th) 17 cells represents one essential prerequisite for maintaining anti-tumor immunity in MM. Tregs play an important role in the preservation of self-tolerance and modulation of overall immune responses against infections and tumor cells. In MM patients, Tregs seem to contribute to myeloma-related immune dysfunction and targeting them could, therefore, help to restore and enhance vital immune responses. Th17 cells protect against fungal and parasitic infections and participate in inflammatory reactions and autoimmunity. The interplay of TGF-ß and IL-6, expressed at high levels in the bone marrow of myeloma patients, may affect generation of Th17 cells both directly or via other pro-inflammatory cytokines and thereby modulate antitumor immune responses. A detailed analysis of the balance between Tregs and Th17 cells seems necessary in order to design more effective and less toxic modes of immunotherapy myeloma which still is an uncurable malignancy.
Assuntos
Mieloma Múltiplo/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Fatores de Transcrição Forkhead/biossíntese , Fatores de Transcrição Forkhead/imunologia , Humanos , Tolerância Imunológica , Interleucina-6/biossíntese , Interleucina-6/imunologia , Mieloma Múltiplo/patologia , Linfócitos T Reguladores/patologia , Células Th17/patologia , Fator de Crescimento Transformador beta/biossíntese , Fator de Crescimento Transformador beta/imunologiaRESUMO
Plant-based management systems implementing deep-rooted, perennial vegetation have been identified as important in mitigating the spread of secondary dryland salinity due to its capacity to influence water table depth. The Glenelg Hopkins catchment is a highly modified watershed in the southwest region of Victoria, where dryland salinity management has been identified as a priority. Empirical relationships between the proportion of native vegetation and in-stream salinity were examined in the Glenelg Hopkins catchment using a linear regression approach. Whilst investigations of these relationships are not unique, this is the first comprehensive attempt to establish a link between land use and in-stream salinity in the study area. The results indicate that higher percentage land cover with native vegetation was negatively correlated with elevated in-stream salinity. This inverse correlation was consistent across the 3 years examined (1980, 1995, and 2002). Recognising the potential for erroneously inferring causal relationships, the methodology outlined here was both a time and cost-effective tool to inform management strategies at a regional scale, particularly in areas where processes may be operating at scales not easily addressed with on-site studies.
Assuntos
Monitoramento Ambiental/métodos , Poluição da Água/análise , Sistemas de Informação Geográfica , Plantas , Rios , Cloreto de Sódio , Fatores de Tempo , VitóriaRESUMO
Pathogen contamination of the public drinking water supply in the New York City watersheds is a serious concern. New York City's Watershed Agriculture Program is working with dairy farms in the watersheds to implement management practices that will reduce the risk of pathogens contaminating the water supply. Solar calf housing (SCH) was suggested as a best management practice (BMP) to control Cryptosporidium parvum, a common protozoan parasite that causes disease in humans. This BMP targets young calves because they are the primary source of C. parvum in dairy herds. The objective of this project was to assess and compare the survivability of C. parvum in SCH and in conventional calf housing (CCH), usually located in the main barn. C. parvum oocysts were secured in sentinel chambers and placed in SCH and CCH bedding on four farms. The chambers were in thermal, chemical, and moisture equilibrium with their microenvironments. An oocyst-filled control chamber, sealed from its surroundings, was placed near each chamber. Chambers and controls were sampled after 4, 6, and 8 wk. Oocyst viability in the chambers decreased to less than 10% in warm months and between 15 and 30% in the winter months. The viability of the control oocysts was similar to the chambers during warm months and generally higher during winter months. There was no significant (P > 0.05) difference in the viability decrease between SCH and CCH. Although oocyst viability was similar in both types of calf housing, SCH allow contaminated calf manure to be isolated from the main barn manure and potentially managed differently and in a way to decrease the number of viable oocysts entering the environment during field spreading.
Assuntos
Cryptosporidium parvum/isolamento & purificação , Abrigo para Animais , Oocistos/isolamento & purificação , Animais , Bovinos , Fezes/parasitologia , Cidade de Nova Iorque , Contagem de Ovos de Parasitas , Abastecimento de ÁguaRESUMO
Though runoff from manure spread fields is recognized as an important mode of nonpoint-source pollution, there are no models that mechanistically describe transport from a field-spread manure-type source. A mechanistic, physically based model for pollutant release from a surface source, such as field-spread manure, was hypothesized, laboratory tested, and field-applied. The primary objective of this study was to demonstrate the potential applicability of a mechanistic model to pollutant release from surface sources. The laboratory investigation used stable sources and a conservative "pollutant" (KCl) so that the dynamic effects of source dissolution and chemical transformations could be ignored and transport processes isolated. The field investigation used runoff and soluble reactive phosphorus (SP) data collected from a dairy-manure-spread field in the Cannonsville watershed in the Catskills region of New York State. The model predictions corroborated well with observations of runoff and pollutant delivery in both the laboratory and the field. "Pollutant" release from surface sources was generally predicted within 11% of laboratory KCl measurements and field SP observations. Laboratory flume runoff predictions with 15 and 26% errors for 25 and 15 mm h(-1) simulated rainfall intensity experiments, respectively, represented root mean square errors of less than 0.2 mLs(-1). A 26% error was calculated for overland flow predictions in the field, which translated into approximately a 39 mLs(-1) error. Results suggest that the hypothesized model satisfactorily represents the primary mechanisms in pollutant release from surface sources.