RESUMO
The combination of continuum and ultrafast pump-probe spectroscopy with DFT and TDDFT calculations, in viscous and non-viscous environments, is effective in unraveling important features of the twisted intramolecular charge transfer mechanism in a new push-pull molecule that possesses aggregation induced emission properties. Long-living optical gain is found when this mechanism is inhibited, highlighting the importance of the environment rigidity in the design of materials for photonic applications.
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This study aimed to analyze laboratory and field data to assess the ecotoxicological risks of calcium nitrate exposure to freshwater tropical biota. Short-term laboratorial tests resulted in estimated EC50 values of 76.72 (67.32-86.12)mg N-NO3â L(-1) for C. silvestrii and 296.46 (277.16-315.76) mg N-NO3â L(-1) for C. xanthus. Long-term laboratorial tests generated IC25 values of 5.05 (4.35-5.75) and 28.73 (26.30-31.15) mg N-NO3â L(-1) for C. silvestrii and C. xanthus, respectively. The results from in situ mesocosm experiments performed in the Ibirité reservoir (a tropical eutrophic urban water body located in SE Brazil) indicated that C. silvestrii and C. xanthus were not under severe deleterious acute impact due to the treatment because the higher nitrate concentrations determined were 5.2 mg N-NO3â L(-1) (t=24 h; sediment-water interface) and 17.5 mg N-NO3â L(-1) (t=600 h; interstitial water). However, an abrupt decrease in the densities of Cyanophyceae members and other benthic taxa was observed. In summary, the present work contributes greatly to the toxicity data linked to two taxonomically distinct organisms that have never been screened for calcium nitrate sensitivity. Furthermore, considering the problem of the management and restoration of eutrophic environments, our study reports a comprehensive field assessment that allows the elucidation of the possible toxic impacts caused by the addition of calcium nitrate (a remediation technique) on aquatic and benthic organisms as well as the implications on the aquatic ecosystem as a whole, which may greatly allow expanding the current knowledgebase on the topic.
Assuntos
Compostos de Cálcio/toxicidade , Nitratos/toxicidade , Animais , Organismos Aquáticos , Brasil , Cladocera , Ecossistema , Ecotoxicologia , Água Doce , Risco , Testes de Toxicidade , Clima TropicalAssuntos
Francisella tularensis/isolamento & purificação , Coelhos , Tularemia/veterinária , Animais , Diagnóstico Diferencial , Fígado/microbiologia , Fígado/patologia , Linfonodos/microbiologia , Linfonodos/patologia , Baço/microbiologia , Baço/patologia , Tularemia/diagnóstico , Tularemia/microbiologia , Tularemia/patologiaRESUMO
The impact of primary cooling on beef microbiota was investigated on six beef carcasses consecutively processed with the parallel use of metataxonomic and culture-dependent analysis. Samples were collected immediately after slaughtering (AS) and after the 24th-hour post-cooling (PC) from three different surfaces, namely neck, flank and thigh. The main objective was to examine whether the microbiota composition of beef carcasses changes as function of the surface sampled, primary cooling (from AS to PC) and animal's origin (breeder). The outcomes underline that primary cooling did not affect qualitatively the composition of the potentially active microbiota or the carcass superficial counts. Although slight changes in chemical-physical parameters like volatile organic compounds (VOCs) were observed after cooling, the carcasses microbiota and its inferred metabolic pathways varied among animals as a function of their origin. Co-occurrence and co-exclusion analyses underlined competition for the colonisation of the carcass surface between Brochothrix-Psychrobacter and Carnobacterium-Serratia-Pseudomonas. Once integrated in a comprehensive monitoring of the supply chain, the metataxonomic characterisation of the beef carcasses microbiota might represent a valid integrative approach to define the cuts' perishability and their appropriateness to specific packaging and storage methods. These new bits of knowledge could be the base to define good strategies for the prevention of meat spoilage.
Assuntos
Microbiologia de Alimentos , Microbiota , Animais , Bovinos , Carne , Temperatura BaixaRESUMO
Cetuximab is a human/mouse chimeric IgG1 monoclonal antibody (mAb) to epidermal growth factor receptor, approved for colorectal carcinoma treatment in combination with chemotherapy. The immune-mediated effects elicited by its human fraction of crystallization moiety might critically contribute to the overall anti-tumor effectiveness of the antibody. We therefore investigated cetuximab ability to promote colon cancer cell opsonization and phagocytosis by human dendritic cells (DCs) that are subsequently engaged in antigen-cross presentation to cytotoxic T-lymphocyte (CTL) precursors. Human colon cancer cell lines were evaluated for susceptibility to DC-mediated phagocytosis before and after treatment with chemotherapy ± cetuximab in vitro. Human DCs loaded with control or drug-treated cetuximab-coated colon cancer cells were used to in vitro generate cytotoxic T cell clones from peripheral blood mononuclear cells of human leucocyte antigen-A(*)02.01(+) donors. T-cell cultures were characterized for immune-phenotype and tumor-antigen specific CTL activity. The results confirmed that treatment of tumor cells with irinotecan + L-folinate + 5-flurouracil (ILF) or with gemcitabine + ILF increased tumor antigen expression. Moreover, malignant cells exposed to chemotherapy and cetuximab were highly susceptible to phagocytosis by human DCs and were able to promote their activation. The consequent DC-mediated cross-priming of antigens derived from mAb-covered/drug-treated cancer cells elicited a robust CTL anti-tumor response. On the basis of our data, we suggest a possible involvement of CTL-dependent immunity in cetuximab anti-cancer effects.
Assuntos
Anticorpos Monoclonais/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/imunologia , Células Dendríticas/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Linfócitos T Citotóxicos/efeitos dos fármacos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados , Células Apresentadoras de Antígenos/efeitos dos fármacos , Células Apresentadoras de Antígenos/imunologia , Antígenos de Neoplasias/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/imunologia , Linhagem Celular Tumoral , Cetuximab , Apresentação Cruzada/efeitos dos fármacos , Apresentação Cruzada/imunologia , Células Dendríticas/imunologia , Células HT29 , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Fagocitose/imunologia , Linfócitos T Citotóxicos/imunologiaRESUMO
Recent advances have highlighted probiotic role in preventing colorectal cancer, by promoting differentiation, inhibiting proliferation, and inducing apoptosis in colonocytes. Here, three ascertained probiotics (L. rhamnosus GG ATCC 53103, L. reuterii DSM 17938 and L. johnsonii LC1) and four food-isolated putative probiotics (L. plantarum S2, L. plantarum O2, L. pentosus S3, L. rhamnosus 14E4) were investigated for their ability to adhere to HT29 cancer cells and to inhibit their and the chemoresistant counterpart (HT29-dx cells) proliferation. Three putative probiotics (S2, S3 and 14E4) were able to decrease viability of both sensitive and chemo-resistant HT-29 cells. Supposing this effect related to secreted metabolites (namely short chain fatty acids (SCFA), exopolysaccharides (EPS) and extracellular proteins) we tested the efficacy of extracellular extracts and butyrate with or without the chemotherapeutic agent doxorubicin (DOXO) (10 µM, 4 h). Increased production of mitochondrial reactive oxygen species (ROS) in HT29 and HT29-dx cells was observed. Moreover, cell exposure to DOXO (10 µM, 24 h) and extracellular extracts (48 h) reduced cell viability. Comparative phenotypic and secretome analyses on the effective/non effective strains, revealed quantitative/qualitative differences in EPS content and protein profiles, suggesting that P40, phage-tail-like and capsid-like proteins may be also involved. These results suggest that food-isolated bacteria releasing bioactive compounds (butyrate, EPS and peculiar proteins) may control cancer cell proliferation and improve their response to chemotherapy.
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Neoplasias , Probióticos , Butiratos/farmacologia , Sobrevivência Celular , Células HT29 , Humanos , Extratos Vegetais , Probióticos/farmacologiaRESUMO
Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare new syndrome occurring after the ChAdOx1 nCoV-19 vaccine immunization. Patients with VITT are characterized by a variable clinical presentation, likewise also the outcome of these patients is very variable. Here we report the lung ultrastructural findings in the course of VITT of a 58-year-old male patient. Alveoli were mainly dilated, irregular in shape, and occupied by a reticular network of fibrin, while interalveolar septa appeared thickened. The proliferation of small capillaries gave rise to plexiform structures and pulmonary capillary hemangiomatosis-like features. Near the alveoli occupied by a dense fibrin network, the medium-sized arteries showed a modified wall and an intraluminal thrombus. This scenario looks quite similar to that found during COVID-19, where the lungs suffer from the attack of the antigen-antibodies complexes and the virus respectively. In both diseases, the final outcome is a severe inflammation, activation of the haemostatic system and fibrinolysis.
Assuntos
ChAdOx1 nCoV-19/efeitos adversos , Lesão Pulmonar/etiologia , Lesão Pulmonar/patologia , Púrpura Trombocitopênica Idiopática/induzido quimicamente , Vacinação/efeitos adversos , COVID-19/prevenção & controle , ChAdOx1 nCoV-19/imunologia , Fibrina , Humanos , Lesão Pulmonar/diagnóstico por imagem , Lesão Pulmonar/imunologia , Masculino , Microscopia Eletrônica de Varredura , Pessoa de Meia-Idade , Tecido Parenquimatoso/patologia , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/imunologiaRESUMO
A low initial contamination level of the meat surface is the sine qua non to extend the subsequent shelf life of ground beef for as long as possible. Therefore, the short- and long-term effects of a pregrinding treatment with electrolyzed water (EW) on the microbiological and physicochemical features of Piedmontese steak tartare were here assessed on site, by following two production runs through storage under vacuum packaging conditions at 4°C. The immersion of muscle meat in EW solution at 100 ppm of free active chlorine for 90 s produced an initial surface decontamination with no side effects or compositional modifications, except for an external color change that was subsequently masked by the grinding step. However, the initially measured decontamination was no longer detectable in ground beef, perhaps due to a quick recovery by bacteria during the grinding step from the transient oxidative stress induced by the EW. We observed different RNA-based metataxonomic profiles and metabolomic biomarkers (volatile organic compounds [VOCs], free amino acids [FAA], and biogenic amines [BA]) between production runs. Interestingly, the potentially active microbiota of the meat from each production run, investigated through operational taxonomic unit (OTU)-, oligotyping-, and amplicon sequence variant (ASV)-based bioinformatic pipelines, differed as soon as the early stages of storage, whereas microbial counts and biomarker dynamics were significantly distinguishable only after the expiration date. Higher diversity, richness, and abundance of Streptococcus organisms were identified as the main indicators of the faster spoilage observed in one of the two production runs, while Lactococcus piscium development was the main marker of shelf life end in both production runs. IMPORTANCE Treatment with EW prior to grinding did not result in an effective intervention to prolong the shelf life of Piedmontese steak tartare. Our RNA-based approach clearly highlighted a microbiota that changed markedly between production runs but little during the first shelf life stages. Under these conditions, an early metataxonomic profiling might provide the best prediction of the microbiological fate of each batch of the product.
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Contaminação de Alimentos/análise , Lactococcus/crescimento & desenvolvimento , Microbiota/efeitos dos fármacos , Carne Vermelha/microbiologia , Streptococcus/crescimento & desenvolvimento , Água/farmacologia , Animais , Bovinos , Manipulação de Alimentos/métodos , Microbiologia de Alimentos , Armazenamento de Alimentos/métodos , Lactococcus/efeitos dos fármacos , Lactococcus/isolamento & purificação , Streptococcus/efeitos dos fármacos , Streptococcus/isolamento & purificação , Água/química , Microbiologia da ÁguaRESUMO
OBJECTIVE: The ongoing Coronavirus pandemic (COVID-19) showed similar characteristics with the severe acute respiratory syndrome (SARS). In the most compromised cases, COVID-19 infection leads to death due to severe respiratory complications. COVID-19-related acute respiratory distress syndrome (ARDS) is the primary cause of death in these patients. In the present study, we show an ultrastructural analysis on the lungs of a patient affected by COVID-19. PATIENTS AND METHODS: Lung specimens obtained at autopsy from a 63-years old patient affected by COVID-19 were fixed in 1% paraformaldehyde. Slices of 300 µm thickness were dehydrated and dried by Critical Point Drying in CO2. Slices were covered with a conductive gold film approximately 30 nm thick and observed at a Zeiss Sigma 300 SEM FEG in the secondary electron (SE) and backscattered electron (BSE) modes. As case control a lung biopsy from a 60-year-old man was considered. RESULTS: At low power in all COVID-19 lung specimens severe changes in the pulmonary architecture were found, due to the collapse of air spaces. Moreover, alveolar cavities were covered by large membranes. At high power, alveolar membranes showed a fibrillar structure, suggestive of a loose network of fibrin. It has been also found that intra-alveolar red blood cells were frequently present in the alveolar spaces, surrounded by a reticular fibrin network, suggestive for fibrin-hemorrhagic alveolitis. Alveolar changes were constantly associated with pathological features related to the pulmonary vessels. Vascular changes were prominent, including endothelial damage and thrombosis of large pulmonary vessels. Fibrinous microthrombi were frequently detected in the inter-alveolar septal capillaries. In addition, it has been frequently detected capillary proliferation in the alveolar septa with finding suggestive for intussusceptive neo-angiogenesis. CONCLUSIONS: In conclusion, our electron microscopy analysis showed that COVID-19-related lung disease is characterized by a substantial architectural distortion, with the interactions between alveolar and vascular changes. Intra-alveolar hyaline membranes are associated with macro- and micro-thrombotic angiopathy, ending with capillary proliferation. The new blood vessel formation originates from the septa and extends into the surrounding parenchyma. Our findings confirm previous reports on the specificity of the multiple and complex morphological pattern typical, and apparently specific, of COVID-19-related lung disease.
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COVID-19/patologia , Pulmão/ultraestrutura , COVID-19/diagnóstico , COVID-19/virologia , Humanos , Pulmão/patologia , Pulmão/virologia , Masculino , Microscopia Eletrônica de Varredura , Pessoa de Meia-Idade , SARS-CoV-2/patogenicidadeRESUMO
As part of an experimental project on the treatment of bleach plant effluents the results of biodegradability and toxicity assessment of effluents from a bench-scale horizontal anaerobic immobilized bioreactor (HAIB) are discussed in this paper. The biodegradability of the bleach plant effluents from a Kraft pulp mill treated in the HAIB was evaluated using the modified Zahn-Wellens test. The inoculum came from a pulp mill wastewater treatment plant and the dissolved organic carbon (DOC) was used as the indicator of organic matter removal. The acute and chronic toxicity removal during the anaerobic treatment was estimated using Daphnia similis and Ceriodaphnia silvestrii respectively. Moreover, the evaluation of chromosome aberrations (CA), micronucleus frequencies (MN) and mitotic index (IM) in Allium cepa cells were used as genotoxicity indicators. The results indicate that the effluents from the anaerobic reactor are amenable to aerobic polishing. Acute and chronic toxicity were reduced by 90 and 81%, respectively. The largest CA and MN incidence in the meristematic cells of A. cepa were observed after exposure to the raw bleach plant effluent. The HAIB was able to reduce the acute and chronic toxicity as well as chromosome aberrations and the occurrence of micronucleus.
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Anaerobiose , Reatores Biológicos/microbiologia , Clareadores , Hidrocarbonetos Clorados , Poluentes Químicos da Água , Purificação da Água/métodos , Aerobiose , Animais , Biodegradação Ambiental , Clareadores/análise , Clareadores/toxicidade , Daphnia/efeitos dos fármacos , Daphnia/crescimento & desenvolvimento , Hidrocarbonetos Clorados/análise , Hidrocarbonetos Clorados/toxicidade , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Cebolas/efeitos dos fármacos , Cebolas/genética , Cebolas/crescimento & desenvolvimento , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/genética , Raízes de Plantas/crescimento & desenvolvimento , Sementes/efeitos dos fármacos , Sementes/genética , Sementes/crescimento & desenvolvimento , Testes de Toxicidade Aguda/métodos , Testes de Toxicidade Crônica/métodos , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade , Purificação da Água/instrumentaçãoRESUMO
Effluents originated in cellulose pulp manufacturing processes are usually toxic and recalcitrant, specially the bleaching effluents, which exhibit high contents of aromatic compounds (e.g. residual lignin derivates). Although biological processes are normally used, their efficiency for the removal of toxic lignin derivates is low. The toxicity and recalcitrance of a bleached Kraft pulp mill were assessed through bioassays and ultraviolet absorption measurements, i.e. acid soluble lignin (ASL), UV(280), and specific ultraviolet absorption (SUVA), before and after treatment by an integrated system comprised of an anaerobic packed-bed bioreactor and oxidation step with ozone. Furthermore, adsorbable organic halides (AOX) were measured. The results demonstrated not only that the toxic recalcitrant compounds can be removed successfully using integrated system, but also the ultraviolet absorption measurements can be an interesting control-parameter in a wastewater treatment.
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Reatores Biológicos , Ozônio/análise , Poluentes Químicos da Água/análise , Purificação da Água/métodos , Anaerobiose , Biodegradação Ambiental , Celulose , Eucalyptus , Lignina/análise , Ozônio/toxicidade , Purificação da Água/normas , MadeiraRESUMO
We present a single layer, polymer white light emitting diode (WOLED) based on novel organic lanthanide complexes. The device is solution processed and possesses CIE coordinates of (0.33, 0.38), corresponding to a high color purity white light emission. The electroluminescence in this diode is found to originate from both the direct charge trapping on the lanthanide complexes and from the efficient diffusion-assisted long-range energy transfer between the conductive matrix and these emissive dopants. An expression for the steady-state transfer efficiency is given, the role of excitation diffusion in the system under study is quantitatively evaluated, and the values for the singlet exciton diffusion coefficients and diffusion lengths in the host are determined.
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The aim of this study was to jointly show the results of three independent ecotoxicological studies performed to investigate pollutants in three Brazilian tropical reservoirs undergoing accelerated eutrophication. In order to accomplish this goal, the full toxicity identification and evaluation procedure (TIE approach) was performed, at Pampulha (Minas Gerais State) and Salto Grande and Barra Bonita reservoirs (São Paulo State). Acute and chronic toxicity tests were performed using the cladocerans Daphnia similis and Ceriodaphnia dubia (exotic) and Daphnia laevis and Ceriodaphnia silvestrii (native) as test organisms. Results from TIE procedure stage I indicated the existence of nonpolar organic and filterable compounds in the water from Pampulha, probably cyanotoxins, and oxidants as part of the toxic agents. TIE results for sediments identified ammonia (Pampulha and Salto Grande), organic compounds (Pampulha), metals (Pampulha, Barra Bonita, and Salto Grande), and acidity (Salto Grande) as responsible for toxicity. Whole-sediment remediation experiments for Pampulha reservoir confirmed, through reproduction decrease, ammonia and organic compounds as contaminants. Such pollutants represent threats to aquatic biota and must be prevented. Higher temperatures as predicted from global climate change will severely affect tropical shallow reservoirs, accelerating eutrophication, the release of contaminants from sediments, and increasing toxicity.
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Eutrofização , Água Doce/análise , Sedimentos Geológicos/química , Animais , Brasil , Cladocera/efeitos dos fármacos , Daphnia/efeitos dos fármacos , Ecotoxicologia , Clima Tropical , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidadeRESUMO
Dendritic cells (DCs) have a key role in regulating tumor immunity, tumor cell growth and drug resistance. We hypothesized that multiple myeloma (MM) cells might recruit and reprogram DCs to a tumor-permissive phenotype by changes within their microRNA (miRNA) network. By analyzing six different miRNA-profiling data sets, miR-29b was identified as the only miRNA upregulated in normal mature DCs and significantly downregulated in tumor-associated DCs. This finding was validated in primary DCs co-cultured in vitro with MM cell lines and in primary bone marrow DCs from MM patients. In DCs co-cultured with MM cells, enforced expression of miR-29b counteracted pro-inflammatory pathways, including signal transducer and activator of transcription 3 and nuclear factor-κB, and cytokine/chemokine signaling networks, which correlated with patients' adverse prognosis and development of bone disease. Moreover, miR-29b downregulated interleukin-23 in vitro and in the SCID-synth-hu in vivo model, and antagonized a Th17 inflammatory response. All together, these effects translated into strong anti-proliferative activity and reduction of genomic instability of MM cells. Our study demonstrates that MM reprograms the DCs functional phenotype by downregulating miR-29b whose reconstitution impairs DCs ability to sustain MM cell growth and survival. These results underscore miR-29b as an innovative and attractive candidate for miRNA-based immune therapy of MM.
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Células Dendríticas/patologia , Inflamação/genética , MicroRNAs/genética , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Animais , Medula Óssea/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Camundongos , Camundongos SCID , NF-kappa B/genética , Fator de Transcrição STAT3/genética , Regulação para Cima/genéticaRESUMO
BACKGROUND: Kidney transplant recipients are at higher risk of developing pulmonary complications related to immunosuppression, and inhibitor of the mammalian target of rapamycin (mTORi) has been reported as a potential cause. METHODS: Five hundred kidney-transplanted patients were retrospectively analyzed for pulmonary complications on the basis of clinical and instrumental data (chest radiography, high-resolution computed tomography, broncho-alveolar lavage, oximetry). RESULTS: We found 26 interstitial lung diseases (ILD) (16%): 12 cases (46.2%) were from infections (42.8% by Pneumocystis jirovecii) and 14 cases of ILD (53.8%) resulted as drug-induced ILD (DI-ILD). According to anti-rejection protocols, DI-ILD occurred in 8 patients (57%) while on triple regimen including steroids, everolimus (EVL), and cyclosporine (CyA) and in 6 patients on double regimen with steroids and mTORi: EVL or sirolimus (43%). In ILD+ patients, everolimus trough-concentration (EVL(TLC)) and cyclosporine (2nd-hour concentration: CyA(C2)) levels were higher than in patients in the same regimen but with ILD- (EVL(TLC) [ng/mL] 9.84 versus 6.85; CyA(C2) [ng/mL] 303.97 versus 298.56). The formula that used the combined blood levels of both drugs (EVL(TLC) + CyA(C2)/100) resulted in a significant difference between groups of patients (12.88 ± 1.61 versus 9.83 ± 1.91). Applying receiver operator characteristic curve (ROC) analysis to detect risk of developing ILD when on combined protocol with EVL and CyA, we obtained an area under the curve of 0.8622 (P = .0081) and 0.9082 (P = .0028), respectively, when using EVL(TLC) or the combination formula with both drugs. CONCLUSIONS: In renal transplant patients, we obtained a relationship of ILD to specific drug concentration. On the basis of ROC analysis, patients on EVL and CyA combined protocol are at risk of ILD when EVL(TLC) is >9.03 ng/mL or >11.41 when a formula with summation of EVL(TLC) and CyA(C2) is used.
Assuntos
Ciclosporina/uso terapêutico , Everolimo/uso terapêutico , Imunossupressores/uso terapêutico , Transplante de Rim/efeitos adversos , Doenças Pulmonares Intersticiais/etiologia , Complicações Pós-Operatórias/etiologia , Quimioterapia Combinada , Feminino , Humanos , Falência Renal Crônica/cirurgia , Doenças Pulmonares Intersticiais/diagnóstico , Masculino , Complicações Pós-Operatórias/diagnóstico , Valor Preditivo dos Testes , Curva ROC , Estudos Retrospectivos , Sirolimo/uso terapêuticoRESUMO
Multiple myeloma (MM) is closely dependent on cross-talk between malignant plasma cells and cellular components of the inflammatory/immunosuppressive bone marrow milieu, which promotes disease progression, drug resistance, neo-angiogenesis, bone destruction and immune-impairment. We investigated the relevance of inflammatory genes in predicting disease evolution and patient survival. A bioinformatics study by Ingenuity Pathway Analysis on gene expression profiling dataset of monoclonal gammopathy of undetermined significance, smoldering and symptomatic-MM, identified inflammatory and cytokine/chemokine pathways as the most progressively affected during disease evolution. We then selected 20 candidate genes involved in B-cell inflammation and we investigated their role in predicting clinical outcome, through univariate and multivariate analyses (log-rank test, logistic regression and Cox-regression model). We defined an 8-genes signature (IL8, IL10, IL17A, CCL3, CCL5, VEGFA, EBI3 and NOS2) identifying each condition (MGUS/smoldering/symptomatic-MM) with 84% accuracy. Moreover, six genes (IFNG, IL2, LTA, CCL2, VEGFA, CCL3) were found independently correlated with patients' survival. Patients whose MM cells expressed high levels of Th1 cytokines (IFNG/LTA/IL2/CCL2) and low levels of CCL3 and VEGFA, experienced the longest survival. On these six genes, we built a prognostic risk score that was validated in three additional independent datasets. In this study, we provide proof-of-concept that inflammation has a critical role in MM patient progression and survival. The inflammatory-gene prognostic signature validated in different datasets clearly indicates novel opportunities for personalized anti-MM treatment.
Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Inflamação/genética , Mieloma Múltiplo/genética , Proteínas de Neoplasias/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biologia Computacional , Progressão da Doença , Feminino , Humanos , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Proteínas de Neoplasias/biossíntese , Transdução de Sinais/genética , Transcriptoma/genéticaRESUMO
The surfactant complex, thanks to its multiple actions including decrease of surface- tension and antimicrobial activity, plays a fundamental role in newborn survival, lowering the risk of respiratory distress syndrome. The aim of this work was to determine if the synthesis of two surfactant proteins (SP), SPA and pro-SPB, shows some inter-individual variability during lung development in the intrauterine life. Immunoreactivity for SPA and pro-SPB was investigated in the lungs of 40 subjects, including 15 fetuses, ranging from 14 to 22 weeks of gestation, and 25 neonates, from 24 to 41 weeks. Lung samples were formalin fixed, paraffin-embedded and routinely processed. SPA and pro-SPB were detected utilizing commercial antibodies. A semi-quantitative grading system (1 to 4) was applied, based on the number of reactive cells and the intensity of immunostaining. Surfactant protein immunostaining was found in three compartments: bronchi, bronchioles and alveoli, starting from 14 weeks of gestation in the bronchial epithelium and from the 21st week in the alveolar spaces. Differences were found regarding SPA and pro-SPB expression in the vast majority of subjects: in some lungs, SPA was more expressed whereas in others pro-SPB showed an higher degree of immunoreactivity. The expression of both surfactant proteins was not strictly correlated with gestational age. Whereas the highest levels of reactivity were detected in at term neonates, on the other hand one case with grade 3 was detected at 22 weeks and one negative case for both proteins was observed at 31 weeks. Our data clearly show a marked inter-individual variability regarding the production of SPA and pro-SPB and suggest the existence of other epigenetic factors, acting during gestation, that might influence surfactant production and, consequently, the survival potential of neonates at birth.
Assuntos
Feto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Pulmão/embriologia , Proteína A Associada a Surfactante Pulmonar/biossíntese , Proteína B Associada a Surfactante Pulmonar/biossíntese , Pré-Escolar , Feminino , Feto/citologia , Humanos , Lactente , Pulmão/citologia , MasculinoRESUMO
The mPEBev is an anticancer regimen which combines a chemotherapy doublet, based on cisplatin and oral etoposide (mPE), with bevacizumab (mPEBev), a mAb targeting the vasculo-endothelial growth factor (VEGF). In previous studies, this regimen showed powerful anti-angiogenetic effects and significant antitumor activity in metastatic non-small-cell lung cancer (mNSCLC) patients. We also recorded the best benefit in patients exhibiting low-systemic inflammatory profile at baseline. On these bases, we hypothesized that mPEBev antitumor activity could be partially related to bevacizumab-associated immunological effects. For this reason, we performed an immunological monitoring in 59 out of 120 stage IIIb-IV NSCLC patients enrolled in the BEVA2007 phase II trial, who received fractioned cisplatin (30 mg/sqm days 1-3q21) and oral etoposide (50 mg, days 1-15q21) (mPE doublet) ±bevacizumab. In this group of patients, 12 received the mPE doublet alone and 47 the doublet in combination with bevacizumab (5 mg/kg on the day 3q21; mPEBev regimen). Blood cell counts, serum analysis, multiplex cytokine assay and immunocytofluorimetric analysis, performed on baseline and post-treatment on blood samples from these patients, revealed that bevacizumab addition to the doublet decreased levels of pro-angiogenic (VEGF, Angiostatin-1 and Follistatin) and inflammatory cytokines (interferon (IFN)γ, IL4 and IL17), improved in vivo and in vitro cytotoxic T-lymphocytes (CTL) response and promoted dendritic cell activation. These results suggest that the mPEBev regimen improve the micro-environmental conditions for an efficient antigen-specific CTL response, making it a feasible candidate regimen to be assessed in combination with immune-checkpoint inhibitors in NSCLC patients.
RESUMO
BACKGROUND: The N-terminal pro-brain natriuretic peptide (NT-proBNP) has been useful in the diagnosis and follow-up of heart failure. Whether it can be useful in the detection of acute rejection (AR) after heart transplantation (HT) has not been addressed. Our aim was to assess the prognostic value of NT-proBNP determinations after HT. METHODS: We analyzed 137 endomyocardial biopsies (EMB) performed in 51 patients as assessment of AR and correlated them with NT-proBNP determinations. The value of NT-proBNP in the early follow-up of the novo HT was also assessed. RESULTS: AR grade > or =3A was diagnosed in 10 of the 137 performed biopsies. There were no significant differences in NT-proBNP values between patients with or without AR (1047 +/- 629 versus 1886 +/- 3026 pg/mL, P = NS). There were 24 de novo HT, in these patients increased NT-proBNP levels showed an inverse significant correlation with time since HT (r = -0.40, P = .0001). During follow-up, 15 of the novo HT had a descending NT-proBNP curve over time, and in the remaining 9 (37%) a late increase of NT-proBNP values were observed. Those 9 patients had the following complications: AR > or =3A in 5 cases, 1 death, 2 required a permanent pacemaker, and in the last patient a significant EMB could not be obtained. CONCLUSIONS: NT-proBNP values follow a descending curve early after HT. During the first months, a late increase of NT-proBNP value was associated with HT complications, with AR being the most frequent. Isolated increased NT-proBNP levels were not useful for the detection of AR. More studies are needed to establish the prognostic value of NT-proBNP after HT.
Assuntos
Transplante de Coração/fisiologia , Peptídeo Natriurético Encefálico/metabolismo , Fragmentos de Peptídeos/metabolismo , Adulto , Idoso , Biomarcadores/metabolismo , Biópsia , Seguimentos , Rejeição de Enxerto/epidemiologia , Transplante de Coração/patologia , Humanos , Pessoa de Meia-Idade , Precursores de Proteínas/metabolismo , Análise de Regressão , Fatores de TempoRESUMO
AIM: Biliopancreatic diversion (BPD) has been accepted as an effective surgical treatment of morbid obesity. The paper presents the results of a personal clinical experience with this procedure, with special focus on the quality of life. METHODS: From January 1, 1992 to June 30, 2002, 122 patients (F/M: 108/14, mean age: 40.2 years, range 21-61) underwent BPD. Mean preoperative body weight was 122.4 kg (range 91-200), with a mean Body Mass Index of 49.1 kg/m2 (range 38-78). Three of these patients were converted from a previous vertical banded gastroplasty to BPD (1 patients with stomach preservation). After at least a 36-month follow-up, 10 patients underwent abdominal dermolipectomy (8 associated to incisional hernia repair, 1 associated to thigh dermolipectomy). RESULTS: Mean postoperative hospital stay was 12 days (range: 11-30). Follow-up is currently in progress in all patients. Weight loss of initial overweight was 75% in 88 patients with a 36-month follow-up, with excellent long-term weight maintenance. Protein deficiency was the main specific complication, encountered in 6 patients (4.9%). Beneficial effects, other than those consequent to weight loss, included permanent normalization of serum cholesterol and glucose without any medication and on a totally free diet. Almost 80% of the patients reported an improvement in their self-esteem, physical activity, work condition and social life. CONCLUSIONS: This clinical experience supports the effectiveness and safety of BPD, despite some criticism. The small number of side effects and complications, the excellent weight loss and the recovery of most co-morbidity leads to a great improvement in quality of life.