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Acknowledgements section was missing.
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PURPOSE: Immunotherapy is a new standard first-line treatment for non-small cell lung cancers (NSCLC) with high programmed cell death-ligand 1 (PD-L1) expression (≥ 50%) and second-line treatment regardless of PD-L1 status, though not all patients benefit from this approach. Much effort is ongoing to identify robust prognostic and predictive biomarkers of response to immune checkpoint inhibitors, overcoming PD-L1 that appears limited in its ability to discriminate patient candidates to this new class of anticancer agents. The purpose of this research study is to identify potential new biomarkers for immunotherapy in lung cancer. METHODS: Fifty-three consecutive patients with advanced NSCLC treated with nivolumab were enrolled in the study. All the patients received a blood analysis looking for the relationship between different populations of baseline white blood cells and granulocytic myeloid-derived suppressor cells (Gr-MDSC) detected by flow cytometry, to identify and characterize patients with poor likelihood of benefit from nivolumab in NSCLC second-line setting, regardless of clinical feature and PDL1 expression. RESULTS: Univariate analysis showed that high baseline levels of Gr-MDSC and low baseline CD8/Gr-MDSC ratio are associated with significantly better (P = 0.02) response to immunotherapy treatment. Log-rank tests suggested a significant improvement in OS and PFS with high baseline levels of Gr-MDSC levels (≥ 6 cell/µl), low absolute neutrophil count (< 5840/µl), high eosinophil count (> 90 /µl), and NLR < 3. The multivariate analysis showed a statistically significant improvement for PFS (P = 0.003) and OS (P = 0.05) in favour of the identified good prognostic Gr-MDSC-linked asset group, compared with the poor prognosis group. CONCLUSION: The role of Gr-MDSC appears interesting as a potential biomarker in NSCLC patients receiving immune-checkpoint inhibitors. Further analyses are needed to confirmed and study in deep the role of these particular cells and their role in cancer response and progression during ICI therapy.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Granulócitos/fisiologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Células Supressoras Mieloides/fisiologia , Nivolumabe/uso terapêutico , Idoso , Biomarcadores , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Imunofenotipagem , Imunoterapia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Marine harbours are the focus of a diverse range of activities and subject to multiple anthropogenically induced pressures. Support for environmental management options aimed at improving degraded harbours depends on understanding the factors which influence people's perceptions of harbour environments. We used an online survey, across 12 harbours, to assess sources of variation people's perceptions of harbour health and ecological engineering. We tested the hypotheses: 1) people living near impacted harbours would consider their environment to be more unhealthy and degraded, be more concerned about the environment and supportive of and willing to pay for ecological engineering relative to those living by less impacted harbours, and 2) people with greater connectedness to the harbour would be more concerned about and have greater perceived knowledge of the environment, and be more supportive of, knowledgeable about and willing to pay for ecological engineering, than those with less connectedness. Across twelve locations, the levels of degradation and modification by artificial structures were lower and the concern and knowledge about the environment and ecological engineering were greater in the six Australasian and American than the six European and Asian harbours surveyed. We found that people's perception of harbours as healthy or degraded, but not their concern for the environment, reflected the degree to which harbours were impacted. There was a positive relationship between the percentage of shoreline modified and the extent of support for and people's willingness to pay indirect costs for ecological engineering. At the individual level, measures of connectedness to the harbour environment were good predictors of concern for and perceived knowledge about the environment but not support for and perceived knowledge about ecological engineering. To make informed decisions, it is important that people are empowered with sufficient knowledge of the environmental issues facing their harbour and ecological engineering options.
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The E3 ubiquitin ligase (E3) WWP1 is an oncogenic factor implicated in the maintenance of different types of epithelial cancers. The role of WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) in haematological neoplasms remains unknown. Acute myeloid leukaemia (AML) is characterized by the expansion of malignant myeloid cells blocked at different stages of differentiation. Here we report that the expression of WWP1 is significantly augmented in a large cohort of primary AML patients and in AML cell lines, compared with haematopoietic cells from healthy donors. We show that WWP1 inactivation severely impairs the growth of primary AML blasts and cell lines in vitro. In vivo, we observed a reduced leukaemogenic potential of WWP1-depleted AML cells upon transplantation into immunocompromised mice. Mechanistically, WWP1 inactivation induces the accumulation of its protein substrate p27Kip1, which ultimately contributes to G0/G1 cell cycle arrest of AML blasts. In addition, WWP1 depletion triggers the autophagy signalling and reduces survival of leukaemic cells. Collectively, our findings provide molecular insights into the anti-cancer potential of WWP1 inhibition, suggesting that this E3 is a promising biomarker and druggable target in AML.
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Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Ubiquitina-Proteína Ligases/metabolismo , Animais , Pontos de Checagem do Ciclo Celular/fisiologia , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Sobrevivência Celular/fisiologia , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Fase G1/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Camundongos , Fase de Repouso do Ciclo Celular/fisiologia , Transdução de Sinais/fisiologia , Células U937 , Ubiquitinação/fisiologiaRESUMO
Interleukin-36γ (IL-36γ) is a member of novel IL-1-like proinflammatory cytokine family that are highly expressed in epithelial tissues and several myeloid-derived cell types. Little is known about the role of the IL-36 family in mucosal immunity, including lung anti-bacterial responses. We used murine models of IL-36γ deficiency to assess the contribution of IL-36γ in the lung during experimental pneumonia. Induction of IL-36γ was observed in the lung in response to Streptococcus pneumoniae (Sp) infection, and mature IL-36γ protein was secreted primarily in microparticles. IL-36γ-deficient mice challenged with Sp demonstrated increased mortality, decreased lung bacterial clearance and increased bacterial dissemination, in association with reduced local expression of type-1 cytokines, and impaired lung macrophage M1 polarization. IL-36γ directly stimulated type-1 cytokine induction from dendritic cells in vitro in a MyD88-dependent manner. Similar protective effects of IL-36γ were observed in a Gram-negative pneumonia model (Klebsiella pneumoniae). Intrapulmonary delivery of IL-36γ-containing microparticles reconstituted immunity in IL-36γ-/- mice. Enhanced expression of IL-36γ was also observed in plasma and bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome because of pneumonia. These studies indicate that IL-36γ assumes a vital proximal role in the lung innate mucosal immunity during bacterial pneumonia by driving protective type-1 responses and classical macrophage activation.
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Interleucina-1/sangue , Interleucina-1/metabolismo , Infecções por Klebsiella/imunologia , Klebsiella pneumoniae/fisiologia , Pulmão/imunologia , Macrófagos/imunologia , Infecções Pneumocócicas/imunologia , Pneumonia/imunologia , Síndrome do Desconforto Respiratório/imunologia , Streptococcus pneumoniae/fisiologia , Adulto , Animais , Células Cultivadas , Feminino , Humanos , Imunidade Inata , Imunidade nas Mucosas , Interleucina-1/genética , Pulmão/microbiologia , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Regulação para CimaRESUMO
Bisphenol A (BPA), a monomer of polycarbonate plastics and epoxide resin, is a high-production-volume chemical implicated in asthma pathogenesis when exposure occurs to the developing fetus. However, few studies have directly examined the effect of in utero and early-life BPA exposure on the pathogenesis of asthma in adulthood. This study examines the influence of perinatal BPA exposure through maternal diet on allergen sensitization and pulmonary inflammation in adult offspring. Two weeks before mating, BALB/c dams were randomly assigned to a control diet or diets containing 50 ng, 50 µg or 50 mg BPA/kg of rodent chow. Dams remained on the assigned diet throughout gestation and lactation until postnatal day (PND) 21 when offspring were weaned onto the control diet. Twelve-week-old offspring were sensitized to ovalbumin (OVA) and subsequently challenged with aerosolized OVA. Sera, splenocytes, bronchoalveolar lavage fluid and whole lungs were harvested to assess allergen sensitization and pulmonary inflammation after OVA challenge. Serum anti-OVA IgE levels were increased two-fold in offspring exposed to 50 µg and 50 mg BPA/kg diet, compared with control animals. In addition, production of interleukin-13 and interferon-γ were increased in OVA-stimulated splenocytes recovered from BPA-exposed mice. Pulmonary inflammation, as indicated by total and differential leukocyte counts, cytokines, chemokines and pulmonary histopathology inflammatory scores, however, was either not different or was reduced in offspring exposed to BPA. Although these data suggest that perinatal BPA exposure beginning before gestation enhances allergen sensitization by increasing serum IgE and splenocyte cytokine production, a substantial impact of BPA on OVA-induced pulmonary inflammation in adulthood was not observed.
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Compostos Benzidrílicos/toxicidade , Exposição Ambiental/efeitos adversos , Hipersensibilidade/etiologia , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos Endogâmicos BALB C , Pneumonia/induzido quimicamente , Pneumonia/patologia , Gravidez , Testes de ToxicidadeRESUMO
Despite their importance for water management, long-term studies on trophic state are relatively scarce in subtropical reservoirs. We analyzed total phosphorus (TP), total nitrogen (TN) and chlorophyll a (Chl a) concentrations in the Billings Reservoir (Brazil) over time: Phase 1 (1977-1992, Tietê River water was pumped to Billings to increase energy generation, 100 m(3) s(-1)); Phase 2 (1992-2007, Tietê water was conveyed to Billings only in special cases for flood avoidance, 8 m(3) s(-1)); and Phase 3 (2007-2010, besides flood control, Billings received Tietê water treated by an in situ flotation system, 13 m(3) s(-1)). We compared our results with data from 12 reservoirs to evaluate current (2005-2009) enrichment conditions. Phosphorus and nitrogen concentrations decreased (p < 0.05, MANOVA) from Phase 1 to 2 and were stable thereafter. TN/TP ratios increment (1977-2010) indicated shift from N- to P-limitation in the reservoir, affecting the phytoplankton. Nutrient levels in Billings are currently between the expected concentrations in mesotrophic and eutrophic reservoirs (0.03 mg L(-1) < TP < 0.42 mg L(-1), 0.8 mg L(-1) < TN < 7.6 mg L(-1)) and Chl a concentrations exceeded 34 µg L(-1), median for the eutrophic waterbodies from the dataset. Although water quality in Billings has improved, nutrient inputs from Tietê River pumping episodes, diffuse and internal sources are still favoring biomass accrual and compromising water uses.
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Ecossistema , Monitoramento Ambiental , Eutrofização , Brasil , Fatores de Tempo , Poluentes Químicos da Água , Abastecimento de ÁguaRESUMO
AIMS: In diabetes, endothelial damage promotes macroangiopathy and endothelial regeneration is impaired, owing to reduced endothelial progenitor cells (EPCs). Given that insulin influences endothelial biology, we compared the effects of add-on basal insulin analogues on endothelial damage and regeneration in type 2 diabetes (T2D). METHODS: This was a 6-month randomized crossover trial comparing add-on insulin detemir versus glargine in poorly controlled T2D with macroangiopathy. At baseline, crossover (3 months) and study end (6 months), we measured HbA1c, EPCs, circulating endothelial cells (CECs), VCAM-1, ICAM-1 and E-selectin. Body weight and hypoglycaemic episodes were also recorded. RESULTS: Forty-two patients completed the study, randomly assigned to the glargine-detemir (n = 21) or the detemir-glargine (n = 21) schedule. At crossover, EPC levels did not change compared with baseline, but significantly increased at study end. CECs decreased over time and were significantly reduced at study end. ICAM-1, VCAM-1 and E-selectin were significantly reduced at crossover and further decreased at study end. No differences were seen in these effects between detemir and glargine. HbA1c showed a carryover effect and its reduction was similar with detemir and glargine in the first arm. Incidence of hypoglycaemia and weight gain was lower with detemir than with glargine in both arms. CONCLUSION: Optimized glycaemic control by add-on basal insulin improved indexes of endothelial damage and regeneration. Compared to glargine, detemir achieved similar endothelial protection with lower weight gain and less hypoglycaemia. These results might have implications for therapy of aging T2D patients with cardiovascular disease.
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Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/tratamento farmacológico , Células Endoteliais/efeitos dos fármacos , Hipoglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/análogos & derivados , Idoso , Estudos Cross-Over , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/induzido quimicamente , Angiopatias Diabéticas/fisiopatologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Células Endoteliais/fisiologia , Feminino , Hemoglobinas Glicadas/efeitos dos fármacos , Humanos , Hipoglicemiantes/efeitos adversos , Insulina/efeitos adversos , Insulina/uso terapêutico , Insulina Detemir , Insulina Glargina , Insulina de Ação Prolongada , Masculino , Resultado do TratamentoAssuntos
Transformação Celular Neoplásica , Fator de Transcrição GATA1/genética , Leucemia Experimental/etiologia , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-myb/genética , Animais , Fator de Transcrição GATA1/metabolismo , Rearranjo Gênico , Leucemia Experimental/patologia , Linfoma/etiologia , Linfoma/patologia , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-myb/metabolismo , Neoplasias do Timo/etiologia , Neoplasias do Timo/patologia , Proteína Supressora de Tumor p53/fisiologiaRESUMO
Pinheiros River (Brazil) plays a pivotal role in supplying water to Billings Reservoir, which presents multiple uses (human drinking, energy generation, irrigation, navigation, fishing and leisure). An intense monitoring program was performed during the years 2007 and 2008 to find out whether on site flotation is a feasible solution or not for improving the water quality of this urban river, attenuating the pollutants load caused by the water pumping to the reservoir (approximately 10 m³ s⻹). The monitoring of 18 variables (13,429 laboratorial analysis during the period of 490 days), suggested that despite the convenience of the on site approach for water treatment, especially for rivers located in fully urbanized areas, the flotation system is not enough itself to recover Pinheiros River water quality, given the several constraints that apply. Total phosphorus removal was high in percentage terms (about 90%), although the remaining concentrations were not so low (mean of 0.05 mg L⻹). The removal efficiency of some variables was insufficient, leading to high final mean concentrations of metals [e.g. aluminium (0.29 mg L⻹), chromium (0.02 mg L⻹) and iron (1.1 mg L⻹)] as well as nitrogen-ammonia (25.8 mg L⻹) and total suspended solids (18 mg L⻹) in the treated water.
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Recuperação e Remediação Ambiental/métodos , Rios/química , Poluição da Água , Brasil , Cidades , Monitoramento Ambiental/estatística & dados numéricos , Estudos de ViabilidadeRESUMO
VAD, (Vincristine, Doxorubicin and Dexamethasone) was initially proposed as a salvage therapy for myeloma patients in whom prior alkylating agent therapy failed, although in recent years VAD has been surpassed by novel combination therapies with new biological agents such as thalidomide (and its derivative, lenalidomide) and bortezomib. After the excellent results obtained by the novel agents, VAD can no longer be proposed in preparation to autologous transplantation, although there are still indications that VAD remains useful and clinically relevant in the initial treatment of symptomatic multiple myeloma.
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The antiangiogenic agent bevacizumab showed synergistic effects when combined with chemotherapy in advanced breast cancer. We presently investigated the activity of bevacizumab in combination with chemotherapy, including capecitabine and vinorelbine, and endocrine therapy, including letrozole (+triptorelin in premenopausal women), as primary therapy for patients with ER and/or PgR > or =10% T2-T4a-c, N0-N2, M0 breast cancer. Biological end point included the proliferative activity (Ki67), whereas clinical end points were clinical response rate, pathological complete response (pCR) and tolerability. Circulating endothelial cells (CECs) and their progenitors, as surrogate markers of antiangiogenic activity, were measured at baseline and at surgery.Thirty-six women are evaluable. A clinical response rate of 86% (95% CI, 70-95) and no pCR were observed; Ki67 was significantly decreased by 71% (interquartile range, -82%, -62%). Toxicity was manageable: two grade 3 hypertension, four grade 3 deep venous thrombosis and no grade >2 proteinuria were observed. Treatment significantly decreased the percentage of viable CECs and prevented the chemotherapy-induced mobilisation of circulating progenitors. Basal circulating progenitors were positively associated with clinical response. In conclusion, bevacizumab is feasible and active in association with primary chemoendocrine therapy for ER-positive tumours in terms of proliferation inhibition, clinical response and antiangiogenic activity.
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Inibidores da Angiogênese/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Nitrilas/administração & dosagem , Triazóis/administração & dosagem , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Bevacizumab , Neoplasias da Mama/metabolismo , Terapia Combinada , Feminino , Humanos , Letrozol , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Cuidados Pré-Operatórios , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismoRESUMO
BACKGROUND: There are limited data concerning the relationships between changes in adipocytokines and cardiovascular disease (CVD) risk factors. OBJECTIVE: To examine the longitudinal associations between leptin, adiponectin, resistin and ghrelin levels and CVD risk factor levels in women at midlife. DESIGN: Prospective, observational study. SUBJECTS AND MEASUREMENTS: Leptin, adiponectin, resistin, ghrelin levels and CVD risk factors were measured in specimens collected from 40 women at 3 points in time corresponding to the pre-, peri- and postmenopause stages of their natural menopause transition. RESULTS: In longitudinal analyses adjusted for CVD risk factors and leptin at the previous menopausal stage, aging, education, smoking and physical activity, greater increases in leptin over the menopause transition were associated with greater decreases in high-density lipoprotein cholesterol (HDL-c) and greater increases in diastolic blood pressure, glucose, insulin and insulin resistance (all P < 0.05). Larger decreases in adiponectin over the menopause transition were associated with greater increases in systolic blood pressure, insulin and insulin resistance and with greater decreases in HDL-c. Greater increases in ghrelin levels over the menopausal transition were associated with greater low-density lipoprotein cholesterol increases (P = 0.014). Resistin was not associated with CVD risk factor changes. CONCLUSION: There were significant adverse associations of adipocytokines and ghrelin with multiple CVD risk factor changes in women across midlife. Given that this time period is dynamic for CVD risk, these data underscore the need for additional prospective studies.
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Adipocinas/sangue , Doenças Cardiovasculares , Grelina/sangue , Menopausa/sangue , Adiponectina/sangue , Adulto , Biomarcadores/sangue , Pesos e Medidas Corporais , Doenças Cardiovasculares/etiologia , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Resistina/sangue , Fatores de RiscoRESUMO
The adipocyte-derived hormone leptin is an important regulator of appetite and energy expenditure and is now appreciated for its ability to control innate and adaptive immune responses. We have reported previously that the leptin-deficient ob/ob mouse exhibited increased susceptibility to the Gram-negative bacterium Klebsiella pneumoniae. In this report we assessed the impact of chronic leptin deficiency, using ob/ob mice, on pneumococcal pneumonia and examined whether restoring circulating leptin to physiological levels in vivo could improve host defences against this pathogen. We observed that ob/ob mice, compared with wild-type (WT) animals, exhibited enhanced lethality and reduced pulmonary bacterial clearance following Streptococcus pneumoniae challenge. These impairments in host defence in ob/ob mice were associated with elevated levels of lung tumour necrosis factor (TNF)-alpha, macrophage inflammatory peptide (MIP)-2 [correction added after online publication 28 September 2007: definition of MIP corrected], prostaglandin E(2) (PGE(2)), lung neutrophil polymorphonuclear leukocyte (PMN) counts, defective alveolar macrophage (AM) phagocytosis and PMN killing of S. pneumoniae in vitro. Exogenous leptin administration to ob/ob mice in vivo improved survival and greatly improved pulmonary bacterial clearance, reduced bacteraemia, reconstituted AM phagocytosis and PMN H(2)O(2) production and killing of S. pneumoniae in vitro. Our results demonstrate, for the first time, that leptin improves pulmonary bacterial clearance and survival in ob/ob mice during pneumococcal pneumonia. Further investigations are warranted to determine whether there is a potential therapeutic role for this adipokine in immunocompromised patients.
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Leptina/uso terapêutico , Pulmão/microbiologia , Pneumonia Pneumocócica/tratamento farmacológico , Streptococcus pneumoniae/patogenicidade , Animais , Bacteriemia/tratamento farmacológico , Citocinas/biossíntese , Suscetibilidade a Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Peróxido de Hidrogênio/metabolismo , Leptina/deficiência , Contagem de Leucócitos , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Infiltração de Neutrófilos/imunologia , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Pneumonia Pneumocócica/imunologia , Pneumonia Pneumocócica/microbiologia , Streptococcus pneumoniae/isolamento & purificação , Análise de SobrevidaRESUMO
As befalls many mediators that act upon the human stage, leukotrienes have become identified with their most powerful roles as villains of the immune system. They are well known for their leading roles in allergic diseases, including asthma. They also have gained recognition for their dramatic role as promoters of inflammation. As new roles for these lipid messengers are sought, it is becoming apparent that the leukotrienes have been typecast as bad guys of the immune system. As examples, their more recent roles have been in atherosclerosis, pulmonary fibrosis and cancer. However, upon further evaluation, we can begin to see their versatility. Thus, leukotrienes stimulate innate immunity against pathogens. In addition, they promote the expression of mediators, receptors and other molecules that are important for immune defense. In these lesser known roles, they lead the fight against bacterial, fungal and viral infection. This review is intended to shed light on the leukotrienes, where they come from and what we really know about them.
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Leucotrienos/imunologia , Animais , Regulação da Expressão Gênica/imunologia , Humanos , Imunidade Inata , Mediadores da InflamaçãoAssuntos
Anticorpos Monoclonais/farmacologia , Clorambucila/farmacologia , Linfoma não Hodgkin/tratamento farmacológico , Subpopulações de Linfócitos T/efeitos dos fármacos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Murinos , Antineoplásicos/uso terapêutico , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Clorambucila/uso terapêutico , Humanos , Células Matadoras Naturais , Contagem de Linfócitos , Linfoma não Hodgkin/imunologia , RituximabRESUMO
AIM: To evaluate the clinical implications of c-kit (CD117) expression in plasma cell myeloma (PCM). METHODS AND RESULTS: We first evaluated the reliability of immunohistochemistry in assessing c-kit expression by comparing the results with those obtained by flow cytometry and gene expression arrays in 22 PCM and in 10 PCM cell lines. Immunohistochemical results showed a perfect concordance with those of flow cytometry; likewise, immunohistochemical and gene expression data were also concordant in all but one PCM and cell lines analysed. Then, we investigated the clinical implications of c-kit immunoreactivity in bone marrow biopsies of 85 PCM patients with a mean follow-up of 41 months. C-kit immunoreactivity was detected in 24 (28.2%) of the 85 cases and it was significantly associated with a high microvessel density, but not with traditional clinicopathological characteristics or with survival. CONCLUSIONS: Our findings suggest that immunohistochemistry is a reliable indicator of c-kit gene expression and reinforce the notion that approximately one-third of PCM express high levels of c-kit. The lack of association with traditional clinicopathological parameters and patient survival suggests that c-kit expression may not be an adjunct in predicting the clinical course of the disease.
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Mieloma Múltiplo/patologia , Proteínas Proto-Oncogênicas c-kit/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Glicoproteínas de Membrana/análise , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Proteoglicanas/análise , Proteínas Proto-Oncogênicas c-kit/genética , Análise de Sobrevida , SindecanasRESUMO
Increased angiogenesis has been demonstrated to be a significant prognostic factor in many solid tumors. In the oncohematological setting, it has been associated with myelodysplastic syndromes (MDS), chronic myeloid leukemia, acute lymphoid, and myeloid leukemias. Recently, increased circulating endothelial cells (CECs) have been associated with breast cancer and non-Hodgkin lymphoma (NHL). Based on these premises we analysed total and activated CECs, and endothelial precursors (CEPs) in 50 MDS patients and 20 healthy donors. CECs and CEPs were quantified by flow cytometry. CEC levels were compared with bone marrow (BM) microvessel density (MVD). In addition, some angiogenic factors, namely vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and soluble VEGF-Receptor2 (VEGFR2), were tested in the sera from 25 MDS patients. Total, activated CECs and CEPs were significantly increased in MDS when compared to control group (p<0.0001); whereas in the MDS cases no association was found with French--American--British (FAB), International Prognostic Scoring System (IPSS) subtypes or survival. Patients with higher CECs also showed higher MVD. Among the cytokines analysed, sVEGFR2 was significantly higher in the lower IPSS risk classes, while the levels of bFGF directly correlated with total and activated CECs. Taken together these data strengthen the hypothesis of a possible role of angiogenesis in MDS pathogenesis.
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Células Endoteliais/fisiologia , Síndromes Mielodisplásicas/sangue , Neovascularização Patológica , Adulto , Idoso , Biomarcadores , Medula Óssea/irrigação sanguínea , Contagem de Células , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Células-Tronco/fisiologiaRESUMO
A case of cervicothoracic spontaneous spinal epidural hematoma (SSEH) following coronary thrombolysis with r-TPA and intravenous heparin is reported. The clinical picture is discussed, as well as the importance of rapid neuroradiological diagnosis (with spinal MRI being the method of choice) and surgical treatment. Anyway, in these patients, thorough cardiac function evaluation and rapid correction of any clotting disorder is necessary prior to surgery. With the increasing use of fibrinolytic therapy this complication would be more frequent. This underlines the importance of prompt recognition and adequate treatment.