RESUMO
Statins and bisphosphonates are two distinct classes of isoprenoid pathway inhibitors targeting downstream enzyme to HMG-CoA reductase (upstream enzyme) and farnesyl-pyrophosphate synthase, respectively. Here, we studied fluvastatin (Fluva) and zoledronate (Zol), representative molecules of each class, respectively. In vivo metastatic potentials of both molecules were assessed. For the first time, we observed a significant reduction in progression of established metastases with Fluva treatment. Treatment with both Zol at 100 µg/kg and Fluva at 15 mg/kg inhibited 80% of the metastasis bioluminescence signal and increased survival of mice. The Zol and Fluva transcriptomic profiles of treated MDA-MB-231 cells revealed analogous patterns of affected genes, but each of them reached with different kinetics. The observable changes in gene expression started after 24 h for Fluva IC(50 72 h) and only after 48 h for Zol IC(50 72 h). To obtain early changes in gene expression of Zol-treated cells, a 3 times higher dose of Zol IC(50 72 h) had to be applied. Combining Fluva and Zol in vivo showed no synergy, but a benefit of several days in survival of mice. This study demonstrated that Zol or Fluva is of potential clinical use for the treatment of established metastasis.
Assuntos
Adenocarcinoma/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Difosfonatos/farmacologia , Ácidos Graxos Monoinsaturados/farmacologia , Imidazóis/farmacologia , Indóis/farmacologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Transcriptoma/efeitos dos fármacos , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Feminino , Fluvastatina , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica/métodos , Humanos , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Nus , Metástase Neoplásica , Ácido ZoledrônicoRESUMO
The existence of multiple VEGF-A isoforms raised the possibility that they may have distinct functions in tumor growth. We have previously published that VEGF189 and VEGF165 contribute to breast cancer progression and angiogenesis, but VEGF165 induced the most rapid tumor uptake. Since VEGF165 has been described as a survival factor for breast tumor cells, we questioned here the effects of VEGF189 on the survival/apoptosis of MDA-MB-231 cells. We used clones which overexpress VEGF189 (V189) or VEGF165 (V165) isoforms and compared them to a control one (cV). Overexpression of VEGF189 resulted in increased cell apoptosis, as determined by Annexin-V apoptosis assay, under serum starvation and doxorubicin treatment, while VEGF 165 was confirmed to be a survival factor. Since MDA-MB-231 highly express NRP1 (a co-receptor for VEGF-A), we used short hairpin RNA (shRNA) to knockdown NRP1 expression. V189shNRP1 clones were characterized by reduced apoptosis and higher necrosis, as compared to V189shCtl, under stress conditions. Unexpectedly, NRP1 knock-down had no effect on the survival or apoptosis of V165 cells. VEGF189 showed greater affinity towards NRP1 than VEGF165 using a BIAcore binding assay. Finally, since endogenously produced urokinase-type plasminogen (uPA) has been found to prevent apoptosis in breast cancers, we analyzed the level of uPA activity in our clones. An inhibition of uPA activity was observed in V189shNRP1 clones. Altogether, these results suggest a major role of NRP1 in apoptosis induced by VEGF189 in stress conditions and confirm VEGF165 as a survival factor.
Assuntos
Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Neuropilina-1/metabolismo , Estresse Fisiológico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Anexina A5/metabolismo , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , L-Lactato Desidrogenase/metabolismo , Neuropilina-1/genética , Isoformas de Proteínas/metabolismo , RNA Mensageiro/análise , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ressonância de Plasmônio de Superfície , Transfecção , Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
INTRODUCTION: The poor efficacy of various anti-cancer treatments against metastatic cells has focused attention on the role of tumor microenvironment in cancer progression. To understand the contribution of the extracellular matrix (ECM) environment to this phenomenon, we isolated ECM surrogate invading cell populations from MDA-MB-231 breast cancer cells and studied their genotype and malignant phenotype. METHODS: We isolated invasive subpopulations (INV) from non invasive populations (REF) using a 2D-Matrigel assay, a surrogate of basal membrane passage. INV and REF populations were investigated by microarray assay and for their capacities to adhere, invade and transmigrate in vitro, and to form metastases in nude mice. RESULTS: REF and INV subpopulations were stable in culture and present different transcriptome profiles. INV cells were characterized by reduced expression of cell adhesion and cell-cell junction genes (44% of down regulated genes) and by a gain in expression of anti-apoptotic and pro-angiogenic gene sets. In line with this observation, in vitro INV cells showed reduced adhesion and increased motility through endothelial monolayers and fibronectin. When injected into the circulation, INV cells induced metastases formation, and reduced injected mice survival by up to 80% as compared to REF cells. In nude mice, INV xenografts grew rapidly inducing vessel formation and displaying resistance to apoptosis. CONCLUSION: Our findings reveal that the in vitro ECM microenvironment per se was sufficient to select for tumor cells with a stable metastatic phenotype in vivo characterized by loss of adhesion molecules expression and induction of pro-angiogenic and survival factors.
Assuntos
Membrana Basal/metabolismo , Neoplasias da Mama/genética , Neoplasias Mamárias Experimentais/genética , Proteínas Angiogênicas/genética , Proteínas Angiogênicas/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Membrana Basal/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Adesão Celular/genética , Linhagem Celular Tumoral , Colágeno , Combinação de Medicamentos , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Laminina , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Nus , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Proteoglicanas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcriptoma , Migração Transendotelial e Transepitelial/genética , Transplante Heterólogo , Carga Tumoral/genéticaRESUMO
For decades, the fight against cancer was based on oncolytic drugs aimed at eradicating malignant cells (killing strategy). The main flaws of this approach were its toxicity and the consequent emergence of resistance. New views on tumour biology consider tumours as complex organs involving dynamic interactions between their components. This implies the existence of dormant states and thus of a new therapeutic strategy aimed at inducing or extending tumour dormancy (containment strategy). The aim of this overview was to quantify the relative importance of these two strategies among the clinical trials (240 phase 1 and 186 phase 2 trials), launched or still in the pipeline and sponsored by the pharmaceutical industry in 2009. The most frequently targeted molecular entities are vascular endothelial growth factors (VEGFRs) (19 drugs), ErBBs (17 drugs), c-met (14 drugs), tubulin (12 drugs), IGFRs (12 drugs). The main result of this overview is that the killing strategy is still largely prevailing since 326 drugs in 2009 (77% of the drugs tested in clinical trials in 2009) referred to this strategy, whereas 100 drugs could be attributed to the containment or mixed strategies in 2009. To obtain a dynamic view of the repartition of drugs between the killing strategy and the containment or mixed strategies, the present work should be renewed every 3-4 years.
Assuntos
Antineoplásicos/farmacologia , Indústria Farmacêutica/métodos , Neoplasias/tratamento farmacológico , Animais , Ensaios Clínicos como Assunto , Tomada de Decisões , HumanosRESUMO
BACKGROUND: In stage III colorectal cancer (CRC), adjuvant chemotherapy (CT) is usually prescribed within two months after curative surgery. Whether or not delaying initiation of CT affects survival is still debated. MATERIAL AND METHODS: We performed a meta-analysis (MA) of all published studies (full papers or abstracts) comparing delayed CT with standard care. Studies were obtained from a PubMed query (keywords: CRC, adjuvant treatment, delay of CT), a review (Chau et al., 2006), cross-checking references and abstracts from the proceedings of ASCO, ASCO GI and WCGI annual meetings. We chose a cutoff delay of 8 weeks. Risk Ratios (RRs) were calculated from the recorded events (deaths, relapses). We used EasyMA software (fixed-effect model). RESULTS: Fourteen studies (including four abstracts) were identified (17,645 patients; 5,952 males, 5,151 females, mean age 70 years). Of these, three could not be statistically analysed and three used another cutoff (4, 5 or 6 weeks), leaving 8 studies for main MA (13,158 patients; 3,932 males, 3,644 females, 5,942 missing data; 5,576 colon cancers, 6,677 rectal, 1,265 missing data). Delaying CT more than 8 weeks was associated to worse Overall Survival (OS) (RR: 1.20; 95% Confidence Interval (CI) 1.15-1.26). In the MA including all studies whatever their cutoff, longer delay was similarly associated to a worse OS but not a worse Relapse-Free Survival (RFS) (five studies). CONCLUSION: Adjuvant chemotherapy should be started within 8 weeks after surgery. Delaying the initiation of adjuvant CT for more than 8 weeks after surgery significantly decreased OS but not RFS. This discrepancy might be due to factors not directly related to cancer (post-operative complications, social status) or to a more accurate appraisal of death.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/cirurgia , Idoso , Quimioterapia Adjuvante , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Masculino , Análise de Sobrevida , Fatores de TempoRESUMO
We have recently reported that the CXC-chemokine stromal cell-derived factor-1 (SDF-1)/CXCL12 induces proliferation, migration, and invasion of the Huh7 human hepatoma cells through its G-protein-coupled receptor CXCR4 and that glycosaminoglycans (GAGs) are involved in these events. Here, we demonstrate by surface plasmon resonance that the chemokine binds to GAG mimetics obtained by grafting carboxylate, sulfate or acetate groups onto a dextran backbone. We also demonstrate that chemically modified dextrans inhibit SDF-1/CXCL12-mediated in vitro chemotaxis and anchorage-independent cell growth in a dose-dependent manner. The binding of GAG mimetics to the chemokine and their effects in modulating the SDF-1/CXCL12 biological activities are mainly related to the presence of sulfate groups. Furthermore, the mRNA expression of enzymes involved in heparan sulfate biosynthesis, such as exostosin-1 and -2 or N-deacetylase N-sulfotransferases remained unchanged, but heparanase mRNA and protein expressions in Huh7 cells were decreased upon GAG mimetic treatment. Moreover, decreasing heparanase-1 mRNA levels by RNA interference significantly reduced SDF-1/CXCL12-induced extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation. Therefore, we suggest that GAG mimetic effects on SDF-1/CXCL12-mediated hepatoma cell chemotaxis may rely on decreased heparanase expression, which impairs SDF-1/CXCL12's signaling. Altogether, these data suggest that GAG mimetics may compete with cellular heparan sulfate chains for the binding to SDF-1/CXCL12 and may affect heparanase expression, leading to reduced SDF-1/CXCL12 mediated in vitro chemotaxis and growth of hepatoma cells.
Assuntos
Carcinoma Hepatocelular/patologia , Movimento Celular/efeitos dos fármacos , Quimiocina CXCL12/antagonistas & inibidores , Glicosaminoglicanos/farmacologia , Neoplasias Hepáticas/patologia , Ligação Competitiva/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Adesão Celular/efeitos dos fármacos , Comunicação Celular/efeitos dos fármacos , Quimiocina CXCL12/metabolismo , Quimiocina CXCL12/farmacologia , Glucuronidase/antagonistas & inibidores , Glucuronidase/biossíntese , Glicosaminoglicanos/agonistas , Glicosaminoglicanos/metabolismo , Heparitina Sulfato/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Invasividade Neoplásica , RNA Interferente Pequeno/farmacologia , Células Tumorais CultivadasRESUMO
BACKGROUND: Microsatellite Instability (MSI) status is a good prognostic factor for colorectal cancer (CRC) but its predictive value for chemosensitivity remains controversial. A previous meta-analysis (MA) in the adjuvant setting showed that MSI-high (H) status did not predict the efficacy of chemotherapy. The predictive value of MSI status on the effect of metastatic chemotherapy was investigated by MA. PATIENTS AND METHODS: Studies were identified by electronic search through PubMed, Embase and ASCO proceedings online databases, using several key words (colorectal cancer, chemotherapy, microsatellite instability). For each study, the ratio of response rate (RR), complete (CR) and partial response (PR) divided by stable disease and progression was calculated. From 190 articles and 100 abstracts, only eight independent studies were selected. The data were analysed with a random-effect model (due to heterogeneity between studies) using EasyMA software. Statistical calculations were performed on six studies representing 964 patients (mean age 63 years; 91 MSI-H; 873 microsatellite stable (MSS) tumours). A total of 287 patients received 5-fluorouracil (5FU)-based chemotherapy, whereas 678 patients received combinations of 5FU or capecitabine with oxaliplatin and/or irinotecan. RESULTS: No benefit of metastatic chemotherapy in terms of RR for MSI-H patients compared with MSS patients was found. The global hazard ratio (HR) for RR was 0.82 (95% confidence interval, CI: 0.95; 0.65-1.03; p=0.09). CONCLUSION: MSI status does not predict the effect of chemotherapy which is similar in MSI-H and MSS metastatic CRC tumours.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/genética , Instabilidade Genômica , Repetições de Microssatélites/genética , Metástase Neoplásica , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Humanos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Microsatellite instability (MSI) status in predicting the efficacy of adjuvant chemotherapy in colorectal cancer remains controversial. MATERIALS AND METHODS: Studies were identified through PubMed, Embase and ASCO proceedings with a combination of keywords (colorectal cancer, chemotherapy and MSI). RESULTS: A MA was performed for treated and non-treated MSI population on seven studies. Statistical calculations were performed on 7 studies representing 3690 patients; mean age: 65.5 years; 810 stage II and 2444 stage III (75%). MSI-high (MSI-H) was found in 454 patients (14% of the global population), and microsatellite stable (MSS) in 2871. A total of 1444 patients received 5-fluorouracil (5FU)-based chemotherapy, whereas 1518 patients did not. For MSI-H patients, there was no statistically significant difference for RFS whether or not they received chemotherapy (5 studies); HR RFS: 0.96 (95% confidence interval (CI): 0.62-1.49); HR OS (6 studies): 0.70 (95% CI: 0.44-1.09; p=0.12). Elsewhere, we found a significant interaction between MSI status (MSI-H or MSS) and therapeutic status suggesting a lesser benefit for MSI-H than for MSS patients (HR interaction RFS: 0.77 (95% CI: 0.67-0.87)). CONCLUSION: We found similar RFS for treated and untreated MSI-H patients, showing that MSI-H status, in addition to being a good prognostic factor is also a predictive factor of non response.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Instabilidade de Microssatélites , Idoso , Quimioterapia Adjuvante , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Although there was growing evidence in the potential use of Bisphosphonates (BPs) in cancer therapy, their strong osseous affinities that contrast their poor soft tissue uptake limited their use. Here, we developed a new strategy to overcome BPs hydrophilicity by masking the phosphonic acid through organic protecting groups and introducing hydrophobic functions in the side chain. METHODOLOGY/PRINCIPAL FINDINGS: We synthesized non-nitrogen BPs (non N-BPs) containing bromobenzyl group (BP7033Br) in their side chain that were symmetrically esterified with hydrophobic 4-methoxphenyl (BP7033BrALK) and assessed their effects on breast cancer estrogen-responsive cells (T47D, MCF-7) as well as on non responsive ones (SKBR3, MDA-MB-231 and its highly metastatic derived D3H2LN subclone). BP7033Br ALK was more efficient in inhibiting tumor cell proliferation, migration and survival when compared to BP7033Br. Although both compounds inhibited tumor growth without side effects, only BP7033Br ALK abrogated tumor angiogenesis and D3H2LN cells-induced metastases formation. CONCLUSION/SIGNIFICANCE: Taken together these data suggest the potential therapeutic use of this new class of esterified Bisphosphonates (BPs) in the treatment of tumor progression and metastasis without toxic adverse effects.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Difosfonatos/química , Difosfonatos/farmacologia , Metástase Neoplásica/prevenção & controle , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Esterificação , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Metástase Neoplásica/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
We previously demonstrated that a non sulfated analogue of heparin, phenylacetate carboxymethyl benzylamide dextran (NaPaC) inhibited angiogenesis. Here, we observed that NaPaC inhibited the VEGF165 binding to both VEGFR2 and NRP-1 and abolished VEGFR2 activity. Further, we explored the effects of NaPaC on VEGF165 interactions with its receptors, VEGFR2 and NRP-1, co-receptor of VEGFR2. Surface plasmon resonance and affinity gel electrophoresis showed that NaPaC interacted directly with VEGF165, VEGFR2 and NRP-1 but not with heparin-independent factor such as VEGF121. NaPaC completely inhibited the heparin binding to VEGF165, NRP-1 and VEGFR2. We found that NaPaC bound to all three molecules, VEGF165, VEGFR2 and NRP-1, but was more effective in inhibiting heparin binding to VEGF165. These results suggested that heparin binding sites of VEGFR2 and NRP-1 were different from those of VEGF165.
Assuntos
Dextranos/metabolismo , Heparina/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Sítios de Ligação , Ligação Competitiva/efeitos dos fármacos , Western Blotting , Células Cultivadas , Dextranos/farmacologia , Relação Dose-Resposta a Droga , Heparina/farmacologia , Neuropilina-1/genética , Neuropilina-1/metabolismo , Ligação Proteica/efeitos dos fármacos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Recombinantes/metabolismo , Suínos , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
We report 6 additional observations of a drug/hormone assay interaction between serum testosterone and phenylbutazone intake. This interaction had been described previously only once. We discuss its potential mechanisms, based upon our experimental findings, and its clinical implications.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Fenilbutazona/efeitos adversos , Testosterona/sangue , Adulto , Idoso , Anti-Inflamatórios não Esteroides/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenilbutazona/uso terapêutico , Estudos ProspectivosRESUMO
BACKGROUND: Ghrelin, a 28 amino-acid acylated orexigenic peptide secreted by the stomach, acts on the hypothalamic arcuate nucleus which stimulates feeding behavior. Serum ghrelin level increases during fasting and decreases after a meal. Serum ghrelin is low in obese patients.Whether ghrelin is implicated in weight loss in obese patients after laparoscopic adjustable gastric banding (LAGB) is still debated. In this study, we assessed serum ghrelin level and gastric fundus expression before and 1 year after LAGB. METHODS: Gastric fundus expression of ghrelin was assessed by immunohistochemistry using a rabbit anti-human ghrelin antibody simultaneously with serum total ghrelin levels (RIA) in 13 obese patients (2 men and 11 women) after an overnight fast, before LAGB and 1 year after. Immunostaining was "blindly" analyzed by a single pathologist, measuring the density of stained fundic cells near muscularis mucosa. RESULTS: Mean age of the 13 patients was 41 years, and mean baseline BMI was 46 kg/m2. Pre- and post-LAGB gastric expression of ghrelin was analyzable in 11 patients. It was always identified, mostly with moderate or intense staining. Mean density of stained cells significantly increased 1 year after LAGB: 31/mm2 (21-38) before vs 38/mm2 (27-57) after surgery (P<0.01). This increase did not correlate with changes in BMI, nor did pre- or postoperative gastric expression of ghrelin correlate with the corresponding serum values. CONCLUSION: We showed for the first time that ghrelin expression assessed by immunohistochemistry was present in the fundus of all 11 obese patients and that it was significantly increased 1 year after LAGB, which would exclude a pathogenetic role of ghrelin in weight loss after LAGB.
Assuntos
Fundo Gástrico/metabolismo , Gastroplastia , Grelina/biossíntese , Obesidade Mórbida/cirurgia , Adulto , Feminino , Grelina/sangue , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The CC-chemokine regulated on activation, normal T-cell expressed, and presumably secreted (RANTES)/CCL5 mediates its biological activities through activation of G protein-coupled receptors, CCR1, CCR3, or CCR5, and binds to glycosaminoglycans. This study was undertaken to investigate whether this chemokine is involved in hepatoma cell migration or invasion and to modulate these effects in vitro by the use of glycosaminoglycan mimetics. We show that the human hepatoma Huh7 and Hep3B cells express RANTES/CCL5 G protein-coupled receptor CCR1 but not CCR3 nor CCR5. RANTES/CCL5 binding to these cells depends on CCR1 and glycosaminoglycans. Moreover, RANTES/CCL5 strongly stimulates the migration and the invasion of Huh7 cells and to a lesser extent that of Hep3B cells. RANTES/CCL5 also stimulates the tyrosine phosphorylation of focal adhesion kinase and activates matrix metalloproteinase-9 in Huh7 hepatoma cells, resulting in increased invasion of these cells. The fact that RANTES/CCL5-induced migration and invasion of Huh7 cells are both strongly inhibited by anti-CCR1 antibodies and heparin, as well as by beta-d-xyloside treatment of the cells, suggests that CCR1 and glycosaminoglycans are involved in these events. We then show by surface plasmon resonance that synthetic glycosaminoglycan mimetics, OTR4120 or OTR4131, directly bind to RANTES/CCL5. The preincubation of the chemokine with each of these mimetics strongly inhibited RANTES-induced migration and invasion of Huh7 cells. Therefore, targeting the RANTES-glycosaminoglycan interaction could be a new therapeutic approach for human hepatocellular carcinoma.
Assuntos
Materiais Biomiméticos/farmacologia , Carcinoma Hepatocelular/patologia , Movimento Celular/efeitos dos fármacos , Quimiocina CCL5/antagonistas & inibidores , Quimiocina CCL5/farmacologia , Glicosaminoglicanos/farmacologia , Neoplasias Hepáticas/patologia , Materiais Biomiméticos/síntese química , Linhagem Celular Tumoral , Quimiotaxia/efeitos dos fármacos , Glicosaminoglicanos/química , Humanos , Invasividade Neoplásica/patologiaRESUMO
CONTEXT: Statins inhibit HMG-CoA reductase, preventing synthesis of mevalonate but also of isoprenoids, which affect osteoclast activity. Amino-bisphosphonates share this effect. In vitro and in vivo, statins show convincing anabolic and anti-resorptive bone effects. However, in a clinical meta-analysis (MA), they did not prevent hip fractures. OBJECTIVE AND DESIGN: Our meta-analysis studied the impact of statins on bone mineral density (BMD) at various sites and compared the effects of lipophilic and more hydrophilic statins. DATA SOURCES: Our PubMed and Embase queries using two keywords (statins, BMD) were updated to October 2006. DATA COLLECTION: Two readers independently collected BMDs from studies. DATA SYNTHESIS: Twenty-one studies, mostly observational (three randomized controlled trials and one pseudo-randomized study), were assessed. Two studies were excluded (no control groups). Three studies could not be analyzed. The sixteen studies analyzed mainly included postmenopausal osteopenic women (2971 patients under statins). Statins significantly increased BMD at total hip (TH) and femoral neck (FN). Effect sizes (ESs) were modest: 0.21 at TH (95% confidence interval [CI]: 0.16-0.25) and 0.20 at FN (CI: 0.08-0.28). Among women, statins acted similarly (ES: 0.20 for TH and 0.18 for FN; CI: 0.14-0.25 and 0.06-0.31 respectively); lipophilic statins (simvastatin, lovastatin) almost entirely caused this effect, at both TH (ES: 0.20; CI: 0.15-0.26) and FN (ES: 0.22; CI: 0.06-0.37). CONCLUSION: Our findings of modest but statistically significant beneficial effects of statins on hip BMD should promote large double-blind randomized controlled trials on their bone effects, in view of their major beneficial cardiovascular effects with excellent safety profile.
Assuntos
Densidade Óssea/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Ensaios Clínicos como Assunto , Feminino , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/prevenção & controle , Resultado do TratamentoRESUMO
BACKGROUND: Procalcitonin (PCT) has been found elevated in complicated forms of Plasmodium falciparum malaria. Its usefulness has almost never been assessed in uncomplicated falciparum malaria. METHOD: We assessed diagnostic and prognostic value of PCT in a prospective series of 25 adults with uncomplicated P. falciparum malaria. Patients originated mainly from western Africa and were infected during a stay back in their native country (19 semi-immune and 6 non-immune subjects; 11 had not received any chemoprophylaxis). RESULTS: Parasitaemia ranged from 0.01 to 3%. Eighteen patients had their first PCT determined at admission or within 24h thereafter (mean +/- SD: 3.0 +/- 4.6 ng/ml; range: 0.1-19.7). PCT was higher than 0.5 ng/ml in 14 patients (78%), higher than 2 ng/ml in 7 (39%). PCT correlated with parasitaemia (r = 0.53; p = 0.027), not with C-reactive protein (CRP). Delay between first symptoms and diagnosis was much longer among patients with PCT higher than 2 ng/ml than among those with a lower PCT. CONCLUSION: PCT was often elevated in uncomplicated malaria, especially when delay between first symptoms and diagnosis was long or parasitaemia was high (prognostic marker).
Assuntos
Calcitonina/sangue , Malária Falciparum/sangue , Parasitemia/sangue , Precursores de Proteínas/sangue , Adolescente , Adulto , África , Animais , Biomarcadores/sangue , Peptídeo Relacionado com Gene de Calcitonina , Progressão da Doença , Feminino , Humanos , Malária Falciparum/diagnóstico , Malária Falciparum/parasitologia , Masculino , Pessoa de Meia-Idade , Plasmodium falciparum/isolamento & purificação , Estudos Prospectivos , MigrantesRESUMO
OBJECTIVE: To quantify the accuracy of serum procalcitonin as a diagnostic test for sepsis, severe sepsis, or septic shock in adults in intensive care units or after surgery or trauma, alone and compared with C-reactive protein. To draw and compare the summary receiver operating characteristics curves for procalcitonin and C-reactive protein from the literature. DATA SOURCE: MEDLINE (keywords: procalcitonin, intensive care, sepsis, postoperative sepsis, trauma); screening of the literature. STUDY SELECTION: Meta-analysis of all 49 published studies in medical, surgical, or polyvalent intensive care units or postoperative wards. Children, medical patients, and immunocompromised patients were excluded. DATA EXTRACTION: Thirty-three studies fulfilled inclusion criteria (3,943 patients, 1,828 males, 922 females; mean age: 56.1 yrs; 1,825 patients with sepsis, severe sepsis, or septic shock; 1,545 with only systemic inflammatory response syndrome); eight studies could not be analyzed statistically. Global mortality rate was 29.3%. DATA SYNTHESIS: Global odds ratios for diagnosis of infection complicated by systemic inflammation were 15.7 for the 25 studies (2,966 patients) using procalcitonin (95% confidence interval, 9.1-27.1) and 5.4 for the 15 studies (1,322 patients) using C-reactive protein (95% confidence interval, 3.2-9.2). The summary receiver operating characteristics curve for procalcitonin was better than for C-reactive protein. In the 15 studies using both markers, the Q* value (intersection of summary receiver operating characteristics curve with the diagonal line where sensitivity equals specificity) was significantly higher for procalcitonin than for C-reactive protein (0.78 vs. 0.71, p = .02), the former test showing better accuracy. CONCLUSIONS: Procalcitonin represents a good biological diagnostic marker for sepsis, severe sepsis, or septic shock, difficult diagnoses in critically ill patients. Procalcitonin is superior to C-reactive protein. Procalcitonin should be included in diagnostic guidelines for sepsis and in clinical practice in intensive care units.
Assuntos
Biomarcadores/sangue , Calcitonina/sangue , Estado Terminal , Complicações Pós-Operatórias/diagnóstico , Precursores de Proteínas/sangue , Sepse/diagnóstico , Ferimentos e Lesões/complicações , Adulto , Proteína C-Reativa/análise , Peptídeo Relacionado com Gene de Calcitonina , Cuidados Críticos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Sepse/mortalidade , Choque Séptico/diagnósticoRESUMO
We performed a meta-analysis of all 87 published studies linking intratumoral microvessel density (MVD), reflecting angiogenesis, to relapse-free survival (RFS) and overall survival (OS). With median MVD as cutoff, MVD impact was measured by risk ratio (RR) between the two survival distributions. Seventeen studies did not mention survival data or fit inclusion criteria. Twenty-two were multiple publications of the same series, leaving 43 independent studies (8936 patients). MVD was assessed by immunohistochemistry, using antibodies against factor VIII (27 studies; n = 5262), CD31 (10 studies; n = 2296), or CD34 (8 studies; n = 1726). MVD might be a better prognostic factor when assessed by CD31 or CD34 versus factor VIII (P = 0.11). For RFS, statistical calculations were performed in 25 studies (6501 patients). High MVD significantly predicted poor survival [RR = 1.54 for RFS and OS with the same 95% confidence interval (CI), 1.29-1.84]. Twenty-two studies analyzed separately lymph node-negative patients (n = 3580), for whom predictors of poor survival are requested. This latter meta-analysis included 15 studies for RFS (2727 patients) and 11 for OS (1926 patients). High MVD significantly predicted poor survival [RR = 1.99 for RFS (95% CI, 1.33-2.98) and RR = 1.54 for OS (95% CI, 1.01-2.33)]. Between-study variations could result from patient selection criteria, techniques to stain and count microvessels, and cutoff selection. MVD was a significant although weak prognostic factor in women with breast cancer. Standardization of MVD assessment is needed.