Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 22
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Plants (Basel) ; 10(7)2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34371559

RESUMO

Soils and plant root rhizospheres have diverse microorganism profiles. Components of this naturally occurring microbiome, arbuscular mycorrhizal (AM) fungi and plant growth promoting rhizobacteria (PGPR), may be beneficial to plant growth. Supplementary application to host plants of AM fungi and PGPR either as single species or multiple species inoculants has the potential to enhance this symbiotic relationship further. Single species interactions have been described; the nature of multi-species tripartite relationships between AM fungi, PGPR and the host plant require further scrutiny. The impact of select Bacilli spp. rhizobacteria and the AM fungus Rhizophagus intraradices as both single and combined inoculations (PGPR[i] and AMF[i]) within field extracted arable soils of two tillage treatments, conventional soil inversion (CT) and zero tillage (ZT) at winter wheat growth stages GS30 and GS39 have been conducted. The naturally occurring soil borne species (PGPR[s] and AMF[s]) have been determined by qPCR analysis. Significant differences (p < 0.05) were evident between inocula treatments and the method of seedbed preparation. A positive impact on wheat plant growth was noted for B. amyloliquefaciens applied as both a single inoculant (PGPR[i]) and in combination with R. intraradices (PGPR[i] + AMF[i]); however, the two treatments did not differ significantly from each other. The findings are discussed in the context of the inocula applied and the naturally occurring soil borne PGPR[s] present in the field extracted soil under each method of tillage.

2.
Access Microbiol ; 3(11): 000292, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35018332

RESUMO

Sheaffer blue ink is an effective method to stain arbuscular mycorrhizal (AM) fungi in a variety of plant species. It has, however, received criticism for its potential rapid degradation and short-term viability. The long and medium term storage and viability of stained samples has not, to date, been described for this particular staining method. This short communication reports on the viability of 730 samples stained with Sheaffer blue ink stored for the duration of 4 years in microscope slide boxes out of direct sunlight. There was no significant difference in micrograph image quality and presence of stain between years as indicated by the number of AM fungal structures quantified. In conclusion Sheaffer blue ink stain does not deteriorate in the medium term.

3.
Microorganisms ; 8(11)2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33207834

RESUMO

Arbuscular mycorrhizal (AM) fungi establish close interactions with host plants, an estimated 80% of vascular plant species. The host plant receives additional soil bound nutrients that would otherwise not be available. Other components of the microbiome, such as rhizobacteria, may influence interactions between AM fungi and the host plant. Within a commercial arable crop selected rhizobacteria in combination with AM fungi may benefit crop yields. The precise nature of interactions between rhizobacteria and AM fungi in a symbiotic relationship overall requires greater understanding. The present study aims to assess this relationship by quantifying: (1) AM fungal intracellular root structures (arbuscules) and soil glomalin as an indicator of AM fungal growth; and (2) root length and tiller number as a measure of crop growth, in response to inoculation with one of three species of Bacillus: B. amyloliquefaciences, B. pumilis, or B. subtilis. The influence of soil management, conventional (CT) or zero tillage (ZT) was a further variable evaluated. A significant (p < 0.0001) species-specific impact on the number of quantifiable AM fungal arbuscules was observed. The inoculation of winter wheat (Triticum aestivum) with B. amyloliquefaciences had a positive impact on AM fungal symbiosis, as indicated by an average of 3226 arbuscules per centimetre of root tissue. Bacillus subtilis increased root length significantly (p < 0.01) but decreased fungal symbiosis (p < 0.01). The inoculation of field soils altered the concentration of glomalin, an indicator of AM fungal growth, significantly (p < 0.00001) for each tillage treatment. The greatest increase was associated with B. amyloliquefaciences for both CT (p < 0.0001) and ZT (p < 0.00001). Bacillus subtilis reduced measured glomalin significantly in both tillage treatments (p < 0.0001 and p < 0.00001 for CT and ZT respectively). The interaction between rhizobacteria and AM fungi is variable, being beneficial or detrimental depending on species. This relationship was evident in both tillage treatments and has important implications for maximizing symbiosis in the crop plant-microbiome present in agricultural systems.

4.
Access Microbiol ; 2(2): acmi000083, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-34568751

RESUMO

Arbuscular mycorrhizal (AM) fungi are one of the most common fungal organisms to exist in symbiosis with terrestrial plants, facilitating the growth and maintenance of arable crops. Wheat has been studied extensively for AM fungal symbiosis using the carcinogen trypan blue as the identifying stain for fungal components, namely arbuscles, vesicles and hyphal structures. The present study uses Sheaffer blue ink with a lower risk as an alternative to this carcinogenic stain. Justification for this is determined by stained wheat root sections (n=120), with statistically significant increases in the observed abundance of intracellular root cortical fungal structures stained with Sheaffer blue ink compared to trypan blue for both Zulu (P=0.003) and Siskin (P=0.0003) varieties of winter wheat. This new alternative combines an improved quantification of intracellular fungal components with a lower hazard risk at a lower cost.

5.
Clin Ther ; 40(4): 536-549.e3, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29395290

RESUMO

PURPOSE: This observational study of oncologic clinical practices was designed to describe real-world patterns of use of emerging therapies (abiraterone acetate, cabazitaxel, enzalutamide, radium-223, sipuleucel-T) in patients with castration-resistant prostate cancer and to characterize their concomitant use with denosumab or zoledronic acid. METHODS: A retrospective cohort study was conducted using a database of electronic health records from oncology practices across the United States. Eligible patients had a diagnosis of prostate cancer (International Classification of Diseases, Ninth Revision [ICD-9] code 185/International Classification of Diseases, Tenth Revision [ICD-10] code C61) before or concurrent with a visit between January 1, 2013, and December 31, 2015; follow-up was performed through June 30, 2016. From this population, we identified those who received an emerging therapy and a subset who also received denosumab or zoledronic acid. FINDINGS: A total of 71,606 men met the eligibility criteria, and 5131 (7%) received emerging therapy. In the emerging therapy cohort (at the time of the first use), median age was 75 years, median prostate-specific antigen value was 22.7 ng/mL, 56% had bone metastases, and 80% were docetaxel naive. Abiraterone and enzalutamide were the most commonly used first emerging therapies (52% and 31%, respectively), followed by sipuleucel-T (9%), cabazitaxel (5%), and radium-223 (1.5%). Of the emerging therapy cohort, 3121 patients (61%) received concomitant denosumab (70%) or zoledronic acid (35%); 5% received both. IMPLICATIONS: Among patients with prostate cancer treated in the United States, most of those treated with an emerging therapy between 2013 and 2015 also received denosumab or zoledronic acid, suggesting that the concomitant use of these therapy types is currently a common practice. Use of denosumab or zoledronic acid was higher in patients with verified bone metastases.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Denosumab/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Ácido Zoledrônico/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/secundário , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangue , Estudos Retrospectivos
6.
Lancet Oncol ; 19(3): 370-381, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29429912

RESUMO

BACKGROUND: Multiple myeloma is characterised by monoclonal paraprotein production and osteolytic lesions, commonly leading to skeletal-related events (spinal cord compression, pathological fracture, or surgery or radiotherapy to affected bone). Denosumab, a monoclonal antibody targeting RANKL, reduces skeletal-related events associated with bone lesions or metastases in patients with advanced solid tumours. This study aimed to assess the efficacy and safety of denosumab compared with zoledronic acid for the prevention of skeletal-related events in patients with newly diagnosed multiple myeloma. METHODS: In this international, double-blind, double-dummy, randomised, active-controlled, phase 3 study, patients in 259 centres and 29 countries aged 18 years or older with symptomatic newly diagnosed multiple myeloma who had at least one documented lytic bone lesion were randomly assigned (1:1; centrally, by interactive voice response system using a fixed stratified permuted block randomisation list with a block size of four) to subcutaneous denosumab 120 mg plus intravenous placebo every 4 weeks or intravenous zoledronic acid 4 mg plus subcutaneous placebo every 4 weeks (both groups also received investigators' choice of first-line antimyeloma therapy). Stratification was by intent to undergo autologous transplantation, antimyeloma therapy, International Staging System stage, previous skeletal-related events, and region. The clinical study team and patients were masked to treatment assignments. The primary endpoint was non-inferiority of denosumab to zoledronic acid with respect to time to first skeletal-related event in the full analysis set (all randomly assigned patients). All safety endpoints were analysed in the safety analysis set, which includes all randomly assigned patients who received at least one dose of active study drug. This study is registered with ClinicalTrials.gov, number NCT01345019. FINDINGS: From May 17, 2012, to March 29, 2016, we enrolled 1718 patients and randomly assigned 859 to each treatment group. The study met the primary endpoint; denosumab was non-inferior to zoledronic acid for time to first skeletal-related event (hazard ratio 0·98, 95% CI 0·85-1·14; pnon-inferiority=0·010). 1702 patients received at least one dose of the investigational drug and were included in the safety analysis (850 patients receiving denosumab and 852 receiving zoledronic acid). The most common grade 3 or worse treatment-emergent adverse events for denosumab and zoledronic acid were neutropenia (126 [15%] vs 125 [15%]), thrombocytopenia (120 [14%] vs 103 [12%]), anaemia (100 [12%] vs 85 [10%]), febrile neutropenia (96 [11%] vs 87 [10%]), and pneumonia (65 [8%] vs 70 [8%]). Renal toxicity was reported in 85 (10%) patients in the denosumab group versus 146 (17%) in the zoledronic acid group; hypocalcaemia adverse events were reported in 144 (17%) versus 106 (12%). Incidence of osteonecrosis of the jaw was not significantly different between the denosumab and zoledronic acid groups (35 [4%] vs 24 [3%]; p=0·147). The most common serious adverse event for both treatment groups was pneumonia (71 [8%] vs 69 [8%]). One patient in the zoledronic acid group died of cardiac arrest that was deemed treatment-related. INTERPRETATION: In patients with newly diagnosed multiple myeloma, denosumab was non-inferior to zoledronic acid for time to skeletal-related events. The results from this study suggest denosumab could be an additional option for the standard of care for patients with multiple myeloma with bone disease. FUNDING: Amgen.


Assuntos
Antineoplásicos/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Neoplasias Ósseas/prevenção & controle , Denosumab/uso terapêutico , Fraturas Espontâneas/prevenção & controle , Mieloma Múltiplo/tratamento farmacológico , Compressão da Medula Espinal/prevenção & controle , Ácido Zoledrônico/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Conservadores da Densidade Óssea/efeitos adversos , Neoplasias Ósseas/complicações , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/secundário , Denosumab/efeitos adversos , Método Duplo-Cego , Feminino , Fraturas Espontâneas/etiologia , Fraturas Espontâneas/mortalidade , Fraturas Espontâneas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Intervalo Livre de Progressão , Fatores de Risco , Compressão da Medula Espinal/etiologia , Compressão da Medula Espinal/mortalidade , Compressão da Medula Espinal/patologia , Fatores de Tempo , Resultado do Tratamento , Ácido Zoledrônico/efeitos adversos
7.
CBE Life Sci Educ ; 17(1)2018.
Artigo em Inglês | MEDLINE | ID: mdl-29326101

RESUMO

National reports have called for the introduction of research experiences throughout the undergraduate curriculum, but practical implementation at many institutions faces challenges associated with sustainability, cost, and large student populations. We describe a novel course-based undergraduate research experience (CURE) that introduces introductory-level students to research in functional genomics in a 3-credit, multisection laboratory class. In the Pathways over Time class project, students study the functional conservation of the methionine biosynthetic pathway between divergent yeast species. Over the five semesters described in this study, students (N = 793) showed statistically significant and sizable growth in content knowledge (d = 1.85) and in self-reported research methods skills (d = 0.65), experimental design, oral and written communication, database use, and collaboration. Statistical analyses indicated that content knowledge growth was larger for underrepresented minority students and that growth in content knowledge, but not research skills, varied by course section. Our findings add to the growing body of evidence that CUREs can support the scientific development of large numbers of students with diverse characteristics. The Pathways over Time project is designed to be sustainable and readily adapted to other institutional settings.


Assuntos
Currículo , Genômica/educação , Laboratórios , Avaliação Educacional , Feminino , Humanos , Conhecimento , Masculino , Metionina/biossíntese , Análise de Regressão , Projetos de Pesquisa , Saccharomyces cerevisiae/metabolismo , Estudantes , Fatores de Tempo
9.
Clin Cancer Res ; 22(23): 5713-5721, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27140926

RESUMO

PURPOSE: Bone antiresorptive agents can significantly reduce bone turnover markers (BTM) in patients with advanced cancer. We evaluated association of changes in BTMs with overall survival (OS), disease progression (DP), and disease progression in bone (DPB) in patients with advanced cancer and bone metastases following denosumab or zoledronic acid treatment. EXPERIMENTAL DESIGN: This is an integrated analysis of patient-level data from three identically designed, blinded, phase III trials with patients randomized to subcutaneous denosumab or intravenous zoledronic acid. Levels of the BTMs urinary N-telopeptide (uNTx) and serum bone-specific alkaline phosphatase (sBSAP) measured at study entry and month 3 were analyzed. OS, DP, and DPB were compared in patients with BTMs ≥ median versus < median based on month 3 assessments. RESULTS: uNTx levels ≥ the median of 10.0 nmol/mmol at month 3 were associated with significantly reduced OS compared with levels < median (HR for death, 1.85; P < 0.0001). sBSAP levels ≥ median of 12.6 ng/mL were associated with significantly reduced OS compared with levels < median (HR, 2.44; P < 0.0001). uNTx and sBSAP levels ≥ median at month 3 were associated with significantly greater risk of DP (HR, 1.31; P < 0.0001 and HR, 1.71; P < 0.0001, respectively) and DPB (HR, 1.11; P = 0.0407 and HR, 1.27; P < 0.0001, respectively). CONCLUSIONS: BTM levels ≥ median after 3 months of bone antiresorptive treatment were associated with reduced OS and increased risk of DP and DPB. Assessment of uNTx and sBSAP levels after bone antiresorptive therapy may add to identification of patients at risk for worse clinical outcomes. Clin Cancer Res; 22(23); 5713-21. ©2016 AACR.


Assuntos
Biomarcadores/metabolismo , Conservadores da Densidade Óssea/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Remodelação Óssea/efeitos dos fármacos , Idoso , Neoplasias Ósseas/secundário , Colágeno Tipo I/metabolismo , Denosumab/uso terapêutico , Difosfonatos/uso terapêutico , Progressão da Doença , Feminino , Humanos , Imidazóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Fator de Transcrição PAX5/metabolismo , Peptídeos/metabolismo , Ácido Zoledrônico
10.
J Clin Oncol ; 33(30): 3431-8, 2015 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-26304872

RESUMO

PURPOSE: Trebananib, an investigational recombinant peptide-Fc fusion protein, neutralizes the receptor-ligand interaction between Tie2 and angiopoietin-1/2. This phase II study was conducted to evaluate trebananib plus sunitinib, a vascular endothelial growth factor receptor inhibitor, in patients with metastatic clear cell renal cell carcinoma. PATIENTS AND METHODS: Adults with metastatic renal cell carcinoma were enrolled sequentially onto two cohorts that received sunitinib 50 mg once per day for 4 weeks on and 2 weeks off and intravenous trebananib once per week at a dose of 10 mg/kg in cohort A or 15 mg/kg in cohort B. The primary end points were incidences of adverse events (AEs) and dose interruptions of sunitinib during the first 12 weeks of treatment. Secondary end points included objective response rate and progression-free survival. RESULTS: Eighty-five patients were enrolled: 43 in cohort A, and 42 in cohort B. During the first 12 weeks of treatment, 58% and 57% of patients in cohorts A and B, respectively, had sunitinib dose interruptions (dose decrease, withholding, or withdrawal). The most frequent AEs were diarrhea (cohort A, 74%; cohort B, 67%), mucosal inflammation (cohort A, 49%; cohort B, 60%), and hypertension (cohort A, 52%; cohort B, 45%). AEs of grade 3 or greater occurred in 58% of patients in cohort A and in 69% of patients in cohort B. The objective response rate was 58% and 63% in cohorts A and B, respectively. The median progression-free survival time was 13.9 months (95% CI, 10.4 to 19.2) and 16.3 months (95% CI, 13.1 to 21.4) in cohorts A and B, respectively. The median overall survival time was 36 months (95% CI, 25.2 to not estimable) in cohort A and was not estimable (median follow-up, 25 months) in cohort B. CONCLUSION: Trebananib plus sunitinib seemed to increase toxicity at the tested doses. Efficacy results suggest a potential benefit for the addition of trebananib to sunitinib.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/patologia , Estudos de Coortes , Esquema de Medicação , Feminino , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Indóis/sangue , Indóis/farmacocinética , Injeções Intravenosas , Neoplasias Renais/sangue , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Pirróis/sangue , Pirróis/farmacocinética , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/sangue , Proteínas Recombinantes de Fusão/farmacocinética , Sunitinibe
11.
Lancet ; 386(9992): 433-43, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-26040499

RESUMO

BACKGROUND: Adjuvant endocrine therapy compromises bone health in patients with breast cancer, causing osteopenia, osteoporosis, and fractures. Antiresorptive treatments such as bisphosphonates prevent and counteract these side-effects. In this trial, we aimed to investigate the effects of the anti-RANK ligand antibody denosumab in postmenopausal, aromatase inhibitor-treated patients with early-stage hormone receptor-positive breast cancer. METHODS: In this prospective, double-blind, placebo-controlled, phase 3 trial, postmenopausal patients with early hormone receptor-positive breast cancer receiving treatment with aromatase inhibitors were randomly assigned in a 1:1 ratio to receive either denosumab 60 mg or placebo administered subcutaneously every 6 months in 58 trial centres in Austria and Sweden. Patients were assigned by an interactive voice response system. The randomisation schedule used a randomly permuted block design with block sizes 2 and 4, stratified by type of hospital regarding Hologic device for DXA scans, previous aromatase inhibitor use, and baseline bone mineral density. Patients, treating physicians, investigators, data managers, and all study personnel were masked to treatment allocation. The primary endpoint was time from randomisation to first clinical fracture, analysed by intention to treat. As an additional sensitivity analysis, we also analysed the primary endpoint on the per-protocol population. Patients were treated until the prespecified number of 247 first clinical fractures was reached. This trial is ongoing (patients are in follow-up) and is registered with the European Clinical Trials Database, number 2005-005275-15, and with ClinicalTrials.gov, number NCT00556374. FINDINGS: Between Dec 18, 2006, and July 22, 2013, 3425 eligible patients were enrolled into the trial, of whom 3420 were randomly assigned to receive denosumab 60 mg (n=1711) or placebo (n=1709) subcutaneously every 6 months. Compared with the placebo group, patients in the denosumab group had a significantly delayed time to first clinical fracture (hazard ratio [HR] 0·50 [95% CI 0·39-0·65], p<0·0001). The overall lower number of fractures in the denosumab group (92) than in the placebo group (176) was similar in all patient subgroups, including in patients with a bone mineral density T-score of -1 or higher at baseline (n=1872, HR 0·44 [95% CI 0·31-0·64], p<0·0001) and in those with a bone mineral density T-score of less than -1 already at baseline (n=1548, HR 0·57 [95% CI 0·40-0·82], p=0·002). The patient incidence of adverse events in the safety analysis set (all patients who received at least one dose of study drug) did not differ between the denosumab group (1366 events, 80%) and the placebo group (1334 events, 79%), nor did the numbers of serious adverse events (521 vs 511 [30% in each group]). The main adverse events were arthralgia and other aromatase-inhibitor related symptoms; no additional toxicity from the study drug was reported. Despite proactive adjudication of every potential osteonecrosis of the jaw by an international expert panel, no cases of osteonecrosis of the jaw were reported. 93 patients (3% of the full analysis set) died during the study, of which one death (in the denosumab group) was thought to be related to the study drug. INTERPRETATION: Adjuvant denosumab 60 mg twice per year reduces the risk of clinical fractures in postmenopausal women with breast cancer receiving aromatase inhibitors, and can be administered without added toxicity. Since a main side-effect of adjuvant breast cancer treatment can be substantially reduced by the addition of denosumab, this treatment should be considered for clinical practice. FUNDING: Amgen.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/complicações , Fraturas Ósseas , Absorciometria de Fóton , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Aromatase/uso terapêutico , Áustria , Densidade Óssea/fisiologia , Neoplasias da Mama/tratamento farmacológico , Denosumab , Método Duplo-Cego , Feminino , Fraturas Ósseas/complicações , Fraturas Ósseas/prevenção & controle , Humanos , Pessoa de Meia-Idade , Pós-Menopausa , Estudos Prospectivos , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Suécia , Resultado do Tratamento
12.
Cancer Chemother Pharmacol ; 75(5): 993-1004, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25772756

RESUMO

PURPOSE: This study assessed the safety, efficacy, and pharmacokinetics of motesanib, a multitargeted small molecule angiogenesis inhibitor, with and without panitumumab, in combination with FOLFIRI or FOLFOX in patients with metastatic colorectal cancer (mCRC). METHODS: This open-label, phase 1b, two-part, multicenter study in patients with mCRC and ≤1 prior treatment evaluated escalating doses (50, 75, 100, or 125 mg QD, 75 mg BID) of motesanib with panitumumab and chemotherapy (Part 1) and the target dose of motesanib with chemotherapy (Part 2). RESULTS: At 17 sites in the USA and Australia, 119 patients were enrolled between December 2004 and February 2010. In Part 1 [motesanib plus panitumumab/FOLFIRI (n = 36) or plus panitumumab/FOLFOX (n = 17)], all motesanib doses tested were tolerated and 125 mg QD was deemed the target dose. Following toxicity results for combination therapy in other trials, panitumumab was withdrawn from the study. Part 2 evaluated motesanib 125 mg with chemotherapy [FOLFIRI (n = 37); FOLFOX (n = 29)]. The primary endpoint, objective response rate in patients with measurable disease by RECIST, was 20 % overall and was higher among patients receiving first-line (27 % overall; FOLFOX, 24 %; FOLFIRI, 27 %) compared with second-line therapy (14 % overall; FOLFOX, 0 %; FOLFIRI, 20 %). The most common adverse events were diarrhea, nausea, fatigue, and hypertension. We observed a low rate of cholecystitis [3 of 119 (2.5 %)], a known adverse event of motesanib and other small molecule VEGF inhibitors. CONCLUSIONS: Motesanib 125 mg QD in combination with FOLFIRI or FOLFOX chemotherapy was tolerated and demonstrated modest efficacy in first-/second-line mCRC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/metabolismo , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Humanos , Indóis/administração & dosagem , Indóis/farmacocinética , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Niacinamida/farmacocinética , Oligonucleotídeos , Compostos Organoplatínicos/administração & dosagem , Panitumumabe , Adulto Jovem
13.
Lancet Oncol ; 15(8): 799-808, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24950985

RESUMO

BACKGROUND: Angiogenesis is a valid target in the treatment of epithelial ovarian cancer. Trebananib inhibits the binding of angiopoietins 1 and 2 to the Tie2 receptor, and thereby inhibits angiogenesis. We aimed to assess whether the addition of trebananib to single-agent weekly paclitaxel in patients with recurrent epithelial ovarian cancer improved progression-free survival. METHODS: For this randomised, double-blind phase 3 study undertaken between Nov 10, 2010, and Nov 19, 2012, we enrolled women with recurrent epithelial ovarian cancer from 32 countries. Patient eligibility criteria included having been treated with three or fewer previous regimens, and a platinum-free interval of less than 12 months. We enrolled patients with a computerised interactive voice response system, and patients were randomly assigned using a permuted block method (block size of four) in a 1:1 ratio to receive weekly intravenous paclitaxel (80 mg/m(2)) plus either weekly masked intravenous placebo or trebananib (15 mg/kg). Patients were stratified on the basis of platinum-free interval (≥0 and ≤6 months vs >6 and ≤12 months), presence or absence of measurable disease, and region (North America, western Europe and Australia, or rest of world). The sponsor, investigators, site staff, and patients were masked to the treatment assignment. The primary endpoint was progression-free survival assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT01204749, and is no longer accruing patients. FINDINGS: 919 patients were enrolled, of whom 461 were randomly assigned to the trebananib group and 458 to the placebo group. Median progression-free survival was significantly longer in the trebananib group than in the placebo group (7·2 months [5·8-7·4] vs 5·4 months [95% CI 4·3-5·5], respectively, hazard ratio 0·66, 95% CI 0·57-0·77, p<0·0001). Incidence of grade 3 or higher adverse events was similar between treatment groups (244 [54%] of 452 patients in the placebo group vs 258 [56%] of 461 patients in the trebananib group). Trebananib was associated with more adverse event-related treatment discontinuations than was placebo (77 [17%] patients vs 27 [6%], respectively) and higher incidences of oedema (294 [64%] patients had any-grade oedema in the trebananib group vs 127 [28%] patients in the placebo group). Grade 3 or higher adverse events included ascites (34 [8%] in the placebo group vs 52 [11%] in the trebananib group), neutropenia (40 [9%] vs 26 [6%]), and abdominal pain (21 [5%] vs 22 [5%]). We recorded serious adverse events in 125 (28%) patients in the placebo group and 159 (34%) patients in the trebananib group. There was a difference of 2% or less in class-specific adverse events associated with anti-VEGF therapy (hypertension, proteinuria, wound-healing complications, thrombotic events, gastrointestinal perforations), except bleeding, which was more common in the placebo group than in the trebananib group (75 [17%] vs 46 [10%]). INTERPRETATION: Inhibition of angiopoietins 1 and 2 with trebananib provided a clinically meaningful prolongation in progression-free survival. This non-VEGF anti-angiogenesis option for women with recurrent epithelial ovarian cancer should be investigated in other settings and in combination with additional agents. Although oedema was increased, typical anti-VEGF associated adverse events were not prominent. FUNDING: Amgen.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Proteínas Recombinantes de Fusão/administração & dosagem , Idoso , Inibidores da Angiogênese/efeitos adversos , Angiopoietina-1/antagonistas & inibidores , Angiopoietina-2/antagonistas & inibidores , Carcinoma Epitelial do Ovário , Intervalo Livre de Doença , Método Duplo-Cego , Edema/induzido quimicamente , Feminino , Humanos , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Suspensão de Tratamento
14.
Virulence ; 4(7): 634-7, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-23921442

RESUMO

Previous data from our laboratory suggest a relationship between increased pmrAB expression and virulence in an Escherichia coli mouse infection model of pyelonephritis. Competitive infections with wild type and pmrAB mutants showed that disruption of pmrAB caused decreased persistence of E. coli within the mouse kidney. These results were confirmed with plasmid-mediated complementation of the pmrAB mutant. Additionally, increased expression of pmrAB from this complementing plasmid in a previously attenuated marA-rob-soxS triple mutant displayed increased bacterial persistence in the infection when compared with the triple mutant alone. These findings suggest a role for this two-component regulatory system in the virulence of E. coli in a murine pyelonephritis model.


Assuntos
Proteínas de Bactérias/metabolismo , Infecções por Escherichia coli/microbiologia , Escherichia coli/patogenicidade , Pielonefrite/microbiologia , Fatores de Transcrição/metabolismo , Fatores de Virulência/metabolismo , Animais , Modelos Animais de Doenças , Escherichia coli/isolamento & purificação , Feminino , Deleção de Genes , Teste de Complementação Genética , Camundongos , Virulência
15.
Antimicrob Agents Chemother ; 57(4): 1935-7, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23318808

RESUMO

A carbapenem-resistant clinical isolate of Escherichia coli, which lacked OmpF and OmpC porins, carried a marR mutation and expressed a functional yedS, a normally nontranslated gene. MarR and YedS are described here as having effects on the ability of this strain to resist carbapenems. Additionally, expression of YedS was regulated by the small RNA MicF in a MarA-dependent way. These findings illustrate how broadly bacteria can mutate within a selective clinical setting, in this case, resistance to carbapenems, by altering three porin genes and one regulatory gene.


Assuntos
Proteínas de Escherichia coli/metabolismo , Escherichia coli/efeitos dos fármacos , Escherichia coli/metabolismo , Proteínas Repressoras/metabolismo , Carbapenêmicos/farmacologia , China , Eletroforese em Gel de Poliacrilamida , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Regulação Bacteriana da Expressão Gênica/genética , Dados de Sequência Molecular , Proteínas Repressoras/genética
16.
Cells Tissues Organs ; 196(2): 151-60, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22301468

RESUMO

Amelogenins containing exons 8 and 9 are alternatively spliced variants of amelogenin. Some amelogenin spliced variants have been found to promote pulp regeneration following pulp exposure. The function of the amelogenin spliced variants with the exons 8 and 9 remains unknown. In this study, we synthesized recombinant leucine rich amelogenin peptide (LRAP, A-4), LRAP plus exons 8 and 9 peptide (LRAP 8, 9) or exons 8 and 9 peptide (P89), to determine their effects on odontoblasts. In vivo analyses were completed following the insertion of agarose beads containing LRAP or LRAP 8, 9 into exposed cavity preparations of rat molars. After 8, 15 or 30 days' exposure, the pulp tissues were analyzed for changes in histomorphometry and cell proliferation by PCNA stainings. In vitro analyses included the effects of the addition of the recombinant proteins or peptide on cell proliferation, differentiation and adhesion of postnatal human dental pulp cells (DPCs). These studies showed that in vivo LRAP 8, 9 enhanced the reparative dentin formation as compared to LRAP. In vitro LRAP 8, 9 promoted DPC proliferation and differentiation to a greater extent than LRAP. These data suggest that amelogenin exons 8 and 9 may be useful in amelogenin-mediated pulp repair.


Assuntos
Amelogenina/genética , Proteínas do Esmalte Dentário/genética , Polpa Dentária/fisiologia , Éxons , Odontoblastos/metabolismo , Animais , Processos de Crescimento Celular/genética , Polpa Dentária/metabolismo , Polpa Dentária/patologia , Modelos Animais de Doenças , Humanos , Masculino , Ratos , Ratos Sprague-Dawley
17.
J Bacteriol ; 194(5): 1177-85, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22210763

RESUMO

Paralogous transcriptional regulators MarA, Rob, and SoxS act individually and together to control expression of more than 80 Escherichia coli genes. Deletion of marA, rob, and soxS from an E. coli clinical isolate prevents persistence beyond 2 days postinfection in a mouse model of pyelonephritis. We used microarray analysis to identify 242 genes differentially expressed between the triple deletion mutant and its parent strain at 2 days postinfection in the kidney. One of these, znuC of the zinc transport system ZnuACB, displayed decreased expression in the triple mutant compared to that in the parental strain, and deletion of znuC from the parental strain reduced persistence. The marA rob soxS triple deletion mutant was less viable in vitro under limited-Zn and Zn-depleted conditions, while disruption of znuC caused a reduction in the growth rates for the parental and triple mutant strains to equally low levels under limited-Zn or Zn-depleted conditions. Complementation of the triple mutant with soxS, but not marA or rob, restored the parental growth rate in Zn-depleted medium, while deletion of only soxS from the parental strain led to low growth in Zn-depleted medium. Both results suggested that SoxS is a major regulator responsible for growth under Zn-depleted conditions. Gel shift experiments failed to show direct binding of SoxS to the znuCB promoter, thus suggesting indirect control of znuCB expression by SoxS. While SoxS expression in the triple mutant fully restored persistence, increased expression of znuACB via a plasmid in this mutant only partially restored wild-type levels of persistence in the kidney. This work implicates SoxS control of znuCB expression as a key factor in persistence of E. coli in murine pyelonephritis.


Assuntos
Transportadores de Cassetes de Ligação de ATP/biossíntese , Proteínas de Transporte de Cátions/biossíntese , Infecções por Escherichia coli/microbiologia , Proteínas de Escherichia coli/biossíntese , Proteínas de Escherichia coli/metabolismo , Escherichia coli/metabolismo , Pielonefrite/microbiologia , Transativadores/metabolismo , Zinco/metabolismo , Animais , Modelos Animais de Doenças , Ensaio de Desvio de Mobilidade Eletroforética , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Deleção de Genes , Perfilação da Expressão Gênica , Regulação Bacteriana da Expressão Gênica , Teste de Complementação Genética , Camundongos , Análise em Microsséries , Transativadores/genética
18.
Microbiology (Reading) ; 156(Pt 2): 570-578, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19926649

RESUMO

Cationic antimicrobial peptides (CAMPs), a component of the mammalian immune system, protect the host from bacterial infections. The roles of the Escherichia coli transcriptional regulators MarA, SoxS and Rob in susceptibility to these peptides were examined. Overexpression of marA, either in an antibiotic-resistant marR mutant or from a plasmid, decreased bacterial susceptibility to CAMPs. Overexpression of the soxS gene from a plasmid, which decreased susceptibility to antibiotics, unexpectedly caused no decrease in CAMP susceptibility; instead it produced increased susceptibility to different CAMPs. Deletion or overexpression of rob had little effect on CAMP susceptibility. The marRAB operon was upregulated when E. coli was incubated in sublethal amounts of CAMPs polymyxin B, LL-37 or human beta-defensin-1; however, this upregulation required Rob. Deletion of acrAB increased bacterial susceptibility to polymyxin B, LL-37 and human beta-defensin-1 peptides. Deletion of tolC yielded an even greater increase in susceptibility to these peptides and also led to increased susceptibility to human alpha-defensin-2. Inhibition of cellular proton-motive force increased peptide susceptibility for wild-type and acrAB deletion strains; however, it decreased susceptibility of tolC mutants. These findings demonstrate that CAMPs are both inducers of marA-mediated drug resistance through interaction with Rob and also substrates for efflux in E. coli. The three related transcriptional regulators show different effects on bacterial cell susceptibility to CAMPs.


Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Proteínas de Ligação a DNA/fisiologia , Proteínas de Escherichia coli/fisiologia , Escherichia coli/efeitos dos fármacos , Óperon , Transativadores/fisiologia , Sequência de Aminoácidos , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/metabolismo , Proteínas da Membrana Bacteriana Externa/metabolismo , Proteínas de Bactérias/genética , Proteínas de Ligação a DNA/genética , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Genes Bacterianos , Humanos , Proteínas de Membrana Transportadoras/metabolismo , Polimixina B/metabolismo , Proteínas Repressoras/genética , Transativadores/genética
19.
Mol Microbiol ; 70(2): 462-78, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18761689

RESUMO

The MtrC-MtrD-MtrE efflux pump system confers resistance to macrolide antibiotics and antimicrobial substances of the host innate defence. Clinical isolates with increased resistance to erythromycin and azithromycin frequently harbour mutations in the mtrR structural gene, which encodes a repressor of the mtrCDE operon, or the mtrR promoter region. The MtrC-MtrD-MtrE system is important for gonococcal survival in the murine genital tract, and derepression of the mtrCDE operon via deletion of mtrR confers increased fitness in vivo. Here we compared isogenic strains with naturally occurring mtrR locus mutations for differences in mtrCDE expression and pump-related phenotypes. Mutations upstream of mtrC, including those within the MtrR binding region and a novel mutation that increases mtrC RNA stability conferred the highest levels of derepression as measured by mtrCDE transcription and resistance to antibiotics, progesterone and antimicrobial peptides. In contrast, mutations within the mtrR coding sequence conferred low to intermediate levels of derepression. In vivo, the mtr mutants were more fit than the wild-type strain, the degree to which paralleled in vitro resistance gradients. These studies establish a hierarchy of mtrR locus mutations with regard to regulation of pump efflux, and suggest selection for more derepressed mutants may occur during mixed infections.


Assuntos
Antibacterianos/farmacologia , Proteínas da Membrana Bacteriana Externa/biossíntese , Proteínas de Bactérias/biossíntese , Farmacorresistência Bacteriana , Lipoproteínas/biossíntese , Proteínas de Membrana/biossíntese , Proteínas de Membrana Transportadoras/biossíntese , Mutação , Neisseria gonorrhoeae/efeitos dos fármacos , Neisseria gonorrhoeae/patogenicidade , Animais , Peptídeos Catiônicos Antimicrobianos/farmacologia , Azitromicina/farmacologia , Proteínas de Bactérias/genética , Eritromicina/farmacologia , Feminino , Perfilação da Expressão Gênica , Gonorreia , Camundongos , Camundongos Endogâmicos BALB C , Neisseria gonorrhoeae/genética , Progesterona/farmacologia , Regiões Promotoras Genéticas , Estabilidade de RNA , Proteínas Repressoras/genética , Virulência
20.
Infect Immun ; 76(8): 3700-9, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18541655

RESUMO

Typing of the porB variable region (VR) is an epidemiological tool that classifies gonococcal strains based on sequence differences in regions of the porB gene that encode surface-exposed loops. The frequent isolation of certain porB VR types suggests that some porin sequences confer a selective advantage during infection and/or transmission. Alternatively, certain porin types may be markers of strains that are successful due to factors unrelated to porin. In support of the first hypothesis, here we show urogenital tract isolates representing the most common PIA VR types identified in an urban clinic in Baltimore, MD, over a 10-year period belonged to several different clonal types, as determined by pulsed-field gel electrophoresis (PFGE). Serum resistance, which was confirmed by factor H and C4b-binding protein binding studies, was more often associated with gonococcal the most common VR types. In contrast, three porin-independent phenotypes, namely, lactoferrin utilization, beta-lactamase production, and multiple transferable resistance (Mtr), were segregated with the PFGE cluster and not with the VR type. Data combined with another PIA strain collection showed a strong correlation between serum resistance and the most common VR types. A comparison of VR typing hybridization patterns and nucleotide sequences of 12 porB1a genes suggests that certain porin loop 1, 3, 6, and/or 7 sequences may play a role in the serum resistance phenotype. We conclude that some PorB PIA sequences confer a survival or transmission advantage in the urogenital tract, perhaps via increased resistance to complement-mediated killing. The capacity of some porin types to evade a porin-specific adaptive immune response must also be considered.


Assuntos
Doenças Urogenitais Femininas/microbiologia , Gonorreia/epidemiologia , Doenças Urogenitais Masculinas/microbiologia , Neisseria gonorrhoeae/classificação , Neisseria gonorrhoeae/isolamento & purificação , Porinas/genética , Técnicas de Tipagem Bacteriana , Baltimore/epidemiologia , Atividade Bactericida do Sangue , Análise por Conglomerados , Proteína de Ligação ao Complemento C4b/metabolismo , Fator H do Complemento/metabolismo , Impressões Digitais de DNA , DNA Bacteriano/genética , Farmacorresistência Bacteriana Múltipla , Eletroforese em Gel de Campo Pulsado , Feminino , Doenças Urogenitais Femininas/epidemiologia , Genótipo , Gonorreia/microbiologia , Humanos , Lactoferrina/metabolismo , Masculino , Doenças Urogenitais Masculinas/epidemiologia , Proteínas Motores Moleculares , Neisseria gonorrhoeae/genética , Neisseria gonorrhoeae/fisiologia , Polimorfismo Genético , Ligação Proteica , População Urbana , beta-Lactamases/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...