RESUMO
PURPOSE: Conflicting evidence indicates that HIV seropositivity may influence the outcome of patients with hepatocellular carcinoma (HCC), a leading cause of mortality in people with HIV. We aimed to verify whether HIV affected the overall survival (OS) of patients with HCC, independent of treatment and geographic origin. PATIENTS AND METHODS: We designed an international multicohort study of patients with HCC accrued from four continents who did not receive any anticancer treatment. We estimated the effect of HIV seropositivity on patients' OS while accounting for common prognostic factors and demographic characteristics in uni- and multivariable models. RESULTS: A total of 1,588 patients were recruited, 132 of whom were HIV positive. Most patients clustered within Barcelona Clinic Liver Cancer (BCLC) C or D criteria (n = 1,168 [74%]) and Child-Turcotte-Pugh (CTP) class B (median score, 7; interquartile range [IQR], 3). At HCC diagnosis, the majority of patients who were HIV-positive (n = 65 [64%]) had been on antiretrovirals for a median duration of 8.3 years (IQR, 8.59 years) and had median CD4+ cell counts of 256 (IQR, 284) with undetectable HIV RNA (n = 68 [52%]). OS decreased significantly throughout BCLC stages 0 to D (16, 12, 7.5, 3.1, and 3 months, respectively; P < .001). Median OS of patients who were HIV-positive was one half that of their HIV-uninfected counterparts (2.2 months [bootstrap 95% CI, 1.2 to 3.1 months] v 4.1 months [95% CI, 3.6 to 4.4 months]). In adjusted analyses, HIV seropositivity increased the hazard of death by 24% ( P = .0333) independent of BCLC ( P < .0001), CTP ( P < .0001), α-fetoprotein ( P < .0001), geographical origin ( P < .0001), and male sex ( P = .0016). Predictors of worse OS in patients who were HIV-positive included CTP ( P = .0071) and α-fetoprotein ( P < .0001). CONCLUSION: Despite adequate antiretroviral treatment, HIV seropositivity is associated with decreased survival in HCC, independent of stage, anticancer treatment, and geographical origin. Mechanistic studies investigating the immunobiology of HIV-associated HCC are urgently required.
Assuntos
Carcinoma Hepatocelular/epidemiologia , Infecções por HIV/epidemiologia , Neoplasias Hepáticas/epidemiologia , Idoso , Fármacos Anti-HIV/uso terapêutico , Austrália/epidemiologia , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/terapia , Europa (Continente)/epidemiologia , Feminino , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/mortalidade , Soropositividade para HIV , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , América do Norte/epidemiologia , Prognóstico , Medição de Risco , Fatores de Risco , América do Sul/epidemiologia , Fatores de TempoRESUMO
The western corn rootworm (WCR) Diabrotica virgifera virgifera causes substantial damage in corn. Genetically modified (GM) plants expressing some Bacillus thuringiensis (Bt) insecticidal Cry proteins efficiently controlled this pest. However, changes in WCR susceptibility to these Bt traits have evolved and identification of insecticidal proteins with different modes of action against WCR is necessary. We show here for the first time that Cyt1Aa from Bt exhibits toxicity against WCR besides to the dipteran Aedes aegypti larvae. Cyt1Aa is a pore-forming toxin that shows no cross-resistance with mosquitocidal Cry toxins. We characterized different mutations in helix α-A from Cyt1Aa. Two mutants (A61C and A59C) exhibited reduced or absent hemolytic activity but retained toxicity to A. aegypti larvae, suggesting that insecticidal and hemolytic activities of Cyt1Aa are independent activities. These mutants were still able to form oligomers in synthetic lipid vesicles and to synergize Cry11Aa toxicity. Remarkably, mutant A61C showed a five-fold increase insecticidal activity against mosquito and almost 11-fold higher activity against WCR. Cyt1Aa A61C mutant was as potent in killing WCR that were selected for resistance to mCry3A as it was against unselected WCR indicating that this toxin could be a useful resistance management option in the control of WCR.
Assuntos
Bacillus thuringiensis , Proteínas de Bactérias , Besouros/crescimento & desenvolvimento , Endotoxinas , Proteínas Hemolisinas , Mutação de Sentido Incorreto , Controle Biológico de Vetores , Animais , Bacillus thuringiensis/genética , Bacillus thuringiensis/metabolismo , Toxinas de Bacillus thuringiensis , Proteínas de Bactérias/genética , Proteínas de Bactérias/toxicidade , Endotoxinas/genética , Endotoxinas/toxicidade , Proteínas Hemolisinas/genética , Proteínas Hemolisinas/toxicidade , Inseticidas/toxicidadeRESUMO
Bacillus thuringiensis Cry1Ab and Cry1Fa toxins are environmentally safe insecticides that control important insect pests. Spodoptera frugiperda is an important maize pest that shows low susceptibility to Cry1A toxins, in contrast to Cry1Fa, which is highly active against this pest and is used in transgenic maize for S. frugiperda control. The ß16 region from domain III of Cry1Ab has been shown to be involved in interactions with receptors such as alkaline phosphatase (ALP) or aminopeptidase (APN) in different lepidopteran insects. Alanine-scanning mutagenesis of amino acids of Cry1Ab ß16 (509STLRVN514) revealed that certain ß16 mutations, such as N514A, resulted in increased toxicity of Cry1Ab for S. frugiperda without affecting the toxicity for other lepidopteran larvae, such as Manduca sexta larvae. Exhaustive mutagenesis of N514 was performed, showing that the Cry1Ab N514F, N514H, N514K, N514L, N514Q, and N514S mutations increased the toxicity toward S. frugiperda A corresponding mutation was constructed in Cry1Fa (N507A). Toxicity assays of wild-type and mutant toxins (Cry1Ab, Cry1AbN514A, Cry1AbN514F, Cry1Fa, and Cry1FaN507A) against four S. frugiperda populations from Mexico and one from Brazil revealed that Cry1AbN514A and Cry1FaN507A consistently showed 3- to 18-fold increased toxicity against four of five S. frugiperda populations. In contrast, Cry1AbN514F showed increased toxicity in only two of the S. frugiperda populations analyzed. The mutants Cry1AbN514A and Cry1AbN514F showed greater stability to midgut protease treatment. In addition, binding analysis of the Cry1Ab mutants showed that the increased toxicity correlated with increased binding to brush border membrane vesicles and increased binding affinity for S. frugiperda ALP, APN, and cadherin receptors.IMPORTANCESpodoptera frugiperda is the main maize pest in South and North America and also is an invasive pest in different African countries. However, it is poorly controlled by Bacillus thuringiensis Cry1A toxins expressed in transgenic crops, which effectively control other lepidopteran pests. In contrast, maize expressing Cry1Fa is effective in the control of S. frugiperda, although its effectiveness is being lost due to resistance evolution. Some of the Cry1Ab domain III mutants characterized here show enhanced toxicity for S. frugiperda without loss of toxicity to Manduca sexta Thus, these Cry1Ab mutants could provide useful engineered toxins that, along with other Cry toxins, would be useful for developing transgenic maize expressing stacked proteins for the effective control of S. frugiperda and other lepidopteran pests in the field.
Assuntos
Bacillus thuringiensis/genética , Proteínas de Bactérias/genética , Endotoxinas/genética , Proteínas Hemolisinas/genética , Spodoptera/microbiologia , Animais , Toxinas de Bacillus thuringiensis , Produtos Agrícolas , Engenharia Genética , Inseticidas , Larva/microbiologia , Mutação , Controle Biológico de Vetores , Ligação Proteica , Estabilidade Proteica , Zea maysRESUMO
BACKGROUND: Vicriviroc, a novel HIV CCR5 antagonist, demonstrated significant efficacy and favorable tolerability in phase II trials in treatment-experienced subjects, supporting further evaluation in phase III studies. METHODS: Two identical double-blind, placebo (PBO)-controlled trials in CCR5-tropic HIV-infected subjects with documented resistance to two antiretroviral classes were conducted. Subjects were randomized to vicriviroc 30 mg QD (N = 571) or PBO (N = 286) with open-label optimized background therapy (OBT) containing ≥2 fully active antiretroviral drugs. The primary endpoint was percentage of subjects with <50 copies/mL HIV RNA at 48 weeks. It was analyzed in a logistic regression with treatment (vicriviroc + OBT/PBO + OBT), use of enfuvirtide in baseline OBT (yes/no), and baseline HIV RNA (≤100,000/>100,000 copies/mL) as covariates. In addition, a pre-planned analysis to examine other efficacy and safety endpoints was conducted. RESULTS: Baseline characteristics of the pooled mITT population (vicriviroc, n = 486; PBO, n = 235) included mean HIV RNA of 4.6 log(10) copies/mL and mean CD4 count of 257 cells/µL. Approximately 60% of subjects received ≥3 active drugs in the OBT. The percentage of subjects with <50 copies/mL HIV RNA was not significantly different between vicriviroc and PBO at week 48 (64% vs 62%, p = 0.6). However, in subjects receiving ≤2 active drugs in their OBT, the proportion achieving <50 copies/mL HIV RNA was higher in those receiving vicriviroc compared with PBO (70% vs 55%, p = 0.02). CONCLUSIONS: The studies failed to show significant efficacy gains when vicriviroc was added to OBT. However, given the efficacy results of earlier vicriviroc trials and other CCR5 antagonist, studies are needed to define the role of this class of drugs in the treatment of HIV. Clinical trial identifier: http://www.clinicaltrial.gov/: VICTOR-E3 (NCT00523211) and VICTOR-E4 (NCT00474370).