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11.
Innominato PF Giacchetti S Moreau T Smaaland R Focan C Bjarnason GA Garufi C Iacobelli S Tampellini M Tumolo S Carvalho C Karaboué A Lévi F;ARTBC International Chronotherapy Group 《Chronobiology international》2011,28(7):586-600
Circadian clocks control cellular proliferation and drug metabolism over the 24?h. However, circadian chronomodulated chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin (chronoFLO4) offered no survival benefit as compared with the non-time-stipulated FOLFOX2, in an international randomized trial involving patients with previously untreated metastatic colorectal cancer (EORTC 05963). The authors hypothesized that treatment near maximum tolerated dose could disrupt circadian clocks thus impairing the efficacy of chronoFLO4 but not of FOLFOX2. Patients with available data (N?=?556) were categorized into three subgroups according to the worst grade (G) of neutropenia experienced during treatment. Distinct multivariate models with time-dependent covariates were constructed for each treatment schedule. Neutropenia incidence (all grades) was 33% on chronoFLO4 and 61% on FOLFOX2 (p?.0001), and G3-4 were 7% and 25%, respectively (p < .0001). Neutropenia was significantly more frequent in women than men on either schedule (FOLFOX2, p = .003; chronoFLO4, p = .04). Median survival was 20.7 mo in patients with G3-4 neutropenia versus 12.5 mo in neutropenia-free patients on FOLFOX2 (p < .0001). Corresponding figures were 13.7 and 19.4 mo, respectively, on chronoFLO4 (p?=?.36). Multivariate analysis confirmed occurrence of severe neutropenia independently predicted for better overall survival on FOLFOX2 (HR?=?0.56; p = .015), and worse survival on chronoFLO4 (HR?=?1.77, p = .06), with a significant interaction test (p < .0001). Prediction of better survival in neutropenic patients on FOLFOX2 supports the administration of conventional chemotherapy near maximum tolerated dose. The opposite trend shown here for chronoFLO4 supports the novel concept of jointly optimized hematologic tolerability and efficacy through personalized circadian-timed therapy. 相似文献
12.
Geoffrey S. Gottlieb Robert A. Smith Ndeye Mery Dia Badiane Selly Ba Stephen E. Hawes Macoumba Toure Alison K. Starling Fatou Traore Fatima Sall Stephen L. Cherne Joshua Stern Kim G. Wong Paul Lu Moon Kim Dana N. Raugi Airin Lam James I. Mullins Nancy B. Kiviat Papa Salif Sow for the UW-Dakar HIV- Study Group 《PloS one》2011,6(7)
Background
Antiretroviral therapy for HIV-2 infection is hampered by intrinsic resistance to many of the drugs used to treat HIV-1. Limited studies suggest that the integrase inhibitors (INIs) raltegravir and elvitegravir have potent activity against HIV-2 in culture and in infected patients. There is a paucity of data on genotypic variation in HIV-2 integrase that might confer intrinsic or transmitted INI resistance.Methods
We PCR amplified and analyzed 122 HIV-2 integrase consensus sequences from 39 HIV-2–infected, INI-naive adults in Senegal, West Africa. We assessed genetic variation and canonical mutations known to confer INI-resistance in HIV-1.Results
No amino acid-altering mutations were detected at sites known to be pivotal for INI resistance in HIV-1 (integrase positions 143, 148 and 155). Polymorphisms at several other HIV-1 INI resistance-associated sites were detected at positions 72, 95, 125, 154, 165, 201, 203, and 263 of the HIV-2 integrase protein.Conclusion
Emerging genotypic and phenotypic data suggest that HIV-2 is susceptible to the new class of HIV integrase inhibitors. We hypothesize that intrinsic HIV-2 integrase variation at “secondary” HIV-1 INI-resistance sites may affect the genetic barrier to HIV-2 INI resistance. Further studies will be needed to assess INI efficacy as part of combination antiretroviral therapy in HIV-2–infected patients. 相似文献13.
14.
Loucoubar C Goncalves B Tall A Sokhna C Trape JF Diène Sarr F Faye J Badiane A Ly AB Diop A Bar-Hen A Bureau JF Sakuntabhai A Paul R 《PloS one》2011,6(11):e26364
Despite considerable success of genome wide association (GWA) studies in identifying causal variants for many human diseases, their success in unraveling the genetic basis to complex diseases has been more mitigated. Pathogen population structure may impact upon the infectious phenotype, especially with the intense short-term selective pressure that drug treatment exerts on pathogens. Rigorous analysis that accounts for repeated measures and disentangles the influence of genetic and environmental factors must be performed. Attempts should be made to consider whether pathogen diversity will impact upon host genetic responses to infection.We analyzed the heritability of two Plasmodium falciparum phenotypes, the number of clinical malaria episodes (PFA) and the proportion of these episodes positive for gametocytes (Pfgam), in a family-based cohort followed for 19 years, during which time there were four successive drug treatment regimes, with documented appearance of drug resistance. Repeated measures and variance components analyses were performed with fixed environmental, additive genetic, intra-individual and maternal effects for each drug period. Whilst there was a significant additive genetic effect underlying PFA during the first drug period of study, this was lost in subsequent periods. There was no additive genetic effect for Pfgam. The intra-individual effect increased significantly in the chloroquine period.The loss of an additive genetic effect following novel drug treatment may result in significant loss of power to detect genes in a GWA study. Prior genetic analysis must be a pre-requisite for more detailed GWA studies. The temporal changes in the individual genetic and the intra-individual estimates are consistent with those expected if there were specific host-parasite interactions. The complex basis to the human response to malaria parasite infection likely includes dominance/epistatic genetic effects encompassed within the intra-individual variance component. Evaluating their role in influencing the outcome of infection through host genotype by parasite genotype interactions warrants research effort. 相似文献
15.
Analysis of the 5q31-q33 locus shows an association between IL13-1055C/T IL-13-591A/G polymorphisms and Schistosoma haematobium infections 总被引:2,自引:0,他引:2
16.
Boucherit N Barry AO Mottola G Trouplin V Capo C Mege JL Ghigo E 《FEMS immunology and medical microbiology》2012,64(1):101-103
Q fever is a disease caused by Coxiella burnetii, an obligate intracellular bacterium. Acute Q fever is characterized by efficient immune response, whereas chronic Q fever is characterized by dysregulated immune response as demonstrated by the lack of granulomas, the failure of C. burnetii to induce lymphoproliferation, and interferon-γ production. The mitogen-activated protein kinase (MAPK) signaling pathway plays crucial roles in innate immune responses and control of bacterial infections. However, its role in Q fever has not been addressed. First, we investigated the activation of MAPKs p38, c-jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) 1/2 in murine macrophages stimulated with C. burnetii. Coxiella burnetii NM phase I (virulent) and NM phase II (avirulent) induced the activation of JNK and ERK1/2. Avirulent C. burnetii activate p38, whereas C. burnetii did not induce the phosphorylation of p38. Second, the level of p38 activation was studied in Q fever patients. We found that p38 was activated in monocyte-derived macrophages from healthy donors and patients with acute Q fever in response to a potent agonist such as lipopolysaccharide. Interestingly, p38 was not activated in patients with active chronic Q fever and was activated in patients with cured chronic Q fever. These results suggest that the determination of p38 activation may serve as a tool for measuring Q fever activity. 相似文献
17.
Diane A Pierce WD Heth CD Russell JC Richard D Proctor SD 《Obesity (Silver Spring, Md.)》2012,20(9):1787-1795
We hypothesized that obese-prone genotype and history of food restriction confer a survival advantage to genetically obese animals under environmental challenge. Male juvenile JCR:LA-cp rats, obese-prone and lean-prone, were exposed to 1.5 h daily meals and 22.5-h voluntary wheel running, a procedure inducing activity anorexia (AA). One week before the AA challenge, obese-prone rats were freely fed (obese-FF), or pair fed (obese-PF) to lean-prone, free-feeding rats (lean-FF). Animals were removed from protocol at 75% of initial body weight (starvation criterion) or after 14 days (survival criterion). AA challenge induced weight loss in all rats, but percent weight loss was more rapid and sustained in lean-FF rats than in obese-FF or obese-PF animals (P < 0.04). Weight loss was significantly higher in obese-FF rats than obese-PF rats, 62% of which achieved survival criterion and stabilized with zero weight loss. Obese-PF rats survived longer, on average (12.0 ± 1.1 day) than obese-FF (8.2 ± 1.1 day) and lean-FF rats (3.5 ± 0.2 day) (P < 0.02). Wheel running increased linearly in all groups; lean-FF increased more rapidly than obese-FF (P < 0.05); obese-PF increased at an intermediate rate (P < 0.02), and those rats that survived stabilized daily rates of wheel running. Prior food restriction of juvenile obese-prone rats induces a survival benefit beyond genotype, that is related to achievement of homeostasis. This metabolic adaptive process may help explain the development of human obesity in the presence of an unstable food environment which subsequently transitions to an abundant food supply. 相似文献
18.
Portugal S Doumtabe D Traore B Miller LH Troye-Blomberg M Doumbo OK Dolo A Pierce SK Crompton PD 《Malaria journal》2012,11(1):162
ABSTRACT: BACKGROUND: Several studies indicate that people of the Fulani ethnic group are less susceptible to malaria compared to those of other ethnic groups living sympatrically in Africa, including the Dogon ethnic group. Although the mechanisms of this protection remain unclear, the Fulani are known to have higher levels of Plasmodium falciparum-specific antibodies of all Ig classes as compared to the Dogon. However, the proportions of B cell subsets in the Fulani and Dogon that may account for differences in the levels of Ig have not been characterized. METHODS: In this cross-sectional study, venous blood was collected from asymptomatic Fulani (n=25) and Dogon (n=25) adults in Mali during the malaria season, and from P. falciparum-naive adults in the U.S. (n=8). At the time of the blood collection, P. falciparum infection was detected by blood-smear in 16% of the Fulani and 40% of the Dogon volunteers. Thawed lymphocytes were analysed by flow cytometry to quantify B cell subsets, including immature and naive B cells; plasma cells; and classical, activated, and atypical memory B cells (MBCs). RESULTS: The overall distribution of B cell subsets was similar between Fulani and Dogon adults, although the percentage of activated MBCs was higher in the Fulani group (Fulani: 11.07% [95% CI: 9.317 - 12.82]; Dogon: 8.31% [95% CI: 6.378 - 10.23]; P=0.016). The percentage of atypical MBCs was similar between Fulani and Dogon adults (Fulani: 28.3% [95% CI: 22.73 - 34.88]; Dogon: 29.3% [95% CI: 25.06 - 33.55], but higher than U.S. adults (U.S.: 3.0% [95% CI: -0.21 - 6.164]; P<0.001). Plasmodium falciparum infection was associated with a higher percentage of plasma cells among Fulani (Fulani infected: 3.3% [95% CI: 1.788 - 4.744]; Fulani uninfected: 1.71% [95% CI: 1.33 - 2.08]; P=0.011), but not Dogon adults. CONCLUSION: These data show that the malaria-resistant Fulani have a higher percentage of activated MBCs compared to the Dogon, and that P. falciparum infection is associated with a higher percentage of plasma cells in the Fulani compared to the Dogon, findings that may account for the higher levels of P. falciparum antibodies in the Fulani. 相似文献
19.
20.
Pere P. Simarro Giuliano Cecchi José R. Franco Massimo Paone Abdoulaye Diarra José Antonio Ruiz-Postigo Eric M. Fèvre Raffaele C. Mattioli Jean G. Jannin 《PLoS neglected tropical diseases》2012,6(10)