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PubMed1998

Risk of population extinction from fixation of deleterious and reverse mutations.

A model is developed for alternate fixations of mildly deleterious and wild-type alleles arising by forward and reverse mutation in a finite population. For almost all parameter values, this gives an equilibrium load that agrees closely with the general expression derived from diffusion theory. Nearly neutral mutations with selection coefficient a few times larger than 1/(2N(e)) do the most damage by increasing the equilibrium load. The model of alternate fixations facilitates dynamical analysis of the expected load and the mean time to extinction in a population that has been suddenly reduced from a very large size to a small size. Reverse mutation can substantially improve population viability, increasing the mean time to extinction by an order of magnitude or more, but because many mutations are irreversible the effects may not be large. Populations with initially high mean fitness and small effective size, N(e) below a few hundred individuals, may be at serious risk of extinction from fixation of deleterious mutations within 10(3) to 10(4) generations.

Animals↗
PubMed2006

Three kinships with ALAS2 P520L (c. 1559 C --> T) mutation, two in association with severe iron overload, and one with sideroblastic anemia and severe iron overload.

Mutations in aminolevulinate synthase 2 (ALAS2) are usually associated with sideroblastic anemia and iron overload. The objective of this study was to determine if "mild" mutations in ALAS2 might increase the severity of primary iron overload. Direct sequencing of the ALAS2 gene was performed on 24 subjects with primary hemochromatosis and one subject with sideroblastic anemia with severe iron overload. We identified a novel mutation P520L (c. 1559 C --> T) in ALAS2 in three subjects. Two had severe iron overload and no anemia: one also had HFE C282Y homozygosity, and the other was wildtype for HFE and other iron-related genes. The third subject had sideroblastic anemia with iron overload, and was hemizygous for both P520L and R560H (c. 1679 G --> A) mutations in ALAS2. The P520L mutation was found at a frequency of 0.0013 (741 alleles) in white control subjects, but was not found in 158 alleles from black control subjects. The proline in this position is highly conserved across species from humans to zebrafish. However, genotype/phenotype studies of the families demonstrate that the P520L mutation alone has no iron-associated phenotype, but it may act as a modifier of iron overload in the presence of mutations in HFE or other uncharacterized hemochromatosis genes. Thus, ALAS2 mutations might contribute to more severe iron loading in persons with primary hemochromatosis.

5-Aminolevulinate Synthetase↗
PubMed2005

Long term probability of detection of HIV-1 drug resistance after starting antiretroviral therapy in routine clinical practice.

BACKGROUND: Little is known about the long term risk of development of HIV-1 drug resistance for patients starting antiretroviral therapy (ART) with three or four drug regimens in routine clinical practice. METHODS: We analysed a large cohort study of patients seen in one of six large HIV clinics in and around London, UK. The focus of this analysis was on patients who started ART with two nucleosides plus either a single protease inhibitor (PI), a PI with ritonavir, abacavir or a non-nucleoside reverse transcriptase inhibitor (NNRTI). RESULTS: 4306 patients were followed; 1436 (33%) started with a single PI, 279 (6%) with a PI plus ritonavir, 156 (4%) with triple nucleosides and 2435 (57%) with an NNRTI. The overall cumulative risk of viral load failure was 38% by 6 years. Risk of > or =1 major IAS-USA mutation was 27% by 6 years; risk of mutations from at least two of the three main drug classes was 20% over the same period. These are lower limit estimates as test results were not available for many with viral load failure. Risk of PI mutations being detected in people who started ART with regimens containing a PI with ritonavir was significantly lower than the risk of NNRTI mutations being detected in those starting with NNRTI-containing regimens (relative hazard 0.3195% CI 0.15-0.61; p = 0.0008). CONCLUSION: In routine practice, rates of viral load failure and of resistance detection in patients who started ART with three or four drugs are appreciable.

Adult↗
PubMed1996

Ex vivo ras peptide vaccination in patients with advanced pancreatic cancer: results of a phase I/II study.

In a pilot I/II study we have tested synthetic ras peptides used as a cancer vaccine in 5 patients with advanced pancreatic carcinoma. The treatment principle used was based on loading professional antigen-presenting cells (APCs) from peripheral blood with a synthetic ras peptide corresponding to the ras mutation found in tumour tissue from the patient. Peptide loading was performed ex vivo and the next day APCs were re-injected into the patients after washing to remove unbound peptide. Patients were vaccinated in the first and second week and thereafter every 4-6 weeks. In 2 of the 5 patients treated, an immune response against the immunising ras peptide could be induced. None of the patients showed evidence of a T-cell response against any of the ras peptides before vaccination. The treatment was well tolerated and could be repeated multiple times in the same patient. Side effects were not observed even if an immunological response against the ras peptide was evident. We conclude that ras peptide vaccination according to the present protocol is safe and may result in a potentially beneficial immune response even in patients with advanced malignant disease.

Adult↗
PubMed2005

Designing a neural network for the constraint optimization of the fitness functions devised based on the load minimization of the genetic code.

Nonrandom patterns in codon assignments are supported by many statistical and biochemical studies in the last two decades. The canonical genetic code is known to be highly efficient in minimizing the effects of mistranslational errors and point mutations, an ability, which in term is designated "load minimization". Prior studies have included many attempts at quantitative estimation of the fraction of randomly generated codes, which in terms of load minimization, score higher than the canonical genetic code. In this study, a neural network, which estimates a highly optimized genetic code in a relatively short period of time has been devised. Several fitness functions were used throughout this text. Meanwhile, we have made use of two cost measure matrices, PAM74-100 and mutation matrix.

Algorithms↗
PubMed2005

Contribution of Hfe expression in macrophages to the regulation of hepatic hepcidin levels and iron loading.

Hereditary hemochromatosis (HH), an iron overload disease associated with mutations in the HFE gene, is characterized by increased intestinal iron absorption and consequent deposition of excess iron, primarily in the liver. Patients with HH and Hfe-deficient (Hfe-/-) mice manifest inappropriate expression of the iron absorption regulator hepcidin, a peptide hormone produced by the liver in response to iron loading. In this study, we investigated the contribution of Hfe expression in macrophages to the regulation of liver hepcidin levels and iron loading. We used bone marrow transplantation to generate wild-type (wt) and Hfe-/- mice chimeric for macrophage Hfe gene expression. Reconstitution of Hfe-deficient mice with wt bone marrow resulted in augmented capacity of the spleen to store iron and in significantly decreased liver iron loading, accompanied by a significant increase of hepatic hepcidin mRNA levels. Conversely, wt mice reconstituted with Hfe-deficient bone marrow had a diminished capacity to store iron in the spleen but no significant alterations of liver iron stores or hepcidin mRNA levels. Our results suggest that macrophage Hfe participates in the regulation of splenic and liver iron concentrations and liver hepcidin expression.

Animals↗
PubMed2001

Frameshift peptide-derived T-cell epitopes: a source of novel tumor-specific antigens.

Microsatellite instability (MSI) caused by defective DNA mismatch repair (MMR) is a hallmark of hereditary nonpolyposis colorectal cancers (HNPCC) but also occurs in about 15% of sporadic tumors. If instability affects microsatellites in coding regions, translational frameshifts lead to truncated proteins often marked by unique frameshift peptide sequences at their C-terminus. Since MSI tumors show enhanced lymphocytic infiltration and our previous analysis identified numerous coding mono- and dinucleotide repeat-bearing candidate genes as targets of genetic instability, we examined the role of frameshift peptides in triggering cellular immune responses. Using peptide pulsed autologous CD40-activated B cells, we have generated cytotoxic T lymphocytes (CTL) that specifically recognize HLA-A2.1-restricted peptides derived from frameshift sequences. Among 16 frameshift peptides predicted from mutations in 8 different genes, 3 peptides conferred specific lysis of target cells exogenously loaded with cognate peptide. One peptide derived from a (-1) frameshift mutation in the TGFbetaIIR gene gave rise to a CTL bulk culture capable of lysing the MSI colorectal cancer cell line HCT116 carrying this frameshift mutation. Given the huge number of human coding microsatellites and assuming only a fraction being mutated and encoding immunologically relevant peptides in MSI tumors, frameshift protein sequences represent a novel subclass of tumor-specific antigens. It is tempting to speculate that a frameshift peptide-directed vaccination approach not only could offer new treatment modalities for existing MSI tumors but also might benefit asymptomatic at-risk individuals in HNPCC families by a prophylactic vaccination strategy.

Amino Acid Sequence↗
PubMed2006

Antiviral efficacy and resistance in patients on antiretroviral therapy in Kigali, Rwanda: the real-life situation in 2002.

Our study aimed to complete the published data on ARV therapy in Africa by describing the baseline situation in Rwanda before the launch of a large ARV programme (ESTHER). Prescription habits, frequency and reasons for treatment interruptions but also antiviral efficay, resistance to ARVs and genotypic variability of the viruses present in Rwanda were analysed. Among the 233 patients included in the study, it appeared that a vast majority (91%) were under triple therapy and that half of them had experienced at least one treatment interruption caused mainly by drug shortage or financial difficulties. Among 60 blood samples analysed, 26 were in virological failure with a viral load above 1000 RNA copies/ml and 11 presented major drug resistance mutations. Finally, virological failure could mainly be explained by the high frequency of treatment interruptions but also by the emergence of drug resistance mutations. Consequently the major objective for the ESTHER programme to improve the situation in Rwanda will be to reduce the drug shortage and facilitate the financial accessibility of the treatments.

Anti-HIV Agents↗
PubMed2005

Combined subcarcinogenic benzo[a]pyrene and UVA synergistically caused high tumor incidence and mutations in H-ras gene, but not p53, in SKH-1 hairless mouse skin.

Combined subcarcinogenic doses of benzo[a]pyrene (BaP) and UVA induced H-ras, but not p53, gene mutations 8 weeks before tumor emergence in SKH-1 mice. Neither UVA (40 kJ/m2) nor BaP (8 nmol) induced any tumors after mice were topically treated 3 times/week for 25 weeks. However, combined BaP-UVA treatment synergistically increased tumor incidence and multiplicity. All tumors induced by BaP-UVA were malignant. The epidermis was collected from mice treated for 2, 6 and 10 weeks. DNA from UVB- (0.3 kJ/m2) or BaP-UVA-(8 nmol and 40 kJ/m2-induced tumors was isolated and screened for H-ras and p53 mutations. Four types of point mutation, GGC-->GAC, GCC, GTC and CGC, occurred in UVB-induced tumors at H-ras codon 13; and one type of point mutation, GGA-->GAA, at codon 12. Treatment with either BaP alone or BaP-UVA for 10 weeks caused GGA-->GAA mutation at codon 12 or GGC-->GAC mutation at codon 13 in nontumor skin, respectively, as well as in tumors induced by BaP-UVA. All of the 10-week samples treated with either BaP or BaP-UVA showed detectable mutations at codons 12 and 13, but the genetic load was significantly higher in BaP-UVA-treated mice than in those exposed only to BaP. UVA alone induced mutations at codon 12 in only one-third of samples. G-->A mutations induced by BaP or BaP-UVA at position 38 of codon 13 have not been reported previously. C-->T transitions were detected in p53 hot spots of exon 8 in 2 of 19 BaP-UVA-induced tumors but were not found in nontumor skin.

Animals↗
PubMed2004

Factors associated with a decrease in the prevalence of drug resistance in newly HIV-1 infected individuals in Montreal.

OBJECTIVE: A decrease in the prevalence of drug resistance (DR) has been observed among recently infected (RI) individuals in Montreal. A study of chronically infected (CI) patients, who represent potential HIV-1 transmitters, was carried out in order to ascertain biological factors associated with this trend change. DESIGN AND METHODS: Retrospective analysis of CI patients was performed for the period 1996-2003. Changes in mean viral load and DR prevalence were assessed in CI patients (n = 2328) and compared to those in RI patients (n = 180) living in the same geographic area. RESULTS: A decrease was observed in the prevalence of DR among RI patients, from 13.0% in 1997-2000 to 4.0% in 2001-2003 (P = 0.04). From 1996 to 2000, the mean viral load in the CI patients decreased by 1.34 log10, to remain steady thereafter. The proportion of CI patients who interrupt treatment increased steadily over 1997-2003 from 3.1% to 16.5% (P < 0.0001). Since 1999, when genotyping analysis became available, we have observed a 0.9 log10 decrease in mean viral load among 602 genotyped CI patients harbouring any major mutations. CONCLUSION: The decrease in transmission of DR documented in Montreal since 2000 coincides with the drop in mean viral load observed in CI patients. Factors that contribute to the decrease in viral load include routine access to genotyping and availability of more potent antiretroviral drugs. Plasma viral load seems to represent the main predictor for the transmission of DR.

Adolescent↗
PubMed2004

Protein markers for Alzheimer disease in the frontal cortex and cerebellum.

OBJECTIVE: To compare proteins related to Alzheimer disease (AD) in the frontal cortex and cerebellum of subjects with early-onset AD (EOAD) with or without presenilin 1 (PS1) mutations with sporadic late-onset AD (LOAD) and nondemented control subjects. METHODS: Immunohistochemistry, immunoblot analysis, and ELISA were used to detect and assess protein levels in brain. RESULTS: In EOAD and to a lesser extent in LOAD, there was increased amyloid beta (Abeta) deposition (by immunohistochemistry), increased soluble Abeta (by immunoblot analysis), and specific increases in Abeta40 and Abeta42 (by ELISA) in the frontal cortex and, in some cases, in the cerebellum. Surprisingly, immunoblot analysis revealed reduced levels of PS1 in many of the subjects with EOAD with or without PS1 mutations. In those PS1 mutation-bearing subjects with the highest Abeta, PS1 was barely, if at all, detectable. This decrease in PS1 was specific and not attributable solely to neuronal loss because amyloid precursor protein (APP) and the PS1-interacting protein beta-catenin levels were unchanged. CONCLUSIONS: This study shows that in the frontal cortex and cerebellum from Alzheimer disease patients harboring certain presenilin 1 mutations, high levels of amyloid beta are associated with low levels of presenilin 1. The study provides the premise for further investigation of mechanisms underlying the downregulation of presenilin 1, which may have considerable pathogenic and therapeutic relevance.

Adult↗
PubMed2004

Efficacy, safety and predictive factors of virological success of a boosted amprenavir-based salvage regimen in heavily antiretroviral-experienced HIV-1-infected patients.

BACKGROUND: Amprenavir (APV) has been shown to be effective in naive or treatment-experienced HIV-1 infected patients. However, the safety and efficacy of the APV 600 mg/ritonavir (RTV) 100 mg twice a day (bid) combination, the usually recommended dosage for boosted APV, have been less well studied. We assessed the predictive factors associated with virological success of APV/RTV-based regimens. METHODS: Patients in the PharmAdapt study receiving an APV/RTV-containing regimen were included in the study. The predictivity of covariates on virological response at 4 months was analysed according to the data analysis plan. We processed logistic regression using bootstrapping to allow several covariates in the models. RESULTS: Forty patients received an APV/RTV-containing regimen, 38 of whom were male (95%). Risk factors were heterosexual contacts (four patients; 10%), homosexual contacts (31 patients; 78%), and intravenous drug use (four patients; 10%). Twenty-seven per cent of patients were Centers for Disease Control and Prevention Classification System (CDC) stage A, 38% were stage B and 35% were stage C. The median baseline CD4 count was 313 cells/microL [interquartile range (IQR) 211, 414], and the median baseline viral load was 4.4 log(10) HIV-1 RNA copies/mL (IQR 3.7, 4.9). Patients were exposed to a median number of 7.5 (IQR 6, 9) drugs for a median number of 3.8 (IQR 3.3, 4.3) years. The baseline number of resistance mutations was 4 [IQR 3, 5 for nucleoside reverse transcriptase inhibitors (NRTIs), 1 (IQR 0, 2)] for non-nucleoside reverse transcriptase inhibitors (NNRTIs) and 6 [IQR 5, 8 for protease inhibitors (PIs)]. At month 4, median viral load decreased to 1.2 log(10) copies/mL (IQR 0.3, 1.6); 50% of patients had a viral load<200 copies/mL by intention-to-treat analysis. The number of APV resistance mutations was associated with viral load changes. Median APV concentration was 1750 ng/mL (IQR 1130, 2520). At month 4, using several cut-offs, neither APV concentration nor the genotypic inhibitory quotient was predictive of viral load changes. Baseline viral load and the number of protease mutations were associated with outcome. CONCLUSIONS: Efficacious APV concentrations need to be determined for antiretroviral-experienced patients. Baseline viral load and the number of mutations on the protease coding region (PRO) were associated with the virological outcome of APV/RTV-based regimens.

Adult↗
PubMed2003

Prevalence and characterization of lamivudine-resistant hepatitis B virus mutations in HIV-HBV co-infected individuals.

OBJECTIVE: To determine the prevalence of hepatitis B virus (HBV) genotypic resistance to lamivudine, identify risk factors associated with lamivudine resistance, and characterize the pattern of HBV polymerase mutations in patients co-infected with HIV. DESIGN: Retrospective cross-sectional study. METHODS: Thirty-three chronic HBV-infected patients were identified from a cohort of 1719 HIV-infected individuals. Patient information was collected from case records, HBV DNA was measured on stored serum by polymerase chain reaction, and positive samples underwent sequencing of HBV polymerase, basal core promoter and precore regions. RESULTS: Three groups of patients were identified: group 1 were viraemic in the absence of lamivudine-resistance mutations, group 2 were viraemic in association with lamivudine-resistance mutations, and group 3 were not viraemic. Group 2 patients with lamivudine-resistant mutations had significantly higher HBV-DNA viral loads but did not differ in duration of lamivudine therapy, HBV genotype, HIV viral load or CD4 cell count compared with patients with wild-type HBV. Group 2 individuals also demonstrated significantly higher serum alanine aminotransferase (ALT) levels than group 1, who were higher than group 3. Unique mutations were detected in HBV polymerase, including rtV173L plus rtL180M plus rtM204V, which occurred in three patients. This virus has the in-vitro characteristics of a 'vaccine escape' mutant of HBV. CONCLUSION: Genotypic HBV lamivudine resistance was found in 39% of HIV-HBV co-infected individuals treated with lamivudine as part of highly active antiretroviral therapy. These patients exhibited significantly elevated HBV viral loads and serum ALT, and three were infected with a lamivudine-resistant HBV strain that was potentially transmissible to HBV-vaccinated individuals.

Adult↗
PubMed2005

T1764G1766 core promoter double mutants are restricted to Hepatitis B virus strains with an A1757 and are common in genotype D.

To investigate the role of pre-core and basal core promoter (BCP) mutants in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (e-CHB) in Iran, Hepatitis B virus strains from 30 patients and 42 anti-HBe-positive asymptomatic carriers (ASCs) were characterized. G1896A pre-core stop mutants, detected in 77 % of e-CHB patients and 85 % of ASCs, showed no association with virus load or aminotransferase levels. Twenty per cent of e-CHB patients and 31 % of ASCs harboured T1762A1764 mutants. When this double mutation was associated with G1757, it was linked to a higher virus load in patients than when it was associated with A1757 (10(5.2+/-1.8) vs 10(3.2+/-0.8) copies ml(-1); P=0.004). Interestingly, the most common BCP mutations were T1764 and G1766, which were present in 33 % of e-CHB patients and 29 % of ASCs. These were associated with higher virus load and aminotransferase levels compared with patients lacking core promoter mutations, although this was not significant. The T1764G1766 double mutation was only present in strains with A1757 (P<0.001), which is more frequent in strains of genotype D than in those belonging to other genotypes. On the other hand, the T1762A1764 double mutation was found more frequently in association with G1757 than with A1757. The T1762A1764 double mutation forms a binding site for hepatocyte nuclear factor 1 (HNF1), which is constrained by A1757. However, the T1764G1766 double mutant may form a binding site for HNF3. Thus, position 1757 affects the emergence of promoter double mutants and would predict a relative genotypic restriction of both the T1762A1764 and the T1764G1766 double mutants.

Adult↗
PubMed1999

Fasting, postprandial, and post-methionine-load homocysteinaemia and methylenetetrahydrofolate reductase polymorphism in vascular disease.

Hyperhomocysteinaemia is an independent risk factor for cardiovascular disease. The C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) is a common genetic cause of increased homocysteine (HCY) levels. Post-methionine-load HCY concentrations allow identification of certain cases of hyperhomocysteinaemia not demonstrated by fasting levels. This study investigated the relationship between MTHFR polymorphism and (1) fasting HCY levels (77 patients); (2) post-methionine HCY levels (54 patients); and (3) postprandial HCY concentrations (36 patients) in cardiovascular disease. As expected, mean fasting HCY value was higher in the +/+ patients. Moreover, patients who were homozygous for the mutation exhibited significantly increased mean post-methionine-load HCY; in contrast, literature results are conflicting. Mean postprandial HCY, which is not known to be increased in controls, was also increased in the (+/+) patients, although the difference did not reach statistical significance, probably owing to the small size of the sample. MTFHR polymorphism is known to be aggravated by a drop in circulating folate. Additional risk factors may be more prevalent in patients with cardiovascular disease.

Adolescent↗
PubMed2003

Antiretroviral therapy in HIV-2-infected patients: changes in plasma viral load, CD4+ cell counts, and drug resistance profiles of patients treated in Abidjan, Côte d'Ivoire.

OBJECTIVE: To describe changes in plasma viral load, CD4+ cell counts, and drug resistance profiles of HIV-2-infected patients receiving antiretroviral (ARV) therapy in Abidjan, Côte d'Ivoire. METHODS: Consecutive blood samples were collected from 18 HIV-2-infected ARV-naive patients who had received ARV therapy in the UNAIDS drug access initiative (UNAIDS-DAI) in Abidjan between August 1998 and July 2000. Changes in HIV-2 plasma viral load, CD4+ cell counts, and genotypic and phenotypic drug resistance testing were determined. RESULTS: At baseline, 11 (61%) of the 18 patients initiated highly active antiretroviral therapy (HAART) and seven (39%) received dual therapy. No significant change in median viral load was observed at 2 months (P = 0.09), at 6 months (P = 0.06), and at 12 months of therapy (P = 0.26). No significant increase in CD4+ cell counts was observed at 12 months (P = 0.10). All four patients on indinavir-containing HAART had undetectable viral loads at 2-4 months of therapy. However, none of seven patients on nelfinavir-containing HAART had a substantial decrease in viral load. Viruses from 14 patients were analyzed, 12 of which (86%) had at least one primary resistance mutation that is known to confer resistance to HIV-1 virus. Three patients had the multi-drug-resistant mutation, Q151M, two of whom showed reduced susceptibility to zidovudine, didanosine, stavudine and zalcitabine. CONCLUSION: Our limited findings show that nelfinavir-containing regimens may have limited virologic benefit to HIV-2-infected patients.

Adult↗