Alterations of 9p in squamous cell carcinoma and adenocarcinoma of the lung: association with smoking, TP53, and survival

Tobacco smoke is well recognized as the major etiological contributor to lung cancer, yet the relationship between tobacco smoke exposure and a specific pattern of molecular abnormalities at somatic loci is less well characterized. We analyzed 100 primary tumors from patients undergoing surgical resection of squamous cell carcinoma and adenocarcinoma of the lung for loss of heterozygosity (LOH) and homozygous deletions at two microsatellite markers in a recombinogenic region of 9p13. We describe the relationship of alterations at these markers with tumor characteristics (both clinical and molecular), patient demographics, survival, and measures of tobacco-smoke exposure. Homozygous deletions in this region occurred in 25% (21/85) and LOH in 33% (28/85) of informative tumors examined. These alterations occurred more often in tumors with intense TP53 protein staining by immunohistochemistry, suggesting that inactivation of the TP53 pathway may contribute to these LOH events. Duration of smoking was greatest in patients with the homozygous deletion, intermediate in patients with LOH, and shortest in patients whose tumor did not demonstrate loss in these markers. Unexpectedly, LOH at 9p13 was a significant predictor of improved survival in patients, while the homozygous deletion was associated with the poorest patient survival. Together, these results suggest that TP53 alteration and long-term tobacco smoke exposure may contribute to genetic alterations at 9p13, and that the mechanism and biologic consequences of allele loss reflect individual biologic differences that determine the extent of loss (LOH or homozygous deletion), such that those patients with the deletion of this region face a more aggressive and deadly disease.     

Clade analysis and surface antigen polymorphism of hepatitis B virus American genotypes

Eight genotypes (A-H) of hepatitis B virus (HBV) have been described, HBV genotypes F and H being autochthonous to America. HBV genotype F has been classified in four clusters. The objective of this study was to gain insight into the molecular epidemiology of HBV American genotypes, as well as to analyze the genotype-related polymorphism in some functional domains of the surface proteins. The sequences of the S region of 106 isolates genotype F and H were analyzed, out of which 47 isolates genotype F circulated in different Venezuelan populations. Most of the Venezuelan isolates genotype F were grouped in cluster III (n = 39) and 7 in cluster II. One isolate obtained from a blood donor could not be classified in any clade and harbored amino acid substitutions characteristic of a vaccine escape mutant (G145R) and a stop codon in the surface antigen. Amino acid analysis of the PreS and S gene products showed unique genetic characteristics in genotype F and H sequences in some important domains involved in the early steps of infection. Out of 30 available sequences, two complete genome sequences of HBV genotype F from Venezuela were obtained. Phylogenetic analysis of these complete genomes confirmed the presence of four clusters inside genotype F, differing in more than 4% nucleotide divergence. Our extended analysis showed that genotype F clades Ia, III, and IV exhibit a restricted geographic distribution (Central America, the North and the South of South America, respectively) while clades Ib and II are found in all the Americas except in the Northern South America and North America respectively.     

Profilin-mediated food-induced allergic reactions are associated with oral epithelial remodeling

1. Download high-res image (218KB)
2. Download full-size image

     

Effect of challenge method on sensitivity, reactivity, and maximal response to methacholine.

BACKGROUND: Recent data suggest that the tidal breathing method may produce methacholine provocation concentration that caused a decrease in forced expiratory volume in 1 second of 20% (PC20) values significantly lower than the dosimeter method; however, the effect of the challenge method on the shape of the concentration-response curve has not been investigated. OBJECTIVE: To determine the effect of the challenge method on sensitivity, reactivity, and maximal response to methacholine. METHODS: We measured airway responsiveness to methacholine using dosimeter and tidal breathing methods in 30 individuals with suspected asthma. Concentration-response curves were characterized by their PC20 (sensitivity), slope (reactivity), and, if possible, level of plateau. RESULTS: Dosimeter PC20 values were significantly higher than tidal breathing values (geometric mean, 8.9 and 5.2 mg/mL, respectively); the mean difference in PC20 values obtained using each method was 0.78 doubling concentrations (P = .01). The mean slopes were 22.7%/log mg/mL using the tidal breathing method and 24.9%/log mg/mL using the dosimeter method; the mean difference in the slopes obtained using each method was -2.17%/log mg/mL (P = .18). In 10 individuals who showed a plateau with the 2 methacholine challenge tests, the mean level of plateau was 19.8% using the tidal breathing method and 19.5% using the dosimeter method; the mean difference in the plateau values obtained with each method was 0.3% (P = .87). CONCLUSIONS: Although the tidal breathing method produces methacholine PC20 values significantly lower than the dosimeter method, both methods provide similar values for slope and level of plateau. These results suggest that the technical factors that affect methacholine sensitivity and the shape of the curve are different.     

Management of chronic viral hepatitis in HIV-infected patients: Spanish Consensus Conference. October 2000

Co-infection by human immunodeficiency virus and hepatitis B and C viruses is quite common because they share similar routes of transmission. The introduction of highly active antiretroviral therapy has significantly improved the life expectancy of HIV-infected patients in the last few years. However, chronic viral hepatitis represents an emerging cause of morbidity and mortality in this population, either as a result of end-stage liver disease or as a consequence of hepatotoxicity induced by antiretroviral drugs. The main goal of the Consensus Conference was to establish specific recommendations for the management of chronic viral hepatitis B and C in HIV-infected patients. The role of orthotopic liver transplantation for co-infected individuals with end-stage liver disease was also assessed.     

The B-cell activation pathway in human systemic lupus erythematosus: Imbalancedin vitro production of lymphokines and association with serum analytical findings

Recent knowledge of B-lymphocyte physiology has clarified the role of T cell-derived lymphokines in clonal proliferation and differentiation of B-cell responses. Lymphokine production was analyzed in 19 systemic lupus erythematosus (SLE) patients and sex- and age-matched controls in relation to clinical activity and steroid treatment. Whenin vitro production of interleukin-2 (IL-2) and B-cell growth factor (BCGF) was tested, both activities were found to be diminished in the group of patients (P<0.01), while B-cell differentiation factor (BCDF) activity was higher in this group with respect to normal controls (P<0.01). Interestingly enough, thisin vitro BCDF synthesis was positively correlated with clinical activity regardless of low-dose steroid treatment. A correlation was also found between BCDF production and the levels of IgG (r=0.64,P<0.01), anti-DNA antibodies (r=0.52,P<0.05), and the IgG/IgM ratio (r=0.7,P<0.01) in serum. Implications of these abnormal T-lymphocyte functions in SLE with respect toin vivo B-cell function are discussed.     

Prevalence of transmitted HIV-1 drug resistance and the role of resistance algorithms: data from seroconverters in the CASCADE collaboration from 1987 to 2003

OBJECTIVES: To examine factors influencing the rate of transmitted drug resistance (TDR) among seroconverters, with particular emphasis on 3 widely used genotypic drug resistance algorithms. METHODS: The study used data from CASCADE (Concerted Action on Seroconversion to AIDS and Death in Europe), a collaboration of seroconverter cohorts in Europe and Canada. Genotypic resistance data were derived within 18 months of the last seronegative test or date of laboratory evidence of acute infection and before the initiation of antiretroviral therapy. The Stanford algorithm was used to analyze each individual's nucleotide sequence. A multivariate logistic model was used to assess independent relationships between the presence of TDR and exposure category, sex, age at seroconversion, and year of seroconversion. The paper also describes 3 alternative definitions of resistance: the Stanford algorithm, the key resistance mutations defined by the International AIDS Society, and the Agence Nationale de Recherches sur le Sida (ANRS) algorithm. RESULTS: Forty-five of 438 patients (10.3%) seroconverting between 1987 and 2003 were infected with a drug-resistant HIV-1 variant. Forty patients (9.1%) showed resistance mutations to only 1 class of antiretroviral drugs, 2 (0.5%) to 2 classes, and 3 (0.7%) to 3 classes of antiretroviral therapy. It was suggested that individuals seroconverting later in calendar time were more likely to have TDR (relative risk 3.89 and 95% CI: 0.84 to 18.02, and relative risk 4.69 and 95% CI: 1.03 to 21.31, for 1996-1999 and 2000-2003, respectively, compared with pre-1996; P trend = 0.08). This trend was apparent regardless of the definition of TDR used. The total estimated proportion of individuals with TDR varied between 10.3% and 15.5% according to which definition was used. CONCLUSIONS: Evidence was found for the rise of TDR over time. A specific definition of what constitutes TDR rather than a simple list of mutations is needed.     

Induction of cellular immune response and anti-Salmonella enterica serovar typhi bactericidal antibodies in healthy volunteers by immunization with a vaccine candidate against typhoid fever

Typhoid fever remains a serious public health problem. We have developed a vaccine from Salmonella enterica serovar typhi (S. typhi) outer-membrane proteins (OMPs) known as porins. A single subcutaneous dose of 10 microg of porins induced a five-fold (P = 0.05) seroconversion index consisting of IgM and IgG at 7 and 15 days after vaccination as well as the production of IgG1 and IgG2 isotypes. The porins-based vaccine induced a two-fold increase (P = 0.05) in bactericidal titres in volunteers, whom also developed a T-cell response characterized by the production of interferon-gamma (INF-gamma). Side effects after vaccination were mild and transient. The data showed that our S. typhi porins-based candidate vaccine is safe and immunogenic in healthy humans.     

Expression of the endothelial markers PECAM-1, vWf,and CD34 in vivo and in vitro

EC culture models are essential to study pathological alterations of endothelial cells (ECs) in pulmonary vascular diseases under standardized conditions. Nevertheless, little is known about the spectrum of alterations of vessel-specific endothelial phenotypes in monolayer cultures. For the comparative study of endothelial markers in vivo and in vitro we investigated immunohistochemically the expression of PECAM-1, vWf, and CD34 by pulmonary ECs in vivo and in stimulated/unstimulated human umbilical vein endothelial cells (HU-VEC) and human pulmonary microvascular endothelial cells (HPMEC). In vivo, vessel type-specific expression patterns were found for vWf and CD34, while PECAM-1 was homogeneously and strongly expressed. While all HUVEC showed a marked vWf staining, about two-thirds of HPMEC exhibited a strong and the rest a moderate vWf staining. In both in vitro models all ECs were clearly PECAM-1-positive. However, only about 20% of the HUVEC and HPMEC were CD34-positive. Our results demonstrate the reduced expression of vessel type-specific endothelial phenotypes by endothelial monolayer cultures, stressing the need to improve culture conditions as well as develop cocultures and three-dimensional culture models. Moreover, the need for endothelial markers specific for single microvascular type ECs becomes obvious in order to establish cultures consisting of only one microvascular ECs subpopulation.