Biomedical subjects

G Yang

Publications and source records attributed to G Yang.

At least 37 records · Page 2Linked to original sources

PubMed2005

MELPREDICT: a logistic regression model to estimate CDKN2A carrier probability.

BACKGROUND: Heritable alterations in CDKN2A account for a subset of familial melanoma cases although no robust method exists to identify those at risk of being a mutation carrier. METHODS: We set out to construct a model for estimating CDKN2A mutation carrier probability using a cohort of 116 consecutive familial cutaneous melanoma patients evaluated at Massachusetts General Hospital Pigmented Lesion Center between April 2001 and September 2004. Germline CDKN2A and CDK4 status on the familial melanoma cases and clinical features associated with mutational status were then used to build a multiple logistic regression model to predict carrier probability and performance of model on external validation. RESULTS: From the 116 kindreds prone to melanoma in the Boston area, 13 CDKN2A mutation carriers were identified and 12 were subsequently used in the modeling. Proband age at diagnosis, number of proband primaries, and number of additional family primaries were most closely associated with germline mutations. The estimated probability of the proband being a mutation carrier based on the logistic regression model (MELPREDICT) is given by e(L)/(1 + e(L) where L = 1.99+[0.92x(no. of proband primaries)]+[0.74x(no. of additional family primaries)]-[2.11xln(age)]. The mean estimated probabilities for subjects in the Boston dataset were 55.4% and 5.1% for the mutation carriers and non-carriers respectively. In a receiver operator characteristic analysis, the area under the curve was 0.881 (95% confidence interval 0.739 to 1.000) for the Boston model set (n = 116) and 0.803 (0.729 to 0.877) for an external Toronto hereditary melanoma cohort (n = 143). CONCLUSIONS: These results represent the first-iteration logistic regression model to approximate CDKN2A carrier probability. Validation of this model with an external dataset revealed relatively robust performance.

Adolescent↗

PubMed2005

Sequence variation and gene duplication at MHC DQB loci of baiji (Lipotes vexillifer), a Chinese river dolphin.

The major histocompatibility complex (MHC) is a fundamental part of the vertebrate immune system, and the high variability in many MHC genes is thought to play an important role in the recognition of parasites. Baiji (Lipotes vexillifer) is one of the most endangered species in the world. Its wild population has declined to fewer than 100 individuals and has a very high risk of becoming extinct in the near future. In this study we present a first step in the molecular characterization of a DQB-like locus of baiji by nucleotide sequence analysis of the polymorphic exon 2 segments. In the examined 172 bp sequences from a group of 18 incidentally captured or stranded individuals, 48 variable sites were determined and 43 alleles were identified, many of which were represented by only one clone. Three to seven alleles were found in each individual, suggesting gene duplications. No deletion, insertion, or exceptional stop codon was detected, suggesting these alleles function in vivo. Phylogenetic reconstruction using neighbor joining grouped the 43 alleles into two distinct lineages, differing by seven nucleotides and four amino acids. Substitutions of amino acids tend to be clustered around sites postulated to be responsible for selective peptide recognition. In the peptide-binding region (PBR) of the DQB locus, the average number of nonsynonymous substitutions per site is greater than that of synonymous substitutions per site (0.1962 versus 0.0256, respectively). Nucleotide and amino acid sequences both showed a relatively high level of similarity (nucleotides 90.6%; amino acids 80.6%) to those of beluga whale (Delphinapterus leucas) and narwhal (Monodon monoceros). The high level of baiji MHC polymorphism revealed in the present study has not been reported in other cetaceans and could be a consequence of the small baiji population adapting to freshwater with a relatively high level of pathogens.

Amino Acid Sequence↗

PubMed2005

Clinical and cytogenetic features of 508 Chinese patients with myelodysplastic syndrome and comparison with those in Western countries.

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by ineffective hematopoiesis and leukemia progression. Racial differences may exist on clinical pictures and the molecular events leading to MDS, which are heterogeneous. To better define the clinical and cytogenetic features in Chinese patients, a retrospective multicentric study was performed in 508 MDS cases. Compared with Western countries, Chinese patients showed younger age (median: 49 vs 65-73 years), lower percentages of RARS (2.8 vs 6.6-15.3%), and CMML (5.2 vs 11.7-30.6%). Cytogenetically, among 367 cases with evaluable data, abnormal karyotypes were found in 136 cases, including 56 numerical and 80 structural changes. Incidences of single chromosome 5 and 7 abnormalities were lower than those in Western countries (2.2 vs 17.8-42.5%). However, complex cytogenetic aberrations and chromosome translocations were frequently observed and related to poor prognosis. Both multiple chromosome deletions and translocations were detected in advanced subtypes (RAEB and RAEB-T). Analysis of 200 cases revealed a higher incidence of hepatitis-B-virus infection than that in non-MDS population (21.00 vs 9.75%). This study further confirmed: (1) different genetic/environmental backgrounds between Asian and Western MDS populations; (2) a strong predictive value of cytogenetic abnormalities on disease outcome and involvement of genomic instability in leukemia clone development.

Adolescent↗

PubMed2005

Current ideas about applications of heat shock proteins in vaccine design and immunotherapy.

Heat shock proteins (HSPs), as molecular chaperones, perform critical functions in maintaining cell homeostasis. Certain HSPs in extra-cellular milieu are capable of modulating innate and adaptive immunity due to their ability to chaperone polypeptides and to interact with the host's immune system, particularly professional antigen presenting cells (APCs). This review summarizes the immunomodulating functions of HSPs and their potential applications in cancer immunotherapy.

Animals↗

PubMed2005

Potentiation and cellular phenotypes of the insecticidal Toxin complexes of Photorhabdus bacteria.

The toxin complex (tc) genes of bacteria comprise a large and growing family whose mode of action remains obscure. In the insect pathogen Photorhabdus, tc genes encode high molecular weight insecticidal toxins with oral activity against caterpillar pests. One protein, TcdA, has recently been expressed in transgenic plants and shown to confer insect resistance. These toxins therefore represent alternatives to toxins from Bacillus thuringiensis (Bt) for deployment in transgenic crops. Levels of TcdA expression in transgenic plants were, however, low and the full toxicity associated with the native toxin was not reconstituted. Here we show that increased activity of the toxin TcdA1 requires potentiation by either of two pairs of gene products, TcdB1 and TccC1 or TcdB2 and TccC3. Moreover, these same pairs of proteins can also cross-potentiate a second toxin, TcaA1B1. To elucidate the likely functional domains present in these large proteins, we expressed fragments of each 'toxin' or 'potentiator' gene within mammalian cells. Several domains produced abnormal cellular morphologies leading to cell death, while others showed specific phenotypes such as nuclear translocation. Our results prove that the Tc toxins are complex proteins with multiple functional domains. They also show that both toxin genes and their potentiator pairs will need to be expressed to reconstitute full activity in insect-resistant transgenic plants. Moreover, they suggest that the same potentiator pair will be able to cross-potentiate more than one toxin in a single plant.

Animals↗

PubMed2005

Antineutrophil cytoplasmic antibodies (ANCA) in Chinese patients with anti-GBM crescentic glomerulonephritis.

OBJECTIVE: To study the prevalence of ANCA and their target antigen in Chinese patients with anti-GBM crescentic glomerulonephritis (CGN), and to evaluate the possible role of ANCA in Chinese anti-GBM CGN patients with coexisting serum ANCA by studying clinicopathologic features of this disease. MATERIAL AND METHODS: Twenty-three sera were collected from 23 renal biopsy-proven anti-GBM CGN patients. According to the standardized procedures, all of the sera were determined by both, indirect immunofluorescence (IIF) ANCA, and enzyme-linked immunosorbent assay (ELISA) MPO-ANCA, PR3-ANCA and BPI-ANCA. The patients were divided into two groups according to serum ANCA positivity (Group A) or negativity (Group B). Thirty-three ANCA-associated pauci-immune CGN patients were regarded as control group (Group C). Their clinicopathologic features were compared to reveal whether ANCA correlated with disease activity. RESULTS: There were 11 (47.8%) cases with positive serum ANCA in 23 anti-GBM glomerulonephritis patients. There were 4/11 MPO-ANCA (one with positive PR3-ANCA and C-ANCA, three with negative IIF-ANCA), 1/11 PR3-ANCA (with positive MPO-ANCA and C-ANCA), 3/11 P-ANCA (with negative ELISA-ANCA) and 5/11 C-ANCA (one with positive PR3-ANCA and MPO-ANCA, and the other four with negative ELISA-ANCA). No BPI-ANCA was detected. No different clinicopathologic features were found between Groups A and B. Both were different from Group C in age, sex ratio, frequence of anuria and ESRD, variety of crescents, glomerular sclerosis, vessel lesion and prognosis. CONCLUSION: Our data demonstrate that ANCA in Chinese patients with anti-GBM CGN is not rare. The major target antigen of ANCA is MPO. ANCA seems not to be correlated with disease activity.

Adolescent↗

PubMed2004

Modern diagnostics in chronic myeloproliferative diseases (CMPDs).

According to the new WHO classification a group of chronic myeloproliferative diseases (CMPDs) were defined: chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia and hypereosinophilic syndrome (CEL/HES), polycythemia vera (PV), chronic idiopathic myelofibrosis (with extramedullary hematopoiesis, CIMF), essential thrombocythemia (ET), and so called CMPD/unclassifiable. As clinical features and laboratory findings differ widely between these diseases several diagnostic approaches are mandatory at diagnosis for classification and are needed also for follow up studies, especially for the measurement of minimal residual disease (MRD). We here outline the laboratory set up at diagnosis and during follow up in CMPDs with specific focus on the respective therapeutical consequences. Only by using a comprehensive diagnostic panel including cytomorphology, cytogenetics, and molecular genetic methods establishing the correct diagnosis, optimizing treatment as well as evaluating treatment response is possible in CMPDs today.

Blood Cell Count↗

PubMed2004

Validity and reproducibility of the food frequency questionnaire used in the Shanghai Women's Health Study.

To evaluate the validity and reliability of the food frequency questionnaire (FFQ) used in the Shanghai Women's Health Study (SWHS), 200 SWHS participants were recruited for a dietary calibration study. Study participants completed an FFQ at baseline and 24-h dietary recalls (24-HDR) twice per month consecutively for 12 months. At the end of the study, a second FFQ was administered. Of the 200 study participants, 196 completed 24 or more days of 24-h dietary recalls, 191 completed two FFQs from whom the results of this report were based. The FFQ included the foods that accounted for 86% of the foods recorded in the 24-HDR surveys. Validity of the FFQ was evaluated by comparing intake levels of major nutrients and foods obtained from the second FFQ with those derived from the multiple 24-HDR. The median intake for major nutrients, rice, poultry and meat derived from the second FFQ and the 24-HDR was similar, with the differences ranging from 1.3 to 12.1%. The FFQ tended to overestimate the intake level of total vegetables and total fruits, and the differences were explained mainly by over-reporting seasonal vegetables and fruits consumption in the FFQ. Nutrient and food intake assessed by the FFQ and the multiple 24-HDR correlated very well, with the correlation coefficients being 0.59-0.66 for macronutrients, 0.41-0.59 for micronutrients, and 0.41-0.66 for major food groups. The reliability of the FFQ was assessed by comparing the correlation and median intake of nutrients and food groups obtained from the two FFQs that were administered approximately 2 y apart. The median intake levels for selected nutrients and food groups derived from the two FFQs were similar with differences below 10%. At the individual level, the intake levels of these dietary variables obtained from two FFQs also correlated well. When nutrient and food group intakes were categorized into quartiles, FFQ and 24-HDR produced exact agreement rates between 33 and 50%. Misclassification to adjacent quartile was common, ranging from 34-48%, while misclassification to an extreme quartile was rare (1-6%). These data indicate that the SWHS FFQ can reliably and accurately measure usual intake of major nutrients and food groups among women in Shanghai.

Calibration↗

PubMed2004

Soyfood consumption and risk of glycosuria: a cross-sectional study within the Shanghai Women's Health Study.

OBJECTIVE: To assess the association between soyfood intake and risk of glycosuria. DESIGN AND METHODS: A cross-sectional study was conducted among participants of the Shanghai Women's Health Study, a population-based cohort study of women aged 40-70 y. Information on usual intake of soyfoods was obtained at baseline survey through an in-person interview using a validated food-frequency questionnaire. Included in this study were 39,385 cohort members screened for diabetes at the baseline survey and free of previously diagnosed diabetes, cardiovascular diseases, kidney diseases, and cancer. There were 323 women who tested positive for urine glucose. Odds ratios (ORs) and 95% confidence intervals (CIs) were employed to measure the association between soyfood intake and glycosuria using unconditional logistic regression. SETTING: Urban communities of Shanghai, China. RESULTS: Overall, soyfood intake was not related to the risk of glycosuria. Among postmenopausal women, however, intake of tofu and other soy products was inversely associated with risk of glycosuria after adjustment for potential confounders. The ORs across quintiles of intake were 1.0, 0.75 (95% CI=0.47-1.20), 0.79 (95% CI=0.51-1.25), 0.53 (95% CI=0.32-0.88), and 0.51 (95% CI=0.26-0.98; P for trend=0.05). Further analyses showed that the inverse association was primarily confined to postmenopausal women with a body mass index (BMI) of <25 kg/m2. The adjusted OR comparing the extreme quintiles was 0.36 (95% CI=0.13-0.97; P for trend=0.004). CONCLUSIONS: Soyfoods may play a role in the development of glycosuria, an important indicator of diabetes, among postmenopausal women with a low BMI.

Adult↗

PubMed2004

Variation in nutrient intakes among women in Shanghai, China.

BACKGROUND: In 1997, we launched a large population-based cohort study, the Shanghai Women Health Study (SWHS), to investigate diet in relation to cancer risk among 74 943 Chinese women. Simultaneously, a dietary calibration study was conducted among 200 SWHS participants with biweekly 24-h dietary recall (24HDR) over a 1-y period in order to evaluate the validity and reliability of the SWHS food frequency questionnaire (FFQ). OBJECTIVE: The objectives of the current study were to evaluate the nature and magnitude of variances for intake of 26 nutrients among SWHS participants, and to estimate the number of 24HDR needed for estimate intake of the 26 nutrients examined in the study population. DESIGN: In all, 1-y biweekly 24HDR collected from 200 healthy, free-living women aged between 40 and 70 y, who participated in the SWHS dietary calibration study, was analyzed by mixed effects model and ratios of within-individual and between-individual dietary intake variances (sigma(w)(2)/sigma(b)(2)) were estimated. RESULTS: In agreement with reports from studies conducted in the US, we found that within-individual variances were larger than between-individual variances in dietary intake of most nutrients. The sum of all other variation (eg, weekday and weekend, seasonal, interviewer) accounted for less than 5% of total variation. Ratios of within- to between-individual variances (for log transformed data) ranged from 1.05 (carbohydrate) to 2.79 (fat) for macronutrient intake, 1.74 (niacin) to 8.48 (delta-tocopherol) for vitamin intake, and 1.35 (phosphorus) to 5.59 (sodium) for mineral intake. CONCLUSIONS: The results of this study suggest that within- and between-individual differences in nutrient intake are the major sources of variation in this population of adult Chinese women. Cultural practices as well as seasonal supply and consumption patterns of vegetable intake are likely the major contributors to the variation. Implications of these results are discussed.

Adult↗

PubMed2004

Body fat distribution and risk of diabetes among Chinese women.

OBJECTIVE: To assess the relationship between measures of central and overall obesity and risk of diabetes. DESIGN: Nested case-control study. SETTING: Shanghai, China. PARTICIPANTS: A total of 57 130 women were screened for diabetes at enrollment for the Shanghai Women's Health Study (SWHS), a population-based cohort study of Chinese women aged 40-70 y. In this study, 345 women diagnosed with diabetes and 2760 age-matched controls (eight controls per case), randomly selected from women who tested negative for urine glucose, were included. RESULTS: Risk of diabetes increased significantly with increasing levels of obesity, particularly with measures of central obesity. Compared to those in the lowest quartile, women in the highest quartile of body mass index (BMI) (>/=26.57) and waist to hip ratio (WHR) (>/=0.855) had a 2.57-fold (95% CI 1.75-3.77) and a 6.05-fold (95% CI 4.05-9.04) increased risk of diabetes, respectively. The risk of diabetes was elevated with increasing WHR at all levels of BMI, while the positive association between BMI and diabetes was observed primarily among women with a low WHR. However, test for multiplicative interaction was not statistically significant. CONCLUSIONS: Our data indicated that central obesity is a stronger risk factor for diabetes than overall obesity, suggesting that WHR may be a better indicator of risk of diabetes than BMI among Chinese women.

Adult↗

PubMed2004

Anthropometric predictors of coronary heart disease in Chinese women.

OBJECTIVE: To evaluate the associations of body size and fat distribution with incidence of coronary heart disease (CHD) in Chinese women. DESIGN: Population-based, prospective cohort study. SUBJECTS: A total of 67 334 women aged 40-70 y, who had no prior history of CHD, stroke, and cancer at study recruitment. MEASUREMENTS: Weight, standing and sitting heights, circumferences of waist and hip, and ratios of the anthropometric measurements. OUTCOME: incidence of CHD (non-fatal myocardial infarction (MI) or fatal CHD). RESULTS: After a mean follow-up of 2.5 y (168 164 person-years), there were 70 incident cases of CHD (49 non-fatal MIs and 21 CHD deaths). Body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), waist-to-standing height ratio (WHtR), waist-to-sitting height ratio (WsHtR), and conicity index were all positively associated with the risk of CHD. With the exception of WHR, all other anthropometric indexes only predicted the risk of CHD among women </=55 y of age at enrollment. The relative risks (RRs) between extreme tertiles of BMI were 9.0 (95% CI, 2.0-41.5; P for trend=0.002) for younger women vs 1.3 (0.6-3.0; P for trend=0.83) for older women. Similarly, the RRs for WC, WHtR, WsHtR, and conicity index were 6.1 (1.8-21.4) vs 1.9 (0.6-5.4), 9.4 (2.6-33.8) vs 1.2 (0.5-3.1), 15.2 (3.3-69.1) vs 1.0 (0.4-2.5), and 7.8 (2.2-28.0) vs 0.9 (0.4-2.3) for the young and elderly, respectively. In contrast, the RR for WHR was 3.2 (1.1-9.1) for the young and 2.9 (1.0-8.4) for the elderly. CONCLUSIONS: WHR was positively associated with the risk of CHD in both younger and older women, while other anthropometrics, including BMI, were related to CHD risk primarily among younger women.

Adult↗

PubMed2004

Genomic organisation of the chicken ghrelin gene and its single nucleotide polymorphisms detected by denaturing high-performance liquid chromatography.

(1) Ghrelin is a novel endogenous ligand for the growth hormone secretagogue receptor (GHS-R) and is expressed primarily in the stomach and hypothalamus with the probable function of stimulating GH secretion and food intake both in mammals and poultry. The complete sequences of ghrelin gene have been reported in humans and mice; however, that of chickens remains unclear. (2) Here, we report the complete sequence of chicken ghrelin gene (submitted to Genbank; accession number AY303688), which consists of 5 exons and 4 introns. As in mice, the first exon of chicken ghrelin gene does not encode any amino acid. (3) Scanning point mutations with denaturing high-performance liquid chromatography (DHPLC) using WAVE DNA Fragment Analysis Systems and confirmed with direct sequencing for polymerase chain reaction (PCR) products, we analysed the single nucleotide polymorphisms (SNPs) in the entire gene of chicken ghrelin. (4) Results showed that there were 19 SNPs in chicken ghrelin gene, and most of these SNPs were scattered in the 4 introns. In these SNPs, one mutation in exon 5 (A2355G) led to the change of amino acid from glutamine to arginine (Gln 113 Arg): as a result a different ghrelin precursor instead of a mature peptide was produced. In addition, one SNP in 5'UTR (C223G) determined the presence or absence of a potential binding site of transcription factor serum response factor (SRF), which might affect the expression of chicken ghrelin gene. Some of the SNPs detected in the present study could be used in quantitative trait loci (QTL) mapping for growth characters in chickens. (5) Because one SNP is located in a polymorphic site of restriction enzyme PagI of intron 4, it was possible to design a PCR-RFLP procedure and analyse the diversity of 10 chicken populations. Results showed the allelic frequencies of C2100T differ among these breeds, however, no significant difference was observed between imported breeds and Chinese native ones, nor between egg layers and meat type chickens. A chi-square test showed that 4 chicken populations of Beijing Fat, Xinghua, Recessive White and Silky followed the Hardy-Weinberg equilibrium.

Amino Acid Sequence↗

PubMed2004

Should preoperative, post-chemoradiotherapy endoscopy be routine for esophageal cancer patients?

Chemoradiation therapy is used widely for locoregional esophageal cancer. Patients with persistent disease may benefit from surgery. Preoperative esophagoscopy can identify persistent tumor but its accuracy is uncertain. The primary objective of this study is to assess the extent of agreement between esophagoscopy and surgical pathology in patients treated with neoadjuvant chemoradiation. A retrospective chart review of patients who underwent chemoradiation, preoperative endoscopy and surgery from January 1996 to December 2002 was performed. Cohen's kappa statistic was used to measure the degree of agreement between findings at endoscopic biopsy and surgical pathology. Thirty cases were identified. All patients received chemoradiation followed by surgical resection. There was insufficient agreement between tumor size (kappa 0.25, standard error 0.17, P = 0.07) and appearance (kappa 0.19, standard error 0.18, P = 0.14). Preoperative endoscopy revealed atypia/inflammation in 15 cases and dysplasia in eight. Of these 23 cases, 11 were adenocarcinomas at surgery. Only nine patients had concurrence between surgical pathology and endoscopy. The positive and negative predictive values of esophagoscopy for identifying residual tumor were 100% and 11%, respectively. Our data suggests that after chemoradiation, esophagoscopy is unreliable for excluding residual disease. The roles of other modalities need to be explored.

Adenocarcinoma↗

PubMed2003

Sociodemographic, behavioral, and reproductive factors associated with weight gain in Chinese women.

OBJECTIVE: To examine whether certain sociodemographic, behavioral, and reproductive factors are associated with an increased weight gain in Chinese women. DESIGN: Baseline survey data, including recalled past weight and measured current weight, from an ongoing prospective cohort study conducted in Shanghai, China. SUBJECTS: The analytical sample included 75 039 nonpregnant women aged 40-70 y. MEASUREMENTS: Statistical associations between certain sociodemographic, behavioral, and reproductive factors and weight gain were evaluated using multiple linear and logistic regression models. RESULTS: Weight gain and waist-to-hip ratio (WHR) increased with age among pre- and postmenopausal women before age 55 y. Weight gain declined but WHR continued rising as aging among postmenopausal women over age 55 y. Lower education levels, more parity and earlier age at the first birth, and earlier menarcheal age were associated with a higher long-term weight gain and current body weight. CONCLUSION: Age, education levels, parity, age at the first live birth, and menarcheal age were associated with long-term weight gain in Chinese women. However, these results concerning weight gain are based on recalled past weight and should be interpreted with caution. Further studies are needed to clarify the association of weight gain with lifestyle factors suggested by this study.

Adult↗

PubMed2002

Estimation of the effective transversely isotropic elastic constants of a material from known values of the material's orthotropic elastic constants.

A method is illustrated for determining the effective transversely isotropic (or isotropic) elastic constants from measured orthotropic elastic constants. This method consists of constructing upper and lower bounds on the effective transversely isotropic (or isotropic) elastic constants using the known orthotropic values. This method is illustrated using three sets of elastic constants for bone. Fortunately, the upper and lower bounds are very close. Thus very good approximations for the effective transversely isotropic (or isotropic) elastic constants for cortical and cancellous bone are obtained from previously published data on the orthotropic elastic constants for those tissue types. This work is undertaken to build a greater database for the transversely isotropic elastic constants of bone with the intention of employing them in a transversely isotropic model of bone poroelasticity. An interesting aspect of the present result is that the Voigt and Reuss bounds are very tight for these anisotropic materials. This is not always the case for these bounds.

Animals↗

PubMed2002

The ukb1 gene encodes a putative protein kinase required for bud site selection and pathogenicity in Ustilago maydis.

Morphogenesis and pathogenesis are closely associated aspects of the life cycle of the fungal pathogen Ustilago maydis. In this fungus, the dimorphic switch from budding to filamentous growth coincides with the transition from non-pathogenic to pathogenic growth on maize. We have cloned and characterized the ukb1 gene that encodes a putative serine/threonine protein kinase with a role in budding and filamentous growth. Mutants defective in ukb1 were altered in bud site selection and produced lateral buds at a greater frequency than wild-type cells. Dikaryotic cells defective in ukb1 were capable of colonizing host tissue and growing with a filamentous morphology in planta. However, the mutants were incapable of inducing tumor formation and they failed to complete sexual development. In addition, the ukb1 gene influenced the ability of colonies to form aerial mycelia in response to environmental stimuli. Overall, the discovery of ukb1 reinforces the connection between morphogenesis and pathogenesis in U. maydis.

Amino Acid Sequence↗

PubMed2002

Gene therapy for prostate cancer: toxicological profile of four HSV-tk transducing adenoviral vectors regulated by different promoters.

Adenoviral vector delivery of the Herpes simplex virus thymidine kinase (HSV-tk) gene in combination with the prodrug ganciclovir (GCV) has been tested in phase I clinical trials for prostate cancer and found to exhibit a satisfactory toxicity profile. We have developed additional adenoviral vectors with differing promoters to optimize the expression profile and in the present study evaluate the potential systemic toxicity of these vectors. Four recombinant adenoviral vectors that express the HSV-tk gene were generated using three different promoters: CMV (leftward orientation); RSV (both rightward and leftward orientation); and the mouse caveolin-1 (cav-1) promoter (leftward orientation). Efficacy was determined in vitro by cytotoxicity assays in a mouse prostate cancer cell line, RM-9, and in vivo by treating orthotopic tumors. Potential toxicity was evaluated from liver histology and apoptotic cell counts and enzyme levels in the serum following intravenous adenoviral vector injection. Although there were differences in HSV-tk expression at the protein level among the four vectors there were no significant differences in in-vitro cytotoxicity studies with GCV or in vivo in tumor growth suppression of an orthotopic mouse prostate cancer model in GCV treated mice. Intravenous delivery of high doses of all adenoviral vectors lead to abnormalities in liver function as measured by specific serum markers and histological evaluation of liver tissue and increased levels of apoptosis in the liver. These abnormalities were most prevalent with the vector containing the CMV promoter and the rightward oriented RSV promoter. They were least prevalent in the vector regulated by the cav-1 promoter. Upregulation of specific chemokines, MIP-2 and MIP-1beta was correlated with apoptotic counts. Our results demonstrate that comprehensive toxicological analysis of adenoviral vectors provides internally consistent information that can differentiate vectors with comparable efficacy based on toxicity. In these studies vectors with the cav-1 promoter-driven and leftward RSV-driven HSV-tk gene demonstrated minimal toxicities with cytotoxic effectiveness comparable to more toxic vectors. Our studies further suggest that promoter selection can influence the toxic effects of an adenoviral gene therapy vector.

Adenocarcinoma↗