ORCID Profile
0000-0001-6458-2773
Current Organisation
James Cook University
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Publisher: American Association for Cancer Research (AACR)
Date: 10-2012
DOI: 10.1158/1055-9965.EPI-12-0695
Abstract: Background: Finasteride, an inhibitor of 5α-reductase (type II), lowers intraprostatic dihydrotestosterone (DHT), which is reflected in serum as reduced 5α-androstane-3α,17β-diol glucuronide (3α-dG). It also modestly increases serum testosterone (T), estrone (E1), and estradiol (E2). In this altered hormonal milieu, it is unknown whether serum concentrations of these hormones are associated with prostate cancer risk. Methods: In this nested case–control study of men in the finasteride arm of the Prostate Cancer Prevention Trial, sex steroid hormones and sex hormone binding globulin were measured at baseline and approximately 3-year posttreatment in 553 prostate cancer cases and 694 controls. Results: Median posttreatment changes in concentrations of 3α-dG, T, E1, and E2 were −73.8%, +10.1%, +11.2%, and +7.5% (all P & 0.001), respectively. Neither the pre- nor posttreatment concentrations of 3α-dG, nor its change, were associated with risk. Pretreatment, high concentrations of E1 and low concentrations of T were associated with increased cancer risk [OR 95% confidence interval (CI) quartile 4 vs. 1: 1.38 (0.99–1.93) Ptrend = 0.03 0.64 (0.43–0.93) Ptrend = 0.07, respectively]. Posttreatment, high concentrations of both E1 and E2 were associated with increased cancer risk [OR 95% CI quartile 4 vs. 1: 1.54 (1.09–2.17) Ptrend = 0.03 1.49 (1.07–2.07) Ptrend = 0.02, respectively]. Conclusions: Among finasteride-treated men, concentrations of 3α-dG were not associated with total or Gleason grades 2 to 6, 7 to 10, or 8 to 10 cancer. High serum estrogens may increase cancer risk when intraprostatic DHT is pharmacologically lowered. Impact: Low posttreatment serum estrogens may identify men more likely to benefit from use of finasteride to prevent prostate cancer. Cancer Epidemiol Biomarkers Prev 21(10) 1823–32. ©2012 AACR.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2000
DOI: 10.1097/00008571-200007000-00004
Abstract: Human prostatic steroid 5alpha-reductase, encoded by the SRD5A2 gene on chromosome band 2p23, catalyses the irreversible conversion of testosterone to dihydrotestosterone (DHT), the most active androgen in the prostate, with NADPH as its cofactor. This enzyme has never been purified but a number of competitive inhibitors have been developed for this enzyme since increased steroid 5alpha-reductase activity may cause benign prostatic hypertrophy and prostate cancer. We report here the detailed biochemical and pharmacogenetic dissection of the human enzyme by analysing 10 missense substitutions and three double mutants which are all naturally found in humans. Nine of these 13 mutants reduce activity (measured as Vmax) by 20% or more, three increase steroid 5alpha-reductase by more than 15% and one results in essentially unaltered kinetic properties suggesting that it is a truly neutral ('polymorphic') amino acid substitution. Substantial pharmacogenetic variation among the mutants was also observed when three competitive inhibitors, finasteride, GG745 (dutasteride) and PNU157706, were investigated. Our studies not only define the substrate and cofactor binding sites of human steroid 5alpha-reductase, but also have significant consequences for the pharmacological usage of steroid 5alpha-reductase inhibitors in human patients treated for prostatic conditions.
Publisher: Oxford University Press (OUP)
Date: 2001
Publisher: Elsevier BV
Date: 08-1994
DOI: 10.1016/S0022-3476(94)70197-0
Abstract: This study was conducted to determine whether there is a genotype henotype correlation between aspects of cognitive, neurologic, and ovarian outcome in patients with galactosemia and the Q188R mutation of the galactose-1-phosphate uridyltransferase gene. The results showed that the Q188R mutation was found in 72% of alleles: 38 patients were homozygous and 21 were heterozygous for Q188R eight patients did not have the mutation. The mean Broad Cognitive score for the group homozygous for Q188R was 75 (SD = 16), which was not statistically different from the outcome for the heterozygous group (mean score, 67 SD = 25) or the negative group (mean score, 88 SD = 21). Tremor, ataxia, and dysmetria were found in 12 subjects, and there was no association with Q188R status. Similarly, there was no association of this mutation with the development of primary amenorrhea (8 subjects) versus secondary amenorrhea (found in 14 women). Our findings suggests that the variability of outcome for patients with classic galactosemia cannot be explained by Q188R status alone, at least with regard to cognitive functioning, presence of neurologic symptoms, and timing of the onset of ovarian failure.
Publisher: Elsevier BV
Date: 1999
DOI: 10.1159/000019909
Abstract: The prostate is an androgen-regulated organ, which has led to longstanding interest in the role of androgens in prostate carcinogenesis. Although evidence of a hormonal etiology for prostate cancer is strong, it is almost entirely circumstantial. Much of the problem in proving a causal relationship relates to the continued difficulties in reliably measuring human tissue-specific exposure to endogenous steroid hormones. The international and racial-ethnic variations in prostate cancer incidence, combined with the effects of migration on risk patterns, have suggested that genetic factors play a central role in determining prostate cancer risk. We are developing a polygenic model of prostate carcinogenesis, focused around a series of genes involved in androgen biosynthesis, transport and metabolism. We have begun to develop this model by utilizing sequence variants to study how polymorphic markers in two genes (SRD5A2 and AR) are related to prostate cancer risk within and between racial-ethnic groups. We are now collaborating with the Whitehead Institute/MIT, Center for Genome Research, to screen for single nucleotide polymorphisms in additional genes relevant to the androgen pathway and prostate cell growth. The model when fully developed can potentially provide a basis for targeting populations for screening interventions and for implementing primary preventive strategies.
Publisher: Oxford University Press (OUP)
Date: 08-12-2017
Publisher: Elsevier BV
Date: 07-2014
Publisher: Proceedings of the National Academy of Sciences
Date: 04-1991
Abstract: We describe the molecular characterization of two mutations responsible for galactosemia, an inherited disorder of galatose metabolism that causes jaundice, cataracts, and mental retardation in humans. The coding region of galactose-1-phosphate uridylyltransferase (GALT UDPglucose:alpha-D-galactose-1-phosphate uridylyltransferase, EC 2.7.7.12) was lified by the polymerase chain reaction from total cDNA of a classic galactosemic in idual and was characterized by direct sequencing of the products. Two missense mutations were identified: (i) replacement of valine-44 by methionine and (ii) replacement of methionine-142 by lysine. These mutations led to a drastic reduction in GALT activity when in idual mutant cDNAs were overexpressed in a mammalian cell system, although full-length protein is synthesized in this assay. The two galactosemia mutations account for 3 of the 15 galactosemia alleles analyzed. These results suggest that galactosemia is caused by a variety of mutations, which might be responsible for the observed clinical heterogeneity of this disorder. We also present the molecular characterization of two GALT polymorphisms: (i) replacement of leucine-62 by methionine and (ii) replacement of asparagine-314 by aspartate. It appears that galactosemia mutations tend to occur in regions that are highly conserved throughout evolution while the polymorphisms change variable residues.
Publisher: S. Karger AG
Date: 1996
DOI: 10.1159/000127096
Abstract: Biological activity of the follicle-stimulating hormone (FSH) is dependent on its pattern of glycosylation and is altered during galactosemia, a genetic disease characterized by deficient activity of galactose-1-phosphate uridyltransferase (GALT). To assess the role of this enzyme in the synthesis of FSH, the expression of GALT at the mRNA and protein levels was measured in the whole anterior pituitary during the estrous cycle of rat. GALT was maximally expressed during the proestrous and estrous phases of the estrous cycle. The expression pattern of GALT was associated with gonadotropin-expressing cells. This close association is in accordance with the postulated role of GALT in modulating biological activity of FSH.
Publisher: Springer Science and Business Media LLC
Date: 03-1995
DOI: 10.1007/BF00225208
Abstract: In this review, we discuss some important aspects of paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS), a new syndrome that is temporally related to previous exposure to SARS-CoV-2 infection. This virus has a broad spectrum of presentation that may overlap with Kawasaki disease in terms of presenting symptoms and laboratory and cardiac findings. Our objective was to review and summarise published evidence regarding the most important aspects of PIMS-TS, with special emphasis on the treatment strategies suggested for middle-income and low-income countries. A systematic review of the literature was performed in the principal medical databases including PubMed, Embase (OVID) and Google Scholar between December 2019 and August 2020. A total of 69 articles were identified in the described databases. Altogether, 13 articles met the inclusion criteria and were eligible. The most frequently described symptoms of PIMS-TS include fever (82%), shock (67%) and gastrointestinal (87%), skin (71%) and cardiac disorders (75%). In most series, it has been observed between 4 and 6 weeks after the pandemic appears in the general population. Multisystem inflammatory syndrome in children is presented as a great systemic inflammatory response syndrome, which sometimes presents as shock requiring fluid resuscitation and vasoactive drug support (26%). Several treatment strategies have been used, including immunoglobulin, steroids, aspirin, anakinra and anticoagulation among others. These general and specific interventions should be guided by an interdisciplinary and multidisciplinary team, especially in settings with limited resources. PIMS-TS COVID-19 is a new type of presentation of SARS-CoV-2 infection, with an exaggerated inflammatory response and frequent-
Publisher: Public Library of Science (PLoS)
Date: 31-12-2010
Publisher: Oxford University Press (OUP)
Date: 1996
Abstract: To follow-up our previous observation that vaginal agenesis might be associated with decreased activity of galactose-1-phosphate uridyl transferase (GALT), we studied activity and genotype of GALT in 13 daughters with vaginal agenesis and their mothers. For comparison, GALT measurements were available from 113 pre-menopausal women with no known Müllerian anomalies selected from the general population. Red cell GALT activity was significantly lower in both the daughters and their mothers in comparison with general population controls. Six out of thirteen (46%) daughters and two mothers of the remaining seven daughters (29%) were carriers for the N314D mutation of GALT associated with the Duarte variant of galactosaemia as compared to 16 out of 113 general population controls (14%) who possessed at least one N314D allele. Pigmentary skin changes and scoliosis were associated phenotypic findings in daughters with vaginal agenesis. We conclude that fetal or maternal GALT mutations that decrease GALT activity may be associated with vaginal agenesis and have, as their possible biological basis, increased intrauterine exposure to galactose which has been demonstrated in rodents to cause decreased oocyte survival and delayed vaginal opening in offspring.
Publisher: Springer Science and Business Media LLC
Date: 04-11-2015
Publisher: Springer Science and Business Media LLC
Date: 29-07-2009
DOI: 10.1038/HDY.2009.84
Abstract: Classical or transferase-deficient galactosaemia is an inherited metabolic disorder caused by mutation in the human Galactose-1-phosphate uridyl transferase (GALT) gene. Of some 170 causative mutations reported, fewer than 10% are observed in more than one geographic region or ethnic group. To better understand the population history of the common GALT mutations, we have established a haplotyping system for the GALT locus incorporating eight single nucleotide polymorphisms and three short tandem repeat markers. We analysed haplotypes associated with the three most frequent GALT gene mutations, Q188R, K285N and Duarte-2 (D2), and estimated their age. Haplotype ersity, in conjunction with measures of genetic ersity and of linkage disequilibrium, indicated that Q188R and K285N are European mutations. The Q188R mutation arose in central Europe within the last 20 000 years, with its observed east-west cline of increasing relative allele frequency possibly being due to population expansion during the re-colonization of Europe by Homo sapiens in the Mesolithic age. K285N was found to be a younger mutation that originated in Eastern Europe and is probably more geographically restricted as it arose after all major European population expansions. The D2 variant was found to be an ancient mutation that originated before the expansion of Homo sapiens out of Africa.
Publisher: Mary Ann Liebert Inc
Date: 11-2017
Publisher: Hindawi Limited
Date: 2010
DOI: 10.1002/HUMU.21137
Publisher: Informa UK Limited
Date: 06-11-2012
DOI: 10.3109/10428194.2012.736981
Abstract: Mutations of isocitrate dehydrogenase 1 and 2 (IDH1/2) are genetic alterations in acute myeloid leukemia (AML). The aim of our study was to investigate the frequency and prognostic effect of IDH1/2 mutations together followed by an in idual analysis of each substitution in a Hungarian cohort consisting of 376 patients with AML. IDH1(mut) and IDH2(mut) were mutually exclusive, detected in 8.5% and 7.5% of cases, respectively. IDH1/2(mut) was associated with: older age (p = 0.001), higher average platelet count (p = 0.001), intermediate karyotype (p < 0.0001), NPM1(mut) (p = 0.022) and lower mRNA expression level of ABCG2 gene (p = 0.006). Overall survival (OS), remission and relapse rates were not different in IDH1(mut) or IDH2(mut) vs. IDH(neg). IDH1(mut) and IDH2(mut) were associated differently with NPM1(mut) co-occurrence was observed in 14.3% of IDH1 R132C vs. 70% of R132H carriers (p = 0.02) and in 47.4% of IDH2 R140Q vs. 0% of R172K carriers (p = 0.02). IDH1 R132H negatively influenced OS compared to IDH(neg) (p = 0.02) or R132C (p = 0.019). Particular amino acid changes affecting the same IDH1 codon influence the clinical characteristics and treatment outcome in AML.
Publisher: Springer Science and Business Media LLC
Date: 12-2019
DOI: 10.1186/S40246-019-0249-8
Abstract: In South America, the history of human genetics is extensive and its beginnings go back to the onset of the twentieth century. In Ecuador, the historical record of human genetics and genomics research is limited. In this context, our work analyzes the current status and historical panorama of these fields, based on bibliographic searches in Scopus, Google Scholar, PubMed, and Web of Science. Our results determined that the oldest paper in human genetics coauthored by an Ecuadorian institution originates from the Central University of Ecuador in 1978. From a historical standpoint, the number of articles has increased since the 1990s. This growth has intensified and it is reflected in 137 manuscripts recorded from 2010 to 2019. Areas such as human population genetics, phylogeography, and forensic sciences are the core of genetics and genomics-associated research in Ecuador. Important advances have been made in the understanding of the bases of cancer, some genetic diseases, and congenital disorders. Fields such as pharmacogenetics and pharmacogenomics have begun to be explored during the last years. This work paints a comprehensive picture and provides additional insights into the future panorama of human genetic and genomic research in Ecuador as an ex le of an emerging, resource-limited country with interesting phylogeographic characteristics and public health implications.
Publisher: Hindawi Limited
Date: 1999
DOI: 10.1002/(SICI)1098-1004(1999)13:4<339::AID-HUMU17>3.0.CO;2-V
Publisher: Elsevier BV
Date: 09-1999
Publisher: Elsevier BV
Date: 04-2001
DOI: 10.1086/319512
Publisher: Springer US
Date: 2009
Publisher: Impact Journals, LLC
Date: 19-08-2016
Publisher: Springer Science and Business Media LLC
Date: 08-2019
Publisher: Elsevier BV
Date: 05-2005
DOI: 10.1016/J.MOLBRAINRES.2005.01.017
Abstract: One of the most promising applications of microarrays is class distinction through gene expression profiling as a diagnostic tool. However, as there is apparent spatial heterogeneity in the morphology of cancer cells within a tumor, it is unclear if tumor s ling can be applied and yield consistent signals. In this report, we examined six brain tumors, four glioblastoma, and two oligodendroglioma biopsies. The six brain tumor tissues from two distinct different classes were dissected in four distinct areas and gene expression was profiled using microarrays. We used hierarchical clustering to compare the variability of gene expression profiles between spatially distinct biopsies of the same tumor as compared to the variability between tumors of the same histologic group. We conclude that, in general, repeat spatially distinct s les are not needed for microarray experiments and the gene expression signatures are robust across the tumor. Predominantly, variation was much greater between s les from different patients than from the multiple s lings of given tumor. Further, we compared biopsy expression profiles to the cell lines derived from those tissues. In general, the tumor cell lines vary greatly from the parental tissues and cluster more strongly with each other than the parental tissue. We select and examine the set of genes altered in expression to allow adaptation to cell culture.
Publisher: Elsevier BV
Date: 08-1991
DOI: 10.1016/0885-4505(91)90054-O
Abstract: Classic galactosemia, an inborn error of human galactose metabolism, is characterized by a deficiency of the enzyme galactose-1-phosphate uridyltransferase (GALT). The current model for the pathophysiology of this disease ascribes most of its symptoms to the toxicity of intracellular galactose-1-phosphate (Gal-1-P), one of the substrates of GALT which accumulates in the untreated disease state. Recently, a reduction in the intracellular concentration of UDP-Gal (uridine diphosphogalactose), one of the products of GALT, has been described in treated galactosemic patients. We investigated whether galactosemic patients might also have reduced amounts of those macromolecules that depend on UDP-Gal for their biosynthesis. We report a reduction in glycolipids that contain either galactose or its derivative N-acetylgalactosamine and an accumulation of the precursors to these compounds in the brain of a neonate with galactosemia. We also found an imbalance in glycolipids in galactosemic lymphoblasts. This novel biochemical abnormality observed in galactosemic patients is not addressed by dietary galactose-restriction therapy and could explain some of the chronic neurologic and other complications of galactosemia.
Publisher: Elsevier BV
Date: 03-2015
Publisher: Proceedings of the National Academy of Sciences
Date: 12-05-2009
Publisher: Oxford University Press (OUP)
Date: 1991
Abstract: Galactosemia is a human inborn error of galactose metabolism due to deficiency of galactose-1-phosphate uridyl transferase. In this paper, I describe the molecular analysis of genomic DNA, mRNA and protein from 11 different galactosemic patients by Southern, Northern and Western blotting. The results of these experiments lead me to conclude that galactosemia is caused mostly by missense mutations. The unusual preponderance of missense mutations in galactosemia led me to investigate its cause. I demonstrate that all 9 patients I investigated have detectable residual enzyme activity (ranging from 0.7-6.9% of normal). This finding is of potential importance in addressing the long-term complications of galactosemia.
Publisher: IMR Press
Date: 2007
DOI: 10.2741/2325
Abstract: Prostate cancer is the most common non-skin cancer and the second leading cause of cancer deaths among men in most Western countries. Despite its high morbidity and mortality, the etiology of prostate cancer remains obscure. Although compelling laboratory data suggest a role for androgens in prostate carcinogenesis, most epidemiologic data, including serological and genetic studies, are inconclusive. In this chapter, we review the status of serologic studies and discuss the importance of intra-prostatic hormone levels in possibly clarifying the often-contradictory data on serologic studies. To provide insights and directions for epidemiologic research on hormones and prostate cancer, this review centers on the molecular epidemiology of hormone-related genetic loci. These loci have been investigated in a number of studies to date and will undoubtedly expand even further as rich new genetic information sources and high-throughput genotyping and analysis methods become available. Due to the enormous number of these loci, we recommend careful analysis and cautious interpretation of studies of genetic markers, including microsatellites and single nucleotide polymorphisms (SNPs), as false positive and negative results are likely due to limited statistical power, multiple hypothesis testing, population stratification, or non-representative population s ling. This review also highlights the need for replication in various populations, as well as reasons for performing functional analyses of SNPs, a critical and often under-appreciated component of molecular epidemiologic investigations. The time is ripe for concerted, large-scale multidisciplinary investigations that incorporate molecular genetics, biochemistry, histopathology, and endocrinology into traditional epidemiologic studies. Such collaboration will lead to a deeper understanding of the etiologic pathways of prostate cancer, ultimately yielding better preventive, diagnostic, and therapeutic strategies.
Publisher: Elsevier BV
Date: 09-2004
DOI: 10.1016/J.YMGME.2004.07.014
Abstract: We have made remarkable progress in understanding the molecular bases of many Mendelian diseases over the past 2-3 decades. The current interest in discovering the molecular basis of complex diseases uses either linkage or candidate gene approaches. The latter often uses case/control (or case/cohort) study designs. We believe it is critically important to have a thorough understanding of SNP (single nucleotide) and haplotype function in such endeavors. Functionally neutral SNPs and haplotypes are probably best suited for linkage studies (far away from the locus of interest). Functionally relevant SNPs and haplotypes seem best suited for candidate gene approaches. The need for functional data may result in a renaissance of biochemical genetics with a new twist in the genomic era. We propose that the functional characterization of SNPs and haplotypes be advanced with great vigor for those genes with defined assayable phenotypes. These systematic investigations will involve classical biochemistry, modern genetics, and genomics and will probably also draw on newer technologies such as microarrays. In short, a renaissance of biochemical genetics will advance our understanding of complex diseases.
Publisher: Oxford University Press (OUP)
Date: 26-09-1988
Abstract: Small patches of identical amino acid sequences commonly occur in proteins that have the same function but are derived from evolutionarily distant organisms. Reverse translation of such patches into degenerate pools of oligonucleotides provide useful hybridization probes for cloning the gene for the corresponding protein from other organisms. Since the conserved patches of identical amino acid sequence are probably important for the protein's biological function, they are preferred targets for reverse genetic studies aimed at defining structure-function relationships.
Publisher: Springer Science and Business Media LLC
Date: 08-2019
Publisher: Oxford University Press (OUP)
Date: 18-07-2011
Publisher: Elsevier BV
Date: 1998
Abstract: The galactosemias are a series of three inborn errors of metabolism caused by deficiency of any one of the three human galactose-metabolic enzymes: galactokinase (GALK), galactose-1-phosphate uridyl transferase (GALT), and UDP-galactose 4' epimerase (GALE). We report here the characterization of the entire coding sequence of the GALE gene and screening for mutations in epimerase-deficient in iduals. The human GALE gene is about 4 kb in size and is ided into 11 exons on chromosome band 1p36. We have identified five mutations in the GALE gene of epimerase-deficient galactosemia patients. The patients were either homozygotes or compound heterozygotes for mutations. These results confirm that epimerase-deficiency galactosemia is the result of missense mutations in the GALE gene and indicate that the disease is characterized by extensive allelic heterogeneity.
Publisher: Future Medicine Ltd
Date: 04-2004
DOI: 10.1517/PHGS.5.3.283.29828
Abstract: Prostate cancer is the most common non-skin cancer in the US it is the second leading cause of death from cancer among US men, and the seventh leading cause of death in the US. This review examines the recent biochemical and pharmacogenetic literature related to prostate cancer, specifically that which focused on constitutional (‘germline’) single nucleotide polymorphisms at ‘functional candidate’ genes for prostate cancer. The investigations summarized in this review demonstrate the need to study the molecular genetics at these loci to rationally develop personalized medicine. In addition, the identification of somatic pharmacogenetic alterations in one of these loci suggests that this may also be a fruitful field of investigations with important clinical applications. Pharmacogenomic investigations of constitutional and tumor DNA may lead to significant advances in chemoprevention, presymptomatic diagnosis and improved treatment of prostate cancer.
Publisher: Wiley
Date: 15-08-1994
DOI: 10.1002/1097-0142(19940815)74:4<1309::AID-CNCR2820740421>3.0.CO;2-W
Abstract: Galactose metabolism may be a risk factor for ovarian cancer based upon evidence that galactose causes ovarian failure and that ovarian cancer arises from premature ovarian failure. This study examines galactose-1-phosphate uridyl transferase (GALT) activity in women with a family history of ovarian cancer (FOC) to determine if low GALT activity occurs in women who are at risk for but in whom ovarian cancer has not yet developed. The authors studied 106 premenopausal women (FOC patients) with one primary or two second-degree relatives with ovarian cancer compared with 116 age matched control subjects without a family history of ovarian cancer (FOC controls). All women completed questionnaires and had blood drawn to measure GALT activity and genotype. Mean erythrocyte GALT activity, in micromoles of hexose conversion per hour per gram of hemoglobin was 21.5 in FOC patients, significantly lower than the mean of 23.1 observed in FOC control subjects, (P = 0.001). FOC patients more frequently displayed the Duarte variant of galactosemia as detected by electrophoresis. In a subset of 87 patients and 113 control subjects for whom DNA was available, the allelelic frequency of the Duarte variant based upon molecular genetic detection of the N314D mutation that is associated with the Duarte variant was 15.5% among FOC cases compared with 7.5% among control subjects (P < 0.02). Galactose consumption did not differ between FOC patients and control subjects. Galactose metabolism differs between women with and without a family history of ovarian cancer, suggesting that it may be a genetic risk factor for ovarian cancer, possibly mediated through oocyte toxicity from galactose.
Publisher: Hindawi Limited
Date: 1992
Abstract: Classic galactosemia is an inborn error of galactose metabolism and results from deficiency of the ubiquitously expressed enzyme galactose-1-phosphate uridyltransferase (GALT). Nine missense mutations, three splicing mutations, three GALT protein polymorphisms, and one silent nucleotide substitution have been identified to date. Most of the disease-causing mutations are rare among patients. The most common mutation, Q188R, has a frequency of only one-fourth in the patient population examined. Three classes of disease-causing mutations have been reported: CRM+ missense mutations (the most common class), CRM- missense mutations, and splicing mutations. Thus, galactosemia is heterogeneous at the molecular level, which is noteworthy in light of the well-documented clinical variability observed in this disorder. It has also been shown that eight of nine galactosemia missense mutations occur in evolutionarily well-conserved domains, suggesting that they affect functionally and/or structurally important residues. In contrast, all protein polymorphisms alter variable amino acids which presumably are not important for the enzyme's function.
Publisher: Oxford University Press (OUP)
Date: 1993
DOI: 10.1093/HMG/2.3.325
Abstract: The clinical impact of different prophylactic anticoagulation regimens among hospitalized patients with coronavirus disease 2019 (COVID-19) remains unclear. We pooled evidence from available randomized controlled trials (RCTs) to provide insights on this topic. We searched for RCTs comparing treatment with an escalated-dose (intermediate-dose or therapeutic-dose) vs. a standard-dose prophylactic anticoagulation regimen in critically and non-critically ill COVID-19 patients requiring hospitalization and without a formal indication for anticoagulation. The primary efficacy endpoint was all-cause death, and the primary safety endpoint was major bleeding. Seven RCTs were identified, including 5154 patients followed on an average of 33 days. Compared to standard-dose prophylactic anticoagulation, escalated-dose prophylactic anticoagulation was not associated with a reduction of all-cause death [17.8% vs. 18.6% risk ratio (RR) 0.96, 95% confidence interval (CI) 0.78-1.18] but was associated with an increase in major bleeding (2.4% vs. 1.4% RR 1.73, 95%CI 1.15-2.60). Compared to prophylactic anticoagulation used at a standard dose, an escalated dose was associated with lower rates of venous thromboembolism (2.5% vs. 4.7% RR 0.55, 95%CI 0.41-0.74) without a significant effect on myocardial infarction (RR 0.80, 95%CI 0.47-1.36), stroke (RR 0.94, 95%CI 0.43-2.09), or systemic arterial embolism (RR 1.20, 95%CI 0.29-4.95). There were no significant interactions in the subgroup analysis for critically and non-critically ill patients. Our findings provide comprehensive and high-quality evidence for the use of standard-dose prophylactic anticoagulation over an escalated-dose regimen as routine standard of care for hospitalized patients with COVID-19 who do not have an indication for therapeutic anticoagulation, irrespective of disease severity. This study is registered in PROSPERO (CRD42021257203).
Publisher: Elsevier BV
Date: 07-1996
Publisher: Springer Science and Business Media LLC
Date: 10-1994
DOI: 10.1007/BF00201593
Publisher: Elsevier BV
Date: 05-2008
Publisher: Elsevier BV
Date: 09-2000
Publisher: Elsevier BV
Date: 11-2006
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2004
Publisher: American Chemical Society (ACS)
Date: 06-1992
DOI: 10.1021/BI00139A002
Abstract: We report here the molecular characterization of two galactosemia mutations, L74P and F171S, and one polymorphism, S135L, in human galactose-1-phosphate uridyltransferase (GALT). Both galactosemia mutations result in reduced enzymatic activity when reconstructed in the cDNA and overexpressed. The polymorphism, in contrast, has near normal activity. Both mutations affect evolutionarily conserved residues, suggesting that they are functionally important, while the polymorphism occurs in a nonconserved domain which is presumably not critical for enzymatic function. The F171S mutation is close to the putative active-site nucleophile. Our data further support the notion of molecular heterogeneity of galactosemia and suggest that galactosemia mutations and GALT polymorphisms may be useful tools in highlighting different functional domains in human GALT.
Publisher: Hindawi Limited
Date: 1996
DOI: 10.1002/(SICI)1098-1004(1996)8:4<369::AID-HUMU12>3.0.CO;2-0
Abstract: Playgrounds are designed to be a safe, enjoyable, and effective means to promote physical activity in children and adolescents. The purpose of this study was to conduct a meta-analysis to determine the effectiveness of playground interventions for improving accelerometer-assessed ambulatory moderate-to-vigorous physical activity (MVPA) and to identify common aspects of playground interventions that may be beneficial to promote behavior change. An internet database search was performed. The final analyzed s le of studies was obtained from several criteria, including being a playground-based intervention targeting children or adolescents, having a control or comparison group, having an accelerometer-assessed MVPA outcome target variable, and reporting of the mean difference scores' variability. A random-effects model meta-analysis was employed to obtain pooled effect sizes. Ten studies (
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/J.UROLONC.2004.12.014
Abstract: The prostate gland is an androgen-dependent, and polymorphisms in androgen synthesis gene steroid 5-alpha reductase type II (SRD5A2) may be associated with benign prostatic hyperplasia (BPH) and prostate cancer. We evaluated the association between 3 polymorphisms in the SRD5A2 gene (2 single nucleotide polymorphism: alanine-49 to threonine [A49T] and valine-89 to leucine [V89L], and a (TA)n dinucleotide repeat in the 3' untranslated region), and BPH and prostate cancer within a multiethnic population. Men between 60 and 86 years of age were recruited from annual prostate cancer screening programs and from a large urology clinic. Unconditional logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (95% CI). We genotyped 606 men (412 Hispanic, 98 Caucasian, 73 African-American, and 23 Asian), of whom 100 had prostate cancer, 393 had BPH (280 symptomatic and 113 asymptomatic), and 113 had normal prostates. Overall, the V89L variant was associated with prostate cancer the OR for men with the leucine-leucine (LL) genotype compared to men with the valine-valine (VV) genotype was 4.47 (95% CI, 1.24-16.18). This association was stronger in Hispanics (OR=7.26 95% CI: 1.49-35.47). Although V89L was nonsignificantly associated with BPH in overall population, BPH risk increased significantly with the number of L alleles in Hispanics (P for trend=0.03). Prostate cancer and BPH were not associated with the alanine-49 to threonine single nucleotide polymorphism and the (TA)n repeat. These results suggest that the SRD5A2 gene may play an important role in both BPH and prostate cancer.
Publisher: IMR Press
Date: 2005
DOI: 10.2741/1745
Abstract: Significant evidence implicates androgens in prostate cancer etiology. We review recent data with regard to the association between several allelic variants of specific androgen-metabolic genes and the predisposition to prostate cancer. We also review the emerging evidence regarding the role of genetic variants of these genes as well as the androgen receptor in prostate cancer progression. Based on the prostate cancer paradigm, we propose that a multidisciplinary attack on the problem--involving biochemistry, genetics, pharmacogenetics, endocrinology and molecular epidemiology--may be important for the understanding and successful treatment of complex (in terms of etiology) human diseases.
Publisher: Springer New York
Date: 2010
Publisher: Public Library of Science (PLoS)
Date: 08-05-2015
Publisher: Springer Science and Business Media LLC
Date: 02-1994
DOI: 10.1007/BF00210604
Publisher: Springer Science and Business Media LLC
Date: 23-12-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2004
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-1999
Publisher: Wiley
Date: 15-09-1997
DOI: 10.1002/(SICI)1097-0045(19970915)33:1<9::AID-PROS2>3.0.CO;2-H
Abstract: Elevated prostatic dihydrotestosterone (DHT) has been suggested to increase the risk of prostate cancer. The HSD3B2 gene encodes the type II 3 beta-hydroxysteroid dehydrogenase: one of two enzymes that initiate the inactivation of DHT. Thus, the HSD3B2 gene is a candidate gene for predisposition to prostate cancer. We have determine the distribution of a complex dinucleotide repeat in the HSD3B2 gene in high-risk African-Americans, intermediate-risk Euro-Americans, and low-risk Asians. Genomic DNA from 312 in iduals was lified by polymerase chain reaction (PCR) and analyzed by electrophoresis on denaturing polyacrylamide gels. We have found that certain alleles are either unique to or much more common in either African-Americans, Asians, or Euro-Americans. Our data also substantially expand the number of alleles reported for the complex dinucleotide repeat polymorphism in the HSD3B2 gene. Our report demonstrates substantial genetic variation in the HSD3B2 gene. We hypothesize that allelic variants of the HSD3B2 gene may play a role in predisposition to prostate cancer, and in explaining the substantial racial/ethnic variation in risk.
Publisher: Springer Science and Business Media LLC
Date: 23-08-2004
Publisher: Informa UK Limited
Date: 1998
DOI: 10.3109/03602539808996320
Abstract: To establish a scoring system to predict the residual back pain after percutaneous kyphoplasty (PKP) for osteoporotic vertebral compression fracture (OVCF). We retrospectively reviewed the clinical records of 98 patients who were diagnosed of single-vertebral OVCF and underwent PKP surgery in our department from January 2015 to December 2017. The following clinical characteristics including age, gender, disease course, fracture location, fracture type, segmental kyphosis, and bone cement volume were all recorded, and the effects of these factors on postoperative pain (at 1-month and 6-month postoperative) were also analyzed respectively. Based on 6-month postoperative VAS score, the included patients were ided into two groups, namely the residual back pain group (19 patients) and the non-residual back pain group (79 patients). The independent risk factors of residual back pain after PKP were screened and the scoring system was established by the multivariate logistic regression analysis. The performance of this scoring system was also prospectively validated using the clinical data of 45 patients with single-vertebral OVCF from January 2018 to December 2019. The scoring system was consist of five clinical characteristics which were confirmed as significant predictors of residual back pain after PKP, namely, age ≥60 years ( This novel scoring system showed satisfactory diagnostic efficacy in predicting residual back pain after PKP for single-vertebral OVCF. Patients with the score of 5-9 had a high risk of postoperative residual back pain, while the patients with score of 0-4 was low.
Publisher: Oxford University Press (OUP)
Date: 15-10-2002
DOI: 10.1093/AJE/KWF104
Abstract: Deficiency in the galactose-1-phosphate uridyltransferase (GALT) enzyme results in accumulation of galactose and its metabolites in the ovary (Am J Epidemiol 1989 :904-10). Galactose may raise gonadotropin levels, resulting in proliferation of ovarian epithelium. In 1993-1999, the authors conducted a population-based case-control study of ovarian cancer in Hawaii and Los Angeles, California, to examine the hypothesis that reduced GALT activity is associated with an increased risk of ovarian cancer. A total of 239 ovarian cancer cases and 244 population controls were interviewed. A blood s le was collected to measure levels of GALT and to assay for the N314D (A940G) polymorphism of the GALT gene. Covariate-adjusted mean GALT activity was similar between cases (23.8 micro mol per hour/g hemoglobin (Hb)) and controls (23.7 micro mol per hour/g Hb) (p = 0.83). No evidence was found for a dose-response relation between the odds ratios for ovarian cancer and GALT activity or the ratio of lactose intake to GALT activity. The risk associated with the presence of at least one variant Asp314 allele was 0.77 (95% confidence interval: 0.42, 1.41). This study did not support the hypothesis that reduced galactose metabolism is a risk factor for ovarian cancer, although increased GALT activity attenuated the inverse association of oral contraceptive pill use with risk.
Publisher: Springer Science and Business Media LLC
Date: 05-1996
DOI: 10.1007/BF02281889
Publisher: Wiley
Date: 27-03-2013
DOI: 10.1007/S10545-013-9602-6
Abstract: Phenylketonuria (PKU, OMIM 261600) is an autosomal recessive inborn error of phenylalanine metabolism, predominantly caused by mutations in the phenylalanine hydroxylase (PAH) gene. Approximately 10% of patients carry a nonsense mutation, which results in an inactive or unstable truncated protein. In some genetic disorders, including cystic fibrosis and Duchenne muscular dystrophy, restoration of full-length protein has been achieved by aminoglycoside antibiotics, such as gentamicin and G-418 (Geneticin). More recently, nonsense read-through has been induced at greater rates using a non-aminoglycoside drug, PTC124 (Ataluren), which has the advantage of being non-toxic in contrast to the antibiotics. The efficacy of read-through induced by three compounds, aminoglycosides G418 and gentamicin, and PTC124 were evaluated for four nonsense mutations of PAH in an in vitro expression system in two mammalian cell lines (COS-7 and HEK293). The production of full-length PAH was investigated using western blotting and the functionality confirmed by enzyme activity. Gentamicin and G-418 induced read-through of nonsense PAH mutations in HEK293 cells. The read-through product partially restored enzymatic activity, which was significantly less than that of wild-type, but comparable to a missense mutation of PAH associated with less severe forms of PKU. Treatment with PTC124 up to 100 μM did not result in full-length PAH polypeptide. Nonsense read-through drugs are a potential form of treatment for PKU, although the high dosage of aminoglycosides used is not appropriate in a clinical setting. In vitro studies with new non-toxic read-through agents as well as in vivo studies would also be essential to determine the extent of read-through required to restore normal phenylalanine levels.
Publisher: Springer Science and Business Media LLC
Date: 10-06-2020
Publisher: Elsevier BV
Date: 11-0010
Abstract: Galactose metabolism in all organisms is catalyzed by three enzymatic steps: the galactokinase, galactose-1-phosphate uridyltransferase, and UDP galactose 4'-epimerase reactions. We report here the molecular cloning, characterization, and mapping of a full-length cDNA encoding human UDP-galactose 4'-epimerase (GALE). Our cDNA is 1488 bp long and matches the mRNA size of 1.5 kg detected in fibroblasts and lymphoblasts. The human GALE cDNA encodes a predicted protein of 348 amino acids with a molecular mass of 38,266. The human GALE enzyme is 87% identical to the rat protein, 53% identical to the homologous GAL10 protein from the yeast Kluyveromyces lactis, and 51% identical to the galE protein from the prokaryote Escherichia coli. This extraordinary degree of sequence identity has allowed us to build a homology model of the human protein based on the bacterial crystal structure. This predicted human structure is very similar to the E. coli galE enzyme, suggesting that both enzymes use similar mechanisms. The human gene encoding GALE maps, as expected, to a single locus on chromosome 1 and appears to be compact. The human GALE gene is structurally intact in 19 patients with epimerase-deficiency galactosemia, an inborn error of metabolism secondary to GALE deficiency. Therefore, we propose that this disorder is due to small mutations within the gene.
Publisher: Wiley
Date: 1996
DOI: 10.1002/(SICI)1097-4644(1996)25+<15::AID-JCB2>3.0.CO;2-5
Abstract: The past four decades of epidemiological research have yielded valuable information on the risks of populations to environmental exposures such as tobacco, asbestos, and dietary components. Prevention efforts have been focused on large-scale population-based interventions to minimize exposure to such external carcinogens. While some cancers are beginning to show a decline from changing environmental exposures, hormone-related cancers, such as breast and prostate, are becoming more prevalent. The development of these cancers appears to be closely related to endogenous exposures to circulating steroid hormones. Although prevention trials using antihormone agents are proving successful in some instances, the long-term control of these cancers necessitates a clearer understanding of the metabolism and transport of the relevant hormone in vivo. The revolution in molecular biology has provided powerful genetic tools for evaluating mechanisms of cancer causation as well as the potential to better define in idual susceptibility. Using tobacco exposure as an ex le, we and others have demonstrated that polymorphisms in genes controlling aromatic amine metabolism provide at least a partial explanation for ethnic and in idual susceptibility to bladder cancer. Similar studies have examined genetic polymorphisms in the metabolism of tobacco smoke and lung cancer risk, red meat and colorectal cancer, and aflatoxin and liver cancer. Our current studies have pursued a similar paradigm of genetic polymorphism and in idual cancer susceptibility in prostate and breast carcinogenesis. We are evaluating polymorphisms in the steroid 5 alpha-reductase type II and androgen receptor genes in relation to prostate cancer based on the evidence that intracellular dihydrotestosterone is the critical "carcinogen." We are pursuing genetic polymorphisms affecting estradiol metabolism, including those in the 17 beta-hydroxysteroid dehydrogenase 2 and estrogen receptor genes as they relate to susceptibility to breast cancer. The potential role of a polymorphism in the cytochrome P450c 17 alpha gene in both breast and prostate cancers is also being examined.
Publisher: IMR Press
Date: 1999
DOI: 10.2741/REICHARDT
Abstract: Prostate cancer will be diagnosed in about 179,300 men in the US in 1999 alone. Some 37,000 in iduals die of this disease annually. Prostate cancer is characterized by a substantial racial/ethnic variation in risk: highest in African-American men, lowest in Asian men and intermediate in Caucasian and Latino men. We set out to investigate as our central hypothesis that genetic variants of genes involved in androgen metabolism by themselves and in combination significantly contribute to prostate cancer progression and its racial/ethnic variation. Specifically, we examined the hypothesis that DNA sequence (allelic) variations in the type II (or prostatic) steroid 5alpha-reductase (SRD5A2) gene contribute substantially to the risk and progression of prostate cancer particularly across racial/ethnic lines. The "candidate gene", SRD5A2, was chosen because the reaction product [i.e. dihydrotestosterone (DHT)] of the enzyme encoded by this gene modulates directly cell ision in the prostate. DHT binds to the androgen receptor (AR) and the DHT-AR complex leads to the transactivation of a variety of genes which ultimately modulates cell ision in the prostate. Epidemiologic evidence suggests that variation in DHT levels play an important role in risk of prostate cancer. Thus, steroid 5alpha-reductase activity encoded by SRD5A2 variant alleles may be important in regulating intraprostatic DHT steady state levels by controlling its biosynthesis. A second candidate gene, the type II 3beta-hydroxysteroid dehydrogenase (HSD3B2) gene, encodes the enzyme that initiates the metabolic inactivation of testosterone (T) to DHT. We have identified allelic variants in this gene as well. Here I review our strategy for identifying candidate genes for prostate cancer, a multifactorial disease. I summarize the significant findings, particularly of allelic variants in the HSD3B2 and SRD5A2 genes and discuss how they by themselves, in combination and through interactions with the environment may play a role in prostate cancer predisposition and its progression. Our approach, a multidisciplinary genomic genetic (GEN GEN) attack on the problem, may be useful in the analysis of other complex phenotypes as well.
Publisher: Bioscientifica
Date: 08-2004
Abstract: The oxidation and isomerization of 3beta-hydroxy-5-ene steroids into keto-4-ene steroids, a pivotal step in the synthesis of all hormonal steroids, is catalyzed by several isoforms of 3beta-hydroxysteroid dehydrogenase. In humans, two highly homologous isoforms exist, type I expressed by the HSD3B1 gene in peripheral tissues, and type II expressed by the HSD3B2 gene in steroidogenic organs. Previously, it was shown that the HSD3B1 gene 3beta1-A element, encompassing 24 nucleotides of intron 1 not perfectly conserved between the two genes and overlapping with a conserved TG box, contributes to maximal basal promoter activity by binding the ubiquitous and unidentified 3beta1-A transcription factor. In this study for the first time we report that similarly, the HSD3B2 gene intron 1 is required for maximal basal promoter activity in reporter gene analyses, as lack of intron 1 results in a 4- to 10-fold reduction in promoter activity. Mutational analysis in gel shift assays revealed that the 3beta1-A factor binds both the HSD3B2 and HSD3B1 gene intron 1 by requiring only seven nucleotides of a conserved segment within the 3beta1-A element. By competition analysis and use of anti-YY1 antibody in both gel shift and Western blot experiments, we identified the 3beta1-A protein as the ubiquitous transcription factor YY1. In addition, we have characterized another similar YY1 binding site differently located with respect to the 3beta1-A element in both genes. Deletion and mutational analysis in transient transfections experiments revealed that contrarily to as previously shown for the HSD3B1 gene, lack of YY1 binding to the type II 3beta1-A element only results in a marginal reduction of basal promoter activity. Instead, YY1 binding to the second site, placed 35 bp downstream from the 3beta1-A element, strongly activates the HSD3B2 gene basal promoter activity, as preventing YY1 binding to this region caused a 50% decrease of basal transcription. Complete abrogation of YY1 binding within type II intron 1 resulted in a gene reporter activity identical to a reporter construct lacking the whole intron 1. These results designate YY1 as the factor responsible for the intron 1-mediated boost of the HSD3B2 gene basal promoter activity. Similarities and dissimilarities between YY1 binding within the HSD3B1 and HSD3B2 gene intron 1 are discussed involving the conserved intron 1 TG box, that suggests different mechanisms are implicated in the YY1-mediated stimulation of these two genes basal promoter activity.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-0001
Publisher: Elsevier BV
Date: 06-2018
Publisher: American Association for the Advancement of Science (AAAS)
Date: 09-2017
Publisher: Springer Science and Business Media LLC
Date: 20-11-2015
Publisher: Hindawi Limited
Date: 2009
DOI: 10.1002/HUMU.20810
Publisher: Wiley
Date: 17-06-2002
DOI: 10.1002/PROS.10108
Abstract: Prostate cancer is the most commonly diagnosed non-skin cancer in men in most western countries. Despite the high morbidity and mortality from prostate cancer, its etiology remains obscure. Although compelling laboratory data suggest a role for androgens in prostate carcinogenesis, most epidemiologic data on humans are inconclusive. To provide insights and directions for future epidemiologic research on hormones and prostate cancer, this review focuses on current perspectives of serum-based studies and polymorphisms in relevant hormone-related genes. We highlight the importance of methodologic studies and investigations of hormone levels in the prostatic tissue to help clarify the often-contradictory data on serologic studies. We recommend careful analysis and cautious interpretation of studies of genetic markers, including repeats and single nucleotide polymorphisms (SNPs), as false positive and negative results may arise in many current and future studies with limited statistical power and non-representative s les from the population. The review also highlights the reasons to perform functional analyses of SNPs, a critical and often under-appreciated component of molecular epidemiologic investigations. The time is ripe for large-scale multidisciplinary investigations that incorporate molecular genetics, biochemistry, histopathology, and endocrinology into traditional epidemiologic studies. Such collaboration will lead to a deeper understanding of the etiologic pathways of prostate cancer, ultimately yielding better preventive, diagnostic, and therapeutic strategies.
Publisher: Future Medicine Ltd
Date: 02-2001
Abstract: Prostate cancer (PCa) and benign prostatic hypertrophy (BPH) are two common and growing public health problems in the Western world. We review here the recent biochemical and pharmacogenetic literature related to these two prostatic disorders. We focus first on constitutional (‘germline’) single nucleotide polymorphism (SNPs) at the steroid 5α-reductase (SRD5A2) locus, which encodes the human prostatic (or Type II) steroid 5α-reductase enzyme. The investigations reviewed point to several uses of personalised medicine at the SRD5A2 locus. In addition, we report on recent identification of somatic pharmacogenetic alterations at the androgen receptor (AR) locus, which encodes the human androgen receptor, suggesting that this also may be a fruitful field of investigation, with important clinical applications. Pharmacogenomic investigation of constitutional and somatic DNA changes in human genes predisposing to cancer may lead to significant advances in chemoprevention, presymptomatic diagnosis and improved treatment of PCa.
Publisher: Informa UK Limited
Date: 06-2012
DOI: 10.1586/ERA.12.53
Abstract: Vitamin D has long been known for its physiological role in mineral homeostasis through its actions on the intestines, kidneys, parathyroid glands and bone. However, recent observations of antiproliferative, prodifferentiating and antiangiogenic effects elicited by the bioactive form of vitamin D (1,25[OH](2)D(3)) in a broad range of cancers is less well understood. Here, we review the increasing epidemiological and experimental evidence that supports the development of 1,25(OH)(2)D(3) and vitamin D analogs as preventative and therapeutic anticancer agents. Furthermore, this review summarizes the preclinical and clinical studies of vitamin D and its analogs over the past decade, indicating the current problems of dose-limiting toxicity from hypercalcemia and large interpatient variability in pharmacokinetics. A better understanding of how genetic variants influence vitamin D status should not only improve cancer risk predictions, but also promote the development of vitamin D analogs with more specific actions to improve therapeutic outcomes.
Publisher: Future Medicine Ltd
Date: 06-2006
Abstract: Genomic approaches to cancer are beginning to have an important impact in unraveling the complex etiologies of this disease, as well as allowing us to rationally treat afflicted patients. In this article, we will focus largely on genomic approaches to breast and prostate cancer susceptibility, as well as pharmacogenomic approaches to treatment. Current genomic approaches to cancer susceptibility have led to some significant, if not spectacular, successes which include breast cancer. More modest achievements, if not outright failures, such as in prostate cancer, are also notable and will be discussed further. We propose interdisciplinary approaches involving basic, clinical and population scientists to vigorously attack the cancer problem scientifically and with more organization. We highlight recent successes and suggest new approaches with a personal, if not provocative, perspective.
Publisher: Springer Science and Business Media LLC
Date: 2002
Abstract: Previous studies have suggested that high levels of galactose consumption and/or low levels of galactose-I-phosphate uridyl transferase (GALT) activity may result in an increased risk of epithelial ovarian cancer. Similarly, some have reported that carriers of the N314D (asparagine at codon 314 replaced by aspartate) GALT polymorphism, which can be associated with low GALT activity, may have a higher risk of ovarian cancer. We examined these issues as part of a large case-control study of ovarian cancer conducted in Los Angeles between 1992 and 1998. A total of 1,439 histologically confirmed borderline and invasive ovarian cancer cases among English-speaking non-Asian women were ascertained through the population-based cancer registry for Los Angeles County and completed in-person interviews were obtained from 689 of these (78% of cases approached). Controls consisted of 645 English-speaking non-Asian women with at least one intact ovary matched to cases on race/ethnicity (African-American, Latina, non-Latina White), date of birth (+/-3 years), and neighborhood of residence. Interviewer-administered questionnaires included information on reproductive factors, exogenous hormone use, medical history, and diet. Dietary information for the year before each case's diagnosis (and the same period for her matched control) was obtained using a self-administered food-frequency questionnaire. Blood s les were obtained from 452 controls, 136 cases with borderline ovarian cancer, and 312 cases with invasive ovarian cancer. The N314D polymorphism was characterized using PCR-RFLP and GALT enzyme activity, and was determined for a s le of the subjects with GALT genotype using an erythrocyte-based radioactive enzyme assay. We found no effect of N314D GALT genotype on the risk of borderline ovarian cancer (odds ratio (OR)=0.91 95% confidence interval (CI)=0.54-1.6) or invasive ovarian cancer (OR=0.78 95% CI= 0.53-1.2). Neither did we observe a relationship between GALT activity or lactose/galactose intake and risk of borderline or invasive ovarian cancer. Among N314D carriers, galactose consumption was associated with an increased risk of borderline (OR = 2.7, p = 0.01), but not invasive (OR = 1.2, p = 0.34), ovarian cancer however, this result was based on only 24 N314D-positive borderline cases. Differences in galactose intake and GALT metabolism do not contribute significantly to the risk of ovarian cancer. There is some evidence that galactose intake may play a role in the development of borderline ovarian cancer among women who carry the uncommon GALT N314D polymorphism. More data are needed if this latter suggestion is to be definitively addressed.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2010
Publisher: Hindawi Limited
Date: 1999
DOI: 10.1002/(SICI)1098-1004(1999)13:6<417::AID-HUMU1>3.0.CO;2-0
Publisher: Elsevier BV
Date: 04-2019
Publisher: Elsevier BV
Date: 03-1992
DOI: 10.1016/0888-7543(92)90453-Y
Abstract: We report the molecular characterization of two novel galactosemia mutations that exhibit different molecular phenotypes. Both are of the missense type with low or no residual enzyme activity. The R148W mutation results in an unstable protein, although messenger RNA is still produced. In contrast, the L195P mutation produces stable but inactive immunoreactive protein. The R148W mutation alters an amino acid that is not evolutionarily conserved, while the L195P mutation affects a well-conserved residue nine amino acids down-stream from the putative active site nucleophile. These mutations provide evidence that different mechanisms can result in galactosemia: destabilizing mutations in any given area of the protein and missense mutations in conserved domains of the enzyme resulting in low or no activity. These two mutant alleles represent the fifth and sixth galactosemia mutations and confirm the hypothesis that galactosemia results from a multiplicity of mutations at the molecular level.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2008
Publisher: Springer Science and Business Media LLC
Date: 14-01-2016
Publisher: Springer Science and Business Media LLC
Date: 12-1995
DOI: 10.1007/BF00210306
Abstract: Antibiotic resistance is spreading at an alarming rate globally, mainly because of antibiotics misuse. The World Health Organization developed guidelines for the rational use of antibiotics to prevent antibiotic misuse and reduce the potential development of antibiotic resistance. Although many countries adhere to these guidelines and have contextualized them to their needs, data on antibiotics use are limited in African countries, particularly in South Sudan. This study explored prescription patterns and use of antibiotics at Juba Teaching Hospital (JTH) to clarify the potential for antibiotic resistance in South Sudan. We conducted a retrospective, cross-sectional study of archived patient data from 2016 to determine the prevalence of inappropriate antibiotics use at JTH. We used methodology developed in a previous study to assess the appropriate use of antibiotics. The study s le comprised 384 files. After reviewing and cleaning the files, 316 files were included in our analyses. This study was approved by the South Sudan Ministry of Health Ethics Review Board (approval number: MoH/ERB 51/2018) and all procedures were consistent with the Declaration of Helsinki. Antibiotics use was highest in the medical ward (75.4%). Most antibiotics prescriptions were for infectious diseases (23.7%), followed by ailments affecting the digestive system (19.9%). Commonly prescribed antibiotics were ceftriaxone (21.2%) and metronidazole (20.0%). The mean number of antibiotics prescribed per patient encounter was 2.09 (95% confidence interval: 1.98-2.19). Most files (n=233, 70.57%) demonstrated incorrect use of antibiotics with 78.8% (n=249) of prescriptions being inappropriate (misuse). This study revealed a high level of inappropriate antibiotics use at JTH despite the existence of local guidelines, which suggested there was an increased risk for antibiotic resistance. Therefore, it is necessary to introduce antibiotic stewardship activity, along with continuous national surveillance. Enforcement of guidelines to reduce irrational antibiotics use may reduce the risk for antibiotic resistance.
Publisher: Wiley
Date: 1994
DOI: 10.1007/BF00735422
Publisher: Wiley
Date: 10-05-2016
DOI: 10.1002/CNCR.30071
Publisher: Bioscientifica
Date: 06-2005
DOI: 10.1677/JME.1.01725
Abstract: Human steroid 5α-reductase type II is a prostate-specific, membrane-associated enzyme that catalyzes the conversion of testosterone to dihydrotestosterone, the most potent androgen in the prostate gland. Genetic variants of this enzyme have been associated with both the development and the progression of prostate cancer. Both finasteride and dutasteride are competitive inhibitors of the type II steroid 5α-reductase that have been effectively used for the treatment of benign prostatic hyperplasia. Finasteride has also been successfully utilized for prostate cancer chemoprevention. We here investigate 5α-reductase inhibition assays in vitro to measure the effect of incubation time on the apparent inhibition constant ( K i ) for both constitutional and somatic (prostate cancer) enzyme variants. Our systematic pharmacogenetic analysis shows that both finasteride and dutasteride are slow, time-dependent inhibitors of steroid 5α-reductase type II, and that the inhibition kinetics depend on the 5α-reductase genotype. We also show that, overall, dutasteride is a more efficient steroid 5α-reductase inhibitor than finasteride. Based on our data, we are able to map areas of the enzyme that are responsible for this time-dependent inhibition for either (or both) enzyme inhibitor(s). This comprehensive pharmacogenetic analysis of steroid 5α-reductase variants unveiled significant pharmacogenetic variation for both finasteride and dutasteride and thus should be taken into account when designing protocols for treatment and/or chemoprevention of prostatic diseases with either one of these 5α-reductase inhibitors since there is considerable pharmacogenetic variation for both drugs.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2004
Publisher: American Association for Cancer Research (AACR)
Date: 12-2010
DOI: 10.1158/1940-6207.CAPR-09-0256
Abstract: Large clinical trials provide a tremendous opportunity to integrate correlative, comprehensive biological studies with invaluable repositories of biospecimens and clinical and other data from the trial. The Prostate Cancer Prevention Trial (PCPT) was a phase III randomized, double-blind, placebo-controlled clinical trial of finasteride in 18,882 men. Clinical data and blood and tissue specimens were collected at baseline and throughout the study, offering an opportunity to create a program project to investigate hypotheses related to the biology underlying the PCPT findings as well as the etiology and risk of prostate cancer. The transition of the randomized PCPT into this translational and epidemiologic scientific investigation required extensive planning and coordination. Five in idual but interrelated projects were brought together with the underlying program theme of the genetic, metabolic, and environmental factors associated with the risks of overall and high-grade prostate cancer and how these factors affected the efficacy of finasteride in preventing cancer. All projects with serum-based measures use a single, shared, nested case–control s le of participants so that each subject provides a more complete biomarker and genetic profile for the evaluation of joint effects of these factors. Strengths of this program include the following: 1) the control group contains only men who are negative for biopsy-detected cancer, 2) the statistical methods to evaluate associations of risk factors with disease are shared across all projects, 3) the large number of cancer cases with fully characterized genetic, metabolic, and behavioral exposures, 4) a central pathology core histopathologically classified the prostate cancer, and 5) cancer cases identified during the PCPT reflect the characteristics of cases currently being detected in the prostate-specific antigen screening era, leading to contemporary and highly relevant results. This article describes the comprehensive methodology and multidisciplinary collaborations, both national and international, essential to a major risk-modeling research program. We provide a framework for doing collaborative research in an international setting structured around a common theme of a clinical trial. Cancer Prev Res 3(12) 1523–33. ©2010 AACR.
Publisher: Elsevier BV
Date: 2000
Publisher: IMR Press
Date: 1999
DOI: 10.2741/A456
Publisher: Springer Science and Business Media LLC
Date: 15-10-2019
Publisher: Elsevier BV
Date: 12-2007
Publisher: Future Medicine Ltd
Date: 08-2008
Abstract: The pharmacogenetics of cancer treatment has been aimed at identifying genetic components of interin idual variability in patients’ response to cancer chemotherapy and toxicity. This, in turn, will establish an in idually based treatment, and also elucidate the molecular basis of the treatment regimen for further improvements. Brain cancer is an instructive ex le for the potential contributions of pharmacogenomics to improved treatment in the 21st century. Patients with oligodendrogliomas have benefited from phamacogenomics, as there is a clear relationship between response to chemotherapy and chromosomal profile. Drug efficacy, safety and response could be improved by using pharmacogenomics to identify genetic markers that differentiate responder from nonresponder patient groups, as well as identifying patients likely to develop adverse drug reactions. This review will focus on how pharmacogenomics by microarray studies may lead to much more accurate tumor classification, drug and biomarker discovery, and drug efficacy testing. We will discuss relevant scientific advances in pharmacogenetics for more personalized chemotherapy.
Publisher: Oxford University Press (OUP)
Date: 07-05-2008
DOI: 10.1093/HMG/DDN145
Publisher: Hindawi Limited
Date: 02-2015
DOI: 10.1002/HUMU.22735
Abstract: It has been established that up to 8.3% of the biallelic coding SNPs present in dbSNP are actually artefactual polymorphism-like errors, previously termed single nucleotide differences, or SNDs. In this study, a previous analysis of SNPs in dbSNP was extended and updated to examine how the incidence of SNDs has changed over an intervening five year period. The incidence of SNDs was found to be lower than in the previous analysis at 2.2% of all biallelic SNPs. There was only a modest reduction in the percentage of SNDs in the original set of biallelic coding SNPs tested. This suggests that the overall reduction in the incidence of SNDs over the intervening 5-year period is related to an improvement in SNP detection methods and more rigorous curation, rather than efforts to ameliorate the presence of SNDs. We note that SNDs contaminating the dbSNP may lead to erroneous conclusions on human conditions.
Publisher: Elsevier BV
Date: 11-2003
Publisher: Springer Science and Business Media LLC
Date: 12-05-2020
DOI: 10.1186/S40246-020-00267-3
Abstract: The recent coronavirus disease (COVID-19), caused by SARS-CoV-2, is inarguably the most challenging coronavirus outbreak relative to the previous outbreaks involving SARS-CoV and MERS-CoV. With the number of COVID-19 cases now exceeding 2 million worldwide, it is apparent that (i) transmission of SARS-CoV-2 is very high and (ii) there are large variations in disease severity, one component of which may be genetic variability in the response to the virus. Controlling current rates of infection and combating future waves require a better understanding of the routes of exposure to SARS-CoV-2 and the underlying genomic susceptibility to this disease. In this mini-review, we highlight possible genetic determinants of COVID-19 and the contribution of aerosol exposure as a potentially important transmission route of SARS-CoV-2.
Publisher: Wiley
Date: 04-1995
DOI: 10.1002/1097-0142(19950401)75:7+<1778::AID-CNCR2820751605>3.0.CO;2-J
Publisher: Future Medicine Ltd
Date: 06-2015
DOI: 10.2217/FON.15.72
Abstract: ABSTRACT Aim: Neurofibromatosis type 2 (NF2)-associated vestibular schwannomas have variable size at presentation which presents a unique challenge in NF2 patient management. Therefore, we investigated the molecular signature characteristic of the differences in size for improved in idualized precise therapy. Materials & methods: RNA expression analysis was performed on 15 small and 27 large NF2-associated vestibular schwannoma tumors using a microarray analyzing over 47,000 transcripts. Results: A signature of 11 genes was found to be correlated with NF2 tumor size. Conclusion: We have identified the genetic hallmark that differentiates large NF2-associated tumors from smaller tumors. This is the first time that these genes have been shown to be the hallmark for NF2 tumor size.
Publisher: Hindawi Limited
Date: 2000
DOI: 10.1155/2000/683607
Abstract: We have investigated the contributions of three polymorphic markers in the SRD5A2 gene to prostate cancer in a group of Italian patients. We have genotyped cases and controls for a polymorphic (TA) n dinucleotide repeat and two functional substitutions, A49T and V89L, substituting respectively alanine with threonine at codon 49, and valine to leucine at codon 89. We found a substantially increased but not significant risk associated with the 49T mutation and a reduction of risk for the V89L substitution. In conclusion, we report on preliminary evidence for both increased and decreased risk associated with separate markers at this locus.
Publisher: Elsevier BV
Date: 03-1998
DOI: 10.1016/S0168-9525(97)01379-6
Abstract: Cloning and characterization of all three human galactose-metabolic genes (GALK, GALT and GALE) has led to the identification of a number of mutations which are generally of the missense type in patients with galactosemia, an inborn error of metabolism. The predominance of missense mutations is interesting, considering the general importance of galactose metabolism for cellular energy production and proper modification of glycoproteins and glycolipids. Abnormalities in both of these macromolecules have been described in transferase-deficiency galactosemia, the most common and best-studied form of galactosemia. Thus, the parallel biochemical and molecular genetic analyses of human galactose metabolism are shedding light on this under-appreciated metabolic pathway that is critical for cellular energy production, modification of cellular macromolecules and normal human development.
Publisher: Future Medicine Ltd
Date: 12-2010
DOI: 10.2217/FON.10.149
Abstract: Incidences of prostate cancer in most countries are increasing owing to better detection methods however, prevention with the use of finasteride, a very effective steroid 5α-reductase type II inhibitor, has been met with mixed success. A wide interin idual variation in response exists and is thought to be due to heritable factors. This article summarizes the literature that attempts to elucidate the molecular mechanisms of finasteride in terms of its metabolism, excretion and interaction with endogenous steroid molecules. We describe previously reported genetic variations of steroid-metabolizing genes and their potential association with finasteride efficacy. Based on the literature, we outline directions of research that may contribute to understanding the interin idual variation in finasteride prevention and to the future development of personalized medicine.
Publisher: Elsevier BV
Date: 12-1999
DOI: 10.1016/S1050-3862(99)00050-9
Abstract: We report a reliable method for PCR (polymerase chain reaction) lification of genomic DNA from PET. This method uses DNA extraction with the QIAquick kit and lification with AmpliTaq Gold. Amplification of up to 959 bp from PET was achieved with this combination which exceeds the current reported upper limit of 800 bp. In summary, the gradual activation of the AmpliTaq Gold during thermal cycling allows both for higher-fidelity and higher-throughput PCR lification from PET. The use of the QIAquick kit for DNA purification of PET is sensitive, reproducible and suitable for management of a high number of s les.
Publisher: The Endocrine Society
Date: 10-1994
DOI: 10.1210/JC.79.4.1105
Publisher: Springer Science and Business Media LLC
Date: 11-06-2011
Publisher: AIP Publishing
Date: 09-2011
DOI: 10.1063/1.3637490
Abstract: We study dynamical reversibility in stationary stochastic processes from an information-theoretic perspective. Extending earlier work on the reversibility of Markov chains, we focus on finitary processes with arbitrarily long conditional correlations. In particular, we examine stationary processes represented or generated by edge-emitting, finite-state hidden Markov models. Surprisingly, we find pervasive temporal asymmetries in the statistics of such stationary processes. As a consequence, the computational resources necessary to generate a process in the forward and reverse temporal directions are generally not the same. In fact, an exhaustive survey indicates that most stationary processes are irreversible. We study the ensuing relations between model topology in different representations, the process’s statistical properties, and its reversibility in detail. A process’s temporal asymmetry is efficiently captured using two canonical unifilar representations of the generating model, the forward-time and reverse-time ε-machines. We analyze ex le irreversible processes whose ε-machine representations change size under time reversal, including one which has a finite number of recurrent causal states in one direction, but an infinite number in the opposite. From the forward-time and reverse-time ε-machines, we are able to construct a symmetrized, but nonunifilar, generator of a process—the bidirectional machine. Using the bidirectional machine, we show how to directly calculate a process’s fundamental information properties, many of which are otherwise only poorly approximated via process s les. The tools we introduce and the insights we offer provide a better understanding of the many facets of reversibility and irreversibility in stochastic processes.
Publisher: Oxford University Press (OUP)
Date: 10-2009
DOI: 10.1093/NAR/GKP761
Publisher: Wiley
Date: 07-08-2002
DOI: 10.1002/PROS.10134
Abstract: Prostate cancer is a significant public health problem in this country. Substantial data support a plausible role for androgens in the etiology of this disease. The human HSD17B3 gene encodes the testicular (or type III) 17 beta-hydroxysteroid dehydrogenase enzyme, which catalyzes testosterone biosynthesis in men. We have investigated the G289S (glycine at codon 289 replaced by serine) polymorphism at the HSD17B3 locus as a candidate single nucleotide polymorphism (SNP) for prostate cancer risk in constitutional DNA from 103 Italian prostate cancer patients and 109 Italian disease-free centenarians to assess the role of this SNP in susceptibility to prostate cancer. The G289S polymorphism confers a significant increase in risk for prostate cancer (odds ratio = 2.5 95% confidence interval, 1.03-6.07) in our study population. Our data are consistent with a plausible role of the G289S SNP in prostate cancer susceptibility. Therefore, the HSD17B3 gene may be a plausible candidate gene for prostate cancer risk.
Publisher: Springer Science and Business Media LLC
Date: 08-07-2020
DOI: 10.1186/S40246-020-00275-3
Abstract: The recent coronavirus disease 2019 (COVID-19) pandemic has caused worldwide disruption which also extends to the arena of scientific meetings around the world. Here, we explore the lessons learned from moving two human genetics and genomics meetings quickly to an online format in early 2020. The tips presented herein may be useful not only for future virtual meetings but may also enrich future physical if not hybrid meetings once they resume.
Publisher: Hindawi Limited
Date: 1995
Abstract: We characterized two novel mutations of the galactose-1-phosphate uridyltransferase (GALT) gene in two Japanese patients with GALT deficiency and identified N314D and R333W mutations, previously found in Caucasians. One novel missense mutation was an G-to-A transition in exon 8, resulting in the substitution of arginine by histidine at the codon 231 (R231H). GALT activity of the R231H mutant construct was reduced to 15% of normal controls in a COS cell expression system. The other was a splicing mutation, an A-to-G transition at the 38th nucleotide in exon 3 (318A-->G), resulting in a 38-bp deletion in the GALT cDNA by activating a cryptic splice acceptor site. In seven Japanese families (14 alleles for classic form and one allele for Duarte variant) with GALT deficiency, the R231H and 318A-->G mutations were found only on both alleles of the proband. The N314D and R333W mutations were found on one allele each. The Q188R was prevalent in the United States but not in Japanese patients. The N314D mutation was associated with the Duarte variant in Japanese persons, as well as in the United States. We speculate that classic galactosemia mutations appear to differ between Japanese and Caucasian patients. Our limited data set on galactosemia mutations in Japanese suggests that the N314D GALT mutation encoding the Duarte variant arose before Asian and Caucasian people erged and that classic galactosemia mutations arose and/or accumulated after the ergence of Asian and Caucasian populations.
Publisher: Frontiers Media SA
Date: 2012
Publisher: American Association for Cancer Research (AACR)
Date: 15-05-2007
Publisher: Future Medicine Ltd
Date: 06-2007
Abstract: Prostate cancer is the most frequent male malignancy diagnosed in western countries and the second leading cause of cancer-related deaths. The growth and function of the prostate gland depends on androgens. Owing to the importance of androgens in prostate development, genes involved in androgen biosynthesis and metabolism have been extensively studied. In this review, we address recent progress toward the use of inherited and acquired genetic variants to predict susceptibility and clinical outcomes of prostate cancer patients. Many of these genetic variants involve several genes related to the biosynthesis and metabolism of androgens, such as steroid-5-α-reductase, α polypeptide 2 (SRD5A2), cytochrome P450 (CYP)19A1, CYP17A1, hydroxy-δ-5-steroid dehydrogenase, 3 β- and steroid δ-isomerase 2 (HSD3B2) and androgen receptor (AR). With increasing knowledge, it may be possible to distinguish indolent from aggressive prostate tumors by molecular fingerprinting. Furthermore, with the emergence of new investigative tools, such as microarray platforms and comparative genomic hybridization (CGH) array, a variety of new genomic biomarkers will be available in the future to provide accurate prognostic and monitoring solutions for in idualized patient care.
Publisher: Springer Science and Business Media LLC
Date: 30-06-2014
Location: United States of America
Start Date: 2010
End Date: 2010
Funder: Australian Research Council
View Funded ActivityStart Date: 2008
End Date: 2008
Funder: Australian Research Council
View Funded ActivityStart Date: 2009
End Date: 2009
Funder: Australian Research Council
View Funded ActivityStart Date: 2007
End Date: 2007
Funder: Australian Research Council
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