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Biomedical subjects

Richard D Williams

Publications and source records attributed to Richard D Williams.

At least 19 recordsLinked to original sources
PubMed2006

Practice patterns in screening and management of prostate cancer in elderly men.

OBJECTIVES: To determine the practice preferences for prostate cancer screening and treatment in men 75 years of age or older among healthcare providers in Iowa. METHODS: Practice patterns were determined by an institutional review board-approved 15-item survey mailed to all 3105 Iowa healthcare providers who care for older men. A modified Dillman method was used for the survey. Actual prostate-specific antigen (PSA) testing practices derived from our institutional database were correlated with the survey data. RESULTS: The survey yielded a response rate of 32% (997 respondents). Of the respondents, 96% of primary care physicians and 97% of urologists preferred to stop PSA-based prostate cancer screening by age 80. This was compatible with our institutional data that indicated a PSA testing rate of 5.2% in men 80 years or older. Most physicians used the digital rectal examination as the first test for screening and reported a lack of educational materials to provide to patients. Older physicians and family practitioners were more likely to continue prostate cancer screening beyond 75 years, and most consented to patient requests for screening. CONCLUSIONS: The predilection for prostate cancer screening among healthcare providers declines with increasing patient age but persists for a small proportion of patients. The education of both patients and healthcare providers to more selectively screen men older than 75 years and the development of educational materials are needed. A consensus among healthcare providers would facilitate adoption of a tailored approach to managing prostate cancer in older men, thereby decreasing healthcare costs and morbidity while limiting the use of unnecessary therapy.

Adult↗
PubMed2006

Accurate prediction of BRCA1 and BRCA2 heterozygous genotype using expression profiling after induced DNA damage.

PURPOSE: In this study, the differential gene expression changes following radiation-induced DNA damage in healthy cells from BRCA1/BRCA1 mutation carriers have been compared with controls using high-density microarray technology. We aimed to establish if BRCA1/BRCA2 mutation carriers could be distinguished from noncarriers based on expression profiling of normal cells. EXPERIMENTAL DESIGN: Short-term primary fibroblast cultures were established from skin biopsies from 10 BRCA1 and 10 BRCA2 mutation carriers and 10 controls, all of whom had previously had breast cancer. The cells were subjected to 15 Gy ionizing irradiation to induce DNA damage. RNA was extracted from all cell cultures, preirradiation and at 1 hour postirradiation. For expression profiling, 15 K spotted cDNA microarrays manufactured by the Cancer Research UK DNA Microarray Facility were used. Statistical feature selection was used with a support vector machine (SVM) classifier to determine the best feature set for predicting BRCA1 or BRCA2 heterozygous genotype. To investigate prediction accuracy, a nonprobabilistic classifier (SVM) and a probabilistic Gaussian process classifier were used. RESULTS: In the task of distinguishing BRCA1 and BRCA2 mutation carriers from noncarriers and from each other following radiation-induced DNA damage, the SVM achieved 90%, and the Gaussian process classifier achieved 100% accuracy. This effect could not be achieved without irradiation. In addition, the SVM identified a set of BRCA genotype predictor genes. CONCLUSIONS: We conclude that after irradiation-induced DNA damage, BRCA1 and BRCA2 mutation carrier cells have a distinctive expression phenotype, and this may have a future role in predicting genotypes, with application to clinical detection and classification of mutations.

Adult↗
PubMed2006

Maximizing clinical information obtained by CT.

CT scanning is an integral part of the urologist's practice today. It is the most commonly used imaging modality and the one with which urologists are most familiar. CT urography, CT angiography, and 3D reconstruction enable the urologist to perform comprehensive evaluations of patients who have different urologic diseases, using a single imaging modality. It is thus prudent that urologists become familiar with CT applications, to maximize the clinical information available from them.

Humans↗
PubMed2006

Variants in the GH-IGF axis confer susceptibility to lung cancer.

We conducted a large-scale genome-wide association study in UK Caucasians to identify susceptibility alleles for lung cancer, analyzing 1529 cases and 2707 controls. To increase the likelihood of identifying disease-causing alleles, we genotyped 1476 nonsynonymous single nucleotide polymorphisms (nsSNPs) in 871 candidate cancer genes, biasing SNP selection toward those predicted to be deleterious. Statistically significant associations were identified for 64 nsSNPs, generating a genome-wide significance level of P=0.002. Eleven of the 64 SNPs mapped to genes encoding pivotal components of the growth hormone/insulin-like growth factor (GH-IGF) pathway, including CAMKK1 E375G (OR=1.37, P=5.4x10(-5)), AKAP9 M463I (OR=1.32, P=1.0x10(-4)) and GHR P495T (OR=12.98, P=0.0019). Significant associations were also detected for SNPs within genes in the DNA damage-response pathway, including BRCA2 K3326X (OR=1.72, P=0.0075) and XRCC4 I137T (OR=1.31, P=0.0205). Our study provides evidence that inherited predisposition to lung cancer is in part mediated through low-penetrance alleles and specifically identifies variants in GH-IGF and DNA damage-response pathways with risk of lung cancer.

Adult↗
PubMed2006

Does the interval between prostate biopsy and radical prostatectomy affect the immediate postoperative outcome?

OBJECTIVE: To determine whether the interval between prostate biopsy and radical prostatectomy (RP) affects the immediate postoperative outcome. PATIENTS AND METHODS: The study was a retrospective chart review of 169 patients who had retropubic RP at our institution. Using a series of univariate and multivariate logistic regression analyses, we evaluated whether the interval between biopsy and RP was a significant independent predictor of operative duration, estimated blood loss, transfusion rate, nerve-sparing (yes/no), positive margin rate, length of stay, complications, and urinary continence after RP. RESULTS: The interval from biopsy to RP was 14-378 days; there were no significant differences in operative duration, estimated intraoperative blood loss, nerve-sparing rate, transfusion rate and amount, hospitalization time, positive margin rate, major postoperative complications, and continence in patients with biopsy to RP intervals above and below the median. The biopsy to RP interval was not an independent predictor of outcomes during or after RP. There were no direct or indirect correlations between biopsy to RP interval and any of the postoperative outcomes. CONCLUSION: The interval between prostate biopsy and retropubic RP appears to have no effect on immediate postoperative outcomes. We were unable to determine a specific minimum required interval beyond 2 weeks after prostate biopsy before proceeding with RP.

Aged↗
PubMed2005

Two-surgeon versus single-surgeon radical cystectomy and urinary diversion: impact on patient outcomes and costs.

OBJECTIVES: To examine the difference in charges and outcomes between patients who underwent radical cystectomy and urinary diversion by a team of two surgeons versus a single surgeon. METHODS: A total of 63 patients with bladder cancer who underwent the procedures were retrospectively analyzed. Two surgeons sequentially performed the cystectomy and ileal conduit (IC, n = 17) or neobladder (NBL, n = 18) or a single surgeon performed both the cystectomy and IC (n = 21) or NBL (n = 7). Procedure-related charges, hospital charges, operating room time, length of stay, and complications were compared between the two groups. RESULTS: For the IC patients, the two-surgeon team had 60% greater mean surgeon charges (P <0.0001), 23% lower mean anesthesia charges (P <0.0001), 121 minutes shorter operating room time (P = 0.001), and 30% lower operating room charges (P = 0.001). For the NBL patients, the two-surgeon team had 32% greater surgeon charges (P <0.0001), 22% lower anesthesia charges (P = 0.003), 149 minutes shorter operating room time (P <0.0001), and 41% less operating room charges (P <0.0001). No differences were found in total hospital charges. The NBL patients who underwent surgery by two surgeons had a longer length of stay (P = 0.008). No differences were found in complications between the groups. CONCLUSIONS: For IC patients, our data showed no differences in the average overall charges, whether a two-surgeon team or a single surgeon performed the procedure. Additional reductions in hospital charges could offset the greater physician charges in the NBL patients and allow full realization of the benefit from the shorter operative time with the two-surgeon team.

Aged↗
PubMed2005

The predicted impact of coding single nucleotide polymorphisms database.

Nonsynonymous single nucleotide polymorphisms (nsSNP) have the potential to affect the structure or function of expressed proteins and are, therefore, likely to represent modifiers of inherited susceptibility. We have classified and catalogued the predicted functionality of nsSNPs in genes relevant to the biology of cancer to facilitate sequence-based association studies. Candidate genes were identified using targeted search terms and pathways to interrogate the Gene Ontology Consortium database, Kyoto Encyclopedia of Genes and Genomes database, Iobion's Interaction Explorer PathwayAssist Program, National Center for Biotechnology Information Entrez Gene database, and CancerGene database. A total of 9,537 validated nsSNPs located within annotated genes were retrieved from National Center for Biotechnology Information dbSNP Build 123. Filtering this list and linking it to 7,080 candidate genes yielded 3,666 validated nsSNPs with minor allele frequencies > or =0.01 in Caucasian populations. The functional effect of nsSNPs in genes with a single mRNA transcript was predicted using three computational tools-Grantham matrix, Polymorphism Phenotyping, and Sorting Intolerant from Tolerant algorithms. The resultant pool of 3,009 fully annotated nsSNPs is accessible from the Predicted Impact of Coding SNPs database at http://www.icr.ac.uk/cancgen/molgen/MolPopGen_PICS_database.htm. Predicted Impact of Coding SNPs is an ongoing project that will continue to curate and release data on the putative functionality of coding SNPs.

Algorithms↗
PubMed2004

Gene expression profiling after radiation-induced DNA damage is strongly predictive of BRCA1 mutation carrier status.

PURPOSE: The impact of the presence of a germ-line BRCA1 mutation on gene expression in normal breast fibroblasts after radiation-induced DNA damage has been investigated. EXPERIMENTAL DESIGN: High-density cDNA microarray technology was used to identify differential responses to DNA damage in fibroblasts from nine heterozygous BRCA1 mutation carriers compared with five control samples without personal or family history of any cancer. Fibroblast cultures were irradiated, and their expression profile was compared using intensity ratios of the cDNA microarrays representing 5603 IMAGE clones. RESULTS: Class comparison and class prediction analysis has shown that BRCA1 mutation carriers can be distinguished from controls with high probability (approximately 85%). Significance analysis of microarrays and the support vector machine classifier identified gene sets that discriminate the samples according to their mutation status. These include genes already known to interact with BRCA1 such as CDKN1B, ATR, and RAD51. CONCLUSIONS: The results of this initial study suggest that normal cells from heterozygous BRCA1 mutation carriers display a different gene expression profile from controls in response to DNA damage. Adaptations of this pilot result to other cell types could result in the development of a functional assay for BRCA1 mutation status.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2004

Prognostic classification of relapsing favorable histology Wilms tumor using cDNA microarray expression profiling and support vector machines.

Treatment of Wilms tumor has a high success rate, with some 85% of patients achieving long-term survival. However, late effects of treatment and management of relapse remain significant clinical problems. If accurate prognostic methods were available, effective risk-adapted therapies could be tailored to individual patients at diagnosis. Few molecular prognostic markers for Wilms tumor are currently defined, though previous studies have linked allele loss on 1p or 16q, genomic gain of 1q, and overexpression from 1q with an increased risk of relapse. To identify specific patterns of gene expression that are predictive of relapse, we used high-density (30 k) cDNA microarrays to analyze RNA samples from 27 favorable histology Wilms tumors taken from primary nephrectomies at the time of initial diagnosis. Thirteen of these tumors relapsed within 2 years. Genes differentially expressed between the relapsing and nonrelapsing tumor classes were identified by statistical scoring (t test). These genes encode proteins with diverse molecular functions, including transcription factors, developmental regulators, apoptotic factors, and signaling molecules. Use of a support vector machine classifier, feature selection, and test evaluation using cross-validation led to identification of a generalizable expression signature, a small subset of genes whose expression potentially can be used to predict tumor outcome in new samples. Similar methods were used to identify genes that are differentially expressed between tumors with and without genomic 1q gain. This set of discriminators was highly enriched in genes on 1q, indicating close agreement between data obtained from expression profiling with data from genomic copy number analyses.

Adolescent↗
PubMed2004

Use of bipolar energy for transurethral resection of bladder tumors: pathologic considerations.

BACKGROUND AND PURPOSE: Bipolar electrocautery has recently been introduced as a modality for transurethral resection of bladder tumors (TURBT). The primary benefits of bipolar TURBT stem from the use of saline irrigant rather than glycine or water. TURBT should be conducted in a fashion such that the resected tissue can be used for proper grading and staging, so excessive cauterization of the tissue should be avoided. In this study, we compared the pathologic characteristics of bladder tumor specimens resected with bipolar versus standard monopolar energy to determine specimen quality. PATIENTS AND METHODS: Bipolar TURBT (Gyrus Medical Inc., Maple Grove, MN) was performed in 11 patients. Pathologic specimens were compared with the specimens from 11 patients who had previously undergone standard monopolar TURBT. Resected tissue was examined by a pathologist who recorded tumor size, grade, location, presence of muscularis propria, presence of muscle invasion, and final diagnosis. The pathologist also determined the degree of cautery artifact in each specimen. The pathologist was blinded to the form of electrocautery used and the clinical diagnosis. RESULTS: Transurethral resection with bipolar electrocautery was carried out without difficulty or complication in all cases. Similarly, there were no complications in resection by standard monopolar electrocautery. The bladder tumor chips obtained with bipolar TURBT were smaller because of the smaller size of the bipolar loop. However, this did not interfere with the pathologic assessment. There were no significant pathologic differences between specimens according to the type of cautery used. A large degree of cautery artifact was noted in the tissue of larger tumors resected using both monopolar and bipolar electrocautery. However, the incidence and degree of cautery artifact were similar in the two groups. No trends between tumor location and degree of cautery effect were noted. The pathologist had no difficulty reaching a full and proper diagnosis in all cases involving either form of electrocautery. CONCLUSIONS: Bipolar electrocautery is well suited for TURBT. Bladder tissue obtained from bipolar TURBT is of the same histologic quality as that obtained from standard monopolar TURBT and provides the urologist with a reliable and complete diagnosis.

Electrosurgery↗
PubMed2004

Gonococcal porin IB activates NF-kappaB in human urethral epithelium and increases the expression of host antiapoptotic factors.

Infection of human urethral epithelial cells (UECs) with Neisseria gonorrhoeae increases the transcription of several host antiapoptotic genes, including bfl-1, cox-2, and c-IAP-2. In order to identify the bacterial factor(s) responsible for eliciting these changes, the transcriptional status of apoptotic machinery was monitored in UECs challenged with certain gonococcal membrane components. Initially, we observed that infection of UECs with gentamicin-killed gonococci increased the expression of the antiapoptotic Bcl-2 family member, bfl-1. This observation indicated that viable, replicating bacteria are not required for induction of antiapoptotic gene expression. Confirming this observation, treatment of UECs with purified gonococcal membrane increased the expression of bfl-1, cox-2, and c-IAP-2. This finding suggested that a factor or multiple factors present in the outer membrane (OM) are responsible for altering UEC antiapoptotic gene expression. Interestingly, treatment of UECs with gonococcal porin IB (PorB IB), a major constituent of the OM, significantly increased the transcription of bfl-1, cox-2, and c-IAP-2. The upregulation of these genes by PorB IB was determined to be dependent on NF-kappaB activation, as inhibiting NF-kappaB blocked induced expression of these genes. This work demonstrates the altered expression of host apoptotic factors in response to gonococcal PorB IB and supports a model whereby UEC cell death may be modulated as a potential mechanism of bacterial survival and proliferation.

Apoptosis↗
PubMed2004

Disruption of WT1 gene expression and exon 5 splicing following cytotoxic drug treatment: antisense down-regulation of exon 5 alters target gene expression and inhibits cell survival.

Deregulated expression of the Wilms' tumor gene (WT1) has been implicated in the maintenance of a malignant phenotype in leukemias and a wide range of solid tumors through interference with normal signaling in differentiation and apoptotic pathways. Expression of high levels of WT1 is associated with poor prognosis in leukemias and breast cancer. Using real-time (Taqman) reverse transcription-PCR and RNase protection assay, we have shown up-regulation of WT1 expression following cytotoxic treatment of cells exhibiting drug resistance, a phenomenon not seen in sensitive cells. WT1 is subject to alternative splicing involving exon 5 and three amino acids (KTS) at the end of exon 9, producing four major isoforms. Exon 5 splicing was disrupted in all cell lines studied following a cytotoxic insult probably due to increased exon 5 skipping. Disruption of exon 5 splicing may be a proapoptotic signal because specific targeting of WT1 exon 5-containing transcripts using a nuclease-resistant antisense oligonucleotide (ASO) killed HL60 leukemia cells, which were resistant to an ASO targeting all four alternatively spliced transcripts simultaneously. K562 cells were sensitive to both target-specific ASOs. Gene expression profiling following treatment with WT1 exon 5-targeted antisense showed up-regulation of the known WT1 target gene, thrombospondin 1, in HL60 cells, which correlated with cell death. In addition, novel potential WT1 target genes were identified in each cell line. These studies highlight a new layer of complexity in the regulation and function of the WT1 gene product and suggest that antisense directed to WT1 exon 5 might have therapeutic potential.

Alternative Splicing↗