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David Duggan

Publications and source records attributed to David Duggan.

9 recordsLinked to original sources
PubMed2026

Genetic risk stratification of common diseases in breast cancer survivors: a population-based cohort study.

IMPORTANCE: Patients diagnosed with breast cancer (BCa) are at increased risk of multiple common diseases; however, the spectrum of these diseases and the contribution of inherited genetic susceptibility remain incompletely characterized. METHODS: We evaluated 15 common diseases and tested their associations with BCa exposure and disease-specific polygenic risk scores (PRS) in the UK Biobank (UKB; N&#x2009;=&#x2009;254,736). Analyses were performed using cause-specific Cox proportional hazards models within a full-cohort framework, with time-updated BCa status, delayed entry at study recruitment, and age as the underlying time scale. RESULTS: After recruitment, incident BCa was diagnosed in 11,386 women (4.47%), including 2,742 (24.08%) with metastatic BCa. Patients with BCa had an increased risk of nine diseases spanning cardiovascular, metabolic, and neuropsychiatric domains (P<0.003, Bonferroni-corrected). Elevated risks were generally observed among patients with both early staged and advanced BCa. Inherited susceptibility further stratified disease risk, with the highest risks observed among patients with BCa with elevated disease-specific PRS. For example, compared with women without BCa, the hazard ratio (HR; 95% CI) for osteoporosis was 2.33 (2.15-2.52) among women with any BCa, 2.38 (2.18-2.59) among those with non-metastatic BCa, and 2.12 (1.78-2.54) among those with metastatic BCa; the HR was 4.48 (3.99-5.02) among patients with BCa in the highest quartile of osteoporosis-specific PRS (all P<0.001). In contrast, BCa was not significantly associated with risk of coronary artery disease. CONCLUSION: BCa and inherited genetic susceptibility jointly contribute to increased risk of multiple common diseases, supporting the integration of genetic risk stratification into survivorship care.

Complications↗
PubMed2026

Prostate Cancer, Genetic Susceptibility, and Risk of Chronic Non-Urological Complications.

BACKGROUND: Chronic nonurological complications are common among prostate cancer (PCa) survivors; however, their spectrum, magnitude, and genetic contribution remain poorly characterized. METHODS: We evaluated 15 commonly reported nonurological complications and tested their associations with exposure to PCa and disease-specific polygenic risk scores (PRS) in the UK Biobank (UKB; N&#x2009;=&#x2009;219,133). Analyses were conducted using cause-specific Cox proportional-hazards models within a full-cohort framework with time-updated PCa status, delayed entry at study recruitment, and age as the underlying time scale. RESULTS: After recruitment, incident PCa was diagnosed in 13,780 men, of which 1,656 (12.02%) had metastatic PCa (mPCa). Risks for seven complications were higher among men with PCa, adjusting for genetic background (all p&#x2009;<&#x2009;0.05), including osteoporosis, venous thromboembolism, depression, and four primary cancers (bladder, kidney, colorectal, and pancreatic). Risks were consistently stronger among men exposed to mPCa than non-mPCa; for example, the hazard ratio (HR) (95% confidence interval) for osteoporosis was 1.88 (1.63-2.18) for any PCa, 4.67 (3.11-7.01) for mPCa, and 1.75 (1.50-2.04) for non-mPCa. Elevated risks for three additional complications (coronary artery disease, type 2 diabetes and chronic obstructive pulmonary disease) were observed only among men with mPCa. The risks for these ten complications were further increased among men with higher disease-specific PRS; for example, the HR for osteoperosis in mPCa patients in the top PRS quartile was 13.57 (8.24-22.34) compared with men without PCa (p&#x2009;<&#x2009;0.001). CONCLUSION: PCa diagnosis and inherited genetic susceptibility jointly contribute to increased risks of multiple chronic non-urological complications among survivors.

Humans↗
PubMed2006

A comprehensive association study for genes in inflammation pathway provides support for their roles in prostate cancer risk in the CAPS study.

BACKGROUND: Recently identified associations of prostate cancer risk with several genes involved in innate immunity support a role of inflammation in the etiology of prostate cancer. Considering inflammation is regulated by a complex system of gene products, we hypothesize sequence variants in many other genes of this pathway are associated with prostate cancer. METHODS: We evaluated 9,275 SNPs in 1,086 genes of the inflammation pathway using a MegAllele genotyping system among 200 familial cases and 200 unaffected controls selected from a large Swedish case-control population (CAPS). RESULTS: We found that significantly more than the expected numbers of SNPs were significant at a nominal P-value of 0.01, 0.05, and 0.1, providing overall support for our hypothesis. The excess was largest when using a more liberal nominal P-value (0.1); we observed 992 significant SNPs compared with the 854 significant SNPs expected by chance, and this difference was significant based on a permutation test (P = 0.0025). We also began the effort of differentiating true associated SNPs by selecting a small subset of significant SNPs (N = 26) and genotyped these in an independent sample of approximately 1,900 CAPS1 subjects. We were able to confirm 3 of these 26 SNPs. It is expected that many more true associated SNPs will be confirmed among the 992 significant SNPs identified in our pathway screen. CONCLUSIONS: Our study provides the first objective support for an association between prostate cancer and multiple modest-effect genes in inflammatory pathways.

Aged↗
PubMed2005

Recent developments in genomewide association scans: a workshop summary and review.

With the imminent availability of ultra-high-volume genotyping platforms (on the order of 100,000-1,000,000 genotypes per sample) at a manageable cost, there is growing interest in the possibility of conducting genomewide association studies for a variety of diseases but, so far, little consensus on methods to design and analyze them. In April 2005, an international group of >100 investigators convened at the University of Southern California over the course of 2 days to compare notes on planned or ongoing studies and to debate alternative technologies, study designs, and statistical methods. This report summarizes these discussions in the context of the relevant literature. A broad consensus emerged that the time was now ripe for launching such studies, and several common themes were identified--most notably the considerable efficiency gains of multistage sampling design, specifically those made by testing only a portion of the subjects with a high-density genomewide technology, followed by testing additional subjects and/or additional SNPs at regions identified by this initial scan.

Data Interpretation, Statistical↗
PubMed2004

Neuregulin induces the expression of transcription factors and myosin heavy chains typical of muscle spindles in cultured human muscle.

Neuregulin (NRG) (also known as ARIA, GGF, and other names) is a heparin sulfate proteoglycan secreted into the neuromuscular junction by innervating motor and sensory neurons. An integral part of synapse formation, we have analyzed NRG-induced changes in gene expression over 48 h in primary human myotubes. We show that in addition to increasing the expression of acetylcholine receptors on the myotube surface, NRG treatment results in a transient increase of several members of the early growth response (Egr) family of transcription factors. Three Egrs, Egr1, -2, and -3, are induced within the first hour of NRG treatment, with Egr1 and -3 RNA levels showing the most significant increases of approximately 9- and 16-fold, respectively. Also noted was a corresponding increase in protein levels for both of these transcription factors. Previous literature indicates that Egr3 expression is required for the formation of muscle spindle fibers, sensory organs that are distinct from skeletal muscle contractile fibers. At the molecular level, muscle spindle fibers express a unique subset of myosin heavy chains. Two isoforms of the myosin heavy chain, the slow development and neonatal, were found to be increased in our myotube cultures after 48 h of treatment with NRG. Taken together, these results indicate that not only can NRG induce the expression of a transcription factor key to spindle fiber development (Egr3), but that a portion of this developmental process can be replicated in vitro.

Agrin↗
PubMed2004

Failure of higher-dose paclitaxel to improve outcome in patients with metastatic breast cancer: cancer and leukemia group B trial 9342.

PURPOSE: Cancer and Leukemia Group B Protocol 9342 was initiated to determine the optimal dose of paclitaxel administered as a 3-hour infusion every 3 weeks to women with metastatic breast cancer. PATIENTS AND METHODS: Four hundred seventy-four women with metastatic breast cancer who had received one or no prior chemotherapy regimens were randomly assigned to one of three paclitaxel dosing regimens-175 mg/m(2), 210 mg/m(2), or 250 mg/m(2)-each administered as a 3-hour infusion every 3 weeks. Women completed self-administered quality of life and symptom assessment questionnaires at baseline and after three cycles of treatment. RESULTS: No evidence of a significant dose-response relationship was demonstrated over the dose range assessed. Response rates were 23%, 26%, and 21% for the three regimens, respectively. A marginally significant association (P =.04) was seen between dose and time to progression; however, in a multivariate analysis, the difference was even less apparent. No statistically significant difference was seen in survival. Neurotoxicity and hematologic toxicity were more severe on the higher dose arms. There was no significant difference in quality of life on the three arms. CONCLUSION: Higher doses of paclitaxel administered as a 3-hour infusion to women with metastatic breast cancer did not improve response rate, survival, or quality of life. There was a slight improvement in time to progression with higher dose therapy, which was offset by greater toxicity. When a 3-hour infusion of paclitaxel is administered every 3 weeks, 175 mg/m(2) should be considered the optimal dose.

Adult↗
PubMed2004

Lack of attenuation in the antitumor effect of tamoxifen by chronic CYP isoform inhibition.

Tamoxifen is a selective estrogen receptor modulator used in estrogen receptor-positive breast cancer. Tamoxifen is metabolized to an extremely potent antiestrogen by cytochrome P450 (CYP) 2D6, 2C9, and 3A isoforms. The selective serotonin reuptake inhibitors (SSRIs) are potent inhibitors of these CYPs. Since the prevalence of depression in breast cancer patients is nearly triple that of the general population, it is likely that a subgroup of breast cancer patients will receive long-term treatment with both an SSRI and tamoxifen. A case control design was used to investigate the possibility that a resultant decrease in production of the 4-hydroxy metabolite from chronic inhibition results in the attenuation of the antitumor effect of tamoxifen. Twenty-eight patients without recurrences of breast cancer (controls) were matched to an equal number of cases (recurrences) by cancer stage and year of diagnosis. Data were analyzed on all chronic medication exposure (> 3 months) in both cases and controls classified as to their status as CYP 2D6, 2C9, and 3A inhibitors, substrates, or inducers. No significant difference was found for CYP inhibitor or substrate exposure between cases and controls. Indeed, controls showed a slightly greater exposure to inhibitors of the relevant CYP isoforms compared to cases. These results suggested a trend toward the null hypothesis. It is unlikely that the effect of chronic exposure to potent CYP isoform inhibitors affects the antitumor effect of tamoxifen and its 4-hydroxy metabolite, supporting the safety of the continued practice of concomitant SSRI administration to breast cancer patients with depression.

Antidepressive Agents, Second-Generation↗
PubMed2003

Vancomycin-induced thrombocytopenia: a case proven with rechallenge.

In a rare case of vancomycin-induced thrombocytopenia, a 50-year-old man with culture-negative subacute bacterial endocarditis underwent mitral valve replacement surgery and was treated with vancomycin. His platelet count dropped from 346 x 10(3)/mm3 to 13 x 10(3)/mm3 on postoperative day 4, and a differential diagnosis of heparin- versus drug-induced thrombocytopenia was considered. Antiheparin antibodies were detected in the patient's serum on day 5. He showed no signs of bleeding. His platelet count remained below 5 x 10(3)/mm3 despite two platelet transfusions on day 5. A hemorrhagic pericardial effusion with tamponade developed, requiring drainage. A trial with intravenous immunoglobulin led to fever and chills, and the infusion was not completed. Vancomycin was changed to clindamycin on day 9, and methylprednisolone therapy was started on day 11. On day 12, the patient's clinical condition improved, and his platelet count increased from 3 x 10(3)/mm3 to 32 x 10(3)/mm3 with no bleeding. On day 18, his platelet count was 424 x 10(3)/mm3, and he was scheduled for discharge with vancomycin therapy for a total of 6 weeks. He received a single dose of intravenous vancomycin 1 g at the hospital; his platelet count dropped to 160 x 10(3)/mm3 1 hour after the infusion and to 58 x 10(3)/mm3 12 hours later. Vancomycin was discontinued and clindamycin and prednisone were restarted. On day 20, the patient's platelet count increased to 105 x 10(3)/mm3 and he was discharged with warfarin, prednisone, and clindamycin therapy. We suspect that our patient's thrombocytopenia was due to vancomycin.

Drug Hypersensitivity↗