Biomedical subjects

Erin M Siegel

Publications and source records attributed to Erin M Siegel.

8 recordsLinked to original sources

PubMed2026

Integrated Genomic and Epigenomic Analysis Reveals Epigenetic Plasticity in Disease Progression and Multidrug Resistance in Multiple Myeloma.

UNLABELLED: Multiple myeloma is marked by recurrent cytogenetic abnormalities and mutations that accumulate as the disease progresses. In this study, we sought to elucidate the transitions driving tumorigenesis and therapy resistance in multiple myeloma using a unique cohort of nearly 900 patients spanning premalignant to late-stage refractory multiple myeloma, comprehensively characterized at molecular and clinical levels. Waves of epigenetic dysregulation drove these critical transitions. In this paradigm, genomic and cytogenetic events unlocked epigenetic plasticity, reshaping multiple myeloma cell biology to evade tumor microenvironment constraints and therapeutic pressures. Functional perturbation studies in an isogenic proteasome inhibitor-resistant cell line model demonstrated enhanced reliance on transcriptional cofactors, supporting a mechanistic link between chromatin plasticity and therapy adaptation. Collectively, these findings support a unifying framework in which genomic heterogeneity unlocks gene regulatory plasticity, enabling plasma cells (PC) to evade microenvironmental constraints and therapeutic pressure. These results provide a mechanistic explanation for sequential relapse without new genomic alterations and nominate epigenetic plasticity-mediated PC adaptation as a therapeutic vulnerability in the heterogeneous genetic background of multiple myeloma. SIGNIFICANCE: Assembly and analysis of a multiple myeloma cohort spanning the continuum from premalignant to late relapse that integrates bulk transcriptomics with single-cell multiomic data provides insights into disease progression and epigenetic plasticity.

Multiple Myeloma↗

PubMed2026

Epigenetic aging of colorectal mucosa in cancer development.

BACKGROUND: The past decade has seen the development of epigenetic models of aging that accurately estimate chronological age and predict disease incidence and mortality. These estimates are modulated by lifestyle and environmental factors linked to carcinogenesis, but to date this has primarily been studied in blood. METHODS: We examined epigenetic aging in normal colonic tissue (n = 96), adjacent mucosa (n = 245) and tumors (n = 208), using models trained on age (Horvath, Hannum, Zhang), mortality (PhenoAge, GrimAge), aging rate (DunedinPACE), cellular mitotic history (EpiTOC, epiTOC2, miAGe), and telomere length (DNAmTL). RESULTS: The Horvath model was the most accurate estimator of chronological age in normal colonic mucosa, with high correlation (r > 0.70) between the Horvath, Hannum, Zhang, PhenoAge and GrimAge models, and between mitotic clocks (r > 0.94). All models showed similar performance in normal tissue and adjacent mucosa, but substantially more variation in estimates in tumors. Significant differences in age acceleration were present between normal and adjacent mucosa by six models (Hannum, Zhang, PhenoAge, EpiTOC, epiTOC2 and miAge), while tumors showed highly significant differences by all models. Age acceleration differed by region of the colon, with varying patterns by model type. Physical activity (PhenoAge), smoking history (GrimAge), and alcohol consumption (Horvath, mitotic clocks) were associated with epigenetic aging in adjacent mucosa, while smoking history, smoking intensity, and alcohol consumption were associated with DNAmTL in tumors. CONCLUSIONS: Our study reveals an impact of tissue type, region, and lifestyle factors on epigenetic aging, but also highlights significant heterogeneity between models and the need for careful consideration within study design.

DNA methylation↗

PubMed2007

Associations between serum carotenoids and tocopherols and type-specific HPV persistence: the Ludwig-McGill cohort study.

Although oncogenic HPV infections have been established as the necessary cause of cervical cancer, most HPV infections are transient and rarely progress to cervical lesions. Current research is focused on identifying factors associated with viral persistence and clearance, such as nutritional status. We evaluated the association between serum antioxidant nutrients (retinol, 10 carotenoids and 3 tocopherols) and type-specific HPV persistence over 4 visits among 405 women participating in the Ludwig-McGill cohort study. We measured circulating carotenoids and tocopherol at 4 different clinical visits for each woman. We report the results from different analytic approaches (a case-control approach at both the woman and viral level, and a prospective approach based on persistent events) that examined the association between these micronutrients and type-specific oncogenic and nononcogenic HPV persistence. In the case-control analysis at the viral level, midcirculating levels of alpha-tocopherol were inversely associated with nononcogenic HPV persistent infection (adjusted odds ratio (AOR) = 0.28, 95% CI 0.14-0.57), while high levels were marginally associated (AOR = 0.59, 95% CI 0.28-1.19). Similarly, utilizing generalized estimating equation models, circulating levels of alpha- and delta-tocopherol in the middle or upper tertiles were inversely associated with type-specific nononcogenic HPV persistence (AOR = 0.44, 95% CI 0.19-0.97 and AOR = 0.46, 95% CI 0.19-1.11, respectively). Our study among Brazilian women suggests that serum levels of tocopherols may be protective against nononcogenic HPV persistence. However, we did not find a strong protective effect (as hypothesized) of other serum antioxidant nutrients and type-specific oncogenic HPV persistence measured over 4 clinical visits.

Adult↗

PubMed2005

Coccidioides posadasii contains a single 1,3-beta-glucan synthase gene that appears to be essential for growth.

1,3-beta-Glucan synthase is responsible for the synthesis of beta-glucan, an essential cell wall structural component in most fungi. We sought to determine whether Coccidioides posadasii possesses genes homologous to known fungal FKS genes that encode the catalytic subunit of 1,3-beta-glucan synthase. A single gene, designated FKS1, was identified, and examination of its predicted protein product showed a high degree of conservation with Fks proteins from other filamentous fungi. FKS1 is expressed at similar levels in mycelia and early spherulating cultures, and expression decreases as the spherules mature. We used Agrobacterium-mediated transformation to create strains that harbor DeltaFKS1::hygB, a null allele of FKS1, and hypothesize that Fks1p function is essential, due to our inability to purify this allele away from a complementing wild-type FKS1 allele in a heterokaryotic strain. The heterokaryon appears normal with respect to growth rate and arthroconidium production; however, microscopic examination of strains with DeltaFKS1::hygB alleles revealed abnormal swelling of hyphal elements.

Alleles↗

PubMed2004

Evaluation of a new oscillometric blood pressure monitor in isoflurane-anesthetized dogs.

OBJECTIVE: This study was conducted to evaluate the performance of a new veterinary oscillometric noninvasive blood pressure (NIBP) monitor in anesthetized dogs. STUDY DESIGN: Assessment was made to determine how closely indirect measurements were associated with direct measurements, and if there were statistically significant differences between the measurements by site. ANIMALS: Six mongrel dogs weighing 27.8 +/- 2.9 kg. METHODS: Dogs were anesthetized with thiopental and maintained with isoflurane, which was delivered with controlled ventilation. Direct pressure measurements were obtained via a percutaneously placed arterial catheter. A range of systolic arterial pressures (SAP) were achieved by changing the isoflurane concentrations. Sites of cuff placement for indirect measurements were identified as metacarpus, metatarsus, and anterior tibial. RESULTS: At pressures below 80 mm Hg, indirect systolic measurements averaged 4 +/- 3 mm Hg, higher than the direct values. At normal and high levels, indirect systolic measurements underestimated direct values by 18 +/- 6 and 23 +/- 6 mm Hg, respectively. Diastolic and mean pressure measurements followed the same trend, with indirect values being lower than the direct arterial pressures. Systolic, diastolic and mean arterial pressure measurements differed by cuff-placement site. CONCLUSIONS: When analyzed by site and level, indirect systolic and mean arterial blood pressures during hypotension were essentially the same as direct pressures. However, at pressures within the normal or high range, indirect measurements underestimated the direct pressures. CLINICAL RELEVANCE: Noninvasive blood pressure measurements with a new oscillometric monitor provided an excellent means of detecting arterial hypotension in anesthetized dogs. The metatarsal site for cuff placement was slightly better than the metacarpal or anterior tibial site, considering that the regression line was closest to complete equality between the indirect and direct measurements for SAP.

Anesthesia↗

PubMed2004

Temporal variation and identification of factors associated with endogenous retinoic acid isomers in serum from Brazilian women.

OBJECTIVE: Retinoids (natural and synthetic derivatives of vitamin A) have cancer chemotherapeutic and chemopreventive activities. Retinoic acid (RA) treatment has been associated with significant regression of preneoplastic lesions. However, serious toxicity associated with some therapies has made long-term chemoprevention in healthy populations unfeasible. Recently, serum RA has been shown to increase in response to oral retinol (vitamin A) supplementation. Here, we assess the variability of circulating RA levels and the lifestyle, demographic, and nutritional factors that explain such variability. METHOD: Total RA concentration and the concentrations of RA isomers (all-trans-RA, 13-cis-RA, and 9-cis-RA) were measured by high-pressure liquid chromatography in serum samples obtained 4 months apart from 502 women participating in the Ludwig-McGill Cohort (Sao Paulo, Brazil). RESULTS: The relative abundance of the three RA isomers was similar for each visit (baseline and month 4), with 13-cis-RA having the highest concentrations followed by 9-cis-RA and all-trans-RA. The within-person variability of total RA and individual isomers was low. Using multivariate logistic regression models (upper tertile versus low/middle tertile of serum RA), we found that age, race, oral contraceptive use, total number of pregnancies, and season of initial blood draw were significantly associated with at least one endogenous RA isomer level. All endogenous RA isomers were positively associated with serum retinol, beta-carotene, and beta-cryptoxanthin levels. CONCLUSION: These results have implications for the design of future epidemiologic studies focused on assessing RA-disease association and intervention studies aimed at modulating RA levels.

Adult↗

PubMed2003

Dietary intake and risk of persistent human papillomavirus (HPV) infection: the Ludwig-McGill HPV Natural History Study.

The association between dietary intake and persistence of type-specific human papillomavirus (HPV) infection, during a 12-month period, among 433 women participating in the Ludwig-McGill HPV Natural History Study was evaluated by use of a nested case-control design. Dietary intake was assessed by a food-frequency questionnaire at the month-4 visit. HPV status was assessed at months 0, 4, 8, and 12 by polymerase chain reaction (MY09/11). Only women who ever tested positive for HPV were included in the present study: 248 had transient HPV infections (1 of 4 positive tests or nonconsecutively positive), and 185 had persistent HPV infections (> or =2 consecutive tests positive for the same HPV type). Risk of type-specific, persistent HPV infection was lower among women reporting intake values of beta-cryptoxanthin and lutein/zeaxanthin in the upper 2 quartiles and intake values of vitamin C in the upper quartile, compared with those reporting intake in the lowest quartile. Consumption of papaya > or =1 time/week was inversely associated with persistent HPV infection.

Adult↗

PubMed2002

Medical surveillance of clandestine drug laboratory investigators.

Law enforcement officers investigating clandestine drug laboratories may be exposed to a wide range of hazardous chemicals. This study was conducted to determine the extent of persistent health effects seen in California drug laboratory investigators after occupational exposure. Study participants with a minimum of 1 year of laboratory investigations completed a questionnaire evaluating occupational and personal health history and consented to review of their medical surveillance examinations and administrative records. The 40 participating investigators averaged 6.1 +/- 2.5 annual medical evaluations for the period 1991 to 1998. Average annual decline in forced expiratory volume in 1 second (FEV1) was 64.0 +/- 138.0 mL/year (median, 40.0 mL/year). For 34 subjects with valid exposure data, longer duration use of respiratory protection was associated with a less rapid decline in FEV1, whereas lack of respiratory protection during the processing phase of laboratory investigation was associated with a more rapid annual decline. There were no significant longitudinal changes in serum alanine aminotransferase, serum aspartate aminotransferase, hemoglobin, and white blood cell count, although platelets declined slightly. Law enforcement personnel investigating clandestine drug laboratories may have long-term respiratory effects from chemical exposure, for which more assiduous use of respiratory protection is recommended.

Adult↗