Christopher D. George, MD

All Publications

• Genetic evolution of keratinocytes to cutaneous squamous cell carcinoma. bioRxiv : the preprint server for biology Tandukar, B., Deivendran, D., Chen, L., Cruz-Pacheco, N., Sharma, H., Xu, A., Bandari, A. K., Chen, D. B., George, C., Marty, A., Cho, R. J., Cheng, J., Saylor, D., Gerami, P., Arron, S. T., Bastian, B. C., Shain, A. H. 2024

  Abstract

  We performed multi-omic profiling of epidermal keratinocytes, precancerous actinic keratoses, and squamous cell carcinomas to understand the molecular transitions during skin carcinogenesis. Single-cell mutational analyses showed that most keratinocytes in normal skin had lower mutation burdens than melanocytes and fibroblasts, however keratinocytes with TP53 or NOTCH1 mutations had substantially higher mutation burdens, suggesting that these mutations prime keratinocytes for transformation by increasing their mutation rate. Mutational profiling and spatial transcriptomics on squamous cell carcinomas adjacent to actinic keratoses revealed TERT promoter and CDKN2A mutations emerging in actinic keratoses, whereas additional mutations inactivating ARID2 and activating the MAPK-pathway delineated the transition to squamous cell carcinomas. Spatial variation in gene expression patterns was common in both tumor and immune cells, with high expression of checkpoint molecules at the invasive front of tumors. In conclusion, this study documents key events during the evolution of cutaneous squamous cell carcinoma.

  View details for DOI 10.1101/2024.07.23.604673

  View details for PubMedID 39091884

  View details for PubMedCentralID PMC11291049

• Association between lifetime smoking and cutaneous squamous cell carcinoma: A 2-sample Mendelian randomization study. JAAD international Lee, T., George, C. D., Jiang, C., Asgari, M. M., Nijsten, T., Pardo, L. M., Choquet, H. 2024; 14: 69-76

  Abstract

  Background/Purpose: Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies worldwide. While several environmental risk factors for cSCC are well established, there is conflicting evidence on cigarette smoking (and its potential causal effect) and cSCC risk. Furthermore, it is unclear if these potential associations represent causal, modifiable risk factors for cSCC development. This study aims to assess the nature of the associations between cigarette smoking traits (smoking initiation, amount smoked, and lifetime smoking exposure) and cSCC risk using two-sample Mendelian randomization analyses.Methods: Genetic instruments, based on common genetic variants associated with cigarette smoking traits (P<5*10-8), were derived from published genome-wide association studies (GWASs). For cSCC, we used GWAS summary statistics from the Kaiser Permanente GERA cohort (7701 cSCC cases and 60,167 controls; all non-Hispanic Whites).Results: We found modest evidence that genetically determined lifetime smoking was associated with cSCC (inverse-variance weighted method: OR[95% CI]=1.47[1.09-1.98]; P=.012), suggesting it may be a causal risk factor for cSCC. We did not detect any evidence of association between genetically determined smoking initiation or amount smoked and cSCC risk.Conclusion: Study findings highlight the importance of smoking prevention and may support risk-stratified cSCC screening strategies based on carcinogen exposure and other genetic and clinical information.

  View details for DOI 10.1016/j.jdin.2023.11.005

  View details for PubMedID 38274396

• Global epidemiology of actinic keratosis in the general population: a systematic review and meta-analysis BRITISH JOURNAL OF DERMATOLOGY George, C. D., Lee, T., Hollestein, L. M., Asgari, M. M., Nijsten, T. 2024; 190 (4): 465-476

  Abstract

  Actinic keratosis (AK) is a common dermatological condition, and among the most common dermatological diagnoses in older populations. Although the prevalence of AK depends on demographic and environmental factors, little is known about the global context of AK.To provide a comprehensive and updated analysis of the global prevalence rate and incidence of AK in the general population through a systematic review and meta-analysis, and - through subgroup analyses - to identify high-risk phenotypes, demographic and lifestyle risk factors and regional variations in disease prevalence.A systematic search of Embase, MEDLINE, Web of Science and Google Scholar was performed on 20 May 2022. Two reviewers independently screened and assessed the quality of each study using a validated critical appraisal checklist. Epidemiological measurements (e.g. prevalence) from individual studies performed in the general population were then pooled in a random-effects meta-analysis. Subgroup analyses (i.e. population age, geographical region, occupation, sex and study quality) were conducted.Of the 65 articles that made it through the full-text screening, 60 reported a point prevalence. A meta-analysis of these articles yielded an overall point prevalence of 14% [95% confidence interval (CI) 14-15]. In further analyses, the calculated prevalence rate varied depending on subgroup. The pooled incidence rate from the seven eligible studies analysed was 1928 per 100 000 person-years (PY; 95% CI -439 to 4294).This comprehensive meta-analysis provides an updated global prevalence rate of AK of 14%, indicating a significant worldwide disease burden. The incidence rate of AK was found to be 1928 per 100 000 PY, emphasizing a growing public health concern. However, high heterogeneity among studies suggests that various factors influence the AK prevalence rate, necessitating further research to understand the observed differences.

  View details for DOI 10.1093/bjd/ljad371

  View details for Web of Science ID 001114148400001

  View details for PubMedID 37890083

• Longitudinal Assessment of the Prevalence of Actinic Keratosis and Extensive Risk Factor Evaluation: An Update from the Rotterdam Study JOURNAL OF INVESTIGATIVE DERMATOLOGY George, C. D., Tokez, S., Hollestein, L., Pardo, L. M., Keurentjes, A. J., Wakkee, M., Nijsten, T. 2023; 143 (11): 2193-+

  Abstract

  Population-based studies available to analyze the prevalence, risk factors, and longitudinal outlook of actinic keratoses (AKs) are limited. These features mentioned earlier were assessed using Rotterdam study participants aged ≥40 years who underwent a full-body skin examination by a dermatology-trained physician. ORs with 95% confidence intervals were calculated for the associations between risk factors and the presence of AK. Among 8,239 eligible participants, the prevalence of one or more AKs was 21.1% (95% confidence interval = 20.2-22.0) and was higher in men. Male sex, age, lighter hair and eye color, baldness, genetic risk score, and digital photoaging measures (digitally assessed pigmented spots, telangiectasias, and global facial wrinkling) had a positive association with AK. Cigarette smokers had reduced odds of having AK, with current smokers having the lowest risk. Among patients with two AK assessments, there was no difference in the presence of AK during follow-up between treated and untreated participants. In conclusion, genetic risk score and digital photoaging measures showed associations with increased lesion count. At the individual level, patients were most likely to decrease in AK severity group over time, possibly regardless of whether or not participants were treated.

  View details for DOI 10.1016/j.jid.2023.02.042

  View details for Web of Science ID 001107340300001

  View details for PubMedID 37169068

• Nocturia and electrocardiographic abnormalities among patients at an inner-city cardiology clinic NEUROUROLOGY AND URODYNAMICS Mekki, P., Monaghan, T. F., Lee, L., Agudelo, C. W., Gong, F., George, C. D., Michelson, K. P., Wu, Z. D., Weiss, J. P., Everaert, K., Dmochowski, R. R., Bliwise, D. L., Wein, A. J., Lazar, J. M. 2021; 40 (1): 509-514

  Abstract

  Nocturia has been increasingly recognized as a potential manifestation of cardiovascular disease. However, the relationship between nocturia and electrocardiographic (ECG) abnormalities has not been studied. This study aims to characterize the diagnostic utility of nocturia in identifying left ventricular hypertrophy (LVH), left atrial enlargement (LAE), and prolonged QTc on ECG.Retrospective analysis of nocturnal voiding frequency and contemporaneous ECG data from consecutive patients evaluated at a university-based outpatient cardiology clinic. Three sets of three incremental binary multiple logistic regression models controlling for (1) age, (2) sex and race, and (3) body mass index, hypertension, diabetes mellitus, and diuretic utilization were performed to determine whether nocturia was predictive of LVH, LAE, and prolonged QTc.Included patients (n = 143, 77.6% nocturia) were predominantly African-American (89.5%), female (74.1%), and obese (61.5%), of whom 44.1%, 41.3%, and 27.3% had LVH, LAE, and prolonged QTc, respectively. Older age, African-American race, obesity, hypertension, diuretic use, LVH, and LAE were significantly associated with nocturia on univariate analysis. No significant differences were observed in the strength of associations between nocturia and LVH, LAE, or QTc prolongation based on age. Nocturia independently predicted LVH in Models I-III (odds ratios [ORs], 2.99-3.20; relative risks [RRs], 1.18 for all, p ≤ .046) and LAE in Models I-III (ORs, 4.24-4.72; RRs, 1.21 for all, p ≤ .015). No significant associations were observed between nocturia and prolonged QTc.Nocturia may be a risk marker for underlying structural cardiac abnormalities.

  View details for DOI 10.1002/nau.24590

  View details for Web of Science ID 000600534500001

  View details for PubMedID 33348456

• Nocturia: a marker of furosemide treatment response? An exploratory study BJU INTERNATIONAL Monaghan, T. F., Gong, F., Vaysblat, M., George, C. D., Michelson, K. P., Wu, Z. D., Agudelo, C. W., Bliwise, D. L., Everaert, K., Weiss, J. P., Sadovsky, R., Wein, A. J., Lazar, J. M. 2020; 125 (5): 636-637

  View details for DOI 10.1111/bju.15017

  View details for Web of Science ID 000516743300001

  View details for PubMedID 31989740

• Sodium restriction improves nocturia in patients at a cardiology clinic JOURNAL OF CLINICAL HYPERTENSION Monaghan, T. F., Michelson, K. P., Wu, Z. D., Gong, F., Agudelo, C. W., George, C. D., Alwis, U. S., Epstein, M. R., Mekki, P., Flores, V. X., Bliwise, D. L., Everaert, K., Vande Walle, J., Weiss, J. P., Lazar, J. M. 2020; 22 (4): 633-638

  Abstract

  This study aims to determine whether dietary sodium restriction counseling decreases nocturnal voiding frequency in cardiology patients with concomitant nocturia. Patients who had established care at a cardiology clinic from 2015 to 2018 reporting ≥1 average nocturnal void(s) underwent a comprehensive sodium intake interview by their cardiologist, who provided them with individualized strategies for dietary sodium reduction and assessed adherence at follow-up. Average nocturnal voiding frequency and dietary adherence were documented in the medical record. A nocturia database was compiled for retrospective analysis. A total of 74 patients were included. Patients considered to be adherent with dietary sodium restriction at follow-up (n = 56) demonstrated a decrease in median nocturia frequency (2.5 [2.3-3.0] vs 1.0 [1.0-2.0] voids, P < .001). Among nonadherent patients (n = 18), median nocturia frequency did not significantly change from baseline to follow-up (2.0 [1.5-3.8] vs 2.0 [1.5-4.8] voids, P = .423). Median changes were significantly different between the adherent and nonadherent groups (P < .001). Examination of second follow-up available from 37 patients showed a continued effect. In conclusion, adherence with dietary sodium counseling appears to improve nocturia. Accordingly, dietary modification may represent an important adjunct therapy to lifestyle and pharmacologic interventions for decreasing nocturia frequency. Reduction in nocturnal voiding frequency may also reflect an additional benefit of dietary sodium restriction in accordance with best practice standards for cardiovascular disease.

  View details for DOI 10.1111/jch.13829

  View details for Web of Science ID 000512826500001

  View details for PubMedID 32049435

  View details for PubMedCentralID PMC8029872

• Polyploid Superficial Cells that Maintain the Urothelial Barrier Are Produced via Incomplete Cytokinesis and Endoreplication CELL REPORTS Wang, J., Batourina, E., Schneider, K., Souza, S., Swayne, T., Liu, C., George, C. D., Tate, T., Dan, H., Wiessner, G., Zhuravlev, Y., Canman, J. C., Mysorekar, I. U., Mendelsohn, C. 2018; 25 (2): 464-+

  Abstract

  The urothelium is an epithelia barrier lined by a luminal layer of binucleated, octoploid, superficial cells. Superficial cells are critical for production and transport of uroplakins, a family of proteins that assemble into a waterproof crystalline plaque that helps protect against infection and toxic substances. Adult urothelium is nearly quiescent, but rapidly regenerates in response to injury. Yet the mechanism by which binucleated, polyploid, superficial cells are produced remains unclear. Here, we show that superficial cells are likely to be derived from a population of binucleated intermediate cells, which are produced from mononucleated intermediate cells via incomplete cytokinesis. We show that binucleated intermediate and superficial cells increase DNA content via endoreplication, passing through S phase without entering mitosis. The urothelium can be permanently damaged by repetitive or chronic injury or disease. Identification of the mechanism by which superficial cells are produced may be important for developing strategies for urothelial repair.

  View details for DOI 10.1016/j.celrep.2018.09.042

  View details for Web of Science ID 000446691400019

  View details for PubMedID 30304685

  View details for PubMedCentralID PMC6351079