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MSTPublications: March 2024

Posted by on Friday, March 29, 2024 in New Publications .

Leveraging generative AI to prioritize drug repurposing candidates for Alzheimer’s disease with real-world clinical validation.
Yan C, Grabowska ME, Dickson AL, Li B, Wen Z, Roden DM, Michael Stein C, Embí PJ, Peterson JF, Feng Q, Malin BA, Wei WQ.
NPJ Digit Med. 2024 Feb 26;7(1):46. doi: 10.1038/s41746-024-01038-3.

Drug repurposing represents an attractive alternative to the costly and time-consuming process of new drug development, particularly for serious, widespread conditions with limited effective treatments, such as Alzheimer’s disease (AD). Emerging generative artificial intelligence (GAI) technologies like ChatGPT offer the promise of expediting the review and summary of scientific knowledge. To examine the feasibility of using GAI for identifying drug repurposing candidates, we iteratively tasked ChatGPT with proposing the twenty most promising drugs for repurposing in AD, and tested the top ten for risk of incident AD in exposed and unexposed individuals over age 65 in two large clinical datasets: (1) Vanderbilt University Medical Center and (2) the All of Us Research Program. Among the candidates suggested by ChatGPT, metformin, simvastatin, and losartan were associated with lower AD risk in meta-analysis. These findings suggest GAI technologies can assimilate scientific insights from an extensive Internet-based search space, helping to prioritize drug repurposing candidates and facilitate the treatment of diseases.


Curating retrospective multimodal and longitudinal data for community cohorts at risk for lung cancer.
Li TZ, Xu K, Chada NC, Chen H, Knight M, Antic S, Sandler KL, Maldonado F, Landman BA, Lasko TA.
Cancer Biomark. 2024 Mar 7. doi: 10.3233/CBM-230340. Online ahead of print.

Background: Large community cohorts are useful for lung cancer research, allowing for the analysis of risk factors and development of predictive models.
Objective: A robust methodology for (1) identifying lung cancer and pulmonary nodules diagnoses as well as (2) associating multimodal longitudinal data with these events from electronic health record (EHRs) is needed to optimally curate cohorts at scale.
Methods: In this study, we leveraged (1) SNOMED concepts to develop ICD-based decision rules for building a cohort that captured lung cancer and pulmonary nodules and (2) clinical knowledge to define time windows for collecting longitudinal imaging and clinical concepts. We curated three cohorts with clinical data and repeated imaging for subjects with pulmonary nodules from our Vanderbilt University Medical Center.
Results: Our approach achieved an estimated sensitivity 0.930 (95% CI: [0.879, 0.969]), specificity of 0.996 (95% CI: [0.989, 1.00]), positive predictive value of 0.979 (95% CI: [0.959, 1.000]), and negative predictive value of 0.987 (95% CI: [0.976, 0.994]) for distinguishing lung cancer from subjects with SPNs.
Conclusion: This work represents a general strategy for high-throughput curation of multi-modal longitudinal cohorts at risk for lung cancer from routinely collected EHRs.


Endoscopic Versus Microscopic Transcanal Resection of Glomus Tympanicum: A Retrospective Comparative Study.
Kunnath AJ, Freeman MH, Witcher R, Patro A, Lindquist NR, Tawfik KO.
Otol Neurotol. 2024 Apr 1;45(4):426-429. doi: 10.1097/MAO.0000000000004147. Epub 2024 Feb 28.

Objective: Comparison of outcomes of microscopic and endoscopic resection of glomus tympanicum (GT) tumors.
Study design: Retrospective case review.
Setting: Single tertiary referral center.
Patients: All adult patients undergoing transcanal GT resection without mastoidectomy from 2007 to 2021.
Interventions: Surgical resection-endoscopic versus microscopic approach.
Main outcome measures: Primary outcomes were tumor recurrence at 1 year and presence of residual tumor at conclusion of surgery. Secondary outcome measures included operative time, postoperative air-bone gap, postoperative symptom resolution, and surgical complications.
Results: Thirty-eight patients underwent resection of GT (74% female; mean age, 59 years). Twenty-nine cases were performed microscopically, and nine cases were performed endoscopically. Both endoscopic and microscopic approaches yielded high rates of complete tumor resection (27/29 microscopic cases, 7/9 endoscopic cases). There was no significant difference in mean operative time (2.3 hours for microscopic; 2.6 hours for endoscopic). On average, air-bone gaps (ABGs) decreased by 6.3 dB after endoscopic resection compared with 1.0 dB after microscopic resection ( p = 0.064). No patients were found to have tumor recurrence during an average follow-up interval of 21 months.
Conclusions: These results suggest comparable outcomes with both endoscopic and microscopic approaches for GT resection, and decisions regarding preferred approach should be dictated by surgeon preference.


Analysis of editor in chief gender and associated journal variables among 126 pathology journals.
Wang DK, Clark LM, Stephens LD, Adkins BD, Khan SS, Booth GS, Jacobs JW.
Am J Clin Pathol. 2024 Mar 4:aqae018. doi: 10.1093/ajcp/aqae018. Online ahead of print.

Objectives: Gender equity studies have shown that women are underrepresented in journal editor in chief positions, which confer major professional opportunities and influence. We sought to systematically investigate editor in chief gender and journal attributes within pathology.
Methods: We constructed a journal data set using the Scimago Journal & Country Rank and Clarivate Journal Citation Reports databases. We also included official journals of the major medical societies for the 12 pathology subspecialties recognized by the Association of American Medical Colleges. The final data set included 126 journals. We obtained editor in chief gender, impact factor, publication model (ie, hybrid access vs open access), year of founding, and geographic location for all included pathology journals.
Results: Women made up only 18% of the 141 total editor in chief positions. This inequity was present irrespective of all pathology journal variables studied. Among 10 journals with 2 editor in chief positions, 5 had only men and 5 had 1 man and 1 woman. All 3 journals with 3 editor in chief positions had 2 men and 1 woman.
Conclusions: Women are significantly underrepresented among editor in chiefs across pathology journals. Journals and affiliated members should advocate for diversity among these influential positions, given their impact on research, science, and medicine.


PTHrP intracrine actions divergently influence breast cancer growth through p27 and LIFR.
Edwards CM, Kane JF, Smith JA, Grant DM, Johnson JA, Diaz MAH, Vecchi LA 3rd, Bracey KM, Omokehinde TN, Fontana JR, Karno BA, Scott HT, Vogel CJ, Lowery JW, Martin TJ, Johnson RW.
Breast Cancer Res. 2024 Feb 26;26(1):34. doi: 10.1186/s13058-024-01791-z.

The role of parathyroid hormone (PTH)-related protein (PTHrP) in breast cancer remains controversial, with reports of PTHrP inhibiting or promoting primary tumor growth in preclinical studies. Here, we provide insight into these conflicting findings by assessing the role of specific biological domains of PTHrP in tumor progression through stable expression of PTHrP (-36-139aa) or truncated forms with deletion of the nuclear localization sequence (NLS) alone or in combination with the C-terminus. Although the full-length PTHrP molecule (-36-139aa) did not alter tumorigenesis, PTHrP lacking the NLS alone accelerated primary tumor growth by downregulating p27, while PTHrP lacking the NLS and C-terminus repressed tumor growth through p27 induction driven by the tumor suppressor leukemia inhibitory factor receptor (LIFR). Induction of p27 by PTHrP lacking the NLS and C-terminus persisted in bone disseminated cells, but did not prevent metastatic outgrowth, in contrast to the primary tumor site. These data suggest that the PTHrP NLS functions as a tumor suppressor, while the PTHrP C-terminus may act as an oncogenic switch to promote tumor progression through differential regulation of p27 signaling.


Incorporation of ChatGPT and Other Large Language Models into a Graduate Level Computational Bioengineering Course.
King MR, Abdulrahman AM, Petrovic MI, Poley PL, Hall SP, Kulapatana S, Lamantia ZE.
Cell Mol Bioeng. 2024 Feb 7;17(1):1-6. doi: 10.1007/s12195-024-00793-3. eCollection 2024 Feb.

Multiomic Profiling of Human Clonal Hematopoiesis Reveals Genotype and Cell-Specific Inflammatory Pathway Activation.
Heimlich JB, Bhat P, Parker A, Jenkins MT, Vlasschaert C, Ulloa J, Van Amburg J, Potts CR, Olson S, Silver AJ, Ahmad A, Sharber B, Brown D, Hu N, van Galen P, Savona MR, Bick AG, Ferrell PB Jr.
Blood Adv. 2024 Mar 20:bloodadvances.2023011445. doi: 10.1182/bloodadvances.2023011445. Online ahead of print.

Measurement matters: A commentary on the state of the science on patient reported outcome measures (PROMs) in autism research.
Schiltz HK, Williams ZJ, Zheng S, Kaplan-Kahn EA, Morton HE, Rosenau KA, Nicolaidis C, Sturm A, Lord C; Autism PROMnet.
Autism Res. 2024 Mar 1. doi: 10.1002/aur.3114. Online ahead of print.

Parent and Provider Differences in Ratings of Mental Health and Neurodevelopmental Concerns in Children with Neurologic Disorders.
Schwartzman JM, Williams ZJ, Molnar AE Jr.
J Clin Psychol Med Settings. 2024 Feb 24. doi: 10.1007/s10880-023-09990-0. Online ahead of print.

The Social Validity of Behavioral Interventions: Seeking Input from Autistic Adults.
Baiden KMP, Williams ZJ, Schuck RK, Dwyer P, Wang M.
J Autism Dev Disord. 2024 Mar 12. doi: 10.1007/s10803-024-06297-3. Online ahead of print.

Effect of a Co-Located Bridging Recovery Initiative on Hospital Length of Stay Among Patients With Opioid Use Disorder: The BRIDGE Randomized Clinical Trial.
Marcovitz D, Dear ML, Donald R, Edwards DA, Kast KA, Le TDV, Shah MV, Ferrell J, Gatto C, Hennessy C, Buie R, Rice TW, Sullivan W, White KD, Van Winkle G, Wolf R, Lindsell CJ; Vanderbilt Learning Healthcare System Platform Investigators.
JAMA Netw Open. 2024 Feb 5;7(2):e2356430. doi: 10.1001/jamanetworkopen.2023.56430.
PMID: 38411964. Clinical Trial.

Multifocal Ectopic Purkinje Premature Contractions due to neutralization of an SCN5A negative charge: structural insights into the gating pore hypothesis.
Glazer AM, Yang T, Li B, Page D, Fouda M, Wada Y, Lancaster MC, O’Neill MJ, Muhammad A, Gao X, Ackerman MJ, Sanatani S, Ruben PC, Roden DM.
bioRxiv [Preprint]. 2024 Feb 16:2024.02.13.580021. doi: 10.1101/2024.02.13.580021.