Medical Sciences Commons^™

Bayesian Learning To Reduce Cardiac Risk Of Patients With Locally Advanced Non-Small Cell Lung Cancer Based On Personalized Radiation Therapy Prescription, Ruitao Lin, Mei Chen, Xiaodong Zhang, Tianlin Xu, Ting Xu, Rachel C Maguire, Kelsey L Corrigan, Efstratios Koutroumpakis, Joe Y Chang, Steven H Lin, Aileen B Chen, Quynh-Nhu Nguyen, Saumil J Gandhi, Matthew S Ning, Julianna Bronk, Stephen Chun, Ali Ajdari, Joshua S Niedzielski, Jinzhong Yang, Xinru Chen, Tinsu Pan, Qing H Meng, Anne S Tsao, Anita Deswal, Radhe Mohan, Zhongxing Liao

Faculty, Staff and Student Publications

Purpose: Radiation-induced heart damage is a significant concern in the treatment of non-small cell lung cancer (NSCLC) that can have debilitating or life-threatening consequences. Current strategies focus on minimizing heart exposure, but individual susceptibility varies. Existing evidence also suggests that a uniform "one-size-fits-all" dosimetric constraint for the heart may not be optimal for all patients.

Methods and materials: We developed a prospective study using Bayesian continuous learning and adaptation to develop a framework for personalized adaptive radiation treatment (PART) to reduce cardiovascular adverse events among patients with locally advanced NSCLC. The trial includes a Bayesian personalized risk prediction model to …

Health-Related Quality Of Life In The Era Of Immune Checkpoint Blockade: What Do Patient-Reported Outcomes Reveal?, Alexandra M Dunker, Neha Malik, Kathryn J Krause, Emily Z Keung, Jason B Liu, Elise F Nassif Haddad, Neeta Somaiah, Heather G Lyu, Christina L Roland

Faculty, Staff and Student Publications

Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by providing durable survival gains, but understanding their effects on patient health-related quality of life (HRQL) is critical.

Methods: We performed a narrative review of cross-sectional surveys, early-phase trials, and large-scale phase II and III randomized controlled clinical trials assessing FDA-approved ICIs, including programmed cell death protein 1 (PD-1) inhibitors, programmed death ligand 1 (PD-L1) inhibitors, and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors, with emphasis on patient-reported HRQL. Validated HRQL instruments were summarized, and for pivotal trials, the positioning of HRQL outcomes as primary, secondary, or exploratory endpoints was taken …

A Review Of Recent And Developing Studies Regarding Percutaneous Coronary Intervention (Pci): A Narrative Review, Bisher Alsabbagh, Azeez Shala, Joshua Rupert, Abdallah Elsayed

School of Integrative Biological & Chemical Sciences (Formerly Dept. of Biology)

This comprehensive literature review synthesizes the most recent evidence and evolving clinical guidelines concerning percutaneous coronary intervention (PCI) from 2015 to 2025. The study integrates findings from 42 peer-reviewed trials, meta-analyses, registries, and international guideline statements issued by the American College of Cardiology/American Heart Association (ACC/AHA), European Society of Cardiology (ESC), and related societies. Results reveal a decade-long evolution in PCI practice marked by a shift from anatomy-driven to physiology and imaging-guided decision-making, supported by tools such as fractional flow reserve (FFR), instantaneous wave-free ratio (iFR), intravascular ultrasound (IVUS), and optical coherence tomography (OCT). Modern guidelines emphasize individualized, team-based revascularization …

Proteome-Wide Association Study Of Prostate Cancer Risk Across Populations, Hua Zhong, Jingjing Zhu, Shuai Liu, Chong Wu, Liang Wang, Seamus P. Whelton, Catherine H. Marshall, Michael J. Blaha, Peter Durda, Xiuqing Guo, Craig W. Johnson, Henry J. Lin, Kent D. Taylor, Russell P. Tracy, Ronit I. Yarden, Ani W. Manichaikul, Stephen S. Rich, Jerome I. Rotter, Rajat Deo, Ruth F. Dubin, Peter Ganz, Lang Wu

School of Graduate Studies Faculty Publications

There is insufficient understanding of the molecular basis of prostate cancer (PCa) across different populations. We perform a large-scale proteome-wide association study (PWAS) to identify proteins with genetically regulated expression in plasma to be associated with PCa risk across populations. We develop genetic prediction models for expression of 1578, 1993, 1218, and 1390 proteins for African (n = 450), European (n = 758), Asian (n = 289), and Hispanic/Latino (n = 474) males, respectively, and evaluate associations of genetically regulated protein expression with PCa risk in 19,391 PCa cases and 61,608 controls of African population, 122,188 cases and 604,640 controls …

Sex Hormones Influence Ormdl3 Expression: Implications For Sex-Associated Asthma Phenotype, Elisabetta Granato, Ida Cerqua, Antonietta Rossi, Maria Antonietta Riemma, Maria Chiara Monti, Giusy Ferraro, Barbara Romano, Maria Francesca Nanì, Danilo D'Avino, Martina Simonelli, Joshua Malo, Francesca Polverino, Bruno D'Agostino, Giuseppe Cirino, Fiorentina Roviezzo

Faculty, Staff and Students Publications

Background: Genetic polymorphisms in sphingolipid metabolism, particularly involving the orosomucoid-like 3 (ORMDL3) gene, have been associated with asthma risk. Notably, asthma prevalence and severity exhibit pronounced sex differences, emerging in childhood and persisting into adulthood. However, the molecular mechanisms underlying this sexual dimorphism remain incompletely elucidated.

Objective: We investigated whether ORMDL3 contributes to sex differences in airway function and asthma-like features.

Methods: ORMDL3 expression was measured in lung tissues from healthy male and female human donors and in human bronchial epithelial cells (BEAS-2B) after exposure to 17β-estradiol (E2), Dermatophagoides pteronyssinus 1 (Der p 1), or both. A murine preparation of …

Actin Dysregulation Induces Neuroendocrine Plasticity And Immune Evasion: A Vulnerability Of Small Cell Lung Cancer, Yoojeong Seo, Shengzhe Zhang, Jinho Jang, Kyung-Pil Ko, Kee-Beom Kim, Yuanjian Huang, Dong-Wook Kim, Bongjun Kim, Gengyi Zou, Jie Zhang, Sohee Jun, Wonhong Chu, Nicole A Kirk, Ye Eun Hwang, Young Ho Ban, Shilpa S Dhar, Joseph M Chan, Min Gyu Lee, Charles M Rudin, Kwon-Sik Park, Jae-Il Park

Faculty, Staff and Student Publications

Small cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options. Capping protein inhibiting regulator of actin dynamics (CRACD) that promotes actin polymerization, is frequently inactivated in SCLC. However, the role of CRACD loss in SCLC is unknown. Here we show that CRACD depletion drives neuroendocrine (NE) cell plasticity and immune evasion in SCLC. Mechanistically, CRACD inactivation disrupts actin organization, leading to suppression of Yap1-NOTCH signaling and subsequent NE gene upregulation. Simultaneously, CRACD loss drives EZH2-mediated histone methylation via nuclear actin disruption, leading to repression of MHC-I genes and depletion of CD8⁺ T cells. Consequently, CRACD-downregulated tumors exhibit …

Proteome-Wide Association Study Of Prostate Cancer Risk Across Populations, Hua Zhong, Jingjing Zhu, Shuai Liu, Chong Wu, Liang Wang, Seamus P Whelton, Catherine H Marshall, Michael J Blaha, Peter Durda, Xiuqing Guo, Craig W Johnson, Henry J Lin, Kent D Taylor, Russell P Tracy, Ronit I Yarden, Ani W Manichaikul, Stephen S Rich, Jerome I Rotter, Rajat Deo, Ruth F Dubin, Peter Ganz, Lang Wu

Faculty, Staff and Student Publications

There is insufficient understanding of the molecular basis of prostate cancer (PCa) across different populations. We perform a large-scale proteome-wide association study (PWAS) to identify proteins with genetically regulated expression in plasma to be associated with PCa risk across populations. We develop genetic prediction models for expression of 1578, 1993, 1218, and 1390 proteins for African (n = 450), European (n = 758), Asian (n = 289), and Hispanic/Latino (n = 474) males, respectively, and evaluate associations of genetically regulated protein expression with PCa risk in 19,391 PCa cases and 61,608 controls of African population, 122,188 cases and 604,640 controls …

Yap-Induced Glycolysis Drives Fibroinflammation And Disrupts Fibroblast Fidelity, Chang-Ru Tsai, Lin Liu, Yi Zhao, Jong H Kim, Paulo Czarnewski, Rich Gang Li, Fansen Meng, Mingjie Zheng, Jeffrey Steimle, Xiaolei Zhao, Francisco Grisanti, Zheng Sun, Jun Wang, Md Abul Hassan Samee, Xiao Li, James F Martin

Faculty, Staff and Students Publications

Background: Separation of the pulmonic and systemic circulation is essential for terrestrial life, and mammals have evolved distinct cardiac chambers with specialized structures and functions. Transcriptomics profiling revealed cellular heterogeneity between heart chambers. However, the mechanisms underlying chamber-specific transcriptomic and metabolic differences-and their functional significance-remain poorly understood. The Hippo/YAP (yes-associated protein) pathway is a conserved signaling network that regulates diverse cellular processes. The Hippo kinases inhibit YAP in cardiac fibroblasts (CF) to restrict fibrosis and inflammation. Nonetheless, how YAP regulates the metabolic microenvironment during homeostasis and fibroinflammation remains unclear.

Methods: We investigated YAP and glycolysis activity in the 4 cardiac …

A Mouse Model Of Lipoatrophy Reveals Relationships Between Beige Fat Appearance And Female Fertility, Elizabeth S Anaya, William Dion, Pradip K Saha, Aaron R Cox, Evelyn De Groot, Avery A Ahmed, Jessica B Felix, Bokai Zhu, Stephanie A Pangas, Sean M Hartig

Faculty, Staff and Students Publications

White adipose tissue (WAT) performs vital metabolic and endocrine functions, but roles in female reproduction remain understudied and poorly understood. Here, we report that female mice experiencing progressive lipoatrophy after knockout of Ubc9 in adipocytes (Ubc9fKO) displayed disrupted estrous cycles, reduced ovarian reserve, and subfertility. During aging, female Ubc9fKO mice lose subcutaneous WAT more quickly than their male counterparts and weigh less than littermate controls. Subcutaneous WAT excised from female Ubc9fKO mice strongly enriched for thermogenesis genes generally associated with metabolic benefits. Female Ubc9fKO mice exhibited hypermetabolism and accumulated thermogenic, Uncoupling Protein 1-expressing beige fat cells in residual subcutaneous WAT …

A Comprehensive Study Of C-Kit-Expressing Amacrine Cells In The Mammalian Retina, Zheng Jiang, Wen Shen

Faculty, Staff and Students Publications

Amacrine cells assemble complex circuits in the inner retina, where they integrate, modulate, and relay spatial and temporal information to retinal ganglion cells. Nevertheless, their organization and functional diversity are still not fully understood. In this study, we identify a distinct group of amacrine cells that express the stem cell factor receptor-c-Kit. Using combined techniques of anti-CD117 (c-Kit) immunolabeling, confocal imaging, and computational algorithms, we characterize the morphological features and spatial distribution of the c-Kit-expressing amacrine cells. Our results show that c-Kit-expressing amacrine cells are GABA-positive neurons with medium to wide dendritic fields that stratify within the specific strata in …

Dinaciclib Improves Treatment Response In Chemoresistant Hepatoblastoma, Brian T Hickner, Andres F Espinoza, Rohit K Srivastava, Roma H Patel, Priyanka Rao, Nicholas A O'Brien, Kalyani R Patel, Andrew A Badachhape, Abhishek Kona, Dolores H López-Terrada, Sarah E Woodfield, Sanjeev A Vasudevan

Faculty, Staff and Students Publications

Chemoresistant hepatoblastoma (HB) is associated with poor outcomes. Cyclin-dependent kinases (CDKs) are potential therapeutic targets because of their critical role in cell growth and chemoresistance. To evaluate the efficacy of CDK inhibition, HB cell lines were treated with dinaciclib and evaluated with cytotoxic, cell-death reversal, and immunoblotting assays. A HB patient-derived xenograft (PDX) model was treated with placebo, vincristine + irinotecan (VI), dinaciclib, or VI + dinaciclib to evaluate tumor growth and response to therapy. We found that dinaciclib had a marked effect on HB cell viability, induced PARP cleavage, and decreased CDK9 protein expression in vitro. Overexpression of CDK9 …

Pitx2 Dosage-Dependent Changes In Pacemaker Cell State Underlie Sinus Node Dysfunction And Atrial Arrhythmias, Lieve E Van Der Maarel, M Ridwane Mungroo, Otto J Mulleners, Mathilde R Rivaud, Arie O Verkerk, Karel Van Duijvenboden, Freek H T Tiel Groenestege, Jeffrey D Steimle, Lianne Fokkert, Corrie De Gier-De Vries, Mischa Klerk, Arie R Boender, James F Martin, Bjarke Jensen, Gerard J J Boink, Harsha D Devalla, Vincent M Christoffels

Faculty, Staff and Students Publications

Physiologically relevant increases in transcription factor dosage and their role in development and disease remain largely unexplored. Genomic deletions upstream of the Paired-like homeodomain transcription factor gene (PITX2), identified in patients with sinus node dysfunction and atrial fibrillation and modeled in mice (delB), rewire the local epigenetic landscape, increasing PITX2 expression. Here, we demonstrate that pacemaker cardiomyocytes in the embryonic delB sinus node ectopically express PITX2 at physiological dosages in a heterogeneous pattern. The prenatal delB sinus node forms discrete subdomains showing PITX2 dosage-dependent mild or severe loss of pacemaker cardiomyocyte identity. Respective subdomain sizes and severity of sinus node …

Functional Vs Anatomical Cortico-Striatal Connectivity In The Macaque Brain, Wei Tang, Megan E Monko, Zoe Liu, Ana M G Manea, Fernando A Ortega, Damyan Hart, Jason Zhou, Jan Zimmermann, Sarah R Heilbronner

Faculty, Staff and Students Publications

The cerebral cortex provides the main input to the striatum, constituting the first step in cortico-basal ganglia loops. Decades of careful anatomical tract-tracing research have established the exquisite topography of each cortical region's projection to the striatum in nonhuman primates. In parallel, neuroimaging research has demonstrated the relationship between cortico-striatal resting-state functional connectivity and specific cognitive, behavioral, psychiatric, and neurological states in humans. However, still unclear is the extent to which functional connectivity recapitulates the specific topographies of cortico-striatal anatomical connectivity. Here, we combined datasets of cortico-striatal anatomical and functional connectivity in macaques to determine the degree of overlap between …

Racial And Ethnic Disparities In Neoadjuvant Chemotherapy Patterns And Outcomes In Early-Stage Her2-Positive Breast Cancer, Inimfon Jackson, Xiudong Lei, Hui Zhao, Rashmi Murthy, Sharon H Giordano, Mariana Chavez-Macgregor

Faculty, Staff and Student Publications

We examined neoadjuvant chemotherapy (NACT) use, pathological complete response (pCR) and the association with overall survival (OS) among patients with early-stage HER2-positive breast cancer (BC). Patients ≥18 years with stage I-III HER2-positive BC from 2010-2022 who had surgery and chemotherapy were identified. Of 195,023 patients treated with chemotherapy, 37.7% received NACT. NACT use increased from 18.6% in 2010 to 63.4% in 2022 (p <  0.001) and pCR rates rose from 21% to 47.6% (p <  0.001). Black patients were less likely to receive NACT (aOR = 0.96;95%CI 0.93-0.99) or achieve pCR (aOR = 0.86;95%CI 0.82-0.90) than White patients. pCR was associated with a reduction in the risk of death (aHR = 0.45;95%CI 0.42-0.48). 3-year OS increased from 91% in 2010 to 95% in 2019 for patients without a pCR (p <  0.001), and from 97% to 99% for patients with pCR (p = 0.002). Further research is needed to understand and address racial and ethnic disparities in treatment access and outcomes.

Fgf13 Regulates Vgsc-Independent Cardiomyocyte Impulse Propagation Via Cx43 Trafficking, Lala Tanmoy Das, Mattia Malvezzi, Aravind R Gade, Maiko Matsui, Margaret Mckay, Eric Q Wei, Matea J Zelich, Keon Mazdisnian, Jared Kushner, Bi-Xing Chen, Isabella Distefano, Daniel Roybal, Lin Yang, Lisa Stoll, James C Lo, Marian Kalocsay, Fadi G Akar, Steven O Marx, Geoffrey S Pitt

Faculty, Staff and Student Publications

Background: FHF (fibroblast growth factor homologous factor) variants associate with arrhythmias. Although FHFs are best characterized as regulators of voltage-gated sodium channel (VGSC) gating, recent studies suggest broader, non-VGSC-related functions, including regulation of Cx43 (connexin 43) gap junctions and hemichannels, mechanisms that have generally been understudied or disregarded.

Methods: We assessed cardiac conduction and cardiomyocyte action potentials in mice with constitutive cardiac-specific Fgf13 ablation (cFgf13KO) while targeting Cx43 gap junctions and hemichannels pharmacologically. We characterized FGF13 regulation of Cx43 abundance and subcellular distribution. With proximity labeling proteomics, we investigated novel candidate mechanisms underlying FGF13 regulation of Cx43. …

Effect Of Various Lactobacillus Probiotic Strains On Oral Antihypertensive Drug Response: A Systematic Review, Khoirunnisa Ramadhani, Keri Lestari

Pharmacology and Clinical Pharmacy Research

Hypertension is a major risk factor for cardiovascular disease, and the effectiveness of antihypertensive therapy can be influenced by metabolic and systemic inflammatory factors associated with gut microbiota conditions. Probiotic strains from the genus Lactobacillus have been reported to modulate antihypertensive effects through complex biological mechanisms. This article evaluates experimental evidence from seven in vivo studies on the influence of Lactobacillus strains on the response to antihypertensive drugs, including pharmacodynamic mechanisms and drug–probiotic interactions. The combination of Lactiplantibacillus plantarum with amlodipine enhanced nitric oxide production, increased eNOS expression, reduced IL-6 levels, and improved drug bioavailability, leading to greater blood pressure …

Β-Glucan As A Potential Modulator Of Tgf-Β Signaling And Emt-Driven Resistance In Triple-Negative Breast Cancer, Hanifa Dinda Hayati, Riezki Amalia, Gemilang Lara Utama, Dika Pramita Destiani

Pharmacology and Clinical Pharmacy Research

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks expression of estrogen, progesterone, and HER2 receptors, limiting the effectiveness of targeted therapies and making chemotherapy the primary treatment option. However, resistance to chemotherapy remains a major clinical challenge, often driven by dysregulation of the transforming growth factor-β (TGF-β) signaling pathway. TGF-β plays a dual role in cancer, initially acting as a tumor suppressor but later promoting tumor progression through mechanisms such as epithelial–mesenchymal transition (EMT), immune evasion, and the establishment of cancer stemness. This review aims to explore the role of TGF-β signaling and EMT …

Optimization Of Guava Leaf Extract Cream Formulation Through Variations Of Xanthan Gum And Stearic Acid For Wound Cure In Rats, Ayudia Cipta Khairani, Mia Ariasti

Pharmacology and Clinical Pharmacy Research

Cuts are among the most common skin injuries caused by sharp objects and can lead to infection if not properly treated. Natural ingredients such as guava leaves have been widely investigated for their wound-healing potential. Guava leaves contain bioactive compounds including flavonoids, saponins, alkaloids, and tannins, which contribute to anti-inflammatory, antibacterial, and tissue regeneration processes. This study aimed to formulate and evaluate the physical properties and wound-healing effectiveness of guava leaf ethanol extract cream with varying concentrations of xanthan gum and stearic acid as emulsifiers. The extract was obtained by maceration using 70% ethanol and formulated into four cream formulas …

Perceived Effects Of Verbal Orders On In-Patient Medication Reconciliation And Safety: A Multi-Center Cross-Sectional Study, Yahaya Jafaru, Abubakar K. Sahabi, Mohammed M. Sani

Pharmacology and Clinical Pharmacy Research

Medication reconciliation presents significant challenges for healthcare professionals, particularly due to communication gaps that contribute to patient safety incidents. The aim of the study was to investigate the perceived effect of verbal orders on in-patient medication reconciliation and safety. The study was a cross-sectional survey with nurse employees of the three tertiary hospitals in Kebbi State, Nigeria as population of the study. The instrument for the data collection was a 21-items researcher-constructed self-administered questionnaire. Chi-square and binomial regression analysis were used in data analysis. Over two-thirds (70.7%) of the respondents reported a negative perceived effect on the patient’s compliance. The …

What Is The Hospital Pharmaceutical Care? Perceptions And Expectations Of Doctors In Interprofessional Collaboration In 2 Types Of Indonesia Hospitals, Anisyah Achmad, Savvy Augustin Tirta, Titi Annisa Bella, Ratna Kurnia Illahi, Bambang Sidharta, Valentina Yurina, Wara Rejeki

Pharmacology and Clinical Pharmacy Research

Hospital Pharmaceutical Care (HPC) is the pharmacist’s direct responsibility to aim for patient safety and quality of life. HPC is a means of avoiding medication and human errors. Carrying out a HPC requires a good collaboration between doctors and pharmacists in treatment management. The aim of the research was to determine the relationship between doctors’ perceptions and expectations of clinical pharmacists at HPC. This research is descriptive quantitative observational with a cross-sectional approach. The data were collected using purposive sampling (type A hospital) and total sampling (type C hospital) through interviews using perception and expectations questionnaires on doctors’ to pharmacists …

Drug-Related Problems In Hemodialysis Patients With Chronic Kidney Disease: A Study At X Hospital (January–May 2022), Muhammad Refki Abrari, Jatmiko Susilo

Pharmacology and Clinical Pharmacy Research

The prevalence of chronic kidney disease (CKD) in Indonesia has increased from 2.0 ‰in 2013 to 3.8 ‰in 2018. The presence of complex comorbidities associated with CKD causes varied therapy regimens (poly-pharmacy), leading to an increased risk of drug-related problems (DRPs). To overcome these complications, dialysis is often used to remove metabolic waste and rebalance electrolytes to maintain life in patients experiencing rapid loss of kidney function. This study aims to evaluate drugs consumed as well as DRPs experienced by patients diagnosed with CKD undergoing hemodialysis at X Hospital from January to May 2022. The study procedures were carried out …

Crosstalk Between Gut Microbiota And Antihypertensive Drugs: A Systematic Review, Dhiya'ul Haq, Keri Lestari

Pharmacology and Clinical Pharmacy Research

Hypertension is a multifactorial condition characterized by persistently elevated blood pressure. In addition to genetic and environmental factors, recent studies suggest that the gut microbiota contributes to the development of hypertension and modulates the response to antihypertensive therapy. This review aims to summarize the latest knowledge on the bidirectional interaction between gut microbiota and antihypertensive drugs. Original studies published up to May 2025 on this topic were collected from two online databases: PubMed and Scopus. A total of 220 articles were identified, and 9 articles met the inclusion criteria for further discussion. Three of these included articles discussed how gut …

Anti-Inflammatory Actions Of Trigonella Foenum-Graecum L. In Acute And Chronic Inflammation: Insights From Preclinical Studies, Angel Christella, Dzava P. F. Ismail, Eli Halimah

Pharmacology and Clinical Pharmacy Research

Chronic inflammation is a major factor in various degenerative diseases. The use of non-steroidal anti-inflammatory drugs (NSAIDs) is often the main choice, but long-term side effects such as gastrointestinal irritation and nephrotoxicity limit their use. Therefore, natural alternatives such as Trigonella foenum-graecum (fenugreek) have attracted attention due to their bioactive compound contents with anti-inflammatory properties. This narrative review was conducted through a systematic search of articles from the last 10 years in PubMed and Scopus. Keywords used a combination of MeSH and free terms related to fenugreek and anti-inflammatory agents. In vitro and in vivo studies evaluating the anti-inflammatory effects …

Protein-Protein Interaction–Interfering Peptide Rescues Dysregulated Nmda Receptor Signaling, Robert E. Featherstone, Hongbin Li, Ameet S. Sengar, Karin E. Borgmann-Winter, Olya Melnychenko, Lindsey M. Crown, Ray L. Gifford, Felix Amirfathi, Anamika Banerjee, Aivi Tran, Krishna Parekh, Margaret Heller, Wenyu Zhang, Robert J. Gallop, Adam D. Marc, Pragya Komal, Michael W. Salter, Steven J. Siegel, Chang-Gyu Hahn

Farber Institute for Neuroscience Faculty Papers

The complex and heterogeneous genetic architecture of neuropsychiatric illnesses compels us to look beyond individual risk genes for therapeutic strategies and target the interactive dynamics and convergence of their protein products. A mechanistic substrate for convergence of synaptic neuropsychiatric risk genes are protein-protein interactions (PPIs) in the N-methyl-D-aspartate receptor (NMDAR) complex. NMDAR hypofunction in schizophrenia is associated with hypoactivity of Src kinase, resulting from convergent alterations in PPIs of Src with its partners. Of these, the association of Src with PSD-95, which inhibits the activity of this kinase in the NMDAR complex, is known to be increased in schizophrenia. Here, …

Can Cta-Based Machine Learning Identify Patients For Whom Successful Endovascular Stroke Therapy Is Insufficient?, Jerome A Jeevarajan, Yingjun Dong, Anjan Ballekere, Sergio Salazar Marioni, Arash Niktabe, Rania Abdelkhaleq, Sunil A Sheth, Luca Giancardo

Faculty, Staff and Student Publications

Background and purpose: Despite advances in endovascular stroke therapy (EST) devices and techniques, many patients are left with substantial disability, even if the final infarct volumes (FIVs) remain small. Here, we evaluate the performance of a machine learning (ML) approach by using pretreatment CTA to identify this cohort of patients that may benefit from additional interventions.

Materials and methods: We identified consecutive subjects with large vessel occlusion (LVO) acute ischemic stroke (AIS) who underwent EST with successful reperfusion in a multicenter prospective registry cohort. We included only subjects with FIV < 30 mL and recorded 90-day outcome (mRS). A deep learning model was pretrained and then fine-tuned to predict 90-day mRS 0-2 by using pretreatment CTA images (DeepsymNet-v3 model pretrained on radiology reports and fine-tuned on detection of unexpected clinical outcomes using brain CTA images [DSN-CTA] model). The primary outcome was the predictive performance of the DSN-CTA model compared with a logistic regression model with clinical variables, measured by the area under the receiver operating characteristic curve (AUROC).

Results: The DSN-CTA model was pretrained on 1542 subjects and …

Design Of An Open-Label Extension Trial Of Nerandomilast (Bi 1015550) In Patients With Idiopathic Pulmonary Fibrosis And Progressive Pulmonary Fibrosis (Fibroneer™-On), Wim A Wuyts, Luca Richeldi, Shervin Assassi, Arata Azuma, Vincent Cottin, Anna-Maria Hoffmann-Vold, Michael Kreuter, Justin M Oldham, Fernando J Martinez, Claudia Valenzuela, Marlies S Wijsenbeek, Madhu Kanakapura, Alexandra James, Gerrit Weimann, Cyril Drzewuski, Carl Coeck, Toby M Maher

Faculty, Staff and Student Publications

Background: There is a need for more effective treatments for idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF). Nerandomilast (BI 1015550), an oral preferential inhibitor of phosphodiesterase 4B, is being evaluated in two randomized Phase III trials: FIBRONEER™-IPF (NCT05321069) and FIBRONEER™-ILD (NCT05321082). FIBRONEER™-ON is an open-label extension (OLE) of these studies that will evaluate the long-term safety and efficacy of nerandomilast. Here, we describe the study design of the OLE.

Methods: This prospective 98-week OLE will follow the Phase III parent trials, which are currently underway with 1177 patients enrolled in FIBRONEER™-IPF and 1178 patients …

The Lived Experiences Of Mothers Of Children With Down Syndrome Using Teleot Services: A Phenomenological Study, Tumini Umukoro

Doctoral Dissertations and Projects

In response to the COVID-19 lockdown in the United States, therapy services for children with developmental delays transitioned to telehealth services. The purpose of this qualitative study was to explore the lived experiences of mothers of children diagnosed with Down syndrome (DS) who received occupational therapy services through telehealth (teleOT) using interpretative phenomenological analysis (IPA). Bronfenbrenner's ecological system theory was the framework used to address the research questions: RQ1: What are the lived experiences of mothers of children with DS regarding teleOT services? RQ2: How do mothers of children with DS perceive the benefits and challenges of telehealth OT services? …

Associations Between County-Level E-Cigarette-Inclusive Tobacco 21 Law Population Coverage And E-Cigarette Use Behaviors Among United States Adolescents In Monitoring The Future, James H. Buszkiewicz, Catherine A. Vander Woude, Yanmei Xie, Steven Cook, Bukola Usidame, Megan E. Patrick, Michael R. Elliott, James F. Thrasher, Nancy L. Fleischer

Department of Health and Kinesiology Faculty Publications

Background and aims

In the United States (US), Tobacco 21 (T21) laws set the minimum legal sale age for all tobacco products to 21 years. This study aimed to examine whether e-cigarette-inclusive T21 laws were associated with e-cigarette use behaviors and related disparities among US adolescents.

Design

We used nationally representative, repeated cross-sectional Monitoring the Future data to compare self-reported current e-cigarette use (2014–2022) and first e-cigarette initiation (2015–2022) among adolescents in counties with 100% ('full') versus < 100% ('partial or no') e-cigarette-inclusive T21 law population coverage using modified Poisson regression, examining differences by sex, race and ethnicity, parental educational attainment and college educational expectations through interactions.

Setting

United States.

Participants

8th, 10th and 12th graders.

Measurements

County-level e-cigarette-inclusive T21 law population coverage was determined using Tobacco 21 Population Coverage …

Super-Fast, Super-Early: High-Frequency Oscillations May Be A Prelude To Alzheimer's Dementia In Down Syndrome, Manuel Silva-Pérez, Jeannie Chin

Faculty, Staff and Students Publications

Alzheimer's disease (AD) dementia has near full penetrance in adults with Down syndrome (DS) and is strongly linked to late-onset myoclonic epilepsy in Down syndrome (LOMEDS). However, promising biomarkers of epileptogenicity, such as high-frequency oscillations (HFOs >250 Hz), have not been studied. This study is the first to use wideband polysomnography in DS to investigate if HFOs occurred and preceded AD dementia and LOMEDS. Methods: Wideband (0.1 to 500 Hz, 2048 Hz) polysomnography was performed using the international 10–20 system. HFOs were automatically detected during slow-wave sleep, followed by manual review. Results: Fourteen individuals with DS and five age-matched euploid …

Hsp90 Buffers Deleterious Genetic Variations In Brca1, Brant Gracia, Xing-Han Zhang, Patricia Montes, Tin Chanh Pham, Min Huang, Junjie Chen, Georgios Ioannis Karras

Faculty, Staff and Student Publications

Protein-folding chaperone heat shock protein 90 (HSP90) buffers genetic variation in diverse organisms, but the clinical significance of HSP90 buffering in human disease remains unclear. Here, we show that HSP90 buffers mutations in the BRCT domain of BRCA1. HSP90-buffered BRCA1 mutations result in protein variants that retain interactions with partner proteins and strongly rely on HSP90 for protein stability and function in cell survival. Moreover, HSP90-buffered BRCA1 variants confer poly (ADP-ribose) polymerase (PARP) inhibitor resistance in cancer cells. Low-level HSP90 inhibition overcomes this resistance, revealing a cryptic and mutant-specific HSP90-contingent synthetic lethality. Furthermore, by stabilizing metastable variants across the entirety …