Medical Specialties Commons^™

Structural Variants: Mechanisms, Mapping, And Interpretation In Human Genetics

Faculty, Staff and Students Publications

Structural variations (SVs) represent genomic variations that involve breakage and rejoining of DNA segments. SVs can alter normal gene dosage, lead to rearrangements of genes and regulatory elements within a topologically associated domain, and potentially contribute to physical traits, genomic disorders, or complex traits. Recent advances in sequencing technologies and bioinformatics have greatly improved SV detection and interpretation at unprecedented resolution and scale. Despite these advances, the functional impact of SVs, the underlying SV mechanism(s) contributing to complex traits, and the technical challenges associated with SV detection and annotation remain active areas of research. This review aims to provide an …

Single-Nuclei Multiomics Analysis Identifies Abnormal Cardiomyocytes In A Murine Model Of Cardiac Development, Kathy Zimmerman, Ariana Batz, Cathy J Hatcher, Robert M Weiss, Mason Sweat, Xiao Li, Brad A Amendt

Faculty, Staff and Students Publications

Transcription factors such as Tbx5, Gata4, Mef2c and Pitx2 are required during cardiac development, and in adult cardiac homeostasis. We demonstrate that the gene dosage and modulation of these factors are mediated in vivo by the miR-200 family. Inhibition of a single miR-200 family member within the cluster results in defects of the left ventricle and cardiomyocyte maturation during development. Inhibition of the entire miR-200 family results in a ventricular septal defect and embryonic lethality by embryonic day (E)16.5. Inhibition of each miR-200 family has distinct heart phenotypes in cell specific differentiation and maturation. snRNA-sequencing reveals an immature cardiomyocyte cell …

Lessons In Longevity From Blood Stem Cells Under Protein Stress, André Catic

Center on Aging Staff Publications

Blood stem cells are among the body's longest-living cells despite being highly vulnerable to proteotoxic damage, which accelerates their aging. To maintain protein homeostasis (proteostasis), hematopoietic stem cells (HSCs) employ mechanisms such as reduced translation rates, high chaperone activity, autophagy, and selective protein degradation. These strategies mitigate protein misfolding, maintain quiescence, and preserve regenerative potential. Disruptions in proteostasis can lead to the elimination of impaired HSCs through differentiation or apoptosis, ensuring the integrity of the stem cell pool. Due to the systemic impact of the blood on aging and its experimental and clinical accessibility, investigating HSC proteostasis provides insights into …

Cell Type-Specific Purifying Selection Of Synonymous Mitochondrial Dna Variation, Caleb A Lareau, Patrick Maschmeyer, Yajie Yin, Jacob C Gutierrez, Ryan S Dhindsa, Anne-Sophie Gribling-Burrer, Sebastian Zielinski, Yu-Hsin Hsieh, Lena Nitsch, Veronika Dimitrova, Benan Nalbant, Frank A Buquicchio, Tsion Abay, Robert R Stickels, Jacob C Ulirsch, Patrick Yan, Fangyi Wang, Zhuang Miao, Katalin Sandor, Bence Daniel, Vincent Liu, Paul L Mendez, Petra Knaus, Manpreet Meyer, William J Greenleaf, Anshul Kundaje, Redmond P Smyth, Mathias Munschauer, Leif S Ludwig, Ansuman T Satpathy

Duncan NRI Faculty and Staff Publications

While somatic variants are well-characterized drivers of tumor evolution, their influence on cellular fitness in nonmalignant contexts remains understudied. We identified a mosaic synonymous variant (m.7076A > G) in the mitochondrial DNA (mtDNA)-encoded cytochrome c-oxidase subunit 1 (MT-CO1, p.Gly391=), present at homoplasmy in 47% of immune cells from a healthy donor. Single-cell multiomics revealed strong, lineage-specific selection against the m.7076G allele in CD8+ effector memory T cells, but not other T cell subsets, mirroring patterns of purifying selection of pathogenic mtDNA alleles. The limited anticodon diversity of mitochondrial tRNAs forces m.7076G translation to rely on wobble pairing, unlike the Watson-Crick-Franklin pairing …

Sleep Drive, Not Total Sleep Amount, Increases Seizure Risk, Vishnu Anand Cuddapah, Cynthia T Hsu, Fernanda Valle Sirias, Yongjun Li, Hrishit M Shah, Christopher Saul, Samantha Killiany, Camilo Guevara, Joy Shon, Zhifeng Yue, Gabrielle L Gionet, Mary E Putt, Amita Sehgal

Duncan NRI Faculty and Staff Publications

Sleep loss has been associated with increased seizure risk since antiquity. Using automated video detection of spontaneous seizures in Drosophila epilepsy models, we show that seizures worsen only when sleep restriction raises homeostatic "sleep drive," not simply when total sleep amount falls. This is supported by the paradoxical finding that acute activation of sleep-promoting circuits worsens seizures, because it increases sleep drive without changing sleep amount. Sleep-promoting circuits become hyperactive after sleep loss and are associated with increased whole-brain activity. During sleep restriction, optogenetic inhibition of sleep-promoting circuits to reduce sleep drive protects against seizures. Downregulation of the 5HT1A serotonin …

A Data Assimilation Framework For Predicting The Spatiotemporal Response Of High-Grade Gliomas To Chemoradiation, Hugo J M Miniere, David A Hormuth, Ernesto A B F Lima, Maguy Farhat, Bikash Panthi, Mihir D Shanker, Sara Thrower, Jodi Goldman, Sophia Ty, Caroline Chung, Thomas E Yankeelov

Faculty, Staff and Student Publications

Background: High-grade gliomas are highly invasive and respond variably to chemoradiation. Accurate, patient-specific predictions of tumor response could enhance treatment planning. We present a novel computational platform that assimilates MRI data to continually predict spatiotemporal tumor changes during chemoradiotherapy.

Methods: Tumor growth and response to chemoradiation was described using a two-species reaction-diffusion model of enhancing and non-enhancing regions of the tumor. Two evaluation scenarios were used to test the predictive accuracy of this model. In scenario 1, the model was calibrated on a patient-specific basis (n = 21) to weekly MRI data during the course of chemoradiotherapy. A data assimilation …

A Phase I Trial Of Evorpacept, Lenalidomide And Rituximab For Patients With B-Cell Non-Hodgkin Lymphoma, Paolo Strati, Lei Feng, Andrey Tyshevich, Darya Shavronskaya, Julia Alesse, Elizabeth Sheehan, Alexander Nesmelov, Tony Z Zhuang, Dai Chihara, Jason R Westin, Sairah Ahmed, Luis E Fayad, Jared Henderson, Kylie Dent, Elizabeth Mcchesney, Sattva S Neelapu, Christopher R Flowers

Faculty, Staff and Student Publications

Introduction: SIRPα+ macrophages can mediate resistance to lenalidomide and rituximab (R2) in patients with B-cell non-Hodgkin lymphoma (B-NHL). Evorpacept (ALX148) is a novel CD47 blocker that abrogates interactions between lymphoma cells and SIRPα+ macrophages.

Methods: Adult patients with B-NHL who had received at least 2 prior lines of systemic therapy were included in this single arm phase I study (NCT05025800). Evorpacept was administered intravenously (IV), in a 28-day cycle, until progression, at two dose levels (DL): 30 mg/Kg on day (D) 1 and D15 (DL1), or 60 mg/Kg on day 1 (DL2); rituximab 375 mg/m2 IV was given …

Who Benefits From Active Music Engagement During Cancer Treatment? Associations Of Sociodemographic Characteristics And Risk Factors With Moderators Of Intervention Effects., Steven J. Holochwost, Elizabeth Harman, Kristin Stegenga, Seethal A. Jacob, Sheri L. Robb

Manuscripts, Articles, Book Chapters and Other Papers

Young children and their parents experience frequent and repeated exposure to potentially traumatic events during treatment for cancer. Active Music Engagement (AME) is a dyadic music therapy intervention that has been found to mitigate traumatic stress symptoms among parents who screened high for traumatic stress symptoms (TSS) and reported higher levels of child distress with cancer-related hospitalizations/treatment (child distress). The current study examined sociodemographic characteristics and risk factors that were associated with higher levels of parent TSS and child distress as a means to identify families that may benefit most from AME in the future. Data were collected from the …

Xpert Mtb/Rif Ultra Assay For Pulmonary Tuberculosis And Rifampicin Resistance In Adults And Adolescents, Elizabeth Chandler Church, Jonah S Kreniske, Alexander W Kay, Katie Scandrett, Karen R Steingart, Yemisi Takwoingi

Faculty, Staff and Students Publications

Background: Xpert MTB/RIF Ultra (Xpert Ultra) is a molecular World Health Organization (WHO)-recommended rapid diagnostic test that simultaneously detects tuberculosis and rifampicin resistance. This review updates a comparative accuracy Cochrane review of Xpert MTB/RIF and Xpert Ultra as Xpert Ultra has replaced Xpert MTB/RIF.

Objectives: To determine the diagnostic accuracy of Xpert MTB/RIF Ultra (Xpert Ultra) for detecting pulmonary tuberculosis and rifampicin resistance in adults and adolescents with presumptive tuberculosis based on signs or symptoms or with an abnormal chest x-ray suggestive of tuberculosis.

Search methods: We searched seven databases including CENTRAL, MEDLINE, and Embase, plus two trial registers (ClinicalTrials.gov …

Maximizing Relief: The Benefits Of Combining Lateral Femoral Cutaneous Nerve Block With Sciatic Nerve Block In The Emergency Department, Courtney Smith, Taryn Hoffman

Florida Journal of Emergency Medicine (FJEM)

Low back pain accounts for more than 2.6 million emergency department (ED) visits annually, with 40% of Americans experiencing sciatica at some point in their lives. Our case report describes a patient presenting with atraumatic right-sided low back pain and paresthesias in her right leg. We utilized a combination of a transgluteal sciatic nerve block and a lateral femoral cutaneous nerve block to achieve improved pain relief after an initial isolated transgluteal sciatic nerve block left her with persistent anterolateral thigh pain.

We detail the technique for performing this procedure under ultrasound guidance. Our patient experienced significant pain improvement and …

"Star Sign" Of Subarachnoid Hemorrhage, Shivani Ruf

Florida Journal of Emergency Medicine (FJEM)

A 60-year-old female who was brought to the emergency department after a syncopal episode. She was found to have a subarachnoid hemorrhage (SAH) from a ruptured anterior communicating artery aneurysm. Her CT showed the classic "star sign" of SAH.

Elderly Woman With Bilateral Finger Pain, Eric Boccio, Claudia Risi

Florida Journal of Emergency Medicine (FJEM)

N/A

Paroxysmal, Severe, And Unilateral Facial Pain In Adult Male, Eric Boccio, Joshua Mcfarlane, Jeannine Bobadilla

Florida Journal of Emergency Medicine (FJEM)

No abstract provided.

Superficial Cervical Plexus Block For Postoperative Pain Management In Occipital Craniotomies: A Narrative Review, Shahab Ahmadzadeh, Bennett M. Ford, Alex V. Hollander, Mary Kathleen Luetkemeier, Tomasina Q. Parker-Actlis, Sahar Shekoohi

School of Medicine Faculty Publications

Post-craniotomy pain is common yet often sub-optimally managed because systemic opioids can obscure postoperative neurologic examinations. The superficial cervical plexus block (SCPB) has, therefore, emerged as a targeted regional anesthesia option for occipital craniotomies. The SCPB targets the C2-C4 nerves to anesthetize the occipital scalp region, covering the lesser occipital nerve territory that lies within typical posterior scalp incisions. Clinical evidence shows the block is effective in reducing acute postoperative pain after occipital craniotomy and diminishes opioid requirements. Studies have demonstrated successful and long-lasting analgesia, reductions in 24-h opioid consumption, and a lower incidence of severe pain. Moreover, the technique …

A Novel Microdosimetry-Based Formalism For Cell Survival Modelling Applicable To Hypofractionated Radiotherapy, Oleg N Vassiliev, Radhe Mohan

Faculty, Staff and Student Publications

Objectives

Hypofractionated radiotherapy requires reliable cell survival models for doses much higher than the standard 2 Gy, for which the linear-quadratic (LQ) model is not applicable. We developed an alternative approach applicable to both low doses and high doses used in hypofractionated treatments and radiobiological experiments.

Approach.

We combined a standard microdosimetric technique with a recently introduced non-LQ cell survival model. Our formulation accounts for cell damage by multi-track events involving any number of particles. This is necessary for modelling cell survival at therapeutic doses. We characterise each cell type by the size �� of the sensitive volume (SV) and …

Dosimetric Effects Of Pinnacle³ Version 18.0 Advanced Auto-Planning Settings In Oropharyngeal Vmat Optimization, Emily Sanden

Masters Projects

This study evaluated the impact of Pinnacle³ version 18.0 auto-planning advanced settings modulation amount, monitor unit (MU) level, and dose fall-off priority on volumetric modulated arc therapy (VMAT) plan quality for bilateral oropharyngeal cancer. A total of 64 plans were generated using all possible combinations of low, medium, high, and very high settings for each parameter. A standardized base of tongue case was optimized once per plan using a single-time point approach, with planned target volume 1 (PTV1) (6996 cGy) and planned target volume 2 (PTV2) (5412 cGy) coverage evaluated. Each parotid gland, the spinal cord, brainstem, and the oral …

Melanoma Antigens In Pediatric Medulloblastoma Contribute To Tumor Heterogeneity And Species-Specificity Of Group 3 Tumors, Rebecca R J Collins, Rebecca R Florke Gee, Sima Tozandehjani, Tara Bayat, Maria Camila Hoyos Sanchez, Barbara Breznik, Samuel T Peters, Jon P Connelly, Shondra M Pruett-Miller, Martine F Roussel, Dinesh Rakheja, Heather S Tillman, Patrick Ryan Potts, Klementina Fon Tacer

Faculty, Staff and Student Publications

Medulloblastoma (MB) is the most malignant childhood brain cancer. Group 3 MB (G3 MB) subtype accounts for about 25% of MB and is associated with the worst outcomes. Herein, we report that more than half of G3 MB tumors express melanoma antigens (MAGEs), which are potential prognostic and therapeutic markers. MAGEs are cancer-testis antigens, aberrantly expressed in several adult cancers, and associated with poorer prognosis and therapy resistance; however, their role in pediatric cancers is mostly unknown. This study aimed to determine whether MAGEs are activated and important in pediatric MB. We obtained formalin-fixed paraffin-embedded tumor samples of 34 patients, …

Use Of Cholic Acid In Smith-Lemli-Opitz Syndrome (Slos): Real-World Patient Outcomes, Edwin Ferren, Paul R Hillman, Amy Kritzer, Joseph Ray, Alvaro Serrano, Paige Roberts, Tiziano Pramparo, Pamela Vig, Robert D Steiner

Faculty, Staff and Student Publications

Background: Smith-Lemli-Opitz Syndrome (SLOS) is an autosomal recessive disorder of cholesterol biosynthesis caused by biallelic pathogenic variants in DHCR7, which encodes the enzyme 7-dehydrocholesterol reductase (DHCR7). SLOS is a multisystemic disorder affecting various aspects of health, including growth, development, behavior, and quality of life, underscoring the need for safe, efficacious interventions that limit disease burden. DHCR7 enzyme deficiency leads to a "metabolic block" resulting in decreased cholesterol production and accumulation of its precursor 7-dehydrocholesterol and the secondary isomer 8-dehydrocholesterol. Reduced cholesterol synthesis, in turn, leads to decreased levels of cholic acid (CA), an endogenous bile acid synthesized from cholesterol and …

Phosphoglycerate Mutase Regulates Treg Differentiation Through Control Of Serine Synthesis And One-Carbon Metabolism, Kaho Cho, Xiaojing Deng, Chandra Shekar R Ambati, Vasanta Putluri, Abu Hena Mostafa Kamal, Paul M Kim, Nagireddy Putluri, Michael D Kornberg

Faculty, Staff and Students Publications

The differentiation and suppressive functions of regulatory CD4 T cells (Tregs) are supported by a broad array of metabolic changes, providing potential therapeutic targets for immune modulation. In this study, we focused on the regulatory role of glycolytic enzymes in Tregs and identified phosphoglycerate mutase (PGAM) as being differentially overexpressed in Tregs and associated with a highly suppressive phenotype. Pharmacologic or genetic inhibition of PGAM reduced Treg differentiation and suppressive function while reciprocally inducing markers of a pro-inflammatory, T helper 17 (Th17)-like state. The regulatory role of PGAM was dependent on the contribution of 3-phosphoglycerate (3 PG), the PGAM substrate, …

Dietary Lipids Induce Ppard And Bcl6 To Repress Macrophage Il-23 Induction After Intestinal Injury And Lps Exposure, Kendra Norwood, Adrien Assie, Buck S Samuel, Angela M Major, Gretchen E Diehl, Andrea A Hill Mcalester

Faculty, Staff and Students Publications

Unresolved tissue damage is a common feature of Inflammatory Bowel Disease (IBD) that facilitates disease progression. Here, we showed that high animal fat diets (HFD), an environmental risk factor associated with IBD pathogenesis, suppress intestinal macrophage production of critical tissue repair responses after damage. This includes reduced IL-23 production, which drives downstream production of IL-22, which is needed for barrier repair. Indicating that dietary lipids interfere with responses to microbial molecules needed to induce barrier protective functions, we found oleic acid could directly suppress macrophage Il23a induction after lipopolysaccharide (LPS) treatment. Deleting the lipid transporter CD36 on macrophages restored the …

Silent Misplacement: Leadless Pacemaker In The Left Ventricle Discovered Over A Year Later-How Did It End Up There? Could It Explain The Stroke?, Abdalhakim Shubietah, Amir Singh, Qutaiba Qafisheh, Pouyan Razminia, Muath Baniowda, Abdalrahman Assaassa, Hosam I. Taha, Roaa Aljunaidi

Division of Cardiology Faculty Papers

Introduction: Leadless intracardiac pacemakers (LICPs) reduce lead-related complications but may be malpositioned in patients with unrecognized structural defects. We report a 69-year-old man with high-grade AV block whose LICP, intended for right ventricular placement, was found in the left ventricle via an undiagnosed ostium secundum ASD after presenting with multifocal embolic strokes 16 months later. Case Presentation: Stroke workup for acute right-sided symptoms revealed the LICP in the LV and a large, previously undiagnosed ASD with bidirectional shunting and severe pulmonary hypertension. Embolic infarcts were attributed to either paradoxical embolism or device-related thromboembolism. Due to high surgical risk, …

Combination Of Irreversible Electroporation And Clostridium Novyi-Nt Bacterial Therapy For Colorectal Liver Metastasis, Zigeng Zhang, Guangbo Yu, Qiaoming Hou, Farideh Amirrad, Sha Webster, Surya M. Nauli, Jianhua Yu, Vahid Yaghmai, Aydin Eresen, Zhuoli Zhang

Pharmacy Faculty Articles and Research

Colorectal liver metastasis (CRLM) poses a significant challenge in oncology due to its high incidence and poor prognosis in unresectable cases. Current treatments, including surgical resection, systemic chemotherapy, and liver-directed therapies, often fail to effectively target hypoxic tumor regions, which are inherently more resistant to these interventions. This review examines the potential of a novel therapeutic strategy combining irreversible electroporation (IRE) ablation and Clostridium novyi-nontoxic (C. novyi-NT) bacterial therapy. IRE is a non-thermal tumor ablation technique that uses high-voltage electric pulses to create permanent nanopores in cell membranes, leading to cell death while preserving surrounding structures, and …

Demystifying The Nuances Of The Lipid Patient: A Guide For Primary Care Providers, Merle Myerson, Kyle Gillett, James O'Hara, Richard Potter, Neil Skolnik

Abington Jefferson Health Papers

Atherosclerosis, a major cause of mortality and morbidity in the United States (US), is driven by complex factors, including the cumulative burden of low-density lipoprotein cholesterol (LDL-C) and other atherogenic lipids and lipoproteins. Lipid management in US primary care aims to prevent atherosclerotic cardiovascular disease (ASCVD) events through screening and LDL-C lowering to risk-based goals. However, lipid screening and ASCVD treatment is often inadequate, with few patients meeting LDL-C goals in clinical practice. Primary care providers have a vital role in identifying patients most at risk of ASCVD to prevent ASCVD events and improve patient outcomes. There are multiple different …

Comparison Of Recurrence Rates In Chemical Matricectomy With Phenol And Nail Bracing: A Scoping Review, Jessica Sima, Amanda Killeen

School of Podiatric Medicine - Student Research

Introduction: Ingrown toenails are one of the most common nail conditions and are usually treated with chemical matricectomy using phenol (CMP). However, this procedure is often contraindicated in patients with diabetes mellitus or peripheral vascular disease. Orthonyxia, or nail braces application, is a non-invasive alternative treatment for ingrown toenails. The nail braces are spring wires with one side shaped into a hook that is placed under one side of the nail, and the other side attached to a plastic pad that is glued to the nail plate. The braces retain the normal shape of the nails without removing them, allowing …

Impact Of Prostate Volume On Dose Fall-Off And Organ-At-Risk Exposure In Vmat For Prostate Cancer, Zhikang Jiang

Masters Projects

Prostate cancer remains one of the most prevalent malignancies among men, with radiotherapy, particularly VMAT—playing a central role in its management. VMAT allows for highly conformal dose delivery, but treatment planning must strike a careful balance between achieving steep dose gradients around the prostate and minimizing radiation exposure to nearby organs at risk (OARs), such as the bladder and rectum. This study aimed to evaluate how prostate volume influences dose fall-off characteristics and OAR dose exposure in VMAT treatment plans, providing insights into optimizing radiotherapy for patients with varying prostate sizes. A retrospective analysis was conducted on 50 prostate cancer …

Inhibition Of The Caveolin-1 Pathway Promotes Apoptosis And Overcomes Pan-Tyrosine Kinase Inhibitor Resistance In Hepatocellular Carcinoma, Tasnuva D. Kabir, Samuel Beck, Lisa M. Stuart, Ji Li, Rui Hou, Peiwen Liu, Shelby Margolius, Claire Kim, Yu Suk Choi, Edward R. Bastow, Dianne J. Beveridge, Lisa Spalding, Ziyi Li, Florent Ginhoux, Pierce Chow, Michael Phillips, Andrew D. Redfern, George C. Yeoh, Alistair Forrest, Andrew J. Woo, Ankur Sharma, Jacob George, Geoffrey Mccaughan, Peter Leedman

Research outputs 2022 to 2026

Resistance to multi-tyrosine kinase inhibitors (TKI) is a major clinical concern in advanced hepatocellular carcinoma (HCC). Herein, we aimed to uncover the mechanisms underlying pan-TKI resistance and to identify potential therapeutic targets. We used multiple TKI-resistant HCC cell lines to identify caveolin-1 (CAV1) as a key driver of therapeutic resistance. CAV1 downregulation induced apoptosis, inhibited metastasis and restored TKI sensitivity in both inherent and acquired TKI-resistant HCC cells. Mechanistically, in acquired TKI-resistant cells aberrant CAV1/STAT3/P70S6K signalling is required for their survival, motility, and invasiveness. CAV1 inhibition reduced expression of dormancy regulators E-cadherin, RAC1 and p21, enhanced cancer stemness markers, and …

Human Ipsc-Based Breast Cancer Model Identifies S100p-Dependent Cancer Stemness Induced By Brca1 Mutation, Jingxin Liu, Cai Zhao, Jiahao Chen, Pengguihang Zeng, Qingjian Li, Xingqiang Lai, Jianing Chen, Xixi Zhu, Xinyi Liu, Jun Sun, Jia Wang, Peihang Fang, Tengfei Wang, Wenjie Chen, Diana Guallar, Nan Cao, Jianli Zhao, Shicheng Su, Andy Peng Xiang, Yi Arial Zeng, Jie Li, Junchao Cai, Dung-Fang Lee, Jinxin Bei, Yongliang Huo, Hai Hu, Shengbao Suo, Dong-Feng Huang, Jin Bai, Junjun Ding

Faculty, Staff and Student Publications

Breast cancer is the most common malignancy in females and remains the leading cause of cancer-related deaths for women worldwide. The cellular and molecular basis of breast tumorigenesis is not completely understood partly due to the lack of human research models which simulate the development of breast cancer. Here, we developed a method for generating functional mammary-like cells (MCs) from human-induced pluripotent stem cells (iPSCs). The iPSC-MCs closely resemble human primary MCs at cellular, transcriptional, and functional levels. Using this method, a breast cancer model was generated using patient-derived iPSCs harboring germline

Adaptive Bayesian Clinical Trials: The Past, Present, And Future Of Clinical Research, Donald A Berry

Faculty, Staff and Student Publications

Background/Objectives: Decision-analytic Bayesian approaches are ideally suited for designing clinical trials. They have been used increasingly over the last 30 years in developing medical devices and drugs. A prototype trial is a bandit problem in which treating participants is as important as treating patients in clinical practice after the trial.

Methods: This article chronicles the use of the Bayesian approach in clinical trials motivated by bandit problems. It provides a comprehensive historical and practical review of Bayesian adaptive trials, with a focus on bandit-inspired designs.

Results: The 20th century saw advances in Bayesian methodology involving computer simulation. In the …

Il-6 Predicts Cdk4/6 Inhibitor Resistance, Identifying Stat3 As A Target In Hr + /Her2-Negative Metastatic Breast Cancer, Nicole M Kettner, Tuyen N Bui, Juliana Navarro-Yepes, Sanaz Ghotbaldini, Bethanie Quintela, Nghi Lam, Akshara Singareeka Raghavendra, Yan Wang, Nancy Azizian, T Kris Eckols, Moses Makokha Kasembeli, Kurt Evans, Min Yi, Hannah Wingate, Jing Wang, Aysegul A Sahin, Funda Meric-Bernstam, Kelly K Hunt, Senthil Damodaran, David J Tweardy, Debu Tripathy, Khandan Keyomarsi

Faculty, Staff and Student Publications

Resistance to CDK4/6 inhibitors (CDK4/6i) is a major challenge in treating hormone receptor-positive, HER2-negative metastatic breast cancer. This study aimed to identify a biomarker predictive of resistance that could also serve as a therapeutic target. Circulating IL-6 levels in 166 patients significantly increased at progression, making IL-6 a non-invasive biomarker to predict CDK4/6i resistance. Knockdown of IL-6 re-sensitized resistant cells to palbociclib and endocrine therapy, underscoring IL-6's critical role in maintaining resistance. Patient-derived xenograft models from patients who progressed within 3 months versus ≥6 months of palbociclib therapy revealed distinct transcriptomic profiles, with later progressors exhibiting IL-6/STAT3 activation, epithelial-to-mesenchymal transition, …

U-Rich Elements Drive Pervasive Cryptic Splicing In 3′ Utr Massively Parallel Reporter Assays, Anthony M Mustoe

Faculty, Staff and Students Publications

Untranslated RNA sequences play essential roles in orchestrating gene expression. However, the sequence codes and mechanisms underpinning post-transcriptional regulation remain incompletely understood. Here, we revisit the finding from a prior massively parallel reporter assay (MPRA) that AU-rich elements in 3' untranslated regions (3' UTRs) can drive upregulation or downregulation of mRNA expression depending on 3' UTR context. We unexpectedly discover that this variable regulation arises from widespread cryptic splicing, predominately from an unannotated splice donor in the coding sequence of GFP to diverse acceptor sites in reporter 3' UTRs. Splicing is activated by U-rich sequences, which function as potent position-dependent …