Medicine and Health Sciences Commons^™

Implementation Of A Dyadic Nomenclature For Monogenic Diseases, Courtney Thaxton, Leslie G Biesecker, Marina Distefano, Melissa Haendel, Ada Hamosh, Emma Owens, Sharon E Plon, Heidi L Rehm, Jonathan S Berg

Center for Medical Ethics and Health Policy Staff Publications

A core task when establishing the strength of evidence for a gene's role in a monogenic disorder is determining the appropriate disease entity to curate. Establishing this concept determines which evidence can be applied and quantified toward the final gene-disease validity, variant pathogenicity, or actionability classification. Genes with implications in more than one phenotype can necessitate a process of lumping and splitting, disease reorganization, and updates to disease nomenclature. Reappraisal of the names that are used as labels for disease entities is therefore a necessary and perpetual process. The Clinical Genome Resource (ClinGen), in collaboration with representatives from Monarch Disease …

Neoadjuvant Parpi Or Chemotherapy In Ovarian Cancer Informs Targeting Effector Treg Cells For Homologous-Recombination-Deficient Tumors, Yikai Luo, Yu Xia, Dan Liu, Xiong Li, Huayi Li, Jiahao Liu, Dongchen Zhou, Yu Dong, Xin Li, Yiyu Qian, Cheng Xu, Kangjia Tao, Guannan Li, Wen Pan, Qing Zhong, Xingzhe Liu, Sen Xu, Zhi Wang, Ronghua Liu, Wei Zhang, Wanying Shan, Tian Fang, Siyuan Wang, Zikun Peng, Ping Jin, Ning Jin, Shennan Shi, Yuxin Chen, Mengjie Wang, Xiaofei Jiao, Mengshi Luo, Wenjian Gong, Ya Wang, Yue Yao, Yi Zhao, Xinlin Huang, Xuwo Ji, Zhaoren He, Guangnian Zhao, Rong Liu, Mingfu Wu, Gang Chen, Li Hong, Cocpo Consortium, Ding Ma, Yong Fang, Han Liang, Qinglei Gao

Faculty, Staff and Student Publications

Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) as key responders to HRD …

A Systematic Review Of The Timing Of Therapeutic Anticoagulation In Adult Patients With Acute Traumatic Brain Injury: Narrative Synthesis Of Observational Studies, Sophie Samuel, Jennifer Cortes, Eugene Uh, Huimahn Alex Choi

Library Staff Publications

Traumatic brain injury (TBI) presents complex management scenarios, particularly in patients requiring anticoagulation for concurrent conditions such as venous thromboembolism (VTE) or atrial fibrillation (AF). A systematic search of PubMed/MEDLINE, Embase, and the Cochrane Library databases was conducted to identify relevant studies. Inclusion criteria encompassed studies assessing the effects of anticoagulation therapy on outcomes such as re-hemorrhage, hematoma expansion, thrombotic events, and hemorrhagic events in TBI patients with subdural hematomas (SDH). This systematic review critically addresses two key questions: the optimal timing for initiating anticoagulation therapy and the differential impact of this timing based on the type of intracranial bleed, …

Rna Interacts With Topoisomerase I To Adjust Dna Topology, Mannan Bhola, Kouki Abe, Paola Orozco, Homa Rahnamoun, Pedro Avila-Lopez, Elijah Taylor, Nefertiti Muhammad, Bei Liu, Prachi Patel, John F Marko, Anne C Starner, Chuan He, Eric L Van Nostrand, Alfonso Mondragón, Shannon M Lauberth

Faculty, Staff and Students Publications

Topoisomerase I (TOP1) is an essential enzyme that relaxes DNA to prevent and dissipate torsional stress during transcription. However, the mechanisms underlying the regulation of TOP1 activity remain elusive. Using enhanced cross-linking and immunoprecipitation (eCLIP) and ultraviolet-cross-linked RNA immunoprecipitation followed by total RNA sequencing (UV-RIP-seq) in human colon cancer cells along with RNA electrophoretic mobility shift assays (EMSAs), biolayer interferometry (BLI), and in vitro RNA-binding assays, we identify TOP1 as an RNA-binding protein (RBP). We show that TOP1 directly binds RNA in vitro and in cells and that most RNAs bound by TOP1 are mRNAs. Using a TOP1 RNA-binding mutant …

Regional Desynchronization Of Microglial Activity Is Associated With Cognitive Decline In Alzheimer's Disease, Artem Zatcepin, Samira Parhizkar, Et Al.

2020-Current year OA Pubs

BACKGROUND: Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker.

METHODS: To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia …

Stat3-Mediated Atg7 Expression Regulates Anti-Tumor Immunity In Mouse Melanoma, Sarah M Zimmerman, Erin Suh, Sofia R Smith, George P Souroullas

2020-Current year OA Pubs

Epigenetic modifications to DNA and chromatin control oncogenic and tumor-suppressive mechanisms in melanoma. Ezh2, the catalytic component of the Polycomb Repressive Complex 2 (PRC2), which mediates methylation of lysine 27 on histone 3 (H3K27me3), can regulate both melanoma initiation and progression. We previously found that mutant Ezh2

Efficacy Of Parp Inhibitor Therapy After Targeted Braf/Mek Failure In Advanced Melanoma, Jordan Phillipps, George Nassief, Renee Morecroft, Tolulope Adeyelu, Andrew Elliott, Farah Abdulla, Ari Vanderwalde, Soo Park, Omar Butt, Alice Zhou, George Ansstas

2020-Current year OA Pubs

Modern advancements in targeted therapy and immunotherapy have significantly improved survival outcomes for advanced melanoma; however, there remains a need for novel approaches to overcome disease progression and treatment resistance. In recent years, PARPi therapy has shown great promise both as a single regimen and in combination with other therapeutics in melanoma. Here, we describe three unique cases of advanced BRAF V600 mutated melanoma that progressed on targeted BRAF/MEK agents that subsequently exhibited partial to near-complete responses to combinatory PARPi and BRAF/MEK inhibitors. This highlights both a potential synergy underlying this combinatory approach and its efficacy as a treatment option …

Taste Masked Of Eplerenone Using Egg Box Method, Asmaa Mohammed Rashid

Maaen Journal for Medical Sciences

Eplerenone is a selective mineralocorticoid receptor antagonist employed to manage hypertension, central serous retinopathy, and chronic heart failure. It has a highly bitter taste, which reduces patient compliance with the drug.

The aim of this study was masking the very bitter taste of the eplerenone to improve patient compliance especially for geriatric patient.

The medication was encapsulated utilizing the ionic gelation process, in which a 1% w/w sodium alginate solution was utilized to form egg box structures.Two different concentrations of CaCl2 (0.5.1%w/v) were used as cross-linkers, and different drug: polymer ratios were tested. The formulas were evaluated based on their …

Developing A Stand-Alone Children’S Hospital In Southern Nevada: Improving Pediatric Care And Diversifying The Regional Economy, The Lincy Institute

Lincy Institute Events

Southern Nevada is the largest metropolitan region in the country without a stand-alone children's hospital. The absence of such a facility results in poor health outcomes for children, fragmented and inadequate specialized care, and a shortage of pediatric medical professionals. Currently ranked last in clinical care nationwide, Nevada urgently needs a centralized, academic-based children's hospital to improve health services.

The Lincy Institute hosted a community forum to release the findings of a new report conducted by Tripp Umbach detailing why Southern Nevada needs a stand-alone children’s hospital. Tripp Umbach is a recognized industry leader, with 30 years of successful partnerships …

The Foodpunk City: Advancing Portland's Food Security Through A Shared Ideology Of Adaptation & Resistance, Nickolas Hash

Dissertations and Theses

Food injustice is a form of violence perpetrated by state and corporate actors against a constituency under their governing power, particularly impacting marginalized and impoverished communities. It denies individuals access to nutritious food, perpetuating cycles of poverty, inequality, physical health risks, and social exclusion. Grassroots movements have emerged to challenge dominant paradigms and advocate for food sovereignty, agroecology, and food anarchy. In Portland, the movement represents a nontraditional approach to food security that closely resembles the reactionary ideology of urban "punk" culture. Both groups prioritize community autonomy over food systems, sustainable agricultural practices, and resistance to oppressive structures that perpetuate …

Fall Prevention Strategies In A Pediatric Epilepsy Monitoring Unit, Bailey Cochrum

EBP Fellowship

No abstract provided.

Physiological And Communicative Emotional Disconcordance In Children On The Autism Spectrum, Emma Finkel, Eric Sah, Mckenna Spaulding, John Herrington, Liza Tomczuk, Aaron Masino, Xueqin Pang, Anushua Bhattacharya, Darren Hedley, Yelena Kushleyeva, Phoebe Thomson, Natalie Doppelt, Jessica Tan, Jeffrey Pennington, Cheryl Dissanayake, Christopher Bonafide, Heather Nuske

SKMC Student Presentations and Publications

BACKGROUND: Individuals on the autism spectrum commonly have differences from non-autistic people in expressing their emotions using communicative behaviors, such as facial expressions. However, it is not yet clear if this reduced expressivity stems from reduced physiological reactivity in emotional contexts or if individuals react internally, but do not show these reactions externally to others. We hypothesized that autism is characterized by a discordance between in-the-moment internal psychophysiological arousal and external communicative expressions of emotion.

METHODS: Forty-one children on the autism spectrum and 39 non-autistic, typically developing (TD) children of two age groups (2-4 and 8-12 years) participated in a …

Assessing The Accuracy And Utility Of Chatgpt Responses To Patient Questions Regarding Posterior Lumbar Decompression, Alec Giakas, Rajkishen Narayanan, Teeto Ezeonu, Jonathan Dalton, Yunsoo Lee, Tyler Henry, John Mangan, Gregory Schroeder, Alex Vaccaro, Christopher Kepler

Department of Orthopaedic Surgery Faculty Papers

Aim: To examine the clinical accuracy and applicability of ChatGPT answers to commonly asked questions from patients considering posterior lumbar decompression (PLD). Methods: A literature review was conducted to identify 10 questions that encompass some of the most common questions and concerns patients may have regarding lumbar decompression surgery. The selected questions were then posed to ChatGPT. Initial responses were then recorded, and no follow-up or clarifying questions were permitted. Two attending fellowship-trained spine surgeons then graded each response from the chatbot using a modified Global Quality Scale to evaluate ChatGPT’s accuracy and utility. The surgeons then analyzed each question, …

Tranq Dope: Characterization Of An Ed Cohort Treated With A Novel Opioid Withdrawal Protocol In The Era Of Fentanyl/Xylazine, Kory London, Yutong Li, Jennifer Kahoud, Davis Cho, Jamus Mulholland, Sebastian Roque, Logan Stugart, Jeffrey Gillingham, Elias Borne, Benjamin Slovis

Department of Emergency Medicine Faculty Papers

BACKGROUND: Treating opioid use disorder has reached a new level of challenge. Synthetic opioids and xylazine have joined the non-medical opioid supply, multiplying the complexities of caring for individuals in emergency departments (ED). This combination, known as 'tranq dope,' is poorly described in literature. Inadequate withdrawal treatment results in a disproportionately high rate of patient-directed discharges (also known as against medical advice dispositions, or AMA). This study aimed to describe a cohort of individuals who received a novel order set for suspected fentanyl and xylazine withdrawal in the ED.

METHODS: This is a descriptive study evaluating a cohort of ED …

Successful Treatment Of A Chronic Recurrent Expanding Hematoma Of The Thigh, Gianfranco Galantini, Bakhtawar Mushtaq, Jesse Ottaway, Charles Long

Abington Jefferson Health Papers

Chronic expanding hematoma (CEH) is a rare entity that poses diagnostic and therapeutic challenges due to persistent growth, risk of recurrence, and potential for blood loss anemia. The most common etiologies of CEH are trauma or surgery. It is thought to occur due to irritant effects of blood breakdown products, causing bleeding from capillaries in chronic granulation tissue. Although treatment of CEH is variable, complete surgical excision of the hematoma and its pseudocapsule is the gold standard. We present a case of a 15-year CEH that was initially treated with limited evacuation of the hematoma and cavity decortication, resulting in …

A Clinician’S Perspective On The New Organ Mesentery And Non-Vascular Mesenteropathies, Monjur Ahmed

Division of Gastroenterology and Hepatology Faculty Papers

Mesentery was discovered as a new organ in 2017. It is a continuous membranous tissue from the duodenojejunal flexure to the anorectal junction. It has distinct anatomy, physiology, and disease states. Primary mesenteropathies include vascular and non-vascular diseases. Some of them are common, and some of them are rarely seen in clinical practice. Secondary mesenteropathies occur when infection or malignancy in another organ spreads to the mesentery. Each entity has specific diagnostic and treatment protocols. Increased awareness of different mesenteropathies and an understanding of their various presentations at different stages of life can help in early diagnosis and improved clinical …

Developing A Stand-Alone Children’S Hospital In Southern Nevada: Needs, Opportunities, And Economic Development Considerations, Tripp Umbach

Policy Briefs and Reports

This independent study developed by Tripp Umbach demonstrates how an independent, research-intensive, stand-alone children’s teaching hospital can significantly enhance the health status of Southern Nevada’s children, reduce outmigration, attract children from neighboring states, and stimulate the healthcare economy. Tripp Umbach evaluated the need for a children’s hospital, the barriers to overcoming its absence, and the advantages of establishing a stand-alone children’s hospital in Southern Nevada for diverse audiences throughout Nevada and nationally.

Different Sensory Information Is Used For State Estimation When Stationary Or Moving., Aaron Wong, Alyssa Eyssalenne, Luke Carter, Amanda S Therrien

Moss-Magee Rehabilitation Papers

The accurate estimation of limb state is necessary for movement planning and execution. While state estimation requires both feedforward and feedback information, we focus here on the latter. Prior literature has shown that integrating visual and proprioceptive feedback improves estimates of static limb position. However, differences in visual and proprioceptive feedback delays suggest that multisensory integration could be disadvantageous when the limb is moving. We formalized this hypothesis by modeling feedback-based state estimation using the long-standing maximum likelihood estimation model of multisensory integration, which we updated to account for sensory delays. Our model predicted that the benefit of multisensory integration …

Chylopericardium And Superior Vena Cava Syndrome Caused By Central Venous Occlusion From Indwelling Hemodialysis Catheters, Daniel Underberg, Nicholas Demario, Sebastian Rodriguez, Khulkar Mirzozoda, Mark Decaro, Gregary Marhefka

Division of Cardiology Faculty Papers

Chylopericardium is a rare condition. Causes include superior vena cava syndrome resulting from indwelling catheters. We present a case of this condition in a 42-year-old man with end-stage renal disease treated with hemodialysis through a right subclavian vein catheter. He underwent successful endovascular stenting with resolution of his symptoms and chylopericardium.

Transorbital Alternating Current Stimulation In A Double-Masked Randomized Clinical Trial: Visual Functional Effect And Quality Of Life, Maria De Los Angeles Ramos Cadena, Ashley Sohn, Heather Livengood, Ting-Fang Lee, Batsheva Rubin, Jiyuan Hu, Bernhard A. Sabel, Rachel Matayev, Joseph Panarelli, Gadi Wollstein, Joel S. Schuman

Wills Eye Hospital Papers

PURPOSE: To determine the efficacy and safety of repetitive transorbital alternating current stimulation (rtACS) treatment by assessing vision-related quality of life and visual function outcome in subjects treated with rtACS versus sham-control.

STUDY DESIGN: Double masked, randomized, sham-controlled clinical trial (NCT03188042).

SUBJECTS: Sixteen subjects with moderate-to-advanced glaucoma (visual field [VF] mean deviation [MD] ≤-6.00 decibels) randomized into sham (9 subjects) or rtACS intervention (7 subjects) groups.

METHODS: Subjects underwent 10 rtACS sessions over 2 weeks. All subjects had comprehensive ocular examination at baseline, 1-week, and 4-weeks posttreatment.

MAIN OUTCOME MEASURES: Visual acuity (VA), contrast sensitivity (CS), VF MD, number of …

Single-Cell And Spatial Proteo-Transcriptomic Profiling Reveals Immune Infiltration Heterogeneity Associated With Neuroendocrine Features In Small Cell Lung Cancer, Ying Jin, Yuefeng Wu, Alexandre Reuben, Liang Zhu, Carl M Gay, Qingzhe Wu, Xintong Zhou, Haomin Mo, Qi Zheng, Junyu Ren, Zhaoyuan Fang, Teng Peng, Nan Wang, Liang Ma, Yun Fan, Hai Song, Jianjun Zhang, Ming Chen

Faculty, Staff and Student Publications

Small cell lung cancer (SCLC) is an aggressive pulmonary neuroendocrine malignancy featured by cold tumor immune microenvironment (TIME), limited benefit from immunotherapy, and poor survival. The spatial heterogeneity of TIME significantly associated with anti-tumor immunity has not been systemically studied in SCLC. We performed ultra-high-plex Digital Spatial Profiling on 132 tissue microarray cores from 44 treatment-naive limited-stage SCLC tumors. Incorporating single-cell RNA-sequencing data from a local cohort and published SCLC data, we established a spatial proteo-transcriptomic landscape covering over 18,000 genes and 60 key immuno-oncology proteins that participate in signaling pathways affecting tumorigenesis, immune regulation, and cancer metabolism across 3 …

Screening Of Anti-Prion Compounds Using The Protein Misfolding Cyclic Amplification Technology, Sandra Pritzkow, Isaac Schauer, Ananya Tupaki-Sreepurna, Rodrigo Morales, Claudio Soto

Faculty, Staff and Student Publications

Prion diseases are 100% fatal infectious neurodegenerative diseases affecting the brains of humans and other mammals. The disease is caused by the formation and replication of prions, composed exclusively of the misfolded prion protein (PrPSc). We invented and developed the protein misfolding cyclic amplification (PMCA) technology for in vitro prion replication, which allow us to replicate the infectious agent and it is commonly used for ultra-sensitive prion detection in biological fluids, tissues and environmental samples. In this article, we studied whether PMCA can be used to screen for chemical compounds that block prion replication. A small set of compounds previously …

Exploring The Feasibility And Acceptability Of Community Paramedicine Programs In Achieving Vaccination Equity: A Qualitative Study, Monica Kasting, Alfu Laily, Sidney J. Smith, Sathveka Sembian, Katharine J. Head, Bukola Usidame, Gregory D. Zimet, Laura M. Schwab Reese

Department of Health and Kinesiology Faculty Publications

Mobile Integrated Health-Community Paramedicine (MIH-CP) is a novel approach that may reduce the rural-urban disparity in vaccination uptake in the United States. MIH-CP providers, as physician extenders, offer clinical follow-up and wrap-around services in homes and communities, uniquely positioning them as trusted messengers and vaccine providers. This study explores stakeholder perspectives on feasibility and acceptability of community paramedicine vaccination programs.

The Prognostic Effect Of Infiltrating Immune Cells Is Shaped By Proximal M2 Macrophages In Lung Adenocarcinoma, Jian-Rong Li, Vikram Shaw, Yupei Lin, Xiang Wang, Muhammad Aminu, Yong Li, Jia Wu, Jianjun Zhang, Christopher I Amos, Chao Cheng

Faculty, Staff and Students Publications

The spatial arrangement of immune cells within the tumor microenvironment (TME) and their interactions play critical roles in the initiation and development of cancer. Several advanced technologies such as imaging mass cytometry (IMC) providing the immunological landscape of the TME with single-cell resolution. In this study, we develop a new method to quantify the spatial proximity between different cell types based on single-cell spatial data. Using this method on IMC data from 416 lung adenocarcinoma patients, we show that the proximity between different cell types is more correlated with patient prognosis compared to the traditional features such immune cell density …

Intracellular Islatravir-Triphosphate Half-Life Supports Extended Dosing Intervals, Xiaowei Zang, Wendy Ankrom, Walter K. Kraft, Ryan Vargo, S Aubrey Stoch, Marian Iwamoto, Randolph P Matthews

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Antiretroviral therapy has substantially reduced morbidity, mortality, and disease transmission in people living with HIV. Islatravir is a nucleoside reverse transcriptase translocation inhibitor that inhibits HIV-1 replication by multiple mechanisms of action, and it is in development for the treatment of HIV-1 infection. In preclinical and clinical studies, islatravir had a long half-life (t½) of 3.0 and 8.7 days (72 and 209 hours, respectively); therefore, islatravir is being investigated as a long-acting oral antiretroviral agent. A study was conducted to definitively elucidate the terminal t½ of islatravir and its active form islatravir-triphosphate (islatravir-TP). A single-site, open-label, non-randomized, single-dose phase 1 …

Molecularly Imprinted Wearable Sensor With Paper Microfluidics For Real-Time Sweat Biomarker Analysis, Mayank Garg, Heng Guo, Ethan Maclam, Elizabeth Zhanov, Sathwika Samudrala, Anton Pavlov, Md Saifur Rahman, Myeong Namkoong, Jennette P Moreno, Limei Tian

Faculty, Staff and Student Publications

The urgent need for real-time and noninvasive monitoring of health-associated biochemical parameters has motivated the development of wearable sweat sensors. Existing electrochemical sensors show promise in real-time analysis of various chemical biomarkers. These sensors often rely on labels and redox probes to generate and amplify the signals for the detection and quantification of analytes with limited sensitivity. In this study, we introduce a molecularly imprinted polymer (MIP)-based biochemical sensor to quantify a molecular biomarker in sweat using electrochemical impedance spectroscopy, which eliminates the need for labels or redox probes. The molecularly imprinted biosensor can achieve sensitive and specific detection of …

Smart Toys For Sensing And Soothing Distress In Pediatric Patients, Jonathan Daniel Bonilla

Dartmouth College Master’s Theses

This thesis develops and evaluates child-centered technologies to support remote monitoring of pediatric patients, with an emphasis on childhood cancer and pediatric chronic pain. For these and many other health conditions, current therapies tend to focus on treating physical symptoms yet neglect the psycho-emotional aspects of managing the illness. However, such mental states play a major role in recovery. Research has shown that cancer patients with better mental health have better prognoses, higher possibilities of remission, and faster healing processes, while chronic pain patients with better mental health report lower levels of pain. To enable more personalized, continuous, and scalable …

Staff Education Program To Enhance Patient Handover Communication, Olufemi Olawale

Walden Dissertations and Doctoral Studies

Patient handover communication is the process that occurs when nurses transfer responsibility for patient care and give status reports to nurses who are assuming care of the patient. The practice problem at the project site was the gap in quality, accuracy, and completeness of information that was shared during the handover process. The purpose of this project was to develop, implement, and evaluate a staff education program on effective communication handover between nurses and care providers. The practice-focused question for this project was: Will a staff education project increase nurses’ and clinicians’ knowledge and competency with using the situation, background, …

G Protein Selectivity Profile Of Gpr56/Adgrg1 And Its Effect On Downstream Effectors, Raida Jallouli, Ana L Moreno-Salinas, Andréanne Laniel, Brian Holleran, Charlotte Avet, Joan Jacob, Trang Hoang, Christine Lavoie, Kendra S Carmon, Michel Bouvier, Richard Leduc

Faculty, Staff and Student Publications

GPR56, an adhesion G-protein coupled receptor (aGPCRs) with constitutive and ligand-promoted activity, is involved in many physiological and pathological processes. Whether the receptor's constitutive or ligand-promoted activation occur through the same molecular mechanism, and whether different activation modes lead to functional selectivity between G proteins is unknown. Here we show that GPR56 constitutively activates both G12 and G13. Unlike constitutive activation and activation with 3-α-acetoxydihydrodeoxygedunin (3αDOG), stimulation with an antibody, 10C7, directed against GPR56's extracellular domain (ECD) led to an activation that favors G13 over G12. An autoproteolytically deficient mutant, GPR56-T383A, was also activated by 10C7 indicating that the tethered …

Crizotinib Enhances Parp Inhibitor Efficacy In Ovarian Cancer Cells And Xenograft Models By Inducing Autophagy, Janice M Santiago-O'Farrill, Alicia Blessing Bollu, Hailing Yang, Vivian Orellana, Marc Pina, Xudong Zhang, Jinsong Liu, Robert C Bast, Zhen Lu

Faculty, Staff and Student Publications

Poly (ADP-ribose) polymerase inhibitors (PARPi) can encounter resistance through various mechanisms, limiting their effectiveness. Our recent research showed that PARPi alone can induce drug resistance by promoting autophagy. Moreover, our studies have revealed that anaplastic lymphoma kinase (ALK) plays a role in regulating the survival of ovarian cancer cells undergoing autophagy. Here, we explored whether the ALK-inhibitor crizotinib could enhance the efficacy of PARPi by targeting drug-induced autophagic ovarian cancer cell and xenograft models. Our investigation demonstrates that crizotinib enhances the anti-tumor activity of PARPi across multiple ovarian cancer cells. Combination therapy with crizotinib and olaparib reduced cell viability and …