Digital Commons Network^™

Diabetes Study Of Children Of Diverse Ethnicity And Race: Study Design, Maria J Redondo, Kylie K Harrall, Deborah H Glueck, Mustafa Tosur, Serife Uysal, Andrew Muir, Elizabeth G Atkinson, Melanie R Shapiro, Liping Yu, William E Winter, Michael Weedon, Todd M Brusko, Richard Oram, Kendra Vehik, William Hagopian, Mark A Atkinson, Dana Dabelea, Discover Study Group

Faculty, Staff and Students Publications

AIMS: Determining diabetes type in children has become increasingly difficult due to an overlap in typical characteristics between type 1 diabetes (T1D) and type 2 diabetes (T2D). The Diabetes Study in Children of Diverse Ethnicity and Race (DISCOVER) programme is a National Institutes of Health (NIH)-supported multicenter, prospective, observational study that enrols children and adolescents with non-secondary diabetes. The primary aim of the study was to develop improved models to differentiate between T1D and T2D in diverse youth.

MATERIALS AND METHODS: The proposed models will evaluate the utility of three existing T1D genetic risk scores in combination with data on …

Environmental Justice: A Missing Core Tenet Of Global Health, Redeat Workneh, Merhawit Abadi, Krystle Perez, Sharla Rent, Elliott Mark Weiss, Stephanie Kukora, Olivia Brandon, Gal Barbut, Sahar Rahiem, Shaphil Wallie, Joseph Mhango, Benjamin C Shayo, Friday Saidi, Gesit Metaferia, Mahlet Abayneh, Gregory C Valentine

Faculty, Staff and Students Publications

No abstract provided.

Advances In Pediatric Acute Kidney Injury Pharmacology And Nutrition: A Report From The 26th Acute Disease Quality Initiative (Adqi) Consensus Conference, Molly Wong Vega, Michelle C Starr, Patrick D Brophy, Prasad Devarajan, Danielle E Soranno, Ayse Akcan-Arikan, Rajit Basu, Stuart L Goldstein, Jennifer R Charlton, Erin Barreto

Faculty, Staff and Students Publications

BACKGROUND: In the past decade, there have been substantial advances in our understanding of pediatric AKI. Despite this progress, large gaps remain in our understanding of pharmacology and nutritional therapy in pediatric AKI.

METHODS: During the 26th Acute Disease Quality Initiative (ADQI) Consensus Conference, a multidisciplinary group of experts reviewed the evidence and used a modified Delphi process to achieve consensus on recommendations for gaps and advances in care for pharmacologic and nutritional management of pediatric AKI. The current evidence as well as gaps and opportunities were discussed, and recommendations were summarized.

RESULTS: Two consensus statements were developed. (1) High-value, …

Targeting Glutamine Dependence With Drp-104 Inhibits Proliferation And Tumor Growth Of Castration-Resistant Prostate Cancer, David Moon, J Spencer Hauck, Xue Jiang, Holly Quang, Lingfan Xu, Fan Zhang, Xia Gao, Robert Wild, Jeffrey I Everitt, Everardo Macias, Yiping He, Jiaoti Huang

Faculty, Staff and Students Publications

BACKGROUND: Prostate cancer (PCa) continues to be one of the leading causes of cancer deaths in men. While androgen deprivation therapy is initially effective, castration-resistant PCa (CRPC) often recurs and has limited treatment options. Our previous study identified glutamine metabolism to be critical for CRPC growth. The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) blocks both carbon and nitrogen pathways but has dose-limiting toxicity. The prodrug DRP-104 is expected to be preferentially converted to DON in tumor cells to inhibit glutamine utilization with minimal toxicity. However, CRPC cells' susceptibility to DRP-104 remains unclear.

METHODS: Human PCa cell lines (LNCaP, LAPC4, C4-2/MDVR, PC-3, 22RV1, …

Increased Plasma Branched Short-Chain Fatty Acids And Improved Glucose Homeostasis: The Microbiome And Insulin Longitudinal Evaluation Study (Miles), Arianne Aslamy, Alexis C Wood, Elizabeth T Jensen, Alain G Bertoni, Patricia A Sheridan, Kari E Wong, Gautam Ramesh, Jerome I Rotter, Yii-Der I Chen, Mark O Goodarzi

Faculty, Staff and Students Publications

Short-chain fatty acids (SCFAs) have been extensively studied for potential beneficial roles in glucose homeostasis and risk of diabetes; however, most of this research has focused on butyrate, acetate, and propionate. The effect on metabolism of branched SCFAs (BSCFAs; isobutyrate, isovalerate, and methylbutyrate) is largely unknown. In a cohort of 219 non-Hispanic White participants and 126 African American participants, we examined the association of BSCFA with dysglycemia (prediabetes and diabetes) and oral glucose tolerance test-based measures of glucose and insulin homeostasis, as well as with demographic, anthropometric, lifestyle, and lipid traits, and other SCFAs. We observed a bimodal distribution of …

Frequency Of Treatment Failure Of Utis In Children With Congenital Urinary Tract Anomalies, Catherine S Forster, Alexis C Wood, Stephanie Davis-Rodriguez, Pearl W Chang, Sanyukta Desai, Michael Tchou, John M Morrison, Jamie D Mudd, Brittany D Casey, Victor Trevisanut, Rana F Hamdy, Vijaya Vemulakonda, Patrick W Brady, Sowdhamini S Wallace, Uti In Children With Cakut Study Group

Faculty, Staff and Students Publications

OBJECTIVES: Children with certain congenital anomalies of the kidney and urinary tract and neurogenic bladder (CAKUT/NGB) are at higher risk of treatment failure for urinary tract infections (UTIs) than children with normal genitourinary anatomy, but the literature describing treatment and outcomes is limited. The objectives of this study were to describe the rate of treatment failure in children with CAKUT/NGB and compare duration of antibiotics between those with and without treatment failure.

METHODS: Multicenter retrospective cohort of children 0 to 17 years old with CAKUT/NGB who presented to the emergency department with fever or hypothermia and were diagnosed with UTI …

Ketamine For Pain In Sickle Cell Disease Reduces Opioid Usage, Christina O Onyebuchi, Corrie E Chumpitazi, Jennifer L Placencia, Andrea N Jackson, Jennifer L Jones, Laura Torres, Venée N Tubman

Faculty, Staff and Students Publications

CONTEXT: Pain attributable to sickle cell disease (SCD) is often unpredictable, recurrent, and requires complex treatments. Subanesthetic ketamine infusion has been studied in other diseases and disorders, but there is still limited data on its efficacy in pain management for SCD.

OBJECTIVES: The primary objective is to determine if subanesthetic ketamine infusion reduces pain scores and opioid requirements in hospitalized pediatric patients with SCD.

RESULTS: Forty-six admissions among 22 patients between February 2018 and December 2019 were analyzed. We observed decrease in pain scores within 24 hours of ketamine initiation in 34 of 46 admissions (mean pain score per patient …

Failure Rate Of Anti-Tumor Necrosis Factor Α Biologics In Very Early Onset Inflammatory Bowel Disease, Ashleigh Watson, Lina B Karam, Richard Kellermayer

Faculty, Staff and Students Publications

No abstract provided.

Advances And Challenges In Conventional And Modern Techniques For Halal Food Authentication: A Review, Ifrah Usman, Saima Sana, Muhammad Afzaal, Ali Imran, Farhan Saeed, Aftab Ahmed, Yasir Abbas Shah, Muniba Munir, Huda Ateeq, Atka Afzal, Iqra Azam, Afaf Ejaz, Gulzar Ahmad Nayik, Mahbubar Rahman Khan

Faculty, Staff and Student Publications

Food is one of the most necessary needs since human civilization. For Muslims, it is mandatory to consume halal food. From a halal authentication perspective, adulteration of food products is an emerging challenge worldwide. The demand for halal food consumption has resulted in an ever-increasing need for halal product validity. In the market, there are several food products in which actual ingredients and their source are not mentioned on the label and cannot be observed by the naked eye. Commonly nonhalal items include pig derivatives like lard, pork, and gelatin derivatives, dead meats, alcohol, blood, and prohibited animals. Purposely, various …

Environmental Justice: A Missing Core Tenet Of Global Health, Redeat Workneh, Merhawit Abadi, Krystle Perez, Sharla Rent, Elliott Mark Weiss, Stephanie Kukora, Olivia Brandon, Gal Barbut, Sahar Rahiem, Shaphil Wallie, Joseph Mhango, Benjamin C Shayo, Friday Saidi, Gesit Metaferia, Mahlet Abayneh, Gregory C Valentine

Faculty, Staff and Students Publications

No abstract provided.

Echocardiographic Image Collection And Evaluation In Infants With Chd: Lessons Learned From The Imaging Core Lab For The Residual Lesion Score Study, Jami C Levine, Steven Colan, Felicia Trachtenberg, Edward Marcus, Matthew Ferguson, Anitha Parthiban, Carolyn Taylor, Andreea Dragulescu, Benjamin Goot, Ronald V Lacro, Carol Mcfarland, Shanthi Narasimhan, Matthew O'Connor, Marcus Schamberger, Shubhika Srivistava, Michael Taylor, Meena Nathan

Faculty, Staff and Students Publications

Many factors affect patient outcome after congenital heart surgery, including the complexity of the heart disease, pre-operative status, patient specific factors (prematurity, nutritional status and/or presence of comorbid conditions or genetic syndromes), and post-operative residual lesions. The Residual Lesion Score is a novel tool for assessing whether specific residual cardiac lesions after surgery have a measurable impact on outcome. The goal is to understand which residual lesions can be tolerated and which should be addressed prior to leaving the operating room. The Residual Lesion Score study is a large multicentre prospective study designed to evaluate the association of Residual Lesion …

Psychosocial Moderators Of Polygenic Risk Scores Of Inflammatory Biomarkers In Relation To Grimage, Amanda J F Tamman, Dora Koller, Sheila Nagamatsu, Brenda Cabrera-Mendoza, Chadi Abdallah, John H Krystal, Joel Gelernter, Janitza L Montalvo-Ortiz, Renato Polimanti, Robert H Pietrzak

Faculty, Staff and Students Publications

GrimAge acceleration has previously predicted age-related morbidities and mortality. In the current study, we sought to examine how GrimAge is associated with genetic predisposition for systemic inflammation and whether psychosocial factors moderate this association. Military veterans from the National Health and Resilience in Veterans study, which surveyed a nationally representative sample of European American male veterans, provided saliva samples for genotyping (N = 1135). We derived polygenic risk scores (PRS) from the UK Biobank as markers of genetic predisposition to inflammation. Results revealed that PRS for three inflammatory PRS markers—HDL (lower), apolipoprotein B (lower), and gamma-glutamyl transferase (higher)—were associated …

A Case Of Diffuse Thyroid Lipomatosis With Amyloid Deposits Presenting With Thyrotoxicosis, Adrian M Gonzalez-Gil, Marco A Ruiz-Santillan, Bahar K Force, Ruchi Gaba

Faculty, Staff and Students Publications

Diffuse thyroid lipomatosis (DTL) is a rare entity of unknown etiology that can be associated with amyloidosis and rarely, thyrotoxicosis. Here, we present a case of DTL with amyloid deposits and concurrent thyrotoxicosis. A 64-year-old South-Asian woman with a several-year history of an enlarging goiter, unintentional weight loss, and work-up 10 months prior suggestive of thyroiditis presented with a viral syndrome in setting of several weeks of progressive fatigue. Her examination was notable for resting sinus tachycardia and massive painless goiter. Initial work-up revealed nephrotic range proteinuria with hypoalbuminemia, which progressed to end-stage-renal disease, elevated inflammatory markers, and elevated free …

Development And Feasibility Pilot Study Of Indigenous Recovery Planning: A Community-Engaged Approach To Addressing Substance Use In A Native Community, Monica C Skewes, Vivian M Gonzalez, Julie A Gameon, Adriann Ricker, Shannon Martell, Martel Reum, Shannon Holder

Faculty, Staff and Student Publications

Although Native (American Indian and Alaska Native [AI/AN]) populations have high rates of abstinence from alcohol, health problems associated with substance use remain a pressing concern in many AI/AN communities. As part of a longstanding community-based participatory research (CBPR) project involving five years of relationship building and three preliminary studies, our team of academic and community co-researchers developed a culturally grounded intervention to facilitate recovery from substance use disorders among tribal members from a rural AI reservation. Our Indigenous Recovery Planning (IRP) intervention consists of six weekly sessions and aims to provide inroads to existing resources in the community, affirm …

Cost Analysis For Robotic And Open Gastrectomy, Yuki Hirata, Heather G Lyu, Ahad M Azimuddin, Pamela Lu, Jeeva Ajith, Jason A Schmeisser, Elizabeth P Ninan, Kyung Hyun Lee, Brian D Badgwell, Paul Mansfield, Naruhiko Ikoma

Faculty, Staff and Student Publications

Objective: To determine the magnitude of the perioperative costs associated with robotic gastrectomy (RG).

Background: A robotic surgery platform has a high implementation cost and requires maintenance costs; however, whether the overall cost of RG, including all perioperative costs, is higher than conventional open gastrectomy (OG) remains unknown.

Methods: Patients who underwent a major gastrectomy during February 2018 through December 2021 were retrospectively identified. We calculated the perioperative costs of RG and OG and compared them overall as well as in different phases, including intraoperative costs and 30-day postsurgery inpatient and outpatient costs. We investigated factors potentially associated with high …

Selective Degradation Of Pl2l60 By Metabolic Stresses-Induced Autophagy Suppresses Multi-Cancer Growth, Lei Sun, Fu Hui, Gao-Yan Tang, Hai-Lian Shen, Xue-Lei Cao, Jian-Xin Gao, Lin-Feng Li

Faculty, Staff and Student Publications

It has been reported that PL2L60 proteins, a product of PIWIL2 gene which might be activated by an intragenic promoter, could mediate a common pathway specifically for tumorigenesis. In the present study, it was further identified by using western blot assay that the PL2L60 proteins could be degraded in cancer cells through a mechanism of selective autophagy in response to oxidative stress. The PL2L60 was downregulated in various types of cancer cells under the hypoxic condition independently of HIF-1α, resulting in apoptosis of cancer cells. Inhibition of autophagy by small interfering RNA targeting of either Beclin-1 (BECN1) or …

Case Of Nocturnal Emesis, Weight Loss, And Aspiration Pneumonia, Roman Babayev, Sharonda Taylor, Elizabeth V Franklin

Faculty, Staff and Students Publications

No abstract provided.

Heterozygous Map3k20 Variants Cause Ectodermal Dysplasia, Craniosynostosis, Sensorineural Hearing Loss, And Limb Anomalies, Daniel Brooks, Elizabeth Burke, Sukyeong Lee, Tanya N Eble, Melanie O'Leary, Ikeoluwa Osei-Owusu, Heidi L Rehm, Shweta U Dhar, Lisa Emrick, David Bick, Michelle Nehrebecky, Ellen Macnamara, Dídac Casas-Alba, Judith Armstrong, Carolina Prat, Antonio F Martínez-Monseny, Francesc Palau, Pengfei Liu, David Adams, Undiagnosed Diseases Network, Seema Lalani, Jill A Rosenfeld, Lindsay C Burrage

Faculty, Staff and Students Publications

Biallelic pathogenic variants in MAP3K20, which encodes a mitogen-activated protein kinase, are a rare cause of split-hand foot malformation (SHFM), hearing loss, and nail abnormalities or congenital myopathy. However, heterozygous variants in this gene have not been definitively associated with a phenotype. Here, we describe the phenotypic spectrum associated with heterozygous de novo variants in the linker region between the kinase domain and leucine zipper domain of MAP3K20. We report five individuals with diverse clinical features, including craniosynostosis, limb anomalies, sensorineural hearing loss, and ectodermal dysplasia-like phenotypes who have heterozygous de novo variants in this specific region of the gene. …

Reply To Ayoub-Charette Et Al Lack Of Biological Plausibility And Major Methodological Issues Cast Doubt On The Association Between Aspartame And Autism Comment On "Fowler Et Al Daily Early-Life Exposures To Diet Soda And Aspartame Are Associated With Autism In Males: A Case-Control Study, Sharon Parten Fowler, David Gimeno Ruiz De Porras, Michael D Swartz, Paula Stigler Granados, Lynne Parsons Heilbrun, Raymond F Palmer

Faculty, Staff and Student Publications

Thank you for the opportunity to respond to the concerns raised by Ayoub-Charette et al [...].

Experience With A Hybrid Recruitment Approach Of Patient-Facing Web Portal Screening And Subsequent Phone And Medical Record Review For A Neurosurgical Intervention Trial For Chronic Ischemic Stroke Disability (Pisces Iii), Brad J Kolls, Keith W Muir, Sean I Savitz, Lawrence R Wechsler, Julie G Pilitsis, Scott Rahimi, Richard L Beckman, Vincent Holmes, Peng R Chen, David S Albers, Daniel T Laskowitz

Faculty, Staff and Student Publications

BACKGROUND: Recruitment of participants is the greatest risk to completion of most clinical trials, with 20-40% of trials failing to reach the targeted enrollment. This is particularly true of trials of central nervous system (CNS) therapies such as intervention for chronic stroke. The PISCES III trial was an invasive trial of stereotactically guided intracerebral injection of CTX0E03, a fetal derived neural stem cell line, in patients with chronic disability due to ischemic stroke. We report on the experience using a novel hybrid recruitment approach of a patient-facing portal to self-identify and perform an initial screen for general trial eligibility (tier …

Estrogen Signaling In The Dorsal Raphe Regulates Binge-Like Drinking In Mice, Valeria C Torres Irizarry, Bing Feng, Xiaohua Yang, Nirali Patel, Sarah Schaul, Lucas Ibrahimi, Hui Ye, Pei Luo, Leslie Carrillo-Sáenz, Penghua Lai, Maya Kota, Devin Dixit, Chunmei Wang, Amy W Lasek, Yanlin He, Pingwen Xu

Faculty, Staff and Students Publications

Estrogens promote binge alcohol drinking and contribute to sex differences in alcohol use disorder. However, the mechanisms are largely unknown. This study aims to test if estrogens act on 5-hydroxytryptamine neurons in the dorsal raphe nucleus (5-HTDRN) to promote binge drinking. We found that female mice drank more alcohol than male mice in chronic drinking in the dark (DID) tests. This sex difference was associated with distinct alterations in mRNA expression of estrogen receptor α (ERα) and 5-HT-related genes in the DRN, suggesting a potential role of estrogen/ERs/5-HT signaling. In supporting this view, 5-HTDRN neurons from naïve male mice had …

Improving Safety And Preventing Falls Using An Evidence-Based, Front-Line Staff Huddling Practice: Protocol For A Pragmatic Trial To Increase Quality Of Care In State Veterans Homes, Princess Nash, Valerie Clark, Eleanor Mcconnell, Whitney Mills, Robert Morgan, Camilla Pimentel, Katherine Ritchey, Cari Levy, A Lynn Snow, Christine Hartmann

Faculty, Staff and Student Publications

Introduction: Falls in nursing homes are a major cause for decreases in residents' quality of life and overall health. This study aims to reduce resident falls by implementing the LOCK Falls Programme, an evidence-based quality improvement intervention. The LOCK Falls Programme involves the entire front-line care team in (1) focusing on evidence of positive change, (2) collecting data through systematic observation and (3) facilitating communication and coordination of care through the practice of front-line staff huddles.

Methods and analysis: The study protocol describes a mixed-methods, 4-year hybrid (type 2) effectiveness-implementation study in State Veterans Homes in the USA. The study …

Polyaminer-Bulk Is A Deep Learning-Based Algorithm That Decodes Alternative Polyadenylation Dynamics From Bulk Rna-Seq Data, Venkata Soumith Jonnakuti, Eric J Wagner, Mirjana Maletić-Savatić, Zhandong Liu, Hari Krishna Yalamanchili

Faculty, Staff and Students Publications

Alternative polyadenylation (APA) is a key post-transcriptional regulatory mechanism; yet, its regulation and impact on human diseases remain understudied. Existing bulk RNA sequencing (RNA-seq)-based APA methods predominantly rely on predefined annotations, severely impacting their ability to decode novel tissue- and disease-specific APA changes. Furthermore, they only account for the most proximal and distal cleavage and polyadenylation sites (C/PASs). Deconvoluting overlapping C/PASs and the inherent noisy 3' UTR coverage in bulk RNA-seq data pose additional challenges. To overcome these limitations, we introduce PolyAMiner-Bulk, an attention-based deep learning algorithm that accurately recapitulates C/PAS sequence grammar, resolves overlapping C/PASs, captures non-proximal-to-distal APA changes, …

Use Of Crispr Interference For Efficient And Rapid Gene Inactivation In Fusobacterium Nucleatum, Peng Zhou, Bibek G C, Flynn Stolte, Chenggang Wu

Faculty, Staff and Student Publications

Gene inactivation by creating in-frame deletion mutations in Fusobacterium nucleatum is time consuming, and most fusobacterial strains are genetically intractable. Addressing these problems, we introduced a riboswitch-based inducible CRISPR interference (CRISPRi) system. This system employs the nuclease-inactive Streptococcus pyogenes Cas9 protein (dCas9), specifically guided to the gene of interest by a constantly expressed single-guide RNA (sgRNA). Mechanistically, this dCas9-sgRNA complex serves as an insurmountable roadblock for RNA polymerase, thus repressing the target gene transcription. Leveraging this system, we first examined two non-essential genes, ftsX and radD, which are pivotal for fusobacterial cytokinesis and coaggregation. Upon adding the inducer, theophylline, …

Revascularization Strategies For Acute And Chronic Mesenteric Ischemia: A Narrative Review, Jacob J Gries, Takashi Sakamoto, Bing Chen, Hafeez Ul Hassan Virk, Mahboob Alam, Chayakrit Krittanawong

Faculty, Staff and Students Publications

Mesenteric ischemia is a challenging condition characterized by insufficient blood perfusion to the mesentery and, consequently, intestinal tissues that continues to perplex clinicians. Despite its low prevalence, the condition’s variable clinical presentation and elusive radiographic diagnosis can delay life-saving interventions in the acute setting and deteriorate the quality of life of patients when left undiagnosed or misdiagnosed. Purpose: Review and summarize recent diagnostic updates and emergent intervention strategies for acute and chronic mesenteric ischemia. Methods: A narrative review of all relevant studies from January 2022 through September 2023. Results: A total of 11 studies from MEDLINE, supplemented with 44 studies …

Association Of Lifestyle Intervention With Risk For Cardiovascular Events Differs By Level Of Glycated Hemoglobin, Michael P Bancks, Scott J Pilla, Ashok Balasubramanyam, Hsin-Chieh Yeh, Karen C Johnson, Joseph Rigdon, Lynne E Wagenknecht, Mark A Espeland

Faculty, Staff and Students Publications

Purpose: We reevaluated the Action for Health in Diabetes (Look AHEAD) intensive lifestyle intervention (ILI) to assess whether the effect of ILI on cardiovascular disease (CVD) prevention differed by baseline glycated hemoglobin (HbA1c).

Methods: Look AHEAD randomized 5145 adults, aged 45 to 76 years with type 2 diabetes and overweight/obesity to ILI or a diabetes support and education (DSE) control group for a median of 9.6 years. ILI focused on achieving weight loss through decreased caloric intake and increased physical activity. We assessed the parent trial's primary composite CVD outcome. We evaluated additive and multiplicative heterogeneity of the intervention on …

A Review Of Olanzapine In The Treatment Of Cancer Anorexia-Cachexia Syndrome, Ivy O Poon, Veronica Ajewole, Ursula K Braun

Center for Medical Ethics and Health Policy Staff Publications

Background: Cancer anorexia-cachexia syndrome (CAS) is a multifactorial condition that is highly prevalent in advanced cancer patients and associated with significant reduction in functional performance, reduction in quality of life, and increased mortality. Currently, no medications are approved for this indication. Recently, the American Society of Clinical Oncology (ASCO) released a rapid recommendation suggesting that low-dose olanzapine once daily may be used to treat cancer cachexia. Many questions still exist on how to use olanzapine for this indication in clinical practice. The objective of this review is to identify existing knowledge on the use of olanzapine for CAS.

Methods: A …

A Small Molecule With Big Impact: Mrtx1133 Targets The Krasg12d Mutation In Pancreatic Cancer, Daoyan Wei, Liang Wang, Xiangsheng Zuo, Anirban Maitra, Robert S Bresalier

Faculty, Staff and Student Publications

KRAS mutations drive oncogenic alterations in numerous cancers, particularly in human pancreatic ductal adenocarcinoma (PDAC). About 93% of PDACs have KRAS mutations, with G12D (∼42% of cases) and G12V (∼32% of cases) being the most common. The recent approval of sotorasib (AMG510), a small-molecule, covalent, and selective KRASG12C inhibitor, for treating patients with non-small cell lung cancer represents a breakthrough in KRAS targeted therapy. However, there is a need to develop other much-needed KRAS-mutant inhibitors for PDAC therapy. Notably, Mirati Therapeutics recently developed MRTX1133, a small-molecule, noncovalent, and selective KRASG12D inhibitor through extensive structure-based drug design. MRTX1133 has demonstrated potent …

Cpsf3 Inhibition Blocks Pancreatic Cancer Cell Proliferation Through Disruption Of Core Histone Mrna Processing, Abdulrahman A Alahmari, Aditi H Chaubey, Venkata S Jonnakuti, Arwen A Tisdale, Carla D Schwarz, Abigail C Cornwell, Kathryn E Maraszek, Emily J Paterson, Minsuh Kim, Swati Venkat, Eduardo Cortes Gomez, Jianmin Wang, Katerina V Gurova, Hari Krishna Yalamanchili, Michael E Feigin

Duncan NRI Faculty and Staff Publications

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited effective treatment options, potentiating the importance of uncovering novel drug targets. Here, we target cleavage and polyadenylation specificity factor 3 (CPSF3), the 3′ endonuclease that catalyzes mRNA cleavage during polyadenylation and histone mRNA processing. We find that CPSF3 is highly expressed in PDAC and is associated with poor prognosis. CPSF3 knockdown blocks PDAC cell proliferation and colony formation in vitro and tumor growth in vivo. Chemical inhibition of CPSF3 by the small molecule JTE-607 also attenuates PDAC cell proliferation and colony formation, while it has no effect on cell proliferation …

Cpsf3 Inhibition Blocks Pancreatic Cancer Cell Proliferation Through Disruption Of Core Histone Mrna Processing, Abdulrahman A Alahmari, Aditi H Chaubey, Venkata S Jonnakuti, Arwen A Tisdale, Carla D Schwarz, Abigail C Cornwell, Kathryn E Maraszek, Emily J Paterson, Minsuh Kim, Swati Venkat, Eduardo Cortes Gomez, Jianmin Wang, Katerina V Gurova, Hari Krishna Yalamanchili, Michael E Feigin

Faculty, Staff and Students Publications

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited effective treatment options, potentiating the importance of uncovering novel drug targets. Here, we target cleavage and polyadenylation specificity factor 3 (CPSF3), the 3′ endonuclease that catalyzes mRNA cleavage during polyadenylation and histone mRNA processing. We find that CPSF3 is highly expressed in PDAC and is associated with poor prognosis. CPSF3 knockdown blocks PDAC cell proliferation and colony formation in vitro and tumor growth in vivo. Chemical inhibition of CPSF3 by the small molecule JTE-607 also attenuates PDAC cell proliferation and colony formation, while it has no effect on cell proliferation …