Digital Commons Network^™

The Effect Of Individual Variation On Epidemiological Dynamics: From Super-Spreaders To Landscapes Of Risk, Alexis Shannon Beagle

Dissertations and Doctoral Documents, University of Nebraska-Lincoln, 2023–

Individuals that make up a population always display some level of variation between members. At the smallest scale, individuals always maintain genetic variation, but variation continues to arise at other scales of biological organization from physiological or immunological variation within individuals to variation in behavior between individuals that can be both genetically and environmentally mediated. The role of individual variation is particularly important in the context of infectious diseases because there is strong evidence that infections are highly heterogenous, indicating that patterns of individual variation drive a significant portion of the epidemiological patterns we observe. Individual variation leads to heterogeneity …

The Pediatric Experience Collaborative: Paving The Way In Pediatric Experience., Lauren Hamilton, Trenton House, Taylor B. Sewell, Harris Baden, Brianna Combs, Sara L. Toomey, Shehzad Saeed, Jana Rojas, Molly Warneke, Maureen Hoff, Andréa Aken'ova, Lisa Rubino, Dana Ileana Williams, Samuel P. Hanke

Manuscripts, Articles, Book Chapters and Other Papers

Positive patient experience is associated with improved patient outcomes, but efforts to improve patient experience are often underprioritized, especially with respect to pediatric care. To address this challenge, leaders at several US children's hospitals established the Pediatric Experience Collaborative (PEC) in 2016 to leverage their collaboration and scale to optimize patient, family, and provider experiences. Since then, the PEC has steadfastly incorporated the patient and family perspective in all its endeavors (e.g., installing a family member as one of the organization's co-chairs); has created both structured opportunities and unstructured opportunities for learning and connection; and has embarked on multi-institutional research …

A Survey Study Of Roadblocks In Translational Science, Fasiha Kanwal, Christopher I Amos, Katherine H Sippel, Claudia Neuhauser, Ariel Harrison, Mary E Dickinson, Charles Minard, Bettina M Beech

Faculty, Staff and Students Publications

Clinical and translational science needs to address roadblocks to the translational processes. We conducted a survey at two institutions, a private medical school and a large public university, to understand the frequency and distribution of barriers and roadblocks to research. We reviewed the literature to compile a pool of barriers and roadblocks and convened a panel of relevant stakeholders to develop a 20-item questionnaire. Survey respondents were asked to select and prioritize the five leading clinical and translational roadblocks, provide information regarding their academic degrees and rank/position, complete open-ended items regarding their areas of research, and optionally add additional remarks …

Inhibition Of The Gsk3Β/Nav16 Complex Suppresses Early-Stage Alzheimer’S Hyperexcitability, Timothy John Baumgartner, Manuel Silva-Pérez, Zahra Haghighijoo, Nolan Michael Dvorak, Aditya Kumar Singh, Nana Aboadwe Goode, Jully Singh, Berenice Gutierrez Grebenkova, Mate Marosi, Jessica Di Re, Leandra Koff, Wissarut Wijitrmektong, Manu Bala, Hanyue Liao, Marijn Lijffijt, Adam Thomas Szafran, Michael James Bolt, Michael A Mancini, Gregory D Cuny, Diana Shu-Lian Chow, Agenor Limon, Jeannie Chin, Fernanda Laezza

Faculty, Staff and Students Publications

Introduction: Network hyperexcitability (NH) is observed in patients with early-stage Alzheimer's disease (AD), emerging decades before cognitive decline. A key molecular determinant of NH is voltage-gated Na+ channel 1.6 (Nav1.6), which mediates action potential firing in CA1 hippocampal neurons. Ameliorating NH through inhibition of the glycogen-synthase kinase 3β (GSK3β/Nav1.6 complex may provide immediate benefits to cognition and memory and slow AD progression.

Methods: Hight-throughput virtual screening and multiple in vitro biological assays were utilized to identify compound 1063. Patch-clamp electrophysiology and electroencephalogram recordings were utilized to functionally assess 1063 in models of AD neuropathology.

Results: Building on previous studies identifying …

Mechanisms Of Experience-Dependent Place-Cell Referencing In Hippocampal Area Ca1, Fish Kunxun Qian, Yiding Li, Jeffrey C Magee

Faculty, Staff and Students Publications

Hippocampal CA1 place cells (PCs) encode both space- and goal-referenced information to support a cognitive map. The mechanism of this referencing and the role of experience remain poorly understood. Here we longitudinally recorded PC activity while head-fixed mice performed a spatial learning task on a treadmill. In a familiar environment, the CA1 representation consisted of PCs that were referenced to either specific spatial locations or a reward goal in approximately equal proportions; however, the CA1 representation became predominately goal-referenced upon exposure to a novel environment, as space-referenced PCs adaptively switched reference frames. Intracellular membrane potential recordings revealed that individual CA1 …

Persistent Imbalance: Women’S Representation In North American Pediatric Cardiology Leadership Roles.Persistent Imbalance: Women’S Representation In North American Pediatric Cardiology Leadership Roles, Alaina K. Kipps, Audrey C. Marshall, Neha Bansal, Holly Bauser-Heaton, Nadine Choueiter, Devyani Chowdhury, Aarti Dalal, Molly Ehrlich, Lindsay R. Freud, Supriya S. Jain, Pei-Ni Jone, Kristin Laraja, Dalia Lopez-Colon, Sonal T. Owens, Christina Ronai, Ritu Sachdeva, Corey Stiver, Nicole Sutton, Terrie Vasilopoulos, Jennifer Co-Vu

Department of Pediatrics Faculty Papers

BACKGROUND: Despite recent gender parity of physicians entering pediatric cardiology, representation of women leaders lags their male colleagues.

OBJECTIVES: We sought to better understand the variation in women in leadership roles in pediatric cardiology.

METHODS: The gender of physicians in 16 prespecified leadership positions was collected by survey between July 2022 and January 2023 from pediatric cardiology programs with >5 cardiologists in North America. We analyzed the association of women leaders with center size (based on surgical volume), geographic region, presence of categorical fellowship program, and gender of division chief and department chair.

RESULTS: Across 99 centers, a median of …

Clearance Of Acute Bilateral Idiopathic Central Corneal Stromal Haze Likely Due To Topical Losartan, Karen Asfar, Jad F. Assaf, Jeremiah Gendy, Sadeer Hannush, Shady T. Awwad

Wills Eye Hospital Papers

To report the use of topical losartan as a potential treatment of acute bilateral central corneal stromal haze in a patient presenting with a syndrome resembling central toxic keratopathy (CTK).Patient and Clinical Findings:A 51-year-old man presented with clinically significant central corneal stromal haze bilaterally 6 days after a periorbital and facial contact dermatitis secondary to pesticide exposure. Uncorrected and corrected distance visual acuity (UDVA and CDVA) were 20/80 and 20/70 in the right eye, and 20/200- and 20/150+ in the left eye, respectively. After unsuccessful treatment with topical antivirals, antibiotics and corticosteroids, the patient started off-label treatment with topical losartan …

Microbial Biosensor For Sensing And Treatment Of Intestinal Inflammation, Duolong Zhu, Jeffrey Galley, Jason Pizzini, Elena Musteata, Martin V Douglas, Walter J Chazin, Eric P Skaar, Jeffrey J Tabor, Robert A Britton

Faculty, Staff and Students Publications

Synthetic biology has enabled the development of biosensors to detect intestinal inflammation, yet few target the clinically validated biomarker of intestinal inflammation calprotectin with both diagnostic and therapeutic capabilities. Here, an optimized calprotectin biosensor is presented that leverages a zinc uptake regulator (Zur) controlled promoter coupled with a memory circuit to detect and record intestinal inflammation in vivo. The level of biosensor activation strongly correlates with calprotectin levels in the colon of two independent mouse models of colitis. Coupling of the biosensor with the production of the anti-inflammatory cytokine IL10 allowed for the resolution of chemically induced colitis, demonstrating the …

Fgf21 Promotes Longevity In Diet-Induced Obesity Through Metabolic Benefits Independent Of Growth Suppression, Christy M Gliniak, Ruth Gordillo, Yun-Hee Youm, Qian Lin, Clair Crewe, Zhuzhen Zhang, Bianca C Field, Teppei Fujikawa, Megan Virostek, Shangang Zhao, Yi Zhu, Clifford J Rosen, Tamas L Horvath, Vishwa Deep Dixit, Philipp E Scherer

Faculty, Staff and Students Publications

Approximately 35% of US adults over 65 are obese, highlighting the need for therapies targeting age-related metabolic issues. Fibroblast growth factor 21 (FGF21), a hormone mainly produced by the liver, improves metabolism and extends lifespan. To explore its effects without developmental confounders, we generated mice with adipocyte-specific FGF21 overexpression beginning in adulthood. When fed a high-fat diet, these mice lived up to 3.3 years, resisted weight gain, improved insulin sensitivity, and showed reduced liver steatosis. Aged transgenic mice also displayed lower levels of inflammatory immune cells and lipotoxic ceramides in visceral adipose tissue, benefits that occurred even in the absence …

Mechanisms Of Change In Exposure Therapy For Anxiety And Related Disorders: A Research Agenda, Kristen Benito, Andre Pittig, Jonathan Abramowitz, Joanna J Arch, Denise Chavira, Rianne De Kleine, Alessandro S De Nadai, Dirk Hermans, Stefan G Hofmann, Jürgen Hoyer, Jonathan D Huppert, Katharina Kircanski, Peter M Mcevoy, Heidi Meyer, Marie-H Monfils, Santiago Papini, Winfried Rief, David Rosenfield, Eric A Storch, Michael J Telch, Michael W Otto, Jasper A J Smits

Faculty, Staff and Students Publications

Anxiety and related disorders are a significant public health burden with rising prevalence in the wake of the COVID-19 pandemic. As demand for effective anxiety treatment increases, so too does the need for strategies to bolster treatment outcomes. Research on the mechanisms of exposure therapy, the frontline behavioral treatment, will be critically important for optimizing clinical outcomes. We outline an initial agenda for future research on the mechanisms of change of exposure therapy, developed in collaboration with a large international team of researchers through the Exposure Therapy Consortium (ETC). Key questions and recommendations for future research focus on five priority …

Endothelium- And Fibroblast-Derived C-Type Natriuretic Peptide Prevents The Development And Progression Of Aortic Aneurysm, Aisah A Aubdool, Amie J Moyes, Cristina Perez-Ternero, Reshma S Baliga, Jaspinder Singh Sanghera, M Taaha Syed, Kareemah Jaigirdar, Anmolpreet K Panesar, Janice C Tsui, Yanming Li, Hernan G Vasquez, Ying H Shen, Scott A Lemaire, Juliette Raffort, Ziad Mallat, Hong S Lu, Alan Daugherty, Adrian J Hobbs

Faculty, Staff and Students Publications

Background: Thoracic (TAA) and abdominal (AAA) aortic aneurysm are life-threatening diseases characterized by dilation, inflammation, and structural weakness; development of pharmacological therapies is desperately needed. CNP (C-type natriuretic peptide) plays a key role in vascular homeostasis, mediating vasodilator, anti-inflammatory, and antiatherogenic actions. Since such processes drive AA, we determined the role of endogenous CNP in offsetting pathogenesis.

Methods: Tissue from patients with AA was analyzed to determine the consequences on CNP signaling. Ascending and suprarenal aortic diameters were assessed at baseline and following Ang II (angiotensin II; 1.44 mg/kg per day) infusion in wild-type, endothelium-restricted (ecCNP-/-), fibroblast-restricted (fbCNP-/-), global CNP …

Development And Diversity Of Astrocytes, Michael R Williamson, Sanjana Murali, Benjamin Deneen

Faculty, Staff and Students Publications

Proper development of the central nervous system (CNS) depends on astrocytes, which are the most abundant glial cells in the CNS. Here, we provide an overview of astrocyte ontogeny and morphogenesis, highlighting mechanisms that regulate astrocyte development. In addition, we describe the roles of astrocytes in regulating the development of other CNS cell types, with emphasis on neural circuits and vascular networks. We also discuss evidence for astrocyte diversity and its implications for CNS development. Finally, we pose open questions related to astrocyte development and its intersection with astrocyte diversity.

Functional Assays In Drosophila Facilitate Classification Of Variants Of Uncertain Significance Associated With Rare Diseases, Jung-Wan Mok, Shelley B Gibson, Haley A Dostalik, Shinya Yamamoto

Faculty, Staff and Students Publications

Individuals living with rare diseases often undergo a frustrating and expensive diagnostic odyssey. Clinical geneticists who analyze exome or genome sequencing data from rare disease patients often encounter a list of variants of uncertain significance (VUS) in known disease-causing genes or rare variants in genes of uncertain significance (GUS) that are difficult to interpret, even with the integration of the latest bioinformatic tools. In this Perspective, we review how studies using the fruit fly Drosophila melanogaster have facilitated rare disease diagnosis by uncovering the clinical relevance of GUS and classifying rare variants into specific allelic categories (loss-of-function or gain-of-function, Muller's …

Ad-Sge-Dkk3 Gene Therapy Overcomes Resistance To Immune Checkpoint Blockade In Pleural Mesothelioma, Hee-Jin Jang, Meera Patel, Daniel Y Wang, Sung Wook Kang, Jong Min Choi, Claire Lee, Monica Vilchis, Ji Seon Shim, Sonali Mitra, Priyanka Ranchod, Allen Kuncheria, William Hudson, Peter Jindra, Veronica Lenge De Rosen, Maheshwari Ramineni, Ernest Ramsay Camp, Farrah Kheradmand, R Taylor Ripley, Shawn S Groth, Hyun-Sung Lee, Bryan M Burt

Faculty, Staff and Students Publications

Purpose: Immune checkpoint inhibitors (ICI) have limited efficacy in pleural mesothelioma. We investigated the role of Dickkopf WNT signaling pathway inhibitor 3 (DKK3) in overcoming treatment resistance.

Patients and methods: We performed preclinical studies to elucidate DKK3's role in ICI-resistant mouse mesothelioma. Based on these findings, we conducted a single-arm, phase II clinical trial of a combination of Ad-SGE-DKK3 and nivolumab for chemotherapy-refractory epithelioid pleural mesothelioma, with the objective response rate as the primary outcome.

Results: DKK3 was significantly reduced in human epithelioid mesothelioma. Overexpression of DKK3 in cancer cells activated the p53 pathway, enhanced glycolysis, increased surface PD-L1, and …

Glioblastoma-Instructed Astrocytes Suppress Tumour-Specific T Cell Immunity, Camilo Faust Akl, Brian M Andersen, Zhaorong Li, Federico Giovannoni, Martin Diebold, Liliana M Sanmarco, Michael Kilian, Luca Fehrenbacher, Florian Pernin, Joseph M Rone, Hong-Gyun Lee, Gavin Piester, Jessica E Kenison, Joon-Hyuk Lee, Tomer Illouz, Carolina M Polonio, Léna Srun, Jazmin Martinez, Elizabeth N Chung, Anton Schüle, Agustin Plasencia, Lucinda Li, Kylynne Ferrara, Mercedes Lewandrowski, Craig A Strathdee, Lorena Lerner, Christophe Quéva, Iain C Clark, Benjamin Deneen, Judy Lieberman, David H Sherr, Jack P Antel, Michael A Wheeler, Keith L Ligon, E Antonio Chiocca, Marco Prinz, David A Reardon, Francisco J Quintana

Faculty, Staff and Students Publications

Glioblastoma is the most common and aggressive primary brain cancer and shows minimal response to therapies. The immunosuppressive tumour microenvironment in glioblastoma contributes to the limited therapeutic response. Astrocytes are abundant in the central nervous system and have important immunoregulatory roles. However, little is known about their role in the immune response to glioblastoma1. Here we used single-cell and bulk RNA sequencing of clinical glioblastoma samples and samples from preclinical models, multiplexed immunofluorescence, in vivo CRISPR-based cell-specific genetic perturbations and in vitro mouse and human experimental systems to address this gap in knowledge. We identified an astrocyte subset …

A Brief Guide To Statistical Analysis Of Grouped Data In Preclinical Research, Colby J Vorland, Lilian Golzarri-Arroyo, David B Allison

Children’s Nutrition Research Center Staff Publications

Clustering and nesting (C&N) arise in many preclinical studies such as when animals are group-housed, share litters, or in cell culture. Ignoring C&N undermines the validity of analyses. We explain how C&N arise and valid designs and analyses.

The Diabetes Prevention Program And Its Outcomes Study: Niddk's Journey Into The Prevention Of Type 2 Diabetes And Its Public Health Impact, Jill P Crandall, Dana Dabelea, William C Knowler, David M Nathan, Marinella Temprosa, Dpp Research Group

Children’s Nutrition Research Center Staff Publications

The current-day epidemic of type 2 diabetes, largely driven by increased adiposity and reduced physical activity in the setting of genetic susceptibility, is a major public health challenge. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) presciently proposed the Diabetes Prevention Program (DPP), a multicenter randomized clinical trial, designed by investigators in conjunction with NIDDK staff and initiated in 1996. The primary goal of DPP was to determine whether an intensive lifestyle intervention (ILS) or metformin in comparison with placebo would reduce the development of diabetes in a high-risk population with prediabetes. After mean 2.8 years, ILS …

To Pause With A Cliffhanger Or A Temporary Closure? The Differential Impact Of Serial Versus Episodic Narratives On Children's Physical Activity Behaviors, Amy Shirong Lu, Melanie C Green, Caio Victor Sousa, Jungyun Hwang, I-Min Lee, Debbe Thompson, Tom Baranowski

Children’s Nutrition Research Center Staff Publications

Research has supported the effectiveness of narratives for promoting health behavior, but different narrative presentation formats (serial vs. episodic) have seldom been compared. Suspense theories suggest that serial narratives, which do not provide a full resolution at the end of an episode, may create higher motivation for continued engagement with a story. Forty-four 8 to 12-year-old children were randomly assigned to watch an animation series designed for an existing active video game in which the plot was delivered either continuously across multiple episodes (serial) or in multiple yet relatively independent self-contained episodes (episodic). Controlling for social desirability, children who watched …

Bibliometric Analysis Of Congenital Toxoplasmosis: A Ten-Year (2013-2023) Review Of Research Publications, Festus Mulakoli, Horatius Musembi, Ann Kimani

School of Nursing & Midwifery, East Africa

Background:Toxoplasma gondii, an obligate intracellular protozoan, infects more than one-third of the global population and causes toxoplasmosis, which can lead to severe fetal complications in pregnant women. The global prevalence of latent toxoplasmosis in pregnant women is 33.8%, with regional variations and risk factors, including the consumption of undercooked meat, exposure to cat feces, and consumption of contaminated water. Pregnant women lack sufficient awareness of these risk factors, necessitating enhanced education, regular screening, and counseling during antenatal care for early detection and management.

Aim: This study performed a comprehensive bibliometric analysis of research on congenital toxoplasmosis published between 2013 …

First-In-Human Phase 1 Study Of Khk2455 Monotherapy And In Combination With Mogamulizumab In Patients With Advanced Solid Tumors, Timothy A Yap, Olivier Rixe, Capucine Baldini, Ursa Brown-Glaberman, Sergey Efuni, David S Hong, Christophe Massard, Jameel Muzaffar, Andreea Varga, Emrullah Yilmaz, Yuta Ikawa, Lisa H Shiue, Yi Liu, Matthew W Hruska, Henry Zhao, Akihiro Tokunaga, Solmaz Sahebjam

Faculty, Staff and Student Publications

Background: Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that degrades tryptophan (Trp) to kynurenine (Kyn), which suppresses effector T cells and reduces antitumor activity. KHK2455 is a long-acting selective IDO1 inhibitor that blocks the heme component of the IDO holoenzyme. Mogamulizumab is a humanized immunoglobulin G1 monoclonal antibody targeting CCR4. KHK2455 + mogamulizumab demonstrated enhanced antitumor activity in preclinical studies, which led to a first-in-human, two-part, multicenter, open-label, phase 1, dose-escalation, cohort-expansion trial (ClinicalTrials.gov identifier NCT02867007) evaluating the safety/tolerability, pharmacokinetics, and IDO1 activity of KHK2455 alone and in combination with mogamulizumab in patients with treatment-refractory advanced solid tumors. …

Renal G Protein-Coupled Estrogen Receptor 1 Regulates The Epithelial Sodium Channel Promoting Natriuresis To A Greater Extent In Females, Victoria L Nasci, Jean C Bopassa, Elena Mironova, Megan Rhoads, Ravneet Singh, Dennis P Buehler, David M Pollock, Oleh M Pochynyuk, James D Stockand, Eman Y Gohar

Faculty, Staff and Student Publications

Hypertension prevalence is lower in women than men. Enhanced renal sodium (Na+) handling in females has been implicated in sex-differences in hypertension. Epithelial Na+ channel (ENaC) is a key contributor to Na+ homeostasis and is regulated by estrogen. Recent evidence suggests G protein-coupled estrogen receptor 1 (GPER1) evokes a female-specific natriuresis that involves endothelin-1 (ET-1). ET-1 has been shown to downregulate ENaC activity, but whether GPER1 regulates ENaC to modulate natriuresis is unknown. We tested the hypothesis that renal GPER1 functionally interacts with ENaC to promote natriuresis in a sex-specific manner. RNAscope confirmed co-expression of GPER1 and ENaC in rat …

Non-Invasive Tools For Analysis Of Plasma Membrane Protein Topology In Living Cells, Daria Savenkova, Leysan Bulatova, Vera Skripova, Ramziya Kiyamova, Mikhail Bogdanov

Faculty, Staff and Student Publications

Membrane protein topology studies offer guidance to membrane protein structure, folding, and function, serving as a credible scaffold for designing site-directed mutagenesis and biochemical experiments, helping to identify functionally significant extracellular and intracellular regions, modeling three-dimensional structures, and building reliable mechanistic models. Membrane protein structure as a function of given lipid composition and physiological state of the cell is best probed in whole intact cells. A described simple and advanced immunofluorescence protocol applied to the transmembrane orientation of extramembrane domains permits a topology analysis of plasma membrane proteins in their native state in living unperturbed eucaryotic cells. The accessibility of …

Long Akap18 Isoforms Anchor Ubiquitin Specific Proteinases And Coordinate Calcium Reuptake At The Sarcoplasmic Reticulum, Taeyeop Park, Katherine Forbush, Yong Li, Oscar Vivas, Kacey J Rosenthal, Jerome Falcone, Cassandra J Wong, James E Bruce, Claudia Moreno, Carmen W Dessauer, John D Scott

Faculty, Staff and Student Publications

Subcellular targeting of signaling enzymes influences where and when various modes of intracellular communication operate. Macromolecular complexes of signal transduction and signal termination elements favor reversible control of repetitive processes. This includes adrenergic stimulation of excitation–contraction coupling in the heart. Long isoforms of A-kinase anchoring protein 18 (AKAP18γ and δ) modulate this process via regulation of calcium uptake into the sarcoplasmic reticulum through the Ca2+ATPase 2a (SERCA2a). AKAP18 proximity-proteomic screening in cardiomyocytes identifies networks for protein kinase A (PKA) and ubiquitin-specific proteinases (USPs). A 2′phosphoesterase domain on AKAP18 interfaces with the USP4 isoform at the Z bands of sarcomeres. PKA …

Myh11 Rare Variant Augments Aortic Growth And Induces Cardiac Hypertrophy And Heart Failure With Pressure Overload, Zhen Zhou, Kgosi Hughes, Nisha Saif, Hyoseon Kim, Michael P Massett, Mingjie Zheng, Alana C Cecchi, Dongchuan Guo, David R Murdock, Ping Pan, Jelita S Clinton, Jun Wang, John M Greally, Dianna M Milewicz

Faculty, Staff and Student Publications

Smooth muscle cell-specific myosin heavy chain, encoded by MYH11, is selectively expressed in smooth muscle cells (SMCs). Pathogenic variants in MYH11 predispose to a number of disorders, including heritable thoracic aortic disease associated with patent ductus arteriosus, visceral myopathy, and megacystis-microcolon-intestinal hypoperistalsis syndrome. Rare variants of uncertain significance occur throughout the gene, including MYH11 p.Glu1892Asp, and we sought to determine if this variant causes thoracic aortic disease in mice. Genomic editing was used to generate Myh11E1892D/E1892D mice. Wild-type (WT) and mutant mice underwent cardiovascular phenotyping with and without transverse aortic constriction (TAC). Myh11E1892D/E1892D and WT mice displayed …

Diagnostic Guidance For Chronic Complex Regional Pain Syndrome Type I And Type Ii From The American Society Of Interventional Physicians (Asipp), Christopher Gharibo, Miles Day, Steve M Aydin, Alan D Kaye, Salahadin Abdi, Sudhir Diwan, Lisa V Doan, Danielle Feng, Kris Ferguson, Kirolos Georges, Andrew Kaufman, Nebojsa Nick Knezevic, Sean Li, Franzes A Liongson, Devi Nampiaparampil, Annu Navani, Mahendra Sanapati, Michael E Schatman, Amol Soin, Peter S Staats, Giustino Varrassi, Jing Wang, Laxmaiah Manchikanti

Faculty, Staff and Student Publications

Background: Complex Regional Pain Syndrome (CRPS) is a challenging and often disabling condition marked by persistent pain, most commonly in a limb following injury or surgery. It presents with a wide array of symptoms, including intense pain, swelling, alterations in skin color and temperature, motor dysfunction, and trophic changes such as skin and tissue atrophy. While the precise cause of CRPS is not fully understood, it is thought to stem from abnormal nervous system activity, leading to heightened pain sensitivity and inflammatory responses. A thorough understanding of CRPS is essential for accurate diagnosis, effective treatment, and enhancing patients' quality of …

Βiv Spectrin Abundancy, Cellular Distribution And Sensitivity To Akt/Gsk3 Regulation In Schizophrenia, Jessica Di Re, Michela Marini, Syed Ibrar Hussain, Aditya K Singh, Akshaya Venkatesh, Musaad A Alshammari, Tahani K Alshammari, Abdul-Rizaq Ali Hamoud, Ali Sajid Imami, Zahra Haghighijoo, Nickolas Fularcyzk, Laura Stertz, Derek Hawes, Angela Mosebarger, Jordan Jernigan, Claire Chaljub, Ralda Nehme, Consuelo Walss-Bass, Anton Schulmann, Marquis P Vawter, Robert Mccullumsmith, Robert D Damoiseaux, Agenor Limon, Demetrio Labate, Michael F Wells, Fernanda Laezza

Faculty, Staff and Student Publications

Schizophrenia (SCZ) is a complex psychiatric disorder with unclear biological mechanisms. Spectrins, cytoskeletal proteins linked to neurodevelopmental disorders, are regulated by the AKT/GSK3 pathway, which is implicated in SCZ. However, the impact of SCZ-related dysregulation of this pathway on spectrin expression and distribution remains unexplored. Here, we show that βIV spectrin protein levels were reduced in neurons of the dorsolateral prefrontal cortex in SCZ postmortem samples compared to healthy control (HC) from the Human Brain Collection Core (HBCC). To investigate potential links between βIV spectrin and the AKT/GSK3 pathway, we analyzed the PsychEncode dataset, revealing elevated SPTBN4 and AKT2 mRNA …

Targeting Cdk2 And Other Novel Cell Cycle Targets For Breast Cancer Therapy, Mei-Kuang Chen, Linjie Luo, Nicole Massoumi, Khandan Keyomarsi

Faculty, Staff and Student Publications

Introduction: The dysregulation of cyclin-dependent kinases (CDKs) is a key driver of cancer progression, making them attractive therapeutic targets. In CDK4/6 inhibitor (CDK4/6i)-resistant breast cancer, targeting CDK2 offers a promising approach. CDK2 is frequently hyperactivated due to cyclin E1 overexpression or retinoblastoma protein loss, acting as a mechanism that sustains proliferation despite CDK4/6 inhibition. CDK2 inhibitors (CDK2i) show strong anti-tumor activity, particularly in combination with CDK4/6i or immune checkpoint inhibitors.

Areas covered: This review explores the biological roles of CDK2 and its regulatory mechanisms. The review highlights the latest advancements in CDK2i, their mechanisms of action, and their potential in …

Institutional Learning Curve And Factors Of Prolonged Operation Time Of Robotic Distal Pancreatectomy: An Analysis Of An Initial 117 Cases, Yuki Hirata, Laura Prakash, Jess Maxwell, Rebecca Snyder, Michael Kim, Hop Tran Cao, Ching-Wei D Tzeng, Jefferey E Lee, Matthew H G Katz, Naruhiko Ikoma

Faculty, Staff and Student Publications

Background: The granular methods by which centers can safely implement and effectively expand robotic distal pancreatectomy (RDP), including those related to appropriate patient selection during the learning curve period, remain unclear. This study aimed to verify that our strategic robotic surgical oncology program effectively implemented RDP as standard practice and to identify factors associated with prolonged operation time.

Materials and methods: We performed a detailed analysis of the intraoperative and short-term outcomes of consecutive patients (October 2018-September 2023) undergoing RDP at our center, beginning with the first patient in our program. Operation time was analyzed using a cumulative sum chart …

Impacts Of Radiation On Metabolism And Vascular Cell Senescence, Junichi Abe, Khanh Chau, Anahita Mojiri, Guangyu Wang, Masayoshi Oikawa, Venkata S K Samanthapudi, Abigail M Osborn, Keila C Ostos-Mendoza, Karla N Mariscal-Reyes, Tammay Mathur, Abhishek Jain, Joerg Herrmann, Syed Wamique Yusuf, Sunil Krishnan, Anita Deswal, Steven H Lin, Sivareddy Kotla, John P Cooke, Nhat-Tu Le

Faculty, Staff and Student Publications

Significance: This review investigates how radiation therapy (RT) increases the risk of delayed cardiovascular disease (CVD) in cancer survivors. Understanding the mechanisms underlying radiation-induced CVD is essential for developing targeted therapies to mitigate these effects and improve long-term outcomes for patients with cancer.

Recent Advances: Recent studies have primarily focused on metabolic alterations induced by irradiation in various cancer cell types. However, there remains a significant knowledge gap regarding the role of chronic metabolic alterations in normal cells, particularly vascular cells, in the progression of CVD after RT.

Critical Issues: This review centers on RT-induced metabolic alterations in vascular cells …

Kap1 Promotes Gastric Adenocarcinoma Progression By Activating Hippo/Yap1 Signaling Via Binding To Hnrnpab, Shumei Song, Yibo Fan, Gengyi Zou, Longfei Huo, Janani Kumar, Yuan Li, Ruiping Wang, Enyu Dai, Jiankang Jin, Ailing W Scott, Shan Shao, Melissa Pool Pizzi, Jody V Vykoukal, Hiroyuki Katayama, Samir Hanash, George A Calin, Xing Zhang, Min Gyu Lee, Zhenning Wang, Yuan-Hung Lo, Qiong Gan, Rebecca E Waters, Feng Yin, Linghua Wang, Xiaodong Cheng, Jaffer A Ajani, Shilpa S Dhar

Faculty, Staff and Student Publications

Gastric adenocarcinoma (GAC) remains a significant global health challenge, with over a million new cases annually. Peritoneal carcinomatosis (PC), detected in ∼20 % of cases at diagnosis and ∼45 % later, is uniformly fatal, with limited treatment options. This study investigated the role of KAP1 in GAC progression, focusing on its interaction with YAP1 and cancer stemness traits. Analysis of over 596 primary GACs and 72 PC samples revealed that high nuclear KAP1 expression correlates with poor prognosis. KAP1 knockdown reduced oncogenic activity and stemness traits in GAC cells. Mechanistically, KAP1 positively regulates YAP1 transcription by binding to its promoter …