Medical Specialties Commons^™

Revolutionizing Diabetic Foot Ulcer Care: The Senotherapeutic Approach, Guiqin Zhang, Priyadarshani Nadeeshika Samarawickrama, Li Gui, Yuan Ma, Mei Cao, Hong Zhu, Wei Li, Honglin Yang, Kecheng Li, Yang Yang, Enfang Zhu, Wen Li, Yonghan He

Faculty, Staff and Student Publications

Diabetic foot ulcers (DFUs) are a prevalent and profoundly debilitating complication that afflicts individuals with diabetes mellitus (DM). These ulcers are associated with substantial morbidity, recurrence rates, disability, and mortality, imposing substantial economic, psychological, and medical burdens. Timely detection and intervention can mitigate the morbidity and disparities linked to DFU. Nevertheless, current therapeutic approaches for DFU continue to grapple with multifaceted limitations. A growing body of evidence emphasizes the crucial role of cellular senescence in the pathogenesis of chronic wounds. Interventions that try to delay cellular senescence, eliminate senescent cells (SnCs), or suppress the senescence-associated secretory phenotype (SASP) have shown …

Microbiome And Cancer Immunotherapies, Haoyan Chen, Laurence Zitvogel, Zhi Peng, Xiaochen Yin, Florencia Mcallister

Faculty, Staff and Student Publications

Here, we present 3 different perspectives on how the microbiome has impacted cancer patients, treatment, and clinical studies. We hear about the challenges of implementing microbiome analyses into the clinics, the impact these analyses might have on patients' care, and treatment in the future, specifically for gastric cancer treatment. These are a few of the many voices that are highlighting the role of the microbiome in cancer development, treatment, and clinical outcomes.

Self-Assembled Sting-Activating Coordination Nanoparticles For Cancer Immunotherapy And Vaccine Applications, Xiaoqi Sun, Xuehui Huang, Kyung Soo Park, Xingwu Zhou, Andrew A Kennedy, Carla D Pretto, Qi Wu, Ziye Wan, Yao Xu, Wang Gong, Jonathan Z Sexton, Andrew W Tai, Yu Leo Lei, James J Moon

Faculty, Staff and Student Publications

The cGAS-STING pathway plays a crucial role in innate immune activation against cancer and infections, and STING agonists based on cyclic dinucleotides (CDN) have garnered attention for their potential use in cancer immunotherapy and vaccines. However, the limited drug-like properties of CDN necessitate an efficient delivery system to the immune system. To address these challenges, we developed an immunostimulatory delivery system for STING agonists. Here, we have examined aqueous coordination interactions between CDN and metal ions and report that CDN mixed with Zn2+ and Mn2+ formed distinctive crystal structures. Further pharmaceutical engineering led to the development of a functional coordination …

Brafv600e-Mutant Metastatic Nsclc: Disease Overview And Treatment Landscape, David Planchard, Rachel E Sanborn, Marcelo V Negrao, Aria Vaishnavi, Egbert F Smit

Faculty, Staff and Student Publications

In this review, we cover the current understanding of BRAF mutations and associated clinical characteristics in patients with metastatic NSCLC, approved and emerging treatment options, BRAF sequencing approaches, and unmet needs. The BRAFV600E mutation confers constitutive activity of the MAPK pathway, leading to enhanced growth, proliferation, and survival of tumor cells. Testing for BRAF mutations enables patients to be treated with therapies that directly target BRAFV600E and the MAPK pathway, but BRAF testing lags behind other oncogene testing in metastatic NSCLC. Additional therapies targeting BRAFV600E mutations provide options for patients with metastatic NSCLC. Emerging therapies and combinations under investigation could …

Genetic Testing For Supravalvar Aortic Stenosis: What To Do When It Is Not Williams Syndrome, Sara B Stephens, Tyler Novy, Gabrielle N Spurzem, Benjamin Jacob, Taylor Beecroft, Emily Soludczyk, Beth A Kozel, Justin Weigand, Shaine A Morris

Faculty, Staff and Students Publications

Background: We aimed to describe the frequency and yield of genetic testing in supravalvar aortic stenosis (SVAS) following negative evaluation for Williams-Beuren syndrome (WS).

Methods and results: This retrospective cohort study included patients with SVAS at our institution who had a negative evaluation for WS from May 1991 to September 2021. SVAS was defined as (1) peak supravalvar velocity of ≥2 meters/second, (2) sinotubular junction or ascending aortic Z score < -2.0, or (3) sinotubular junction Z score < -1.5 with family history of SVAS. Patients with complex congenital heart disease, aortic valve disease as the primary condition, or only postoperative SVAS were excluded. Genetic testing and diagnoses were reported. Of 162 patients who were WS negative meeting inclusion criteria, 61 had genetic testing results available (38%). Chromosomal microarray had been performed in 44 of 61 and was nondiagnostic for non-WS causes of SVAS. Sequencing of 1 or more genes was performed in 47 of 61. Of these, 39 of 47 underwent ELN sequencing, 20 of 39 (51%) of whom had a diagnostic variant. Other diagnoses made by gene sequencing were Noonan syndrome (3 PTPN11, 1 RIT1), Alagille …

Multilocus Pathogenic Variants Contribute To Intrafamilial Clinical Heterogeneity: A Retrospective Study Of Sibling Pairs With Neurodevelopmental Disorders, Tugce Bozkurt-Yozgatli, Davut Pehlivan, Richard A Gibbs, Ugur Sezerman, Jennifer E Posey, James R Lupski, Zeynep Coban-Akdemir

Faculty, Staff and Students Publications

BACKGROUND: Multilocus pathogenic variants (MPVs) are genetic changes that affect multiple gene loci or regions of the genome, collectively leading to multiple molecular diagnoses. MPVs may also contribute to intrafamilial phenotypic variability between affected individuals within a nuclear family. In this study, we aim to gain further insights into the influence of MPVs on a disease manifestation in individual research subjects and explore the complexities of the human genome within a familial context.

METHODS: We conducted a systematic reanalysis of exome sequencing data and runs of homozygosity (ROH) regions of 47 sibling pairs previously diagnosed with various neurodevelopmental disorders (NDD). …

Us Population Qualifying For Aspirin Use For Primary Prevention Of Cardiovascular Disease, Athena L Huang, Ann Marie Navar, Colby Ayers, Anand Rohatgi, Erin D Michos, Salim S Virani, Parag Joshi, Eric D Peterson, Amit Khera

Faculty, Staff and Students Publications

Objective: Aspirin has been used for primary prevention of atherosclerotic cardiovascular disease (ASCVD) for decades, but this indication has become controversial with recent trial data. The 2022 US Preventive Services Task Force (USPSTF) provided a recommendation to consider aspirin use for primary prevention in adults 40-59 years with a 10-year ASCVD risk ≥10 % and not at increased risk of bleeding, yet population estimates for the impact of this recommendation are unknown. The objective of this study is to determine the prevalence and demographics of the US population who meet eligibility criteria for aspirin under the new 2022 USPSTF guidelines. …

Identifying Covariate-Related Subnetworks For Whole-Brain Connectome Analysis, Shuo Chen, Yuan Zhang, Qiong Wu, Chuan Bi, Peter Kochunov, L Elliot Hong

Faculty, Staff and Student Publications

Whole-brain connectome data characterize the connections among distributed neural populations as a set of edges in a large network, and neuroscience research aims to systematically investigate associations between brain connectome and clinical or experimental conditions as covariates. A covariate is often related to a number of edges connecting multiple brain areas in an organized structure. However, in practice, neither the covariate-related edges nor the structure is known. Therefore, the understanding of underlying neural mechanisms relies on statistical methods that are capable of simultaneously identifying covariate-related connections and recognizing their network topological structures. The task can be challenging because of false-positive …

Hammerhead-Type Fxr Agonists Induce An Enhancer Rna Fincor That Ameliorates Nonalcoholic Steatohepatitis In Mice, Jinjing Chen, Ruoyu Wang, Feng Xiong, Hao Sun, Byron Kemper, Wenbo Li, Jongsook Kemper

Faculty, Staff and Student Publications

The nuclear receptor, farnesoid X receptor (FXR/NR1H4), is increasingly recognized as a promising drug target for metabolic diseases, including nonalcoholic steatohepatitis (NASH). Protein-coding genes regulated by FXR are well known, but whether FXR also acts through regulation of long non-coding RNAs (lncRNAs), which vastly outnumber protein-coding genes, remains unknown. Utilizing RNA-seq and global run-on sequencing (GRO-seq) analyses in mouse liver, we found that FXR activation affects the expression of many RNA transcripts from chromatin regions bearing enhancer features. Among these we discovered a previously unannotated liver-enriched enhancer-derived lncRNA (eRNA), termed FXR-induced non-coding RNA (

Assessment Of Potentially Toxic And Mineral Elements In Paddy Soils And Their Uptake By Rice (Oryza Sativa L) With Associated Health Hazards In District Malakand, Pakistan, Asghar Khan, Muhammad Saleem Khan, Munib Ahmed Shafique, Qaisar Khan, Ghulam Saddiq

Faculty, Staff and Student Publications

Rice, a primary food source in many countries of the world accumulate potentially harmful elements which pose a significant health hazard to consumers. The current study aimed to evaluate potentially toxic and mineral elements in both paddy soils and rice grains associated with allied health risks in Malakand, Pakistan. Rice plants with intact root soil were randomly collected from paddy fields and analyzed for mineral and potentially toxic elements (PTEs) through inductively coupled plasma optical emission spectrometry (ICP‒OES). Through deterministic and probabilistic risk assessment models, the daily intake of PTEs with allied health risks from consumption of rice were estimated …

Refractory Chronic Spontaneous Urticaria After Heterologous Covid-19 Booster Vaccination, Miranda Crista Tomaras, Leah Michelle Douglas, Rosa Michelle Schmidt, Maria Suzanne Bloomquist, Abdul Hafeez Diwan, Soo Jung Kim

Faculty, Staff and Students Publications

Chronic spontaneous urticaria (CSU) involves recurrent, pruritic wheals lasting more than 6 weeks in response to various etiologies, including unknown causality. Though most cutaneous reactions to the COVID-19 vaccine series are self-limited and of short duration, more complex presentations including chronic spontaneous urticaria have been described. To the best of our knowledge, this is the first report of chronic spontaneous urticaria following heterologous mRNA COVID-19 booster vaccination that includes vaccination with both forms of the mRNA vaccine. Our patient received Pfizer-BioNTech for the primary series and Moderna for the booster. After failing several therapies, our patient's urticaria was refractory even …

Safety Profile And Adverse Event Management For Futibatinib, An Irreversible Fgfr1-4 Inhibitor: Pooled Safety Analysis Of 469 Patients, Funda Meric-Bernstam, Antoine Hollebecque, Junji Furuse, Do-Youn Oh, John A Bridgewater, Masashi Shimura, Bailey Anderson, Nanae Hangai, Volker Wacheck, Lipika Goyal

Faculty, Staff and Student Publications

PURPOSE: Futibatinib, a covalently-binding inhibitor of fibroblast growth factor receptor (FGFR)1-4 gained approval for the treatment of refractory, advanced intrahepatic cholangiocarcinoma (iCCA) harboring an FGFR2 fusion/other rearrangement. An integrated analysis was performed to evaluate safety and provide guidance on the management of futibatinib-associated adverse events (AEs) in patients with unresectable/metastatic tumors, including iCCA.

PATIENTS AND METHODS: Data from three global phase I or II studies of futibatinib (NCT02052778; JapicCTI-142552) were pooled. AEs were graded per NCI CTCAE v4.03, where applicable. Safety was analyzed for patients receiving any futibatinib starting dose (overall population) and in those receiving the approved starting dose …

Vhl Governs M6a Modification And Pik3r3 Mrna Stability In Clear Cell Renal Cell Carcinomas, Hyemin Lee, Li Zhuang, Boyi Gan

Faculty, Staff and Student Publications

N6-Methyladenosine (m6A), a prevalent posttranscriptional modification, plays an important role in cancer progression. Clear cell renal cell carcinoma (ccRCC) is chiefly associated with the loss of the von Hippel-Lindau (VHL) gene, encoding a component of the E3 ubiquitin ligase complex. In this issue of the JCI, Zhang and colleagues unveiled a function of VHL beyond its canonical role as an E3 ubiquitin ligase in regulating hypoxia-inducible factors (HIFs). It also governed m6A modification by orchestrating the assembly of m6A writer proteins METTL3 and METTL14, thereby stabilizing PIK3R3 mRNA. Mechanistically, PIK3R3 contributed to p85 ubiquitination, which restrained PI3K/AKT signaling and consequently …

Multi-Omics Analysis Reveals Immune Features Associated With Immunotherapy Benefit In Patients With Squamous Cell Lung Cancer From Phase Iii Lung-Map S1400i Trial, Edwin Roger Parra, Jiexin Zhang, Dzifa Yawa Duose, Edgar Gonzalez-Kozlova, Mary W Redman, Hong Chen, Ganiraju C Manyam, Gayatri Kumar, Jianhua Zhang, Xingzhi Song, Rossana Lazcano, Mario L Marques-Piubelli, Caddie Laberiano-Fernandez, Frank Rojas, Baili Zhang, Len Taing, Aashna Jhaveri, Jacob Geisberg, Jennifer Altreuter, Franziska Michor, James Provencher, Joyce Yu, Ethan Cerami, Radim Moravec, Kasthuri Kannan, Rajyalakshmi Luthra, Gheath Alatrash, Hsin-Hui Huang, Hui Xie, Manishkumar Patel, Kai Nie, Jocelyn Harris, Kimberly Argueta, James Lindsay, Roshni Biswas, Stephen Van Nostrand, Seunghee Kim-Schulze, Jhanelle E Gray, Roy S Herbst, Ignacio I Wistuba, Scott Gettinger, Karen Kelly, Lyudmila Bazhenova, Sacha Gnjatic, J Jack Lee, Jianjun Zhang, Cara Haymaker

Faculty, Staff and Student Publications

PURPOSE: Identifying molecular and immune features to guide immune checkpoint inhibitor (ICI)-based regimens remains an unmet clinical need.

EXPERIMENTAL DESIGN: Tissue and longitudinal blood specimens from phase III trial S1400I in patients with metastatic squamous non-small cell carcinoma (SqNSCLC) treated with nivolumab monotherapy (nivo) or nivolumab plus ipilimumab (nivo+ipi) were subjected to multi-omics analyses including multiplex immunofluorescence (mIF), nCounter PanCancer Immune Profiling Panel, whole-exome sequencing, and Olink.

RESULTS: Higher immune scores from immune gene expression profiling or immune cell infiltration by mIF were associated with response to ICIs and improved survival, except regulatory T cells, which were associated with worse …

Sensitivity Analysis With Iterative Outlier Detection For Systematic Reviews And Meta-Analyses, Zhuo Meng, Jingshen Wang, Lifeng Lin, Chong Wu

Faculty, Staff and Student Publications

Meta-analysis is a widely used tool for synthesizing results from multiple studies. The collected studies are deemed heterogeneous when they do not share a common underlying effect size; thus, the factors attributable to the heterogeneity need to be carefully considered. A critical problem in meta-analyses and systematic reviews is that outlying studies are frequently included, which can lead to invalid conclusions and affect the robustness of decision-making. Outliers may be caused by several factors such as study selection criteria, low study quality, small-study effects, and so on. Although outlier detection is well-studied in the statistical community, limited attention has been …

Clearing The Air: Innovations In Imaging For Early Detection And Management Of Chronic Obstructive Pulmonary Disease, Francesca Polverino

Faculty, Staff and Students Publications

No abstract provided.

Non-Adherent Dressings To Make Skin Flaps Stick, Yelena Dokic, Suzanna Alkul, Ikue Shimizu, Jennifer Song Ranario

Faculty, Staff and Students Publications

No abstract provided.

First-Principles Study Of Electronic Properties Of Substitutionally Doped Monolayer Snp3, Junfeng Jin, Fang Lv, Wei Cao, Ziyu Wang

Faculty, Staff and Student Publications

Isovalent doping offers a method to enhance the thermoelectric properties of semiconductors, yet its influence on the phonon structure and propagation is often overlooked. Here, we take CdX (X=Te, Se) compounds as an example to study the role of isovalent doping in thermoelectrics by first-principles calculations in combination with the Boltzmann transport theory. The electronic and phononic properties of Cd8Se8, Cd8Se7Te, Cd8Te8, and Cd8Te7Se are compared. The results suggest that isovalent doping with CdX significantly improves the thermoelectric performance. Due to the similar properties of Se and Te atoms, the electronic properties remain unaffected. Moreover, doping enhances anharmonic phonon scattering, …

Risk Assessment And Sources Apportionment Of Toxic Metals In Two Commonly Consumed Fishes From A Subtropical Estuarine Wetland System, Md Moudud Ahmed, As-Ad Ujjaman Nur, Salma Sultana, Yeasmin N Jolly, Bilal Ahamad Paray, Takaomi Arai, Jimmy Yu, Mohammad Belal Hossain

Faculty, Staff and Student Publications

The widespread occurrence of heavy metals in aquatic environments, resulting in their bioaccumulation within aquatic organisms like fish, presents potential hazards to human health. This study investigates the concentrations of five toxic heavy metals (Pb, Hg, Zn, Cu, and Cr) and their potential health implications in two economically important fish species (Otolithoides pama and Labeo bata) from a subtropical estuarine wetland system (Feni estuary, Bangladesh). Muscle and gill samples from 36 individual fish were analyzed using energy dispersive X-ray fluorescence (EDXRF). The results revealed that the average quantities of heavy metals in both fishes' muscle followed the declining …

Afamitresgene Autoleucel For Advanced Synovial Sarcoma And Myxoid Round Cell Liposarcoma (Spearhead-1): An International, Open-Label, Phase 2 Trial, Sandra P D'Angelo, Dejka M Araujo, Albiruni R Abdul Razak, Mark Agulnik, Steven Attia, Jean-Yves Blay, Irene Carrasco Garcia, John A Charlson, Edwin Choy, George D Demetri, Mihaela Druta, Edouard Forcade, Kristen N Ganjoo, John Glod, Vicki L Keedy, Axel Le Cesne, David A Liebner, Victor Moreno, Seth M Pollack, Scott M Schuetze, Gary K Schwartz, Sandra J Strauss, William D Tap, Fiona Thistlethwaite, Claudia Maria Valverde Morales, Michael J Wagner, Breelyn A Wilky, Cheryl Mcalpine, Laura Hudson, Jean-Marc Navenot, Tianjiao Wang, Jane Bai, Stavros Rafail, Ruoxi Wang, Amy Sun, Lilliam Fernandes, Erin Van Winkle, Erica Elefant, Colin Lunt, Elliot Norry, Dennis Williams, Swethajit Biswas, Brian A Van Tine

Faculty, Staff and Student Publications

Background: Afamitresgene autoleucel (afami-cel) showed acceptable safety and promising efficacy in a phase 1 trial (NCT03132922). The aim of this study was to further evaluate the efficacy of afami-cel for the treatment of patients with HLA-A*02 and MAGE-A4-expressing advanced synovial sarcoma or myxoid round cell liposarcoma.

Methods: SPEARHEAD-1 was an open-label, non-randomised, phase 2 trial done across 23 sites in Canada, the USA, and Europe. The trial included three cohorts, of which the main investigational cohort (cohort 1) is reported here. Cohort 1 included patients with HLA-A*02, aged 16-75 years, with metastatic or unresectable synovial sarcoma or myxoid …

Multicenter Us Clinical Experience With The Scepter Mini Balloon Catheter, Mohamed M Salem, Paz Kelmer, Georgios S Sioutas, Sophie Ostmeier, Alex Hoang, Gustavo Cortez, Kareem El Naamani, Rawad Abbas, Ricardo Hanel, Omar Tanweer, Visish M Srinivasan, Pascal Jabbour, Peter Kan, Brian T Jankowitz, Jeremy J Heit, Jan-Karl Burkhardt

Faculty, Staff and Students Publications

INTRODUCTION: Distal navigability and imprecise delivery of embolic agents are two limitations encountered during liquid embolization of cerebrospinal lesions. The dual-lumen Scepter Mini balloon (SMB) microcatheter was introduced to overcome these conventional microcatheters' limitations with few small single-center reports suggesting favorable results.

METHODS: A series of consecutive patients undergoing SMB-assisted endovascular embolization were extracted from prospectively maintained registries in seven North-American centers (November 2019 to September 2022).

RESULTS: Fifty-four patients undergoing 55 embolization procedures utilizing SMB were included (median age 58.5; 48.1% females). Cranial dural arteriovenous fistula embolization was the most common indication (54.5%) followed by cranial arteriovenous malformation (27.3%). …

Chromosomal 3q Amplicon Encodes Essential Regulators Of Secretory Vesicles That Drive Secretory Addiction In Cancer, Xiaochao Tan, Shike Wang, Guan-Yu Xiao, Chao Wu, Xin Liu, Biyao Zhou, Yu Jiang, Dzifa Y. Duose, Yuanxin Xi, Jing Wang, Kunika Gupta, Apar Pataer, Jack A. Roth, Michael P. Kim, Fengju Chen, Chad J. Creighton, William K. Russell, Jonathan M. Kurie

Markey Cancer Center Faculty Publications

Cancer cells exhibit heightened secretory states that drive tumor progression. Here, we identified a chromosome 3q amplicon that serves as a platform for secretory regulation in cancer. The 3q amplicon encodes multiple Golgi-resident proteins, including the scaffold Golgi integral membrane protein 4 (GOLIM4) and the ion channel ATPase secretory pathway Ca2+ transporting 1 (ATP2C1). We show that GOLIM4 recruited ATP2C1 and Golgi phosphoprotein 3 (GOLPH3) to coordinate Ca2+ -dependent cargo loading, Golgi membrane bending, and vesicle scission. GOLIM4 depletion disrupted the protein complex, resulting in a secretory blockade that inhibited the progression of 3q-amplified malignancies. In addition to its role …

Serum Neuroactive Metabolites Of The Tryptophan Pathway In Patients With Acute Phase Of Affective Disorders, Yanli Li, Leilei Wang, Junchao Huang, Ping Zhang, Yanfang Zhou, Jinghui Tong, Wenjin Chen, Mengzhuang Gou, Baopeng Tian, Wei Li, Xingguang Luo, Li Tian, L Elliot Hong, Chiang-Shan R Li, Yunlong Tan

Faculty, Staff and Student Publications

BACKGROUND: Many studies showed disrupted tryptophan metabolism in patients with affective disorders. The aims of this study were to explore the differences in the metabolites of tryptophan pathway (TP) and the relationships between TP metabolites and clinical symptoms, therapeutic effect in patients with bipolar disorder with acute manic episode (BD-M), depressive episode (BD-D) and major depressive disorder (MDD).

METHODS: Patients with BD-M (n=52) and BD-D (n=39), MDD (n=48) and healthy controls (HCs, n=49) were enrolled. The serum neuroactive metabolites levels of the TP were measured by liquid chromatography-tandem mass spectrometry. Hamilton Depression Scale-17 item (HAMD-17) and Young Mania Rating Scale …

Phase 1b Study Of Intraperitoneal Ipilimumab And Nivolumab In Patients With Recurrent Gynecologic Malignancies With Peritoneal Carcinomatosis, Anne Knisely, Emily Hinchcliff, Bryan Fellman, Ann Mosley, Kathryn Lito, Sara Hull, Shannon N Westin, Anil K Sood, Kathleen M Schmeler, Jolyn S Taylor, Steven Y Huang, Rahul A Sheth, Karen H Lu, Amir A Jazaeri

Faculty, Staff and Student Publications

Background: Intravenous immune checkpoint blockade (ICB) has shown poor response rates in recurrent gynecologic malignancies. Intraperitoneal (i.p.) ICB may result in enhanced T cell activation and anti-tumor immunity.

Methods: In this phase 1b study, registered at Clinical.

Trials: gov (NCT03508570), initial cohorts received i.p. nivolumab monotherapy, and subsequent cohorts received combination i.p. nivolumab every 2 weeks and i.p. ipilimumab every 6 weeks, guided by a Bayesian design. The primary objective was determination of the recommended phase 2 dose (RP2D) of the combination. Secondary outcomes included toxicity, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).

Findings: …

In Silico And In Vitro Study Of Isoquercitrin Against Kidney Cancer And Inflammation By Triggering Potential Gene Targets, Safia Iqbal, Md Rezaul Karim, Shahnawaz Mohammad, Jong Chan Ahn, Anjali Kariyarath Valappil, Ramya Mathiyalagan, Deok-Chun Yang, Dae-Hyo Jung, Hyocheol Bae, Dong Uk Yang

Faculty, Staff and Student Publications

Kidney cancer has emerged as a major medical problem in recent times. Multiple compounds are used to treat kidney cancer by triggering cancer-causing gene targets. For instance, isoquercitrin (quercetin-3-O-β-d-glucopyranoside) is frequently present in fruits, vegetables, medicinal herbs, and foods and drinks made from plants. Our previous study predicted using protein-protein interaction (PPI) and molecular docking analysis that the isoquercitrin compound can control kidney cancer and inflammation by triggering potential gene targets of IGF1R, PIK3CA, IL6, and PTGS2. So, the present study is about further in silico and in vitro validation. We performed molecular dynamic (MD) simulation, gene ontology (GO), Kyoto …

Combined Deletion Of Men1, Atrx And Pten Triggers Development Of High-Grade Pancreatic Neuroendocrine Tumors In Mice, Mary Esmeralda Fuentes, Xiaoyin Lu, Natasha M Flores, Simone Hausmann, Pawel K Mazur

Faculty, Staff and Student Publications

Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of tumors that exhibit an unpredictable and broad spectrum of clinical presentations and biological aggressiveness. Surgical resection is still the only curative therapeutic option for localized PanNET, but the majority of patients are diagnosed at an advanced and metastatic stage with limited therapeutic options. Key factors limiting the development of new therapeutics are the extensive heterogeneity of PanNETs and the lack of appropriate clinically relevant models. In that context, genomic sequencing of human PanNETs revealed recurrent mutations and structural alterations in several tumor suppressors. Here, we demonstrated that combined loss of MEN1, …

Genome-Wide Screening Identifies Trim33 As An Essential Regulator Of Dendritic Cell Differentiation, Ioanna Tiniakou, Pei-Feng Hsu, Lorena S Lopez-Zepeda, Görkem Garipler, Eduardo Esteva, Nicholas M Adams, Geunhyo Jang, Chetna Soni, Colleen M Lau, Fan Liu, Alireza Khodadadi-Jamayran, Tori C Rodrick, Drew Jones, Aristotelis Tsirigos, Uwe Ohler, Mark T Bedford, Stephen D Nimer, Vesa Kaartinen, Esteban O Mazzoni, Boris Reizis

Faculty, Staff and Student Publications

The development of dendritic cells (DCs), including antigen-presenting conventional DCs (cDCs) and cytokine-producing plasmacytoid DCs (pDCs), is controlled by the growth factor Flt3 ligand (Flt3L) and its receptor Flt3. We genetically dissected Flt3L-driven DC differentiation using CRISPR-Cas9-based screening. Genome-wide screening identified multiple regulators of DC differentiation including subunits of TSC and GATOR1 complexes, which restricted progenitor growth but enabled DC differentiation by inhibiting mTOR signaling. An orthogonal screen identified the transcriptional repressor Trim33 (TIF-1γ) as a regulator of DC differentiation. Conditional targeting in vivo revealed an essential role of Trim33 in the development of all DCs, but not of monocytes …

Storylines Of Family Medicine Xii: Family Medicine And The Healthcare System, William B Ventres, Leslie A Stone, Jeannette E South-Paul, Kendall M Campbell, Aerial R Petty, Hima Ekanadham, Kurt C Stange, Rebecca S Etz, William L Miller, Robert L Ferrer, Marianna Kong, Thomas Bodenheimer, Roger Strasser, Sharon C M Reece, Joshua Freeman, John M Westfall

Faculty, Staff and Students Publications

Storylines of Family Medicine is a 12-part series of thematically linked mini-essays with accompanying illustrations that explore the many dimensions of family medicine, as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world. In ‘XII: Family medicine and the future of the healthcare system’, authors address the following themes: ‘Leadership in family medicine’, ‘Becoming an academic family physician’, ‘Advocare—our call to act’, ‘The paradox of primary care and three simple rules’, ‘The quadruple aim—melding the patient and the health system’, ‘Fit-for-purpose medical workforce’, ‘Universal healthcare—coverage for all’, ‘The futures of family …

Akap12 Upregulation Associates With Pde8a To Accelerate Cardiac Dysfunction, Hanan Qasim, Mehrdad Rajaei, Ying Xu, Arfaxad Reyes-Alcaraz, Hala Y Abdelnasser, M David Stewart, Satadru K Lahiri, Xander H T Wehrens, Bradley K Mcconnell

Faculty, Staff and Students Publications

BACKGROUND: In heart failure, signaling downstream the β2-adrenergic receptor is critical. Sympathetic stimulation of β2-adrenergic receptor alters cAMP (cyclic adenosine 3',5'-monophosphate) and triggers PKA (protein kinase A)-dependent phosphorylation of proteins that regulate cardiac function. cAMP levels are regulated in part by PDEs (phosphodiesterases). Several AKAPs (A kinase anchoring proteins) regulate cardiac function and are proposed as targets for precise pharmacology. AKAP12 is expressed in the heart and has been reported to directly bind β2-adrenergic receptor, PKA, and PDE4D. However, its roles in cardiac function are unclear.

METHODS: cAMP accumulation in real time downstream of the β2-adrenergic receptor was detected for …

Structural Basis Of Dna Crossover Capture By Escherichia Coli Dna Gyrase, Marlène Vayssières, Nils Marechal, Long Yun, Brian Lopez Duran, Naveen Kumar Murugasamy, Jonathan M Fogg, Lynn Zechiedrich, Marc Nadal, Valérie Lamour

Faculty, Staff and Students Publications

DNA supercoiling must be precisely regulated by topoisomerases to prevent DNA entanglement. The interaction of type IIA DNA topoisomerases with two DNA molecules, enabling the transport of one duplex through the transient double-stranded break of the other, remains elusive owing to structures derived solely from single linear duplex DNAs lacking topological constraints. Using cryo–electron microscopy, we solved the structure of Escherichia coli DNA gyrase bound to a negatively supercoiled minicircle DNA. We show how DNA gyrase captures a DNA crossover, revealing both conserved molecular grooves that accommodate the DNA helices. Together with molecular tweezer experiments, the structure shows that the …