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Persistence Of Oncogenic And Non-Oncogenic Human Papillomavirus Is Associated With Human Immunodeficiency Virus Infection In Kenyan Women, Yan Tong, Philip Tonui, Aaron Ermel, Elkanah Omenge, Nelson Wong, Titus Maina, Stephen Kiptoo, Kapten Muthoka, Patrick J. Loehrer, Darron R. Brown

Obstetrics and Gynaecology, East Africa

Objectives: Cervical cancer is caused by persistent infection with oncogenic, or “high-risk” types of human papillomaviruses, and is the most common malignancy in Kenyan women. A longitudinal study was initiated to investigate factors associated with persistent human papillomavirus detection among HIV-infected and HIV-uninfected Kenyan women without evidence of cervical dysplasia.

Methods: Demographic/behavioral data and cervical swabs were collected from HIV-uninfected women (n = 82) and HIV-infected women (n = 101) at enrollment and annually for 2 years. Human papillomavirus typing was performed on swabs (Roche Linear Array). Logistic regression models of human papillomavirus persistence were adjusted for demographic …

Dosimetric Comparison Of Hypofractionated Prostate Radiation With Simultaneous Integrated Boost And Conventional Fractionation With Sequential Boost, Kristina Sammon

Masters Projects

Introduction: Hypofractionated treatment delivery regimens are associated with better overall long-term disease control for prostate cancer. For patients with high-risk disease, there may be an indication for treatment of the surrounding pelvic lymph nodes for better over-all disease control. In order to achieve a hypofractionated regimen with treatment to the surrounding pelvic lymph nodes a simultaneous integrated boost technique is employed. There are concerns regarding achievability of target dose coverage and limitation of dose to the surrounding organs at risk with this fractionation.

Methods: This study is a retrospective dosimetric analysis of 7 randomly selected patients with high-risk prostate cancer. …

Aggressive Angiomyxoma In The Ischiorectal Fossa, Asra Wahid, Abdul Hakeem, Sadaf Khan

Medical College Documents

Aggressive Angiomyxoma (AA) is a soft tissue tumour that principally affects women of the reproductive age, primarily involving the pelvis and the perineum. Despite being slow growing, it is classified as aggressive due to its locally infiltrative nature and high recurrence. It is rare, often asymptomatic and is misdiagnosed. However, it has characteristic features on radiographic imaging. Complete surgical resection is the ideal approach to treat AA. We report a case of an aggressive angiomyxoma in a 17 year old female, located in the ischiorectal fossa and diagnosed incidentally on a magnetic resonance imaging (MRI). The lesion was excised without …

Igf1r Immunohistochemistry In Ewing's Sarcoma As Predictor Of Response To Targeted Therapy., Elizabeth Gonzalez, Marilyn Bui, Atif Ahmed

Manuscripts, Articles, Book Chapters and Other Papers

Objectives: Ewing's sarcoma is an aggressive malignancy of bone and soft tissue in children and young adults. Despite advances in modern therapy, metastasis can occur and results in high mortality. The objective of this study was to identify whether the signaling transduction proteins, insulin growth factor receptor (IGF1R) and S6 kinase (S6K), can predict poor prognosis in Ewing's sarcoma.

Methods: After the Institutional Research Board approval, immunohistochemical experiments on tissue microarray slides containing 32 archived Ewing's sarcoma tumor samples were performed with antibodies against IGF1Rb and p-S6K. Immunohistochemical staining results were correlated with patients' clinical data including clinical stage and …

Palbociclib Treatment Alters Nucleotide Biosynthesis And Glutamine Dependency In A549 Cells, Lindsey R. Conroy, Pawel Lorkiewicz, Liqing He, Xinmin Yin, Xiang Zhang, Shesh N. Rai, Brian F. Clem

Neuroscience Faculty Publications

Background

Aberrant activity of cell cycle proteins is one of the key somatic events in non-small cell lung cancer (NSCLC) pathogenesis. In most NSCLC cases, the retinoblastoma protein tumor suppressor (RB) becomes inactivated via constitutive phosphorylation by cyclin dependent kinase (CDK) 4/6, leading to uncontrolled cell proliferation. Palbociclib, a small molecule inhibitor of CDK4/6, has shown anti-tumor activity in vitro and in vivo, with recent studies demonstrating a functional role for palbociclib in reprogramming cellular metabolism. While palbociclib has shown efficacy in preclinical models of NSCLC, the metabolic consequences of CDK4/6 inhibition in this context are largely unknown.

Methods

In …

Predictors Of Biologic Use And Satisfaction Among Patients With Psoriasis: An Analysis And Geographic Visualization Of The 2016 And 2017 National Psoriasis Foundation Annual Surveys, Clinton W. Enos, Hadiza I. Galadima, Arjun Saini, Stacie Bell, Michael Siegel, Abby S. Van Voorhees

Community & Environmental Health Faculty Publications

Background: There are an increasing number of biologic therapies approved for the treatment of psoriasis. Previous reports have identified undertreatment as a concern in the United States. Undertreatment has been associated with decreased patient satisfaction and increased morbidity.

Objectives: Assess biologic use and satisfaction among respondents to the 2016 and 2017 National Psoriasis Foundation (NPF) Annual Surveys.

Methods: Retrospective data analysis of the 2016 and 2017 NPF Annual Survey responses from individuals with psoriasis. ArcGIS Pro software was utilized to generate maps and perform an optimized hot spot analysis of moderate-to-severe psoriasis and biologic use.

Results: …

Calculating Life And Death In A Time Of Covid, Larry Hirschhorn, Phd

School of Continuing and Professional Studies Coronavirus Papers

The current pandemic makes us feel helpless. We can respond to its predation pragmatically but its silent march through the population promotes dread. Our helplessness undermines our belief in our culture as the source of our self-esteem and felt significance. One response to our experience of helplessness is the omnipotent stance, the idea that we can master the virus, stop it in its tracks, command one another to comply with injunctions and wreak a path of destruction by devastating the economy. Omnipotence promotes magical thinking. In the service of defeating death, we ignore actual suffering; deaths of despair and deaths …

Sugammadex Versus Neostigmine In Reducing Postoperative Adverse Effects In The Pediatric Population, Robert Vieto Jr.

Nurse Anesthesia MSNA Student Capstones

Neostigmine and sugammadex are two medications used to reverse the neuromuscular blockade caused by nondepolarizing aminosteroidal neuromuscular blocking agents. Research has shown an association between the use of acetylcholinesterase inhibitors, such as neostigmine, and residual neuromuscular blockade in pediatric patients. Sugammadex has been shown to reduce residual neuromuscular blockade in adults without adverse effects, but minimal research has been performed on the effects of sugammadex in the pediatric population. Therefore, the objective of the present study is to compare sugammadex and neostigmine to determine if using sugammadex instead of neostigmine reduces postoperative adverse effects in the pediatric population. A systematic, …

Reducing Anesthesia Workstation Contamination, Taryn Giese

Nurse Anesthesia MSNA Student Capstones

Healthcare-associated infections are a source of morbidity and mortality in the United States and have been shown to be more preventable than current incidence. Anesthesia providers may be a source of and vector for some of these infections. Nurse anesthetists provide direct individual care for numerous patients daily, managing airways and invasive devices that contaminate hands with secretions which then may be transferred to the anesthesia workstation. Due to its complexity, the anesthesia machine is difficult to thoroughly clean and may become a reservoir for contaminants.

The purpose of this paper will be to examine new interventions being explored to …

Detection Of Types Of Hpv Among Hiv-Infected And Hiv-Uninfected Kenyan Women Undergoing Cryotherapy Or Loop Electrosurgical Excision Procedure, Elkanah Omenge, Jordan P. Emont, Aaron Ermel, Tao Liu, Victor Omodi, Yan Tong, Peter Itsura, Philip Tonui, Titus Maina, John M. Ong’Echa

Obstetrics and Gynaecology, East Africa

Objective: To assess the baseline types of HPV infection among HIV-positive and HIV-negative women in western Kenya undergoing cryotherapy or loop electrosurgical excision procedure (LEEP) for cervical intraepithelial neoplasia.

Methods: A prospective observational study was conducted of baseline HPV characteristics of women undergoing visual inspection with acetic acid (VIA) and cryotherapy or LEEP. After a positive VIA in HIV-positive and HIV-negative women, data on demographics, CD4 count, and use of antiretroviral therapy and a cervical swab were collected. HPV typing was performed using the Roche Linear Array.

Results: Of 175 participants, 86 (49.1%) were HIV-positive and had a higher prevalence …

The Write Stuff - Summer 2020 (Vol. 17, No. 3), Research Medical Library

Write Stuff 2020

• Boost your chances of publication by following journals’ instructions to authors
• EndNote, Mendeley, Zotero: which citation management software is best?
• Building your data management plan
• Search for funding opportunities with Pivot
• Expanding use of digital object identifiers in scientific publishing

Medicine And Media: The Ranitidine Debate., Jennifer A. Wagner, Jennifer Colombo

Manuscripts, Articles, Book Chapters and Other Papers

Ranitidine has been the topic of recent media reports. Current findings, confirmed by the US Food and Drug Administration, indicate that some ranitidine products contain a substance that may be carcinogenic. Providers and patients require additional information on the risks of continuing therapy vs. the benefits of the medication. This article comments on what is currently known about the evolving situation of elevated N-nitrosodimethylamine levels in ranitidine and the limits of the existing information to assess best practices.

Bortezomib With Standard Chemotherapy For Children With Acute Myeloid Leukemia Does Not Improve Treatment Outcomes: A Report From The Children's Oncology Group., Richard Aplenc, Soheil Meshinchi, Lillian Sung, Todd Alonzo, John Choi, Brian Fisher, Robert Gerbing, Betsy Hirsch, Terzah Horton, Samir Kahwash, John Levine, Michael Loken, Lisa Brodersen, Jessica Pollard, Susana Raimondi, Edward Anders Kolb, A S. Gamis

Manuscripts, Articles, Book Chapters and Other Papers

New therapeutic strategies are needed for pediatric acute myeloid leukemia (AML) to reduce disease recurrence and treatment-related morbidity. The Children's Oncology Group Phase III AAML1031 trial tested whether the addition of bortezomib to standard chemotherapy improves survival in pediatric patients with newly diagnosed AML. AAML1031 randomized patients younger than 30 years of age with de novo AML to standard treatment with or without bortezomib. All patients received the identical chemotherapy backbone with either four intensive chemotherapy courses or three courses followed by allogeneic hematopoietic stem cell transplantation for high-risk patients. For those randomized to the intervention arm, bortezomib 1.3 mg/m2 …

Parenteral Lipids Shape Gut Bile Acid Pools And Microbiota Profiles In The Prevention Of Cholestasis In Preterm Pigs, Lee Call, Tiffany Molina, Barbara Stoll, Greg Guthrie, Shaji Chacko, Jogchum Plat, Jason Robinson, Sen Lin, Caitlin Vonderohe, Mahmoud Mohammad, Dennis Kunichoff, Stephanie Cruz, Patricio Lau, Muralidhar Premkumar, Jon Nielsen, Zhengfeng Fang, Oluyinka Olutoye, Thomas Thymann, Robert Britton, Per Sangild, Douglas Burrin

Children’s Nutrition Research Center Staff Publications

Multi-component lipid emulsions, rather than soy-oil emulsions, prevent cholestasis by an unknown mechanism. Here, we quantified liver function, bile acid pools, and gut microbial and metabolite profiles in premature parenterally fed pigs given a soy-oil lipid emulsion, Intralipid (IL), a multi component lipid emulsion, SMOFlipid (SMOF), a novel emulsion with a modified fatty-acid composition [experimental emulsion (EXP)], or a control enteral diet (ENT) for 22 days. We assayed serum cholestasis markers, measured total bile acid levels in plasma, liver, and gut contents, and analyzed colonic bacterial 16S rRNA gene sequences and metabolomic profiles. Serum cholestasis markers (i.e., bilirubin, bile acids, …

C1q/Tnf-Related Protein 5 Contributes To Diabetic Vascular Endothelium Dysfunction Through Promoting Nox-1 Signaling., Jing Liu, Zhijun Meng, Lu Gan, Rui Guo, Jia Gao, Caihong Liu, Di Zhu, Demin Liu, Ling Zhang, Zhen Zhang, Dina Xie, Xiangying Jiao, Wayne Bond Lau, Bernard L. Lopez, Theodore A. Christopher, Xin-Liang Ma, Jimin Cao, Yajing Wang

Department of Emergency Medicine Faculty Papers

OBJECTIVE: Dysregulated adipokine profiles contribute to the pathogenesis of diabetic cardiovascular complications. Endothelial cell (EC) dysfunction, a common pathological alteration in cardiovascular disorders, is exaggerated in diabetes. However, it is unclear whether and how dysregulated adipokines may contribute to diabetic EC dysfunction.

METHODS AND RESULTS: Serum C1q/TNF-Related Protein 5 (CTRP5) were determined in control/diabetes patients, and control/diabetic mice (high-fat diet, HFD). We observed for the first time that serum total CTRP5 was increased, high molecular weight (HMW) form was decreased, but the globular form (gCTRP5) was significantly increased in diabetic patients. These pathological alterations were reproduced in diabetic mice. To …

Awareness Of And Willingness To Use Prep Among Black And Latinx Adolescents Residing In Higher Prevalence Areas In The United States, Tamara Taggart, Yilin Liang, Paolo Pina, Tashuna Albritton

Publications and Research

This mixed-methods study examined awareness of and willingness to use pre-exposure prophylaxis (PrEP) among sexually active Black and Latinx adolescents (13–17 years) residing in five cities in the United States with some of the highest burden of HIV. Data are from adolescents who participated in a cross-sectional survey (n = 208) and one-on-one interviews and focus groups (n = 26) conducted from September 2017—August 2019. Approximately 50% of the sample were recruited through community efforts, and the other half through a panel. Logistic regression with covariates including sexual orientation, relationship status, socioeconomic status, and race/ethnicity were used to assess factors …

Correlation Of Ape1 With Vegfa And Cd163+ Macrophage Infiltration In Bladder Cancer And Their Prognostic Significance, Lin-Ang Wang, Bo Yang, Tang Tang, Yuxin Yang, Dianzheng Zhang, Hualing Xiao, Jing Xu, Luofu Wang, Li Lin, Jun Jiang

PCOM Scholarly Works

The present study sought to estimate the applicability of apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1), vascular endothelial growth factor A (VEGFA) expression and CD163+ tumor‑associated macrophage (TAM) ratio as prognostic factors in bladder cancer (BCa). A total of 127 patients with bladder urothelial cancer who underwent radical cystectomy at Daping Hospital were recruited between January 2013 and January 2017, including 45 cases of non‑muscle invasive BCa (NMIBC) and 82 of MIBC. Immunohistochemical detection of APE1, VEGFA and CD163, as well as multiple immunofluorescence staining for APE1, VEGFA, CD163 and CD34, were performed on tissue samples. For APE1 and VEGFA, the staining was …

Dosimetric Effect When Treating Multiple Lesion Srs Using Vmat With And Without Jaw Tracking, Mindy Bui

Masters Projects

The main purpose of this study was to determine if jaw tracking or non-jaw tracking is the superior technique for patients with multiple brain metastasis that are treated with Volumetric Modulated Radiation Therapy (VMAT) Stereotactic Radiosurgery (SRS). Doses to the organs at risk (OAR) and the target volumes were analyzed using the dose volume histogram (DVH) and dose statistics for each plan. The goal of this study included analyzing the dosimetric effect on the organs at risk and the normal tissue when using jaw tracking versus non jaw tracking. The pros and cons for each technique were identified as well …

The Membrane Protein Ankh Is Crucial For Bone Mechanical Performance By Mediating Cellular Export Of Citrate And Atp, Flóra Szeri, Stefan Lundkvist, Sylvia Donnelly, Udo F H Engelke, Kyu Rhee, Charlene J Williams, John P Sundberg, Ron A Wevers, Ryan Tomlinson, Robert S Jansen, Koen Van De Wetering

Department of Dermatology and Cutaneous Biology Faculty Papers

The membrane protein ANKH was known to prevent pathological mineralization of joints and was thought to export pyrophosphate (PPi) from cells. This did not explain, however, the presence of ANKH in tissues, such as brain, blood vessels and muscle. We now report that in cultured cells ANKH exports ATP, rather than PPi, and, unexpectedly, also citrate as a prominent metabolite. The extracellular ATP is rapidly converted into PPi, explaining the role of ANKH in preventing ankylosis. Mice lacking functional Ank (Ankank/ank mice) had plasma citrate concentrations that were 65% lower than those detected in wild type control animals. Consequently, citrate …

Bayesian Modelling Of High-Throughput Sequencing Assays With Malacoda., Andrew R Ghazi, Xianguo Kong, Ed S Chen, Leonard C Edelstein, Chad A Shaw

Cardeza Foundation for Hematologic Research

NGS studies have uncovered an ever-growing catalog of human variation while leaving an enormous gap between observed variation and experimental characterization of variant function. High-throughput screens powered by NGS have greatly increased the rate of variant functionalization, but the development of comprehensive statistical methods to analyze screen data has lagged. In the massively parallel reporter assay (MPRA), short barcodes are counted by sequencing DNA libraries transfected into cells and the cell's output RNA in order to simultaneously measure the shifts in transcription induced by thousands of genetic variants. These counts present many statistical challenges, including overdispersion, depth dependence, and uncertain …

The Pulmonary Venous Ridge Length To Stratify Stroke Risk In Atrial Fibrillation, Varun Singh, Joy Li, Mark Keroles, Daniel Frisch, Behzad B. Pavri, Baskaran Sundaram, Md, Jason Jacobson, Rajiv Kabadi

Department of Radiology Faculty Papers

Purpose of Study: To evaluate the left superior pulmonary venous ridge length (RL) and the left atrial appendage fractal dimension (LAA FD) as predictors of cardioembolic ischemic stroke (CVA) and transient ischemic attack (TIA) in patients with atrial fibrillation (AF).

Materials, Methods and Procedures: A multicenter, retrospective multicenter study was conducted on patients with AF who underwent cardiac CT prior to catheter ablation between 01/01/2010 and 12/31/2015. Patients were grouped by the presence or absence of prior CVA/TIA. Patients with mitral stenosis, prior mechanical aortic valve replacement, ascending aortic arch atheroma, highrisk patent foramen ovale, history of atrial septal repair …

The Air Gap Effect Between A Bolus And The Skin Surface For Chest Wall Irradiation, Marisa Clark

Masters Projects

Planning technique and bolus choice are important aspects in planning chest wall irradiation (CWI). Many previous studies have tested various combinations of photon energies, electron energies, bolus types and sizes, air gaps sizes, and treatment methods. This study aims to assess the effect of smaller, clinically relevant air gap sizes on specific chest wall treatments using a variety of common bolus types. Due to the Covid-19 pandemic, no data was able to be collected and was instead fabricated by the researcher. Four different treatment plans were created on a phantom patient using various energies of photons (6MV and 10MV) and …

Igf1r Immunohistochemistry In Ewing's Sarcoma As Predictor Of Response To Targeted Therapy., Elizabeth Gonzalez, Marilyn Bui, Atif Ahmed

Manuscripts, Articles, Book Chapters and Other Papers

Objectives: Ewing's sarcoma is an aggressive malignancy of bone and soft tissue in children and young adults. Despite advances in modern therapy, metastasis can occur and results in high mortality. The objective of this study was to identify whether the signaling transduction proteins, insulin growth factor receptor (IGF1R) and S6 kinase (S6K), can predict poor prognosis in Ewing's sarcoma.

Methods: After the Institutional Research Board approval, immunohistochemical experiments on tissue microarray slides containing 32 archived Ewing's sarcoma tumor samples were performed with antibodies against IGF1Rb and p-S6K. Immunohistochemical staining results were correlated with patients' clinical data including clinical stage and …

Hur/Elavl1 Drives Malignant Peripheral Nerve Sheath Tumor Growth And Metastasis, Marta Palomo-Irigoyen, Encarni Pérez-Andrés, Marta Iruarrizaga-Lejarreta, Adrián Barreira-Manrique, Miguel Tamayo-Caro, Laura Vila-Vecilla, Leire Moreno-Cugnon, Nagore Beitia, Daniela Medrano, David Fernández-Ramos, Juan José Lozano, Satoshi Okawa, José L Lavín, Natalia Martín-Martín, James D Sutherland, Virginia Guitiérez De Juan, Monika Gonzalez-Lopez, Nuria Macías-Cámara, David Mosén-Ansorena, Liyam Laraba, C Oliver Hanemann, Emanuela Ercolano, David B Parkinson, Christopher W. Schultz, Bs, Marcos J Araúzo-Bravo, Alex M Ascensión, Daniela Gerovska, Haizea Iribar, Ander Izeta, Peter Pytel, Philipp Krastel, Alessandro Provenzani, Pierfausto Seneci, Ruben D Carrasco, Antonio Del Sol, María Luz Martinez-Chantar, Rosa Barrio, Eduard Serra, Conxi Lazaro, Adrienne M Flanagan, Myriam Gorospe, Nancy Ratner, Ana M Aransay, Arkaitz Carracedo, Marta Varela-Rey, Ashwin Woodhoo

Department of Surgery Faculty Papers

Cancer cells can develop a strong addiction to discrete molecular regulators, which control the aberrant gene expression programs that drive and maintain the cancer phenotype. Here, we report the identification of the RNA-binding protein HuR/ELAVL1 as a central oncogenic driver for malignant peripheral nerve sheath tumors (MPNSTs), which are highly aggressive sarcomas that originate from cells of the Schwann cell lineage. HuR was found to be highly elevated and bound to a multitude of cancer-associated transcripts in human MPNST samples. Accordingly, genetic and pharmacological inhibition of HuR had potent cytostatic and cytotoxic effects on tumor growth, and strongly suppressed metastatic …

Improving Nutrition And Immunity With Dry Chain And Integrated Pest Management Food Technologies In Lmics., Peetambar Dahal, Meghnath Dhimal, Krishna Belbase, Sundar Tiwari, John Groopman, Keith West, Bradley Pollock, Subodh Pyakurel, Ganga Acharya, Sunil Aryal, Yug Nath Ghimire, Manish Neupane, Rosina Poudel, Johan Van Ashbrouck, Keshavulu Kunusoth, Sarah De Saeger, Marthe De Boevre, Gokarna Gharti-Chhetri, Tek Bahadur Gurung, Kent J Bradford

Department of Medical Oncology Faculty Papers

No abstract provided.

Epstein Barr Virus-Immortalizedｂlymphocytes Exacerbate Experimental Autoimmune Encephalomyelitis In Xenograft Mice, Pascal Polepole, Alison Bartenslager, Yutong Liu, Thomas M. Petro, Samodha C. Fernando, Luwen Zhang

Nebraska Center for Virology: Faculty Publications

Multiple sclerosis (MS) is the most common autoimmune disorder affecting the central nervous system. Epstein-Barr virus (EBV) is a causative agent for infectious mononucleosis (IM) that is associated with MS pathogenesis. However, the exact mechanism by which EBV, specifically in IM, increases the risk for MS remains unknown. EBV immortalizes primary B lymphocytes in vitro and causes excessive B lymphocyte proliferation in IM in vivo. In asymptomatic carriers, EBV-infected B lymphocytes still proliferate to certain degrees, the process of which is tightly controlled by the host immune systems. Experimental autoimmune encephalomyelitis (EAE) mimics key features of MS in humans …

Association Analysis Of Driver Gene-Related Genetic Variants Identified Novel Lung Cancer Susceptibility Loci With 20,871 Lung Cancer Cases And 15,971 Controls, Yuzhuo Wang, Olga Y Gorlova, Ivan P Gorlov, Meng Zhu, Juncheng Dai, Demetrius Albanes, Stephen Lam, Adonina Tardon, Chu Chen, Gary E Goodman, Stig E Bojesen, Maria Teresa Landi, Mattias Johansson, Angela Risch, Heunz-Erich Wichmann, Heike Bickeboller, David C Christiani, Gad Rennert, Susanne M Arnold, Paul Brennan, John K Field, Sanjay Shete, Loïc Le Marchand, Olle Melander, Hans Brunnstrom, Geoffrey Liu, Rayjean J Hung, Angeline S Andrew, Lambertus A Kiemeney, Shanbeh Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil E Caporaso, Penella J Woll, Philip Lazarus, Matthew B Schabath, Melinda C Aldrich, Victoria L Stevens, Hongxia Ma, Guangfu Jin, Zhibin Hu, Christopher I Amos, Hongbing Shen

Faculty, Staff and Students Publications

BACKGROUND: A substantial proportion of cancer driver genes (CDG) are also cancer predisposition genes. However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated.

METHODS: We selected expression-related single-nucleotide polymorphisms (eSNP) and nonsynonymous variants of lung CDGs, and tested their associations with lung cancer risk in two large-scale genome-wide association studies (20,871 cases and 15,971 controls of European descent). Conditional and joint association analysis was performed to identify independent risk variants. The associations of independent risk variants with somatic alterations in lung CDGs or recurrently altered pathways were investigated using data …

Mechanism Of Ligand Activation Of A Eukaryotic Cyclic Nucleotide-Gated Channel, Xiangdong Zheng, Ziao Fu, Deyuan Su, Yuebin Zhang, Minghui Li, Yaping Pan, Huan Li, Shufang Li, Robert A Grassucci, Zhenning Ren, Zhengshan Hu, Xueming Li, Ming Zhou, Guohui Li, Joachim Frank, Jian Yang

Faculty, Staff and Students Publications

Cyclic nucleotide-gated (CNG) channels convert cyclic nucleotide (CN) binding and unbinding into electrical signals in sensory receptors and neurons. The molecular conformational changes underpinning ligand activation are largely undefined. We report both closed- and open-state atomic cryo-EM structures of a full-length Caenorhabditis elegans cyclic GMP-activated channel TAX-4, reconstituted in lipid nanodiscs. These structures, together with computational and functional analyses and a mutant channel structure, reveal a double-barrier hydrophobic gate formed by two S6 amino acids in the central cavity. cGMP binding produces global conformational changes that open the cavity gate located ~52 Å away but do not alter the structure …

Combined Lenvatinib And Pembrolizumab As Salvage Therapy In Advanced Adrenal Cortical Carcinoma, Sara Bedrose, Kevin Charles Miller, Lina Altameemi, Mohamed S Ali, Sameh Nassar, Naveen Garg, Marilyne Daher, Keith D Eaton, Jeffrey Thomas Yorio, Davey B Daniel, Matthew Campbell, Keith C Bible, Mabel Ryder, Ashish V Chintakuntlawar, Mouhammed Amir Habra

Faculty, Staff and Students Publications

BACKGROUND: There is no effective systemic therapy for metastatic adrenal cortical carcinoma (ACC) after failure of platinum-based chemotherapy. The efficacies of single-agent oral multikinase inhibitors (MKIs) or salvage immune checkpoint inhibitors (CPIs) have been very limited. It is unknown whether combining CPIs, such as pembrolizumab (PEM), with other therapies, such as MKIs, could yield higher response rates in ACC, yet this combination has shown promise in other cancers. Herein, we describe the first case series using PEM in combination with the MKI lenvatinib (LEN) in patients with progressive, metastatic ACC.

METHODS: A retrospective case series describing the use of LEN/PEM …

Rna-Gps Predicts High-Resolution Rna Subcellular Localization And Highlights The Role Of Splicing, Kevin E Wu, Kevin R Parker, Furqan M Fazal, Howard Y Chang, James Zou

Faculty, Staff and Students Publications

Subcellular localization is essential to RNA biogenesis, processing, and function across the gene expression life cycle. However, the specific nucleotide sequence motifs that direct RNA localization are incompletely understood. Fortunately, new sequencing technologies have provided transcriptome-wide atlases of RNA localization, creating an opportunity to leverage computational modeling. Here we present RNA-GPS, a new machine learning model that uses nucleotide-level features to predict RNA localization across eight different subcellular locations-the first to provide such a wide range of predictions. RNA-GPS's design enables high-throughput sequence ablation and feature importance analyses to probe the sequence motifs that drive localization prediction. We find localization …