Digital Commons Network^™

Informed Consent For Placebo-Controlled Trials: Do Ethics And Science Conflict?, Hope A Feldman, James A Feldman, Charles C Miller, Garrett Walsh, Jon E Tyson

Faculty, Staff and Student Publications

The use of a placebo has been considered the best method for controlling bias in a prospective randomized clinical trial and provides the most rigorous test of treatment efficacy for evaluating a medical therapy. Placebos commonly produce clinically important effects particularly in studies where the primary outcomes are subjective. Yet the potential beneficial or harmful effects of placebos are often not addressed in designing a clinical trial, calculating the sample size, seeking consent, or interpreting clinical trial results. In this manuscript, we use an actual study to indicate three approaches that might be considered in seeking informed consent for placebo-controlled …

Biophysical And Biochemical Characterization Of The Receptor Binding Domain Of Sars-Cov-2 Variants, Ritika Khatri, Hilal Ahmad Parray, Gazala Siddiqui, Adarsh Kumar Chiranjivi, Sneha Raj, Rachel Kaul, Vikas Maithil, Sweety Samal, Shubbir Ahmed

Faculty, Staff and Student Publications

The newly emerging SARS-CoV-2 variants are potential threat and posing new challenges for medical intervention due to high transmissibility and escaping neutralizing antibody (NAb) responses. Many of these variants have mutations in the receptor binding domain (RBD) of SARS-CoV-2 spike protein that interacts with the host cell receptor. Rapid mutation in the RBD through natural selection to improve affinity for host receptor and antibody pressure from vaccinated or infected individual will greatly impact the presently adopted strategies for developing interventions. Understanding the nature of mutations and how they impact the biophysical, biochemical and immunological properties of the RBD will help …

Outcomes Of The Second Aqueous Shunt Implant Versus Transscleral Cyclophotocoagulation Treatment Study: A Randomized Comparative Trial, Robert M Feldman, Alice Z Chuang, Steve L Mansberger, Angelo P Tanna, Lauren S Blieden, Nicholas P Bell, Ronald L Gross, Louis R Pasquale, David S Greenfield, Jeffrey M Liebmann, Robert N Weinreb

Faculty, Staff and Student Publications

PRCIS: Short-term overall success rates were high with either SGDD or CPC. However, SGDD was associated with more clinic visits and an increased risk of additional glaucoma surgery. Both treatments were reasonable options for eyes with inadequately controlled IOP after a single GDD.

PURPOSE: The purpose of this study is to compare the implantation of a second glaucoma drainage device (SGDD) and transscleral cyclophotocoagulation (CPC) in eyes with inadequately controlled intraocular pressure (IOP), despite the presence of a preexisting glaucoma drainage device.

METHODS: Patients with inadequately controlled IOP, despite the medical therapy and a preexisting glaucoma drainage device, were enrolled …

Frosted Branch Angiitis After Smallpox Vaccination, Kristen Collister, Sam S Dahr

Faculty, Staff and Student Publications

PURPOSE: To describe a patient presenting with frosted branch angiitis soon after small-pox vaccination.

OBSERVATIONS: Frosted branch angiitis (FBA) is an acute onset retinal vasculitis featuring prominent perivascular sheathing in otherwise healthy individuals. FBA has been associated with noninfectious and infectious etiologies. This report describes a twenty-year-old African American female who developed bilateral frosted branch angiitis one week after small-pox vaccination. At presentation, the patient had bilateral, para-central visual field defects and subjective visual disturbances. On dilated exam, the patient demonstrated diffuse vasculitis bilaterally. The patient's field defects and clinical exam responded dramatically to oral prednisone therapy.

CONCLUSIONS AND IMPORTANCE: …

Comparison Of The Neer Classification To The 2018 Update Of The Orthopedic Trauma Association/Ao Fracture Classification For Classifying Proximal Humerus Fractures, Meir T Marmor, Julie Agel, Jarrod Dumpe, James F Kellam, Geoffrey S Marecek, Eric Meinberg, Mai P Nguyen, Stephen Sims, Gillian L Soles, Matthew D Karam

Faculty, Staff and Student Publications

BACKGROUND: The classification of fractures is necessary to ensure a reliable means of communication for clinical interaction, education and research. The Neer classification is the most commonly used classification for proximal humerus fractures. In 2018 the Orthopedic Trauma Association (OTA) and the AO Foundation provided an update to the OTA/AO Fracture Classification Scheme addressing many of the concerns about the previous versions of the classification. The objective of the present study was to evaluate the rater reliability of the 2 classifications and if the classifications subjectively better characterized the fracture patterns.

METHODS: X-rays and CT scans of 24 proximal humerus …

Is Prior Hip Arthroscopy Associated With Higher Complication Rates Or Prolonged Opioid Claims After Total Hip Arthroplasty? A Matched Cohort Study, Bailey J Ross, Ryan J Wortman, Olivia C Lee, Alfred A Mansour, Wendell W Cole, William F Sherman

Faculty, Staff and Student Publications

BACKGROUND: Hip arthroscopy (HA) procedures have increased exponentially in recent years. Their effect on outcomes after subsequent total hip arthroplasty (THA) remains unclear.

PURPOSE: To compare rates of complications and opioid claims after elective THA among patients with prior HA versus controls.

STUDY DESIGN: Cohort study; Level of evidence, 3.

METHODS: Patients who underwent THA were identified in the PearlDiver database. Arthroplasty performed for hip fractures and hip avascular necrosis were excluded. Within this population, patients with HA before arthroplasty (n = 3156) were propensity score matched 1:1 with controls on age, sex, US region, and several comorbidities. Rates of …

Development Of A Personalized Shared Decision-Making Tool For Knee Osteoarthritis And User-Testing With African American And Latina Women, Lynne C Jones, Anne M Maurer, Michael L Parks, Philip C Noble, Carla Harwell, Melvyn Harrington, Katherine G Bay, Charles L Nelson, Mary I O'Connor

Faculty, Staff and Student Publications

BACKGROUND: Patients with chronic knee pain are often unaware of treatment options and likely outcomes-information that is critical to decision-making. A consistent framework for communicating patient-personalized information enables clinicians to provide consistent, targeted, and relevant information. Our objective was to user-test a shared decision-making (SDM) tool for chronic knee pain.

METHODS: A cross-functional team developed a Markov-based health economics model and tested the model outputs with patient panels, patient and clinician focus groups, and clinical specialists. The resulting SDM tool was user-tested in a parallel-designed, randomized controlled study with 52 African American and 52 Latina women from geographically representative areas …

Metaphyseal Dysplasia, Spahr Type; A Case Report Of Variable Expressivity In Non-Consanguineous Filipino Siblings, Kailash Panchapakesan, Brennan Roper, Kate Mowrey, Paul Hillman, Shiraz Younas

Faculty, Staff and Student Publications

Introduction:

Metaphyseal dysplasia describes a heterogenous group of skeletal dysplasias with varying inheritance patterns, which preferentially demonstrate dysplastic changes within the metaphyseal region of long bones. The clinical consequences of these dysplastic changes are highly variable, but most uniformly include decreased stature, increased upper-to-lower segment proportions, genu varus, and knee pain. Metaphyseal dysplasia, Spahr type (MDST) [MIM: 250400] is a rare primary bone dysplasia that was first clinically described in 1961 in four of five siblings with moderate short stature, metaphyseal dysplasia, mild genu vara, and no biochemical signs of rickets. For many decades, MDST was a clinical diagnosis, but …

Ureteroscopy Under Conscious Sedation: A Proof-Of-Concept Study, Kunal Jain, Ruben Blachman-Braun, Esha Jain, Amanda Eng, Brian Peters, Premal Patel

Faculty, Staff and Student Publications

INTRODUCTION: Ureteroscopy (URS) is commonly performed under general anesthesia (GA) to maximize patient tolerability and minimize surgical complications; however, given the improvements in endoscopic technology and risks associated with GA, alternate forms of anesthesia have been postulated. We aimed to evaluate the outcomes of URS under conscious sedation.

METHODS: We completed a retrospective cohort study from November 2019 to June 2020 at a tertiary-level hospital. All URSs that were performed under urologist-directed conscious sedation were included. Our primary outcome was the ability to complete URS, defined as success rate. Secondary outcomes included: stone-free rate, intraoperative complication rate, hospital admission rate, …

Altered Bladder-Related Brain Network In Multiple Sclerosis Women With Voiding Dysfunction, Zhaoyue Shi, Christof Karmonik, Amelia Soltes, Khue Tran, John A Lincoln, Timothy Boone, Rose Khavari

Faculty, Staff and Student Publications

Objectives:

A number of neuro-urology imaging studies have mainly focused on investigating the brain activations during micturition in healthy and neuropathic patients. It is, however, also necessary to study brain functional connectivity (FC) within bladder-related regions in order to understand the brain organization during the execution of bladder function. This study aims to identify the altered brain network associated with bladder function in multiple sclerosis (MS) women with voiding dysfunction through comparisons with healthy subjects via concurrent urodynamics (UDS)/fMRI.

Materials and Methods:

Ten healthy adult women and nine adult ambulatory women with clinically stable MS for ≥ 6 months and …

Hepatic Circadian And Differentiation Factors Control Liver Susceptibility For Fatty Liver Disease And Tumorigenesis, Baharan Fekry, Aleix Ribas-Latre, Rachel Van Drunen, Rafael Bravo Santos, Samay Shivshankar, Yulin Dai, Zhongming Zhao, Seung-Hee Yoo, Zheng Chen, Kai Sun, Frances M Sladek, Mamoun Younes, Kristin Eckel-Mahan

Faculty, Staff and Student Publications

Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths, and the most common primary liver malignancy to present in the clinic. With the exception of liver transplant, treatment options for advanced HCC are limited, but improved tumor stratification could open the door to new treatment options. Previously, we demonstrated that the circadian regulator Aryl Hydrocarbon-Like Receptor Like 1 (ARNTL, or Bmal1) and the liver-enriched nuclear factor 4 alpha (HNF4α) are robustly co-expressed in healthy liver but incompatible in the context of HCC. Faulty circadian expression of HNF4α- either by isoform switching, or loss of expression- results in an increased …

Gastrocnemius Venous Aneurysm-A Diagnostic Dilemma, Akiko Tanaka, Taha Syed Zaidi, S Keisin Wang, Arash Keyhani, Kourosh Keyhani

Faculty, Staff and Student Publications

A 63-year-old man with multiple previous orthopedic procedures in both lower extremities had presented to us for a third opinion regarding the point-specific pain in his right lateral calf. The initial diagnosis had been venous reflux at two other institutions. However, repeat imaging studies demonstrated an aneurysmal gastrocnemius vein without any other abnormalities, such as venous reflux or thrombosis. The patient had received compression stocking therapy for 6 months but had continued to experience increasing pain at night, especially when lying in bed. The patient was reexamined in the supine position, which showed a prominent bulge in the lateral calf. …

Dockopathies: A Systematic Review Of The Clinical Pathologies Associated With Human Dock Pathogenic Variants, Adrienne Samani, Katherine G English, Michael A Lopez, Camille L Birch, Donna M Brown, Gurpreet Kaur, Elizabeth A Worthey, Matthew S Alexander

Faculty, Staff and Student Publications

The Dedicator of Cytokinesis (DOCK) family (DOCK1-11) of genes are essential mediators of cellular migration, growth, and fusion in a variety of cell types and tissues. Recent advances in whole-genome sequencing of patients with undiagnosed genetic disorders have identified several rare pathogenic variants in DOCK genes. We conducted a systematic review and performed a patient database and literature search of reported DOCK pathogenic variants that have been identified in association with clinical pathologies such as global developmental delay, immune cell dysfunction, muscle hypotonia, and muscle ataxia among other categories. We then categorized these pathogenic DOCK variants and their associated clinical …

Informed Consent For Placebo-Controlled Trials: Do Ethics And Science Conflict?, Hope A Feldman, James A Feldman, Charles C Miller, Garrett Walsh, Jon E Tyson

Faculty, Staff and Student Publications

The use of a placebo has been considered the best method for controlling bias in a prospective randomized clinical trial and provides the most rigorous test of treatment efficacy for evaluating a medical therapy. Placebos commonly produce clinically important effects particularly in studies where the primary outcomes are subjective. Yet the potential beneficial or harmful effects of placebos are often not addressed in designing a clinical trial, calculating the sample size, seeking consent, or interpreting clinical trial results. In this manuscript, we use an actual study to indicate three approaches that might be considered in seeking informed consent for placebo-controlled …

The Effect Of Body Mass Index On Therapeutic Response To Bacterial Vaginosis In Pregnancy, Kevin P Lee, Misha V Koshelev, D3code Team, Omar Pacha

Faculty, Staff and Student Publications

No abstract provided.

Amphotericin B Resistance In Leishmania Mexicana: Alterations To Sterol Metabolism And Oxidative Stress Response, Edubiel A Alpizar-Sosa, Nur Raihana Binti Ithnin, Wenbin Wei, Andrew W Pountain, Stefan K Weidt, Anne M Donachie, Ryan Ritchie, Emily A Dickie, Richard J S Burchmore, Paul W Denny, Michael P Barrett

Faculty, Staff and Student Publications

Amphotericin B is increasingly used in treatment of leishmaniasis. Here, fourteen independent lines of Leishmania mexicana and one L. infantum line were selected for resistance to either amphotericin B or the related polyene antimicrobial, nystatin. Sterol profiling revealed that, in each resistant line, the predominant wild-type sterol, ergosta-5,7,24-trienol, was replaced by other sterol intermediates. Broadly, two different profiles emerged among the resistant lines. Whole genome sequencing then showed that these distinct profiles were due either to mutations in the sterol methyl transferase (C24SMT) gene locus or the sterol C5 desaturase (C5DS) gene. In three lines an additional deletion of …

Covid-19 And Blood Clots: A Report Of Massive Pulmonary Embolism In Covid-19 Patient Supported On Veno-Venous Ecmo And The Utility Of Thrombolysis, Bindu Akkanti, Joseph Zwischenberger, Mark T Warner, Kha Dinh, Rahat Hussain, Farah Kazzaz, Pascal Kingah, Lisa M Janowiak, Biswajit Kar, Igor D Gregoric

Faculty, Staff and Student Publications

COVID-19 morbidity and mortality are not equivalent to other etiologies of acute respiratory distress syndrome (ARDS) as fulminant activation of coagulation can occur, thereby resulting in widespread microvascular thrombosis and consumption of coagulation factors. A 53-year-old female presented to an emergency center on two occasions with progressive gastrointestinal and respiratory symptoms. She was diagnosed with COVID-19 pneumonia and admitted to a satellite intensive care unit with hypoxemic respiratory failure. She was intubated and mechanically ventilated, but her ARDS progressed over the next 48 hours. The patient was emergently cannulated for veno-venous extracorporeal membrane oxygenation (V-V ECMO) and transferred to our …

Post–Lung Transplantation Outcomes And Ex Vivo Histopathological Findings In Severe Post-Covid-19 Pulmonary Disease—A Single-Center Experience, Hana Javaid, Masayuki Nigo, Bihong Zhao, Daniel Ocazionez Trujillo, Rodrigo Hasbun, Luis Ostrosky-Zeichner, Manish Patel, Soma Jyothula

Faculty, Staff and Student Publications

BACKGROUND: A significant proportion of patients with severe and persistent coronavirus disease 2019 (COVID-19) require continuous ventilatory support and occasional extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS). Lung transplantation is a treatment option for patients who develop severe ARDS.

METHODS: Our lung transplant database was retrospectively reviewed for patients who underwent lung transplantation for COVID-19 pulmonary disease at Memorial Hermann Hospital, Texas Medical Center, Houston, Texas, from January 2020 to March 2022. We evaluated outcomes of patients who were followed in our clinic at least 6 months post-transplant. Pretransplant patient characteristics, COVID-19-related treatment, histopathology results, and postdischarge …

Modulation Of The Association Between Age And Death By Risk Factor Burden In Critically Ill Patients With Covid-19, Ashwin Sunderraj, Chloe Cho, Xuan Cai, Shruti Gupta, Rupal Mehta, Tamara Isakova, David E Leaf, Anand Srivastava

Faculty, Staff and Student Publications

Older age is a key risk factor for adverse outcomes in critically ill patients with COVID-19. However, few studies have investigated whether preexisting comorbidities and acute physiologic ICU factors modify the association between age and death.

DESIGN: Multicenter cohort study.

SETTING: ICUs at 68 hospitals across the United States.

PATIENTS: A total of 5,037 critically ill adults with COVID-19 admitted to ICUs between March 1, 2020, and July 1, 2020.

INTERVENTIONS: None.

MEASUREMENTS AND MAIN RESULTS: The primary exposure was age, modeled as a continuous variable. The primary outcome was 28-day inhospital mortality. Multivariable logistic regression tested the association between …

Coronary-To-Coronary Bypass Grafting In Aortoarteritis: A Case Report, Immaneni Sathyamurthy, Narra Lavanya, Kanthallu Narayanamoorthy Srinivasan, Maligail Ramkrishna Girinath

Faculty, Staff and Student Publications

Takayasu's arteritis (TA) is an idiopathic vasculitis affecting the aorta and its major branches. In TA, coronary artery involvement is rare and it mainly consists of stenosis or occlusion of the coronary ostia. In TA, as the arterial tree is diseased, often, arterial grafts are unsuitable for grafting so the saphenous vein grafts (SVG) are commonly used. We present a case of a young female with TA with an ostial left main stenosis who has undergone a right coronary-to-left anterior descending artery SVG and put on immunosuppression and steroids. She was asymptomatic with a patent graft during 7 years follow-up.

Membrane-Anchored And Tumor-Targeted Il12 (Attil12)-Pbmc Therapy For Osteosarcoma, Qing Yang, Jiemiao Hu, Zhiliang Jia, Qi Wang, Jing Wang, Long Hoang Dao, Wendong Zhang, Sheng Zhang, Xueqing Xia, Richard Gorlick, Shulin Li

Faculty, Staff and Student Publications

Purpose: Chimeric antigen receptor (CAR) T-cell therapy has shown great promise for treating hematologic malignancies but requires a long duration of T-cell expansion, is associated with severe toxicity, and has limited efficacy for treating solid tumors. We designed experiments to address those challenges.

Experimental design: We generated a cell membrane-anchored and tumor-targeted IL12 (attIL12) to arm peripheral blood mononuclear cells (PBMC) instead of T cells to omit the expansion phase for required CAR T cells.

Results: This IL12-based attIL12-PBMC therapy showed significant antitumor efficacy in both heterogeneous osteosarcoma patient-derived xenograft tumors and metastatic osteosarcoma tumors with no observable toxic effects. …

Mass Transport Model Of Radiation Response: Calibration And Application To Chemoradiation For Pancreatic Cancer, Charles X Wang, Dalia Elganainy, Mohamed M Zaid, Joseph D Butner, Anshuman Agrawal, Sara Nizzero, Bruce D Minsky, Emma B Holliday, Cullen M Taniguchi, Grace L Smith, Albert C Koong, Joseph M Herman, Prajnan Das, Anirban Maitra, Huamin Wang, Robert A Wolff, Matthew H G Katz, Christopher H Crane, Vittorio Cristini, Eugene J Koay

Faculty, Staff and Student Publications

PURPOSE: The benefit of radiation therapy for pancreatic ductal adenocarcinoma (PDAC) remains unclear. We hypothesized that a new mechanistic mathematical model of chemotherapy and radiation response could predict clinical outcomes a priori, using a previously described baseline measurement of perfusion from computed tomography scans, normalized area under the enhancement curve (nAUC).

METHODS AND MATERIALS: We simplified an existing mass transport model that predicted cancer cell death by replacing previously unknown variables with averaged direct measurements from randomly selected pathologic sections of untreated PDAC. This allowed using nAUC as the sole model input to approximate tumor perfusion. We then compared the …

Clinical Acceptability Of Fully Automated External Beam Radiotherapy For Cervical Cancer With Three Different Beam Delivery Techniques, Dong Joo Rhee, Anuja Jhingran, Kai Huang, Tucker J Netherton, Nazia Fakie, Ingrid White, Alicia Sherriff, Carlos E Cardenas, Lifei Zhang, Surendra Prajapati, Stephen F Kry, Beth M Beadle, William Shaw, Frederika O'Reilly, Jeannette Parkes, Hester Burger, Chris Trauernicht, Hannah Simonds, Laurence E Court

Faculty, Staff and Student Publications

Purpose: To fully automate CT-based cervical cancer radiotherapy by automating contouring and planning for three different treatment techniques.

Methods: We automated three different radiotherapy planning techniques for locally advanced cervical cancer: 2D 4-field-box (4-field-box), 3D conformal radiotherapy (3D-CRT), and volumetric modulated arc therapy (VMAT). These auto-planning algorithms were combined with a previously developed auto-contouring system. To improve the quality of the 4-field-box and 3D-CRT plans, we used an in-house, field-in-field (FIF) automation program. Thirty-five plans were generated for each technique on CT scans from multiple institutions and evaluated by five experienced radiation oncologists from three different countries. Every plan was …

Development And Validation Of A Checklist For Use With Automatically Generated Radiotherapy Plans, Kelly A Nealon, Laurence E Court, Raphael J Douglas, Lifei Zhang, Eun Young Han

Faculty, Staff and Student Publications

Purpose: To develop a checklist that improves the rate of error detection during the plan review of automatically generated radiotherapy plans.

Methods: A custom checklist was developed using guidance from American Association of Physicists in Medicine task groups 275 and 315 and the results of a failure modes and effects analysis of the Radiation Planning Assistant (RPA), an automated contouring and treatment planning tool. The preliminary checklist contained 90 review items for each automatically generated plan. In the first study, eight physicists were recruited from our institution who were familiar with the RPA. Each physicist reviewed 10 artificial intelligence-generated resident …

Dynamic S-Acylation Of The Er-Resident Protein Stromal Interaction Molecule 1 (Stim1) Is Required For Store-Operated Ca2+ Entry, Goutham Kodakandla, Savannah J West, Qiaochu Wang, Ritika Tewari, Michael X Zhu, Askar M Akimzhanov, Darren Boehning

Faculty, Staff and Student Publications

Many cell surface stimuli cause calcium release from endoplasmic reticulum (ER) stores to regulate cellular physiology. Upon ER calcium store depletion, the ER-resident protein stromal interaction molecule 1 (STIM1) physically interacts with plasma membrane protein Orai1 to induce calcium release-activated calcium (CRAC) currents that conduct calcium influx from the extracellular milieu. Although the physiological relevance of this process is well established, the mechanism supporting the assembly of these proteins is incompletely understood. Earlier we demonstrated a previously unknown post-translational modification of Orai1 with long-chain fatty acids, known as S-acylation. We found that S-acylation of Orai1 is dynamically regulated in a …

Idh1 Prr32h Ctdna And D-2-Hydroxyglutarate As Csf Biomarkers In Patients With Idh-Mutant Gliomas, Yoko Fujita, Luis Nunez-Rubiano, Antonio Dono, Allison Bellman, Mauli Shah, Juan C Rodriguez, Vasanta Putluri, Abu Hena Mostafa Kamal, Nagireddy Putluri, Roy F Riascos, Jay-Jiguang Zhu, Yoshua Esquenazi, Leomar Y Ballester

Faculty, Staff and Student Publications

INTRODUCTION: We aimed to evaluate IDH1 p.R132H mutation and 2-hydroxyglutarate (2HG) in cerebrospinal fluid (CSF) as biomarkers for patients with IDH-mutant gliomas.

METHODS: CSF was collected from patients with infiltrating glioma, and 2HG levels were measured by liquid chromatography-mass spectrometry. IDH1 p.R132H mutant allele frequency (MAF) in CSF-ctDNA was measured by digital droplet PCR (ddPCR). Tumor volume was measured from standard-of-care magnetic resonance images.

RESULTS: The study included 48 patients, 6 with IDH-mutant and 42 with IDH-wildtype gliomas, and 57 samples, 9 from the patients with IDH-mutant and 48 from the patients with IDH-wildtype gliomas. ctDNA was detected in 7 …

Automation Of Radiation Treatment Planning For Rectal Cancer, Kai Huang, Prajnan Das, Adenike M Olanrewaju, Carlos Cardenas, David Fuentes, Lifei Zhang, Donald Hancock, Hannah Simonds, Dong Joo Rhee, Sam Beddar, Tina M Briere, Laurence Court

Faculty, Staff and Student Publications

PURPOSE: To develop an automated workflow for rectal cancer three-dimensional conformal radiotherapy (3DCRT) treatment planning that combines deep learning (DL) aperture predictions and forward-planning algorithms.

METHODS: We designed an algorithm to automate the clinical workflow for 3DCRT planning with field aperture creations and field-in-field (FIF) planning. DL models (DeepLabV3+ architecture) were trained, validated, and tested on 555 patients to automatically generate aperture shapes for primary (posterior-anterior [PA] and opposed laterals) and boost fields. Network inputs were digitally reconstructed radiographs, gross tumor volume (GTV), and nodal GTV. A physician scored each aperture for 20 patients on a 5-point scale (>3 …

Genetic Loci And Prioritization Of Genes For Kidney Function Decline Derived From A Meta-Analysis Of 62 Longitudinal Genome-Wide Association Studies, Mathias Gorski, Humaira Rasheed, Alexander Teumer, Laurent F Thomas, Sarah E Graham, Gardar Sveinbjornsson, Thomas W Winkler, Felix Günther, Klaus J Stark, Jin-Fang Chai, Bamidele O Tayo, Matthias Wuttke, Yong Li, Adrienne Tin, Tarunveer S Ahluwalia, Johan Ärnlöv, Bjørn Olav Åsvold, Stephan J L Bakker, Bernhard Banas, Nisha Bansal, Mary L Biggs, Ginevra Biino, Michael Böhnke, Eric Boerwinkle, Erwin P Bottinger, Hermann Brenner, Ben Brumpton, Robert J Carroll, Layal Chaker, John Chalmers, Miao-Li Chee, Miao-Ling Chee, Ching-Yu Cheng, Audrey Y Chu, Marina Ciullo, Massimiliano Cocca, James P Cook, Josef Coresh, Daniele Cusi, Martin H De Borst, Frauke Degenhardt, Kai-Uwe Eckardt, Karlhans Endlich, Michele K Evans, Mary F Feitosa, Andre Franke, Sandra Freitag-Wolf, Christian Fuchsberger, Piyush Gampawar, Ron T Gansevoort, Mohsen Ghanbari, Sahar Ghasemi, Vilmantas Giedraitis, Christian Gieger, Daniel F Gudbjartsson, Stein Hallan, Pavel Hamet, Asahi Hishida, Kevin Ho, Edith Hofer, Bernd Holleczek, Hilma Holm, Anselm Hoppmann, Katrin Horn, Nina Hutri-Kähönen, Kristian Hveem, Shih-Jen Hwang, M Arfan Ikram, Navya Shilpa Josyula, Bettina Jung, Mika Kähönen, Irma Karabegović, Chiea-Chuen Khor, Wolfgang Koenig, Holly Kramer, Bernhard K Krämer, Brigitte Kühnel, Johanna Kuusisto, Markku Laakso, Leslie A Lange, Terho Lehtimäki, Man Li, Wolfgang Lieb, Lifelines Cohort Study, Lars Lind, Cecilia M Lindgren, Ruth J F Loos, Mary Ann Lukas, Leo-Pekka Lyytikäinen, Anubha Mahajan, Pamela R Matias-Garcia, Christa Meisinger, Thomas Meitinger, Olle Melander, Yuri Milaneschi, Pashupati P Mishra, Nina Mononen, Andrew P Morris, Josyf C Mychaleckyj, Girish N Nadkarni, Mariko Naito, Masahiro Nakatochi, Mike A Nalls, Matthias Nauck, Kjell Nikus, Boting Ning, Ilja M Nolte, Teresa Nutile, Michelle L O'Donoghue, Jeffrey O'Connell, Isleifur Olafsson, Marju Orho-Melander, Afshin Parsa, Sarah A Pendergrass, Brenda W J H Penninx, Mario Pirastu, Michael H Preuss, Bruce M Psaty, Laura M Raffield, Olli T Raitakari, Myriam Rheinberger, Kenneth M Rice, Federica Rizzi, Alexander R Rosenkranz, Peter Rossing, Jerome I Rotter, Daniela Ruggiero, Kathleen A Ryan, Charumathi Sabanayagam, Erika Salvi, Helena Schmidt, Reinhold Schmidt, Markus Scholz, Ben Schöttker, Christina-Alexandra Schulz, Sanaz Sedaghat, Christian M Shaffer, Karsten B Sieber, Xueling Sim, Mario Sims, Harold Snieder, Kira J Stanzick, Unnur Thorsteinsdottir, Hannah Stocker, Konstantin Strauch, Heather M Stringham, Patrick Sulem, Silke Szymczak, Kent D Taylor, Chris H L Thio, Johanne Tremblay, Simona Vaccargiu, Pim Van Der Harst, Peter J Van Der Most, Niek Verweij, Uwe Völker, Kenji Wakai, Melanie Waldenberger, Lars Wallentin, Stefan Wallner, Judy Wang, Dawn M Waterworth, Harvey D White, Cristen J Willer, Tien-Yin Wong, Mark Woodward, Qiong Yang, Laura M Yerges-Armstrong, Martina Zimmermann, Alan B Zonderman, Tobias Bergler, Kari Stefansson, Carsten A Böger, Cristian Pattaro, Anna Köttgen, Florian Kronenberg, Iris M Heid

Faculty, Staff and Student Publications

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine …

Tumor Immune Microenvironment Changes By Multiplex Immunofluorescence Staining In A Pilot Study Of Neoadjuvant Talazoparib For Early-Stage Breast Cancer Patients With A Hereditary Brca Mutation, Tapsi Kumar, Evie Hobbs, Fei Yang, Jeffrey T Chang, Alejandro Contreras, Edwin Roger Parra Cuentas, Haven Garber, Sanghoon Lee, Yiling Lu, Marion E Scoggins, Beatriz E Adrada, Gary J Whitman, Banu K Arun, Elizabeth A Mittendorf, Jennifer K Litton

Faculty, Staff and Student Publications

PURPOSE: The immunological profile of early-stage breast cancer treated with neoadjuvant PARP inhibitors has not been described. The aim of this study was to delineate the changes in the tumor immune microenvironment (TiME) induced by talazoparib.

PATIENTS AND METHODS: Patients with operable germline BRCA1/2 pathogenic variant (gBRCA1/2+) breast cancer were enrolled in a feasibility study of neoadjuvant talazoparib. Thirteen patients who received 8 weeks of neoadjuvant talazoparib were available for analysis, including 11 paired pre- and post-talazoparib core biopsies. Treatment-related changes in tumor-infiltrating lymphocytes were examined and immune cell phenotypes and their spatial distribution in the TiME were identified and …

Cisplatin And Gemcitabine Exert Opposite Effects On Immunotherapy With Pd-1 Antibody In K-Ras-Driven Cancer, Christophe Glorieux, Xiaojun Xia, Xin You, Zining Wang, Yi Han, Jing Yang, Gauthier Noppe, Christophe De Meester, Jianhua Ling, Annie Robert, Hui Zhang, Sheng-Ping Li, Huamin Wang, Paul J Chiao, Li Zhang, Xiaobing Li, Peng Huang

Faculty, Staff and Student Publications

INTRODUCTION: Immunochemotherapy using PD-1/PD-L1 antibodies in combination with chemotherapeutic agents has become a mainstream treatment for cancer patients, but it remains unclear which drug combinations would produce best therapeutic outcome.

OBJECTIVES: The purpose of this study was to investigate two common chemotherapeutic drugs, gemcitabine and cisplatin, for their impacts on the therapeutic efficacy of PD-1 antibody in K-ras-driven cancers known to overexpress PD-L1.

METHODS: Both in vitro assays and syngeneic mouse tumor models were used in this study. Biochemical and molecular assays were used to determine the effects of drugs on T cell functions in cell culture models and in …