Medical Specialties Commons^™

Developing High-Affinity Decoy Receptors To Treat Multiple Myeloma And Diffuse Large B Cell Lymphoma, Yu Rebecca Miao, Kaushik Thakkar, Can Cenik, Dadi Jiang, Kazue Mizuno, Chenjun Jia, Caiyun Grace Li, Hongjuan Zhao, Anh Diep, Yu Xu, Xin Eric Zhang, Teddy Tat Chi Yang, Michaela Liedtke, Parveen Abidi, Wing-Sze Leung, Albert C Koong, Amato J Giaccia

Faculty, Staff and Student Publications

Disease relapse and treatment-induced immunotoxicity pose significant clinical challenges for patients with hematological cancers. Here, we reveal distinctive requirements for neutralizing TNF receptor ligands APRIL and BAFF and their receptor activity in MM and DLBCL, impacting protein translation and production in MM cells and modulating the translation efficiency of the ATM interactor (ATMIN/ACSIZ). Therapeutically, we investigated the use of BCMA decoy receptor (sBCMA-Fc) as an inhibitor of APRIL and BAFF. While wild-type sBCMA-Fc effectively blocked APRIL signaling in MM, it lacked activity in DLBCL due to its weak BAFF binding. To expand the therapeutic utility of sBCMA-Fc, we engineered an …

The Third Joint Meeting On Lung Cancer Of The Fhu Oncoage (University Côte D'Azur, Nice, France) And The University Of Texas Md Anderson Cancer Center (Houston, Tx, Usa) Understanding New Therapeutic Options And Promising Predictive Biomarkers For Lung Cancer Patients, Paul Hofman, George A Calin, Sandurai A Mani, Christophe Bontoux, Marius Ilié, Ignacio I Wistuba

Faculty, Staff and Student Publications

We are proud and happy to present this Special Issue, a follow-up to the third joint meeting on lung cancer of the FHU OncoAge (University Côte d’Azur, Nice, France) and the University of Texas MD Anderson Cancer Center (Houston, TX, USA), which was held virtually on 4 October 2021. This meeting was devoted to better understanding new mechanisms of lung carcinogenesis and novel therapeutic options for lung cancer patients. Moreover, some promising biomarkers for non-small cell lung carcinoma (NSCLC) were also discussed.

A Potential Role For Substance P In West Nile Virus Neuropathogenesis, Shannon E Ronca, Sarah M Gunter, Rebecca Berry Kairis, Allison Lino, Jonathan Romero, Robia G Pautler, Alan Nimmo, Kristy O Murray

Faculty, Staff and Students Publications

Of individuals who develop West Nile neuroinvasive disease (WNND), ~10% will die and >40% will develop long-term complications. Current treatment recommendations solely focus on supportive care; therefore, we urgently need to identify novel and effective therapeutic options. We observed a correlation between substance P (SP), a key player in neuroinflammation, and its receptor Neurokinin-1 (NK1R). Our study in a wild-type BL6 mouse model found that SP is upregulated in the brain during infection, which correlated with neuroinvasion and damage to the blood−brain barrier. Blocking the SP/NK1R interaction beginning at disease onset modestly improved survival and prolonged time to death in …

Rolling Stones: An Instructive Case Of Neonatal Cholestasis, Paige Killelea, Shruti Sakhuja, Jose Hernandez, M John Hicks, Sanjiv Harpavat

Faculty, Staff and Students Publications

BACKGROUND: Jaundice within the first 1-2 weeks of a neonate's life will generally self-resolve; however, if it lasts longer than this time frame it warrants further work up. Direct or conjugated hyperbilirubinemia can suggest neonatal cholestasis, which in turn reflects marked reduction in bile secretion and flow. The differential diagnosis for neonatal cholestasis is broad. Neonatal choledocholithiasis is a rare cause of neonatal cholestasis, but should be considered on the differential diagnosis for patients presenting with elevated conjugated bilirubin.

CASE PRESENTATION: We describe an infant who presented with neonatal cholestasis. He subsequently underwent work up for biliary atresia, as this …

Impact Of Social Determinants Of Health On Anticoagulant Use Among Patients With Atrial Fibrillation: Systemic Review And Meta-Analysis, Rasha Khatib, Nicole Glowacki, John Byrne, Peter Brady

Faculty, Staff and Student Publications

BACKGROUND: A growing body of literature now exists examining associations between social determinants of health (SDOH) and adverse outcomes in patients with atrial fibrillation; however, little is available on anticoagulant prescriptions and the impact of SDOH.

PURPOSE: Evaluate the impact of SDOH on anticoagulant prescriptions in patients with atrial fibrillation.

DATA SOURCES: Medline and Embase databases up to January 2021.

STUDY SELECTION: Noninterventional studies were included if they reported associations between at least 1 of 14 SDOH domains and anticoagulant prescription in patients with atrial fibrillation. Two investigators independently screened and collected data.

DATA EXTRACTION: Two investigators independently screened and …

Biomolecular Condensation: A New Phase In Cancer Research, Anupam K Chakravarty, Daniel J Mcgrail, Thomas M Lozanoski, Brandon S Dunn, David J H Shih, Kara M Cirillo, Sueda H Cetinkaya, Wenjin Jim Zheng, Gordon B Mills, S Stephen Yi, Daniel F Jarosz, Nidhi Sahni

Faculty, Staff and Student Publications

Multicellularity was a watershed development in evolution. However, it also meant that individual cells could escape regulatory mechanisms that restrict proliferation at a severe cost to the organism: cancer. From the standpoint of cellular organization, evolutionary complexity scales to organize different molecules within the intracellular milieu. The recent realization that many biomolecules can "phase-separate" into membraneless organelles, reorganizing cellular biochemistry in space and time, has led to an explosion of research activity in this area. In this review, we explore mechanistic connections between phase separation and cancer-associated processes and emerging examples of how these become deranged in malignancy.

SIGNIFICANCE: One …

Retinoic Acid Receptor Activation Reduces Metastatic Prostate Cancer Bone Lesions By Blocking The Endothelial-To-Osteoblast Transition, Guoyu Yu, Paul G Corn, Pengfei Shen, Jian H Song, Yu-Chen Lee, Song-Chang Lin, Jing Pan, Sandeep K Agarwal, Theocharis Panaretakis, Maurizio Pacifici, Christopher J Logothetis, Li-Yuan Yu-Lee, Sue-Hwa Lin

Faculty, Staff and Students Publications

Metastatic prostate cancer (PCa) in the bone induces bone-forming lesions that contribute to progression and therapy resistance. PCa-induced bone originates from endothelial cells (EC) that have undergone endothelial-to-osteoblast (EC-to-OSB) transition in response to tumor-secreted BMP4. Current strategies targeting PCa-induced bone formation are lacking. Here, we show that activation of retinoic acid receptor (RAR) inhibits EC-to-OSB transition and reduces PCa-induced bone formation. Treatment with palovarotene, an RARγ agonist being tested for heterotopic ossification in fibrodysplasia ossificans progressiva, inhibited EC-to-OSB transition and osteoblast mineralization in vitro and decreased tumor-induced bone formation and tumor growth in several osteogenic PCa models, and similar effects …

Chd1 Promotes Sensitivity To Aurora Kinase Inhibitors By Suppressing Interaction Of Aurka With Its Coactivator Tpx2, Haoyan Li, Yin Wang, Kevin Lin, Varadha Balaji Venkadakrishnan, Martin Bakht, Wei Shi, Chenling Meng, Jie Zhang, Kaitlyn Tremble, Xin Liang, Jian H Song, Xu Feng, Vivien Van, Pingna Deng, Jared K Burks, Ana Aparicio, Khandan Keyomarsi, Junjie Chen, Yue Lu, Himisha Beltran, Di Zhao

Faculty, Staff and Student Publications

UNLABELLED: Clinical studies have shown that subsets of patients with cancer achieve a significant benefit from Aurora kinase inhibitors, suggesting an urgent need to identify biomarkers for predicting drug response. Chromodomain helicase DNA binding protein 1 (CHD1) is involved in chromatin remodeling, DNA repair, and transcriptional plasticity. Prior studies have demonstrated that CHD1 has distinct expression patterns in cancers with different molecular features, but its impact on drug responsiveness remains understudied. Here, we show that CHD1 promotes the susceptibility of prostate cancer cells to inhibitors targeting Aurora kinases, while depletion of CHD1 impairs their efficacy in vitro and in vivo. …

Association Study Between Polymorphisms In Dna Methylation-Related Genes And Testicular Germ Cell Tumor Risk, Chiara Grasso, Maja Popovic, Elena Isaevska, Fulvio Lazzarato, Valentina Fiano, Daniela Zugna, John Pluta, Benita Weathers, Kurt D'Andrea, Kristian Almstrup, Lynn Anson-Cartwright, D Timothy Bishop, Stephen J Chanock, Chu Chen, Victoria K Cortessis, Marlene D Dalgaard, Siamak Daneshmand, Alberto Ferlin, Carlo Foresta, Megan N Frone, Marija Gamulin, Jourik A Gietema, Mark H Greene, Tom Grotmol, Robert J Hamilton, Trine B Haugen, Russ Hauser, Robert Karlsson, Lambertus A Kiemeney, Davor Lessel, Patrizia Lista, Ragnhild A Lothe, Chey Loveday, Coby Meijer, Kevin T Nead, Jérémie Nsengimana, Rolf I Skotheim, Clare Turnbull, David J Vaughn, Fredrik Wiklund, Tongzhang Zheng, Andrea Zitella, Stephen M Schwartz, Katherine A Mcglynn, Peter A Kanetsky, Katherine L Nathanson, Lorenzo Richiardi

Faculty, Staff and Student Publications

Background: Testicular germ cell tumors (TGCT), histologically classified as seminomas and nonseminomas, are believed to arise from primordial gonocytes, with the maturation process blocked when they are subjected to DNA methylation reprogramming. SNPs in DNA methylation machinery and folate-dependent one-carbon metabolism genes have been postulated to influence the proper establishment of DNA methylation.

Methods: In this pathway-focused investigation, we evaluated the association between 273 selected tag SNPs from 28 DNA methylation-related genes and TGCT risk. We carried out association analysis at individual SNP and gene-based level using summary statistics from the Genome Wide Association Study meta-analysis recently conducted by the …

Does A Multiple Myeloma Polygenic Risk Score Predict Overall Survival Of Patients With Myeloma?, Angelica Macauda, Alyssa Clay-Gilmour, Thomas Hielscher, Michelle A T Hildebrandt, Marcin Kruszewski, Robert Z Orlowski, Shaji K Kumar, Elad Ziv, Enrico Orciuolo, Elizabeth E Brown, Asta Försti, Rosalie G Waller, Mitchell J Machiela, Stephen J Chanock, Nicola J Camp, Marcin Rymko, Małgorzata Raźny, Wendy Cozen, Judit Várkonyi, Chiara Piredda, Matteo Pelosini, Alem A Belachew, Edyta Subocz, Kari Hemminki, Malwina Rybicka-Ramos, Graham G Giles, Roger L Milne, Jonathan N Hofmann, Jan Maciej Zaucha, Annette Juul Vangsted, Hartmut Goldschmidt, S Vincent Rajkumar, Waldemar Tomczak, Juan Sainz, Aleksandra Butrym, Marzena Watek, Elżbieta Iskierka-Jazdzewska, Gabriele Buda, Dennis P Robinson, Artur Jurczyszyn, Marek Dudziński, Joaquin Martinez-Lopez, Jason P Sinnwell, Susan L Slager, Krzysztof Jamroziak, Rui Manuel Vieira Reis, Niels Weinhold, Parveen Bhatti, Luis G Carvajal-Carmona, Daria Zawirska, Aaron D Norman, Grzegorz Mazur, Sonja I Berndt, Daniele Campa, Celine M Vachon, Federico Canzian

Faculty, Staff and Student Publications

Background: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival.

Methods: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association …

Exercise Promotes Pro-Apoptotic Ceramide Signaling In A Mouse Melanoma Model, Jonghae Lee, Hannah Savage, Shinji Maegawa, Riccardo Ballarò, Sumedha Pareek, Bella Samia Guerrouahen, Vidya Gopalakrishnan, Keri Schadler

Faculty, Staff and Student Publications

Ceramides are essential sphingolipids that mediate cell death and survival. Low ceramide content in melanoma is one mechanism of drug resistance. Thus, increasing the ceramide content in tumor cells is likely to increase their sensitivity to cytotoxic therapy. Aerobic exercise has been shown to modulate ceramide metabolism in healthy tissue, but the relationship between exercise and ceramide in tumors has not been evaluated. Here, we demonstrate that aerobic exercise causes tumor cell apoptosis and accumulation of pro-apoptotic ceramides in B16F10 but not BP melanoma models using mice. B16F10 tumor-bearing mice were treated with two weeks of moderate treadmill exercise, or …

Pramlintide: A Novel Therapeutic Approach For Osteosarcoma Through Metabolic Reprogramming, Yuanzheng Yang, Zhanglong Peng, Elsa R Flores, Eugenie S Kleinerman

Faculty, Staff and Student Publications

Despite aggressive combination chemotherapy and surgery, outcomes for patients with osteosarcoma have remained stagnant for more than 25 years, and numerous clinical trials have identified no new therapies. p53 deletion or mutation is found in more than 80% of osteosarcoma tumors. In p53-deficient cancers with structurally altered p63 and p73, interfering with tumor cell metabolism using Pramlintide (an FDA-approved drug for type 2 diabetes) results in tumor regression. Pramlintide response is mediated through upregulation of islet amyloid polypeptide (IAPP). Here, we showed that osteosarcoma cells have altered p63, p73, and p53, and decreased IAPP expression but have the two main …

Smyd3 Impedes Small Cell Lung Cancer Sensitivity To Alkylation Damage Through Rnf113a Methylation-Phosphorylation Cross-Talk, Valentina Lukinović, Simone Hausmann, Gael S Roth, Clement Oyeniran, Tanveer Ahmad, Ning Tsao, Joshua R Brickner, Alexandre G Casanova, Florent Chuffart, Ana Morales Benitez, Jessica Vayr, Rebecca Rodell, Marianne Tardif, Pascal W T C Jansen, Yohann Couté, Michiel Vermeulen, Pierre Hainaut, Pawel K Mazur, Nima Mosammaparast, Nicolas Reynoird

Faculty, Staff and Student Publications

Small cell lung cancer (SCLC) is the most fatal form of lung cancer, with dismal survival, limited therapeutic options, and rapid development of chemoresistance. We identified the lysine methyltransferase SMYD3 as a major regulator of SCLC sensitivity to alkylation-based chemotherapy. RNF113A methylation by SMYD3 impairs its interaction with the phosphatase PP4, controlling its phosphorylation levels. This cross-talk between posttranslational modifications acts as a key switch in promoting and maintaining RNF113A E3 ligase activity, essential for its role in alkylation damage response. In turn, SMYD3 inhibition restores SCLC vulnerability to alkylating chemotherapy. Our study sheds light on a novel role of …

The Emerging Spectrum Of Cardiopulmonary Pathology Of The Coronavirus Disease 2019 (Covid-19): Report Of 3 Autopsies From Houston, Texas, And Review Of Autopsy Findings From Other United States Cities, Manish Bodas, Bharathiraja Subramaniyan, Harry Karmouty-Quintana, Peter F Vitiello, Matthew S Walters

Faculty, Staff and Student Publications

The mammalian respiratory system or lung is a tree-like branching structure, and the main site of gas exchange with the external environment. Structurally, the lung is broadly classified into the proximal (or conducting) airways and the distal alveolar region, where the gas exchange occurs. In parallel with the respiratory tree, the pulmonary vasculature starts with large pulmonary arteries that subdivide rapidly ending in capillaries adjacent to alveolar structures to enable gas exchange. The NOTCH signalling pathway plays an important role in lung development, differentiation and regeneration post-injury. Signalling via the NOTCH pathway is mediated through activation of four NOTCH receptors …

Ppm1d In Solid And Hematologic Malignancies: Friend And Foe?, Linda Zhang, Joanne I Hsu, Margaret A Goodell

Faculty, Staff and Students Publications

In the face of constant genomic insults, the DNA damage response (DDR) is initiated to preserve genome integrity; its disruption is a classic hallmark of cancer. Protein phosphatase Mg2+/Mn2+-dependent 1D (PPM1D) is a central negative regulator of the DDR that is mutated or amplified in many solid cancers. PPM1D overexpression is associated with increased proliferative and metastatic behavior in multiple solid tumor types and patients with PPM1D-mutated malignancies have poorer prognoses. Recent findings have sparked an interest in the role of PPM1D in hematologic malignancies. Acquired somatic mutations may provide hematopoietic stem cells with a competitive advantage, leading to a …

Mab21l4 Deficiency Drives Squamous Cell Carcinoma Via Activation Of Ret, Ankit Srivastava, Cristina Tommasi, Dane Sessions, Angela Mah, Tomas Bencomo, Jasmine M Garcia, Tiffany Jiang, Michael Lee, Joseph Y Shen, Lek Wei Seow, Audrey Nguyen, Kimal Rajapakshe, Cristian Coarfa, Kenneth Y Tsai, Vanessa Lopez-Pajares, Carolyn S Lee

Faculty, Staff and Students Publications

UNLABELLED: Epithelial squamous cell carcinomas (SCC) most commonly originate in the skin, where they display disruptions in the normally tightly regulated homeostatic balance between keratinocyte proliferation and terminal differentiation. We performed a transcriptome-wide screen for genes of unknown function that possess inverse expression patterns in differentiating keratinocytes compared with cutaneous SCC (cSCC), leading to the identification of MAB21L4 (C2ORF54) as an enforcer of terminal differentiation that suppresses carcinogenesis. Loss of MAB21L4 in human cSCC organoids increased expression of RET to enable malignant progression. In addition to transcriptional upregulation of RET, deletion of MAB21L4 preempted recruitment of the CacyBP-Siah1 E3 ligase …

Screening And Assessment Of Cancer-Related Fatigue: An Executive Summary And Road Map For Clinical Implementation, Joy C. Cohn, Shana Harrington, Jeannette Lee, Daniel Malone, Mary I. Fisher

Physical Therapy Faculty Publications

Background: Cancer-related fatigue (CRF) prevalence is reported as high as 90%. Cancer-related fatigue is multidimensional and associated with lower health-related quality of life. Effective screening and assessment are dependent upon use of valid, reliable, and clinically feasible measures. This Executive Summary of the Screening and Assessment of Cancer-related Fatigue Clinical Practice Guideline provides recommendations for best measures to screen and assess for CRF based on the quality and level of evidence, psychometric strength of the tools, and clinical utility.

Methods: After a systematic review of the literature, studies evaluating CRF measurement tools were assessed for quality; data extraction included psychometrics …

Heterogeneity In The Prevalence Of Premature Hypertension Among Asian American Populations Compared With White Individuals: A National Health Interview Survey Study, Sina Kianoush, Mahmoud Al Rifai, Anwar T. Merchant, Xiaoming Jia, Zainab Samad, Aneil Bhalla, Ayesha Khan, Dongshan Zhu, Salim S. Virani

Section of Cardiology

Background: Differences in prevalence of risk factors such as hypertension may explain heterogeneity in cardiovascular risk across Asian American populations.
Methods: We used National Health Interview Survey (NHIS) data from 2006 to 2018 among White, Chinese, Asian Indian, Filipino, and 'other Asians' (Japanese, Korean, and Vietnamese). Unadjusted and adjusted odds ratios (aOR) with 95% confidence intervals were reported using logistic regression models for the association between race and self-reported premature hypertension (age old). Models were adjusted for sex, education, body mass index, smoking status, diabetes, and coronary heart disease.
Results: We studied 99,864 participants with history of hypertension (mean age, …

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 …

Major Pathologic Response And Prognostic Score Predict Survival In Patients With Lung Cancer Receiving Neoadjuvant Chemotherapy, Apar Pataer, Annikka Weissferdt, Arlene M Correa, Ara A Vaporciyan, Boris Sepesi, John V Heymach, Sabina Berezowska, Tina Cascone, Stephen G Swisher

Faculty, Staff and Student Publications

INTRODUCTION: Complete pathologic response (CPR) is an acceptable surrogate for survival in clinical trials but it occurs infrequently in patients with NSCLC receiving neoadjuvant chemotherapy (NCT). Therefore, we studied the impact of major pathologic response (MPR) for predicting survival of patients with NSCLC receiving NCT. We also tested a newly reported scoring system-the prognostic score (PRSC)-which combines T category, lymph node status, and MPR status.

METHODS: We analyzed CPR and MPR, defined as 0% and less than or equal to 10% viable tumor cells, respectively, in 339 patients with NSCLC with various histologic types who had been treated with NCT …

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 …

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 …

Plasmonic Gadolinium Oxide Nanomatryoshkas: Bifunctional Magnetic Resonance Imaging Enhancers For Photothermal Cancer Therapy, Luke Henderson, Oara Neumann, Yara Kadria-Vili, Burak Gerislioglu, James Bankson, Peter Nordlander, Naomi J Halas

Faculty, Staff and Student Publications

Nanoparticle-assisted laser-induced photothermal therapy (PTT) is a promising method for cancer treatment; yet, visualization of nanoparticle uptake and photothermal response remain a critical challenge. Here, we report a magnetic resonance imaging-active nanomatryoshka (Gd2O3-NM), a multilayered (Au core/Gd2O3 shell/Au shell) sub-100 nm nanoparticle capable of combining T1 MRI contrast with PTT. This bifunctional nanoparticle demonstrates an r1 of 1.28 × 108 mM-1 s-1, an MRI contrast enhancement per nanoparticle sufficient for T1 imaging in addition to tumor ablation. Gd2O3-NM also shows excellent stability in an acidic environment, retaining 99% of the internal Gd(3). This report details the synthesis and characterization of …

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 …

Factors Associated With Severe Illness In Patients Aged <21 Years Hospitalized For Covid-19, Rewa Choudhary, Bryant J Webber, Lindsay S Womack, Hannah K Dupont, Sophia K Chiu, Valentine Wanga, Megan E Gerdes, Sophia Hsu, Dallas S Shi, Theresa M Dulski, Osatohamwen I Idubor, Arthur M Wendel, Nickolas T Agathis, Kristi Anderson, Tricia Boyles, Eleanor S Click, Juliana Da Silva, Mary E Evans, Jeremy A W Gold, Julia C Haston, Pamela Logan, Susan A Maloney, Marisol Martinez, Pavithra Natarajan, Kevin B Spicer, Mark Swancutt, Valerie A Stevens, Jessica Rogers-Brown, Gyan Chandra, Megan Light, Frederick E Barr, Jessica Snowden, Larry K Kociolek, Matthew Mchugh, David L Wessel, Joelle N Simpson, Kathleen C Gorman, Kristen A Breslin, Roberta L Debiasi, Aaron Thompson, Mark W Kline, Julie A Boom, Ila R Singh, Michael Dowlin, Mark Wietecha, Beth Schweitzer, Sapna Bamrah Morris, Emilia H Koumans, Jean Y Ko, David A Siegel, Anne A Kimball

Faculty, Staff and Students Publications

OBJECTIVES: To describe coronavirus disease 2019 (COVID-19)-related pediatric hospitalizations during a period of B.1.617.2 (Δ) variant predominance and to determine age-specific factors associated with severe illness.

METHODS: We abstracted data from medical charts to conduct a cross-sectional study of patients agedchildren's hospitals from July to August 2021 for COVID-19 or with an incidental positive severe acute respiratory syndrome coronavirus 2 test. Among patients with COVID-19, we assessed factors associated with severe illness by calculating age-stratified prevalence ratios (PR). We defined severe illness as receiving high-flow nasal cannula, positive airway pressure, or invasive mechanical ventilation.

RESULTS: Of 947 hospitalized patients, 759 …

Cell-Intrinsic Melanin Fails To Protect Melanocytes From Ultraviolet-Mutagenesis In The Absence Of Epidermal Melanin, Tirzah J. Weiss, Emma R. Crawford, Valentina Posada, Hafeez Rahman, Tong Liu, Brandon M. Murphy, Tiffany E. Arnold, Shannon Gray, Zhexuan Hu, Rebecca C. Hennessey, Lianbo Yu, John August D'Orazio, Craig J. Burd, Jonathan H. Zippin, Douglas Grossman, Christin E. Burd

Markey Cancer Center Faculty Publications

Melanin is a free-radical scavenger, antioxidant, and broadband absorber of ultraviolet (UV) radiation which protects the skin from environmental carcinogenesis. However, melanin synthesis and UV-induced reactive melanin species are also implicated in melanocyte genotoxicity. Here, we attempted to reconcile these disparate functions of melanin using a UVB- sensitive, NRAS-mutant mouse model, TpN. We crossed TpN mice heterozygous for an inactivating mutation in Tyrosinase to produce albino and black littermates on a C57BL/6J background. These animals were then exposed to a single UVB dose on postnatal day three when keratinocytes in the skin have yet to be melanized. Approximately one-third (35%) …

Patient-Specific Genome-Scale Metabolic Models For Individualized Predictions Of Liver Disease, Alexandra Manchel, Jan B. Hoek, Ramon Bataller, Radhakrishnan Mahadevan, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The prevalence of liver disease is steadily increasing, coupled with the limited availability of therapeutic treatments. Recent literature points to metabolic reprogramming as a key feature of liver failure. Hence, we sought to uncover the metabolic pathways and mechanisms associated with liver disease and acute liver failure. We generated patient-specific genome scale metabolic models by integrating RNA-seq data from patient liver samples with a generalized human metabolic model. Flux balance analysis simulations showed a distinct separation of non-alcohol associated and alcohol-associated disease states. Our analysis suggests that the alcohol associated liver has an increased flux through nucleotide and glycerophospholipid metabolic …

Risk Of Type 2 Diabetes Among Individuals With Excess Weight: Weight Trajectory Effects, Arthur H Owora, David B Allison, Xuan Zhang, Nana Gletsu-Miller, Kishore M Gadde

Children’s Nutrition Research Center Staff Publications

PURPOSE OF REVIEW: Increased risk of type 2 diabetes mellitus (T2D) among individuals with overweight or obesity is well-established; however, questions remain about the temporal dynamics of weight change (gain or loss) on the natural course of T2D in this at-risk population. Existing epidemiologic evidence is limited to studies that discretely sample and assess excess weight and T2D risk at different ages with limited follow-up, yet changes in weight may have time-varying and possibly non-linear effects on T2D risk. Predicting the impact of weight change on the risk of T2D is key to informing primary prevention. We critically review the …

The Associations Between Relative And Absolute Body Mass Index With Mortality Rate Based On Predictions From Stigma Theory, Gregory Pavela, Nengjun Yi, Luis Mestre, Stella Lartey, Pengcheng Xun, David B Allison

Children’s Nutrition Research Center Staff Publications

Background: The social consequences of obesity may influence health and mortality rate (MR), given obesity's status as a highly stigmatized condition. Hence, a high absolute body mass index (BMI) in conjunction with the stigmatization of a high BMI may each independently increase the rate of MR.

Objectives: We tested whether relative BMI, defined as ordinal rank within a social reference group jointly defined by age, sex, and race/ethnicity, is associated with MR independent of absolute BMI.

Methods: Data were from three nationally representative datasets: the Health and Retirement Study (n = 31,115), the National Health Interview Survey (NHIS, n = …

Redox-Engineering Enhances Maize Thermotolerance And Grain Yield In The Field, Stuart A Sprague, Tej Man Tamang, Trevor Steiner, Qingyu Wu, Ying Hu, Tayebeh Kakeshpour, Jungeun Park, Jian Yang, Zhao Peng, Blake Bergkamp, Impa Somayanda, Morgan Peterson, Ely Oliveira Garcia, Yangfan Hao, Paul St Amand, Guihua Bai, Paul A Nakata, Ivo Rieu, David P Jackson, Ninghui Cheng, Barbara Valent, Kendal D Hirschi, Sv Krishna Jagadish, Sanzhen Liu, Frank F White, Sunghun Park

Children’s Nutrition Research Center Staff Publications

Increasing populations and temperatures are expected to escalate food demands beyond production capacities, and the development of maize lines with better performance under heat stress is desirable. Here, we report that constitutive ectopic expression of a heterologous glutaredoxin S17 from Arabidopsis thaliana (AtGRXS17) can provide thermotolerance in maize through enhanced chaperone activity and modulation of heat stress-associated gene expression. The thermotolerant maize lines had increased protection against protein damage and yielded a sixfold increase in grain production in comparison to the non-transgenic counterparts under heat stress field conditions. The maize lines also displayed thermotolerance in the reproductive stages, resulting in …