Medical Specialties Commons^™

Functional Variants Identify Sex-Specific Genes And Pathways In Alzheimer’S Disease, Thomas Bourquard, Kwanghyuk Lee, Ismael Al-Ramahi, Minh Pham, Dillon Shapiro, Yashwanth Lagisetty, Shirin Soleimani, Samantha Mota, Kevin Wilhelm, Maryam Samieinasab, Young Won Kim, Eunna Huh, Jennifer Asmussen, Panagiotis Katsonis, Juan Botas, Olivier Lichtarge

Faculty, Staff and Students Publications

The incidence of Alzheimer's Disease in females is almost double that of males. To search for sex-specific gene associations, we build a machine learning approach focused on functionally impactful coding variants. This method can detect differences between sequenced cases and controls in small cohorts. In the Alzheimer's Disease Sequencing Project with mixed sexes, this approach identified genes enriched for immune response pathways. After sex-separation, genes become specifically enriched for stress-response pathways in male and cell-cycle pathways in female. These genes improve disease risk prediction in silico and modulate Drosophila neurodegeneration in vivo. Thus, a general approach for machine learning on …

Dynamic Conformational Switching Underlies Tfiih Function In Transcription And Dna Repair And Impacts Genetic Diseases, Jina Yu, Chunli Yan, Thomas Dodd, Chi-Lin Tsai, John A Tainer, Susan E Tsutakawa, Ivaylo Ivanov

Faculty, Staff and Student Publications

Transcription factor IIH (TFIIH) is a protein assembly essential for transcription initiation and nucleotide excision repair (NER). Yet, understanding of the conformational switching underpinning these diverse TFIIH functions remains fragmentary. TFIIH mechanisms critically depend on two translocase subunits, XPB and XPD. To unravel their functions and regulation, we build cryo-EM based TFIIH models in transcription- and NER-competent states. Using simulations and graph-theoretical analysis methods, we reveal TFIIH's global motions, define TFIIH partitioning into dynamic communities and show how TFIIH reshapes itself and self-regulates depending on functional context. Our study uncovers an internal regulatory mechanism that switches XPB and XPD activities …

Predict Validity For Prognosis Of Breast Cancer Patients With Pathogenic Brca1/2 Variants, Taru A Muranen, Anna Morra, Sofia Khan, Daniel R Barnes, Manjeet K Bolla, Joe Dennis, Renske Keeman, Goska Leslie, Michael T Parsons, Qin Wang, Thomas U Ahearn, Kristiina Aittomäki, Irene L Andrulis, Banu K Arun, Sabine Behrens, Katarzyna Bialkowska, Stig E Bojesen, Nicola J Camp, Jenny Chang-Claude, Kamila Czene, Peter Devilee, Susan M Domchek, Alison M Dunning, Christoph Engel, D Gareth Evans, Manuela Gago-Dominguez, Montserrat García-Closas, Anne-Marie Gerdes, Gord Glendon, Pascal Guénel, Eric Hahnen, Ute Hamann, Helen Hanson, Maartje J Hooning, Reiner Hoppe, Louise Izatt, Anna Jakubowska, Paul A James, Vessela N Kristensen, Fiona Lalloo, Geoffrey J Lindeman, Arto Mannermaa, Sara Margolin, Susan L Neuhausen, William G Newman, Paolo Peterlongo, Kelly-Anne Phillips, Miquel Angel Pujana, Johanna Rantala, Karina Rønlund, Emmanouil Saloustros, Rita K Schmutzler, Andreas Schneeweiss, Christian F Singer, Maija Suvanto, Yen Yen Tan, Manuel R Teixeira, Mads Thomassen, Marc Tischkowitz, Vishakha Tripathi, Barbara Wappenschmidt, Emily Zhao, Douglas F Easton, Antonis C Antoniou, Georgia Chenevix-Trench, Paul D P Pharoah, Marjanka K Schmidt, Carl Blomqvist, Heli Nevanlinna

Faculty, Staff and Student Publications

We assessed the PREDICT v 2.2 for prognosis of breast cancer patients with pathogenic germline BRCA1 and BRCA2 variants, using follow-up data from 5453 BRCA1/2 carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC). PREDICT for estrogen receptor (ER)-negative breast cancer had modest discrimination for BRCA1 carrier patients overall (Gönen & Heller unbiased concordance 0.65 in CIMBA, 0.64 in BCAC), but it distinguished clearly the high-mortality group from lower risk categories. In an analysis of low to high risk categories by PREDICT score percentiles, the observed mortality was consistently lower than …

Common Signaling Pathways Involved In Alzheimer's Disease And Stroke: Two Faces Of The Same Coin, Tushar Kanti Das, Bhanu Priya Ganesh, Kaneez Fatima-Shad

Faculty, Staff and Student Publications

Alzheimer's disease (AD) and stroke are two interrelated neurodegenerative disorders which are the leading cause of death and affect the neurons in the brain and central nervous system. Although amyloid-β aggregation, tau hyperphosphorylation, and inflammation are the hallmarks of AD, the exact cause and origin of AD are still undefined. Recent enormous fundamental discoveries suggest that the amyloid hypothesis of AD has not been proven and anti-amyloid therapies that remove amyloid deposition have not yet slowed cognitive decline. However, stroke, mainly ischemic stroke (IS), is caused by an interruption in the cerebral blood flow. Significant features of both disorders are …

Meqtl Mapping In The Genoa Study Reveals Genetic Determinants Of Dna Methylation In African Americans, Lulu Shang, Wei Zhao, Yi Zhe Wang, Zheng Li, Jerome J Choi, Minjung Kho, Thomas H Mosley, Sharon L R Kardia, Jennifer A Smith, Xiang Zhou

Faculty, Staff and Student Publications

Identifying genetic variants that are associated with variation in DNA methylation, an analysis commonly referred to as methylation quantitative trait locus (meQTL) mapping, is an important first step towards understanding the genetic architecture underlying epigenetic variation. Most existing meQTL mapping studies have focused on individuals of European ancestry and are underrepresented in other populations, with a particular absence of large studies in populations with African ancestry. We fill this critical knowledge gap by performing a large-scale cis-meQTL mapping study in 961 African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. We identify a total of 4,565,687 cis-acting meQTLs …

Social Cognition Across Bipolar Disorder And Behavioral Variant Frontotemporal Dementia: An Exploratory Study, Izabela Guimarães Barbosa, Flávia Da Mata Chiácchio Leite, Maxime Bertoux, Henrique Cerqueira Guimarães, Luciano Inácio Mariano, Leandro Boson Gambogi, Antônio Lúcio Teixeira, Paulo Caramelli, Leonardo Cruz De Souza

Faculty, Staff and Student Publications

OBJECTIVES: Bipolar disorder type 1 (BD1) and behavioral-variant frontotemporal dementia (bvFTD) share similar behavioral and cognitive symptoms, rendering the differential diagnosis between them a clinical challenge. We investigated the accuracy of social cognition (SC) measures to differentiate bvFTD from BD.

METHODS: We included three groups of participants: early-onset BD1 (in remission, n=20), bvFTD (n=18), and cognitively healthy controls (HC) (n=40), matched for age, schooling, and sex. All participants underwent cognitive assessment, including the Facial Emotion Recognition (FER) and Modified Faux-Pas (mFP) tests, which assess mentalizing.

RESULTS: Compared to HC, BD1 and bvFTD patients underperformed on both SC measures. BD1 and …

Five-Year Follow-Up Of Zuma-1 Supports The Curative Potential Of Axicabtagene Ciloleucel In Refractory Large B-Cell Lymphoma, Sattva S Neelapu, Caron A Jacobson, Armin Ghobadi, David B Miklos, Lazaros J Lekakis, Olalekan O Oluwole, Yi Lin, Ira Braunschweig, Brian T Hill, John M Timmerman, Abhinav Deol, Patrick M Reagan, Patrick Stiff, Ian W Flinn, Umar Farooq, Andre H Goy, Peter A Mcsweeney, Javier Munoz, Tanya Siddiqi, Julio C Chavez, Alex F Herrera, Nancy L Bartlett, Adrian A Bot, Rhine R Shen, Jinghui Dong, Kanwarjit Singh, Harry Miao, Jenny J Kim, Yan Zheng, Frederick L Locke

Faculty, Staff and Student Publications

In phase 2 of ZUMA-1, a single-arm, multicenter, registrational trial, axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy demonstrated durable responses at 2 years in patients with refractory large B-cell lymphoma (LBCL). Here, we assessed outcomes in ZUMA-1 after 5 years of follow-up. Eligible adults received lymphodepleting chemotherapy followed by axi-cel (2 × 106 cells per kg). Investigator-assessed response, survival, safety, and pharmacokinetics were assessed in patients who had received treatment. The objective response rate in these 101 patients was 83% (58% complete response rate); with a median follow-up of 63.1 months, responses were ongoing in 31% …

3-Phosphoinositide-Dependent Kinase 1 Drives Acquired Resistance To Osimertinib, Ismail M Meraz, Mourad Majidi, Bingliang Fang, Feng Meng, Lihui Gao, Ruping Shao, Renduo Song, Feng Li, Yonathan Lissanu, Huiqin Chen, Min Jin Ha, Qi Wang, Jing Wang, Elizabeth Shpall, Sung Yun Jung, Franziska Haderk, Philippe Gui, Jonathan Wesley Riess, Victor Olivas, Trever G Bivona, Jack A Roth

Faculty, Staff and Students Publications

Osimertinib sensitive and resistant NSCLC NCI-H1975 clones are used to model osimertinib acquired resistance in humanized and non-humanized mice and delineate potential resistance mechanisms. No new EGFR mutations or loss of the EGFR T790M mutation are found in resistant clones. Resistant tumors grown under continuous osimertinib pressure both in humanized and non-humanized mice show aggressive tumor regrowth which is significantly less sensitive to osimertinib as compared with parental tumors. 3-phosphoinositide-dependent kinase 1 (PDK1) is identified as a potential driver of osimertinib acquired resistance, and its selective inhibition by BX795 and CRISPR gene knock out, sensitizes resistant clones. In-vivo inhibition of …

Phase Ii Trial Of Neoadjuvant Sitravatinib Plus Nivolumab In Patients Undergoing Nephrectomy For Locally Advanced Clear Cell Renal Cell Carcinoma, Jose A Karam, Pavlos Msaouel, Cara L Haymaker, Surena F Matin, Matthew T Campbell, Amado J Zurita, Amishi Y Shah, Ignacio I Wistuba, Enrica Marmonti, Dzifa Y Duose, Edwin R Parra, Luisa Maren Solis Soto, Caddie Laberiano-Fernandez, Marisa Lozano, Alice Abraham, Max Hallin, Curtis D Chin, Peter Olson, Hirak Der-Torossian, Xiaohong Yan, Nizar M Tannir, Christopher G Wood

Faculty, Staff and Student Publications

Sitravatinib is an immunomodulatory tyrosine kinase inhibitor that can augment responses when combined with programmed death-1 inhibitors such as nivolumab. We report a single-arm, interventional, phase 2 study of neoadjuvant sitravatinib in combination with nivolumab in patients with locally advanced clear cell renal cell carcinoma (ccRCC) prior to curative nephrectomy (NCT03680521). The primary endpoint was objective response rate (ORR) prior to surgery with a null hypothesis ORR = 5% and the alternative hypothesis set at ORR = 30%. Secondary endpoints were safety; pharmacokinetics (PK) of sitravatinib; immune effects, including changes in programmed cell death-ligand 1 expression; time-to-surgery; and disease-free survival …

Late Health Outcomes Among Survivors Of Wilms Tumor Diagnosed Over Three Decades: A Report From The Childhood Cancer Survivor Study, Brent R Weil, Andrew J Murphy, Qi Liu, Rebecca M Howell, Susan A Smith, Christopher B Weldon, Elizabeth A Mullen, Arin L Madenci, Wendy M Leisenring, Joseph P Neglia, Lucie M Turcotte, Kevin C Oeffinger, Amanda M Termuhlen, Sogol Mostoufi-Moab, Jennifer M Levine, Kevin R Krull, Yutaka Yasui, Leslie L Robison, Gregory T Armstrong, Eric J Chow, Saro H Armenian

Faculty, Staff and Student Publications

Purpose: To evaluate long-term morbidity and mortality among unilateral, nonsyndromic Wilms tumor (WT) survivors according to conventional treatment regimens.

Methods: Cumulative incidence of late mortality (≥ 5 years from diagnosis) and chronic health conditions (CHCs) were evaluated in WT survivors from the Childhood Cancer Survivor Study. Outcomes were evaluated by treatment, including nephrectomy combined with vincristine and actinomycin D (VA), VA + doxorubicin + abdominal radiotherapy (VAD + ART), VAD + ART + whole lung radiotherapy, or receipt of ≥ 4 chemotherapy agents.

Results: Among 2,008 unilateral WT survivors, 142 deaths occurred (standardized mortality ratio, 2.9, 95% CI, 2.5 to …

Sirolimus Versus Cyclosporine A In Patients With Primary Acquired Pure Red Cell Aplasia: A Prospective Cohort Study, Yuan Yang, Zengwei Tang, Yuzhou Huang, Qinglin Hu, Shuqing Wang, Jiang Ji, Yali Du, Chen Yang, Miao Chen, Shimin Hu, Bing Han

Faculty, Staff and Student Publications

No abstract provided.

A Stability Indicating Lc-Ms/Ms Method For Quantification Of A Nox Inhibitor R14 In Its Bisulfite Adduct Form For Pharmacokinetic Studies, Yang Wang, Jing Ma, Shiaw-Yih Lin, Huan Xie, Dong Liang

Faculty, Staff and Student Publications

R14, also known as NOX Inhibitor VII, is a potent inhibitor of NADPH oxidases (NOX) which has recently been identified as a novel agent targeting to triple-negative breast cancer. It is also rapidly degraded in collected pharmacokinetic plasma and blood samples even stored under - 70 °C. The purpose of this study was to develop a stability indicating LC-MS/MS assay that would be suitable for quantification of R14 in plasma and blood. In the presence of sodium sulfite under acidic pH, R14, an aryl lactam compound which is not a typically reactive compound for bisulfite addition, readily and completely converted …

Immune Checkpoint B7-H3 Is A Therapeutic Vulnerability In Prostate Cancer Harboring Pten And Tp53 Deficiencies, Wei Shi, Yin Wang, Yuehui Zhao, Justin Jimin Kim, Haoyan Li, Chenling Meng, Feiyu Chen, Jie Zhang, Duncan H Mak, Vivien Van, Javier Leo, Brad St Croix, Ana Aparicio, Di Zhao

Faculty, Staff and Student Publications

Checkpoint immunotherapy has yielded meaningful responses across many cancers but has shown modest efficacy in advanced prostate cancer. B7 homolog 3 protein (B7-H3/CD276) is an immune checkpoint molecule and has emerged as a promising therapeutic target. However, much remains to be understood regarding B7-H3's role in cancer progression, predictive biomarkers for B7-H3-targeted therapy, and combinatorial strategies. Our multi-omics analyses identified B7-H3 as one of the most abundant immune checkpoints in prostate tumors containing PTEN and TP53 genetic inactivation. Here, we sought in vivo genetic evidence for, and mechanistic understanding of, the role of B7-H3 in PTEN/TP53-deficient prostate …

Brexucabtagene Autoleucel For Relapsed Or Refractory Mantle Cell Lymphoma In Standard-Of-Care Practice: Results From The Us Lymphoma Car T Consortium, Yucai Wang, Preetesh Jain, Frederick L Locke, Matthew J Maurer, Matthew J Frank, Javier L Munoz, Saurabh Dahiya, Amer M Beitinjaneh, Miriam T Jacobs, Joseph P Mcguirk, Julie M Vose, Andre Goy, Charalambos Andreadis, Brian T Hill, Kathleen A Dorritie, Olalekan O Oluwole, Abhinav Deol, Jonas Paludo, Bijal Shah, Trent Wang, Rahul Banerjee, David B Miklos, Aaron P Rapoport, Lazaros Lekakis, Armin Ghobadi, Sattva S Neelapu, Yi Lin, Michael L Wang, Michael D Jain

Faculty, Staff and Student Publications

Purpose: Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory mantle cell lymphoma (MCL). This therapy was approved on the basis of the single-arm phase II ZUMA-2 trial, which showed best overall and complete response rates of 91% and 68%, respectively. We report clinical outcomes with brexu-cel in the standard-of-care setting for the approved indication.

Patients and methods: Patients who underwent leukapheresis between August 1, 2020 and December 31, 2021, at 16 US institutions, with an intent to manufacture commercial brexu-cel for relapsed/refractory MCL, were included. Patient data were collected for analyses of …

Polymorphisms Within Autophagy-Related Genes As Susceptibility Biomarkers For Multiple Myeloma: A Meta-Analysis Of Three Large Cohorts And Functional Characterization, Esther Clavero, José Manuel Sanchez-Maldonado, Angelica Macauda, Rob Ter Horst, Belém Sampaio-Marques, Artur Jurczyszyn, Alyssa Clay-Gilmour, Angelika Stein, Michelle A T Hildebrandt, Niels Weinhold, Gabriele Buda, Ramón García-Sanz, Waldemar Tomczak, Ulla Vogel, Andrés Jerez, Daria Zawirska, Marzena Wątek, Jonathan N Hofmann, Stefano Landi, John J Spinelli, Aleksandra Butrym, Abhishek Kumar, Joaquín Martínez-López, Sara Galimberti, María Eugenia Sarasquete, Edyta Subocz, Elzbieta Iskierka-Jażdżewska, Graham G Giles, Malwina Rybicka-Ramos, Marcin Kruszewski, Niels Abildgaard, Francisco García Verdejo, Pedro Sánchez Rovira, Miguel Inacio Da Silva Filho, Katalin Kadar, Małgorzata Razny, Wendy Cozen, Matteo Pelosini, Manuel Jurado, Parveen Bhatti, Marek Dudzinski, Agnieszka Druzd-Sitek, Enrico Orciuolo, Yang Li, Aaron D Norman, Jan Maciej Zaucha, Rui Manuel Reis, Miroslaw Markiewicz, Juan José Rodríguez Sevilla, Vibeke Andersen, Krzysztof Jamroziak, Kari Hemminki, Sonja I Berndt, Vicent Rajkumar, Grzegorz Mazur, Shaji K Kumar, Paula Ludovico, Arnon Nagler, Stephen J Chanock, Charles Dumontet, Mitchell J Machiela, Judit Varkonyi, Nicola J Camp, Elad Ziv, Annette Juul Vangsted, Elizabeth E Brown, Daniele Campa, Celine M Vachon, Mihai G Netea, Federico Canzian, Asta Försti, Juan Sainz

Faculty, Staff and Student Publications

Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of …

Preclinical Investigations Of The Efficacy Of The Glutaminase Inhibitor Cb-839 Alone And In Combinations In Chronic Lymphocytic Leukemia, Natalia Timofeeva, Mary L Ayres, Natalia Baran, Janice M Santiago-O'Farrill, Gamze Bildik, Zhen Lu, Marina Konopleva, Varsha Gandhi

Faculty, Staff and Student Publications

INTRODUCTION: Chronic lymphocytic leukemia (CLL) cells are metabolically flexible and adapt to modern anticancer treatments. Bruton tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL-2) inhibitors have been widely used to treat CLL, but CLL cells become resistant to these treatments over time. CB-839 is a small-molecule glutaminase-1 (GLS-1) inhibitor that impairs glutamine use, disrupts downstream energy metabolism, and impedes the elimination of reactive oxygen species.

METHODS: To investigate the

RESULTS: We found that CB-839 caused dose-dependent decreases in GLS-1 activity and glutathione synthesis. CB-839-treated cells also showed increased mitochondrial superoxide metabolism and impaired energy metabolism, which were reflected in decreases in …

Curing Cll: One Clone At A Time, Burcu Aslan, Shady I Tantawy, Varsha Gandhi

Faculty, Staff and Student Publications

No abstract provided.

Angiotensin Ii Receptor Inhibition Ameliorates Liver Fibrosis And Enhances Hepatocellular Carcinoma Infiltration By Effector T Cells, Li Gu, Yahui Zhu, Maiya Lee, Albert Nguyen, Nicolas T Ryujin, Jian Yu Huang, Shusil K Pandit, Shadi Chamseddine, Lianchun Xiao, Yehia I Mohamed, Ahmed O Kaseb, Michael Karin, Shabnam Shalapour

Faculty, Staff and Student Publications

Although viral hepatocellular carcinoma (HCC) is declining, nonviral HCC, which often is the end stage of nonalcoholic or alcoholic steatohepatitis (NASH, ASH), is on an upward trajectory. Immune checkpoint inhibitors (ICIs) that block the T cell inhibitory receptor PD-1 were approved for treatment of all HCC types. However, only a minority of HCC patients show a robust and sustained response to PD-1 blockade, calling for improved understanding of factors that negatively impact response rate and duration and the discovery of new adjuvant treatments that enhance ICI responsiveness. Using a mouse model of NASH-driven HCC, we identified peritumoral fibrosis as a …

Mesoporous Silica Nanoparticles As A Gene Delivery Platform For Cancer Therapy, Nisar Ul Khaliq, Juyeon Lee, Joohyeon Kim, Yejin Kim, Sohyeon Yu, Jisu Kim, Sangwoo Kim, Daekyung Sung, Hyungjun Kim

Faculty, Staff and Student Publications

Cancer remains a major global health challenge. Traditional chemotherapy often results in side effects and drug resistance, necessitating the development of alternative treatment strategies such as gene therapy. Mesoporous silica nanoparticles (MSNs) offer many advantages as a gene delivery carrier, including high loading capacity, controlled drug release, and easy surface functionalization. MSNs are biodegradable and biocompatible, making them promising candidates for drug delivery applications. Recent studies demonstrating the use of MSNs for the delivery of therapeutic nucleic acids to cancer cells have been reviewed, along with their potential as a tool for cancer therapy. The major challenges and future interventions …

Lifetime Ovulatory Years And Risk Of Epithelial Ovarian Cancer: A Multinational Pooled Analysis, Zhuxuan Fu, Maria Mori Brooks, Sarah Irvin, Susan Jordan, Katja K H Aben, Hoda Anton-Culver, Elisa V Bandera, Matthias W Beckmann, Andrew Berchuck, Angela Brooks-Wilson, Jenny Chang-Claude, Linda S Cook, Daniel W Cramer, Kara L Cushing-Haugen, Jennifer A Doherty, Arif B Ekici, Peter A Fasching, Renée T Fortner, Simon A Gayther, Aleksandra Gentry-Maharaj, Graham G Giles, Ellen L Goode, Marc T Goodman, Holly R Harris, Alexander Hein, Rudolf Kaaks, Lambertus A Kiemeney, Martin Köbel, Joanne Kotsopoulos, Nhu D Le, Alice W Lee, Keitaro Matsuo, Valerie Mcguire, John R Mclaughlin, Usha Menon, Roger L Milne, Kirsten B Moysich, Celeste Leigh Pearce, Malcolm C Pike, Bo Qin, Susan J Ramus, Marjorie J Riggan, Joseph H Rothstein, Joellen M Schildkraut, Weiva Sieh, Rebecca Sutphen, Kathryn L Terry, Pamela J Thompson, Linda Titus, Anne M Van Altena, Emily White, Alice S Whittemore, Anna H Wu, Wei Zheng, Argyrios Ziogas, Sarah E Taylor, Lu Tang, Thomas Songer, Nicolas Wentzensen, Penelope M Webb, Aocs Group, Harvey A Risch, Francesmary Modugno

Faculty, Staff and Student Publications

BACKGROUND: The role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC.

METHODS: LOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26 204 control participants and 21 267 case patients from 25 studies. To assess whether LOY components act through ovulation suppression alone, we compared beta coefficients obtained from regression models with …

Integrative Molecular Subtypes Of Acute Myeloid Leukemia, Qianxing Mo, Seongseok Yun, David A Sallman, Nicole D Vincelette, Guang Peng, Ling Zhang, Jeffrey E Lancet, Eric Padron

Faculty, Staff and Student Publications

No abstract provided.

Medical-Legal Partnership Effects On Mental Health, Health Care Use, And Quality Of Life In Primary Care: A Randomized Clinical Trial, Winston Liaw, Thomas F Northrup, Angela L Stotts, Christine Bakos-Block, Robert Suchting, Alvin Chen, Abigail Hernandez, Lisandra Finzetto, Charles Green, Thomas Murphy

Faculty, Staff and Student Publications

Purpose: To determine whether an immediate referral to a medical-legal partnership (MLP), compared with a 6-month waitlist control, improved mental health, health care use, and quality of life.

Methods: This trial randomly assigned individuals to an immediate referral or a wait-list control. The MLP involved a collaboration between the primary care clinic and a legal services organization. The primary outcome was stress (6 months) as measured by the Perceived Stress Scale (PSS). Secondary measures included the Center for Epidemiologic Studies Depression Scale; Generalized Anxiety Disorder scale (GAD-7); Patient-Reported Outcomes Measurement Information System (PROMIS); and emergency department (ED), urgent care, and …

Immune Checkpoint Therapy Combinations In Adult Advanced Mit Family Translocation Renal Cell Carcinomas, Omar Alhalabi, Jonathan Thouvenin, Sylvie Négrier, Yann-Alexandre Vano, Luca Campedel, Elshad Hasanov, Ziad Bakouny, Andrew W Hahn, Mehmet Asim Bilen, Pavlos Msaouel, Toni K Choueiri, Srinivas R Viswanathan, Kanishka Sircar, Laurence Albiges, Gabriel G Malouf, Nizar M Tannir

Faculty, Staff and Student Publications

Background: There remains a paucity of data regarding the efficacy of immune checkpoint therapy (ICT) combinations ± vascular endothelial growth factor (VEGF) targeted therapy (TT) in translocation renal cell carcinoma (tRCC).

Methods: This is a retrospective study of patients with advanced tRCC treated with ICT combinations at 11 centers in the US, France, and Belgium. Only cases with confirmed fluorescence in situ hybridization (FISH) were included. Objective response rates (ORR) and progression-free survival (PFS) were assessed by RECIST, and overall survival (OS) was estimated by Kaplan-Meier methods.

Results: There were 29 patients identified with median age of 38 (21-70) years, …

Immune Checkpoint Therapy Combinations In Adult Advanced Mit Family Translocation Renal Cell Carcinomas, Omar Alhalabi, Jonathan Thouvenin, Sylvie Négrier, Yann-Alexandre Vano, Luca Campedel, Elshad Hasanov, Ziad Bakouny, Andrew W Hahn, Mehmet Asim Bilen, Pavlos Msaouel, Toni K Choueiri, Srinivas R Viswanathan, Kanishka Sircar, Laurence Albiges, Gabriel G Malouf, Nizar M Tannir

Faculty, Staff and Student Publications

Background: There remains a paucity of data regarding the efficacy of immune checkpoint therapy (ICT) combinations ± vascular endothelial growth factor (VEGF) targeted therapy (TT) in translocation renal cell carcinoma (tRCC).

Methods: This is a retrospective study of patients with advanced tRCC treated with ICT combinations at 11 centers in the US, France, and Belgium. Only cases with confirmed fluorescence in situ hybridization (FISH) were included. Objective response rates (ORR) and progression-free survival (PFS) were assessed by RECIST, and overall survival (OS) was estimated by Kaplan-Meier methods.

Results: There were 29 patients identified with median age of 38 (21-70) years, …

Higher Dose Corticosteroids In Patients Admitted To Hospital With Covid-19 Who Are Hypoxic But Not Requiring Ventilatory Support (Recovery): A Randomised, Controlled, Open-Label, Platform Trial, Recovery Collaborative Group

Faculty, Staff and Student Publications

BACKGROUND: Low-dose corticosteroids have been shown to reduce mortality for patients with COVID-19 requiring oxygen or ventilatory support (non-invasive mechanical ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation). We evaluated the use of a higher dose of corticosteroids in this patient group.

METHODS: This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting adult patients with clinical evidence of hypoxia (ie, receiving oxygen or with oxygen saturation

FINDINGS: Between May 25, 2021, and May 13, 2022, 1272 patients with COVID-19 and hypoxia receiving no oxygen …

Loss Of Lgr5 Through Therapy-Induced Downregulation Or Gene Ablation Is Associated With Resistance And Enhanced Met-Stat3 Signaling In Colorectal Cancer Cells, Tressie A Posey, Joan Jacob, Ashlyn Parkhurst, Shraddha Subramanian, Liezl E Francisco, Zhengdong Liang, Kendra S Carmon

Faculty, Staff and Student Publications

Leucine-rich repeat-containing, G protein-coupled receptor 5 (LGR5) is highly expressed in colorectal cancer and cancer stem cells (CSCs) that play important roles in tumor initiation, progression, and metastasis. Loss of LGR5 has been shown to enhance therapy resistance. However, the molecular mechanisms that mediate this resistance remain elusive. In this study, we demonstrate conversion of LGR5+ colorectal cancer cells to an LGR5- state in response to chemotherapy, LGR5- targeted antibody-drug conjugates (ADCs), or LGR5 gene ablation led to activation of STAT3. Further investigation revealed increased STAT3 activation occurred as a result of increased mesenchymal epithelial transition (MET) factor receptor activity. …

Insights Into The Formation And Diversification Of A Novel Chiropteran Wing Membrane From Embryonic Development, Neal Anthwal, Daniel J Urban, Alexa Sadier, Risa Takenaka, Simon Spiro, Nancy Simmons, Richard R Behringer, Chris J Cretekos, John J Rasweiler, Karen E Sears

Faculty, Staff and Student Publications

BACKGROUND: Through the evolution of novel wing structures, bats (Order Chiroptera) became the only mammalian group to achieve powered flight. This achievement preceded the massive adaptive radiation of bats into diverse ecological niches. We investigate some of the developmental processes that underlie the origin and subsequent diversification of one of the novel membranes of the bat wing: the plagiopatagium, which connects the fore- and hind limb in all bat species.

RESULTS: Our results suggest that the plagiopatagium initially arises through novel outgrowths from the body flank that subsequently merge with the limbs to generate the wing airfoil. Our findings further …

Twas_Sim, A Python-Based Tool For Simulation And Power Analysis Of Transcriptome-Wide Association Analysis, Xinran Wang, Zeyun Lu, Arjun Bhattacharya, Bogdan Pasaniuc, Nicholas Mancuso

Faculty, Staff and Student Publications

Genome-wide association studies (GWASs) have identified numerous genetic variants associated with complex disease risk; however, most of these associations are non-coding, complicating identifying their proximal target gene. Transcriptome-wide association studies (TWASs) have been proposed to mitigate this gap by integrating expression quantitative trait loci (eQTL) data with GWAS data. Numerous methodological advancements have been made for TWAS, yet each approach requires ad hoc simulations to demonstrate feasibility. Here, we present twas_sim, a computationally scalable and easily extendable tool for simplified performance evaluation and power analysis for TWAS methods.

Software and documentation are available at https://github.com/mancusolab/twas_sim.

Usp36 Promotes Tumorigenesis And Drug Sensitivity Of Glioblastoma By Deubiquitinating And Stabilizing Alkbh5, Guoqiang Chang, Gloria S Xie, Li Ma, Peng Li, Linlin Li, Hope T Richard

Faculty, Staff and Student Publications

Background: ALKBH5 is aberrantly activated and exerts critical roles in facilitating the development of glioblastoma. However, the underlying activation mechanism by which ALKBH5 protein is increased in glioblastoma is not completely understood. Our study aimed to elucidate the signaling pathways involved in mediating ALKBH5 protein stability.

Methods: The contribution of deubiquitinating enzymes (DUB) to the fluctuation of ALKBH5 protein expression was globally profiled with western blot analysis. Mass spectrometry and immunoprecipitation were performed to identify the USP36 and ALKBH5 interaction. The effects of USP36 on the stability of ALKBH5 were detected with in vivo and in vitro ubiquitination assays. Cell …

Igfbp2 Expressing Midlobular Hepatocytes Preferentially Contribute To Liver Homeostasis And Regeneration, Yu-Hsuan Lin, Yonglong Wei, Qiyu Zeng, Yunguan Wang, Chase A Pagani, Lin Li, Min Zhu, Zixi Wang, Meng-Hsiung Hsieh, Natasha Corbitt, Yu Zhang, Tripti Sharma, Tao Wang, Hao Zhu

Faculty, Staff and Student Publications

Although midlobular hepatocytes in zone 2 are a recently identified cellular source for liver homeostasis and regeneration, these cells have not been exclusively fate mapped. We generated an Igfbp2-CreER knockin strain that specifically labels midlobular hepatocytes. During homeostasis over 1 year, zone 2 hepatocytes increased in abundance from occupying 21%-41% of the lobular area. After either pericentral injury with carbon tetrachloride or periportal injury with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), IGFBP2+ cells replenished lost hepatocytes in zones 3 and 1, respectively. IGFBP2+ cells also preferentially contributed to regeneration after 70% partial hepatectomy, as well as liver growth during pregnancy. Because IGFBP2 labeling increased …