Genetic Phenomena Commons^™

Droid: Dose-Ranging Approach To Optimizing Dose In Oncology Drug Development, Beibei Guo, Ying Yuan

Faculty, Staff and Student Publications

In the era of targeted therapy, there has been increasing concern about the development of oncology drugs based on the "more is better" paradigm, developed decades ago for chemotherapy. Recently, the US Food and Drug Administration (FDA) initiated Project Optimus to reform the dose optimization and dose selection paradigm in oncology drug development. To accommodate this paradigm shifting, we propose a dose-ranging approach to optimizing dose (DROID) for oncology trials with targeted drugs. DROID leverages the well-established dose-ranging study framework, which has been routinely used to develop non-oncology drugs for decades, and bridges it with established oncology dose-finding designs to …

The Clinicopathologic Features And Molecular Signatures Of Blastoid High-Grade B Cell Lymphoma, Not Otherwise Specified, Lianqun Qiu, Pei Lin, Mahsa Khanlari, Jie Xu, Evan N Cohen, Sofia Garces, Roberto N Miranda, Wei Wang, Hong Fang, Carlos E Bueso-Ramos, L Jeffrey Medeiros, Shaoying Li

Faculty, Staff and Student Publications

A small subset of high-grade B-cell lymphoma (HGBL) with blastoid morphology remains poorly understood. We assessed 55 cases of blastoid HGBL, not otherwise specified (NOS) and compared their clinicopathologic characteristics with those of 81 non-blastoid HGBL-NOS and 62 blastoid HGBL with MYC and BCL2, with or without BCL6 rearrangements (double/triple-hit lymphoma [D/THL]). Patients with blastoid HGBL-NOS showed similar clinicopathologic features to patients with blastoid D/THLs and non-blastoid HGBL-NOS, except more frequently with a history of low-grade B-cell lymphoma, bone marrow involvement, and BCL2 rearrangement (P < .05) compared to the latter. MYC rearrangement (MYC-R), detected in 40% of blastoid HGBL-NOS, was associated with aggressive clinicopathologic features and poorer overall survival, even worse than that of blastoid D/THL (P < .05). Transcriptome profiling revealed a distinct gene expression pattern with differentially expressed genes enriched in MYC and P53-targeted genes in MYC-R blastoid HGBL-NOS. Fifty-two percent of blastoid HGBL-NOS had a double hit-like signature, similar to non-blastoid HGBL-NOS (P = .73). The overall survival of the blastoid HGBL-NOS group was similar to that of the blastoid D/THL group but appeared poorer than that of its non-blastoid counterparts (P = .07). Taken together, blastoid HGBL-NOS is an aggressive B-cell lymphoma that shares overlapping clinicopathologic and genetic features with non-blastoid HGBL-NOS. MYC-R in patients with blastoid HGBL-NOS identifies a highly aggressive subgroup with distinct aggressive clinicopathologic features, unique molecular signatures, and a dismal clinical outcome.

Quantitative Dual-Energy Computed Tomography With Cesium As A Novel Contrast Agent For Localization Of Thermochemical Ablation In Phantoms And Ex Vivo Models, Emily A Thompson, Megan C Jacobsen, David T Fuentes, Rick R Layman, Erik N K Cressman

Faculty, Staff and Student Publications

Background: Thermochemical ablation (TCA) is a minimally invasive therapy under development for hepatocellular carcinoma. TCA simultaneously delivers an acid (acetic acid, AcOH) and base (sodium hydroxide, NaOH) directly into the tumor, where the acid/base chemical reaction produces an exotherm that induces local ablation. However, AcOH and NaOH are not radiopaque, making monitoring TCA delivery difficult.

Purpose: We address the issue of image guidance for TCA by utilizing cesium hydroxide (CsOH) as a novel theranostic component of TCA that is detectable and quantifiable with dual-energy CT (DECT).

Materials and methods: To quantify the minimum concentration of CsOH that can be positively …

Isolated Vaginal Recurrence In Women With Stage I Endometrial Cancer, Eric Rios-Doria, Han T Cun, Olga T Filippova, Jennifer J Mueller, Kaled M Alektiar, Lora H Ellenson, Vicky Makker, Yulia Lakhman, Mario M Leitao, Anuja Jhingran, Pamela T Soliman, Nadeem R Abu-Rustum

Faculty, Staff and Student Publications

Objective: To compare clinical and pathologic characteristics of women with surgical stage I endometrial carcinoma by location of first recurrence and describe characteristics of isolated vaginal recurrence.

Methods: Patients with 2009 International Federation of Obstetrics and Gynecology (FIGO) stage I endometrial carcinoma treated at two large cancer centers from 1/1/2009-12/31/2017 were identified. Sarcoma histology was excluded. Recurrences were grouped into isolated vaginal or extravaginal. Isolated vaginal recurrences were localized by anatomic location within the vaginal vault. Clinical and pathologic variables were compared with chi-square analysis, and Kaplan-Meier curves with log-rank tests.

Results: Of 2815 women identified, 278 (10%) experienced a …

Skin Cancers In Medicare Beneficiaries With Actinic Keratoses, Cassandra Mohr, Yao Li, Lucy J Navsaria, Candice L Hinkston, Sanjay S Shete, David J Margolis, Mackenzie R Wehner

Faculty, Staff and Student Publications

Importance: Actinic keratoses (AK) are common premalignant skin lesions with a small risk of progressing to cutaneous squamous cell carcinoma (SCC). There is some evidence that patients with AKs also have increased risks of other skin cancers beyond SCC. However, the absolute risks of skin cancer in patients with AKs are unknown.

Objective: To calculate the absolute and relative risks of future skin cancer in Medicare beneficiaries with AKs.

Design, setting, and participants: This retrospective cohort study was performed using a deidentified, random sample of 4 999 999 fee-for-service Medicare beneficiaries from 2009 through 2018. Patients with treated AKs were …

Angiotensin Ii Type 2 Receptor Signalling As A Pain Target: Bench, Bedside And Back-Translation, Andrew J Shepherd, Andrew Sc Rice, Maree T Smith

Faculty, Staff and Student Publications

Translating promising preclinical pain relief data for novel molecules from drug discovery to positive clinical trial outcomes is challenging. The angiotensin II type 2 (AT2) receptor is a clinically-validated target based upon positive proof-of-concept clinical trial data in patients with post-herpetic neuralgia. This trial was conducted because AT2 receptor antagonists evoked pain relief in rodent models of neuropathic pain. EMA401 was selected as the drug candidate based upon its suitable preclinical toxicity and safety profile and good pharmacokinetics. Herein, we provide an overview of the discovery, preclinical and clinical development of EMA401, for the alleviation of peripheral neuropathic pain.

Delineating The Interplay Between Oncogenic Pathways And Immunity In Anaplastic Wilms Tumors, Xiaoping Su, Xiaofan Lu, Sehrish Khan Bazai, Linda Dainese, Arnauld Verschuur, Benoit Dumont, Roger Mouawad, Li Xu, Wenxuan Cheng, Fangrong Yan, Sabine Irtan, Véronique Lindner, Catherine Paillard, Yves Le Bouc, Aurore Coulomb, Gabriel G Malouf

Faculty, Staff and Student Publications

Wilms tumors are highly curable in up to 90% of cases with a combination of surgery and radio-chemotherapy, but treatment-resistant types such as diffuse anaplastic Wilms tumors pose significant therapeutic challenges. Our multi-omics profiling unveils a distinct desert-like diffuse anaplastic Wilms tumor subtype marked by immune/stromal cell depletion, TP53 alterations, and cGAS-STING pathway downregulation, accounting for one-third of all diffuse anaplastic cases. This subtype, also characterized by reduced CD8 and CD3 infiltration and active oncogenic pathways involving histone deacetylase and DNA repair, correlates with poor clinical outcomes. These oncogenic pathways are found to be conserved in anaplastic Wilms tumor cell …

Case Of New-Onset Scleromyxoedema-Scleroedema Spectrum Disorder In A Patient With Cll, Yuanteng Jeff Li, Victor G Prieto, Jean Tayar

Faculty, Staff and Student Publications

No abstract provided.

Sustained Remissions In Cll After Frontline Fcr Treatment With Very-Long-Term Follow-Up, Philip A Thompson, Alexandre Bazinet, William G Wierda, Constantine S Tam, Susan M O'Brien, Satabdi Saha, Christine B Peterson, William Plunkett, Michael J Keating

Faculty, Staff and Student Publications

Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) achieves durable remissions, with flattening of the progression-free survival (PFS) curve in patients with mutated immunoglobulin heavy chain variable gene (IGHV-M). We updated long-term follow-up results from the original 300-patient FCR study initiated at MD Anderson in 1999. The current median follow-up is 19.0 years. With this extended follow-up, the median PFS for patients with IGHV-M was 14.6 years vs 4.2 years for patients with unmutated IGHV (IGHV-UM). Disease progression beyond 10 years was uncommon. In total, 16 of 94 (17%) patients in remission at 10 years subsequently progressed with the additional follow-up …

Silencing Of Genes By Promoter Hypermethylation Shapes Tumor Microenvironment And Resistance To Immunotherapy In Clear-Cell Renal Cell Carcinomas, Xiaofan Lu, Yann-Alexandre Vano, Xiaoping Su, Alexandra Helleux, Véronique Lindner, Roger Mouawad, Jean-Philippe Spano, Morgan Rouprêt, Eva Compérat, Virginie Verkarre, Cheng-Ming Sun, Mostefa Bennamoun, Hervé Lang, Philippe Barthelemy, Wenxuan Cheng, Li Xu, Irwin Davidson, Fangrong Yan, Wolf Hervé Fridman, Catherine Sautes-Fridman, Stéphane Oudard, Gabriel G Malouf

Faculty, Staff and Student Publications

The efficacy of immune checkpoint inhibitors varies in clear-cell renal cell carcinoma (ccRCC), with notable primary resistance among patients. Here, we integrate epigenetic (DNA methylation) and transcriptome data to identify a ccRCC subtype characterized by cancer-specific promoter hypermethylation and epigenetic silencing of Polycomb targets. We develop and validate an index of methylation-based epigenetic silencing (iMES) that predicts primary resistance to immune checkpoint inhibition (ICI) in the BIONIKK trial. High iMES is associated with VEGF pathway silencing, endothelial cell depletion, immune activation/suppression, EZH2 activation, BAP1/SETD2 deficiency, and resistance to ICI. Combination therapy with hypomethylating agents or tyrosine kinase inhibitors may benefit …

Prediagnostic Selenium Status, Selenoprotein Gene Variants And Association With Breast Cancer Risk In A European Cohort Study, David J Hughes, Lutz Schomburg, Mazda Jenab, Carine Biessy, Catherine Méplan, Aurelie Moskal, Qian Sun, Kamil Demircan, Veronika Fedirko, Elisabete Weiderpass, Maryam Mukhtar, Anja Olsen, Anne Tjønneland, Kim Overvad, Matthias Schulze, Therese Haugdahl Nøst, Guri Skeie, Karina Standahl Olsen, Fulvio Ricceri, Sara Grioni, Domenico Palli, Giovanna Masala, Rosario Tumino, Fabrizio Pasanisi, Pilar Amiano, Sandra M Colorado Yohar, Antonio Agudo, Maria-Jose Sánchez, Eva Ardanaz, Malin Sund, Anne Andersson, Aurora Perez-Cornago, Ruth Travis, Alicia K Heath, Laure Dossus

Faculty, Staff and Student Publications

Selenium (Se) may help prevent breast cancer (BC) development. Owing to limited observational evidence, we investigated whether prediagnostic Se status and/or variants in the selenoprotein genes are associated with BC risk in a large European cohort. Se status was assessed by plasma measures of Se and its major circulating proteins, selenoprotein P (SELENOP) and glutathione peroxidase 3 (GPX3), in matched BC case-control pairs (2208 for SELENOP; 1785 for GPX3 and Se) nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). Single nucleotide polymorphisms (SNPs, n = 452) in 55 selenoprotein and Se metabolic pathway genes and an additional …

Dissociable Effects Of Alzheimer's Disease-Related Cognitive Dysfunction And Aging On Functional Brain Network Segregation, Ziwei Zhang, Micaela Y Chan, Liang Han, Claudia A Carreno, Ezra Winter-Nelson, Gagan S Wig

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is associated with changes in large-scale functional brain network organization. Individuals with AD exhibit less segregated resting-state brain networks compared with individuals without dementia. However, declines in brain network segregation are also evident as adult individuals grow older. Determining whether these observations reflect unique or overlapping alterations on the functional connectome of the brain is essential for understanding the impact of AD on network organization and incorporating measures of functional brain network organization toward AD characterization. Relationships between AD dementia severity and participant's age on resting-state brain system segregation were examined in 326 cognitively healthy and 275 …

The Landscape Of Alterations From 1407 Ultra-Rare Sarcomas From The Aacr Genie Database: Clinical Implications, Ryan A Denu, Justin T Moyers, Mohamed A Gouda, Anthony P Conley, Alexander J Lazar, Vivek Subbiah

Faculty, Staff and Student Publications

Purpose: Ultra-rare sarcomas (URS) comprise a group of orphan diseases with an incidence of ≤1/1,000,000 people per year. We aimed to assess clinically actionable genomic alterations in URS.

Experimental design: Data were extracted from the GENIE database using cBioPortal. OncoKB was used to assess for clinical actionability of mutations. Tumor mutational burden (TMB) was inferred from clinical sequencing data.

Results: Soft tissue (ST) URS made up 23.5% of ST sarcoma cases, and bone URS made up 16.5% of bone sarcoma cases. The most commonly mutated gene in all four groups was TP53. The most common fusions involved EWSR1. The most …

A Phase 1 Study Of Prophylactic Anakinra To Mitigate Icans In Patients With Large B-Cell Lymphoma, Paolo Strati, Andrew Jallouk, Qing Deng, Xubin Li, Lei Feng, Ryan Sun, Sherry Adkins, Swapna Johncy, Taylor Cain, Raphael E Steiner, Sairah Ahmed, Dai Chihara, Luis E Fayad, Swaminathan P Iyer, Sandra Horowitz, Loretta J Nastoupil, Ranjit Nair, Ahmed Hassan, Taher E Daoud, Misha Hawkins, Maria A Rodriguez, Elizabeth J Shpall, Jeremy L Ramdial, Partow Kebriaei, David S Hong, Jason R Westin, Sattva S Neelapu, Michael R Green

Faculty, Staff and Student Publications

No abstract provided.

Cigarette Smoke Exposure Accelerates Aml Progression In Flt3-Itd Models, Mary Figueroa, Huaxian Ma, Mansour Alfayez, Daniel Enrique Morales-Mantilla, Fei Wang, Yue Lu, Marcos R Estecio, Katherine Y King, Eugenie Kleinerman, Seyed Javad Moghaddam, Naval Daver, Michael Andreeff, Marina Konopleva, Courtney Dinardo, Joya Chandra

Faculty, Staff and Student Publications

No abstract provided.

Phase 1 Study Of Vibecotamab Identifies An Optimized Dose For Treatment Of Relapsed/Refractory Acute Myeloid Leukemia, Farhad Ravandi, Asad Bashey, James Foran, Wendy Stock, Raya Mawad, Nicholas Short, Musa Yilmaz, Hagop Kantarjian, Olatoyosi Odenike, Anand Patel, Raman Garcha, William Barrett Ainsworth, Raphael Clynes, Jitendra Kanodia, Ying Ding, Huajiang Li, Steve Kye, Alice Mims

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML), an aggressive malignancy with unmet medical need, lacks immunotherapeutic options. CD123, the cellular receptor for interleukin-3, expressed in AML is an attractive target for tumor-specific therapy. Vibecotamab (XmAb14045), a humanized bispecific antibody, monovalently binds both CD3 and CD123 to recruit cytotoxic T cells to kill CD123+ tumor cells. This phase 1 study's primary objectives were safety and tolerability and identification of a maximum tolerated dose/recommended dose for use as monotherapy in patients with relapsed/refractory AML. Identification of a recommended phase 2 vibecotamab dose comprised 3 step-up doses (Week 1), which were noted to reduce cytokine response …

A Single-Cell Atlas Of Cd19 Chimeric Antigen Receptor T Cells, Xubin Li, Jared Henderson, Max J Gordon, Irtiza Sheikh, Loretta J Nastoupil, Jason Westin, Christopher Flowers, Sairah Ahmed, Linghua Wang, Sattva S Neelapu, Paolo Strati, Qing Deng, Michael R Green

Faculty, Staff and Student Publications

Li et al. present a resource of single-cell RNA sequencing (scRNA-seq) data from the infusion products of relapsed or refractory large B cell lymphoma (rrLBCL) patients treated with standard-of-care axicabtagene ciloleucel and identify features that are significantly different between products from responders and non-responders at 3-month followup by PET/CT, an important landmark for long-term outcomes.

A Longitudinal Study Of Polygenic Score And Cognitive Function Decline Considering Baseline Cognitive Function, Lifestyle Behaviors, And Diabetes Among Middle-Aged And Older Us Adults, Tingting Liu, Changwei Li, Ruiyuan Zhang, Eugenia Flores Millender, Hongyu Miao, Michael Ormsbee, Jinzhen Guo, Adrianna Westbrook, Yang Pan, Jing Wang, Tanika N Kelly

Faculty, Staff and Student Publications

Background: Genomic study of cognition decline while considering baseline cognition and lifestyle behaviors is scarce. We aimed to evaluate the impact of a polygenic score for general cognition on cognition decline rate, while considering baseline cognition and lifestyle behaviors, among the general population and people with diabetes, a patient group commonly affected by cognition impairment.

Methods: We tested associations of the polygenic score for general cognition with annual changing rates of cognition measures in 8 years of follow-up among 12,090 White and 3100 Black participants of the Health and Retirement Study (HRS), a nationally representative sample of adults aged 50 …

Venetoclax Abrogates The Prognostic Impact Of Splicing Factor Gene Mutations In Newly Diagnosed Acute Myeloid Leukemia, Jayastu Senapati, Samuel Urrutia, Sanam Loghavi, Nicholas J Short, Ghayas C Issa, Abhishek Maiti, Hussein A Abbas, Naval G Daver, Naveen Pemmaraju, Sherry Pierce, Kelly S Chien, Koji Sasaki, Tapan M Kadia, Danielle E Hammond, Gautam Borthakur, Keyur Patel, Farhad Ravandi, Hagop M Kantarjian, Guillermo Garcia-Manero, Courtney D Dinardo

Faculty, Staff and Student Publications

Mutations in splicing factor (SF) genes SRSF2, U2AF1, SF3B1, and ZRSR2 are now considered adverse risk in the European LeukemiaNet 2022 acute myeloid leukemia (AML) risk stratification. The prognostic impact of SF mutations in AML has been predominantly derived from younger patients treated with intensive (INT) therapy. We evaluated 994 patients with newly diagnosed AML, including 266 (27%) with a SFmut. Median age was 67 years overall, with patients with SFmut being older at 72 years. SRSF2 (n = 140, 53%) was the most common SFmut. In patients treated with INT, median relapse-free survival (RFS) (9.6 vs 21.4 months, P …

Efficacy Of Sotagliflozin In Adults With Type 2 Diabetes In Relation To Baseline Hemoglobin A1c, Rahul Aggarwal, Deepak L Bhatt, Michael Szarek, Christopher P Cannon, Darren K Mcguire, Silvio E Inzucchi, Renato D Lopes, Michael J Davies, Phillip Banks, Bertram Pitt, Philippe Gabriel Steg

Faculty, Staff and Student Publications

Background: The SCORED (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) and SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure) trials demonstrated that sotagliflozin, an SGLT1 and SGLT2 inhibitor, improves outcomes in individuals with type 2 diabetes who have heart failure (HF) or kidney disease.

Objectives: We assessed the efficacy of sotagliflozin on HF clinical outcomes in individuals with differing baseline glycosylated hemoglobin (HbA1c) levels.

Methods: We included all adults from SCORED and SOLOIST-WHF. The primary …

A Randomized Phase Iii Study Of Standard Versus High-Dose Cytarabine With Or Without Vorinostat For Aml, Guillermo Garcia-Manero, Nikolai A Podoltsev, Megan Othus, John M Pagel, Jerald P Radich, Min Fang, David A Rizzieri, Guido Marcucci, Stephen A Strickland, Mark R Litzow, M Lynn Savoie, Bruno C Medeiros, Mikkael A Sekeres, Tara L Lin, Geoffrey L Uy, Bayard L Powell, Jonathan E Kolitz, Richard A Larson, Richard M Stone, David Claxton, James Essell, Selina M Luger, Sanjay R Mohan, Anna Moseley, Frederick R Appelbaum, Harry P Erba

Faculty, Staff and Student Publications

Prior experience indicated that use of higher doses of cytarabine during induction for acute myeloid leukemia (AML) with a histone deacetylase inhibitor resulted in high response rates. S1203 was a randomized multicenter trial for previously untreated patients aged 18-60 with AML which compared daunorubicin and cytarabine (DA), idarubicin with higher dose cytarabine (IA) and IA with vorinostat (IA + V). The primary endpoint was event free survival (EFS). 738 patients were randomized: 261 to each DA and IA arms and 216 to the IA + V arm. 96, 456, and 150 patients had favorable-, intermediate-, and unfavorable-risk cytogenetics, respectively. 152 …

A Drosophila Model Relevant To Chemotherapy-Related Cognitive Impairment, Matthew Torre, Hassan Bukhari, Vanitha Nithianandam, Camila A Zanella, Douglas A Mata, Mel B Feany

Duncan NRI Faculty and Staff Publications

Chemotherapy-related cognitive impairment (CRCI) is a common adverse effect of treatment and is characterized by deficits involving multiple cognitive domains including memory. Despite the significant morbidity of CRCI and the expected increase in cancer survivors over the coming decades, the pathophysiology of CRCI remains incompletely understood, highlighting the need for new model systems to study CRCI. Given the powerful array of genetic approaches and facile high throughput screening ability in Drosophila, our goal was to validate a Drosophila model relevant to CRCI. We administered the chemotherapeutic agents cisplatin, cyclophosphamide, and doxorubicin to adult Drosophila. Neurologic deficits were observed with all …

Identification Of Blood Protein Biomarkers Associated With Prostate Cancer Risk Using Genetic Prediction Models: Analysis Of Over 140,000 Subjects, Hua Zhong, Jingjing Zhu, Shuai Liu, Dalia H Ghoneim, Praveen Surendran, Tao Liu, Sarah Fahle, Adam Butterworth, Md Ashad Alam, Hong-Wen Deng, Herbert Yu, Chong Wu, Lang Wu

Faculty, Staff and Student Publications

Prostate cancer (PCa) brings huge public health burden in men. A growing number of conventional observational studies report associations of multiple circulating proteins with PCa risk. However, the existing findings may be subject to incoherent biases of conventional epidemiologic studies. To better characterize their associations, herein, we evaluated associations of genetically predicted concentrations of plasma proteins with PCa risk. We developed comprehensive genetic prediction models for protein levels in plasma. After testing 1308 proteins in 79 194 cases and 61 112 controls of European ancestry included in the consortia of BPC3, CAPS, CRUK, PEGASUS, and PRACTICAL, 24 proteins showed significant …

Potentiation Of Apoptosis In Drug-Resistant Mantle Cell Lymphoma Cells By Mcl-1 Inhibitor Involves Downregulation Of Inhibitor Of Apoptosis Proteins, Yijing Li, Heng-Huan Lee, Vivian Changying Jiang, Yuxuan Che, Joseph Mcintosh, Alexa Jordan, Jovanny Vargas, Tianci Zhang, Fangfang Yan, Margaret Elizabeth Simmons, Wei Wang, Lei Nie, Yixin Yao, Preetesh Jain, Michael Wang, Yang Liu

Faculty, Staff and Student Publications

Bruton's tyrosine kinase inhibitors (BTKi) and CAR T-cell therapy have demonstrated tremendous clinical benefits in mantle cell lymphoma (MCL) patients, but intrinsic or acquired resistance inevitably develops. In this study, we assessed the efficacy of the highly potent and selective MCL-1 inhibitor AZD5991 in various therapy-resistant MCL cell models. AZD5991 markedly induced apoptosis in these cells. In addition to liberating BAK from the antiapoptotic MCL-1/BAK complex for the subsequent apoptosis cascade, AZD5991 downregulated inhibitor of apoptosis proteins (IAPs) through a BAK-dependent mechanism to amplify the apoptotic signal. The combination of AZD5991 with venetoclax enhanced apoptosis and reduced mitochondrial oxygen consumption …

Racial Disparities In Mit Family Translocation Renal Cell Carcinoma, Xiaofan Lu, Nassim Tawanaie Pour Sedehi, Xiaoping Su, Fangrong Yan, Omar Alhalabi, Nizar M Tannir, Gabriel G Malouf

Faculty, Staff and Student Publications

Racial disparities have been documented in the biology and outcome of certain renal cell carcinomas (RCCs) among Black patients. However, little is known about racial differences in MiT family translocation RCC (TRCC). To investigate this issue, we performed a case-control study using data from The Cancer Genome Atlas (TCGA) and the Chinese OrigiMed2020 cohort. A total of 676 patients with RCC (14 Asian, 113 Black, and 525 White) were identified in TCGA, and TRCC was defined as RCC with TFE3/TFEB translocation or TFEB amplification, leading to 21 patients with TRCC (2 Asian, 8 Black, 10 White, and 1 unknown). Asian …

Loss Of Adar1 In Macrophages In Combination With Interferon Gamma Suppresses Tumor Growth By Remodeling The Tumor Microenvironment, Weiwei Lin, Yikai Luo, Jie Wu, Haowan Zhang, Ge Jin, Chahua Guo, Hang Zhou, Han Liang, Xiaoyan Xu

Faculty, Staff and Student Publications

Background: ADAR1, the major enzyme for RNA editing, has emerged as a tumor-intrinsic key determinant for cancer immunotherapy efficacy through modulating interferon-mediated innate immunity. However, the role of ADAR1 in innate immune cells such as macrophages remains unknown.

Methods: We first analyzed publicly accessible patient-derived single-cell RNA-sequencing and perturbed RNA sequencing data to elucidate the ADAR1 expression and function in macrophages. Subsequently, we evaluated the combined effects of ADAR1 conditional knockout in macrophages and interferon (IFN)-γ treatment on tumor growth in three distinct disease mouse models: LLC for lung cancer, B16-F10 for melanoma, and MC38 for colon cancer. To gain …

Genome-Wide Interaction Analysis Of Folate For Colorectal Cancer Risk, Emmanouil Bouras, Andre E Kim, Yi Lin, John Morrison, Mengmeng Du, Demetrius Albanes, Elizabeth L Barry, James W Baurley, Sonja I Berndt, Stephanie A Bien, Timothy D Bishop, Hermann Brenner, Arif Budiarto, Andrea Burnett-Hartman, Peter T Campbell, Robert Carreras-Torres, Graham Casey, Tjeng Wawan Cenggoro, Andrew T Chan, Jenny Chang-Claude, David V Conti, Michelle Cotterchio, Matthew Devall, Virginia Diez-Obrero, Niki Dimou, David A Drew, Jane C Figueiredo, Graham G Giles, Stephen B Gruber, Marc J Gunter, Tabitha A Harrison, Akihisa Hidaka, Michael Hoffmeister, Jeroen R Huyghe, Amit D Joshi, Eric S Kawaguchi, Temitope O Keku, Anshul Kundaje, Loic Le Marchand, Juan Pablo Lewinger, Li Li, Brigid M Lynch, Bharuno Mahesworo, Satu Männistö, Victor Moreno, Neil Murphy, Polly A Newcomb, Mireia Obón-Santacana, Jennifer Ose, Julie R Palmer, Nikos Papadimitriou, Bens Pardamean, Andrew J Pellatt, Anita R Peoples, Elizabeth A Platz, John D Potter, Lihong Qi, Conghui Qu, Gad Rennert, Edward Ruiz-Narvaez, Lori C Sakoda, Stephanie L Schmit, Anna Shcherbina, Mariana C Stern, Yu-Ru Su, Catherine M Tangen, Duncan C Thomas, Yu Tian, Caroline Y Um, Franzel Jb Van Duijnhoven, Bethany Van Guelpen, Kala Visvanathan, Jun Wang, Emily White, Alicja Wolk, Michael O Woods, Cornelia M Ulrich, Li Hsu, W James Gauderman, Ulrike Peters, Konstantinos K Tsilidis

Faculty, Staff and Student Publications

Background: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC.

Objectives: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk.

Methods: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) …

Dicarboxylic Acylcarnitine Biomarkers In Peroxisome Biogenesis Disorders, Michael F Wangler, Barbara Lesko, Rejwi Dahal, Sharayu Jangam, Pradnya Bhadane, Theodore E Wilson, Molly Mcpheron, Marcus J Miller

Duncan NRI Faculty and Staff Publications

The peroxisome is an essential eukaryotic organelle with diverse metabolic functions. Inherited peroxisomal disorders are associated with a wide spectrum of clinical outcomes and are broadly divided into two classes, those impacting peroxisome biogenesis (PBD) and those impacting specific peroxisomal factors. Prior studies have indicated a role for acylcarnitine testing in the diagnosis of some peroxisomal diseases through the detection of long chain dicarboxylic acylcarnitine abnormalities (C16-DC and C18-DC). However, there remains limited independent corroboration of these initial findings and acylcarnitine testing for peroxisomal diseases has not been widely adopted in clinical laboratories. To explore the utility of acylcarnitine testing …

Methods For Objective Assessment Of Skin Involvement In Systemic Sclerosis, Ruhani Desai, Harshdeep Chawla, Kirill Larin, Shervin Assassi

Faculty, Staff and Student Publications

Purpose of review: Skin fibrosis is the most prominent disease manifestation of systemic sclerosis (SSc). Although the treatment for other SSc manifestations has expanded over the years, there is limited progress in identifying effective treatment options for SSc skin involvement. This is in part due to limitations in the utilized outcome measures for assessment of skin fibrosis. This review focuses on different emerging assessment tools for SSc skin involvement and their potential use for clinical care and multicenter trials.

Recent findings: Durometer and other device-based methodologies requiring application of direct pressure to the affected skin have been studied in SSc. …

Valosin-Containing Protein (Vcp/P97) Is Prognostically Unfavorable In Pediatric Aml, And Negatively Correlates With Unfolded Protein Response Proteins Ire1 And Grp78: A Report From The Children’S Oncology Group, Fieke W Hoff, Yihua Qiu, Brandon D Brown, Robert B Gerbing, Amanda R Leonti, Rhonda E Ries, Alan S Gamis, Richard Aplenc, Edward Anders Kolb, Todd A Alonzo, Soheil Meshinchi, Gaye N Jenkins, Terzah M Horton, Steven M Kornblau

Faculty, Staff and Student Publications

Purpose: The endoplasmic reticulum (ER) is the major site of protein synthesis and folding in the cell. ER-associated degradation (ERAD) and unfolded protein response (UPR) are the main mechanisms of ER-mediated cell stress adaptation. Targeting the cell stress response is a promising therapeutic approach in acute myeloid leukemia (AML).

Experimental design: Protein expression levels of valosin-containing protein (VCP), a chief element of ERAD, were measured in peripheral blood samples from in 483 pediatric AML patients using reverse phase protein array methodology. Patients participated in the Children's Oncology Group AAML1031 phase 3 clinical trial that randomized patients to standard chemotherapy (cytarabine …