Medical Genetics Commons^™

Daratumumab/Lenalidomide/Dexamethasone In Transplant-Ineligible Newly Diagnosed Myeloma: Maia Long-Term Outcomes, Thierry Facon, Philippe Moreau, Katja Weisel, Hartmut Goldschmidt, Saad Z Usmani, Ajai Chari, Torben Plesner, Robert Z Orlowski, Nizar Bahlis, Supratik Basu, Cyrille Hulin, Hang Quach, Michael O'Dwyer, Aurore Perrot, Caroline Jacquet, Christopher P Venner, Noopur Raje, Mourad Tiab, Margaret Macro, Laurent Frenzel, Xavier Leleu, Gordon Cook, George Wang, Huiling Pei, Maria Krevvata, Robin Carson, Fredrik Borgsten, Shaji K Kumar

Faculty, Staff and Student Publications

In the MAIA study, daratumumab plus lenalidomide and dexamethasone (D-Rd) improved progression-free survival (PFS) and overall survival (OS) versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). We report updated efficacy and safety from MAIA (median follow-up, 64.5 months), including a subgroup analysis by patient age (< 70, ≥70 to < 75, ≥75, and ≥80 years). Overall, 737 transplant-ineligible patients with NDMM were randomized 1:1 to D-Rd or Rd. The primary endpoint, PFS, was improved with D-Rd versus Rd (median, 61.9 vs 34.4 months; hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.45-0.67; P <  0.0001). Median OS was not reached in the D-Rd group versus 65.5 months in the Rd group (HR, 0.66; 95% CI, 0.53-0.83; P = 0.0003); estimated 60-month OS rates were 66.6% and 53.6%, respectively. D-Rd achieved higher rates of complete response or better (≥CR; 51.1% vs 30.1%), minimal residual disease (MRD) negativity (32.1% vs 11.1%), and sustained MRD negativity (≥18 months: 16.8% vs 3.3%) versus Rd (all P <  0.0001). D-Rd demonstrated clinically meaningful efficacy benefits across age groups. No new safety concerns were observed. Updated results (median follow-up, >5 years) continue to support frontline use of D-Rd in transplant-ineligible patients with NDMM.

Staged Screening Identifies People With Biomarkers Related To Neuronal Alpha-Synuclein Disease, Ethan G Brown, Lana M Chahine, Andrew Siderowf, Caroline Gochanour, Ryan Kurth, Micah J Marshall, Chelsea Caspell-Garcia, Michael C Brumm, Craig E Stanley, Monica Korell, Bridget Mcmahon, Maggie Kuhl, Kimberly Fabrizio, Laura Heathers, Luis Concha-Marambio, Claudio Soto, Sohini Chowdhury, Christopher S Coffey, Tatiana M Foroud, Tanya Simuni, Kenneth Marek, Caroline M Tanner

Faculty, Staff and Student Publications

Objective: Remote identification of individuals with severe hyposmia may enable scalable recruitment of participants with underlying alpha-synuclein aggregation. We evaluated the performance of a staged screening paradigm using remote smell testing to enrich for abnormal dopamine transporter single-photon emission computed tomography imaging (DAT-SPECT) and alpha-synuclein aggregation.

Methods: The Parkinson's Progression Markers Initiative (PPMI) recruited participants for the prodromal cohort who were 60-years and older without a Parkinson's disease diagnosis. Participants were invited to complete a University of Pennsylvania Smell Identification Test (UPSIT) independently through an online portal. Hyposmic participants were invited to complete DAT-SPECT, which determined eligibility for enrollment in …

Playbook Workflow Builder: Interactive Construction Of Bioinformatics Workflows, Daniel J B Clarke, John Erol Evangelista, Zhuorui Xie, Giacomo B Marino, Anna I Byrd, Mano R Maurya, Sumana Srinivasan, Keyang Yu, Varduhi Petrosyan, Matthew E Roth, Miroslav Milinkov, Charles Hadley King, Jeet Kiran Vora, Jonathon Keeney, Christopher Nemarich, William Khan, Alexander Lachmann, Nasheath Ahmed, Alexandra Agris, Juncheng Pan, Srinivasan Ramachandran, Eoin Fahy, Emmanuel Esquivel, Aleksandar Mihajlovic, Bosko Jevtic, Vuk Milinovic, Sean Kim, Patrick Mcneely, Tianyi Wang, Eric Wenger, Miguel A Brown, Alexander Sickler, Yuankun Zhu, Sherry L Jenkins, Philip D Blood, Deanne M Taylor, Adam C Resnick, Raja Mazumder, Aleksandar Milosavljevic, Shankar Subramaniam, Avi Ma'ayan

Faculty, Staff and Students Publications

The Playbook Workflow Builder (PWB) is a web-based platform to dynamically construct and execute bioinformatics workflows by utilizing a growing network of input datasets, semantically annotated API endpoints, and data visualization tools contributed by an ecosystem of collaborators. Via a user-friendly user interface, workflows can be constructed from contributed building-blocks without technical expertise. The output of each step of the workflow is added into reports containing textual descriptions, figures, tables, and references. To construct workflows, users can click on cards that represent each step in a workflow, or construct workflows via a chat interface that is assisted by a large …

Acute Kidney Injury In Severe Alcohol-Associated Hepatitis Treated With Anakinra Plus Zinc Or Prednisone, Kavish R Patidar, Wanzhu Tu, Thomas G Cotter, Douglas A Simonetto, Amon Asgharpour, Muhammad Y Jan, Qing Tang, Yunpeng Yu, Yang Li, Moyinoluwa Taiwo, Prashanth Thevkar Nagesh, Srinivasan Dasarathy, Patrick S Kamath, Craig J Mcclain, Naga Chalasani, Gyongyi Szabo, Ramon Bataller, Mack Mitchell, Wajahat Z Mehal, Laura E Nagy, Vijay H Shah, Samer Gawrieh, Arun J Sanyal

Faculty, Staff and Students Publications

Background and aims: In a recent trial, patients with severe alcohol-associated hepatitis treated with anakinra plus zinc (A+Z) had lower survival and higher acute kidney injury (AKI) rates versus prednisone (PRED). We characterize the clinical factors and potential mechanisms associated with AKI development in that trial.

Approach and results: Data from 147 participants in a multicenter randomized clinical trial (74 A+Z, 73 PRED) were analyzed. AKI, AKI phenotypes, and kidney injury biomarkers were compared between participants who did/did not develop AKI in the 2 treatment arms. Multivariable competing risk analyses were performed to identify baseline risk factors for incident AKI, …

Clinical And Genetic Delineation Of Autosomal Recessive And Dominant Actl6b-Related Developmental Brain Disorders, Elisa Cali, Tania Quirin, Clarissa Rocca, Stephanie Efthymiou, Antonella Riva, Dana Marafi, Maha S Zaki, Mohnish Suri, Roberto Dominguez, Hasnaa M Elbendary, Shahryar Alavi, Mohamed S Abdel-Hamid, Heba Morsy, Frederic Tran Mau-Them, Mathilde Nizon, Pavel Tesner, Lukáš Ryba, Faisal Zafar, Nuzhat Rana, Nebal W Saadi, Zahra Firoozfar, Pinar Gencpinar, Bulent Unay, Canan Ustun, Ange-Line Bruel, Christine Coubes, Jennifer Stefanich, Ozlem Sezer, Emanuele Agolini, Antonio Novelli, Gessica Vasco, Donatella Lettori, Mathieu Milh, Laurent Villard, Shimriet Zeidler, Henry Opperman, Vincent Strehlow, Mahmoud Y Issa, Hebatallah El Khassab, Prem Chand, Shahnaz Ibrahim, Ali Rashidi-Nezhad, Mohammad Miryounesi, Pegah Larki, Jennifer Morrison, Ingrid Cristian, Isabelle Thiffault, Nicole L Bertsch, Grace J Noh, John Pappas, Ellen Moran, Nikolaos M Marinakis, Joanne Traeger-Synodinos, Susan Hosseini, Mohammad Reza Abbaszadegan, Roseline Caumes, Lisenka E L M Vissers, Maedeh Neshatdoust, Mostafa Montazer Zohour, Elmostafa El Fahime, Christina Canavati, Lara Kamal, Moien Kanaan, Omar Askander, Victoria Voinova, Olga Levchenko, Shahzhad Haider, Sara S Halbach, Rayana Elias Maia, Salehi Mansoor, Vivek Jain, Sanjukta Tawde, Viveka Santhosh R Challa, Vykuntaraju K Gowda, Varunvenkat M Srinivasan, Lucas Alves Victor, Benito Pinero-Banos, Jennifer Hague, Heba Ahmed Elawady, Adelia Maria De Miranda Henriques-Souza, Huma Arshad Cheema, Muhammad Nadeem Anjum, Sara Idkaidak, Firas Alqarajeh, Osama Atawneh, Hagar Mor-Shaked, Tamar Harel, Giovanni Zifarelli, Peter Bauer, Fernando Kok, Joao Paulo Kitajima, Fabiola Monteiro, Juliana Josahkian, Gaetan Lesca, Nicolas Chatron, Dorothe Ville, David Murphy, Jeffrey L Neul, Sureni V Mullegama, Amber Begtrup, Isabella Herman, Tadahiro Mitani, Jennifer E Posey, Chee Geap Tay, Iram Javed, Lucinda Carr, Farah Kanani, Fiona Beecroft, Lee Hane, Elsayed Abdelkreem, Milan Macek, Luciana Bispo, Marwa Abd Elmaksoud, Farzad Hashemi-Gorji, Davut Pehlivan, David J Amor, Rami Abou Jamra, Wendy K Chung, Eshan Ghayoor Karimiani, Philippe M Campeau, Fowzan S Alkuraya, Alistair T Pagnamenta, Joseph G Gleeson, James R Lupski, Pasquale Striano, Andres Moreno-De-Luca, Denis L J Lafontaine, Henry Houlden, Reza Maroofian

Faculty, Staff and Students Publications

Purpose: This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear.

Methods: We identified 105 affected individuals, including 39 previously reported cases, and systematically analyzed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis.

Results: Biallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability, infantile intractable seizures, absent speech, autistic features, dystonia, …

Time Tracking And Comparison Of Genetic Counseling Tasks In Inpatient And Outpatient Settings, Alexandra Osborne, Emily Magness Bland, Callie Diamonstein, Kristen Fishler

Faculty, Staff and Students Publications

Genetic counselors (GCs) practice in critical care settings. Some GCs have full-time inpatient roles, while most GCs who see inpatients do so as needed or on a rotating schedule in addition to seeing patients in an outpatient setting. Few studies have tracked and compared the amount of time it takes GCs to perform tasks in the inpatient and outpatient settings. Genetic counselors were invited to participate in this study via the National Society of Genetic Counselors research listserv. Participants completed an online survey asking how their role is structured and what types of support are available to them while seeing …

Oral Decitabine Cedazuridine With And Without Venetoclax In Higher-Risk Myelodysplastic Syndromes Or Chronic Myelomonocytic Leukemia: A Propensity Score-Matched Study, Alex Bataller, Koji Sasaki, Samuel Urrutia, Guillermo Montalban-Bravo, Alexandre Bazinet, Kelly Chien, Danielle Hammond, Ian M Bouligny, Mahesh Swaminathan, Ghayas Issa, Nicholas Short, Naval Daver, Courtney D Dinardo, Tapan Kadia, Elias Jabbour, Farhad Ravandi, Gail J Roboz, Michael Savona, Elizabeth A Griffiths, James Mccloskey, Olatoyosi Odenike, Aram Oganesian, Harold N Keer, Mohammad Azab, Hagop Kantarjian, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

Hypomethylating agents (HMA) are indicated in the treatment of higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). The combination of hypomethylating agents with venetoclax (Ven) has demonstrated promising results in these diseases, although randomized clinical trials are needed for validation. In this retrospective study, we compared two matched cohorts of patients with MDS or CMML: one receiving oral decitabine-cedazuridine (DEC-C, n = 73) and one receiving DEC-C and Ven (DEC-C-Ven, n = 51), in three contemporary clinical trials. The aim is to determine the impact of the addition of Ven to HMA in MDS and CMML. Individuals were matched …

Oral Decitabine Cedazuridine With And Without Venetoclax In Higher-Risk Myelodysplastic Syndromes Or Chronic Myelomonocytic Leukemia: A Propensity Score-Matched Study, Alex Bataller, Koji Sasaki, Samuel Urrutia, Guillermo Montalban-Bravo, Alexandre Bazinet, Kelly Chien, Danielle Hammond, Ian M Bouligny, Mahesh Swaminathan, Ghayas Issa, Nicholas Short, Naval Daver, Courtney D Dinardo, Tapan Kadia, Elias Jabbour, Farhad Ravandi, Gail J Roboz, Michael Savona, Elizabeth A Griffiths, James Mccloskey, Olatoyosi Odenike, Aram Oganesian, Harold N Keer, Mohammad Azab, Hagop Kantarjian, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

Hypomethylating agents (HMA) are indicated in the treatment of higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). The combination of hypomethylating agents with venetoclax (Ven) has demonstrated promising results in these diseases, although randomized clinical trials are needed for validation. In this retrospective study, we compared two matched cohorts of patients with MDS or CMML: one receiving oral decitabine-cedazuridine (DEC-C, n = 73) and one receiving DEC-C and Ven (DEC-C-Ven, n = 51), in three contemporary clinical trials. The aim is to determine the impact of the addition of Ven to HMA in MDS and CMML. Individuals were matched …

Galectin-1 Inhibition As A Strategy For Malignant Peripheral Nerve Sheath Tumor Treatment, Hsiao-Chi Wang, Keila E Torres, Roger Xia, Marcio H Malogolowkin, Ssu-Wei Hsu, Ching-Hsien Chen, Tsung-Chieh Shih

Faculty, Staff and Student Publications

Neurofibromatosis type 1 (NF1) is an inherited disorder that predisposes individuals to malignant peripheral nerve sheath tumors (MPNSTs), a highly aggressive sarcoma with limited treatment options and poor prognosis. This study explores the potential of targeting the interaction between Galectin-1 and Ras as a novel therapeutic strategy for MPNSTs. Through molecular docking, we identified critical residues involved in the Galectin-1 and H-Ras interaction. We developed LLS30, a compound designed to target this Ras-binding pocket on Galectin-1, and tested its efficacy. LLS30 effectively disrupted the Galectin-1/Ras interaction, causing Ras delocalization from the plasma membrane and inhibiting Ras signaling. In vitro experiments …

Histone Acetylation Modulators In Breast Cancer, Xueying Yuan, Jeffrey M Rosen

Faculty, Staff and Students Publications

Breast cancer is the most prevalent cancer in women worldwide. Aberrant epigenetic reprogramming such as dysregulation of histone acetylation has been associated with the development of breast cancer. Histone acetylation modulators have been targeted as potential treatments for breast cancer. This review comprehensively discusses the roles of these modulators and the effects of their inhibitors on breast cancer. In addition, epigenetic reprogramming not only affects breast cancer cells but also the immunosuppressive myeloid cells, which can facilitate breast cancer progression. Therefore, the review also highlights the roles of these immunosuppressive myeloid cells and summarizes how histone acetylation modulators affect their …

Systemic Antitumor Immune Response Of Doped Yttria Nanoscintillators Under Low-Dose X-Ray Irradiation, Onur Sahin, Yuri Mackeyev, Geraldine V Vijay, Soumyabrata Roy, Ashokkumar Meiyazhagan, Yasmin Zahra, Okan Tezcan, Valeria Gonzalez, Belal Abousaida, Holden R Wagner, Pearl Fernandes, Riaz Mowzoon-Mogharrabi, Bhanu P Venkatesulu, Cheng-En Hsieh, Joseph B K Kim, Subhiksha Raghuram, Xiang Zhang, Kristen A Miller, Guanhui Gao, Pankaj K Singh, Sang Hyun Cho, Rao V L Papineni, Pulickel M Ajayan, Sunil Krishnan

Faculty, Staff and Student Publications

Inadequate light penetration in tissues restricts photodynamic therapy to treating only superficial tumors. To enable x-ray-excited photodynamic therapy (XPDT) that targets deep-seated tumors, we synthesized a nanoscintillator-photosensitizer complex containing 5% Eu-doped Y2O3 fluorescing at 611 nanometers and decorated with SiO2 containing the scintillation-coupled photosensitizer methylene blue and a polyethylene glycol coating [PEGylated Y2O3:Eu@SiO2-methylene blue (pYSM)]. When irradiated, pYSMs generate singlet oxygen species in vitro, causing cytotoxicity with hallmarks of immunogenic cell death (calreticulin translocation to the cell membrane). Intravenously administered pYSMs home passively to pancreatic tumor xenografts and, upon 10 gray irradiation, cause significant tumor regression (P < 0.01). On combining XPDT with anti-PD1 immunotherapy, a distant nonirradiated tumor also regresses via an increase in intratumoral activated CD8+ cytotoxic T cells. Collectively, we advance a systemically delivered XPDT strategy that mediates an antitumor effect in both irradiated and nonirradiated (abscopal) tumors when coupled with immunotherapy, converting an immunologically "cold" tumor to an immunologically "hot" tumor.

Sitc Strategic Vision: Prevention, Premalignant Immunity, Host And Environmental Factors, Sasha E Stanton, Kristin G Anderson, Tullia C Bruno, Christian M Capitini, Mary L Disis, Jennifer Mcquade, Laszlo Radvanyi, Claire Vanpouille-Box, Jennifer Wargo, Kelly J Baines, Megan M Y Hong, Adnan Rajeh, Raymond H Kim, Phillip Awadalla, Lauren K Hughes, Saman Maleki Vareki

Faculty, Staff and Student Publications

Cancer immunotherapy has improved the survival of a subset of patients by harnessing the power of the immune system to find and destroy malignant cells. The immune system also protects the host by destroying developing premalignant and malignant tumors. Advancing our knowledge of premalignant immunity and immune changes seen in lesions that develop into invasive cancer versus those that regress offers an exciting opportunity to leverage the immune system for immune prevention and immune interception of premalignancy. Understanding the immune environment of premalignant lesions and how chronic inflammation plays a central role in the evolution of premalignancy is essential for …

Cigarette Smoke Induces Angiogenic Activation In The Cancer Field Through Dysregulation Of An Endothelial Microrna, Asawari Korde, Anuradha Ramaswamy, Seth Anderson, Lei Jin, Jian-Ge Zhang, Buqu Hu, Walter V Velasco, Lixia Diao, Jing Wang, Margaret A Pisani, Maor Sauler, Daniel J Boffa, Jonathan T Puchalski, Xiting Yan, Seyed Javad Moghaddam, Shervin S Takyar

Faculty, Staff and Student Publications

Cigarette smoke (CS) creates a "cancer field" in the lung that promotes malignant transformation. The molecular changes within this field are not fully characterized. We examined the significance of microRNA-1 (miR-1) downregulation as one of these changes. We found that tumor miR-1 levels in three non-small cell lung cancer cohorts show inverse correlations with the smoking burden. Lung MiR-1 levels follow a spatial gradient, have prognostic significance, and correlate inversely with the molecular markers of injury. In CS-exposed lungs, miR-1 is specifically downregulated in the endothelium. Exposure to CS induces angiogenesis by selectively degrading mature miR-1 via a vascular endothelial …

Dock2 Deficiency And Gata2 Haploinsufficiency Can Underlie Critical Coronavirus Disease 2019 (Covid-19) Pneumonia, Sajjad Biglari, Leila Youssefian, Mohammad Amin Tabatabaiefar, Amir Hossein Saeidian, Bahareh Abtahi-Naeini, Erfan Khorram, Roya Sherkat, Atefeh Sohanforooshan Moghaddam, Fatemeh Mohaghegh, Maziyar Rahimi, Hamid Rahimi, Sharareh Babaei, Mohammad Shahrooei, Nikoo Mozafari, Shirin Zaresharifi, Fatemeh Vahidnezhad, Vida Homayouni, Lam C Tsoi, Johann E Gudjonsson, Hakon Hakonarson, Jean-Laurent Casanova, Emmanuelle Jouanguy, Vivien Béziat, Qian Zhang, Aurélie Cobat, Hassan Vahidnezhad

Faculty, Staff and Students Publications

The life-threatening coronavirus disease 2019 (COVID-19) affects about 1 in 1,000 healthy people under 50 without underlying conditions. Among patients with critical COVID-19 pneumonia, rare germline variants at genes controlling type I IFN immunity have been reported in up to 5% of patients. Causal etiologies in 80-85% of cases are still unknown. We analyzed two families with hypoxemic COVID-19 pneumonia for known single-gene inborn errors of immunity. In Family 1, two siblings with critical COVID-19 were homozygous for a DOCK2 variant, c.3624+5G>A. DOCK2 deficiency is a known T-cell disorder underlying severe viral diseases. The variant resulted in skipping exon …

Reducing Clinical Trial Eligibility Barriers For Patients With Mds: An Icmds Position Statement, Uma Borate, Kelly Pugh, Allyson Waller, Rina Li Welkie, Ying Huang, Jan Philipp Bewersdorf, Maximilian Stahl, Amy E Dezern, Uwe Platzbecker, Mikkael A Sekeres, Andrew H Wei, Rena J Buckstein, Gail J Roboz, Michael R Savona, Sanam Loghavi, Robert P Hasserjian, Pierre Fenaux, David A Sallman, Christopher S Hourigan, Matteo Giovanni Della Porta, Stephen Nimer, Richard F Little, Valeria Santini, Fabio Efficace, Justin Taylor, Guillermo Garcia-Manero, Olatoyosi Odenike, Tae Kon Kim, Stephanie Halene, Rami S Komrokji, Elizabeth A Griffiths, Peter L Greenberg, Mina L Xu, Zhuoer Xie, Rafael Bejar, Guillermo F Sanz, Mrinal M Patnaik, Maria Figueroa, Hetty E Carraway, Omar Abdel-Wahab, Daniel Starczynowski, Eric Padron, Jacqueline Boultwood, Steven Gore, Naval G Daver, Jane E Churpek, Ravindra Majeti, John M Bennett, Alan F List, Andrew M Brunner, Amer M Zeidan

Faculty, Staff and Student Publications

Excessively restrictive inclusion and exclusion criteria in clinical trials are one of many barriers to clinical trial enrollment for patients with myelodysplastic syndromes/neoplasms (MDSs). Many organizations are developing efforts to increase clinical trial eligibility; yet, several recent publications focused on patients with MDS suggest that many patients with this disease may be excluded from clinical trials unnecessarily. Clinical trial eligibility should reflect the phase of the study and risks of the agent being studied. Phase 3 trials should be less restrictive than early-phase trials to represent the real-world population as closely as possible. We hypothesize that many clinical trials, particularly …

The Tumor Microenvironment Is An Ecosystem Sustained By Metabolic Interactions, Emily Jane Kay, Sara Zanivan

Faculty, Staff and Student Publications

Cancer-associated fibroblasts (CAFs) and immune cells make up two major components of the tumor microenvironment (TME), contributing to an ecosystem that can either support or restrain cancer progression. Metabolism is a key regulator of the TME, providing a means for cells to communicate with and influence each other, modulating tumor progression and anti-tumor immunity. Cells of the TME can metabolically interact directly through metabolite secretion and consumption or by influencing other aspects of the TME that, in turn, stimulate metabolic rewiring in target cells. Recent advances in understanding the subtypes and plasticity of cells in the TME both open up …

Clinical Use Of Measurable Residual Disease In Adult All: Recommendations From A Panel Of Us Experts, Nicholas J Short, Ibrahim Aldoss, Daniel J Deangelo, Marina Konopleva, Jessica Leonard, Aaron C Logan, Jae Park, Bijal Shah, Wendy Stock, Elias Jabbour

Faculty, Staff and Student Publications

Measurable residual disease (MRD) is a powerful predictor of clinical outcomes in acute lymphoblastic leukemia (ALL). In addition to its clear prognostic importance, MRD information is increasingly used in clinical decision algorithms to guide therapeutic interventions. Although it is well established that achievement of MRD-negative remission is an important end point of ALL therapy, the prognostic and therapeutic implications of MRD in an individual patient are influenced by both disease-related factors (eg, cytomolecular risk) and assay-related factors (eg, sensitivity, specimen source, and timing of assessment), which add complexity to MRD-guided treatment decisions. In this review, we discuss the data supporting …

Treatment Group-Specific Inferences In Phase Iii Randomized Oncology Trials, Alexander D Sherry, Adina H Passy, Joseph Abi Jaoude, Timothy A Lin, Ramez Kouzy, Pavlos Msaouel, Ethan B Ludmir

Faculty, Staff and Student Publications

Background: Estimation of comparative treatment effects between randomized groups is well-supported in randomized trials. By contrast, treatment group-specific inferences are challenging, as patients are selectively chosen for enrollment, and such inferences are formally discouraged by the CONSORT guidelines. The present study is the first-large scale assessment of the proportion of phase III oncology trials that present treatment group-specific inferences.

Methods: Published phase III randomized oncology trials were screened from ClinicalTrials.gov. Treatment group-specific inferences were defined by the presence of 95% CI or standard error for treatment-specific outcomes.

Results: A total of 774 phase III trials enrolling 568,080 patients were included. …

Protocol For Unlocking Alternative Polyadenylation Insights From Bulk Rna-Seq Data With Polyaminer-Bulk, Venkata Jonnakuti, Sriya Jonnakuti, Hari Krishna Yalamanchili

Duncan NRI Faculty and Staff Publications

PolyAMiner-Bulk, a deep-learning-based algorithm to decode alternative polyadenylation (APA) dynamics from bulk RNA sequencing (RNA-seq) data, enables scientists to identify and quantify APA events from processed bulk RNA-seq data. The protocol allows researchers to explore differential APA usage between two conditions and gain a better understanding of post-transcriptional regulatory mechanisms. The major steps involve input data preparation, executing PolyAMiner-Bulk, and interpreting the results. A basic familiarity with pre-processing bulk RNA-seq data and command-line tools is suggested.

For complete details on the use and execution of this protocol, please refer to Jonnakuti et al.¹

Rare Damaging Ccr2 Variants Are Associated With Lower Lifetime Cardiovascular Risk, Marios K Georgakis, Rainer Malik, Omar El Bounkari, Natalie R Hasbani, Jiang Li, Jennifer E Huffman, Gabrielle Shakt, Reinier W P Tack, Tamara N Kimball, Yaw Asare, Alanna C Morrison, Noah L Tsao, Renae Judy, Braxton D Mitchell, Huichun Xu, May E Montasser, Ron Do, Eimear E Kenny, Ruth J F Loos, James G Terry, John Jeffrey Carr, Joshua C Bis, Bruce M Psaty, W T Longstreth, Kendra A Young, Sharon M Lutz, Michael H Cho, Jai Broome, Alyna T Khan, Fei Fei Wang, Nancy Heard-Costa, Sudha Seshadri, Ramachandran S Vasan, Nicholette D Palmer, Barry I Freedman, Donald W Bowden, Lisa R Yanek, Brian G Kral, Lewis C Becker, Patricia A Peyser, Lawrence F Bielak, Farah Ammous, April P Carson, Michael E Hall, Laura M Raffield, Stephen S Rich, Wendy S Post, Russel P Tracy, Kent D Taylor, Xiuqing Guo, Michael C Mahaney, Joanne E Curran, John Blangero, Shoa L Clarke, Jeffrey W Haessler, Yao Hu, Themistocles L Assimes, Charles Kooperberg, Jürgen Bernhagen, Christopher D Anderson, Scott M Damrauer, Ramin Zand, Jerome I Rotter, Paul S De Vries, Martin Dichgans

Faculty, Staff and Student Publications

BACKGROUND: Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease.

METHODS: Computationally predicted damaging or loss-of-function (REVEL > 0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested …

Evaluation And Surgical Management Of Pediatric Cutaneous Melanoma And Atypical Spitz And Non-Spitz Melanocytic Tumors (Melanocytomas): A Report From Children's Oncology Group, Michael R Sargen, Raymond L Barnhill, David E Elder, Susan M Swetter, Victor G Prieto, Jennifer S Ko, Armita Bahrami, Pedram Gerami, Arivarasan Karunamurthy, Alberto S Pappo, Lynn M Schuchter, Philip E Leboit, Iwei Yeh, John M Kirkwood, Melinda Jen, Ira J Dunkel, Megan M Durham, Emily R Christison-Lagay, Mary T Austin, Jennifer H Aldrink, Casey Mehrhoff, Elena B Hawryluk, Emily Y Chu, Klaus J Busam, Vernon Sondak, Jane Messina, Susana Puig, Andrew J Colebatch, Carrie C Coughlin, Kristen G Berrebi, Theodore W Laetsch, Sarah G Mitchell, Brittani Seynnaeve

Faculty, Staff and Student Publications

Purpose: The purpose of this study was to develop recommendations for the diagnostic evaluation and surgical management of cutaneous melanoma (CM) and atypical Spitz tumors (AST) and non-Spitz melanocytic tumors (melanocytomas) in pediatric (age 0-10 years) and adolescent (age 11-18 years) patients.

Methods: A Children's Oncology Group-led panel with external, multidisciplinary CM specialists convened to develop recommendations on the basis of available data and expertise.

Results: Thirty-three experts from multiple specialties (cutaneous/medical/surgical oncology, dermatology, and dermatopathology) established recommendations with supporting data from 87 peer-reviewed publications.

Recommendations: (1) Excisional biopsies with 1-3 mm margins should be performed when feasible for clinically …

Deciphering The Dark Cancer Phosphoproteome Using Machine-Learned Co-Regulation Of Phosphosites, Wen Jiang, Eric J Jaehnig, Yuxing Liao, Zhiao Shi, Tomer M Yaron-Barir, Jared L Johnson, Lewis C Cantley, Bing Zhang

Faculty, Staff and Students Publications

Mass spectrometry-based phosphoproteomics offers a comprehensive view of protein phosphorylation, yet our limited knowledge about the regulation and function of most phosphosites hampers the extraction of meaningful biological insights. To address this challenge, we integrate machine learning with phosphoproteomic data from 1195 tumor specimens spanning 11 cancer types to construct CoPheeMap, a network that maps the co-regulation of 26,280 phosphosites. By incorporating network features from CoPheeMap into a second machine learning model, namely CoPheeKSA, we achieve superior performance in predicting kinase-substrate associations. CoPheeKSA uncovers 24,015 associations between 9399 phosphosites and 104 serine/threonine kinases, shedding light on many unannotated phosphosites and …

Diverse Ancestral Representation Improves Genetic Intolerance Metrics, Alexander L Han, Chloe F Sands, Dorota Matelska, Jessica C Butts, Vida Ravanmehr, Fengyuan Hu, Esmeralda Villavicencio Gonzalez, Nicholas Katsanis, Carlos D Bustamante, Quanli Wang, Slavé Petrovski, Dimitrios Vitsios, Ryan S Dhindsa

Duncan NRI Faculty and Staff Publications

The unprecedented scale of genomic databases has revolutionized our ability to identify regions in the human genome intolerant to variation—regions often implicated in disease. However, these datasets remain constrained by limited ancestral diversity. Here, we analyze whole-exome sequencing data from 460,551 UK Biobank and 125,748 Genome Aggregation Database (gnomAD) participants across multiple ancestries to test several key intolerance metrics, including the Residual Variance Intolerance Score (RVIS), Missense Tolerance Ratio (MTR), and Loss-of-Function Observed/Expected ratio (LOF O/E). We demonstrate that increasing ancestral representation, rather than sample size alone, critically drives their performance. Scores trained on variation observed in African and Admixed …

Mathematical Modeling To Address Questions In Breast Cancer Screening: An Overview Of The Breast Cancer Models Of The Cancer Intervention And Surveillance Modeling Network, Oguzhan Alagoz, Jennifer L Caswell-Jin, Harry J De Koning, Hui Huang, Xuelin Huang, Sandra J Lee, Yisheng Li, Sylvia K Plevritis, Swarnavo Sarkar, Clyde B Schechter, Natasha K Stout, Amy Trentham-Dietz, Nicolien Van Ravesteyn, Kathryn P Lowry

Faculty, Staff and Student Publications

The National Cancer Institute-funded Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer mathematical models have been increasingly utilized by policymakers to address breast cancer screening policy decisions and influence clinical practice. These well-established and validated models have a successful track record of use in collaborations spanning over 2 decades. While mathematical modeling is a valuable approach to translate short-term screening performance data into long-term breast cancer outcomes, it is inherently complex and requires numerous inputs to approximate the impacts of breast cancer screening. This review article describes the 6 independently developed CISNET breast cancer models, with a particular focus …

Near-Infrared Fluorescence Imaging With An Met-Targeting Probe For Biopsy Site Selection In Patients With Oral Potentially Malignant Disorders, Jingbo Wang, Xuemin Shen, Qifan Ma, Lin Yang, Xiaoyu Zhou, Luting Wang, Junqi Cui, Chunye Zhang, Guojun Li, Neil Gross, Siyi Li, Ruimin Huang, Changyou Zhan, Zhen Cheng, Kun Wang, Jie Tian, Ying Yuan, Xiaofeng Tao

Faculty, Staff and Student Publications

Accurate detection of malignant transformation in oral potentially malignant disorders (OPMDs) is crucial for guiding effective treatment and improving patient management. This study evaluates the potential of MET-binding peptide-indocyanine green (cMBP-ICG), a mesenchymal-epithelial transition factor (MET)-targeted near-infrared fluorescence imaging (NIRFI) probe, for biopsy site selection in OPMDs. Preclinical results demonstrate the superior accuracy of NIRFI-assisted biopsy over conventional oral examination (COE)-based biopsy in detecting high-grade dysplasia (HGD) or squamous cell carcinoma (SCC) and reducing missed detection rates. In a clinical trial with 50 patients, NIRFI-assisted biopsy achieves significantly higher diagnostic accuracy compared to COE-based biopsy (91% vs. 72%, p = …

Icos-Expressing Car-T Cells Mediate Durable Eradication Of Triple-Negative Breast Cancer And Metastasis, Shelley Herbrich, Mehdi Chaib, Padmanee Sharma

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) remains one of the most aggressive and therapeutically challenging breast cancer subtypes. In their recent study, Cao et al introduced a B7H3-specific chimeric antigen receptor (CAR)-T cell with constitutive inducible co-stimulator (ICOS) expression (ICOS-B7H3-CAR-T), which demonstrated eradication of TNBC, including metastases, in preclinical models. These CAR-T cells exploit the expression of ICOS ligand on TNBC cells, enhancing antitumor cytotoxicity through ICOS signaling. Compared with conventional B7H3-CAR-T cells, the ICOS-B7H3-CAR-T cells exhibited superior antitumor efficacy, increased cytokine secretion, and prolonged survival in xenograft murine models. This study highlights ICOS as a promising co-stimulatory molecule for improving CAR-T …

Guanine Nucleotide Biosynthesis Blockade Impairs Mll Complex Formation And Sensitizes Leukemias To Menin Inhibition, Xiangguo Shi, Minhua Li, Zian Liu, Jonathan Tiessen, Yuan Li, Jing Zhou, Yudan Zhu, Swetha Mahesula, Qing Ding, Lin Tan, Mengdie Feng, Yuki Kageyama, Yusuke Hara, Jacob J Tao, Xuan Luo, Kathryn A Patras, Philip L Lorenzi, Suming Huang, Alexandra M Stevens, Koichi Takahashi, Ghayas C Issa, Md Abul Hassan Samee, Michalis Agathocleous, Daisuke Nakada

Faculty, Staff and Student Publications

Targeting the dependency of MLL-rearranged (MLLr) leukemias on menin with small molecule inhibitors has opened new therapeutic strategies for these poor-prognosis diseases. However, the rapid development of menin inhibitor resistance calls for combinatory strategies to improve responses and prevent resistance. Here we show that leukemia stem cells (LSCs) of MLLr acute myeloid leukemia (AML) exhibit enhanced guanine nucleotide biosynthesis, the inhibition of which leads to myeloid differentiation and sensitization to menin inhibitors. Mechanistically, targeting inosine monophosphate dehydrogenase 2 (IMPDH2) reduces guanine nucleotides and rRNA transcription, leading to reduced protein expression of LEDGF and menin. Consequently, the formation and chromatin binding …

Genetic Associations With C-Peptide Levels Before Type 1 Diabetes Diagnosis In At-Risk Relatives, Taylor M Triolo, Hemang M Parikh, Mustafa Tosur, Lauric A Ferrat, Lu You, Peter A Gottlieb, Richard A Oram, Suna Onengut-Gumuscu, Jeffrey P Krischer, Stephen S Rich, Andrea K Steck, Maria J Redondo

Children’s Nutrition Research Center Staff Publications

Objective: We sought to determine whether the type 1 diabetes genetic risk score-2 (T1D-GRS2) and single nucleotide polymorphisms are associated with C-peptide preservation before type 1 diabetes diagnosis.

Methods: We conducted a retrospective analysis of 713 autoantibody-positive participants who developed type 1 diabetes in the TrialNet Pathway to Prevention Study who had T1DExomeChip data. We evaluated the relationships of 16 known single nucleotide polymorphisms and T1D-GRS2 with area under the curve (AUC) C-peptide levels during oral glucose tolerance tests conducted in the 9 months before diagnosis.

Results: Higher T1D-GRS2 was associated with lower C-peptide AUC in the 9 months before …

An Exosome-Based Liquid Biopsy Predicts Depth Of Response And Survival Outcomes To Cetuximab And Panitumumab In Metastatic Colorectal Cancer: The Exonerate Study, Caiming Xu, Alessandro Mannucci, Francis Esposito, Helena Oliveres, Vicente Alonso-Orduña, Alfonso Yubero, Carlos Fernández-Martos, Antonieta Salud, Javier Gallego, Marta Martín-Richard, Julen Fernández-Plana, Mónica Guillot, Jorge Aparicio, Marwan Fakih, Scott Kopetz, Jaime Feliu, Joan Maurel, Ajay Goel

Faculty, Staff and Student Publications

Purpose: The EXOsome and cell-free miRNAs of anti-EGFR ResistAnce (EXONERATE) study was an open-label, biomarker interventional study designed to develop, test, and validate a liquid biopsy predictive of progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) for first-line EGFR inhibitors in metastatic colorectal cancer (mCRC).

Patients and methods: Patients with newly diagnosed RAS wild-type, chemotherapy-naïve mCRC, both right- and left-sided, were enrolled in two nationwide trials to receive cetuximab or panitumumab along with chemotherapy. The primary endpoint was 12-month PFS, which was hierarchically tested in left- and right-sided mCRCs to predict PFS, OS, and ORR.

Results: Genome-wide …

Impact Of Co-Mutations And Transcriptional Signatures In Non-Small Cell Lung Cancer Patients Treated With Adagrasib In The Krystal-1 Trial, Marcelo V Negrao, Alvaro G Paula, David Molkentine, Laura Hover, Monique Nilsson, Natalie Vokes, Lars Engstrom, Andrew Calinisan, David M Briere, Laura Waters, Jill Hallin, Lixia Diao, Mehmet Altan, George R Blumenschein, Ferdinandos Skoulidis, Jing Wang, Scott E Kopetz, David S Hong, Don L Gibbons, Peter Olson, James G Christensen, John V Heymach

Faculty, Staff and Student Publications

Purpose: KRAS inhibitors are revolutionizing the treatment of non-small cell lung cancer (NSCLC), but clinico-genomic determinants of treatment efficacy warrant continued exploration.

Experimental design: Patients with advanced KRASG12C-mutant NSCLC treated with adagrasib [KRYSTAL-1 (NCT03785249)] were included in the analysis. Pretreatment next-generation sequencing data were collected per protocol. HTG EdgeSeq Transcriptome Panel was used for gene expression profiling. Clinical endpoints included objective response, progression-free survival (PFS), and overall survival (OS). KRASG12C-mutant NSCLC cell lines and xenograft models were used for sensitivity analyses and combination drug screens.

Results: KEAP1 MUT and STK11MUT were associated with shorter survival to adagrasib [KEAP1: …