Genetic Phenomena Commons^™

Current Status And Research Directions In Acute Myeloid Leukemia, Hagop Kantarjian, Gautam Borthakur, Naval Daver, Courtney D Dinardo, Ghayas Issa, Elias Jabbour, Tapan Kadia, Koji Sasaki, Nicholas J Short, Musa Yilmaz, Farhad Ravandi

Faculty, Staff and Student Publications

The understanding of the molecular pathobiology of acute myeloid leukemia (AML) has spurred the identification of therapeutic targets and the development of corresponding novel targeted therapies. Since 2017, twelve agents have been approved for the treatment of AML subsets: the BCL2 inhibitor venetoclax; the CD33 antibody drug conjugate gemtuzumab ozogamicin; three FLT3 inhibitors (midostaurin, gilteritinib, quizartinib); three IDH inhibitors (ivosidenib and olutasidenib targeting IDH1 mutations; enasidenib targeting IDH2 mutations); two oral hypomethylating agents (oral poorly absorbable azacitidine; fully absorbable decitabine-cedazuridine [latter approved as an alternative to parenteral hypomethylating agents in myelodysplastic syndrome and chronic myelomonocytic leukemia but commonly used in …

Exploring The Complexity Of Systemic Sclerosis Etiology By Trio Whole Genome Sequencing, Hongzheng Dai, Shamika Ketkar, Taotao Tan, Elizabeth G Atkinson, Lindsay Burrage, Kim C Worley, Brian Christopher, Marka A Lyons, Shervin Assassi, Maureen D Mayes, Brendan Lee

Faculty, Staff and Students Publications

Systemic sclerosis (SSc) is a heterogeneous rare autoimmune fibrosing disorder affecting connective tissue. The etiology of systemic sclerosis is largely unknown and many genes have been suggested as susceptibility loci of modest impact by genome-wide association study (GWAS). Multiple factors can contribute to the pathological process of the disease, which makes it more difficult to identify possible disease-causing genetic alterations. In this study, we have applied whole genome sequencing (WGS) in 101 indexed family trios, supplemented with transcriptome sequencing on cultured fibroblast cells of four patients and five family controls where available. Single nucleotide variants (SNVs) and copy number variants …

Effects Of Sotagliflozin On Health Status In Patients With Worsening Heart Failure: Results From Soloist-Whf, Ankeet S Bhatt, Deepak L Bhatt, Ph Gabriel Steg, Michael Szarek, Christopher P Cannon, Lawrence A Leiter, Darren K Mcguire, Julia B Lewis, Matthew C Riddle, Adriaan A Voors, Marco Metra, Lars H Lund, Jeffrey M Testani, Christopher S Wilcox, Michael Davies, Bertram Pitt, Mikhail N Kosiborod

Faculty, Staff and Student Publications

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve health status in heart failure (HF) across the left ejection fraction ejection spectrum. However, the effects of SGLT1 and SGLT2 inhibition on health status are unknown.

Objectives: These prespecified analyses of the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure) trial examined the effects of sotagliflozin vs placebo on HF-related health status.

Methods: SOLOIST-WHF randomized patients hospitalized or recently discharged after a worsening HF episode to receive sotagliflozin or placebo. The primary endpoint was total number of HF hospitalizations, urgent HF visits, and cardiovascular …

Perfusion-Weighted Imaging With Dynamic Contrast Enhancement (Pwi/Dce) Morphologic, Qualitative, Semiquantitative, And Radiomics Features Predicting Undifferentiated Pleomorphic Sarcoma (Ups) Treatment Response, R F Valenzuela, E Duran-Sierra, M Canjirathinkal, B Amini, K E Torres, R S Benjamin, J Ma, W L Wang, K P Hwang, R J Stafford, C Wu, A M Zarzour, A J Bishop, S Lo, J E Madewell, R Kumar, W A Murphy, C M Costelloe

Faculty, Staff and Student Publications

Undifferentiated pleomorphic sarcoma (UPS) is the largest subgroup of soft tissue sarcomas. This study determined the value of perfusion-weighted imaging with dynamic-contrast-enhancement (PWI/DCE) morphologic, qualitative, and semiquantitative features for predicting UPS pathology-assessed treatment effect (PATE). This retrospective study included 33 surgically excised extremity UPS patients with pre-surgical MRI. Volumetric tumor segmentation from PWI/DCE was obtained at Baseline (BL), Post-Chemotherapy (PC), and Post-Radiation Therapy (PRT). The surgical specimens' PATE separated cases into Responders (R) (≥ 90%, 16 patients), Partial-Responders (PR) (89 - 31%, 10 patients), and Non-Responders (NR) (≤ 30%, seven patients). Seven semiquantitative kinetic parameters and maps were extracted from …

Loss Of Hd-Ptp Function Results In Lipodystrophy, Defective Cellular Signaling And Altered Lipid Homeostasis, Destiny F Schultz, Brian A Davies, Johanna A Payne, Cole P Martin, Annabel Y Minard, Bennett G Childs, Cheng Zhang, Karthik B Jeganathan, Ines Sturmlechner, Thomas A White, Alain De Bruin, Liesbeth Harkema, Huiqin Chen, Michael A Davies, Sarah Jachim, Nathan K Lebrasseur, Robert C Piper, Hu Li, Darren J Baker, Jan Van Deursen, Daniel D Billadeau, David J Katzmann

Faculty, Staff and Student Publications

His domain protein tyrosine phosphatase (HD-PTP; also known as PTPN23) facilitates function of the endosomal sorting complexes required for transport (ESCRTs) during multivesicular body (MVB) formation. To uncover its role in physiological homeostasis, embryonic lethality caused by a complete lack of HD-PTP was bypassed through generation of hypomorphic mice expressing reduced protein, resulting in animals that are viable into adulthood. These mice exhibited marked lipodystrophy and decreased receptor-mediated signaling within white adipose tissue (WAT), involving multiple prominent pathways including RAS/MAPK, phosphoinositide 3-kinase (PI3K)/AKT and receptor tyrosine kinases (RTKs), such as EGFR. EGFR signaling was dissected in vitro to assess the …

Longitudinal Intravascular Antibody Labeling Identified Regulatory T Cell Recruitment As A Therapeutic Target In A Mouse Model Of Lung Cancer, Sean-Luc Shanahan, Nikesh Kunder, Charles Inaku, Natalie B Hagan, Grace Gibbons, Nicolas Mathey-Andrews, Gayathri Anandappa, Shawn Soares, Kristen E Pauken, Tyler Jacks, Jason M Schenkel

Faculty, Staff and Student Publications

Anticancer immunity is predicated on leukocyte migration into tumors. Once recruited, leukocytes undergo substantial reprogramming to adapt to the tumor microenvironment. A major challenge in the field is distinguishing recently recruited from resident leukocytes in tumors. In this study, we developed an intravascular Ab technique to label circulating mouse leukocytes before they migrate to tissues, providing unprecedented insight into the kinetics of recruitment. This approach unveiled the substantial role of leukocyte migration in tumor progression using a preclinical mouse model of lung adenocarcinoma. Regulatory T cells (Tregs), critical mediators of immunosuppression, were continuously and rapidly recruited into tumors throughout cancer …

Spatially Fractionated Grid Radiation Potentiates Immune-Mediated Tumor Control, Rebecca A Bekker, Nina Obertopp, Gage Redler, José Penagaricano, Jimmy J Caudell, Kosj Yamoah, Shari Pilon-Thomas, Eduardo G Moros, Heiko Enderling

Faculty, Staff and Student Publications

Background: Tumor-immune interactions shape a developing tumor and its tumor immune microenvironment (TIME) resulting in either well-infiltrated, immunologically inflamed tumor beds, or immune deserts with low levels of infiltration. The pre-treatment immune make-up of the TIME is associated with treatment outcome; immunologically inflamed tumors generally exhibit better responses to radio- and immunotherapy than non-inflamed tumors. However, radiotherapy is known to induce opposing immunological consequences, resulting in both immunostimulatory and inhibitory responses. In fact, it is thought that the radiation-induced tumoricidal immune response is curtailed by subsequent applications of radiation. It is thus conceivable that spatially fractionated radiotherapy (SFRT), administered through …

Minimally Invasive Therapies For Knee Osteoarthritis, Uchenna Osuala, Megan H Goh, Arian Mansur, John B Smirniotopoulos, Arielle Scott, Christine Vassell, Bardia Yousefi, Neil K Jain, Alan A Sag, Allison Lax, Kevin W Park, Alexander Kheradi, Marc Sapoval, Jafar Golzarian, Peiman Habibollahi, Osman Ahmed, Shamar Young, Nariman Nezami

Faculty, Staff and Student Publications

Knee osteoarthritis (KOA) is a musculoskeletal disorder characterized by articular cartilage degeneration and chronic inflammation, affecting one in five people over 40 years old. The purpose of this study was to provide an overview of traditional and novel minimally invasive treatment options and role of artificial intelligence (AI) to streamline the diagnostic process of KOA. This literature review provides insights into the mechanisms of action, efficacy, complications, technical approaches, and recommendations to intra-articular injections (corticosteroids, hyaluronic acid, and plate rich plasma), genicular artery embolization (GAE), and genicular nerve ablation (GNA). Overall, there is mixed evidence to support the efficacy of …

Batf Is A Major Driver Of Nk Cell Epigenetic Reprogramming And Dysfunction In Aml, Bijender Kumar, Anand Singh, Rafet Basar, Nadima Uprety, Ye Li, Huihui Fan, Ana Karen Nunez Cortes, Mecit Kaplan, Sunil Acharya, Hila Shaim, Anna C Xu, Manrong Wu, Emily Ensley, Dexing Fang, Pinaki P Banerjee, Luciana Melo Garcia, Silvia Tiberti, Paul Lin, Hind Rafei, Maliha Nuzhat Munir, Madison Moore, Mayra Shanley, Mayela Mendt, Lucila N Kerbauy, Bin Liu, Alexander Biederstädt, Elif Gokdemir, Susmita Ghosh, Kiran Kundu, Francia Reyes-Silva, Xin Ru Jiang, Xinhai Wan, April L Gilbert, Merve Dede, Vakul Mohanty, Jinzhuang Dou, Patrick Zhang, Enli Liu, Luis Muniz-Feliciano, Gary M Deyter, Abhinav K Jain, Juan Jose Rodriguez-Sevilla, Simona Colla, Guillermo Garcia-Manero, Elizabeth J Shpall, Ken Chen, Hussein A Abbas, Kunal Rai, Katayoun Rezvani, May Daher

Faculty, Staff and Student Publications

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) belong to a continuous disease spectrum of myeloid malignancies with poor prognosis in the relapsed/refractory setting necessitating novel therapies. Natural killer (NK) cells from patients with myeloid malignancies display global dysfunction with impaired killing capacity, altered metabolism and exhausted phenotype at the single cell transcriptomic and proteomic levels. In this study we identified that this dysfunction was mediated through a crosstalk between NK cells and myeloid blasts necessitating cell-cell contact. NK cell dysfunction could be prevented by targeting the αvβ integrin/TGF-β/SMAD pathway but, once established, was persistent due to profound epigenetic reprogramming. …

Bacteroides Ovatus Alleviates Dysbiotic Microbiota-Induced Graft-Versus-Host Disease, Eiko Hayase, Tomo Hayase, Akash Mukherjee, Stuart C Stinson, Mohamed A Jamal, Miriam R Ortega, Christopher A Sanchez, Saira S Ahmed, Jennifer L Karmouch, Chia-Chi Chang, Ivonne I Flores, Lauren K Mcdaniel, Alexandria N Brown, Rawan K El-Himri, Valerie A Chapa, Lin Tan, Bao Q Tran, Yao Xiao, Christopher Fan, Dung Pham, Taylor M Halsey, Yimei Jin, Wen-Bin Tsai, Rishika Prasad, Israel K Glover, Altai Enkhbayar, Aqsa Mohammed, Maren Schmiester, Katherine Y King, Robert A Britton, Pavan Reddy, Matthew C Wong, Nadim J Ajami, Jennifer A Wargo, Samuel Shelburne, Pablo C Okhuysen, Chen Liu, Stephanie W Fowler, Margaret E Conner, Zoe Katsamakis, Natalie Smith, Marina Burgos Da Silva, Doris M Ponce, Jonathan U Peled, Marcel R M Van Den Brink, Christine B Peterson, Gabriela Rondon, Jeffrey J Molldrem, Richard E Champlin, Elizabeth J Shpall, Philip L Lorenzi, Rohtesh S Mehta, Eric C Martens, Amin M Alousi, Robert R Jenq

Faculty, Staff and Student Publications

Acute lower gastrointestinal GVHD (aLGI-GVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation. Although the intestinal microbiota is associated with the incidence of aLGI-GVHD, how the intestinal microbiota impacts treatment responses in aLGI-GVHD has not been thoroughly studied. In a cohort of patients with aLGI-GVHD (n = 37), we found that non-response to standard therapy with corticosteroids was associated with prior treatment with carbapenem antibiotics and a disrupted fecal microbiome characterized by reduced abundances of Bacteroides ovatus. In a murine GVHD model aggravated by carbapenem antibiotics, introducing B. ovatus reduced GVHD severity and improved survival. These beneficial effects …

Clinical Outcomes After Idecabtagene Vicleucel In Older Patients With Multiple Myeloma: A Multicenter Real-World Experience, Nilesh M Kalariya, Michelle A T Hildebrandt, Doris K Hansen, Surbhi Sidana, Jack Khouri, Christopher J Ferreri, William N Doyle, Omar Castaneda-Puglianini, Ciara L Freeman, Vanna Hovanky, Hitomi Hosoya, Leyla O Shune, Krina K Patel

Faculty, Staff and Student Publications

The safety and efficacy of chimeric antigen receptor T-cell therapy is not well described in older patients, a population that has higher frailty and comorbidities. In this multicenter retrospective study, we evaluated clinical outcomes along with frailty and geriatric characteristics such as comorbidities, polypharmacy, falls, neuropathy, organ dysfunction, and performance status in younger (aged < 65 years) vs older (aged ≥65 years) patients who received commercial idecabtagene vicleucel (ide-cel). A total of 156 patients (n = 75, aged ≥65 years) were infused with ide-cel by data cutoff. In older patients (median age: 69 years; range, 65-83; 66.7% frail; 77.3% did not meet KarMMa eligibility criteria), with a median follow-up duration of 14.2 months, best overall response rate (ORR) was 86.7%, which was comparable with pivotal KarMMa study results (ORR: 73%). Median progression-free survival and overall survival in older patients were 9.1 months and 26.5 months, respectively. Grade ≥3 cytokine-release syndrome and immune effector cell-associated neurotoxicity syndrome were observed in 1% and 4% of older patients, respectively. Compared with younger patients, the older patients had significantly higher prevalence of frailty, geriatric characteristics such as polypharmacy (≥5 drugs; 97%), ≥4 comorbidities (69%), and organ dysfunction (35%; P < .05). The safety and efficacy of ide-cel therapy were similar in younger and older patients. Frailty and geriatric characteristics such as polypharmacy, comorbidities, and organ dysfunction in older patients did not confer an inferior overall outcome.

Transcriptomic And Proteomic Differences In Btk-Wt And Btk-Mutated Cll And Their Changes During Therapy With Pirtobrutinib, Burcu Aslan, Ganiraju Manyam, Lakesla R Iles, Shady I Tantawy, Sai Prasad Desikan, William G Wierda, Varsha Gandhi

Faculty, Staff and Student Publications

Covalent Bruton tyrosine kinase inhibitors (cBTKis), which bind to the BTK C481 residue, are now primary therapeutics for chronic lymphocytic leukemia (CLL). Alterations at C481, primarily C481S, prevent cBTKi binding and lead to the emergence of resistant clones. Pirtobrutinib is a noncovalent BTKi that binds to both wild-type (WT) and C481S-mutated BTK and has shown efficacy in BTK-WT and -mutated CLL patient groups. To compare baseline clinical, transcriptomic, and proteomic characteristics and their changes during treatment in these 2 groups, we used 67 longitudinal peripheral blood samples obtained during the first 3 cycles of treatment with pirtobrutinib from 18 patients …

Parp-1 Selectively Impairs Kras-Driven Phenotypic And Molecular Features In Intrahepatic Cholangiocarcinoma, Friederike L Keggenhoff, Darko Castven, Diana Becker, Stojan Stojkovic, Jovana Castven, Carolin Zimpel, Beate K Straub, Tiemo Gerber, Harald Langer, Patricia Hähnel, Thomas Kindler, Jörg Fahrer, Colm J O'Rourke, Ursula Ehmer, Anna Saborowski, Lichun Ma, Xin Wei Wang, Timo Gaiser, Matthias S Matter, Christian Sina, Stefanie Derer, Ju-Seog Lee, Stephanie Roessler, Bernd Kaina, Jesper B Andersen, Peter R Galle, Jens U Marquardt

Faculty, Staff and Student Publications

Objective: Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer with limited therapeutic options. KRAS mutations are among the most abundant genetic alterations in iCCA associated with poor clinical outcome and treatment response. Recent findings indicate that Poly(ADP-ribose)polymerase1 (PARP-1) is implicated in KRAS-driven cancers, but its exact role in cholangiocarcinogenesis remains undefined.

Design: PARP-1 inhibition was performed in patient-derived and established iCCA cells using RNAi, CRISPR/Cas9 and pharmacological inhibition in KRAS-mutant, non-mutant cells. In addition, Parp-1 knockout mice were combined with iCCA induction by hydrodynamic tail vein injection to evaluate an impact on phenotypic and molecular …

The Kras Mutational Spectrum And Its Clinical Implications In Pancreatic Cancer, Luigi Perelli, Giannicola Genovese, Giulio F Draetta

Faculty, Staff and Student Publications

In this issue of Cancer Cell, McIntyre et al. show that specific mutations in the KRAS proto-oncogene shape clinical progression of pancreatic ductal adenocarcinoma (PDAC). Importantly, they find that the KRASG12R mutation is enriched in early-stage PDAC, and it is characterized by distinctly activated molecular programs.

The Kras Mutational Spectrum And Its Clinical Implications In Pancreatic Cancer, Luigi Perelli, Giannicola Genovese, Giulio F Draetta

Faculty, Staff and Student Publications

In this issue of Cancer Cell, McIntyre et al. show that specific mutations in the KRAS proto-oncogene shape clinical progression of pancreatic ductal adenocarcinoma (PDAC). Importantly, they find that the KRASG12R mutation is enriched in early-stage PDAC, and it is characterized by distinctly activated molecular programs.

Fibrotic Response To Anti-Csf-1r Therapy Potentiates Glioblastoma Recurrence, Spencer S Watson, Anoek Zomer, Nadine Fournier, Joao Lourenco, Manfredo Quadroni, Agnieszka Chryplewicz, Sina Nassiri, Pauline Aubel, Simona Avanthay, Davide Croci, Erik Abels, Marike L D Broekman, Douglas Hanahan, Jason T Huse, Roy T Daniel, Monika E Hegi, Krisztian Homicsko, Giulia Cossu, Andreas F Hottinger, Johanna A Joyce

Faculty, Staff and Student Publications

Glioblastoma recurrence is currently inevitable despite extensive standard-of-care treatment. In preclinical studies, an alternative strategy of targeting tumor-associated macrophages and microglia through CSF-1R inhibition was previously found to regress established tumors and significantly increase overall survival. However, recurrences developed in ∼50% of mice in long-term studies, which were consistently associated with fibrotic scars. This fibrotic response is observed following multiple anti-glioma therapies in different preclinical models herein and in patient recurrence samples. Multi-omics analyses of the post-treatment tumor microenvironment identified fibrotic areas as pro-tumor survival niches that encapsulated surviving glioma cells, promoted dormancy, and inhibited immune surveillance. The fibrotic treatment …

Single-Cell Chromatin Accessibility Reveals Malignant Regulatory Programs In Primary Human Cancers, Laksshman Sundaram, Arvind Kumar, Matthew Zatzman, Adriana Salcedo, Neal Ravindra, Shadi Shams, Bryan H Louie, S Tansu Bagdatli, Matthew A Myers, Shahab Sarmashghi, Hyo Young Choi, Won-Young Choi, Kathryn E Yost, Yanding Zhao, Jeffrey M Granja, Toshinori Hinoue, D Neil Hayes, Andrew Cherniack, Ina Felau, Hani Choudhry, Jean C Zenklusen, Kyle Kai-How Farh, Andrew Mcpherson, Christina Curtis, Peter W Laird, Cancer Genome Atlas Analysis Network, John A Demchok, Liming Yang, Roy Tarnuzzer, Samantha J Caesar-Johnson, Zhining Wang, Ashley S Doane, Ekta Khurana, Mauro A A Castro, Alexander J Lazar, Bradley M Broom, John N Weinstein, Rehan Akbani, Shwetha V Kumar, Benjamin J Raphael, Christopher K Wong, Joshua M Stuart, Rojin Safavi, Christopher C Benz, Benjamin K Johnson, Cindy Kyi, Hui Shen, M Ryan Corces, Howard Y Chang, William J Greenleaf

Faculty, Staff and Student Publications

To identify cancer-associated gene regulatory changes, we generated single-cell chromatin accessibility landscapes across eight tumor types as part of The Cancer Genome Atlas. Tumor chromatin accessibility is strongly influenced by copy number alterations that can be used to identify subclones, yet underlying cis-regulatory landscapes retain cancer type-specific features. Using organ-matched healthy tissues, we identified the "nearest healthy" cell types in diverse cancers, demonstrating that the chromatin signature of basal-like-subtype breast cancer is most similar to secretory-type luminal epithelial cells. Neural network models trained to learn regulatory programs in cancer revealed enrichment of model-prioritized somatic noncoding mutations near cancer-associated genes, suggesting …

90y Sir-Spheres Activity Measurement With New Siros D-Vial Delivery Kit, Benjamin P Lopez, S Cheenu Kappadath

Faculty, Staff and Student Publications

A new 90Y SIR-Spheres delivery kit (SIROS D-vial and shield) has been introduced with a different physical form from the legacy V-Vial kit. Here, we establish the dose calibrator settings and exposure-rate-to-activity conversion factor to assay 90Y SIR-Spheres activity in the new SIROS kit.

Methods: Eight D-vials with initial 90Y activities from 1.2 to 6.6 GBq within acrylic shields were assayed with dose calibrators and exposure-rate meters until activities decayed to approximately 0.1 GBq. The dose calibrator settings resulting in the lowest median activity errors and the best-fit slope of exposure rate versus activity were identified.

Results: SIROS D-vial 90Y …

Neoadjuvant Parpi Or Chemotherapy In Ovarian Cancer Informs Targeting Effector Treg Cells For Homologous-Recombination-Deficient Tumors, Yikai Luo, Yu Xia, Dan Liu, Xiong Li, Huayi Li, Jiahao Liu, Dongchen Zhou, Yu Dong, Xin Li, Yiyu Qian, Cheng Xu, Kangjia Tao, Guannan Li, Wen Pan, Qing Zhong, Xingzhe Liu, Sen Xu, Zhi Wang, Ronghua Liu, Wei Zhang, Wanying Shan, Tian Fang, Siyuan Wang, Zikun Peng, Ping Jin, Ning Jin, Shennan Shi, Yuxin Chen, Mengjie Wang, Xiaofei Jiao, Mengshi Luo, Wenjian Gong, Ya Wang, Yue Yao, Yi Zhao, Xinlin Huang, Xuwo Ji, Zhaoren He, Guangnian Zhao, Rong Liu, Mingfu Wu, Gang Chen, Li Hong, Cocpo Consortium, Ding Ma, Yong Fang, Han Liang, Qinglei Gao

Faculty, Staff and Student Publications

Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) as key responders to HRD …

G Protein Selectivity Profile Of Gpr56/Adgrg1 And Its Effect On Downstream Effectors, Raida Jallouli, Ana L Moreno-Salinas, Andréanne Laniel, Brian Holleran, Charlotte Avet, Joan Jacob, Trang Hoang, Christine Lavoie, Kendra S Carmon, Michel Bouvier, Richard Leduc

Faculty, Staff and Student Publications

GPR56, an adhesion G-protein coupled receptor (aGPCRs) with constitutive and ligand-promoted activity, is involved in many physiological and pathological processes. Whether the receptor's constitutive or ligand-promoted activation occur through the same molecular mechanism, and whether different activation modes lead to functional selectivity between G proteins is unknown. Here we show that GPR56 constitutively activates both G12 and G13. Unlike constitutive activation and activation with 3-α-acetoxydihydrodeoxygedunin (3αDOG), stimulation with an antibody, 10C7, directed against GPR56's extracellular domain (ECD) led to an activation that favors G13 over G12. An autoproteolytically deficient mutant, GPR56-T383A, was also activated by 10C7 indicating that the tethered …

Parasitic Contamination Of Soil In The Southern United States, Christine Crudo Blackburn, Sally Mingshuang Yan, David Mccormick, Lauren Nicholas Herrera, Roumen Borilov Iordanov, Mark Daniel Bailey, Maria Elena Bottazzi, Peter J Hotez, Rojelio Mejia

Faculty, Staff and Students Publications

Parasites are generally associated with lower income countries in tropical and subtropical areas. Still, they are also prevalent in low-income communities in the southern United States. Studies characterizing the epidemiology of parasites in the United States are limited, resulting in little comprehensive understanding of the problem. This study investigated the environmental contamination of parasites in the southern United States by determining each parasite's contamination rate and burden in five low-income communities. A total of 499 soil samples of approximately 50 g were collected from public parks and private residences in Alabama, Louisiana, Mississippi, South Carolina, and Texas. A technique using …

Tomivosertib Reduces Ectopic Activity In Dorsal Root Ganglion Neurons From Patients With Radiculopathy, Yan Li, Megan L Uhelski, Robert Y North, Juliet M Mwirigi, Claudio E Tatsui, Kathleen E Mcdonough, Juan P Cata, German Corrales, Greg Dussor, Theodore J Price, Patrick M Dougherty

Faculty, Staff and Student Publications

Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in patients suffering from this largely untreated disease. While many intracellular signalling mechanisms have been examined in preclinical models that drive spontaneous activity, none have been tested directly on spontaneously active human nociceptors.

Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we showed that inhibition of mitogen-activated protein kinase interacting kinase (MNK) with tomivosertib (eFT508, 25 nM) reversibly suppresses spontaneous activity in human sensory neurons that are likely nociceptors based on size and action potential characteristics associated with painful dermatomes within minutes of treatment. …

Angiotensin-(1-9) Retro-Enantiomer Peptide With Cardioprotective Activity, Yvo Flores, Gerald Zapata-Torres, Agustín Nuñez, Douglas J Matthies, Larissa Alemán, Carolina Hernández-Fuentes, Gina Sánchez, Eyleen Araya, Fanny Guzman, Zully Pedrozo, Salvador Guardiola, Mónica Varese, Ernest Giralt, Ivan Maslov, Mark Del Borgo, Robert E Widdop, Silvana Valdebenito, Eliseo A Eugenin, Mario Chiong, Joseph A Hill, María Paz Ocaranza, Marcelo J Kogan, Sergio Lavandero

Faculty, Staff and Student Publications

No abstract provided.

The Cancer-Associated Secretory Phenotype: A New Frontier In Targeted Therapeutics, Xiaochao Tan, Guan-Yu Xiao, Priyam Banerjee, Shike Wang, Jonathan M Kurie

Faculty, Staff and Student Publications

No abstract provided.

Glycemic Control In Diabetic Patients Improved Overall Lung Cancer Survival Across Diverse Populations, Wayne Y Wu, Brian Luke, Xiao-Cheng Wu, J Jack Lee, Yong Yi, Samuel C Okpechi, Barry Gause, Paras Mehta, Steven I Sherman, Augusto Ochoa, Ethan Dmitrovsky, Xi Liu

Faculty, Staff and Student Publications

Background: The consequence of diabetes on lung cancer overall survival (OS) is debated. This retrospective study used 2 large lung cancer databases to assess comprehensively diabetes effects on lung cancer OS in diverse demographic populations, including health disparity.

Methods: The University of Texas MD Anderson Cancer Center database (32 643 lung cancer patients with 11 973 patients with diabetes) was extracted from electronic health records (EHRs) using natural language processing (NLP). Associations were between diabetes and lung cancer prognostic features (age, sex, race, body mass index [BMI], insurance status, smoking, stage, and histopathology). Hemoglobin A1C (HgbA1c) and glucose levels assessed …

Scintruler: Guiding The Integration Of Multiple Single-Cell Rna-Seq Datasets With A Novel Statistical Metric, Yue Lyu, Steven H Lin, Hao Wu, Ziyi Li

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Motivation: The growing number of single-cell RNA-seq (scRNA-seq) studies highlights the potential benefits of integrating multiple datasets, such as augmenting sample sizes and enhancing analytical robustness. Inherent diversity and batch discrepancies within samples or across studies continue to pose significant challenges for computational analyses. Questions persist in practice, lacking definitive answers: Should we use a specific integration method or opt for simply merging the datasets during joint analysis? Among all the existing data integration methods, which one is more suitable in specific scenarios?

Result: To fill the gap, we introduce SCIntRuler, a novel statistical metric for guiding the integration of …

Lifr Regulates Cholesterol-Driven Bidirectional Hepatocyte-Neutrophil Cross-Talk To Promote Liver Regeneration, Yalan Deng, Zilong Zhao, Marisela Sheldon, Yang Zhao, Hongqi Teng, Consuelo Martinez, Jie Zhang, Chunru Lin, Yutong Sun, Fan Yao, Michael A Curran, Hao Zhu, Li Ma

Faculty, Staff and Student Publications

Liver regeneration is under metabolic and immune regulation. Despite increasing recognition of the involvement of neutrophils in regeneration, it is unclear how the liver signals to the bone marrow to release neutrophils after injury and how reparative neutrophils signal to hepatocytes to reenter the cell cycle. Here we report that loss of the liver tumour suppressor Lifr in mouse hepatocytes impairs, whereas overexpression of leukaemia inhibitory factor receptor (LIFR) promotes liver repair and regeneration after partial hepatectomy or toxic injury. In response to physical or chemical damage to the liver, LIFR from hepatocytes promotes the secretion of cholesterol and CXCL1 …

Panel Stacking Is A Threat To Consensus Statement Validity, Kasper P Kepp, Preben Aavitsland, Marcel Ballin, Francois Balloux, Stefan Baral, Kevin Bardosh, Howard Bauchner, Eran Bendavid, Raj Bhopal, Daniel T Blumstein, Paolo Boffetta, Florence Bourgeois, Adam Brufsky, Peter J Collignon, Sally Cripps, Ioana A Cristea, Nigel Curtis, Benjamin Djulbegovic, Oliver Faude, Maria Elena Flacco, Gordon H Guyatt, George Hajishengallis, Lars G Hemkens, Tammy Hoffmann, Ari R Joffe, Terry P Klassen, Despina Koletsi, Dimitrios P Kontoyiannis, Ellen Kuhl, Carlo La Vecchia, Tea Lallukka, John Lambris, Michael Levitt, Spyros Makridakis, Helena C Maltezou, Lamberto Manzoli, Ana Marusic, Clio Mavragani, David Moher, Ben W Mol, Taulant Muka, Florian Naudet, Paul W Noble, Anna Nordström, Peter Nordström, Nikolaos Pandis, Stefania Papatheodorou, Chirag J Patel, Irene Petersen, Stefan Pilz, Nikolaus Plesnila, Anne-Louise Ponsonby, Manuel A Rivas, Andrea Saltelli, Manuel Schabus, Michaéla C Schippers, Holger Schünemann, Marco Solmi, Andreas Stang, Hendrik Streeck, Joachim P Sturmberg, Lehana Thabane, Brett D Thombs, Athanasios Tsakris, Simon N Wood, John P A Ioannidis

Faculty, Staff and Student Publications

Consensus statements can be very influential in medicine and public health. Some of these statements use systematic evidence synthesis but others fail on this front. Many consensus statements use panels of experts to deduce perceived consensus through Delphi processes. We argue that stacking of panel members toward one particular position or narrative is a major threat, especially in absence of systematic evidence review. Stacking may involve financial conflicts of interest, but nonfinancial conflicts of strong advocacy can also cause major bias. Given their emerging importance, we describe here how such consensus statements may be misleading, by analyzing in depth a …

Long-Term Results Of The Sequential Combination Of Cladribine And Rituximab In Hairy Cell Leukemia, Jennifer Marvin-Peek, Wei-Ying Jen, Hagop M Kantarjian, David Mccue, Fadi G Haddad, William Wierda, Alessandra Ferrajoli, Jan Burger, Tareq Abusab, Jeffrey Jorgensen, Sa A Wang, Keyur Patel, Sanam Loghavi, Susan O'Brien, Farhad Ravandi

Faculty, Staff and Student Publications

We report on the long-term efficacy and safety of a phase 2 trial of sequential cladribine and rituximab in hairy cell leukemia (HCL). One-hundred and thirty-nine patients were enrolled: 111 in the frontline setting, 18 in first relapse, and 10 with variant HCL (HCLv). A complete response (CR) was achieved in 133 of 137 evaluable participants (97%) with measurable residual disease (MRD) negativity in 102 (77%). MRD status was not associated with significant differences in event free survival (EFS) or overall survival (OS). With a median follow up of 7·8 years (range: 0·40–18·8), eight patients have experienced disease relapse (5·8%), …

Radiation Therapy Quality Assurance Analysis Of Alliance A021501: Preoperative Mfolfirinox Or Mfolfirinox Plus Hypofractionated Radiation Therapy For Borderline Resectable Adenocarcinoma Of The Pancreas, Leila T Tchelebi, Diana Segovia, Koren Smith, Qian Shi, T J Fitzgerald, Michael D Chuong, Tyler J Zemla, Eileen M O'Reilly, Jeffrey A Meyerhardt, Eugene J Koay, Jessica Lowenstein, Ardaman Shergill, Matthew H G Katz, Joseph M Herman

Faculty, Staff and Student Publications

Purpose: Alliance A021501 is the first randomized trial to evaluate stereotactic body radiation therapy (SBRT) for borderline resectable pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant chemotherapy. In this post hoc study, we reviewed the quality of radiation therapy (RT) delivered.

Methods and materials: SBRT (6.6 Gy × 5) was intended but hypofractionated RT (5 Gy × 5) was permitted if SBRT specifications could not be met. Institutional credentialing through the National Cancer Institute-funded Imaging and Radiation Oncology Core (IROC) was required. Rigorous RT quality assurance (RT QA) was mandated, including pretreatment review by a radiation oncologist. Revisions were required for unacceptable …