Genetic Phenomena Commons^™

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 …

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. …

Immunoactive Signatures Of Circulating Trna- And Rrna-Derived Rnas In Chronic Obstructive Pulmonary Disease, Megumi Shigematsu, Takuya Kawamura, Deepak Deshpande, Yohei Kirino

Computational Medicine Center Faculty Papers

Chronic obstructive pulmonary disease (COPD) is the most prevalent lung disease, and macrophages play a central role in the inflammatory response in COPD. We here report a comprehensive characterization of circulating short non-coding RNAs (sncRNAs) in plasma from patients with COPD. While circulating sncRNAs are increasingly recognized for their regulatory roles and biomarker potential in various diseases, the conventional RNA sequencing (RNA-seq) method cannot fully capture these circulating sncRNAs due to their heterogeneous terminal structures. By pre-treating the plasma RNAs with T4 polynucleotide kinase, which converts all RNAs to those with RNA-seq susceptible ends (5′-phosphate and 3′-hydroxyl), we comprehensively sequenced …

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

Faculty, Staff and Student Publications

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 …

Dominant Missense Variants In Srebf2 Are Associated With Complex Dermatological, Neurological, And Skeletal Abnormalities, Matthew J Moulton, Kristhen Atala, Yiming Zheng, Debdeep Dutta, Dorothy K Grange, Wen-Wen Lin, Daniel J Wegner, Jennifer A Wambach, Angela L Duker, Michael B Bober, Lisa Kratz, Carol A Wise, Ila Oxendine, Anas Khanshour, Undiagnosed Diseases Network, Michael F Wangler, Shinya Yamamoto, F Sessions Cole, Jonathan Rios, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

Purpose: We identified 2 individuals with de novo variants in SREBF2 that disrupt a conserved site 1 protease (S1P) cleavage motif required for processing SREBP2 into its mature transcription factor. These individuals exhibit complex phenotypic manifestations that partially overlap with sterol regulatory element binding proteins (SREBP) pathway-related disease phenotypes, but SREBF2-related disease has not been previously reported. Thus, we set out to assess the effects of SREBF2 variants on SREBP pathway activation.

Methods: We undertook ultrastructure and gene expression analyses using fibroblasts from an affected individual and utilized a fly model of lipid droplet (LD) formation to investigate the consequences …

Phase Ii Study Of Samotolisib In Children And Young Adults With Tumors Harboring Phosphoinositide 3-Kinase/Mammalian Target Of Rapamycin Pathway Alterations: Pediatric Match Apec1621d, Theodore W Laetsch, Kathleen Ludwig, P Mickey Williams, Sinchita Roy-Chowdhuri, David R Patton, Brent Coffey, Joel M Reid, Jin Piao, Lauren Saguilig, Todd A Alonzo, Stacey L Berg, Joyce Mhlanga, Elizabeth Fox, Brenda J Weigel, Douglas S Hawkins, Margaret M Mooney, Naoko Takebe, James V Tricoli, Katherine A Janeway, Nita L Seibel, Donald Williams Parsons

Faculty, Staff and Students Publications

Purpose: Patients age 1-21 years with relapsed or refractory solid and CNS tumors were assigned to phase II studies of molecularly targeted therapies on the National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial. Patients whose tumors harbored predefined genetic alterations in the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway and lacked mitogen-activated protein kinase pathway activating alterations were treated with the PI3K/mTOR inhibitor samotolisib.

Methods: Patients received samotolisib twice daily in 28-day cycles until disease progression or unacceptable toxicity. A rolling 6 limited dose escalation was performed as, to our knowledge, this was …

Arcuate Dopaminergic/Gabaergic Neurons Project Within The Hypothalamus And To The Median Eminence, Somya Mittal, Benjamin R Arenkiel, Ariel M Lyons-Warren

Duncan NRI Faculty and Staff Publications

Cotransmission, meaning the release of multiple neurotransmitters from one synapse, allows for increased diversity of signaling in the brain. Dopamine (DA) and γ-aminobutyric acid (GABA) are known to coexpress in many regions such as the olfactory bulb and the ventral tegmental area. Tuberoinfundibular dopaminergic neurons (TIDA) in the arcuate nucleus of the hypothalamus (Arc) project to the median eminence (ME) and regulate prolactin release from the pituitary, and prior work suggests dopaminergic Arc neurons also cotransmit GABA. However, the extent of cotransmission, and the projection patterns of these neurons have not been fully revealed. Here, we used a genetic intersectional …

Mondoa And Aki And Aki-To-Ckd Transition, Shihomi Maeda, Shinsuke Sakai, Yoshitsugu Takabatake, Takeshi Yamamoto, Satoshi Minami, Jun Nakamura, Tomoko Namba-Hamano, Atsushi Takahashi, Jun Matsuda, Hiroaki Yonishi, Sho Matsui, Atsuhiro Imai, Ryuya Edahiro, Hitomi Yamamoto-Imoto, Isao Matsui, Seiji Takashima, Ryoichi Imamura, Norio Nonomura, Motoko Yanagita, Yukinori Okada, Andrea Ballabio, Shuhei Nakamura, Tamotsu Yoshimori, Yoshitaka Isaka

Duncan NRI Faculty and Staff Publications

Key Points:

1. The expression of MondoA was decreased in the renal tubules of patients with CKD.

2. Genetic ablation of MondoA in proximal tubules inhibited autophagy and increased vulnerability to AKI through increased expression of Rubicon.

3. MondoA ablation during the recovery phase after ischemia-reperfusion aggravated kidney injury through downregulation of the transcription factor EB-peroxisome proliferator-activated receptor-γ coactivator-1α axis.

Background: Elderly individuals and patients with CKD are at a higher risk of AKI. The transcription factor MondoA is downregulated in the kidneys of aged individuals or patients with AKI; however, its roles in AKI development and the AKI-to-CKD transition remain …

The Cerebellum Modulates Thirst, Ila Mishra, Bing Feng, Bijoya Basu, Amanda M Brown, Linda H Kim, Tao Lin, Mir Abbas Raza, Amelia Moore, Abigayle Hahn, Samantha Bailey, Alaina Sharp, Juan C Bournat, Claire Poulton, Brian Kim, Amos Langsner, Aaron Sathyanesan, Roy V Sillitoe, Yanlin He, Atul R Chopra

Duncan NRI Faculty and Staff Publications

The cerebellum, a phylogenetically ancient brain region, has long been considered strictly a motor control structure. Recent studies have implicated the cerebellum in cognition, sensation, emotion and autonomic function, making it an important target for further investigation. Here, we show that cerebellar Purkinje neurons in mice are activated by the hormone asprosin, leading to enhanced thirst, and that optogenetic or chemogenetic activation of Purkinje neurons induces rapid manifestation of water drinking. Purkinje neuron-specific asprosin receptor (Ptprd) deletion results in reduced water intake without affecting food intake and abolishes asprosin's dipsogenic effect. Purkinje neuron-mediated motor learning and coordination were unaffected by …

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 …

Magnetic Particle Imaging Enables Nonradioactive Quantitative Sentinel Lymph Node Identification: Feasibility Proof In Murine Models, Olivia C Sehl, Kelvin Guo, Abdul Rahman Mohtasebzadeh, Petrina Kim, Benjamin Fellows, Marcela Weyhmiller, Patrick W Goodwill, Max Wintermark, Stephen Y Lai, Paula J Foster, Joan M Greve

Faculty, Staff and Student Publications

Background: Sentinel lymph node biopsy (SLNB) is an important cancer diagnostic staging procedure. Conventional SLNB procedures with 99mTc radiotracers and scintigraphy are constrained by tracer half-life and, in some cases, insufficient image resolution. Here, we explore an alternative magnetic (nonradioactive) image-guided SLNB procedure.

Purpose: To demonstrate that magnetic particle imaging (MPI) lymphography can sensitively, specifically, and quantitatively identify and map sentinel lymph modes (SLNs) in murine models in multiple regional lymphatic basins.

Materials and methods: Iron oxide nanoparticles were administered intradermally to healthy C57BL/6 mice (male, 12-week-old, n = 5). The nanoparticles (0.675 mg Fe/kg) were injected into the tongue, …

Strategies For The Development Of Metalloimmunotherapies, Xiaoqi Sun, Xingwu Zhou, Xiaoyue Shi, Omar A Abed, Xinran An, Yu Leo Lei, James J Moon

Faculty, Staff and Student Publications

Metal ions play crucial roles in the regulation of immune pathways. In fact, metallodrugs have a long record of accomplishment as effective treatments for a wide range of diseases. Here we argue that the modulation of interactions of metal ions with molecules and cells involved in the immune system forms the basis of a new class of immunotherapies. By examining how metal ions modulate the innate and adaptive immune systems, as well as host-microbiota interactions, we discuss strategies for the development of such metalloimmunotherapies for the treatment of cancer and other immune-related diseases.

Co-Targeting Sos1 Enhances The Antitumor Effects Of Krasg12c Inhibitors By Addressing Intrinsic And Acquired Resistance, Venu Thatikonda, Hengyu Lyu, Sabine Jurado, Kaja Kostyrko, Christopher A Bristow, Christoph Albrecht, Donat Alpar, Heribert Arnhof, Oliver Bergner, Karin Bosch, Ningping Feng, Sisi Gao, Daniel Gerlach, Michael Gmachl, Melanie Hinkel, Simone Lieb, Astrid Jeschko, Annette A Machado, Thomas Madensky, Ethan D Marszalek, Mikhila Mahendra, Gabriella Melo-Zainzinger, Jessica M Molkentine, Philipp A Jaeger, David H Peng, Robyn L Schenk, Alexey Sorokin, Sandra Strauss, Francesca Trapani, Scott Kopetz, Christopher P Vellano, Mark Petronczki, Norbert Kraut, Timothy P Heffernan, Joseph R Marszalek, Mark Pearson, Irene C Waizenegger, Marco H Hofmann

Faculty, Staff and Student Publications

Combination approaches are needed to strengthen and extend the clinical response to KRASG12C inhibitors (KRASG12Ci). Here, we assessed the antitumor responses of KRASG12C mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRASG12C inhibitor, adagrasib. We found that responses to BI-3406 plus adagrasib were stronger than to adagrasib alone, comparable to adagrasib with SHP2 (SHP2i) or EGFR inhibitors and correlated with stronger suppression of RAS-MAPK signaling. BI-3406 plus adagrasib treatment also delayed the emergence of acquired resistance and elicited antitumor responses from adagrasib-resistant models. Resistance to KRASG12Ci seemed to be driven by …

Rewiring Cancer Cell Death: Lpcat1 Shapes Lipid Composition And Ferroptosis Resistance, Hyemin Lee, Li Zhuang, Boyi Gan

Faculty, Staff and Student Publications

No abstract provided.