Medical Specialties Commons^™

Phase 1b Study Of Intraperitoneal Ipilimumab And Nivolumab In Patients With Recurrent Gynecologic Malignancies With Peritoneal Carcinomatosis, Anne Knisely, Emily Hinchcliff, Bryan Fellman, Ann Mosley, Kathryn Lito, Sara Hull, Shannon N Westin, Anil K Sood, Kathleen M Schmeler, Jolyn S Taylor, Steven Y Huang, Rahul A Sheth, Karen H Lu, Amir A Jazaeri

Faculty, Staff and Student Publications

Background: Intravenous immune checkpoint blockade (ICB) has shown poor response rates in recurrent gynecologic malignancies. Intraperitoneal (i.p.) ICB may result in enhanced T cell activation and anti-tumor immunity.

Methods: In this phase 1b study, registered at Clinical.

Trials: gov (NCT03508570), initial cohorts received i.p. nivolumab monotherapy, and subsequent cohorts received combination i.p. nivolumab every 2 weeks and i.p. ipilimumab every 6 weeks, guided by a Bayesian design. The primary objective was determination of the recommended phase 2 dose (RP2D) of the combination. Secondary outcomes included toxicity, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).

Findings: …

Combined Deletion Of Men1, Atrx And Pten Triggers Development Of High-Grade Pancreatic Neuroendocrine Tumors In Mice, Mary Esmeralda Fuentes, Xiaoyin Lu, Natasha M Flores, Simone Hausmann, Pawel K Mazur

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Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of tumors that exhibit an unpredictable and broad spectrum of clinical presentations and biological aggressiveness. Surgical resection is still the only curative therapeutic option for localized PanNET, but the majority of patients are diagnosed at an advanced and metastatic stage with limited therapeutic options. Key factors limiting the development of new therapeutics are the extensive heterogeneity of PanNETs and the lack of appropriate clinically relevant models. In that context, genomic sequencing of human PanNETs revealed recurrent mutations and structural alterations in several tumor suppressors. Here, we demonstrated that combined loss of MEN1, …

Miniature Battery-Free Epidural Cortical Stimulators, Joshua E Woods, Amanda L Singer, Fatima Alrashdan, Wendy Tan, Chunfeng Tan, Sunil A Sheth, Sameer A Sheth, Jacob T Robinson

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Miniaturized neuromodulation systems could improve the safety and reduce the invasiveness of bioelectronic neuromodulation. However, as implantable bioelectronic devices are made smaller, it becomes difficult to store enough power for long-term operation in batteries. Here, we present a battery-free epidural cortical stimulator that is only 9 millimeters in width yet can safely receive enough wireless power using magnetoelectric antennas to deliver 14.5-volt stimulation bursts, which enables it to stimulate cortical activity on-demand through the dura. The device has digitally programmable stimulation output and centimeter-scale alignment tolerances when powered by an external transmitter. We demonstrate that this device has enough power …

Enhancing Nsclc Recurrence Prediction With Pet/Ct Habitat Imaging, Ctdna, And Integrative Radiogenomics-Blood Insights, Sheeba J Sujit, Muhammad Aminu, Tatiana V Karpinets, Pingjun Chen, Maliazurina B Saad, Morteza Salehjahromi, John D Boom, Mohamed Qayati, James M George, Haley Allen, Mara B Antonoff, Lingzhi Hong, Xin Hu, Simon Heeke, Hai T Tran, Xiuning Le, Yasir Y Elamin, Mehmet Altan, Natalie I Vokes, Ajay Sheshadri, Julie Lin, Jianhua Zhang, Yang Lu, Carmen Behrens, Myrna C B Godoy, Carol C Wu, Joe Y Chang, Caroline Chung, David A Jaffray, Ignacio I Wistuba, J Jack Lee, Ara A Vaporciyan, Don L Gibbons, John Heymach, Jianjun Zhang, Tina Cascone, Jia Wu

Faculty, Staff and Student Publications

While we recognize the prognostic importance of clinicopathological measures and circulating tumor DNA (ctDNA), the independent contribution of quantitative image markers to prognosis in non-small cell lung cancer (NSCLC) remains underexplored. In our multi-institutional study of 394 NSCLC patients, we utilize pre-treatment computed tomography (CT) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) to establish a habitat imaging framework for assessing regional heterogeneity within individual tumors. This framework identifies three PET/CT subtypes, which maintain prognostic value after adjusting for clinicopathologic risk factors including tumor volume. Additionally, these subtypes complement ctDNA in predicting disease recurrence. Radiogenomics analysis unveil the molecular underpinnings of these …

‘Joining The Dots: Linking Prenatal Drug Exposure To Childhood And Adolescence’ – Research Protocol Of A Population Cohort Study, Kate Lawler, Mithilesh Dronavalli, Andrew Page, Evelyn Lee, Hannah Uebel, Barbara Bajuk, Lucinda Burns, Michelle Dickson, Charles Green, Lauren Dicair, John Eastwood, Ju Lee Oei

Faculty, Staff and Student Publications

INTRODUCTION: Prenatal drug exposure (PDE) is one of the most important causes of child harm, but comprehensive information about the long-term outcomes of the families is difficult to ascertain. The

METHODS AND ANALYSIS: Information from routinely collected administrative databases was linked for all births registered in New South Wales (NSW), Australia between 1 July 2001 and 31 December 2020 (n=1 834 550). Outcomes for seven mutually exclusive groups of children with varying prenatal exposure to maternal substances of addiction, including smoking, alcohol, prescription/illicit drugs and neonatal abstinence syndrome will be assessed. Key exposure measures include maternal drug use type, maternal …

‘Joining The Dots: Linking Prenatal Drug Exposure To Childhood And Adolescence’ – Research Protocol Of A Population Cohort Study, Kate Lawler, Mithilesh Dronavalli, Andrew Page, Evelyn Lee, Hannah Uebel, Barbara Bajuk, Lucinda Burns, Michelle Dickson, Charles Green, Lauren Dicair, John Eastwood, Ju Lee Oei

Faculty, Staff and Student Publications

INTRODUCTION: Prenatal drug exposure (PDE) is one of the most important causes of child harm, but comprehensive information about the long-term outcomes of the families is difficult to ascertain. The

METHODS AND ANALYSIS: Information from routinely collected administrative databases was linked for all births registered in New South Wales (NSW), Australia between 1 July 2001 and 31 December 2020 (n=1 834 550). Outcomes for seven mutually exclusive groups of children with varying prenatal exposure to maternal substances of addiction, including smoking, alcohol, prescription/illicit drugs and neonatal abstinence syndrome will be assessed. Key exposure measures include maternal drug use type, maternal …

Nardilysin-Regulated Scission Mechanism Activates Polo-Like Kinase 3 To Suppress The Development Of Pancreatic Cancer, Jie Fu, Jianhua Ling, Ching-Fei Li, Chi-Lin Tsai, Wenjuan Yin, Junwei Hou, Ping Chen, Yu Cao, Ya'an Kang, Yichen Sun, Xianghou Xia, Zhou Jiang, Kenei Furukawa, Yu Lu, Min Wu, Qian Huang, Jun Yao, David H Hawke, Bih-Fang Pan, Jun Zhao, Jiaxing Huang, Huamin Wang, E I Mustapha Bahassi, Peter J Stambrook, Peng Huang, Jason B Fleming, Anirban Maitra, John A Tainer, Mien-Chie Hung, Chunru Lin, Paul J Chiao

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) develops through step-wise genetic and molecular alterations including Kras mutation and inactivation of various apoptotic pathways. Here, we find that development of apoptotic resistance and metastasis of KrasG12D-driven PDAC in mice is accelerated by deleting Plk3, explaining the often-reduced Plk3 expression in human PDAC. Importantly, a 41-kDa Plk3 (p41Plk3) that contains the entire kinase domain at the N-terminus (1-353 aa) is activated by scission of the precursor p72Plk3 at Arg354 by metalloendopeptidase nardilysin (NRDC), and the resulting p32Plk3 C-terminal Polo-box domain (PBD) is removed by proteasome degradation, preventing the inhibition of p41Plk3 by PBD. We find …

Genomes Of Bacteroides Ovatus, B Cellulosilyticus, B Uniformis, Phocaeicola Vulgatus, And P Dorei Isolated From Gut Cavernous Fistulous Tract Micropathologies In Crohn’S Disease, Vaidhvi Singh, Gail West, Claudio Fiocchi, Fabio Cominelli, Caryn E Good, Michael R Jacobs, Alexander Rodriguez-Palacios

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Surgically removed bowels from Crohn's disease patients exhibit a novel form of micropathologies known as cavernous fistulous tract microlesions (CavFT), resembling fissures. We announce the genomes/plasmids and antimicrobial resistance genes of six CavFT bacterial isolates representing the Bacteroidota genera Bacteroides and Phocaeicola. Plasmids were identified in Bacteroides cellulosilyticus and Phocaeicola vulgatus.

A Novel Lentiviral Vector-Based Approach To Generate Chimeric Antigen Receptor T Cells Targeting, Pappanaicken R Kumaresan, Sebastian Wurster, Karishma Bavisi, Thiago Aparecido Da Silva, Paul Hauser, Jordan Kinnitt, Nathaniel D Albert, Uddalak Bharadwaj, Sattva Neelapu, Dimitrios P Kontoyiannis

Faculty, Staff and Student Publications

Invasive aspergillosis (IA) is a common and deadly mold infection in immunocompromised patients. As morbidity and mortality of IA are primarily driven by poor immune defense, adjunct immunotherapies, such as chimeric antigen receptor (CAR) T cells, are direly needed. Here, we propose a novel approach to generate Aspergillus fumigatus (AF)-CAR T cells using the single-chain variable fragment domain of monoclonal antibody AF-269-5 and a lentiviral vector system. These cells successfully targeted mature hyphal filaments of representative clinical and reference AF isolates and elicited a potent release of cytotoxic effectors and type 1 T cell cytokines. Furthermore, AF-CAR T cells generated …

Nivolumab Plus Chemotherapy In Epidermal Growth Factor Receptor-Mutated Metastatic Non-Small-Cell Lung Cancer After Disease Progression On Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: Final Results Of Checkmate 722, Tony Mok, Kazuhiko Nakagawa, Keunchil Park, Yuichiro Ohe, Nicolas Girard, Hye Ryun Kim, Yi-Long Wu, Justin Gainor, Se-Hoon Lee, Chao-Hua Chiu, Sang-We Kim, Cheng-Ta Yang, Chien Liang Wu, Lin Wu, Meng-Chih Lin, Jens Samol, Kazuya Ichikado, Mengzhao Wang, Xiaoqing Zhang, Judi Sylvester, Sunney Li, Ann Forslund, James Chih-Hsin Yang

Faculty, Staff and Student Publications

PURPOSE: The phase III CheckMate 722 trial (ClinicalTrials.gov identifier: NCT02864251) evaluated nivolumab plus chemotherapy versus chemotherapy in patients with epidermal growth factor receptor (

METHODS: Patients with disease progression after first- or second-generation EGFR TKI therapy (without

RESULTS: Overall, 294 patients were randomly assigned. At final analysis (median follow-up, 38.1 months), PFS was not significantly improved with nivolumab plus chemotherapy versus chemotherapy (median, 5.6

CONCLUSION: Nivolumab plus chemotherapy did not significantly improve PFS versus chemotherapy in patients with

Fusobacterium Nucleatum Subsp Animalis Comes To The Spotlight In Oral Diseases, Bibek G C, Peng Zhou, Chenggang Wu

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Krieger et al.'s study in this issue of Cell Host & Microbe reveals that Fusobacterium nucleatum subsp. animalis strains, previously underestimated, are significant in disease-affected oral areas. This challenges the long-held notion of the dominance of Fusobacterium nucleatum subsp. nucleatum, reshaping our understanding of Fusobacterium distribution in the oral microbiome.

Fusobacterium Nucleatum Subsp Animalis Comes To The Spotlight In Oral Diseases, Bibek G C, Peng Zhou, Chenggang Wu

Faculty, Staff and Student Publications

Krieger et al.'s study in this issue of Cell Host & Microbe reveals that Fusobacterium nucleatum subsp. animalis strains, previously underestimated, are significant in disease-affected oral areas. This challenges the long-held notion of the dominance of Fusobacterium nucleatum subsp. nucleatum, reshaping our understanding of Fusobacterium distribution in the oral microbiome.

A Revamped Rat Reference Genome Improves The Discovery Of Genetic Diversity In Laboratory Rats, Tristan V De Jong, Yanchao Pan, Pasi Rastas, Daniel Munro, Monika Tutaj, Huda Akil, Chris Benner, Denghui Chen, Apurva S Chitre, William Chow, Vincenza Colonna, Clifton L Dalgard, Wendy M Demos, Peter A Doris, Erik Garrison, Aron M Geurts, Hakan M Gunturkun, Victor Guryev, Thibaut Hourlier, Kerstin Howe, Jun Huang, Ted Kalbfleisch, Panjun Kim, Ling Li, Spencer Mahaffey, Fergal J Martin, Pejman Mohammadi, Ayse Bilge Ozel, Oksana Polesskaya, Michal Pravenec, Pjotr Prins, Jonathan Sebat, Jennifer R Smith, Leah C Solberg Woods, Boris Tabakoff, Alan Tracey, Marcela Uliano-Silva, Flavia Villani, Hongyang Wang, Burt M Sharp, Francesca Telese, Zhihua Jiang, Laura Saba, Xusheng Wang, Terence D Murphy, Abraham A Palmer, Anne E Kwitek, Melinda R Dwinell, Robert W Williams, Jun Z Li, Hao Chen

Faculty, Staff and Student Publications

The seventh iteration of the reference genome assembly for Rattus norvegicus-mRatBN7.2-corrects numerous misplaced segments and reduces base-level errors by approximately 9-fold and increases contiguity by 290-fold compared with its predecessor. Gene annotations are now more complete, improving the mapping precision of genomic, transcriptomic, and proteomics datasets. We jointly analyzed 163 short-read whole-genome sequencing datasets representing 120 laboratory rat strains and substrains using mRatBN7.2. We defined ∼20.0 million sequence variations, of which 18,700 are predicted to potentially impact the function of 6,677 genes. We also generated a new rat genetic map from 1,893 heterogeneous stock rats and annotated transcription start sites …

Synovial Fibroblast Gene Expression Is Associated With Sensory Nerve Growth And Pain In Rheumatoid Arthritis, Zilong Bai, Nicholas Bartelo, Maryam Aslam, Elisabeth A Murphy, Caryn R Hale, Nathalie E Blachere, Salina Parveen, Edoardo Spolaore, Edward Dicarlo, Ellen M Gravallese, Melanie H Smith, Accelerating Medicines Partnership Ra/Sle Network, Mayu O Frank, Caroline S Jiang, Haotan Zhang, Christina Pyrgaki, Myles J Lewis, Shafaq Sikandar, Costantino Pitzalis, Joseph B Lesnak, Khadijah Mazhar, Theodore J Price, Anne-Marie Malfait, Rachel E Miller, Fan Zhang, Susan Goodman, Robert B Darnell, Fei Wang, Dana E Orange

Faculty, Staff and Student Publications

It has been presumed that rheumatoid arthritis (RA) joint pain is related to inflammation in the synovium; however, recent studies reveal that pain scores in patients do not correlate with synovial inflammation. We developed a machine-learning approach (graph-based gene expression module identification or GbGMI) to identify an 815-gene expression module associated with pain in synovial biopsy samples from patients with established RA who had limited synovial inflammation at arthroplasty. We then validated this finding in an independent cohort of synovial biopsy samples from patients who had early untreated RA with little inflammation. Single-cell RNA sequencing analyses indicated that most of …

Funcpep V20: An Updated Database Of Functional Short Peptides Translated From Non-Coding Rnas, Swati Mohapatra, Anik Banerjee, Paola Rausseo, Mihnea P Dragomir, Ganiraju C Manyam, Bradley M Broom, George A Calin

Faculty, Staff and Student Publications

Over the past decade, there have been reports of short novel functional peptides (less than 100 aa in length) translated from so-called non-coding RNAs (ncRNAs) that have been characterized using mass spectrometry (MS) and large-scale proteomics studies. Therefore, understanding the bivalent functions of some ncRNAs as transcripts that encode both functional RNAs and short peptides, which we named ncPEPs, will deepen our understanding of biology and disease. In 2020, we published the first database of functional peptides translated from non-coding RNAs-FuncPEP. Herein, we have performed an update including the newly published ncPEPs from the last 3 years along with the …

Wnk Kinase Is A Vasoactive Chloride Sensor In Endothelial Cells, Tessa A C Garrud, Briar Bell, Alejandro Mata-Daboin, Dieniffer Peixoto-Neves, Daniel M Collier, Julio F Cordero-Morales, Jonathan H Jaggar

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Endothelial cells (ECs) line the wall of blood vessels and regulate arterial contractility to tune regional organ blood flow and systemic pressure. Chloride (Cl-) is the most abundant anion in ECs and the Cl- sensitive With-No-Lysine (WNK) kinase is expressed in this cell type. Whether intracellular Cl- signaling and WNK kinase regulate EC function to alter arterial contractility is unclear. Here, we tested the hypothesis that intracellular Cl- signaling in ECs regulates arterial contractility and examined the signaling mechanisms involved, including the participation of WNK kinase. Our data obtained using two-photon microscopy and cell-specific inducible knockout mice indicated that acetylcholine, …

The Role Of Computational Methods In Cardiovascular Medicine: A Narrative Review, Salvatore Facciorusso, Stefania Spina, Alessandro Picelli, Alessio Baricich, Gerard E Francisco, Franco Molteni, Jörg Wissel, Andrea Santamato

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Botulinum toxin type-A (BoNT-A) has emerged as a key therapeutic agent for the management of spasticity. This paper presents a comprehensive bibliometric and visual analysis of research concerning BoNT-A treatment of spasticity to elucidate current trends and future directions in this research area. A search was conducted in the Web of Science database for articles focused on the use of BoNT-A in spasticity published between 2000 and 2022. We extracted various metrics, including counts of publications and contributions from different countries, institutions, authors, and journals. Analytical methods in CiteSpace were employed for the examination of co-citations, collaborations, and the co-occurrence …

Chromatin Profiles Are Prognostic Of Clinical Response To Bortezomib-Containing Chemotherapy In Pediatric Acute Myeloid Leukemia: Results From The Cog Aaml1031 Trial, Anneke D Van Dijk, Fieke W Hoff, Yihua Qiu, Stefan E Hubner, Robin L Go, Vivian R Ruvolo, Amanda R Leonti, Robert B Gerbing, Alan S Gamis, Richard Aplenc, Edward A Kolb, Todd A Alonzo, Soheil Meshinchi, Eveline S J M De Bont, Terzah M Horton, Steven M Kornblau

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The addition of the proteasome inhibitor bortezomib to standard chemotherapy did not improve survival in pediatric acute myeloid leukemia (AML) when all patients were analyzed as a group in the Children's Oncology Group phase 3 trial AAML1031 (NCT01371981). Proteasome inhibition influences the chromatin landscape and proteostasis, and we hypothesized that baseline proteomic analysis of histone- and chromatin-modifying enzymes (HMEs) would identify AML subgroups that benefitted from bortezomib addition. A proteomic profile of 483 patients treated with AAML1031 chemotherapy was generated using a reverse-phase protein array. A relatively high expression of 16 HME was associated with lower EFS and …

Funcpep V20: An Updated Database Of Functional Short Peptides Translated From Non-Coding Rnas, Swati Mohapatra, Anik Banerjee, Paola Rausseo, Mihnea P Dragomir, Ganiraju C Manyam, Bradley M Broom, George A Calin

Faculty, Staff and Student Publications

Over the past decade, there have been reports of short novel functional peptides (less than 100 aa in length) translated from so-called non-coding RNAs (ncRNAs) that have been characterized using mass spectrometry (MS) and large-scale proteomics studies. Therefore, understanding the bivalent functions of some ncRNAs as transcripts that encode both functional RNAs and short peptides, which we named ncPEPs, will deepen our understanding of biology and disease. In 2020, we published the first database of functional peptides translated from non-coding RNAs-FuncPEP. Herein, we have performed an update including the newly published ncPEPs from the last 3 years along with the …

Patient Characteristics Of, And Remedial Interventions For, Complaints And Medico-Legal Claims Against Doctors: A Rapid Review Of The Literature, Timothy J Schultz, Michael Zhou, Jodi Gray, Jackie Roseleur, Richard Clark, Dylan A Mordaunt, Peter D Hibbert, Georgie Haysom, Michael Wright

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BACKGROUND: It is uncertain if patient's characteristics are associated with complaints and claims against doctors. Additionally, evidence for the effectiveness of remedial interventions on rates of complaints and claims against doctors has not been synthesised.

METHODS: We conducted a rapid review of recent literature to answer: Question 1 "What are the common characteristics and circumstances of patients who are most likely to complain or bring a claim about the care they have received from a doctor?" and Question 2 "What initiatives or interventions have been shown to be effective at reducing complaints and claims about the care patients have received …

Mir-574-5p Activates Human Tlr8 To Promote Autoimmune Signaling And Lupus, Tao Wang, Dan Song, Xuejuan Li, Yu Luo, Dianqiang Yang, Xiaoyan Liu, Xiaodan Kong, Yida Xing, Shulin Bi, Yan Zhang, Tao Hu, Yunyun Zhang, Shuang Dai, Zhiqiang Shao, Dahan Chen, Jinpao Hou, Esteban Ballestar, Jianchun Cai, Feng Zheng, James Y Yang

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Endosomal single-stranded RNA-sensing Toll-like receptor-7/8 (TLR7/8) plays a pivotal role in inflammation and immune responses and autoimmune diseases. However, the mechanisms underlying the initiation of the TLR7/8-mediated autoimmune signaling remain to be fully elucidated. Here, we demonstrate that miR-574-5p is aberrantly upregulated in tissues of lupus prone mice and in the plasma of lupus patients, with its expression levels correlating with the disease activity. miR-574-5p binds to and activates human hTLR8 or its murine ortholog mTlr7 to elicit a series of MyD88-dependent immune and inflammatory responses. These responses include the overproduction of cytokines and interferons, the activation of STAT1 signaling …

Arterial Spin-Labeling And Dsc Perfusion Metrics Improve Agreement In Neuroradiologists' Clinical Interpretations Of Posttreatment High-Grade Glioma Surveillance Mr Imaging-An Institutional Experience, Ghiam Yamin, Eric Tranvinh, Bryan A Lanzman, Elizabeth Tong, Syed S Hashmi, Chirag B Patel, Michael Iv

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Background and purpose: MR perfusion has shown value in the evaluation of posttreatment high-grade gliomas, but few studies have shown its impact on the consistency and confidence of neuroradiologists' interpretation in routine clinical practice. We evaluated the impact of adding MR perfusion metrics to conventional contrast-enhanced MR imaging in posttreatment high-grade glioma surveillance imaging.

Materials and methods: This retrospective study included 45 adults with high-grade gliomas who had posttreatment perfusion MR imaging. Four neuroradiologists assigned Brain Tumor Reporting and Data System scores for each examination on the basis of the interpretation of contrast-enhanced MR imaging and then after the addition …

Author Correction: Comparative Analysis Of Dimension Reduction Methods For Cytometry By Time-Of-Flight Data, Kaiwen Wang, Yuqiu Yang, Fangjiang Wu, Bing Song, Xinlei Wang, Tao Wang

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No abstract provided.

The Roles Of Ferroptosis In Cancer: Tumor Suppression, Tumor Microenvironment, And Therapeutic Interventions, Guang Lei, Li Zhuang, Boyi Gan

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In cancer treatment, the recurrent challenge of inducing apoptosis through conventional therapeutic modalities, often thwarted by therapy resistance, emphasizes the critical need to explore alternative cell death pathways. Ferroptosis, an iron-dependent form of regulated cell death triggered by the lethal accumulation of lipid peroxides on cellular membranes, has emerged as one such promising frontier in oncology. Induction of ferroptosis not only suppresses tumor growth but also holds potential for augmenting immunotherapy responses and surmounting resistance to existing cancer therapies. This review navigates the role of ferroptosis in tumor suppression. Furthermore, we delve into the complex role of ferroptosis within the …

Arid1a Orchestrates Swi/Snf-Mediated Sequential Binding Of Transcription Factors With Arid1a Loss Driving Pre-Memory B Cell Fate And Lymphomagenesis, Darko Barisic, Christopher R Chin, Cem Meydan, Matt Teater, Ioanna Tsialta, Coraline Mlynarczyk, Amy Chadburn, Xuehai Wang, Margot Sarkozy, Min Xia, Sandra E Carson, Santo Raggiri, Sonia Debek, Benedikt Pelzer, Ceyda Durmaz, Qing Deng, Priya Lakra, Martin Rivas, Christian Steidl, David W Scott, Andrew P Weng, Christopher E Mason, Michael R Green, Ari Melnick

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ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. We show that ARID1A orchestrates B cell fate during the germinal center (GC) response, facilitating cooperative and sequential binding of PU.1 and NF-kB at crucial genes for cytokine and CD40 signaling. The absence of ARID1A tilts GC cell fate toward immature IgM+CD80-PD-L2- memory B cells, known for their potential to re-enter new GCs. When combined with BCL2 oncogene, ARID1A haploinsufficiency hastens the progression of aggressive follicular lymphomas (FLs) in mice. Patients with FL with ARID1A-inactivating mutations preferentially display an immature memory B cell-like state with …

Smarca4 Is A Haploinsufficient B Cell Lymphoma Tumor Suppressor That Fine-Tunes Centrocyte Cell Fate Decisions, Qing Deng, Priya Lakra, Panhong Gou, Haopeng Yang, Cem Meydan, Matthew Teater, Christopher Chin, Wenchao Zhang, Tommy Dinh, Usama Hussein, Xubin Li, Estela Rojas, Weiguang Liu, Patrick K Reville, Atish Kizhakeyil, Darko Barisic, Sydney Parsons, Ashley Wilson, Jared Henderson, Brooks Scull, Channabasavaiah Gurumurthy, Francisco Vega, Amy Chadburn, Branko Cuglievan, Nader Kim El-Mallawany, Carl Allen, Christopher Mason, Ari Melnick, Michael R Green

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SMARCA4 encodes one of two mutually exclusive ATPase subunits in the BRG/BRM associated factor (BAF) complex that is recruited by transcription factors (TFs) to drive chromatin accessibility and transcriptional activation. SMARCA4 is among the most recurrently mutated genes in human cancer, including ∼30% of germinal center (GC)-derived Burkitt lymphomas. In mice, GC-specific Smarca4 haploinsufficiency cooperated with MYC over-expression to drive lymphomagenesis. Furthermore, monoallelic Smarca4 deletion drove GC hyperplasia with centroblast polarization via significantly increased rates of centrocyte recycling to the dark zone. Mechanistically, Smarca4 loss reduced the activity of TFs that are activated in centrocytes to drive GC-exit, including SPI1 …

Single-Cell Systems Pharmacology Identifies Development-Driven Drug Response And Combination Therapy In B Cell Acute Lymphoblastic Leukemia, Xin Huang, Yizhen Li, Jingliao Zhang, Lei Yan, Huanbin Zhao, Liang Ding, Sheetal Bhatara, Xu Yang, Satoshi Yoshimura, Wenjian Yang, Seth E Karol, Hiroto Inaba, Charles Mullighan, Mark Litzow, Xiaofan Zhu, Yingchi Zhang, Wendy Stock, Nitin Jain, Elias Jabbour, Steven M Kornblau, Marina Konopleva, Ching-Hon Pui, Elisabeth Paietta, William Evans, Jiyang Yu, Jun J Yang

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Leukemia can arise at various stages of the hematopoietic differentiation hierarchy, but the impact of developmental arrest on drug sensitivity is unclear. Applying network-based analyses to single-cell transcriptomes of human B cells, we define genome-wide signaling circuitry for each B cell differentiation stage. Using this reference, we comprehensively map the developmental states of B cell acute lymphoblastic leukemia (B-ALL), revealing its strong correlation with sensitivity to asparaginase, a commonly used chemotherapeutic agent. Single-cell multi-omics analyses of primary B-ALL blasts reveal marked intra-leukemia heterogeneity in asparaginase response: resistance is linked to pre-pro-B-like cells, with sensitivity associated with the pro-B-like population. By …

A Structured Curriculum Supporting Biomedical Trainees’ Transition Into Independent Academic Positions And Early Career Success, Mabel Perez-Oquendo, Gabriele Romano, David P Farris, Varsha Gandhi, Ignacio I Wistuba, Robert E Tillman, Ryan Udan, Paolo Mangahas, Rama Soundararajan

Faculty, Staff and Student Publications

The United States government makes a substantial investment in biomedical training programs each year. However, for most trainees, these opportunities do not translate into career progression in academic research pathways. Only about one-fifth of postdoctoral fellows eventually secure a tenure-track faculty position, and even among these candidates, attrition is high. Although a number of factors govern career choices and career longevity, the transition from trainee to faculty is a challenging process and requires knowledge and skills that are not necessarily developed during a traditional university experience. Many postdoctoral fellows receive adequate training in research skills and scientific communication, but new …

Enhanced Plant-Derived Vesicles For Nucleotide Delivery For Cancer Therapy, Sara Corvigno, Yuan Liu, Emine Bayraktar, Elaine Stur, Nazende Nur Bayram, Adrian Lankenau Ahumada, Supriya Nagaraju, Cristian Rodriguez-Aguayo, Hu Chen, Thanh Chung Vu, Yunfei Wen, Han Liang, Li Zhao, Sanghoon Lee, Gabriel Lopez-Berestein, Anil K Sood

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Small RNAs (microRNAs [miRNAs] or small interfering RNAs [siRNAs]) are effective tools for cancer therapy, but many of the existing carriers for their delivery are limited by low bioavailability, insufficient loading, impaired transport across biological barriers, and low delivery into the tumor microenvironment. Extracellular vesicle (EV)-based communication in mammalian and plant systems is important for many physiological and pathological processes, and EVs show promise as carriers for RNA interference molecules. However, some fundamental issues limit their use, such as insufficient cargo loading and low potential for scaling production. Plant-derived vesicles (PDVs) are membrane-coated vesicles released in the apoplastic fluid of …

Human Brain Glycoform Coregulation Network And Glycan Modification Alterations In Alzheimer's Disease, Qi Zhang, Cheng Ma, Lih-Shen Chin, Sheng Pan, Lian Li

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Despite the importance of protein glycosylation to brain health, current knowledge of glycosylated proteoforms or glycoforms in human brain and their alterations in Alzheimer's disease (AD) is limited. Here, we report a proteome-wide glycoform profiling study of human AD and control brains using intact glycopeptide-based quantitative glycoproteomics coupled with systems biology. Our study identified more than 10,000 human brain N-glycoforms from nearly 1200 glycoproteins and uncovered disease signatures of altered glycoforms and glycan modifications, including reduced sialylation and N-glycan branching and elongation as well as elevated mannosylation and N-glycan truncation in AD. Network analyses revealed a higher-order organization of brain …