Biomedical Informatics Commons^™

Author Correction: Global Proteomic Identifies Multiple Cancer-Related Signaling Pathways Altered By A Gut Pathobiont Associated With Colorectal Cancer, Ewa Pasquereau-Kotula, Giulia Nigro, Florent Dingli, Damarys Loew, Patrick Poullet, Yi Xu, Scott Kopetz, Jennifer Davis, Lucie Peduto, Catherine Robbe-Masselot, Philippe Sansonetti, Patrick Trieu-Cuot, Shaynoor Dramsi

Faculty, Staff and Student Publications

No abstract provided.

Priorities And Progress In Gram-Positive Bacterial Infection Research By The Antibacterial Resistance Leadership Group: A Narrative Review, Sarah B Doernberg, Cesar A Arias, Deena R Altman, Ahmed Babiker, Helen W Boucher, C Buddy Creech, Sara E Cosgrove, Scott R Evans, Vance G Fowler, Stephanie A Fritz, Toshimitsu Hamasaki, Brendan J Kelly, Sixto M Leal, Catherine Liu, Thomas P Lodise, Loren G Miller, Jose M Munita, Barbara E Murray, Melinda M Pettigrew, Felicia Ruffin, Marc H Scheetz, Bo Shopsin, Truc T Tran, Nicholas A Turner, Derek J Williams, Smitha Zaharoff, Thomas L Holland

Faculty, Staff and Student Publications

The Antibacterial Resistance Leadership Group (ARLG) has prioritized infections caused by gram-positive bacteria as one of its core areas of emphasis. The ARLG Gram-positive Committee has focused on studies responding to 3 main identified research priorities: (1) investigation of strategies or therapies for infections predominantly caused by gram-positive bacteria, (2) evaluation of the efficacy of novel agents for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci, and (3) optimization of dosing and duration of antimicrobial agents for gram-positive infections. Herein, we summarize ARLG accomplishments in gram-positive bacterial infection research, including studies aiming to (1) inform optimal vancomycin dosing, …

Sptan1/Numb Axis Senses Cell Density To Restrain Cell Growth And Oncogenesis Through Hippo Signaling, Dongxue Su, Yuxi Li, Weiji Zhang, Huan Gao, Yao Cheng, Yongqiang Hou, Junhong Li, Yi Ye, Zhangjian Lai, Zhe Li, Haitao Huang, Jiaxin Li, Jinhuan Li, Mengyu Cheng, Cheng Nian, Na Wu, Zhien Zhou, Yunzhi Xing, Yu Zhao, He Liu, Jiayu Tang, Qinghua Chen, Lixin Hong, Wengang Li, Zhihai Peng, Bin Zhao, Randy L Johnson, Pingguo Liu, Wanjin Hong, Lanfen Chen, Dawang Zhou

Faculty, Staff and Student Publications

The loss of contact inhibition is a key step during carcinogenesis. The Hippo-Yes-associated protein (Hippo/YAP) pathway is an important regulator of cell growth in a cell density-dependent manner. However, how Hippo signaling senses cell density in this context remains elusive. Here, we report that high cell density induced the phosphorylation of spectrin α chain, nonerythrocytic 1 (SPTAN1), a plasma membrane-stabilizing protein, to recruit NUMB endocytic adaptor protein isoforms 1 and 2 (NUMB1/2), which further sequestered microtubule affinity-regulating kinases (MARKs) in the plasma membrane and rendered them inaccessible for phosphorylation and inhibition of the Hippo kinases sterile 20-like kinases MST1 and …

Possible Delayed Foreign Body Reactions Against Titanium Clips And Coating Materials After Unruptured Cerebral Aneurysm Surgery, Ryota Tatezawa, Taku Sugiyama, Shuho Gotoh, Takafumi Shindo, Hiroshi Ikeda, Masaaki Hokari, Katsumi Takizawa, Naoki Nakayama, Miki Fujimura

Faculty, Staff and Student Publications

Delayed foreign body reactions to either or both clipping and coating materials have been reported in several small series; however, studies in the titanium clip era are scarce. This study aims to survey the contemporary status of such reactions to titanium clips and coating materials. Among patients who received a total of 2327 unruptured cerebral aneurysmal surgeries, 12 developed delayed intraparenchymal reactions during outpatient magnetic resonance imaging (MRI) follow-up. A retrospective investigation was conducted. The patients' average age was 58.6 (45-73) years, and 11 were women. The aneurysms were located in the middle cerebral artery (n = 7), internal carotid …

Associations Between Birth Defects And Childhood And Adolescent Germ Cell Tumors According To Sex, Histologic Subtype, And Site, Jeremy M Schraw, Pagna Sok, Tania A Desrosiers, Amanda E Janitz, Peter H Langlois, Mark A Canfield, A Lindsay Frazier, Sharon E Plon, Philip J Lupo, Jenny N Poynter

Faculty, Staff and Students Publications

BACKGROUND: Studies have reported increased rates of birth defects among children with germ cell tumors (GCTs). However, few studies have evaluated associations by sex, type of defect, or tumor characteristics.

METHODS: Birth defect-GCT associations were evaluated among pediatric patients (N = 552) with GCTs enrolled in the Germ Cell Tumor Epidemiology Study and population-based controls (N = 6380) without cancer from the Genetic Overlap Between Anomalies and Cancer in Kids Study. The odds ratio (OR) and 95% confidence interval (CI) of GCTs according to birth defects status were estimated by using unconditional logistic regression. All defects were considered collectively and …

Guide-Specific Loss Of Efficiency And Off-Target Reduction With Cas9 Variants, Liang Zhang, Wei He, Rongjie Fu, Shuyue Wang, Yiwen Chen, Han Xu

Faculty, Staff and Student Publications

High-fidelity clustered regularly interspaced palindromic repeats (CRISPR)-associated protein 9 (Cas9) variants have been developed to reduce the off-target effects of CRISPR systems at a cost of efficiency loss. To systematically evaluate the efficiency and off-target tolerance of Cas9 variants in complex with different single guide RNAs (sgRNAs), we applied high-throughput viability screens and a synthetic paired sgRNA-target system to assess thousands of sgRNAs in combination with two high-fidelity Cas9 variants HiFi and LZ3. Comparing these variants against wild-type SpCas9, we found that ∼20% of sgRNAs are associated with a significant loss of efficiency when complexed with either HiFi or LZ3. …

Novobiocin Blocks Nucleic Acid Binding To Polθ And Inhibits Stimulation Of Its Atpase Activity, Aleem Syed, Frantisek Filandr, Jeffrey Patterson-Fortin, Albino Bacolla, Ramya Ravindranathan, Jia Zhou, Drew T Mcdonald, Mohammed E Albuhluli, Amy Verway-Cohen, Joseph A Newman, Miaw-Sheue Tsai, Darin E Jones, David C Schriemer, Alan D D'Andrea, John A Tainer

Faculty, Staff and Student Publications

Polymerase theta (Polθ) acts in DNA replication and repair, and its inhibition is synthetic lethal in BRCA1 and BRCA2-deficient tumor cells. Novobiocin (NVB) is a first-in-class inhibitor of the Polθ ATPase activity, and it is currently being tested in clinical trials as an anti-cancer drug. Here, we investigated the molecular mechanism of NVB-mediated Polθ inhibition. Using hydrogen deuterium exchange-mass spectrometry (HX-MS), biophysical, biochemical, computational and cellular assays, we found NVB is a non-competitive inhibitor of ATP hydrolysis. NVB sugar group deletion resulted in decreased potency and reduced HX-MS interactions, supporting a specific NVB binding orientation. Collective results revealed that NVB …

Reap-2: An Interactive Quantitative Tool For Robust And Efficient Dose-Response Curve Estimation, Xinying Fang, Xinyi Liu, Vernon M Chinchilli, Michael Wang, Hong-Gang Wang, Nikolay V Dokholyan, Chan Shen, J Jack Lee, Shouhao Zhou

Faculty, Staff and Student Publications

REAP-2 is an interactive dose-response curve estimation tool for Robust and Efficient Assessment of drug Potency. It provides user-friendly dose-response curve estimation for in vitro studies and conducts statistical testing for model comparisons with a redesigned user interface. We also make a major update of the underlying estimation method with penalized beta regression, which demonstrates great reliability and accuracy in dose estimation and uncertainty quantification. In this note, we describe the method and implementation of REAP-2 with a highlight on potency estimation and drug comparison.

Bacterial And Fungal Characterization Of Pancreatic Adenocarcinoma From Endoscopic Ultrasound-Guided Biopsies, Robin D Wright, Thais F Bartelli, Seyda Baydogan, James Robert White, Michael P Kim, Manoop S Bhutani, Florencia Mcallister

Faculty, Staff and Student Publications

INTRODUCTION: The tumor microbiome (TM) has been linked to pancreatic cancer prognosis. Specific microbes can confer tumor resistance to therapies. Early knowledge of the TM at time of diagnosis would be clinically relevant for precision therapy based on microbial composition. However, it is difficult to define the TM prior to surgical resection.

METHODS: In this pilot feasibility study, patients underwent Endoscopic Ultrasound-Fine Needle Aspiration (EUS-FNA) biopsy of pancreatic adenocarcinoma. These samples were analyzed using 16S rRNA and internal transcribed spacer (ITS) sequencing for characterization of the tumor bacteria and fungi.

RESULT: After in silico decontamination and comparison to non-matched tumor, …

Immune-Depleted Tumor Microenvironment Is Associated With Poor Outcomes And Btk Inhibitor Resistance In Mantle Cell Lymphoma, Preetesh Jain, Krystle Nomie, Nikita Kotlov, Vitaiy Segodin, Holly Hill, Chi Young Ok, Ahmed Fetooh, Rashmi Kanagal-Shamanna, Francisco Vega, Alexander Bagaev, Nathan Fowler, Christopher R Flowers, Michael Wang

Faculty, Staff and Student Publications

Mantle cell lymphoma (MCL) is a generally aggressive B cell non-Hodgkin lymphoma (B-NHL). Outcomes of patients have improved in the era of Bruton’s tyrosine kinase inhibitors (BTKi). However, MCL patients can develop resistance to BTKi over time and can progress [1]. Ibrutinib resistance in MCL is correlated with an overexpression of OXPHOS, MYC and PI3K/AKT/m-TOR pathways. Somatic mutations in TP53, KMT2D, NSD2, SMARCA4, CCND1, TRAF2, NFKBIE genes are reported with ibrutinib resistance [2]. A few reports have also demonstrated that a decrease in T cell numbers [3, 4] or a downregulation of effector/cytotoxic …

Complete Loss Of Tp53 And Rb1 Is Associated With Complex Genome And Low Immune Infiltrate In Pleomorphic Rhabdomyosarcoma, Hannah C Beird, Chia-Chin Wu, Michael Nakazawa, Davis Ingram, Joseph R Daniele, Rossana Lazcano, Latasha Little, Christopher Davies, Najat C Daw, Khalida Wani, Wei-Lien Wang, Xingzhi Song, Curtis Gumbs, Jianhua Zhang, Brian Rubin, Anthony Conley, Adrienne M Flanagan, Alexander J Lazar, P Andrew Futreal

Faculty, Staff and Student Publications

Rhabdomyosarcoma accounts for roughly 1% of adult sarcomas, with pleomorphic rhabdomyosarcoma (PRMS) as the most common subtype. Survival outcomes remain poor for patients with PRMS, and little is known about the molecular drivers of this disease. To better characterize PRMS, we performed a broad array of genomic and immunostaining analyses on 25 patient samples. In terms of gene expression and methylation, PRMS clustered more closely with other complex karyotype sarcomas than with pediatric alveolar and embryonal rhabdomyosarcoma. Immune infiltrate levels in PRMS were among the highest observed in multiple sarcoma types and contrasted with low levels in other rhabdomyosarcoma subtypes. …

Unleashing The Potential Of 1,3-Diketone Analogues As Selective Lh2 Inhibitors, Juhoon Lee, Hou-Fu Guo, Shike Wang, Yazdan Maghsoud, Erik Antonio Vázquez-Montelongo, Zhifeng Jing, Rae M Sammons, Eun Jeong Cho, Pengyu Ren, G Andrés Cisneros, Jonathan M Kurie, Kevin N Dalby

Faculty, Staff and Student Publications

Lysyl hydroxylase 2 (LH2) catalyzes the formation of highly stable hydroxylysine aldehyde-derived collagen cross-links (HLCCs), thus promoting lung cancer metastasis through its capacity to modulate specific types of collagen cross-links within the tumor stroma. Using 1 and 2 from our previous high-throughput screening (HTS) as lead probes, we prepared a series of 1,3-diketone analogues, 1-18, and identified 12 and 13 that inhibit LH2 with IC50's of approximately 300 and 500 nM, respectively. Compounds 12 and 13 demonstrate selectivity for LH2 over LH1 and LH3. Quantum mechanics/molecular mechanics (QM/MM) modeling indicates that the selectivity of 12 and 13 …

Usp1 Promotes Cholangiocarcinoma Progression By Deubiquitinating Parp1 To Prevent Its Proteasomal Degradation, Deng Yong Zhang, Yan Zhu, Qiong Wu, Shuoshuo Ma, Yang Ma, Zheng Chao Shen, Zhonglin Wang, Wanliang Sun, Yong Chun Zhou, Dongdong Wang, Shuo Zhou, Zhong Liu, Lawrence N Kwong, Zheng Lu

Faculty, Staff and Student Publications

Despite its involvement in various cancers, the function of the deubiquitinase USP1 (ubiquitin-specific protease 1) is unexplored in cholangiocarcinoma (CCA). In this study, we provide evidence that USP1 promotes CCA progression through the stabilization of Poly (ADP-ribose) polymerase 1 (PARP1), consistent with the observation that both USP1 and PARP1 are upregulated in human CCA. Proteomics and ubiquitylome analysis of USP1-overexpressing CCA cells nominated PARP1 as a top USP1 substrate. Indeed, their direct interaction was validated by a series of immunofluorescence, co-immunoprecipitation (CO-IP), and GST pull-down assays, and their interaction regions were identified using deletion mutants. Mechanistically, USP1 removes the ubiquitin …

Vaccination With A Replication-Defective Cytomegalovirus Vaccine Elicits A Glycoprotein B-Specific Monoclonal Antibody Repertoire Distinct From Natural Infection, Sarah M Valencia, Eric Rochat, Melissa J Harnois, Maria Dennis, Helen S Webster, Bhavna Hora, Amit Kumar, Hsuan-Yuan Sherry Wang, Leike Li, Daniel Freed, Ningyan Zhang, Zhiqiang An, Dai Wang, Sallie R Permar

Faculty, Staff and Student Publications

Human Cytomegalovirus (HCMV) is the leading infectious congenital infection globally and the most common viral infection in transplant recipients, therefore identifying a vaccine for HCMV is a top priority. Humoral immunity is a correlate of protection for HCMV infection. The most effective vaccine tested to date, which achieved 50% reduction in acquisition of HCMV, was comprised of the glycoprotein B protein given with an oil-in-water emulsion adjuvant MF59. We characterize gB-specific monoclonal antibodies isolated from individuals vaccinated with a disabled infectious single cycle (DISC) CMV vaccine, V160, and compare these to the gB-specific monoclonal antibody repertoire isolated from naturally-infected individuals. …

Integrated Molecular Characterization Of Intraductal Papillary Mucinous Neoplasms: An Nci Cancer Moonshot Precancer Atlas Pilot Project, Alexander Semaan, Vincent Bernard, Justin Wong, Yuki Makino, Daniel B Swartzlander, Kimal I Rajapakshe, Jaewon J Lee, Adam Officer, Christian Max Schmidt, Howard H Wu, Courtney L Scaife, Kajsa E Affolter, Daniela Nachmanson, Matthew A Firpo, Michele Yip-Schneider, Andrew M Lowy, Olivier Harismendy, Subrata Sen, Anirban Maitra, Yasminka A Jakubek, Paola A Guerrero

Faculty, Staff and Student Publications

Intraductal papillary mucinous neoplasms (IPMN) are cystic precursor lesions to pancreatic ductal adenocarcinoma (PDAC). IPMNs undergo multistep progression from low-grade (LG) to high-grade (HG) dysplasia, culminating in invasive neoplasia. While patterns of IPMN progression have been analyzed using multiregion sequencing for somatic mutations, there is no integrated assessment of molecular events, including copy-number alterations (CNA) and transcriptional changes that accompany IPMN progression. We performed laser capture microdissection on surgically resected IPMNs of varying grades of histologic dysplasia obtained from 23 patients, followed by whole-exome and whole-transcriptome sequencing. Overall, HG IPMNs displayed a significantly greater aneuploidy score than LG lesions, with …

First-In-Human, Phase I Dose-Escalation And Dose-Expansion Study Of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan In Non-Small-Cell Lung Cancer: Tropion-Pantumor01, Toshio Shimizu, Jacob Sands, Kiyotaka Yoh, Alexander Spira, Edward B Garon, Satoru Kitazono, Melissa L Johnson, Funda Meric-Bernstam, Anthony W Tolcher, Noboru Yamamoto, Jon Greenberg, Yui Kawasaki, Hong Zebger-Gong, Fumiaki Kobayashi, Penny Phillips, Aaron E Lisberg, Rebecca S Heist

Faculty, Staff and Student Publications

PURPOSE: This first-in-human, dose-escalation and dose-expansion study evaluated the safety, tolerability, and antitumor activity of datopotamab deruxtecan (Dato-DXd), a novel trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugate in solid tumors, including advanced non-small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Adults with locally advanced/metastatic NSCLC received 0.27-10 mg/kg Dato-DXd once every 3 weeks during escalation or 4, 6, or 8 mg/kg Dato-DXd once every 3 weeks during expansion. Primary end points were safety and tolerability. Secondary end points included objective response rate (ORR), survival, and pharmacokinetics.

RESULTS: Two hundred ten patients received Dato-DXd, including 180 in the 4-8 mg/kg dose-expansion cohorts. …

Outcomes Of Breakthrough Covid-19 Infections In Patients With Hematologic Malignancies, Kelly S Chien, Christine B Peterson, Elliana Young, Dai Chihara, Elizabet E Manasanch, Jeremy L Ramdial, Philip A Thompson

Faculty, Staff and Student Publications

Patients with hematologic malignancies have both an increased risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and higher morbidity/mortality. They have lower seroconversion rates after vaccination, potentially leading to inferior coronavirus disease 2019 (COVID-19) outcomes, despite vaccination. We consequently evaluated the clinical outcomes of COVID-19 infections in 243 vaccinated and 175 unvaccinated patients with hematologic malignancies. Hospitalization rates were lower in the vaccinated group when compared with the unvaccinated group (31.3% vs 52.6%). However, the rates of COVID-19-associated death were similar at 7.0% and 8.6% in vaccinated and unvaccinated patients, respectively. By univariate logistic regression, females, older patients, …

Collective Motion In Hcp-Fe At Earth's Inner Core Conditions, Youjun Zhang, Yong Wang, Yuqian Huang, Junjie Wang, Zhixin Liang, Long Hao, Zhipeng Gao, Jun Li, Qiang Wu, Hong Zhang, Yun Liu, Jian Sun, Jung-Fu Lin

Faculty, Staff and Student Publications

Earth's inner core is predominantly composed of solid iron (Fe) and displays intriguing properties such as strong shear softening and an ultrahigh Poisson's ratio. Insofar, physical mechanisms to explain these features coherently remain highly debated. Here, we have studied longitudinal and shear wave velocities of hcp-Fe (hexagonal close-packed iron) at relevant pressure-temperature conditions of the inner core using in situ shock experiments and machine learning molecular dynamics (MLMD) simulations. Our results demonstrate that the shear wave velocity of hcp-Fe along the Hugoniot in the premelting condition, defined as

Bronchial Epithelial Gene Expression And Interstitial Lung Abnormalities, Aravind A Menon, Minyi Lee, Xu Ke, Rachel K Putman, Takuya Hino, Jonathan A Rose, Fenghai Duan, Samuel Y Ash, Michael H Cho, George T O'Connor, Josée Dupuis, Hiroto Hatabu, Marc E Lenburg, Ehab S Billatos, Gary M Hunninghake, Decamp Investigators

Faculty, Staff and Student Publications

INTRODUCTION: Interstitial lung abnormalities (ILA) often represent early fibrotic changes that can portend a progressive fibrotic phenotype. In particular, the fibrotic subtype of ILA is associated with increased mortality and rapid decline in lung function. Understanding the differential gene expression that occurs in the lungs of participants with fibrotic ILA may provide insight into development of a useful biomarker for early detection and therapeutic targets for progressive pulmonary fibrosis.

METHODS: Measures of ILA and gene expression data were available in 213 participants in the Detection of Early Lung Cancer Among Military Personnel (DECAMP1 and DECAMP2) cohorts. ILA was defined using …

The Significant Impacts Of Interleukin-8 Genotypes On The Risk Of Colorectal Cancer In Taiwan, Chia-Wen Tsai, Wen-Shin Chang, Te-Cheng Yueh, Yun-Chi Wang, Yu-Ting Chin, Mei-Due Yang, Yi-Chih Hung, Mei-Chin Mong, Ya-Chen Yang, Jian Gu, Da-Tian Bau

Faculty, Staff and Student Publications

Interleukin-8 (IL-8), a pro-inflammatory cytokine, is upregulated in CRC and plays an important role in its development and progression. Genetic variants in the IL-8 gene may impact the risk of CRC by modulating IL-8 levels. Our primary objective was to investigate the role of IL-8 genotypes in the development of CRC. To accomplish this, we employed the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to analyze the genotypes of IL-8 rs4017, rs2227306, rs2227543, and rs1126647 in 362 CRC patients and 362 controls. Additionally, we evaluated the interactions between these genotypes and factors such as age, gender, smoking, alcohol consumption, …

Dendritic Cells As Shepherds Of T Cell Immunity In Cancer, Mikael J Pittet, Mauro Di Pilato, Christopher Garris, Thorsten R Mempel

Faculty, Staff and Student Publications

In cancer patients, dendritic cells (DCs) in tumor-draining lymph nodes can present antigens to naive T cells in ways that break immunological tolerance. The clonally expanded progeny of primed T cells are further regulated by DCs at tumor sites. Intratumoral DCs can both provide survival signals to and drive effector differentiation of incoming T cells, thereby locally enhancing antitumor immunity; however, the paucity of intratumoral DCs or their expression of immunoregulatory molecules often limits antitumor T cell responses. Here, we review the current understanding of DC-T cell interactions at both priming and effector sites of immune responses. We place emerging …

Mathematical Modeling Of Radiotherapy: Impact Of Model Selection On Estimating Minimum Radiation Dose For Tumor Control, Achyudhan R Kutuva, Jimmy J Caudell, Kosj Yamoah, Heiko Enderling, Mohammad U Zahid

Faculty, Staff and Student Publications

INTRODUCTION: Radiation therapy (RT) is one of the most common anticancer therapies. Yet, current radiation oncology practice does not adapt RT dose for individual patients, despite wide interpatient variability in radiosensitivity and accompanying treatment response. We have previously shown that mechanistic mathematical modeling of tumor volume dynamics can simulate volumetric response to RT for individual patients and estimation personalized RT dose for optimal tumor volume reduction. However, understanding the implications of the choice of the underlying RT response model is critical when calculating personalized RT dose.

METHODS: In this study, we evaluate the mathematical implications and biological effects of 2 …

Cancer Survivors’ Health Behaviors And Outcomes: A Population-Based Study Of Sexual And Gender Minorities, Ulrike Boehmer, Shine Chang, Nelson F Sanchez, Bill M Jesdale, Matthew B Schabath

Faculty, Staff and Student Publications

BACKGROUND: Most case-control studies compare cancer survivors with general population controls without considering sexual orientation or gender identity. This case-control analysis compared health risk behaviors and health outcomes among sexual and gender minority cancer survivors to those of matched sexual and gender minority participants without cancer (controls).

METHODS: Using data from the 2014-2021 Behavioral Risk Factor Surveillance System, a population-based sample of 4507 cancer survivors who self-identified as transgender, gay men, bisexual men, lesbian women, or bisexual women were 1:1 propensity score matched, using age at survey, race and ethnicity, marital status, education, access to health care, and US census …

Znf683 Marks A Cd8+ T Cell Population Associated With Anti-Tumor Immunity Following Anti-Pd-1 Therapy For Richter Syndrome, Erin M Parry, Camilla K Lemvigh, Stephanie Deng, Nathan Dangle, Neil Ruthen, Binyamin A Knisbacher, Julien Broséus, Sébastien Hergalant, Romain Guièze, Shuqiang Li, Wandi Zhang, Connor Johnson, Jaclyn M Long, Shanye Yin, Lillian Werner, Annabelle Anandappa, Noelia Purroy, Satyen Gohil, Giacomo Oliveira, Pavan Bachireddy, Sachet A Shukla, Teddy Huang, Joseph D Khoury, Beenu Thakral, Michael Dickinson, Constantine Tam, Kenneth J Livak, Gad Getz, Donna Neuberg, Pierre Feugier, Peter Kharchenko, William Wierda, Lars Rønn Olsen, Nitin Jain, Catherine J Wu

Faculty, Staff and Student Publications

Unlike many other hematologic malignancies, Richter syndrome (RS), an aggressive B cell lymphoma originating from indolent chronic lymphocytic leukemia, is responsive to PD-1 blockade. To discover the determinants of response, we analyze single-cell transcriptome data generated from 17 bone marrow samples longitudinally collected from 6 patients with RS. Response is associated with intermediate exhausted CD8 effector/effector memory T cells marked by high expression of the transcription factor ZNF683, determined to be evolving from stem-like memory cells and divergent from terminally exhausted cells. This signature overlaps with that of tumor-infiltrating populations from anti-PD-1 responsive solid tumors. ZNF683 is found to directly …

Ccdc50 Promotes Tumor Growth Through Regulation Of Lysosome Homeostasis, Penghui Jia, Tian Tian, Zibo Li, Yicheng Wang, Yuxin Lin, Weijie Zeng, Yu Ye, Miao He, Xiangrong Ni, Ji'an Pan, Xiaonan Dong, Jian Huang, Chun-Mei Li, Deyin Guo, Panpan Hou

Faculty, Staff and Student Publications

The maintenance of lysosome homeostasis is crucial for cell growth. Lysosome-dependent degradation and metabolism sustain tumor cell survival. Here, we demonstrate that CCDC50 serves as a lysophagy receptor, promoting tumor progression and invasion by controlling lysosomal integrity and renewal. CCDC50 monitors lysosomal damage, recognizes galectin-3 and K63-linked polyubiquitination on damaged lysosomes, and specifically targets them for autophagy-dependent degradation. CCDC50 deficiency causes the accumulation of ruptured lysosomes, impaired autophagic flux, and superfluous reactive oxygen species, consequently leading to cell death and tumor suppression. CCDC50 expression is associated with malignancy, progression to metastasis, and poor overall survival in human melanoma. Targeting CCDC50 …

Enzyme-Mediated Depletion Of Methylthioadenosine Restores T Cell Function In Mtap-Deficient Tumors And Reverses Immunotherapy Resistance, Donjeta Gjuka, Elio Adib, Kendra Garrison, Jianfeng Chen, Yuxue Zhang, Wenjiao Li, Daniel Boutz, Candice Lamb, Yuri Tanno, Amin Nassar, Talal El Zarif, Neil Kale, Mehrdad Rakaee, Tarek H Mouhieddine, Sarah Abou Alaiwi, Alexander Gusev, Thomas Rogers, Jianjun Gao, George Georgiou, David J Kwiatkowski, Everett Stone

Faculty, Staff and Student Publications

Chromosomal region 9p21 containing tumor suppressors CDKN2A/B and methylthioadenosine phosphorylase (MTAP) is one of the most frequent genetic deletions in cancer. 9p21 loss is correlated with reduced tumor-infiltrating lymphocytes (TILs) and resistance to immune checkpoint inhibitor (ICI) therapy. Previously thought to be caused by CDKN2A/B loss, we now show that it is loss of MTAP that leads to poor outcomes on ICI therapy and reduced TIL density. MTAP loss causes accumulation of methylthioadenosine (MTA) both intracellularly and extracellularly and profoundly impairs T cell function via the inhibition of protein arginine methyltransferase 5 (PRMT5) and by adenosine receptor agonism. Administration of …

Influence Of Macrophages On Vascular Invasion Of Inflammatory Breast Cancer Emboli Measured Using An In Vitro Microfluidic Multi-Cellular Platform, Manasa Gadde, Melika Mehrabi-Dehdezi, Bisrat G Debeb, Wendy A Woodward, Marissa Nichole Rylander

Faculty, Staff and Student Publications

Inflammatory breast cancer (IBC) is an aggressive disease with a poor prognosis and a lack of effective treatments. It is widely established that understanding the interactions between tumor-associated macrophages (TAMs) and the tumor microenvironment is essential for identifying distinct targeting markers that help with prognosis and subsequent development of effective treatments. In this study, we present a 3D in vitro microfluidic IBC platform consisting of THP1 M0, M1, or M2 macrophages, IBC cells, and endothelial cells. The platform comprises a collagen matrix that includes an endothelialized vessel, creating a physiologically relevant environment for cellular interactions. Through the utilization of this …

The Neuroimmune Regulation And Potential Therapeutic Strategies Of Optic Pathway Glioma, Khushboo Irshad, Yu-Kai Huang, Paul Rodriguez, Jung Lo, Benjamin E Aghoghovwia, Yuan Pan, Kun-Che Chang

Faculty, Staff and Student Publications

Optic pathway glioma (OPG) is one of the causes of pediatric visual impairment. Unfortunately, there is as yet no cure for such a disease. Understanding the underlying mechanisms and the potential therapeutic strategies may help to delay the progression of OPG and rescue the visual morbidities. Here, we provide an overview of preclinical OPG studies and the regulatory pathways controlling OPG pathophysiology. We next discuss the role of microenvironmental cells (neurons, T cells, and tumor-associated microglia and macrophages) in OPG development. Last, we provide insight into potential therapeutic strategies for treating OPG and promoting axon regeneration.

The Gut Microbiome As A Biomarker And Therapeutic Target In Hepatocellular Carcinoma, Betul Gok Yavuz, Saumil Datar, Shadi Chamseddine, Yehia I Mohamed, Michael Lapelusa, Sunyoung S Lee, Zishuo Ian Hu, Eugene J Koay, Hop S Tran Cao, Prasun Kumar Jalal, Carrie Daniel-Macdougall, Manal Hassan, Dan G Duda, Hesham M Amin, Ahmed O Kaseb

Faculty, Staff and Student Publications

The microbiome is pivotal in maintaining health and influencing disease by modulating essential inflammatory and immune responses. Hepatocellular carcinoma (HCC), ranking as the third most common cause of cancer-related fatalities globally, is influenced by the gut microbiome through bidirectional interactions between the gut and liver, as evidenced in both mouse models and human studies. Consequently, biomarkers based on gut microbiota represent promising non-invasive tools for the early detection of HCC. There is a growing body of evidence suggesting that the composition of the gut microbiota may play a role in the efficacy of immunotherapy in different types of cancer; thus, …

Multiphoton In Vivo Microscopy Of Embryonic Thrombopoiesis Reveals The Generation Of Platelets Through Budding, Huan Liu, Hellen Ishikawa-Ankerhold, Julia Winterhalter, Michael Lorenz, Mykhailo Vladymyrov, Steffen Massberg, Christian Schulz, Mathias Orban

Faculty, Staff and Student Publications

Platelets are generated by specialized cells called megakaryocytes (MKs). However, MK's origin and platelet release mode have remained incompletely understood. Here, we established direct visualization of embryonic thrombopoiesis in vivo by combining multiphoton intravital microscopy (MP-IVM) with a fluorescence switch reporter mouse model under control of the platelet factor 4 promoter (Pf4CreRosa26mTmG). Using this microscopy tool, we discovered that fetal liver MKs provide higher thrombopoietic activity than yolk sac MKs. Mechanistically, fetal platelets were released from MKs either by membrane buds or the formation of proplatelets, with the former constituting the key process. In E14.5 c-Myb-deficient …