Medical Specialties Commons^™

Cedar: Incorporating Cell Type Hierarchy Improves Cell Type-Specific Differential Analyses In Bulk Omics Data, Luxiao Chen, Ziyi Li, Hao Wu

Faculty, Staff and Student Publications

Bulk high-throughput omics data contain signals from a mixture of cell types. Recent developments of deconvolution methods facilitate cell type-specific inferences from bulk data. Our real data exploration suggests that differential expression or methylation status is often correlated among cell types. Based on this observation, we develop a novel statistical method named CeDAR to incorporate the cell type hierarchy in cell type-specific differential analyses of bulk data. Extensive simulation and real data analyses demonstrate that this approach significantly improves the accuracy and power in detecting cell type-specific differential signals compared with existing methods, especially in low-abundance cell types.

Recovering False Negatives In Crispr Fitness Screens With Jloe, Merve Dede, Traver Hart

Faculty, Staff and Student Publications

It is widely accepted that pooled library CRISPR knockout screens offer greater sensitivity and specificity than prior technologies in detecting genes whose disruption leads to fitness defects, a critical step in identifying candidate cancer targets. However, the assumption that CRISPR screens are saturating has been largely untested. Through integrated analysis of screen data in cancer cell lines generated by the Cancer Dependency Map, we show that a typical CRISPR screen has a ∼20% false negative rate, in addition to library-specific false negatives. Replicability falls sharply as gene expression decreases, while cancer subtype-specific genes within a tissue show distinct profiles compared …

Analysis Of Acquired Resistance Mechanisms To Osimertinib In Patients With Egfr-Mutated Advanced Non-Small Cell Lung Cancer From The Aura3 Trial, Juliann Chmielecki, Tony Mok, Yi-Long Wu, Ji-Youn Han, Myung-Ju Ahn, Suresh S Ramalingam, Thomas John, Isamu Okamoto, James Chih-Hsin Yang, Frances A Shepherd, Krishna C Bulusu, Gianluca Laus, Barbara Collins, J Carl Barrett, Ryan J Hartmaier, Vassiliki Papadimitrakopoulou

Faculty, Staff and Student Publications

Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits EGFR-TKI-sensitizing and EGFR T790M resistance mutations. This analysis evaluates acquired resistance mechanisms to second-line osimertinib (n = 78) in patients with EGFR T790M advanced non-small cell lung cancer (NSCLC) from AURA3 (NCT02151981), a randomized phase 3 study comparing osimertinib with chemotherapy. Plasma samples collected at baseline and disease progression/treatment discontinuation are analyzed using next-generation sequencing. Half (50%) of patients have undetectable plasma EGFR T790M at disease progression and/or treatment discontinuation. Fifteen patients (19%) have >1 resistance-related genomic alteration; MET amplification (14/78, 18%) and EGFR C797X mutation …

Kras-Mutant Lung Cancer: Targeting Molecular And Immunologic Pathways, Therapeutic Advantages And Restrictions, Nastaran Karimi, Seyed Javad Moghaddam

Faculty, Staff and Student Publications

RAS mutations are among the most common oncogenic mutations in human cancers. Among RAS mutations, KRAS has the highest frequency and is present in almost 30% of non-small-cell lung cancer (NSCLC) patients. Lung cancer is the number one cause of mortality among cancers as a consequence of outrageous aggressiveness and late diagnosis. High mortality rates have been the reason behind numerous investigations and clinical trials to discover proper therapeutic agents targeting KRAS. These approaches include the following: direct KRAS targeting; synthetic lethality partner inhibitors; targeting of KRAS membrane association and associated metabolic rewiring; autophagy inhibitors; downstream inhibitors; and immunotherapies and …

Impact Of Timing To Initiate Adjuvant Therapy On Survival Of Elderly Glioblastoma Patients Using The Seer-Medicare And National Cancer Databases, Ping Zhu, Xianglin L Du, Lu-Yu Hwang, David Lairson, Ruosha Li, Yoshua Esquenazi, Jay-Jiguang Zhu

Faculty, Staff and Student Publications

The optimal time to initiate adjuvant therapy (AT) in elderly patients with glioblastoma (GBM) remains unclear. We investigated the impact of timing to start AT on overall survival (OS) using two national-scale datasets covering elderly GBM populations in the United States. A total of 3159 and 8161 eligible elderly GBM patients were derived from the Surveillance, Epidemiology and End Results (SEER)-Medicare linked dataset (2004-2013) and the National Cancer Database (NCDB) (2004-2014), respectively. The intervals in days from the diagnosis to the initiation of AT were categorized based on two scenarios: Scenario I (quartiles), ≤ 15, 16-26, 27-37, and ≥ 38 …

Microrna Profiles In Intestinal Epithelial Cells In A Mouse Model Of Sepsis, Siqingaowa Caidengbate, Yuichi Akama, Anik Banerjee, Khwanchanok Mokmued, Eiji Kawamoto, Arong Gaowa, Louise D Mccullough, Motomu Shimaoka, Juneyoung Lee, Eun Jeong Park

Faculty, Staff and Student Publications

Sepsis is a systemic inflammatory disorder that leads to the dysfunction of multiple organs. In the intestine, the deregulation of the epithelial barrier contributes to the development of sepsis by triggering continuous exposure to harmful factors. However, sepsis-induced epigenetic changes in gene-regulation networks within intestinal epithelial cells (IECs) remain unexplored. In this study, we analyzed the expression profile of microRNAs (miRNAs) in IECs isolated from a mouse model of sepsis generated via cecal slurry injection. Among 239 miRNAs, 14 miRNAs were upregulated, and 9 miRNAs were downregulated in the IECs by sepsis. Upregulated miRNAs in IECs from septic mice, particularly …

Feasibility Of [18f]Fspg Pet For Early Response Assessment To Combined Blockade Of Egfr And Glutamine Metabolism In Wild-Type Kras Colorectal Cancer, Seong-Woo Bae, Jianbo Wang, Dimitra K Georgiou, Xiaoxia Wen, Allison S Cohen, Ling Geng, Mohammed Noor Tantawy, H Charles Manning

Faculty, Staff and Student Publications

Early response assessment is critical for personalizing cancer therapy. Emerging therapeutic regimens with encouraging results in the wild-type (WT) KRAS colorectal cancer (CRC) setting include inhibitors of epidermal growth factor receptor (EGFR) and glutaminolysis. Towards predicting clinical outcome, this preclinical study evaluated non-invasive positron emission tomography (PET) with (4S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG) in treatment-sensitive and treatment-resistant WT KRAS CRC patient-derived xenografts (PDXs). Tumor-bearing mice were imaged with [18F]FSPG PET before and one week following the initiation of treatment with either EGFR-targeted monoclonal antibody (mAb) therapy, glutaminase inhibitor therapy, or the combination. Imaging was correlated with tumor volume and histology. In PDX …

A Scanning-To-Incision Switch In Tfiih-Xpg Induced By Dna Damage Licenses Nucleotide Excision Repair, Amer Bralić, Muhammad Tehseen, Mohamed A Sobhy, Chi-Lin Tsai, Lubna Alhudhali, Gang Yi, Jina Yu, Chunli Yan, Ivaylo Ivanov, Susan E Tsutakawa, John A Tainer, Samir M Hamdan

Faculty, Staff and Student Publications

Nucleotide excision repair (NER) is critical for removing bulky DNA base lesions and avoiding diseases. NER couples lesion recognition by XPC to strand separation by XPB and XPD ATPases, followed by lesion excision by XPF and XPG nucleases. Here, we describe key regulatory mechanisms and roles of XPG for and beyond its cleavage activity. Strikingly, by combing single-molecule imaging and bulk cleavage assays, we found that XPG binding to the 7-subunit TFIIH core (coreTFIIH) stimulates coreTFIIH-dependent double-strand (ds)DNA unwinding 10-fold, and XPG-dependent DNA cleavage by up to 700-fold. Simultaneous monitoring of rates for coreTFIIH single-stranded (ss)DNA translocation and dsDNA unwinding …

Hyperprogression Of Cutaneous T Cell Lymphoma After Anti-Pd-1 Treatment, Yumei Gao, Simeng Hu, Ruoyan Li, Shanzhao Jin, Fengjie Liu, Xiangjun Liu, Yingyi Li, Yicen Yan, Weiping Liu, Jifang Gong, Shuxia Yang, Ping Tu, Lin Shen, Fan Bai, Yang Wang

Faculty, Staff and Student Publications

BACKGROUND

Immune checkpoint blockade is an emerging treatment for T cell non-Hodgkin’s lymphoma (T-NHL), but some patients with T-NHL have experienced hyperprogression with undetermined mechanisms upon anti–PD-1 therapy.

METHODS

Single-cell RNA-Seq, whole-genome sequencing, whole-exome sequencing, and functional assays were performed on primary malignant T cells from a patient with advanced cutaneous T cell lymphoma who experienced hyperprogression upon anti–PD-1 treatment.

RESULTS

The patient was enrolled in a clinical trial of anti–PD-1 therapy and experienced disease hyperprogression. Single-cell RNA-Seq revealed that PD-1 blockade elicited a remarkable activation and proliferation of the CD4+ malignant T cells, which showed functional PD-1 expression and …

Evofosfamide For The Treatment Of Human Papillomavirus-Negative Head And Neck Squamous Cell Carcinoma, Stephen Mf Jamieson, Peter Tsai, Maria K Kondratyev, Pratha Budhani, Arthur Liu, Neil N Senzer, E Gabriela Chiorean, Shadia I Jalal, John J Nemunaitis, Dennis Kee, Avik Shome, Way W Wong, Dan Li, Nooriyah Poonawala-Lohani, Purvi M Kakadia, Nicholas S Knowlton, Courtney Rh Lynch, Cho R Hong, Tet Woo Lee, Reidar A Grénman, Laura Caporiccio, Trevor D Mckee, Mark Zaidi, Sehrish Butt, Andrew Mj Macann, Nicholas P Mcivor, John M Chaplin, Kevin O Hicks, Stefan K Bohlander, Bradly G Wouters, Charles P Hart, Cristin G Print, William R Wilson, Michael A Curran, Francis W Hunter

Faculty, Staff and Student Publications

Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug of a DNA-crosslinking nitrogen mustard that has potential utility for human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC), in which tumor hypoxia limits treatment outcome. We report the preclinical efficacy, target engagement, preliminary predictive biomarkers and initial clinical activity of evofosfamide for HPV-negative HNSCC. Evofosfamide was assessed in 22 genomically characterized cell lines and 7 cell line–derived xenograft (CDX), patient-derived xenograft (PDX), orthotopic, and syngeneic tumor models. Biomarker analysis used RNA sequencing, whole-exome sequencing, and whole-genome CRISPR knockout screens. Five advanced/metastatic HNSCC patients received evofosfamide monotherapy (480 mg/m2 qw × …

A Cryptic Oxidoreductase Safeguards Oxidative Protein Folding In Corynebacterium Diphtheriae, Melissa E Reardon-Robinson, Minh Tan Nguyen, Belkys C Sanchez, Jerzy Osipiuk, Christian Rückert, Chungyu Chang, Bo Chen, Rahul Nagvekar, Andrzej Joachimiak, Andreas Tauch, Asis Das, Hung Ton-That

Faculty, Staff and Student Publications

In many gram-positive Actinobacteria, including Actinomyces oris and Corynebacterium matruchotii, the conserved thiol-disulfide oxidoreductase MdbA that catalyzes oxidative folding of exported proteins is essential for bacterial viability by an unidentified mechanism. Intriguingly, in Corynebacterium diphtheriae, the deletion of mdbA blocks cell growth only at 37 °C but not at 30 °C, suggesting the presence of alternative oxidoreductase enzyme(s). By isolating spontaneous thermotolerant revertants of the mdbA mutant at 37 °C, we obtained genetic suppressors, all mapped to a single T-to-G mutation within the promoter region of tsdA, causing its elevated expression. Strikingly, increased expression of tsdA—via …

Identification Of Small-Molecule Inhibitors Of The Salmonella Frab Deglycase Using A Live-Cell Assay, Anice Sabag-Daigle, Erin F Boulanger, Pankajavalli Thirugnanasambantham, Jamison D Law, Alex J Bogard, Edward J Behrman, Venkat Gopalan, Brian M M Ahmer

Faculty, Staff and Student Publications

Nontyphoidal salmonellosis is one of the most significant foodborne diseases in the United States and globally. There are no vaccines available for human use to prevent this disease, and only broad-spectrum antibiotics are available to treat complicated cases of the disease. However, antibiotic resistance is on the rise and new therapeutics are needed. We previously identified the Salmonella fraB gene, that mutation of causes attenuation of fitness in the murine gastrointestinal tract. The FraB gene product is encoded in an operon responsible for the uptake and utilization of fructose-asparagine (F-Asn), an Amadori product found in several human foods. Mutations in …

Predicting Patient-Specific Tumor Dynamics: How Many Measurements Are Necessary?, Isha Harshe, Heiko Enderling, Renee Brady-Nicholls

Faculty, Staff and Student Publications

Acquiring sufficient data is imperative to accurately predict tumor growth dynamics and effectively treat patients. The aim of this study was to investigate the number of volume measurements necessary to predict breast tumor growth dynamics using the logistic growth model. The model was calibrated to tumor volume data from 18 untreated breast cancer patients using a varying number of measurements interpolated at clinically relevant timepoints with different levels of noise (0-20%). Error-to-model parameters and the data were compared to determine the sufficient number of measurements needed to accurately determine growth dynamics. We found that without noise, three tumor volume measurements …

Emerging Treatments For Myelodysplastic Syndromes: Biological Rationales And Clinical Translation, Juan Jose Rodriguez-Sevilla, Vera Adema, Guillermo Garcia-Manero, Simona Colla

Faculty, Staff and Student Publications

Myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by myeloid dysplasia, peripheral blood cytopenias, and increased risk of progression to acute myeloid leukemia (AML). The standard of care for patients with MDS is hypomethylating agent (HMA)-based therapy; however, nearly 50% of patients have no response to the treatment. Patients with MDS in whom HMA therapy has failed have a dismal prognosis and no approved second-line therapy options, so enrollment in clinical trials of experimental agents represents these patients' only chance for improved outcomes. A better understanding of the molecular and biological mechanisms underpinning MDS …

Positioning Transclival Tumor-Treating Fields For The Treatment Of Diffuse Intrinsic Pontine Gliomas, Walid Ibn Essayed, Casey A Jarvis, Joshua D Bernstock, Anna Slingerland, John Albanese, Gregory K Friedman, Omar Arnaout, Lissa Baird

Faculty, Staff and Student Publications

Diffuse intrinsic pontine glioma (DIPG) carries an extremely poor prognosis, with 2-year survival rates of <10% despite the maximal radiation therapy. DIPG cells have previously been shown to be sensitive to low-intensity electric fields in vitro. Accordingly, we sought to determine if the endoscopic endonasal (EE) implantation of an electrode array in the clivus would be feasible for the application of tumor-treating fields (TTF) in DIPG. Anatomic constraints are the main limitation in pediatric EE approaches. In our Boston Children’s Hospital’s DIPG cohort, we measured the average intercarotid distance (1.68 ± 0.36 cm), clival width (1.62 ± 0.19 cm), and clival length from the base of the sella (1.43 ± 0.69 cm). Using a linear regression model, we found that only clival length and sphenoid pneumatization were significantly associated with age (R² = 0.568, p = 0.005 *; R² = 0.605, p = 0.0002 *). Critically, neither of these parameters represent limitations to the implantation of a device within the dimensions of those currently available. Our findings confirm that the anatomy present within this age group is amenable to the placement of a 2 × 1 cm electrode array in 94% of patients examined. Our work serves to demonstrate the feasibility of implantable transclival devices for the provision of TTFs as a novel adjunctive therapy …

State Variation In Squamous Cell Carcinoma Of The Anus Incidence And Mortality, And Association With Hiv/Aids And Smoking In The United States, Haluk Damgacioglu, Yueh-Yun Lin, Ana Patricia Ortiz, Chi-Fang Wu, Zahed Shahmoradi, Shiang Shiuan Shyu, Ruosha Li, Alan G Nyitray, Keith Sigel, Gary M Clifford, Naomi Jay, Vivian Colon Lopez, Gregory M Barnell, Elizabeth Y Chiao, Elizabeth A Stier, Karen J Ortiz-Ortiz, Jeslie M Ramos-Cartagena, Kalyani Sonawane, Ashish A Deshmukh

Faculty, Staff and Student Publications

PURPOSE: Squamous cell carcinoma of the anus (SCCA) incidence and mortality rates are rising in the United States. Understanding state-level incidence and mortality patterns and associations with smoking and AIDS prevalence (key risk factors) could help unravel disparities and provide etiologic clues.

METHODS: Using the US Cancer Statistics and the National Center for Health Statistics data sets, we estimated state-level SCCA incidence and mortality rates. Rate ratios (RRs) were calculated to compare incidence and mortality in 2014-2018 versus 2001-2005. The correlations between SCCA incidence with current smoking (from the Behavioral Risk Factor Surveillance System) and AIDS (from the HIV Surveillance …

Decision-Making Under Risk And Theory Of Mind In Adolescent Offenders In Provisional Deprivation Of Liberty, Rubens José Loureiro, Flavio Takemi Kataoka, Thiago Wendt Viola, Gisele Iesbich Vargas, Breno Sanvicente-Vieira, Rodrigo Grassi-Oliveira, Bruno Kluwe-Schiavon

Faculty, Staff and Student Publications

INTRODUCTION: Delinquent behaviors are risky behaviors that increase during puberty and reach their highest peak in late adolescence. It has been proposed that poor decision-making and theory of mind (ToM) are key cognitive processes implicated with delinquency during adolescence, affecting evaluation of risks and impairing appreciation of social norms. Nevertheless, it is not yet clear whether adolescent offenders who are subjected to provisional deprivation of liberty due to conflict with the law (adolescents in conflict with the law [ACL]) might, in fact, present a specific profile with regard to these cognitive processes.

OBJECTIVES: To assess deliberative decision-making and ToM among …

Identification Of And Mechanistic Insights Into Sars-Cov-2 Main Protease Non-Covalent Inhibitors: An In-Silico Study, Jian-Xin Shen, Wen-Wen Du, Yuan-Ling Xia, Zhi-Bi Zhang, Ze-Fen Yu, Yun-Xin Fu, Shu-Qun Liu

Faculty, Staff and Student Publications

The indispensable role of the SARS-CoV-2 main protease (Mpro) in the viral replication cycle and its dissimilarity to human proteases make Mpro a promising drug target. In order to identify the non-covalent Mpro inhibitors, we performed a comprehensive study using a combined computational strategy. We first screened the ZINC purchasable compound database using the pharmacophore model generated from the reference crystal structure of Mpro complexed with the inhibitor ML188. The hit compounds were then filtered by molecular docking and predicted parameters of drug-likeness and pharmacokinetics. The final molecular dynamics (MD) simulations identified three effective candidate inhibitors (ECIs) capable of maintaining …

Differential Regulation Of H3k9/H3k14 Acetylation By Small Molecules Drives Neuron-Fate-Induction Of Glioma Cell, Xincheng Liu, Cui Guo, Tiandong Leng, Zhen Fan, Jialuo Mai, Jiehong Chen, Jinhai Xu, Qianyi Li, Bin Jiang, Ke Sai, Wenzhuo Yang, Jiayu Gu, Jingyi Wang, Shuxin Sun, Zhijie Chen, Yingqian Zhong, Xuanming Liang, Chaoxin Chen, Jing Cai, Yuan Lin, Jiankai Liang, Jun Hu, Guangmei Yan, Wenbo Zhu, Wei Yin

Faculty, Staff and Student Publications

Differentiation therapy using small molecules is a promising strategy for improving the prognosis of glioblastoma (GBM). Histone acetylation plays an important role in cell fate determination. Nevertheless, whether histone acetylation in specific sites determines GBM cells fate remains to be explored. Through screening from a 349 small molecule-library, we identified that histone deacetylase inhibitor (HDACi) MS-275 synergized with 8-CPT-cAMP was able to transdifferentiate U87MG GBM cells into neuron-like cells, which were characterized by cell cycle arrest, rich neuron biomarkers, and typical neuron electrophysiology. Intriguingly, acetylation tags of histone 3 at lysine 9 (H3K9ac) were decreased in the promoter of multiple …

Braf V600e-Mutant Cancers Treated With Vemurafenib Alone Or In Combination With Everolimus, Sorafenib, Or Crizotinib Or With Paclitaxel And Carboplatin (Vem-Plus) Study, Blessie Elizabeth Nelson, Jason Roszik, Filip Janku, David S Hong, Shumei Kato, Aung Naing, Sarina Piha-Paul, Siqing Fu, Apostolia Tsimberidou, Maria Cabanillas, Naifa Lamki Busaidy, Milind Javle, Lauren Averett Byers, John V Heymach, Funda Meric-Bernstam, Vivek Subbiah

Faculty, Staff and Student Publications

Combined BRAF + MEK inhibition is FDA approved for BRAF V600E-mutant solid tumors except for colorectal cancer. However, beyond MAPK mediated resistance several other mechanisms of resistance such as activation of CRAF, ARAF, MET, P13K/AKT/mTOR pathway exist among other complex pathways. In the VEM-PLUS study, we performed a pooled analysis of four phase one studies evaluating the safety and efficacy of vemurafenib monotherapy and vemurafenib combined with targeted therapies (sorafenib, crizotinib, or everolimus) or carboplatin plus paclitaxel in advanced solid tumors harboring BRAF V600 mutations. When vemurafenib monotherapy was compared with the combination regimens, no significant differences in OS or …

Adjuvant Chemotherapy Versus Adjuvant Concurrent Chemoradiotherapy After Radical Surgery For Early-Stage Cervical Cancer: A Randomized, Non-Inferiority, Multicenter Trial, Danhui Weng, Huihua Xiong, Changkun Zhu, Xiaoyun Wan, Yaxia Chen, Xinyu Wang, Youzhong Zhang, Jie Jiang, Xi Zhang, Qinglei Gao, Gang Chen, Hui Xing, Changyu Wang, Kezhen Li, Yaheng Chen, Yuyan Mao, Dongxiao Hu, Zimin Pan, Qingqin Chen, Baoxia Cui, Kun Song, Cunjian Yi, Guangcai Peng, Xiaobing Han, Ruifang An, Liangsheng Fan, Wei Wang, Tingchuan Xiong, Yile Chen, Zhenzi Tang, Lin Li, Xingsheng Yang, Xiaodong Cheng, Weiguo Lu, Hui Wang, Beihua Kong, Xing Xie, Ding Ma

Faculty, Staff and Student Publications

We conducted a prospective study to assess the non-inferiority of adjuvant chemotherapy alone versus adjuvant concurrent chemoradiotherapy (CCRT) as an alternative strategy for patients with early-stage (FIGO 2009 stage IB-IIA) cervical cancer having risk factors after surgery. The condition was assessed in terms of prognosis, adverse effects, and quality of life. This randomized trial involved nine centers across China. Eligible patients were randomized to receive adjuvant chemotherapy or CCRT after surgery. The primary end-point was progression-free survival (PFS). From December 2012 to December 2014, 337 patients were subjected to randomization. Final analysis included 329 patients, including 165 in the adjuvant …

Cd5 Expression By Dendritic Cells Directs T Cell Immunity And Sustains Immunotherapy Responses, Mingyu He, Kate Roussak, Feiyang Ma, Nicholas Borcherding, Vince Garin, Mike White, Charles Schutt, Trine I Jensen, Yun Zhao, Courtney A Iberg, Kairav Shah, Himanshi Bhatia, Daniel Korenfeld, Sabrina Dinkel, Judah Gray, Alina Ulezko Antonova, Stephen Ferris, David Donermeyer, Cecilia Lindestam Arlehamn, Matthew M Gubin, Jingqin Luo, Laurent Gorvel, Matteo Pellegrini, Alessandro Sette, Thomas Tung, Rasmus Bak, Robert L Modlin, Ryan C Fields, Robert D Schreiber, Paul M Allen, Eynav Klechevsky

Faculty, Staff and Student Publications

The induction of proinflammatory T cells by dendritic cell (DC) subtypes is critical for antitumor responses and effective immune checkpoint blockade (ICB) therapy. Here, we show that human CD1c+CD5+ DCs are reduced in melanoma-affected lymph nodes, with CD5 expression on DCs correlating with patient survival. Activating CD5 on DCs enhanced T cell priming and improved survival after ICB therapy. CD5+ DC numbers increased during ICB therapy, and low interleukin-6 (IL-6) concentrations promoted their de novo differentiation. Mechanistically, CD5 expression by DCs was required to generate optimally protective CD5hi T helper and CD8+ T cells; further, deletion of CD5 from T …

Exploiting Prmt5 As A Target For Combination Therapy In Mantle Cell Lymphoma Characterized By Frequent Atm And Tp53 Mutations, Yuxuan Che, Yang Liu, Yixin Yao, Holly A Hill, Yijing Li, Qingsong Cai, Fangfang Yan, Preetesh Jain, Wei Wang, Lixin Rui, Michael Wang

Faculty, Staff and Student Publications

Constant challenges for the treatment of mantle cell lymphoma (MCL) remain to be recurrent relapses and therapy resistance, especially in patients harboring somatic mutations in the tumor suppressors ATM and TP53, which are accumulated as therapy resistance emerges and the disease progresses, consistent with our OncoPrint results that ATM and TP53 alterations were most frequent in relapsed/refractory (R/R) MCL. We demonstrated that protein arginine methyltransferase-5 (PRMT5) was upregulated in R/R MCL, which predicted a poor prognosis. PRMT5 inhibitors displayed profound antitumor effects in the mouse models of MCL with mutated ATM and/or TP53, or refractory to CD19-targeted CAR T-cell therapy. …

Drug-Like Small Molecules That Inhibit Expression Of The Oncogenic Microrna-21, Matthew D Shortridge, Bhawna Chaubey, Huanyu J Zhang, Thomas Pavelitz, Venkata Vidadala, Changyan Tang, Gregory L Olsen, George A Calin, Gabriele Varani

Faculty, Staff and Student Publications

We report the discovery of drug-like small molecules that bind specifically to the precursor of the oncogenic and pro-inflammatory microRNA-21 with mid-nanomolar affinity. The small molecules target a local structure at the Dicer cleavage site and induce distinctive structural changes in the RNA, which correlate with specific inhibition of miRNA processing. Structurally conservative single nucleotide substitutions eliminate the conformational change induced by the small molecules, which is also not observed in other miRNA precursors. The most potent of these compounds reduces cellular proliferation and miR-21 levels in cancer cell lines without inhibiting kinases or classical receptors, while closely related compounds …

Exploiting Metabolic Vulnerabilities After Anti-Vegf Antibody Therapy In Ovarian Cancer, Deanna Glassman, Mark S Kim, Meredith Spradlin, Sunil Badal, Mana Taki, Pratip Bhattacharya, Prasanta Dutta, Charles V Kingsley, Katherine I Foster, Olamide Animasahun, Jin Heon Jeon, Abhinav Achreja, Anusha Jayaraman, Praveen Kumar, Minal Nenwani, Fulei Wuchu, Emine Bayraktar, Yutuan Wu, Elaine Stur, Lingegowda Mangala, Sanghoon Lee, Timothy A Yap, Shannon N Westin, Livia S Eberlin, Deepak Nagrath, Anil K Sood

Faculty, Staff and Student Publications

Despite modest clinical improvement with anti-vascular endothelial growth factor antibody (AVA) therapy in ovarian cancer, adaptive resistance is ubiquitous and additional options are limited. A dependence on glutamine metabolism, via the enzyme glutaminase (GLS), is a known mechanism of adaptive resistance and we aimed to investigate the utility of a GLS inhibitor (GLSi). Our in vitro findings demonstrated increased glutamine abundance and a significant cytotoxic effect in AVA-resistant tumors when GLSi was administered in combination with bevacizumab. In vivo, GLSi led to a reduction in tumor growth as monotherapy and when combined with AVA. Furthermore, GLSi initiated after the emergence …

Endothelial-To-Osteoblast Transition In Normal Mouse Bone Development, Song-Chang Lin, Guoyu Yu, Yu-Chen Lee, Jian H Song, Xingzhi Song, Jianhua Zhang, Theocharis Panaretakis, Christopher J Logothetis, Yoshihiro Komatsu, Li-Yuan Yu-Lee, Guocan Wang, Sue-Hwa Lin

Faculty, Staff and Student Publications

Metastatic prostate cancer (PCa) in bone induces bone-forming lesions. We have previously shown that PCa-induced bone originates from endothelial cells (ECs) that have undergone EC-to-osteoblast (OSB) transition. Here, we investigated whether EC-to-OSB transition also occurs during normal bone formation. We developed an EC and OSB dual-color reporter mouse (DRM) model that marks EC-OSB hybrid cells with red and green fluorescent proteins. We observed EC-to-OSB transition (RFP and GFP co-expression) in both endochondral and intramembranous bone formation during embryonic development and in adults. Co-expression was confirmed in cells isolated from DRM. Bone marrow– and lung-derived ECs underwent transition to OSBs and …

Functional Connectivity Signatures Of Nmdar Dysfunction In Schizophrenia—Integrating Findings From Imaging Genetics And Pharmaco-Fmri, Arnim J Gaebler, Nilüfer Fakour, Felix Stöhr, Jana Zweerings, Arezoo Taebi, Mariia Suslova, Juergen Dukart, Joerg F Hipp, Bhim M Adhikari, Peter Kochunov, Suresh D Muthukumaraswamy, Anna Forsyth, Thomas Eggermann, Florian Kraft, Ingo Kurth, Michael Paulzen, Gerhard Gründer, Frank Schneider, Klaus Mathiak

Faculty, Staff and Student Publications

Both, pharmacological and genome-wide association studies suggest N-methyl-D-aspartate receptor (NMDAR) dysfunction and excitatory/inhibitory (E/I)-imbalance as a major pathophysiological mechanism of schizophrenia. The identification of shared fMRI brain signatures of genetically and pharmacologically induced NMDAR dysfunction may help to define biomarkers for patient stratification. NMDAR-related genetic and pharmacological effects on functional connectivity were investigated by integrating three different datasets: (A) resting state fMRI data from 146 patients with schizophrenia genotyped for the disease-associated genetic variant rs7191183 of GRIN2A (encoding the NMDAR 2 A subunit) as well as 142 healthy controls. (B) Pharmacological effects of the NMDAR antagonist ketamine and the GABA-A …

A Deep Learning Approach To Identify Missing Is-A Relations In Snomed Ct, Rashmie Abeysinghe, Fengbo Zheng, Elmer V Bernstam, Jay Shi, Olivier Bodenreider, Licong Cui

Faculty, Staff and Student Publications

OBJECTIVE: SNOMED CT is the largest clinical terminology worldwide. Quality assurance of SNOMED CT is of utmost importance to ensure that it provides accurate domain knowledge to various SNOMED CT-based applications. In this work, we introduce a deep learning-based approach to uncover missing is-a relations in SNOMED CT.

MATERIALS AND METHODS: Our focus is to identify missing is-a relations between concept-pairs exhibiting a containment pattern (ie, the set of words of one concept being a proper subset of that of the other concept). We use hierarchically related containment concept-pairs as positive instances and hierarchically unrelated containment concept-pairs as negative instances …

Structural Basis Of Impaired Disaggregase Function In The Oxidation-Sensitive Skd3 Mutant Causing 3-Methylglutaconic Aciduria, Jose J Gorbea Colón, Leon Palao, Shin-Fu Chen, Hee Jong Kim, Laura Snyder, Yi-Wei Chang, Kuang-Lei Tsai, Kenji Murakami

Faculty, Staff and Student Publications

Most eukaryotic promoter regions are divergently transcribed. As the RNA polymerase II pre-initiation complex (PIC) is intrinsically asymmetric and responsible for transcription in a single direction, it is unknown how divergent transcription arises. Here, the Saccharomyces cerevisiae Mediator complexed with a PIC (Med-PIC) was assembled on a divergent promoter and analyzed by cryoelectron microscopy. The structure reveals two distinct Med-PICs forming a dimer through the Mediator tail module, induced by a homodimeric activator protein localized near the dimerization interface. The tail dimer is associated with ∼80-bp upstream DNA, such that two flanking core promoter regions are positioned and oriented in …

Genome-Wide Identification, Characterization, And Expression Analysis Of Spiral1 Family Genes In Legume Species, Qianxia Yu, Junjie Liu, Jiayu Jiang, Fudong Liu, Zhen Zhang, Xiaoye Yu, Mengru Li, Intikhab Alam, Liangfa Ge

Faculty, Staff and Student Publications

The SPIRAL1 (SPR1) gene family encodes microtubule-associated proteins that are essential for the anisotropic growth of plant cells and abiotic stress resistance. Currently, little is known about the characteristics and roles of the gene family outside of Arabidopsis thaliana. This study intended to investigate the SPR1 gene family in legumes. In contrast to that of A. thaliana, the gene family has undergone shrinking in the model legume species Medicago truncatula and Glycine max. While the orthologues of SPR1 were lost, very few SPR1-Like (SP1L) genes were identified given the genome size of the two …