Medical Specialties Commons^™

Deep Learning Prediction Boosts Phosphoproteomics-Based Discoveries Through Improved Phosphopeptide Identification, Xinpei Yi, Bo Wen, Shuyi Ji, Alexander B Saltzman, Eric J Jaehnig, Jonathan T Lei, Qiang Gao, Bing Zhang

Faculty, Staff and Students Publications

Shotgun phosphoproteomics enables high-throughput analysis of phosphopeptides in biological samples. One of the primary challenges associated with this technology is the relatively low rate of phosphopeptide identification during data analysis. This limitation hampers the full realization of the potential offered by shotgun phosphoproteomics. Here we present DeepRescore2, a computational workflow that leverages deep learning-based retention time and fragment ion intensity predictions to improve phosphopeptide identification and phosphosite localization. Using a state-of-the-art computational workflow as a benchmark, DeepRescore2 increases the number of correctly identified peptide-spectrum matches by 17% in a synthetic dataset and identifies 19% to 46% more phosphopeptides in biological …

A Novel Polymer-Encapsulated Multi-Imaging Modality Fiducial Marker With Positive Signal Contrast For Image-Guided Radiation Therapy, Li Wang, Jeremiah Sanders, John F Ward, Stephen R Lee, Falk Poenisch, David Michael Swanson, Narayan Sahoo, Xiaorong Ronald Zhu, Jingfei Ma, Rajat J Kudchadker, Seungtaek L Choi, Quynh-Nhu Nguyen, Lauren L Mayo, Shalin J Shah, Steven J Frank

Faculty, Staff and Student Publications

BACKGROUND: Current fiducial markers (FMs) in external-beam radiotherapy (EBRT) for prostate cancer (PCa) cannot be positively visualized on magnetic resonance imaging (MRI) and create dose perturbation and significant imaging artifacts on computed tomography (CT) and MRI. We report our initial experience with clinical imaging of a novel multimodality FM, NOVA.

METHODS: We tested Gold Anchor [G-FM], BiomarC [carbon, C-FM], and NOVA FMs in phantoms imaged with kilovoltage (kV) X-rays, transrectal ultrasound (TRUS), CT, and MRI. Artifacts of the FMs on CT were quantified by the relative streak artifacts level (rSAL) metric. Proton dose perturbations (PDPs) were measured with Gafchromic EBT3 …

Management Of Infliximab Refractory Immune Checkpoint Inhibitor Gastrointestinal Toxicity: A Multicenter Case Series, Catriona Harvey, Kazi J Nahar, Janet Mckeown, Serigne N Lo, Sheima Farag, Nadia Yousaf, Kate Young, Liselotte Tas, Aafke Meerveld-Eggink, Christian Blank, Austin Thomas, Jennifer Mcquade, Bastian Schilling, Douglas B Johnson, Roberto Martín Huertas, Ana Arance, Joanna Lee, Lisa Zimmer, Georgina V Long, Matteo S Carlino, Yinghong Wang, Alexander Maxwell Menzies

Faculty, Staff and Student Publications

Background: Immune checkpoint inhibitor (ICI) gastrointestinal toxicity (gastritis, enteritis, colitis) is a major cause of morbidity and treatment-related death. Guidelines agree steroid-refractory cases warrant infliximab, however best management of infliximab-refractory ICI gastrointestinal toxicity (IRIGItox) is unknown.

Methods: We conducted an international multicenter retrospective case series. IRIGItox was defined as failure of symptom resolution ≤grade 1 (Common Terminology Criteria for Adverse Events V.5.0) following ≥2 infliximab doses or failure of symptom resolution ≤grade 2 after one dose. Data were extracted regarding demographics, steroid use, response to treatment, and survival outcomes. Toxicity was graded at symptom onset and time of infliximab failure. …

Cytoskeleton Remodeling Induced By Smyd2 Methyltransferase Drives Breast Cancer Metastasis, Alexandre G Casanova, Gael S Roth, Simone Hausmann, Xiaoyin Lu, Ludivine J M Bischoff, Emilie M Froeliger, Lucid Belmudes, Ekaterina Bourova-Flin, Natasha M Flores, Ana Morales Benitez, Tourkian Chasan, Marcello Caporicci, Jessica Vayr, Sandrine Blanchet, Francesco Ielasi, Sophie Rousseaux, Pierre Hainaut, Or Gozani, Muriel Le Romancer, Yohann Couté, Andres Palencia, Pawel K Mazur, Nicolas Reynoird

Faculty, Staff and Student Publications

Malignant forms of breast cancer refractory to existing therapies remain a major unmet health issue, primarily due to metastatic spread. A better understanding of the mechanisms at play will provide better insights for alternative treatments to prevent breast cancer cell dispersion. Here, we identify the lysine methyltransferase SMYD2 as a clinically actionable master regulator of breast cancer metastasis. While SMYD2 is overexpressed in aggressive breast cancers, we notice that it is not required for primary tumor growth. However, mammary-epithelium specific SMYD2 ablation increases mouse overall survival by blocking the primary tumor cell ability to metastasize. Mechanistically, we identify BCAR3 as …

Measures Of Resting-State Brain Network Segregation And Integration Vary In Relation To Data Quantity: Implications For Within And Between Subject Comparisons Of Functional Brain Network Organization, Liang Han, Micaela Y Chan, Phillip F Agres, Ezra Winter-Nelson, Ziwei Zhang, Gagan S Wig

Faculty, Staff and Student Publications

Measures of functional brain network segregation and integration vary with an individual's age, cognitive ability, and health status. Based on these relationships, these measures are frequently examined to study and quantify large-scale patterns of network organization in both basic and applied research settings. However, there is limited information on the stability and reliability of the network measures as applied to functional time-series; these measurement properties are critical to understand if the measures are to be used for individualized characterization of brain networks. We examine measurement reliability using several human datasets (Midnight Scan Club and Human Connectome Project [both Young Adult …

Dynamic Prognosis Prediction For Patients On Dapt After Drug-Eluting Stent Implantation: Model Development And Validation, Fang Li, Laila Rasmy, Yang Xiang, Jingna Feng, Ahmed Abdelhameed, Xinyue Hu, Zenan Sun, David Aguilar, Abhijeet Dhoble, Jingcheng Du, Qing Wang, Shuteng Niu, Yifang Dang, Xinyuan Zhang, Ziqian Xie, Yi Nian, Jianping He, Yujia Zhou, Jianfu Li, Mattia Prosperi, Jiang Bian, Degui Zhi, Cui Tao

School of Medicine Faculty Publications

BACKGROUND: The rapid evolution of artificial intelligence (AI) in conjunction with recent updates in dual antiplatelet therapy (DAPT) management guidelines emphasizes the necessity for innovative models to predict ischemic or bleeding events after drug-eluting stent implantation. Leveraging AI for dynamic prediction has the potential to revolutionize risk stratification and provide personalized decision support for DAPT management. METHODS AND RESULTS: We developed and validated a new AI-based pipeline using retrospective data of drug-eluting stent-treated patients, sourced from the Cerner Health Facts data set (n=98 236) and Optum’s de-identified Clinformatics Data Mart Database (n=9978). The 36 months following drug-eluting stent implantation were …

Harnessing Physical Activity Monitoring And Digital Biomarkers Of Frailty From Pendant Based Wearables To Predict Chemotherapy Resilience In Veterans With Cancer, Gozde Cay, Yvonne H Sada, Mohammad Dehghan Rouzi, Md Moin Uddin Atique, Naima Rodriguez, Mehrnaz Azarian, M G Finco, Sarvari Yellapragada, Bijan Najafi

Center on Aging Staff Publications

This study evaluated the use of pendant-based wearables for monitoring digital biomarkers of frailty in predicting chemotherapy resilience among 27 veteran cancer patients (average age: 64.6 ± 13.4 years), undergoing bi-weekly chemotherapy. Immediately following their first day of chemotherapy cycle, participants wore a water-resistant pendant sensor for 14 days. This device tracked frailty markers like cadence (slowness), daily steps (inactivity), postural transitions (weakness), and metrics such as longest walk duration and energy expenditure (exhaustion). Participants were divided into resilient and non-resilient groups based on adverse events within 6 months post-chemotherapy, including dose reduction, treatment discontinuation, unplanned hospitalization, or death. A …

Myd88 In Myofibroblasts Enhances Nonalcoholic Fatty Liver Disease-Related Hepatocarcinogenesis Via Promoting Macrophage M2 Polarization, Yu Liu, Haiqiang Chen, Xuanxuan Yan, Jie Zhang, Zhenzhong Deng, Maosheng Huang, Jianchun Gu, Jinhua Zhang

Faculty, Staff and Student Publications

Background: Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver diseases and has emerged as the leading factor in the pathogenesis of hepatocellular carcinoma (HCC). MyD88 contributes to the development of HCC. However, the underlying mechanism by which MyD88 in myofibroblasts regulates NAFLD-associated liver cancer development remains unknown.

Results: Myofibroblast MyD88-deficient (SMAMyD88-/-) mice were protected from diet-induced obesity and developed fewer and smaller liver tumors. MyD88 deficiency in myofibroblasts attenuated macrophage M2 polarization and fat accumulation in HCC tissues. Mechanistically, MyD88 signaling in myofibroblasts enhanced CCL9 secretion, thereby promoting macrophage M2 polarization. This process may depend on …

Expression Of Atoh1, Gfi1, And Pou4f3 In The Mature Cochlea Reprograms Nonsensory Cells Into Hair Cells, Melissa M Mcgovern, Ishwar V Hosamani, Yichi Niu, Ken Y Nguyen, Chenghang Zong, Andrew K Groves

Faculty, Staff and Students Publications

Mechanosensory hair cells of the mature mammalian organ of Corti do not regenerate; consequently, loss of hair cells leads to permanent hearing loss. Although nonmammalian vertebrates can regenerate hair cells from neighboring supporting cells, many humans with severe hearing loss lack both hair cells and supporting cells, with the organ of Corti being replaced by a flat epithelium of nonsensory cells. To determine whether the mature cochlea can produce hair cells in vivo, we reprogrammed nonsensory cells adjacent to the organ of Corti with three hair cell transcription factors: Gfi1, Atoh1, and Pou4f3. We generated numerous hair cell–like …

Frozen Tissue Coring And Layered Histological Analysis Improves Cell Type-Specific Proteogenomic Characterization Of Pancreatic Adenocarcinoma, Sara R Savage, Yuefan Wang, Lijun Chen, Scott Jewell, Chelsea Newton, Yongchao Dou, Qing Kay Li, Oliver F Bathe, Ana I Robles, Gilbert S Omenn, Mathangi Thiagarajan, Hui Zhang, Galen Hostetter, Bing Zhang

Faculty, Staff and Students Publications

BACKGROUND: Omics characterization of pancreatic adenocarcinoma tissue is complicated by the highly heterogeneous and mixed populations of cells. We evaluate the feasibility and potential benefit of using a coring method to enrich specific regions from bulk tissue and then perform proteogenomic analyses.

METHODS: We used the Biopsy Trifecta Extraction (BioTExt) technique to isolate cores of epithelial-enriched and stroma-enriched tissue from pancreatic tumor and adjacent tissue blocks. Histology was assessed at multiple depths throughout each core. DNA sequencing, RNA sequencing, and proteomics were performed on the cored and bulk tissue samples. Supervised and unsupervised analyses were performed based on integrated molecular …

Longitudinal Varying Coefficient Single-Index Model With Censored Covariates, Shikun Wang, Jing Ning, Ying Xu, Ya-Chen Tina Shih, Yu Shen, Liang Li

Faculty, Staff and Student Publications

It is of interest to health policy research to estimate the population-averaged longitudinal medical cost trajectory from initial cancer diagnosis to death, and understand how the trajectory curve is affected by patient characteristics. This research question leads to a number of statistical challenges because the longitudinal cost data are often non-normally distributed with skewness, zero-inflation, and heteroscedasticity. The trajectory is nonlinear, and its length and shape depend on survival, which are subject to censoring. Modeling the association between multiple patient characteristics and nonlinear cost trajectory curves of varying lengths should take into consideration parsimony, flexibility, and interpretation. We propose a …

Accounting For Network Noise In Graph-Guided Bayesian Modeling Of Structured High-Dimensional Data, Wenrui Li, Changgee Chang, Suprateek Kundu, Qi Long

Faculty, Staff and Student Publications

There is a growing body of literature on knowledge-guided statistical learning methods for analysis of structured high-dimensional data (such as genomic and transcriptomic data) that can incorporate knowledge of underlying networks derived from functional genomics and functional proteomics. These methods have been shown to improve variable selection and prediction accuracy and yield more interpretable results. However, these methods typically use graphs extracted from existing databases or rely on subject matter expertise, which are known to be incomplete and may contain false edges. To address this gap, we propose a graph-guided Bayesian modeling framework to account for network noise in regression …

Leveraging Trop2 Antibody-Drug Conjugates In Solid Tumors, Blessie Elizabeth Nelson, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Antibody-drug conjugates (ADCs) have become the cornerstone of effective therapeutics in solid and hematological malignancies by harnessing potent cytotoxic payloads with targeted tumoricidal delivery. Since the monumental shift occurred with HER2-targeted ADCs, the discovery of the TROP2 antigen has revolutionized the landscape of ADC development. Moving beyond the traditional ADC design, multiple novel ADCs have successfully shaped and improved survival outcomes in patients with various tumor histologies. Here we review and contrast the clinical impact of the well-known TROP2 ADCs currently in clinical use. We also shed light on upcoming investigational TROP2 ADCs showing promise with novel ADC platforms.

Patient-Derived Models Of Cancer In The Nci Pdmc Consortium: Selection, Pitfalls, And Practical Recommendations, Amber N Habowski, Deepthi P Budagavi, Sandra D Scherer, Arin B Aurora, Giuseppina Caligiuri, William F Flynn, Ellen M Langer, Jonathan R Brody, Rosalie C Sears, Giorgia Foggetti, Anna Arnal Estape, Don X Nguyen, Katerina A Politi, Xiling Shen, David S Hsu, Donna M Peehl, John Kurhanewicz, Renuka Sriram, Milagros Suarez, Sophie Xiao, Yuchen Du, Xiao-Nan Li, Nora M Navone, Estefania Labanca, Christopher D Willey

Faculty, Staff and Student Publications

For over a century, early researchers sought to study biological organisms in a laboratory setting, leading to the generation of both in vitro and in vivo model systems. Patient-derived models of cancer (PDMCs) have more recently come to the forefront of preclinical cancer models and are even finding their way into clinical practice as part of functional precision medicine programs. The PDMC Consortium, supported by the Division of Cancer Biology in the National Cancer Institute of the National Institutes of Health, seeks to understand the biological principles that govern the various PDMC behaviors, particularly in response to perturbagens, such as …

Ahp Db: A Reference Database Of Proteins In The Human Aqueous Humor, Tae Jin Lee, Arnav Goyal, Garrett Jones, Joshua Glass, Vishal Doshi, Kathryn Bollinger, Lane Ulrich, Saleh Ahmed, Sai Karthik Kodeboyina, Amy Estes, Marc Töteberg-Harms, Wenbo Zhi, Shruti Sharma, Ashok Sharma

Faculty, Staff and Student Publications

The aqueous humor (AH) is a low-viscosity biofluid that continuously circulates from the posterior chamber to the anterior chamber of the eye. Recent advances in high-resolution mass-spectrometry workflows have facilitated the study of proteomic content in small-volume biofluids like AH, highlighting the potential clinical implications of the AH proteome. Nevertheless, in-depth investigations into the role of AH proteins in ocular diseases have encountered challenges due to limited accessibility to these workflows, difficulties in large-scale AH sample collection and the absence of a reference AH proteomic database. In response to these obstacles, and to promote further research on the involvement of …

A Generalized Phase 1-2-3 Design Integrating Dose Optimization With Confirmatory Treatment Comparison, Yong Zang, Peter F Thall, Ying Yuan

Faculty, Staff and Student Publications

A generalized phase 1-2-3 design, Gen 1-2-3, that includes all phases of clinical treatment evaluation is proposed. The design extends and modifies the design of Chapple and Thall (2019), denoted by CT. Both designs begin with a phase 1-2 trial including dose acceptability and optimality criteria, and both select an optimal dose for phase 3. The Gen 1-2-3 design has the following key differences. In stage 1, it uses phase 1-2 criteria to identify a set of candidate doses rather than 1 dose. In stage 2, which is intermediate between phase 1-2 and phase 3, it randomizes additional patients fairly …

Reconstitution Of Human Pdac Using Primary Cells Reveals Oncogenic Transcriptomic Features At Tumor Onset, Yi Xu, Michael H Nipper, Angel A Dominguez, Zhenqing Ye, Naoki Akanuma, Kevin Lopez, Janice J Deng, Destiny Arenas, Ava Sanchez, Francis E Sharkey, Colin M Court, Aatur D Singhi, Huamin Wang, Martin E Fernandez-Zapico, Lu-Zhe Sun, Siyuan Zheng, Yidong Chen, Jun Liu, Pei Wang

Faculty, Staff and Student Publications

Animal studies have demonstrated the ability of pancreatic acinar cells to transform into pancreatic ductal adenocarcinoma (PDAC). However, the tumorigenic potential of human pancreatic acinar cells remains under debate. To address this gap in knowledge, we expand sorted human acinar cells as 3D organoids and genetically modify them through introduction of common PDAC mutations. The acinar organoids undergo dramatic transcriptional alterations but maintain a recognizable DNA methylation signature. The transcriptomes of acinar organoids are similar to those of disease-specific cell populations. Oncogenic KRAS alone do not transform acinar organoids. However, acinar organoids can form PDAC in vivo after acquiring the …

Single-Cell Multiomics Decodes Regulatory Programs For Mouse Secondary Palate Development, Fangfang Yan, Akiko Suzuki, Chihiro Iwaya, Guangsheng Pei, Xian Chen, Hiroki Yoshioka, Meifang Yu, Lukas M Simon, Junichi Iwata, Zhongming Zhao

Faculty, Staff and Student Publications

Perturbations in gene regulation during palatogenesis can lead to cleft palate, which is among the most common congenital birth defects. Here, we perform single-cell multiome sequencing and profile chromatin accessibility and gene expression simultaneously within the same cells (n = 36,154) isolated from mouse secondary palate across embryonic days (E) 12.5, E13.5, E14.0, and E14.5. We construct five trajectories representing continuous differentiation of cranial neural crest-derived multipotent cells into distinct lineages. By linking open chromatin signals to gene expression changes, we characterize the underlying lineage-determining transcription factors. In silico perturbation analysis identifies transcription factors SHOX2 and MEOX2 as important regulators …

Systematic Review Of Mortality And Survival Rates For Apds, Jennifer Hanson, Penelope E Bonnen

Faculty, Staff and Students Publications

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare genetic disorder that presents clinically as a primary immunodeficiency. Clinical presentation of APDS includes severe, recurrent infections, lymphoproliferation, lymphoma, and other cancers, autoimmunity and enteropathy. Autosomal dominant variants in two independent genes have been demonstrated to cause APDS. Pathogenic variants in PIK3CD and PIK3R1, both of which encode components of the PI3-kinase, have been identified in subjects with APDS. APDS1 is caused by gain of function variants in the PIK3CD gene, while loss of function variants in PIK3R1 have been reported to cause APDS2. We conducted a review of the medical …

Psychological Distress In Low-Income And Economically Marginalized Populations In India: Protective And Risk Factors, Dipti Singh, Shagufta Nasir, Juhi Sharma, Lydia Giménez-Llort, Mohammad Ghazi Shahnawaz

Faculty, Staff and Student Publications

Studies at the juncture of development economics and public health take on considerable responsibility in addressing inequality and related mental health distress. Mental healthcare in economically marginalized populations requires depicting the linkages between socioeconomic status and psychological distress. In the present work, a sequential mixed-methods design was used to study 190 people in such communities in India. Gender-dependent psychological distress was found according to the Kessler Psychological Distress Scale (K-10) with moderate distress in women (M = 26.30, SD = 9.15) and mild distress in men (M = 21.04, SD = 8.35). Regression analysis indicated that gender significantly predicted psychological …

Interplay Between Atrx And Idh1 Mutations Governs Innate Immune Responses In Diffuse Gliomas, Seethalakshmi Hariharan, Benjamin T Whitfield, Christopher J Pirozzi, Matthew S Waitkus, Michael C Brown, Michelle L Bowie, David M Irvin, Kristen Roso, Rebecca Fuller, Janell Hostettler, Sharvari Dharmaiah, Emiley A Gibson, Aaron Briley, Avani Mangoli, Casey Fraley, Mariah Shobande, Kevin Stevenson, Gao Zhang, Prit Benny Malgulwar, Hannah Roberts, Martin Roskoski, Ivan Spasojevic, Stephen T Keir, Yiping He, Maria G Castro, Jason T Huse, David M Ashley

Faculty, Staff and Student Publications

Stimulating the innate immune system has been explored as a therapeutic option for the treatment of gliomas. Inactivating mutations in ATRX, defining molecular alterations in IDH-mutant astrocytomas, have been implicated in dysfunctional immune signaling. However, little is known about the interplay between ATRX loss and IDH mutation on innate immunity. To explore this, we generated ATRX-deficient glioma models in the presence and absence of the IDH1R132H mutation. ATRX-deficient glioma cells are sensitive to dsRNA-based innate immune agonism and exhibit impaired lethality and increased T-cell infiltration in vivo. However, the presence of IDH1R132H dampens baseline expression of key innate immune genes …

Short-Term Impact Of Low-Intensity Exercise With Blood Flow Restriction On Mild Knee Osteoarthritis In Older Adults: A Pilot Study, Kang-Ho Kim, Seung-Ho Kang, Nackhwan Kim, Jaehyeong Choi, Seok Kang

Faculty, Staff and Student Publications

This pilot study aimed to investigate the immediate impact of low-intensity exercises with blood flow restriction (BFR) on older adults with knee osteoarthritis (KOA). Fifteen patients with KOA who were over 50 years old, participated and underwent low-intensity resistance knee exercises at 30% of their one-repetition maximum with BFR three times/week for two weeks. Pre- and post-exercise assessments included pain levels, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, isokinetic knee strength, lower extremity muscle volume (via leg circumference and muscle thickness), functional performance tests (timed up-and-go [TUG] and sit-to-stand [STS]), skeletal muscle index (SMI) using bioelectrical impedance analysis, …

Novel Strategies To Improve The Cardioprotective Effects Of Cardioplegia, Estefanie Osorio-Llanes, Jairo Castellar-López, Wendy Rosales-Rada, Yulieth Montoya, John Bustamante, Ricardo Zalaquett, Roberto Bravo-Sagua, Jaime A Riquelme, Gina Sánchez, Mario Chiong, Sergio Lavandero, Evelyn Mendoza-Torres

Faculty, Staff and Student Publications

The use of cardioprotective strategies as adjuvants of cardioplegic solutions has become an ideal alternative for the improvement of post-surgery heart recovery. The choice of the optimal cardioplegia, as well as its distribution mechanism, remains controversial in the field of cardiovascular surgery. There is still a need to search for new and better cardioprotective methods during cardioplegic procedures. New techniques for the management of cardiovascular complications during cardioplegia have evolved with new alternatives and additives, and each new strategy provides a tool to neutralize the damage after ischemia/reperfusion events. Researchers and clinicians have committed themselves to studying the effect of …

Exploring Novel Frontiers: Leveraging Stat3 Signaling For Advanced Cancer Therapeutics, Taiwo Adesoye, Debasish Tripathy, Kelly K Hunt, Khandan Keyomarsi

Faculty, Staff and Student Publications

Signal Transducer and Activator of Transcription 3 (STAT3) plays a significant role in diverse physiologic processes, including cell proliferation, differentiation, angiogenesis, and survival. STAT3 activation via phosphorylation of tyrosine and serine residues is a complex and tightly regulated process initiated by upstream signaling pathways with ligand binding to receptor and non-receptor-linked kinases. Through downstream deregulation of target genes, aberrations in STAT3 activation are implicated in tumorigenesis, metastasis, and recurrence in multiple cancers. While there have been extensive efforts to develop direct and indirect STAT3 inhibitors using novel drugs as a therapeutic strategy, direct clinical application remains in evolution. In this …

Crispr Screening Identifies Bet And Mtor Inhibitor Synergy In Cholangiocarcinoma Through Serine Glycine One Carbon, Yan Zhu, Dengyong Zhang, Pooja Shukla, Young-Ho Jung, Prit Benny Malgulwar, Sharmeen Chagani, Medina Colic, Sarah Benjamin, John A Copland, Lin Tan, Philip L Lorenzi, Milind Javle, Jason T Huse, Jason Roszik, Traver Hart, Lawrence N Kwong

Faculty, Staff and Student Publications

Patients with cholangiocarcinoma have poor clinical outcomes due to late diagnoses, poor prognoses, and limited treatment strategies. To identify drug combinations for this disease, we have conducted a genome-wide CRISPR screen anchored on the bromodomain and extraterminal domain (BET) PROTAC degrader ARV825, from which we identified anticancer synergy when combined with genetic ablation of members of the mTOR pathway. This combination effect was validated using multiple pharmacological BET and mTOR inhibitors, accompanied by increased levels of apoptosis and cell cycle arrest. In a xenograft model, combined BET degradation and mTOR inhibition induced tumor regression. Mechanistically, the 2 inhibitor classes converged …

Hedgehog Activation Promotes Osteogenic Fates Of Growth Plate Resting Zone Chondrocytes Through Transient Clonal Competency, Shion Orikasa, Yuki Matsushita, Hiroaki Manabe, Michael Fogge, Zachary Lee, Koji Mizuhashi, Naoko Sakagami, Wanida Ono, Noriaki Ono

Faculty, Staff and Student Publications

The resting zone of the postnatal growth plate is organized by slow-cycling chondrocytes expressing parathyroid hormone-related protein (PTHrP), which include a subgroup of skeletal stem cells that contribute to the formation of columnar chondrocytes. The PTHrP-Indian hedgehog feedback regulation is essential for sustaining growth plate activities; however, molecular mechanisms regulating cell fates of PTHrP+ resting chondrocytes and their eventual transformation into osteoblasts remain largely undefined. Here, in a mouse model, we specifically activated Hedgehog signaling in PTHrP+ resting chondrocytes and traced the fate of their descendants using a tamoxifen-inducible Pthrp-creER line with patched-1-floxed and tdTomato reporter alleles. Hedgehog-activated PTHrP+ chondrocytes …

Trex2 Deficiency Suppresses Spontaneous And Genotoxin-Associated Mutagenesis, Teresa Marple, Mi Young Son, Xiaodong Cheng, Jun Ho Ko, Patrick Sung, Paul Hasty

Faculty, Staff and Student Publications

TREX2, a 3'-5' exonuclease, is a part of the DNA damage tolerance (DDT) pathway that stabilizes replication forks (RFs) by ubiquitinating PCNA along with the ubiquitin E3 ligase RAD18 and other DDT factors. Mismatch repair (MMR) corrects DNA polymerase errors, including base mismatches and slippage. Here we demonstrate that TREX2 deletion reduces mutations in cells upon exposure to genotoxins, including those that cause base lesions and DNA polymerase slippage. Importantly, we show that TREX2 generates most of the spontaneous mutations in MMR-mutant cells derived from mice and people. TREX2-induced mutagenesis is dependent on the nuclease and DNA-binding attributes of TREX2. …

Non-Canonical Hedgehog Signaling Mediates Profibrotic Hematopoiesis-Stroma Crosstalk In Myeloproliferative Neoplasms, Jessica E Pritchard, Juliette E Pearce, Inge A M Snoeren, Stijn N R Fuchs, Katrin Götz, Fabian Peisker, Silke Wagner, Adam Benabid, Niklas Lutterbach, Vanessa Klöker, James S Nagai, Monica T Hannani, Anna K Galyga, Ellen Sistemich, Bella Banjanin, Niclas Flosdorf, Eric Bindels, Kathrin Olschok, Katharina Biaesch, Nicolas Chatain, Neha Bhagwat, Andrew Dunbar, Rita Sarkis, Olaia Naveiras, Marie-Luise Berres, Steffen Koschmieder, Ross L Levine, Ivan G Costa, Hélène F E Gleitz, Rafael Kramann, Rebekka K Schneider

Faculty, Staff and Student Publications

The role of hematopoietic Hedgehog signaling in myeloproliferative neoplasms (MPNs) remains incompletely understood despite data suggesting that Hedgehog (Hh) pathway inhibitors have therapeutic activity in patients. We aim to systematically interrogate the role of canonical vs. non-canonical Hh signaling in MPNs. We show that Gli1 protein levels in patient peripheral blood mononuclear cells (PBMCs) mark fibrotic progression and that, in murine MPN models, absence of hematopoietic Gli1, but not Gli2 or Smo, significantly reduces MPN phenotype and fibrosis, indicating that GLI1 in the MPN clone can be activated in a non-canonical fashion. Additionally, we establish that hematopoietic Gli1 has a …

A Study To Assess The Efficacy Of Enasidenib And Risk-Adapted Addition Of Azacitidine In Newly Diagnosed Idh2-Mutant Aml, Sheng F Cai, Ying Huang, Jennie R Lance, Hsiaoyin Charlene Mao, Andrew J Dunbar, Samantha N Mcnulty, Todd Druley, Yan Li, Maria R Baer, Wendy Stock, Tibor Kovacsovics, William G Blum, Gary J Schiller, Rebecca L Olin, James M Foran, Mark Litzow, Tara Lin, Prapti Patel, Matthew C Foster, Michael Boyiadzis, Robert H Collins, Jordan Chervin, Abigail Shoben, Jo-Anne Vergilio, Nyla A Heerema, Leonard Rosenberg, Timothy L Chen, Ashley O Yocum, Franchesca Druggan, Sonja Marcus, Mona Stefanos, Brian J Druker, Alice S Mims, Uma Borate, Amy Burd, John C Byrd, Ross L Levine, Eytan M Stein

Faculty, Staff and Student Publications

Enasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENA monotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of …

Neural Correlates Of Automatic Emotion Regulation And Their Association With Suicidal Ideation In Adolescents During The First 90-Days Of Residential Care, Matthew Dobbertin, Karina S Blair, Joseph Aloi, Sahil Bajaj, Johannah Bashford-Largo, Avantika Mathur, Ru Zhang, Erin Carollo, Amanda Schwartz, Jaimie Elowsky, J L Ringle, Patrick Tyler, R James Blair

Faculty, Staff and Student Publications

Background: Suicide is the second leading cause of death for adolescents in the United States. However, relatively little is known about the forms of atypical neuro-cognitive function that are correlates of suicidal ideation (SI). One form of cognitive/affective function that, when dysfunctional, is associated with SI is emotion regulation. However, very little work has investigated the neural correlates of emotion dysregulation in adolescents with SI.

Methods: Participants (N = 111 aged 12-18, 32 females, 31 [27.9%] reporting SI) were recruited shortly after their arrival at a residential care facility where they had been referred for behavioral and mental health problems. …