Medical Specialties Commons^™

Biological And Procedural Predictors Of Outcome In The Stroke Preclinical Assessment Network (Span) Trial, Andreia Morais, Takahiko Imai, Xuyan Jin, Joseph J Locascio, Ligia Boisserand, Alison L Herman, Anjali Chauhan, Jessica Lamb, Karisma Nagarkatti, Marcio A Diniz, Mariia Kumskova, Nirav Dhanesha, Pradip K Kamat, Mohammad Badruzzaman Khan, Krishnan M Dhandapani, Rakesh B Patel, Brijesh Sutariya, Yanrong Shi, Klaus Van Leyen, W Taylor Kimberly, David C Hess, Jaroslaw Aronowski, Enrique C Leira, Raymond C Koehler, Anil K Chauhan, Lauren H Sansing, Patrick D Lyden, Cenk Ayata

Faculty, Staff and Student Publications

BACKGROUND: The SPAN trial (Stroke Preclinical Assessment Network) is the largest preclinical study testing acute stroke interventions in experimental focal cerebral ischemia using endovascular filament middle cerebral artery occlusion (MCAo). Besides testing interventions against controls, the prospective design captured numerous biological and procedural variables, highlighting the enormous heterogeneity introduced by the multicenter structure that might influence stroke outcomes. Here, we leveraged the unprecedented sample size achieved by the SPAN trial and the prospective design to identify the biological and procedural variables that affect experimental stroke outcomes in transient endovascular filament MCAo.

METHODS: The study cohort included all mice enrolled and …

A Thalamic Nucleus Reuniens-Lateral Septum-Lateral Hypothalamus Circuit For Comorbid Anxiety-Like Behaviors In Chronic Itch, Su-Shan Guo, Yu Gong, Ting-Ting Zhang, Xin-Yu Su, Yan-Jiao Wu, Yi-Xiao Yan, Yue Cao, Xing-Lei Song, Jian-Cheng Xie, Dehua Wu, Qin Jiang, Ying Li, Xuan Zhao, Michael X Zhu, Tian-Le Xu, Ming-Gang Liu

Faculty, Staff and Student Publications

Chronic itch often clinically coexists with anxiety symptoms, creating a vicious cycle of itch-anxiety comorbidities that are difficult to treat. However, the neuronal circuit mechanisms underlying the comorbidity of anxiety in chronic itch remain elusive. Here, we report anxiety-like behaviors in mouse models of chronic itch and identify γ-aminobutyric acid-releasing (GABAergic) neurons in the lateral septum (LS) as the key player in chronic itch-induced anxiety. In addition, chronic itch is accompanied with enhanced activity and synaptic plasticity of excitatory projections from the thalamic nucleus reuniens (Re) onto LS GABAergic neurons. Selective chemogenetic inhibition of the Re → LS circuit notably …

Monitoring Response To Neoadjuvant Chemotherapy In Triple Negative Breast Cancer Using Circulating Tumor Dna, Jennifer H Chen, Sridevi Addanki, Dhruvajyoti Roy, Roland Bassett, Ekaterina Kalashnikova, Erik Spickard, Henry M Kuerer, Salyna Meas, Vanessa N Sarli, Anil Korkut, Jason B White, Gaiane M Rauch, Debu Tripathy, Banu K Arun, Carlos H Barcenas, Clinton Yam, Himanshu Sethi, Angel A Rodriguez, Minetta C Liu, Stacy L Moulder, Anthony Lucci

Faculty, Staff and Student Publications

BACKGROUND: Triple negative breast cancer (TNBC) is an aggressive subtype with poor prognosis. We aimed to determine whether circulating tumor DNA (ctDNA) and circulating tumor cell (CTC) could predict response and long-term outcomes to neoadjuvant chemotherapy (NAC).

METHODS: Patients with TNBC were enrolled between 2017-2021 at The University of Texas MD Anderson Cancer Center (Houston, TX). Serial plasma samples were collected at four timepoints: pre-NAC (baseline), 12-weeks after NAC (mid-NAC), after NAC/prior to surgery (post-NAC), and one-year after surgery. ctDNA was quantified using a tumor-informed ctDNA assay (Signatera

RESULTS: In total, 37 patients were enrolled. The mean age was 50 …

Patient And Family Contributions To Improve The Diagnostic Process Through The Ourdx Electronic Health Record Tool: A Mixed Method Analysis, Sigall K Bell, Kendall Harcourt, Joe Dong, Catherine Desroches, Nicholas J Hart, Stephen K Liu, Long Ngo, Eric J Thomas, Fabienne C Bourgeois

Faculty, Staff and Student Publications

Background: Accurate and timely diagnosis relies on sharing perspectives among team members and avoiding information asymmetries. Patients/Families hold unique diagnostic process (DxP) information, including knowledge of diagnostic safety blindspots-information that patients/families know, but may be invisible to clinicians. To improve information sharing, we co-developed with patients/families an online tool called 'Our Diagnosis (OurDX)'. We aimed to characterise patient/family contributions in OurDX and how they differed between individuals with and without diagnostic concerns.

Method: We implemented OurDX in two academic organisations serving patients/families living with chronic conditions in three subspecialty clinics and one primary care clinic. Prior to each visit, patients/families …

In Vitro Antibacterial, Antibiofilm Activities, And Phytochemical Properties Of Posidonia Oceanica (L) Delile: An Endemic Mediterranean Seagrass, Ertugrul Ozbil, Mehmet Ilktac, Sultan Ogmen, Ovgu Isbilen, Jesus M Duran Ramirez, Jana Gomez, Jennifer N Walker, Ender Volkan

Faculty, Staff and Student Publications

In the antibiotic resistance era, utilizing understudied sources for novel antimicrobials or antivirulence agents can provide new advances against antimicrobial resistant pathogens. In this study, we aimed to investigate antibacterial and antibiofilm activities of Posidonia oceanica (L.) Delile against Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922 and Klebsiella pneumoniae ATCC 700603 and several S. aureus clinical isolates obtained from medical devices, including patient urinary catheters and breast implant infections, with varying antibiotic recalcitrance profiles. The ethanolic and methanolic extracts from P. oceanica rhizome exhibited significant antibacterial activity against E. faecalis and S. aureus, as well …

Hematopoietic Growth Factors Regulate The Entry Of Monocytes Into The Adult Brain Via Chemokine Receptor Ccr5, Xuefang Sophie Ren, Junchi He, Songruo Li, Heng Hu, Michele Kyle, Shinichi Kohsaka, Li-Ru Zhao

Faculty, Staff and Student Publications

Monocytes are circulating macrophage precursors generated from bone marrow hematopoietic stem cells. In adults, monocytes continuously replenish cerebral border-associated macrophages under physiological conditions. Monocytes also rapidly infiltrate the brain in pathological settings. The mechanisms of recruiting monocyte-derived macrophages into the brain under pathological conditions have been extensively studied. However, it remains unclear how monocytes enter the brain to renew border-associated macrophages under physiological conditions. Using both in vitro and in vivo approaches, this study reveals that a combination of two hematopoietic growth factors, stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF), complementarily and synergistically enhances the adhesion of monocytes …

Factors Associated With Elevated Sars-Cov-2 Immune Response In Children And Adolescents, Sarah E Messiah, Rhiana Abbas, Emma Bergqvist, Harold W Kohl, Michael D Swartz, Yashar Talebi, Rachit Sabharwal, Haoting Han, Melissa A Valerio-Shewmaker, Stacia M Desantis, Ashraf Yaseen, Henal A Gandhi, Ximena Flandes Amavisca, Jessica A Ross, Lindsay N Padilla, Michael O Gonzalez, Leqing Wu, Mark A Silberman, David Lakey, Jennifer A Shuford, Stephen J Pont, Eric Boerwinkle

Faculty, Staff and Student Publications

BACKGROUND: Understanding the distinct immunologic responses to SARS-CoV-2 infection among pediatric populations is pivotal in navigating the COVID-19 pandemic and informing future public health strategies. This study aimed to identify factors associated with heightened antibody responses in children and adolescents to identify potential unique immune dynamics in this population.

METHODS: Data collected between July and December 2023 from the Texas Coronavirus Antibody REsponse Survey (Texas CARES), a statewide prospective population-based antibody survey among 1-to-19-year-old participants, were analyzed. Each participant had the following data available for analysis: (1) Roche Elecsys® Anti-SARS-CoV-2 Immunoassay for Nucleocapsid protein antibodies (Roche N-test), (2) qualitative and …

The Sod1 Inhibitor, Lcs-1, Oxidizes H2s To Reactive Sulfur Species, Directly And Indirectly, Through Conversion Of Sod1 To An Oxidase, Kenneth R Olson, Tsuyoshi Takata, Kasey J Clear, Yan Gao, Zhilin Ma, Ella Pfaff, Karthik Mouli, Thomas A Kent, Prentiss Jones, Jon Fukuto, Gang Wu, Karl D Straub

Faculty, Staff and Student Publications

LCS-1, a putative selective inhibitor of SOD1, is a substituted pyridazinone with rudimentary similarity to quinones and naphthoquinones. As quinones catalytically oxidize H2S to biologically active reactive sulfur species (RSS), we hypothesized LCS-1 might have similar attributes. Here, we examine LCS-1 reactions with H2S and SOD1 using thiol-specific fluorophores, liquid chromatography–mass spectrometry, electron paramagnetic resonance (EPR), UV–vis spectrometry, and oxygen consumption. We show that LCS-1 catalytically oxidizes H2S in buffer solutions to form RSS, namely per- and polyhydrosulfides (H2Sn, n = 2–6). These reactions consume oxygen and produce hydrogen peroxide, but they do not have an EPR signature, nor do …

Affinity Purification Mass Spectrometry Characterisation Of The Interactome Of Receptor Tyrosine Kinase Proline-Rich Motifs In Cancer, Christopher M Jones, Arndt Rohwedder, Kin Man Suen, Safoura Zahed Mohajerani, Antonio N Calabrese, Sabine Knipp, Mark T Bedford, John E Ladbury

Faculty, Staff and Student Publications

Receptor tyrosine kinase (RTK) overexpression is linked to the development and progression of multiple cancers. RTKs are classically considered to initiate cytoplasmic signalling pathways via ligand-induced tyrosine phosphorylation, however recent evidence points to a second tier of signalling contingent on interactions mediated by the proline-rich motif (PRM) regions of non-activated RTKs. The presence of PRMs on the C-termini of >40 % of all RTKs and the abundance of PRM-binding proteins encoded by the human genome suggests that there is likely to be a large number of previously unexplored interactions which add to the RTK intracellular interactome. Here, we explore the …

Chatgpt And Google Assistant As A Source Of Patient Education For Patients With Amblyopia: Content Analysis, Gloria Wu, David A Lee, Weichen Zhao, Adrial Wong, Rohan Jhangiani, Sri Kurniawan

Faculty, Staff and Student Publications

Background: We queried ChatGPT (OpenAI) and Google Assistant about amblyopia and compared their answers with the keywords found on the American Association for Pediatric Ophthalmology and Strabismus (AAPOS) website, specifically the section on amblyopia. Out of the 26 keywords chosen from the website, ChatGPT included 11 (42%) in its responses, while Google included 8 (31%).

Objective: Our study investigated the adherence of ChatGPT-3.5 and Google Assistant to the guidelines of the AAPOS for patient education on amblyopia.

Methods: ChatGPT-3.5 was used. The four questions taken from the AAPOS website, specifically its glossary section for amblyopia, are as follows: (1) What …

Hyperpolarized Magnetic Resonance Imaging, Nuclear Magnetic Resonance Metabolomics, And Artificial Intelligence To Interrogate The Metabolic Evolution Of Glioblastoma, Kang Lin Hsieh, Qing Chen, Travis C Salzillo, Jian Zhang, Xiaoqian Jiang, Pratip K Bhattacharya, Shyan Shams

Faculty, Staff and Student Publications

Glioblastoma (GBM) is a malignant Grade VI cancer type with a median survival duration of only 8-16 months. Earlier detection of GBM could enable more effective treatment. Hyperpolarized magnetic resonance spectroscopy (HPMRS) could detect GBM earlier than conventional anatomical MRI in glioblastoma murine models. We further investigated whether artificial intelligence (A.I.) could detect GBM earlier than HPMRS. We developed a deep learning model that combines multiple modalities of cancer data to predict tumor progression, assess treatment effects, and to reconstruct in vivo metabolomic information from ex vivo data. Our model can detect GBM progression two weeks earlier than conventional MRIs …

Hybridizing Mechanistic Modeling And Deep Learning For Personalized Survival Prediction After Immune Checkpoint Inhibitor Immunotherapy, Joseph D Butner, Prashant Dogra, Caroline Chung, Eugene J Koay, James W Welsh, David S Hong, Vittorio Cristini, Zhihui Wang

Faculty, Staff and Student Publications

We present a study where predictive mechanistic modeling is combined with deep learning methods to predict individual patient survival probabilities under immune checkpoint inhibitor (ICI) immunotherapy. This hybrid approach enables prediction based on both measures that are calculable from mechanistic models of key mechanisms underlying ICI therapy that may not be directly measurable in the clinic and easily measurable quantities or patient characteristics that are not always readily incorporated into predictive mechanistic models. A deep learning time-to-event predictive model trained on a hybrid mechanistic + clinical data set from 93 patients achieved higher per-patient predictive accuracy based on event-time concordance, …

Regulatory Complexity Of Cellular Differentiation In Candida Albicans Revealed Through Systematic Screening Of Protein Kinase Mutants, Michael C Lorenz

Faculty, Staff and Student Publications

A recent study in mBio reports the construction and preliminary screening of a library containing mutants of 99 of the 119 predicted protein kinases in Candida albicans (the majority of the remaining 20 are probably essential) (J. Kramara, M.-J. Kim, T. L. Ollinger, L. C. Ristow, et al., mBio e01249-24, 2024, https://doi.org/10.1128/mbio.01249-24). Using a quantitative competition assay in 10 conditions that represent nutritional, osmotic, cell wall, and pH stresses that are considered to model various aspects of the host environment allowed them to phenotypically cluster kinases, which highlight both the integration and specialization of signaling pathways, suggesting novel functions …

Role Of The Antiparallel Double-Stranded Filament Form Of Ftsa In Activating The Escherichia Coli Divisome, Abbigale Perkins, Mwidy Sava Mounange-Badimi, William Margolin

Faculty, Staff and Student Publications

The actin-like FtsA protein is essential for function of the cell division machinery, or divisome, in many bacteria including Escherichia coli. Previous in vitro studies demonstrated that purified wild-type FtsA assembles into closed mini-rings on lipid membranes, but oligomeric variants of FtsA such as FtsAR286W and FtsAG50E can bypass certain divisome defects and form arc and double-stranded (DS) oligomeric states, respectively, which may reflect conversion of an inactive to an active form of FtsA. However, it remains unproven which oligomeric forms of FtsA are responsible for assembling and activating the divisome. Here, we used an in vivo crosslinking assay …

Persistence Of Daptomycin-Resistant And Vancomycin-Resistant Enterococci In Hospitalized Patients With Underlying Malignancies: A 7-Year Follow-Up Study, Lynn El Haddad, Georgios Angelidakis, Yuting Zhai, Layale Yaghi, Cesar A Arias, Samuel A Shelburne, Kwangcheol Casey Jeong, Roy F Chemaly

Faculty, Staff and Student Publications

Vancomycin-resistant enterococci (VRE) commonly colonize the gut of individuals with hematologic malignancies or undergoing hematopoietic cell transplant (HCT) and may cause bacteremia. In 2012, we identified VRE isolates from patients and patients' rooms and showed transmission networks of highly genetically related daptomycin-resistant (DR)-VRE strains. This is a follow-up study performing whole-genome sequencing (WGS) and phylogenetic analyses on 82 clinical VRE strains isolated from stools and blood cultures of patients with leukemia and HCT between 2015 and 2019. Here, we observed transmission of highly genetically related strains between rooms on the same or on different floors, including a DR-VRE strain identified …

A Comparative Analysis Of The Immunoglobulin Repertoire In Leukemia Cells And B Cells In Chinese Acute Myeloid Leukemia By High-Throughput Sequencing, Huige Yan, Lina Wu, Pingzhang Wang, Miaoran Xia, Zhan Shi, Xinmei Huang, Sha Yin, Qian Jiang, C Cameron Yin, Xiangyu Zhao, Xiaoyan Qiu

Faculty, Staff and Student Publications

It is common knowledge that immunoglobulin (Ig) is produced by B lymphocytes and mainly functions as an antibody. However, it has been shown recently that myeloblasts from acute myeloid leukemia (AML) could also express Ig and that AML-Ig played a role in leukemogenesis and AML progression. The difference between Ig from myeloblasts and B cells has not been explored. Studying the characteristics of the Ig repertoire in myeloblasts and B cells will be helpful to understand the function and significance of AML-Ig. We performed 5' RACE-related PCR coupled with PacBio sequencing to analyze the Ig repertoire in myeloblasts and B …

Association Of Genetic Ancestry With Molecular Tumor Profiles In Colorectal Cancer, Brooke Rhead, David M Hein, Yannick Pouliot, Justin Guinney, Francisco M De La Vega, Nina N Sanford

Faculty, Staff and Student Publications

Background: There are known disparities in incidence and outcomes of colorectal cancer (CRC) by race and ethnicity. Some of these disparities may be mediated by molecular changes in tumors that occur at different rates across populations. Genetic ancestry is a measure complementary to race and ethnicity that can overcome missing data issues and better capture genetic similarity in admixed populations. We aimed to identify somatic mutations and tumor gene expression differences associated with both genetic ancestry and imputed race and ethnicity.

Methods: Sequencing was performed with the Tempus xT NGS 648-gene panel and whole exome capture RNA-Seq for 8454 primarily …

The Biology And Function Of Extracellular Vesicles In Immune Response And Immunity, Raghu Kalluri

Faculty, Staff and Student Publications

Extracellular vesicles (EVs), such as ectosomes and exosomes, contain DNA, RNA, proteins and are encased in a phospholipid bilayer. EVs provide intralumenal cargo for delivery into the cytoplasm of recipient cells with an impact on the function of immune cells, in part because their biogenesis can also intersect with antigen processing and presentation. Motile EVs from activated immune cells may increase the frequency of immune synapses on recipient cells in a proximity-independent manner for local and long-distance modulation of systemic immunity in inflammation, autoimmunity, organ fibrosis, cancer, and infections. Natural and engineered EVs exhibit the ability to impact innate and …

Prostate Cancer-Induced Endothelial-Cell-To-Osteoblast Transition Drives Immunosuppression In The Bone-Tumor Microenvironment Through Wnt Pathway-Induced M2 Macrophage Polarization, Guoyu Yu, Paul G Corn, Celia Sze Ling Mak, Xin Liang, Miao Zhang, Patricia Troncoso, Jian H Song, Song-Chang Lin, Xingzhi Song, Jingjing Liu, Jianhua Zhang, Christopher J Logothetis, Marites P Melancon, Theocharis Panaretakis, Guocan Wang, Sue-Hwa Lin

Faculty, Staff and Student Publications

Immune checkpoint therapy has limited efficacy for patients with bone-metastatic castration-resistant prostate cancer (bmCRPC). To improve immunotherapy for bmCRPC, we aimed to identify the mechanism of bmCRPC-induced changes in the immune microenvironment. Among bmCRPC patients, higher levels of a 32-gene M2-like macrophage signature in bone metastasis samples correlated with shorter overall survival. Immunohistochemistry showed that CD206-positive (CD206+) macrophages were enriched in bmCRPC bone biopsy specimens compared with primary tumors or lymph node metastases. In preclinical osteogenic prostate cancer (Pca) xenograft models, CD206+ macrophages were recruited to areas with tumor-induced bone. RNA sequencing (RNAseq) analysis showed higher expression of an M2-like …

Metal(Loid) Uptake And Physiological Response Of Coix Lacryma-Jobi L To Soil Potentially Toxic Elements In A Polluted Metal-Mining Area, Qun Zhao, Hongyan Liu, Longhua Wu, Peter Christie, Xuewen Wang, Ghulam Rasool, Guilan Peng

Faculty, Staff and Student Publications

Coix lacryma-jobi L. is a traditional medicinal plant in east Asia and is an important crop in Guizhou province, southwest China, where there are elevated levels of soil mercury and arsenic (As). Exposure to multiple potentially toxic elements (PTEs) may affect plant accumulation of metal(loid)s and food safety in regions with high geological metal concentrations. Field experiments were conducted to study the effects of PTEs on metal(loid) accumulation and physiological response of C. lacryma in different plant parts at three pollution levels. Total root length, number of root tips, number of branches, and number of root crosses increased with increasing …

Final Phase 1 Substudy Results Of Ivosidenib For Patients With Mutant Idh1 Relapsed/Refractory Myelodysplastic Syndrome, Courtney D Dinardo, Gail J Roboz, Justin M Watts, Yazan F Madanat, Gabrielle T Prince, Praneeth Baratam, Stéphane De Botton, Anthony Stein, James M Foran, Martha L Arellano, David A Sallman, Mohammad Hossain, Dylan M Marchione, Xiaofei Bai, Prapti A Patel, Stephanie M Kapsalis, Guillermo Garcia-Manero, Amir T Fathi

Faculty, Staff and Student Publications

Ivosidenib is a first-in-class mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor with efficacy and tolerability in patients with advanced mIDH1 hematologic malignancies, leading to approval in frontline and relapsed/refractory (R/R) mIDH1 acute myeloid leukemia. We report final data from a phase 1 single-arm substudy of once-daily ivosidenib in patients with R/R mIDH1 myelodysplastic syndrome (MDS) after failure of standard-of-care therapies. Primary objectives were to determine safety, tolerability, and clinical activity. The primary efficacy end point was the complete remission (CR) + partial remission (PR) rate. Nineteen patients were enrolled; 18 were included in the efficacy analysis. Treatment-related adverse events occurred in …

Pressing Issues For Oral Care Quality Improvement: Findings From The Eu Deliver Project, Paulo Melo, Leonor Frey-Furtado, Daniela Correia, Stefan Listl, Michael Lorenz, Nagihan Bostanci, Álvaro Azevedo, Maria Lurdes Pereira

Faculty, Staff and Student Publications

BACKGROUND: While oral health often takes a backseat to other health domains, it silently affects nearly half of the Worldwide population. The DELIVER project, funded by the EU's Horizon Europe program, seeks to develop a blueprint model for improving the quality of oral health care for everyone.

METHODS: Applying the Nominal Group Technique (NGT), 17 stakeholders from various backgrounds participated in identifying pressing issues for oral care quality improvement across practice, community, and policy levels.

RESULTS: The results revealed significant differences at the different levels, with accessibility emerging as a prominent issue, encompassing affordability, availability, and acceptability of oral healthcare …

Interleukin-21 Engineering Enhances Nk Cell Activity Against Glioblastoma Via Cebpd, Mayra Shanley, May Daher, Jinzhuang Dou, Sufang Li, Rafet Basar, Hind Rafei, Merve Dede, Joy Gumin, Jezreel Pantaleόn Garcίa, Ana Karen Nunez Cortes, Shan He, Corry M Jones, Sunil Acharya, Natalie W Fowlkes, Donghai Xiong, Sanjay Singh, Hila Shaim, Samantha Claire Hicks, Bin Liu, Abhinav Jain, Mohammad Fayyad Zaman, Qi Miao, Ye Li, Nadima Uprety, Enli Liu, Luis Muniz-Feliciano, Gary M Deyter, Vakul Mohanty, Patrick Zhang, Scott E Evans, Elizabeth J Shpall, Frederick F Lang, Ken Chen, Katayoun Rezvani

Faculty, Staff and Student Publications

Glioblastoma (GBM) is an aggressive brain cancer with limited therapeutic options. Natural killer (NK) cells are innate immune cells with strong anti-tumor activity and may offer a promising treatment strategy for GBM. We compared the anti-GBM activity of NK cells engineered to express interleukin (IL)-15 or IL-21. Using multiple in vivo models, IL-21 NK cells were superior to IL-15 NK cells both in terms of safety and long-term anti-tumor activity, with locoregionally administered IL-15 NK cells proving toxic and ineffective at tumor control. IL-21 NK cells displayed a unique chromatin accessibility signature, with CCAAT/enhancer-binding proteins (C/EBP), especially CEBPD, serving as …

Mif/Nr3c2 Axis Regulates Glucose Metabolism Reprogramming In Pancreatic Cancer Through Mapk-Erk And Ap-1 Pathways, Shouhui Yang, Wei Tang, Azadeh Azizian, Jochen Gaedcke, Yuuki Ohara, Helen Cawley, Nader Hanna, Michael Ghadimi, Trisha Lal, Subrata Sen, Chad J Creighton, Jianjun Gao, Nagireddy Putluri, Stefan Ambs, Perwez Hussain

Faculty, Staff and Student Publications

Inflammation and aberrant cellular metabolism are widely recognized as hallmarks of cancer. In pancreatic ductal adenocarcinoma (PDAC), inflammatory signaling and metabolic reprogramming are tightly interwoven, playing pivotal roles in the pathogenesis and progression of the disease. However, the regulatory functions of inflammatory mediators in metabolic reprogramming in pancreatic cancer have not been fully explored. Earlier, we demonstrated that pro-inflammatory mediator macrophage migration inhibitory factor (MIF) enhances disease progression by inhibiting its downstream transcriptional factor nuclear receptor subfamily 3 group C member 2 (NR3C2). Here, we provide evidence that MIF and NR3C2 interactively regulate metabolic reprogramming, resulting in MIF-induced cancer growth …

A Social Media Game To Increase Physical Activity Among Older Adult Women: Protocol Of A Randomized Controlled Trial To Evaluate Challenge, Michael C Robertson, Maria Chang Swartz, Karen M Basen-Engquist, Yisheng Li, Kristofer Jennings, Debbe Thompson, Tom Baranowski, Elena Volpi, Elizabeth J Lyons

Faculty, Staff and Student Publications

BACKGROUND: Older adult women often do not engage in sufficient physical activity (PA) and can encounter biological changes that exacerbate the negative effects of inadequate activity. Wearable activity monitors can facilitate PA initiation, but evidence of sustained behavior change is lacking. Supplementing wearable technologies with intervention content that evokes enjoyment, interest, meaning, and personal values associated with PA may support long term adherence. In this paper, we present the protocol of an NIA-funded study designed to evaluate the efficacy of CHALLENGE for increasing step count and motivation for PA in insufficiently active older women (Challenges for Healthy Aging: Leveraging Limits …

Personalized Neoantigen Vaccines As Early Intervention In Untreated Patients With Lymphoplasmacytic Lymphoma: A Non-Randomized Phase 1 Trial, Szymon J Szymura, Lin Wang, Tiantian Zhang, Soung-Chul Cha, Joo Song, Zhenyuan Dong, Aaron Anderson, Elizabeth Oh, Vincent Lee, Zhe Wang, Sapna Parshottam, Sheetal Rao, Jasper B Olsem, Brandon N Crumpton, Hans C Lee, Elisabet E Manasanch, Sattva Neelapu, Larry W Kwak, Sheeba K Thomas

Faculty, Staff and Student Publications

Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade lymphoma with no standard therapy. Nine asymptomatic patients treated with a first-in-human, neoantigen DNA vaccine experienced no dose limiting toxicities (primary endpoint, NCT01209871). All patients achieve stable disease or better, with one minor response, and median time to progression of 72+ months. Post-vaccine single-cell transcriptomics reveal dichotomous antitumor responses, with reduced tumor B-cells (tracked by unique B cell receptor) and their survival pathways, but no change in clonal plasma cells. Downregulation of human leukocyte antigen (HLA) class II molecules and paradoxical upregulation of insulin-like growth factor (IGF) by the latter suggest resistance mechanisms. …

Dual Inhibition Of The Trka And Jak2 Pathways Using Entrectinib And Pacritinib Suppresses The Growth And Metastasis Of Her2-Positive And Triple-Negative Breast Cancers, Angelina T Regua, Shivani Bindal, Mariana K Najjar, Chuling Zhuang, Munazza Khan, Austin B J Arrigo, Anneliese O Gonzalez, Xinhai R Zhang, Jay-Jiguang Zhu, Kounosuke Watabe, Hui-Wen Lo

Faculty, Staff and Student Publications

HER2-positive and triple-negative breast cancers (TNBC) are difficult to treat and associated with poor prognosis. Despite showing initial response, HER2-positive breast cancers often acquire resistance to HER2-targeted therapies, and TNBC lack effective therapies. To overcome these clinical challenges, we evaluated the therapeutic utility of co-targeting TrkA and JAK2/STAT3 pathways in these breast cancer subtypes. Here, we report the novel combination of FDA-approved TrkA inhibitors (Entrectinib or Larotrectinib) and JAK2 inhibitors (Pacritinib or Ruxolitinib) synergistically inhibited in vitro growth of HER2-positive breast cancer cells and TNBC cells. The Entrectinib-Pacritinib combination inhibited the breast cancer stem cell subpopulation, reduced expression of stemness …

Mitochondrial Permeability Transition Dictates Mitochondrial Maturation Upon Switch In Cellular Identity Of Hematopoietic Precursors, Sandeep P Dumbali, Paulina D Horton, Travis I Moore, Pamela L Wenzel

Faculty, Staff and Student Publications

The mitochondrial permeability transition pore (mPTP) is a supramolecular channel that regulates exchange of solutes across cristae membranes, with executive roles in mitochondrial function and cell death. The contribution of the mPTP to normal physiology remains debated, although evidence implicates the mPTP in mitochondrial inner membrane remodeling in differentiating progenitor cells. Here, we demonstrate that strict control over mPTP conductance shapes metabolic machinery as cells transit toward hematopoietic identity. Cells undergoing the endothelial-to-hematopoietic transition (EHT) tightly control chief regulatory elements of the mPTP. During EHT, maturing arterial endothelium restricts mPTP activity just prior to hematopoietic commitment. After transition in cellular …

3d Chromatin Architecture, Brd4, And Mediator Have Distinct Roles In Regulating Genome-Wide Transcriptional Bursting And Gene Network, Pawel Trzaskoma, Seolkyoung Jung, Aleksandra Pękowska, Christopher H Bohrer, Xiang Wang, Faiza Naz, Stefania Dell'orso, Wendy D Dubois, Ana Olivera, Supriya V Vartak, Yongbing Zhao, Subhashree Nayak, Andrew Overmiller, Maria I Morasso, Vittorio Sartorelli, Daniel R Larson, Carson C Chow, Rafael Casellas, John J O'Shea

Faculty, Staff and Student Publications

Discontinuous transcription is evolutionarily conserved and a fundamental feature of gene regulation; yet, the exact mechanisms underlying transcriptional bursting are unresolved. Analyses of bursting transcriptome-wide have focused on the role of cis-regulatory elements, but other factors that regulate this process remain elusive. We applied mathematical modeling to single-cell RNA sequencing data to infer bursting dynamics transcriptome-wide under multiple conditions to identify possible molecular mechanisms. We found that Mediator complex subunit 26 (MED26) primarily regulates frequency, MYC regulates burst size, while cohesin and Bromodomain-containing protein 4 (BRD4) can modulate both. Despite comparable effects on RNA levels among these perturbations, acute depletion …

Novel Il-4/Hb-Egf-Dependent Crosstalk Between Eosinophils And Macrophages Controls Liver Regeneration After Ischaemia And Reperfusion Injury, Yang Yang, Long Xu, Constance Atkins, Lily Kuhlman, Jie Zhao, Jong-Min Jeong, Yankai Wen, Nicolas Moreno, Kang Ho Kim, Yu A An, Fenfen Wang, Steve Bynon, Vincenzo Villani, Bin Gao, Frank Brombacher, Raymond Harris, Holger K Eltzschig, Elizabeth Jacobsen, Cynthia Ju

Faculty, Staff and Student Publications

OBJECTIVE: Previous studies indicate that eosinophils are recruited into the allograft following orthotopic liver transplantation and protect from ischaemia reperfusion (IR) injury. In the current studies, we aim to explore whether their protective function could outlast during liver repair.

DESIGN: Eosinophil-deficient mice and adoptive transfer of bone marrow-derived eosinophils (bmEos) were employed to investigate the effects of eosinophils on tissue repair and regeneration after hepatic IR injury. Aside from exogenous cytokine or neutralising antibody treatments, mechanistic studies made use of a panel of mouse models of eosinophil-specific IL-4/IL-13-deletion, cell-specific IL-4rα-deletion in liver macrophages and hepatocytes and macrophage-specific deletion of heparin-binding …