Digital Commons Network^™

Preclinical Study And Parallel Phase Ii Trial Evaluating Antisense Stat3 Oligonucleotide And Checkpoint Blockade For Advanced Pancreatic, Non-Small Cell Lung Cancer And Mismatch Repair-Deficient Colorectal Cancer, Chad Tang, Genevieve P Hartley, Coline Couillault, Ying Yuan, Heather Lin, Courtney Nicholas, Anupallavi Srinivasamani, James Dai, Ecaterina E Ileana Dumbrava, Siqing Fu, Daniel D Karp, Aung Naing, Sarina A Piha-Paul, Jordi Rodon Ahnert, Shubham Pant, Vivek Subbiah, Timonthy A Yap, Apostolia M Tsimberidou, Paola Guerrero, Sarah Dhebat, Theresa Proia, Michael A Curran, David S Hong

Faculty, Staff and Student Publications

Objective: To evaluate signal transducer and activator of transcription 3 (STAT3) inhibition we conducted a co-clinical trial testing danvatirsen, a STAT3 antisense oligonucleotide (ASO) and checkpoint inhibition in conjunction with preclinical experiments.

Methods and analysis: Orthotopically implanted pancreatic cancer (pancreatic adenocarcinoma (PDAC)) was treated with STAT3 ASO with immune checkpoint inhibition. Tumour infiltrating immune cell populations were characterised via flow cytometry. In vitro experiments evaluated STAT3 inhibition in pancreatic stellate cells (PSCs) and myeloid-derived suppressor cells (MDSCs).A phase II trial employing a Simon II stage design tested the clinical efficacy of danvatirsen and durvalumab in non-small cell lung cancer (NSCLC), …

Crosstalk Between Breast Cancer-Derived Micrornas And Brain Microenvironmental Cells In Breast Cancer Brain Metastasis, Munazza S Khan, Grace L Wong, Chuling Zhuang, Mariana K Najjar, Hui-Wen Lo

Faculty, Staff and Student Publications

Breast cancer is the most frequent malignancy in women, constituting 15.2% of all new cancers diagnosed in the United States. Distant breast cancer metastasis accounts for the majority of breast cancer-related deaths; brain metastasis is the third most common site for metastatic breast cancer but is associated with worst prognosis of approximately eight months of survival. Current treatment options for breast cancer brain metastasis (BCBM) are limited and ineffective. To help identify new and effective therapies for BCBM, it is important to investigate the mechanisms by which breast cancer cells metastasize to the brain and thrive in the brain microenvironment. …

Does Varicocele Repair Improve Conventional Semen Parameters? A Meta-Analytic Study Of Before-After Data, Rossella Cannarella, Rupin Shah, Taha Abo-Almagd Abdel-Meguid Hamoda, Florence Boitrelle, Ramadan Saleh, Murat Gul, Amarnath Rambhatla, Parviz Kavoussi, Tuncay Toprak, Ahmed M Harraz, Edmund Ko, Gökhan Çeker, Damayanthi Durairajanayagam, Noora Alkahidi, Shinnosuke Kuroda, Andrea Crafa, Ralf Henkel, Gianmaria Salvio, Berk Hazir, Mahsa Darbandi, Marion Bendayan, Sara Darbandi, Marco Falcone, Nicolas Garrido, Raghavender Kosgi, Raneen Sawaid Kaiyal, Keshab Karna, Nguyen Ho Vinh Phuoc, Ponco Birowo, Giovanni M Colpi, Jean De La Rosette, Germar-Michael Pinggera, Quang Nguyen, Armand Zini, Wael Zohdy, Rajender Singh, Pallavi Saini, Sidney Glina, Haocheng Lin, Taymour Mostafa, Cesar Rojas-Cruz, Mohamed Arafa, Aldo E Calogero, Fotios Dimitriadis, Priyank Kothari, Vilvapathy Senguttuvan Karthikeyan, Keisuke Okada, Koji Chiba, Ates Kadıoglu, Baris Altay, Tahsin Turunc, Birute Zilaitiene, Fatih Gokalp, Aram Adamyan, Darren Katz, Eric Chung, Tiago Cesar Mierzwa, Daniel Suslik Zylbersztejn, Gustavo Marquesine Paul, Nikolaos Sofikitis, Ioannis Sokolakis, Vineet Malhotra, Sakti Ronggowardhana Brodjonegoro, Ricky Adriansjah, Akira Tsujimura, Toshiyasu Amano, Giancarlo Balercia, Imad Ziouziou, Isaac Ardianson Deswanto, Marlon Martinez, Hyun Jun Park, Mustafa Emre Bakırcıoglu, Erman Ceyhan, Kaan Aydos, Jonathan Ramsay, Suks Minhas, Manaf Al Hashimi, Ramy Abou Ghayda, Nicholas Tadros, Puneet Sindhwani, Christopher C K Ho, Rinaldo Indra Rachman, Marcelo Rodriguez Pena, Ahmad Motawi, Arun Karthik Ponnusamy, Satish Dipankar, Azwar Amir, Saleh Binsaleh, Ege Can Serefoglu, Ravi Banthia, Kareim Khalafalla, Ari Basukarno, Nguyen Hoai Bac, Karun Singla, Rafael F Ambar, Konstantinos Makarounis, Shivam Priyadarshi, Gede Wirya Kusuma Duarsa, Widi Atmoko, Sunil Jindal, Eko Arianto, Hamed Akhavizadegan, Haitham El Bardisi, Ohad Shoshany, Gian Maria Busetto, Mohamad Moussa, Mounir Jamali, Mohamed S Al-Marhoon, Mikhail Ruzaev, Hasan M A Farsi, Shingai Mutambirwa, Dong Sup Lee, Deniz Kulaksiz, Yu-Sheng Cheng, Abderrazak Bouzouita, Selcuk Sarikaya, Hussein Kandil, Georgios Tsampoukas, Ala'a Farkouh, Kasonde Bowa, Missy Savira, Nasser Mogharabian, Tan V Le, Maruto Harjanggi, Dang Tuan Anh, Tran Quang Tien Long, Mohammad Ayodhia Soebadi, Lukman Hakim, Marko Tanic, Umut Cagin Ari, Firuza R Parikh, Gokhan Calik, Vinod Kv, Gyem Dorji, Andri Rezano, Osvaldo Rajmil, Dung Mai Ba Tien, Yiming Yuan, Juan Francisco Lizarraga-Salas, Balantine Eze, Kay Seong Ngoo, Joe Lee, Umut Arslan, Ashok Agarwal, Global Andrology Forum

Faculty, Staff and Student Publications

Purpose: The purpose of this meta-analysis is to study the impact of varicocele repair in the largest cohort of infertile males with clinical varicocele by including all available studies, with no language restrictions, comparing intra-person conventional semen parameters before and after the repair of varicoceles.

Materials and methods: The meta-analysis was performed according to PRISMA-P and MOOSE guidelines. A systematic search was performed in Scopus, PubMed, Cochrane, and Embase databases. Eligible studies were selected according to the PICOS model (Population: infertile male patients with clinical varicocele; Intervention: varicocele repair; Comparison: intra-person before-after varicocele repair; Outcome: conventional semen parameters; Study type: …

Technical Aspects And Clinical Limitations Of Sperm Dna Fragmentation Testing In Male Infertility: A Global Survey, Current Guidelines, And Expert Recommendations, Ashok Agarwal, Ala'a Farkouh, Ramadan Saleh, Taha Abo-Almagd Abdel-Meguid Hamoda, Gianmaria Salvio, Florence Boitrelle, Ahmed M Harraz, Ramy Abou Ghayda, Parviz Kavoussi, Murat Gül, Tuncay Toprak, Giorgio Ivan Russo, Damayanthi Durairajanayagam, Amarnath Rambhatla, Ponco Birowo, Rossella Cannarella, Nguyen Ho Vinh Phuoc, Armand Zini, Mohamed Arafa, Christine Wyns, Kelton Tremellen, Selçuk Sarıkaya, Sheena Lewis, Donald P Evenson, Edmund Ko, Aldo E Calogero, Fahmi Bahar, Marlon Martínez, Rafael F Ambar, Giovanni M Colpi, Mustafa Emre Bakircioglu, Ralf Henkel, Hussein Kandil, Ege Can Serefoglu, Abdullah Alfakhri, Akira Tsujimura, Alireza Kheradmand, Angelo Marino, Aram Adamyan, Birute Zilaitiene, Cevahir Ozer, Edoardo Pescatori, Paraskevi Vogiatzi, Gian Maria Busetto, Giancarlo Balercia, Haitham Elbardisi, Hamed Akhavizadegan, Hesamoddin Sajadi, Hisanori Taniguchi, Hyun Jun Park, Israel Maldonado Rosas, Mohamed Al-Marhoon, Mohammad Ali Sadighi Gilani, Naif Alhathal, Nguyen Quang, Germar-Michael Pinggera, Priyank Kothari, Sava Micic, Sheryl Homa, Tran Quang Tien Long, Wael Zohdy, Widi Atmoko, Wael Ibrahim, Marjan Sabbaghian, Saad Mohammed Abumelha, Eric Chung, Muhammet Rasit Ugur, Mehmet Serkan Ozkent, Osama Selim, Mahsa Darbandi, Shinichiro Fukuhara, Mounir Jamali, Jean De La Rosette, Shinnosuke Kuroda, Ryan P Smith, Aykut Baser, Arif Kalkanli, Nicholas N Tadros, Kaan Aydos, Tiago Cesar Mierzwa, Kareim Khalafalla, Vineet Malhotra, Mohamad Moussa, Federica Finocchi, Rinaldo Indra Rachman, Carlo Giulioni, Tomer Avidor-Reiss, Oguzhan Kahraman, Gökhan Çeker, Cătălina Zenoaga-Barbăroșie, Trenton L Barrett, Mehmet Yilmaz, Ates Kadioglu, Sunil Jindal, Huda Omran, Kadir Bocu, Vilvapathy Senguttuvan Karthikeyan, Giorgio Franco, Jesús Fernando Solorzano, Ranjit B Vishwakarma, Eko Arianto, Nicolas Garrido, Divyanu Jain, Nazim Gherabi, Ioannis Sokolakis, Ayad Palani, Gokhan Calik, Deniz Kulaksiz, Vaida Simanaviciene, Mara Simopoulou, Nur Dokuzeylül Güngör, Gideon Blecher, Marco Falcone, Davor Jezek, Mirko Preto, Edouard Amar, Tan V Le, Sun Tae Ahn, Andri Rezano, Keerti Singh, Lucia Rocco, Missy Savira, Osvaldo Rajmil, Sara Darbandi, Emrullah Sogutdelen, Luca Boeri, Guadalupe Hernández, Lukman Hakim, Yoshiharu Morimoto, Andrian Japari, Nikolaos Sofikitis, Baris Altay, Asli Metin Mahmutoglu, Manaf Al Hashimi, Imad Ziouziou, Christina Anagnostopoulou, Haocheng Lin, Rupin Shah

Faculty, Staff and Student Publications

Purpose: Sperm DNA fragmentation (SDF) is a functional sperm abnormality that can impact reproductive potential, for which four assays have been described in the recently published sixth edition of the WHO laboratory manual for the examination and processing of human semen. The purpose of this study was to examine the global practices related to the use of SDF assays and investigate the barriers and limitations that clinicians face in incorporating these tests into their practice.

Materials and methods: Clinicians managing male infertility were invited to complete an online survey on practices related to SDF diagnostic and treatment approaches. Their responses …

Configuring Thermal Ablation Volumes For Treatment Of Distinct Tumor Shapes: A Repeatability Study Using A Robotic Approach, Milica Bulatović, Jan Hermann, Pascale Tinguely, Iwan Paolucci, Stefan Weber

Faculty, Staff and Student Publications

Objectives: In the current clinical practice of thermal ablation treatment for liver tumors, achieving consistent and effective clinical outcomes across tumors of varying shapes, sizes and locations remains challenging. The aim of this study was to evaluate the repeatability of a novel robotic approach for configurable ablation of distinct tumor shapes and compare it to the standard ablation technique for creating ellipsoidal ablation volumes.

Materials and methods: The repeatability was evaluated in terms of width variability in created ablation volumes. Using a robotic navigation platform, custom ablation profiles configured with power, time, and distance parameters were designed to create four …

Transcriptomics Analysis Reveals Potential Mechanisms Underlying Mitochondrial Dysfunction And T Cell Exhaustion In Astronauts’ Blood Cells In Space, Maria Moreno-Villanueva, Luis E Jimenez-Chavez, Stephanie Krieger, Liang-Hao Ding, Ye Zhang, Adriana Babiak-Vazquez, Mark Berres, Sandra Splinter, Kristen E Pauken, Brian C Schaefer, Brian E Crucian, Honglu Wu

Faculty, Staff and Student Publications

Introduction: The impact of spaceflight on the immune system and mitochondria has been investigated for decades. However, the molecular mechanisms underlying spaceflight-induced immune dysregulations are still unclear.

Methods: In this study, blood from eleven crewmembers was collected before and during International Space Station (ISS) missions. Transcriptomic analysis was performed in isolated peripheral blood mononuclear cells (PBMCs) using RNA-sequencing. Differentially expresses genes (DEG) in space were determined by comparing of the inflight to the preflight samples. Pathways and statistical analyses of these DEG were performed using the Ingenuity Pathway Analysis (IPA) tool.

Results: In comparison to pre-flight, a total of 2030 …

Diagnostic Imaging Approaches: Pet Imaging In Monitoring Immune Responses In Oncology And Tuberculosis, Chanelle Hunter

All ETDs from UAB

Positron emission tomography (PET) imaging agents play a transformative role in personalized medicine through their application in disease diagnosis and immunotherapy monitoring, focusing on chemokine receptors, TH1-activated immune cells, and tuberculosis (TB) diagnostics. In immuno-oncology, accurately assessing TH1-activated immune cells in the tumor microenvironment (TME) is vital for evaluating cancer immunotherapy efficacy. Chemokine receptors, crucial in cellular signaling and inflammatory reactions, play a significant role in TH1 responses, thus serving as a potential area of interest in elucidating these anti-tumor responses. Through our work a novel CXCR3-targeting immunoPET probe, [89Zr]DFO-αCXCR3, was developed to detect and quantify these cells. This probe …

Novel Roles Of Rab35 In Development And Disease, Kelsey Ruth Clearman

All ETDs from UAB

As the largest and most dynamic family of GTPases within the mammalian cell, Rabs play an essential role as molecular switches in regulating intracellular vesicular trafficking and serve as significant signaling transducers. Over the last few decades, Rabs have been identified to regulate endocytic, transcytosis, and exocytotic pathways, and mutations in Rabs, or alterations in downstream effectors lead to embryonic lethality and diseases such as cancer and ciliopathies. Ciliopathies are a class of pathologies that result from defects in structure or function of the primary cilia. Primary cilia, found on virtually all mammalian cells, is a microtubule-derived appendage that relies …

Catecholamines And Catecholamine Resistance In Animal Models Of Metabolic Syndrome, Robert Follett Rosencrans

All ETDs from UAB

The sympathetic nervous system is a key regulator of energy homeostasis, in part, through the control of white adipose tissue lipolysis. Sympathetic nerves modulate adipose tissue physiology through the release of catecholamines, particularly norepinephrine, onto alpha- and beta-adrenergic receptors (a-AR; B-AR). Lipolysis refers to the breakdown of triglycerides into glycerol and free fatty acids, often in response to activation of B2/3-AR. Beta adrenergic activation of lipolysis is widely known to be impaired in patients with metabolic syndrome and animal models thereof (catecholamine resistance). Recent studies have demonstrated that catecholamine regulation of adipokine release is also disrupted, suggesting that catecholamine resistance …

Clostridioides Difficile: Identification Of Rival Organisms & Evaluation Of Non-Antibiotic Treatment Implementation, Justin Davis

Honors Undergraduate Theses

Clostrioides difficile is a common cause of nosocomial (hospital-acquired) infections. Patients receiving antibiotic treatment experience dysbiosis of gut microbiota, and C. difficile, normally held in check by the various other organisms, takes this opportunity to propagate. Symptoms of infection generally include diarrhea, colitis, dehydration, and fever. Understanding that C. difficile generally only causes illness when it is the dominant bacterium (i.e. when growth is relatively unchecked by other microbes), it is appropriate to investigate potential competitive organisms that may be introduced after antibiotic courses or during active C. difficile infection to effectively displace it. Fecal samples from the University …

Using Education To Improve Glycemic Management Within An Emergency Department, Rebecca Olson

Master's Theses and Capstones

Background: Patients with diabetes mellitus (DM) frequently visit acute care facilities for a variety of reasons. Proper management of this comorbidity increases patient safety, satisfaction, and quality care. Patients with persistent dysglycemic events in acute care facilities have an increased risk of complications and death during their stay. Lack of education can contribute to gaps in proper management within this population and therefore must be improved for better patient outcomes.

Methods: The Plan-Do-Check-Act design from the A3 Problem Solving model was used to guide a quality improvement project which focused on improving staff education and confidence surrounding glycemic management. The …

Assessing Discharge Knowledge For Caregivers Of Newborn (Using Video Discharge Instructions As An Adjunct To Standard Written Instructions) In Covid Period – A Randomized Controlled Trial, Jayesh Yadav, Khyati Gupta, Vishal D. Sawant

Digital Journal of Clinical Medicine

Background: Studies have demonstrated that caregivers of newborn frequently face challenges in comprehending the instructions provided to them upon discharge. Video discharge instructions provide a clear and concise message and can potentially alleviate factors which have an impact on comprehension of caregivers like illiteracy, communication barriers and limited physician time. We aim to assess the impact of incorporating video-based discharge instructions on caregivers' comprehension of newborn care and post-discharge follow-up, specifically in the context of the COVID-19 pandemic.

Methods: Caregivers of newborn in the COVID times were randomized into written only and written with video discharge instruction groups; …

Fgf5, Evelyn A Carrion, Malcolm M Moses, Richard R Behringer

Faculty, Staff and Student Publications

FGF5 functions as a negative regulator of the hair cycle in mammals. It is expressed in the outer root sheath of hair follicles during the late anagen phase of the hair cycle. It functions as a signaling molecule, mediating the transition of the anagen growth phase to catagen regression phase of the hair cycle. Spontaneous and engineered FGF5 mutations in mammalian animal models result in long hair phenotypes. In humans, inherited FGF5 mutations result in trichomegaly (long eyelashes). Knockdown of fgf5 in zebrafish embryos results in inner ear alterations. Alterations in FGF5 expression are also associated with various human pathologies.

Failure To Mate Enhances Investment In Behaviors That May Promote Mating Reward And Impairs The Ability To Cope With Stressors Via A Subpopulation Of Neuropeptide F Receptor Neurons, Julia Ryvkin, Liora Omesi, Yong-Kyu Kim, Mali Levi, Hadar Pozeilov, Lital Barak-Buchris, Bella Agranovich, Ifat Abramovich, Eyal Gottlieb, Avi Jacob, Dick R Nässel, Ulrike Heberlein, Galit Shohat-Ophir

Faculty, Staff and Student Publications

Living in dynamic environments such as the social domain, where interaction with others determines the reproductive success of individuals, requires the ability to recognize opportunities to obtain natural rewards and cope with challenges that are associated with achieving them. As such, actions that promote survival and reproduction are reinforced by the brain reward system, whereas coping with the challenges associated with obtaining these rewards is mediated by stress-response pathways, the activation of which can impair health and shorten lifespan. While much research has been devoted to understanding mechanisms underlying the way by which natural rewards are processed by the reward …

Systematic Review And Meta-Analysis Of Acupuncture For Modulation Of Immune And Inflammatory Markers In Cancer Patients, Wenli Liu, Baisong Zhong, Richard W Wagner, M Kay Garcia, Jennifer L Mcquade, Wen Huang, Yisheng Li, Graciela M Nogueras Gonzalez, Michael R Spano, Alessandro Cohen, Yimin Geng, Lorenzo Cohen

Faculty, Staff and Student Publications

Introduction: Inflammation is associated with tumor initiation, and existing tumors are associated with immune suppression locally and systemically. Cancer treatment is also associated with immune suppression. This review evaluates evidence related to the use of acupuncture for modulation of inflammation and the immune system in cancer patients.

Methods: Nine databases were searched for prospective, randomized, controlled trials evaluating the use of acupuncture for modulation of the immune system in cancer patients through March 2024. Only studies involving needle insertion into acupuncture points were included. No language limitations were applied. Studies were assessed for risk of bias (ROB) according to Cochrane …

Commitment Complex Splicing Factors In Cancers Of The Gastrointestinal Tract-An In Silico Study, Yun Zhang, Alexandria Carrasquillo Simko, Uzondu Okoro, Deja Jamese Sibert, Jin Hyung Moon, Bin Liu, Angabin Matin

Faculty, Staff and Student Publications

The initial step in pre-mRNA splicing involves formation of a spliceosome commitment complex (CC) or E-complex by factors that serve to bind and mark the exon-intron boundaries that will undergo splicing. The CC component U1 snRNP assembles at the 5'-splice site (ss), whereas SF1, U2AF2, and U2AF1 define the 3'-ss of the intron. A PRP40 protein bridges U1 snRNP with factors at the 3'-ss. To determine how defects in CC components impact cancers, we analyzed human gastrointestinal (GI) cancer patient tissue and clinical data from cBioPortal. cBioPortal datasets were analyzed for CC factor alterations and patient outcomes in GI cancers …

Harnessing Endoscopic Ultrasound-Guided Radiofrequency Ablation To Reshape The Pancreatic Ductal Adenocarcinoma Microenvironment And Elicit Systemic Immunomodulation, Vishali Moond, Bhumi Maniyar, Prateek Suresh Harne, Jennifer M Bailey-Lundberg, Nirav C Thosani

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognostics and substantial therapeutic challenges, with dismal survival rates. Tumor resistance in PDAC is primarily attributed to its fibrotic, hypoxic, and immune-suppressive tumor microenvironment (TME). Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA), an Food and Drug Administration (FDA)-approved minimally invasive technique for treating pancreatic cancer, disrupts tumors with heat and induces coagulative necrosis, releasing tumor antigens that may trigger a systemic immune response-the abscopal effect. We aim to elucidate the roles of EUS-RFA-mediated thermal and mechanical stress in enhancing anti-tumor immunity in PDAC. A comprehensive literature review focused on radiofrequency immunomodulation and immunotherapy in …

Individual Ingredients Of Np-101 (Thymoquinone Formula) Inhibit Sars-Cov-2 Pseudovirus Infection, Abdelrahim Maen, Betul Gok Yavuz, Yehia I Mohamed, Abdullah Esmail, Jianming Lu, Amr Mohamed, Asfar S Azmi, Mohamed Kaseb, Osama Kasseb, Dan Li, Michelle Gocio, Mehmet Kocak, Abdelhafez Selim, Qing Ma, Ahmed O Kaseb

Faculty, Staff and Student Publications

Thymoquinone TQ, an active ingredient of Nigella Sativa, has been shown to inhibit COVID-19 symptoms in clinical trials. Thymoquinone Formulation (TQF or NP-101) is developed as a novel enteric-coated medication derivative from Nigella Sativa. TQF consists of TQ with a favorable concentration and fatty acids, including palmitic, oleic, and linoleic acids. In this study, we aimed to investigate the roles of individual ingredients of TQF on infection of SARS-CoV-2 variants

Leptomeningeal Disease In Melanoma: An Update On The Developments In Pathophysiology And Clinical Care, Inna Smalley, Adrienne Boire, Priscilla Brastianos, Harriet M Kluger, Eva Hernando-Monge, Peter A Forsyth, Kamran A Ahmed, Keiran S M Smalley, Sherise Ferguson, Michael A Davies, Isabella C Glitza Oliva

Faculty, Staff and Student Publications

Leptomeningeal disease (LMD) remains a major challenge in the clinical management of metastatic melanoma patients. Outcomes for patient remain poor, and patients with LMD continue to be excluded from almost all clinical trials. However, recent trials have demonstrated the feasibility of conducting prospective clinical trials in these patients. Further, new insights into the pathophysiology of LMD are identifying rational new therapeutic strategies. Here we present recent advances in the understanding of, and treatment options for, LMD from metastatic melanoma. We also annotate key areas of future focus to accelerate progress for this challenging but emerging field.

Editorial: Mathematical Modeling And Computational Predictions In Oncoimmunology, Vladimir A Kuznetsov, Heiko Enderling, Mark Chaplain

Faculty, Staff and Student Publications

No abstract provided.

Spatial Multiplexing And Omics, Julienne L Carstens, Santhoshi N Krishnan, Arvind Rao, Anna G Sorace, Erin H Seeley, Sammy Ferri-Borgogno, Jared K Burks

Faculty, Staff and Student Publications

Much like solving a game of Clue, understanding physiological mysteries involves answering who, what, when, and where. Multi-omics approaches delve into cellular and molecular identities (the who and what), while longitudinal data collection addresses the when. Spatial dimensions address the where. This Primer discusses current technologies enabling quantification across biological scales, emphasizing the importance of retaining the spatial dimension of that data. We outline experimental design considerations, including targeted versus untargeted approaches, sample types, biological scale, and four main classes of molecule detection. Spatial analytics are explored, covering questioning approaches, analytical platforms, image segmentation and sampling. Example applications, reproducibility considerations, …

Fueling Cardiac Myocyte Proliferation, Manisha Deogharia, Priyatansh Gurha

Faculty, Staff and Student Publications

No abstract provided.

Metformin In Conjunction With Stereotactic Radiotherapy For Early-Stage Non-Small Cell Lung Cancer: Long-Term Results Of A Prospective Phase Ii Clinical Trial, Molly K Tate, Mike Hernandez, Joe Y Chang, Steven H Lin, Zhongxing Liao, Suja M Koshy, Heath D Skinner, Stephen G Chun

Faculty, Staff and Student Publications

Background/aim: Non-small cell lung cancer (NSCLC) is increasingly detected in early stages and there is interest in improving outcomes with stereotactic body radiotherapy (SBRT). As metformin affects NSCLC signaling pathways, it might alter the metabolism of NSCLC treated with SBRT. This study investigated the long-term outcomes of a phase II clinical trial evaluating metformin in conjunction with SBRT for early-stage NSCLC.

Patients and methods: The trial evaluated patients with American Joint Commission on Cancer (AJCC) 7th edition Stage I-II, cT1-T2N0M0 NSCLC who were randomized 6:1 to receive metformin versus placebo in conjunction with SBRT. The outcomes analyzed included local failure …

Epigallocatechin Gallate Regulates The Myeloid-Specific Transcription Factor Pu1 In Macrophages, Manjula Karpurapu, Kavita Kumari Kakarala, Sangwoon Chung, Yunjuan Nie, Amritendu Koley, Patrick Dougherty, John W Christman

Faculty, Staff and Student Publications

Our previous research demonstrated that PU.1 regulates expression of the genes involved in inflammation in macrophages. Selective knockdown of PU.1 in macrophages ameliorated LPS-induced acute lung injury (ALI) in bone marrow chimera mice. Inhibitors that block the transcriptional activity of PU.1 in macrophages have the potential to mitigate the pathophysiology of LPS-induced ALI. However, complete inactivation of PU.1 gene disrupts normal myelopoiesis. Although the green tea polyphenol Epigallocatechin gallate (EGCG) has been shown to regulate inflammatory genes in various cell types, it is not known if EGCG alters the transcriptional activity of PU.1 protein. Using Schrodinger Glide docking, we have …

Suppression Of Il-1Β Promotes Beneficial Accumulation Of Fibroblast-Like Cells In Atherosclerotic Plaques In Clonal Hematopoiesis, Trevor P Fidler, Andrew Dunbar, Eunyoung Kim, Brian Hardaway, Jessica Pauli, Chenyi Xue, Sandra Abramowicz, Tong Xiao, Kavi O'Connor, Nadja Sachs, Nan Wang, Lars Maegdefessel, Ross Levine, Muredach Reilly, Alan R Tall

Faculty, Staff and Student Publications

Clonal hematopoiesis (CH) is an independent risk factor for atherosclerotic cardiovascular disease. Murine models of CH suggest a central role of inflammasomes and IL-1β in accelerated atherosclerosis and plaque destabilization. Here we show using single-cell RNA sequencing in human carotid plaques that inflammasome components are enriched in macrophages, while the receptor for IL-1β is enriched in fibroblasts and smooth muscle cells (SMCs). To address the role of inflammatory crosstalk in features of plaque destabilization, we conducted SMC fate mapping in Ldlr-/- mice modeling Jak2VF or Tet2 CH treated with IL-1β antibodies. Unexpectedly, this treatment minimally affected SMC differentiation, …

Loss Of The Auxiliary Α 2Δ1 Voltage-Sensitive Calcium Channel Subunit Impairs Bone Formation And Anabolic Responses To Mechanical Loading, Madison M Kelly, Karan Sharma, Christian S Wright, Xin Yi, Perla C Reyes Fernandez, Aaron T Gegg, Taylor A Gorrell, Megan L Noonan, Ahmed Baghdady, Jacob A Sieger, Annette C Dolphin, Stuart J Warden, Padmini Deosthale, Lilian I Plotkin, Uma Sankar, Julia M Hum, Alexander G Robling, Mary C Farach-Carson, William R Thompson

Faculty, Staff and Student Publications

Voltage-sensitive calcium channels (VSCCs) influence bone structure and function, including anabolic responses to mechanical loading. While the pore-forming (α1) subunit of VSCCs allows Ca2+ influx, auxiliary subunits regulate the biophysical properties of the pore. The α2δ1 subunit influences gating kinetics of the α1 pore and enables mechanically induced signaling in osteocytes; however, the skeletal function of α2δ1 in vivo remains unknown. In this work, we examined the skeletal consequences of deleting Cacna2d1, the gene encoding α2δ1. Dual-energy X-ray absorptiometry and microcomputed tomography imaging demonstrated that deletion of α2δ1 diminished bone mineral content and density in both male and female …

Editorial: Immunological Aspects Of Emerging And Re-Emerging Zoonoses, Wei Wang, Jingxin Li, Yuejin Liang, Wenping Gong

Faculty, Staff and Student Publications

No abstract provided.

Foxp1 And Klf2 Reciprocally Regulate Checkpoints Of Stem-Like To Effector Transition In Car T Cells, Ziang Zhu, Guohua Lou, Xiao-Lu Teng, Haixia Wang, Ying Luo, Wangke Shi, Kiddist Yihunie, Shumeng Hao, Kole Degolier, Chengheng Liao, Huocong Huang, Qing Zhang, Terry Fry, Tao Wang, Chen Yao, Tuoqi Wu

Faculty, Staff and Student Publications

During cancers and infections, self-renewing stem-like CD8+ T cells mediate the response of immunotherapies and replenish terminally exhausted T cells and effector-like T cells. However, the programs governing the lineage choice in chimeric antigen receptor (CAR) T cells are unclear. Here, by simultaneously profiling single-cell chromatin accessibility and transcriptome in the same CAR T cells, we identified heterogeneous chromatin states within CD8+ T cell subsets that foreshadowed transcriptional changes and were primed for regulation by distinct transcription factors. Transcription factors that controlled each CD8+ T cell subset were regulated by high numbers of enhancers and positioned as hubs of gene …

An Image-Driven Micromechanical Approach To Characterize Multiscale Remodeling In Infarcted Myocardium, Emilio A Mendiola, Sunder Neelakantan, Qian Xiang, Shuda Xia, Jianyi Zhang, Vahid Serpooshan, Peter Vanderslice, Reza Avazmohammadi

Faculty, Staff and Student Publications

Myocardial infarction (MI) is accompanied by the formation of a fibrotic scar in the left ventricle (LV) and initiates significant alterations in the architecture and constituents of the LV free wall (LVFW). Previous studies have shown that LV adaptation is highly individual, indicating that the identification of remodeling mechanisms post-MI demands a fully subject-specific approach that can integrate a host of structural alterations at the fiber-level to changes in bulk biomechanical adaptation at the tissue-level. We present an image-driven micromechanical approach to characterize remodeling, assimilating new biaxial mechanical data, histological studies, and digital image correlation data within an in-silico framework …

Her4 And Egfr Activate Cell Signaling In Nrg1 Fusion-Driven Cancers: Implications For Her2-Her3-Specific Versus Pan-Her Targeting Strategies, Hibiki Udagawa, Monique B Nilsson, Jacqulyne P Robichaux, Junqin He, Alissa Poteete, Hong Jiang, Simon Heeke, Yasir Y Elamin, Yuji Shibata, Shingo Matsumoto, Kiyotaka Yoh, Shogo Okazaki, Takashi Masuko, Igor Odintsov, Romel Somwar, Marc Ladanyi, Koichi Goto, John V Heymach

Faculty, Staff and Student Publications

Introduction: NRG1 gene fusions are clinically actionable alterations identified in NSCLC and other tumors. Previous studies have reported that NRG1 fusions signal through HER2 and HER3 but, thus far, strategies targeting HER3 specifically or HER2-HER3 signaling have exhibited modest activity in patients with NSCLC bearing NRG1 fusions. Although NRG1 fusion proteins can bind HER4 in addition to HER3, the contribution of HER4 and other HER family members in NRG1 fusion-positive cancers is not fully understood.

Methods: We investigated the role of HER4 and EGFR-HER3 signaling in NRG1 fusion-positive cancers using Ba/F3 models engineered to express various HER family members in …