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Tsyn-Seq: A T-Cell Synapse-Based Antigen Identification Platform, Yimei Jin, Takahiko Miyama, Alexandria Brown, Tomo Hayase, Xingzhi Song, Anand K Singh, Licai Huang, Ivonne I Flores, Lauren K Mcdaniel, Israel Glover, Taylor M Halsey, Rishika Prasad, Valerie Chapa, Saira Ahmed, Jianhua Zhang, Kunal Rai, Christine B Peterson, Gregory Lizee, Jennifer Karmouch, Eiko Hayase, Jeffrey J Molldrem, Chia-Chi Chang, Wen-Bin Tsai, Robert R Jenq May 2024

Tsyn-Seq: A T-Cell Synapse-Based Antigen Identification Platform, Yimei Jin, Takahiko Miyama, Alexandria Brown, Tomo Hayase, Xingzhi Song, Anand K Singh, Licai Huang, Ivonne I Flores, Lauren K Mcdaniel, Israel Glover, Taylor M Halsey, Rishika Prasad, Valerie Chapa, Saira Ahmed, Jianhua Zhang, Kunal Rai, Christine B Peterson, Gregory Lizee, Jennifer Karmouch, Eiko Hayase, Jeffrey J Molldrem, Chia-Chi Chang, Wen-Bin Tsai, Robert R Jenq

Faculty, Staff and Student Publications

Tools for genome-wide rapid identification of peptide-major histocompatibility complex targets of T-cell receptors (TCR) are not yet universally available. We present a new antigen screening method, the T-synapse (Tsyn) reporter system, which includes antigen-presenting cells (APC) with a Fas-inducible NF-κB reporter and T cells with a nuclear factor of activated T cells (NFAT) reporter. To functionally screen for target antigens from a cDNA library, productively interacting T cell-APC aggregates were detected by dual-reporter activity and enriched by flow sorting followed by antigen identification quantified by deep sequencing (Tsyn-seq). When applied to a previously characterized TCR specific for the E7 antigen …


Fam86a Methylation Of Eef2 Links Mrna Translation Elongation To Tumorigenesis, Joel William Francis, Simone Hausmann, Sabeen Ikram, Kunlun Yin, Robert Mealey-Farr, Natasha Mahealani Flores, Annie Truc Trinh, Tourkian Chasan, Julia Thompson, Pawel Karol Mazur, Or Gozani May 2024

Fam86a Methylation Of Eef2 Links Mrna Translation Elongation To Tumorigenesis, Joel William Francis, Simone Hausmann, Sabeen Ikram, Kunlun Yin, Robert Mealey-Farr, Natasha Mahealani Flores, Annie Truc Trinh, Tourkian Chasan, Julia Thompson, Pawel Karol Mazur, Or Gozani

Faculty, Staff and Student Publications

eEF2 post-translational modifications (PTMs) can profoundly affect mRNA translation dynamics. However, the physiologic function of eEF2K525 trimethylation (eEF2K525me3), a PTM catalyzed by the enzyme FAM86A, is unknown. Here, we find that FAM86A methylation of eEF2 regulates nascent elongation to promote protein synthesis and lung adenocarcinoma (LUAD) pathogenesis. The principal physiologic substrate of FAM86A is eEF2, with K525me3 modeled to facilitate productive eEF2-ribosome engagement during translocation. FAM86A depletion in LUAD cells causes 80S monosome accumulation and mRNA translation inhibition. FAM86A is overexpressed in LUAD and eEF2K525me3 levels increase through advancing LUAD disease stages. FAM86A knockdown attenuates LUAD cell proliferation and suppression …


Mdm2 Inhibitors For Cancer Therapy: The Past, Present, And Future, Wei Wang, Najah Albadari, Yi Du, Josef F Fowler, Hannah T Sang, Wa Xian, Frank Mckeon, Wei Li, Jia Zhou, Ruiwen Zhang May 2024

Mdm2 Inhibitors For Cancer Therapy: The Past, Present, And Future, Wei Wang, Najah Albadari, Yi Du, Josef F Fowler, Hannah T Sang, Wa Xian, Frank Mckeon, Wei Li, Jia Zhou, Ruiwen Zhang

Faculty, Staff and Student Publications

Since its discovery over 35 years ago, MDM2 has emerged as an attractive target for the development of cancer therapy. MDM2's activities extend from carcinogenesis to immunity to the response to various cancer therapies. Since the report of the first MDM2 inhibitor more than 30 years ago, various approaches to inhibit MDM2 have been attempted, with hundreds of small-molecule inhibitors evaluated in preclinical studies and numerous molecules tested in clinical trials. Although many MDM2 inhibitors and degraders have been evaluated in clinical trials, there is currently no Food and Drug Administration (FDA)-approved MDM2 inhibitor on the market. Nevertheless, there are …


Response Of Treatment-Naive Brain Metastases To Stereotactic Radiosurgery, Chibawanye I Ene, Christina Abi Faraj, Thomas H Beckham, Jeffrey S Weinberg, Clark R Andersen, Ali S Haider, Ganesh Rao, Sherise D Ferguson, Christopher A Alvarez-Brenkenridge, Betty Y S Kim, Amy B Heimberger, Ian E Mccutcheon, Sujit S Prabhu, Chenyang Michael Wang, Amol J Ghia, Susan L Mcgovern, Caroline Chung, Mary Frances Mcaleer, Martin C Tom, Subha Perni, Todd A Swanson, Debra N Yeboa, Tina M Briere, Jason T Huse, Gregory N Fuller, Frederick F Lang, Jing Li, Dima Suki, Raymond E Sawaya May 2024

Response Of Treatment-Naive Brain Metastases To Stereotactic Radiosurgery, Chibawanye I Ene, Christina Abi Faraj, Thomas H Beckham, Jeffrey S Weinberg, Clark R Andersen, Ali S Haider, Ganesh Rao, Sherise D Ferguson, Christopher A Alvarez-Brenkenridge, Betty Y S Kim, Amy B Heimberger, Ian E Mccutcheon, Sujit S Prabhu, Chenyang Michael Wang, Amol J Ghia, Susan L Mcgovern, Caroline Chung, Mary Frances Mcaleer, Martin C Tom, Subha Perni, Todd A Swanson, Debra N Yeboa, Tina M Briere, Jason T Huse, Gregory N Fuller, Frederick F Lang, Jing Li, Dima Suki, Raymond E Sawaya

Faculty, Staff and Student Publications

With improvements in survival for patients with metastatic cancer, long-term local control of brain metastases has become an increasingly important clinical priority. While consensus guidelines recommend surgery followed by stereotactic radiosurgery (SRS) for lesions >3 cm, smaller lesions (≤3 cm) treated with SRS alone elicit variable responses. To determine factors influencing this variable response to SRS, we analyzed outcomes of brain metastases ≤3 cm diameter in patients with no prior systemic therapy treated with frame-based single-fraction SRS. Following SRS, 259 out of 1733 (15%) treated lesions demonstrated MRI findings concerning for local treatment failure (LTF), of which 202 /1733 (12%) …


The Clinical Utility And Diagnostic Implementation Of Human Subject Cell Transdifferentiation Followed By Rna Sequencing, Shenglan Li, Sen Zhao, Jefferson C Sinson, Aleksandar Bajic, Jill A Rosenfeld, Matthew B Neeley, Mezthly Pena, Kim C Worley, Lindsay C Burrage, Monika Weisz-Hubshman, Shamika Ketkar, William J Craigen, Gary D Clark, Seema Lalani, Carlos A Bacino, Keren Machol, Hsiao-Tuan Chao, Lorraine Potocki, Lisa Emrick, Jennifer Sheppard, My T T Nguyen, Anahita Khoramnia, Paula Patricia Hernandez, Sandesh Cs Nagamani, Zhandong Liu, Christine M Eng, Brendan Lee, Pengfei Liu May 2024

The Clinical Utility And Diagnostic Implementation Of Human Subject Cell Transdifferentiation Followed By Rna Sequencing, Shenglan Li, Sen Zhao, Jefferson C Sinson, Aleksandar Bajic, Jill A Rosenfeld, Matthew B Neeley, Mezthly Pena, Kim C Worley, Lindsay C Burrage, Monika Weisz-Hubshman, Shamika Ketkar, William J Craigen, Gary D Clark, Seema Lalani, Carlos A Bacino, Keren Machol, Hsiao-Tuan Chao, Lorraine Potocki, Lisa Emrick, Jennifer Sheppard, My T T Nguyen, Anahita Khoramnia, Paula Patricia Hernandez, Sandesh Cs Nagamani, Zhandong Liu, Christine M Eng, Brendan Lee, Pengfei Liu

Faculty, Staff and Students Publications

RNA sequencing (RNA-seq) has recently been used in translational research settings to facilitate diagnoses of Mendelian disorders. A significant obstacle for clinical laboratories in adopting RNA-seq is the low or absent expression of a significant number of disease-associated genes/transcripts in clinically accessible samples. As this is especially problematic in neurological diseases, we developed a clinical diagnostic approach that enhanced the detection and evaluation of tissue-specific genes/transcripts through fibroblast-to-neuron cell transdifferentiation. The approach is designed specifically to suit clinical implementation, emphasizing simplicity, cost effectiveness, turnaround time, and reproducibility. For clinical validation, we generated induced neurons (iNeurons) from 71 individuals with primary …


The Role Of Myocardin And Its Effector Proteins In Tgf-Β Induced Cytoskeletal Remodeling Of Ipf Fibroblasts, Khadijat Abolore Olawuyi May 2024

The Role Of Myocardin And Its Effector Proteins In Tgf-Β Induced Cytoskeletal Remodeling Of Ipf Fibroblasts, Khadijat Abolore Olawuyi

Biotechnology Theses

Idiopathic pulmonary fibrosis (IPF) is characterized by thickening and stiffness around the air sacs. Approved treatments like nintedanib and pirfenidone slow disease progression in IPF and often have tolerability issues. More research is needed to fully grasp the mechanisms behind abnormal cytoskeletal changes in lung cells, notably fibroblasts and epithelial cells, and their role in fibrosis progression. Previous studies suggest that myocardin expression and function, traditionally limited to smooth/cardiac development in physiology, become active in pathophysiological conditions like pleural fibrosis. Myocardin's role in liver and kidney fibrosis is known, but its involvement in IPF is unclear. To get more insights, …


The Role Of Microrna-152 In The Pathogenesis Of Diabetic Cardiomyopathy, Joy Olaoluwa Gbadegoye May 2024

The Role Of Microrna-152 In The Pathogenesis Of Diabetic Cardiomyopathy, Joy Olaoluwa Gbadegoye

Alternative Theses and Dissertations (AETDs)

Diabetes mellitus, one of the world’s fast-growing diseases, is characterized by high death rates from cardiac complications named diabetic cardiomyopathy (DCM). DCM is a heart disease that occurs in both type 1 and 2 diabetes mellitus patients. Many management options have been explored in the management of DCM, including ACE inhibitors, beta-blockers, etc.; however, limited success has been recorded from these. MicroRNAs, recently discovered gene regulators, have been reported to be associated with various physiology and pathological processes in the mammalian body. These include cell proliferation, cell death, senesis, carcinogenesis, diabetes, and heart failure, among others. Various miRs have been …


The Pam-1 Aminopeptidase Protects Against Neurodegeneration In Caenorhabditis Elegans, Caleb Coil May 2024

The Pam-1 Aminopeptidase Protects Against Neurodegeneration In Caenorhabditis Elegans, Caleb Coil

Honors College Theses

The deteriorating effects of neurodegenerative conditions seem inescapable for many as they age. The experimental exploration of the molecular and cellular mechanisms responsible for neurodegeneration is aided using animal models. For instance, genetic screens have identified the puromycin-sensitive aminopeptidase (PSA) as a novel effector of neurodegeneration, as mutations in PSA in fruit flies result in perturbations of neuron anatomy and an accelerated onset of neuron death. We have tested the hypothesis that PAM-1, the Caenorhabditis elegans ortholog of PSA, plays a similar role in governing neurodegeneration in nematodes. Genetic strains were created that express the green fluorescent protein (GFP) in …


Stopping The Bleed At Uri, Emily Lefebre May 2024

Stopping The Bleed At Uri, Emily Lefebre

Senior Honors Projects

The number one cause of preventable death is uncontrolled bleeding from traumatic injury. From the unlikely scenario of a school shooting, to a campus car accident or an injury during a sports or club event, possessing skills to effectively stop a life-threatening bleed becomes a matter of life or death. The American College of Surgeons Committee on Trauma (ACS COT) STOP THE BLEED® program is a campaign to teach communities how to respond effectively and efficiently to life-threatening bleeding in emergencies. STOP THE BLEED® aims to empower individuals with the knowledge and skills to stop severe bleeding by tourniquet application, …


Examining The Effects Of Menstrual Cycle Phase And Hormonal Contraceptive Use On Women's Sleep, Charles Ethan Coombs May 2024

Examining The Effects Of Menstrual Cycle Phase And Hormonal Contraceptive Use On Women's Sleep, Charles Ethan Coombs

Psychological Science Undergraduate Honors Theses

Women overrepresent men for sub-optimal sleep, a consequence of hormone fluctuation in the menstrual cycle affecting sleep regulatory pathways. While research has examined the prevalence of sub-optimal sleep through cycle phases, little research has examined how hormonal contraceptives (HC’s) could similarly affect women’s sleep, while also neglecting to utilize subjective sleep measures. In this study, we examine subjective sleep quality among naturally cycling (NC) women, women using different HC types, and between active and inactive phase pill users by subjecting 463 women to a subjective sleep battery. We hypothesized that HC users would report more sub-optimal sleep than NC women. …


Mutational Landscape Of Noncoding Ultraconserved Elements In Human Cancers: Functional Relevance And Clinical Utility, Recep Bayraktar May 2024

Mutational Landscape Of Noncoding Ultraconserved Elements In Human Cancers: Functional Relevance And Clinical Utility, Recep Bayraktar

Dissertations and Theses (Open Access)

The mutational landscape of phylogenetically ultraconserved elements (UCEs), especially those in noncoding DNA regions (ncUCEs), and their functional and clinical relevance in cancers remain poorly characterized. In this thesis, we perform a systematic analysis of whole-genome sequencing (WGS) data from the International Cancer Genome Consortium (ICGC) and in-house targeted sequencing of 13,736 UCEs and demonstrate that ncUCE somatic alterations are pervasive. Using a genome-wide multiplexed CRISPR knockout screen in colorectal cancer (CRC) cell lines, we show that the loss of several mutated ncUCEs impacts cancer cell proliferation. In-depth functional studies in vitro and in vivo further reveal that UCE_11311 is …


Table Of Contents May 2024

Table Of Contents

Journal of the South Carolina Academy of Science

No abstract provided.


Seasonal Climate And Environmental Conditions Associated With Physiological Variations Of Southwestern United States Pines, Taylor Brewer May 2024

Seasonal Climate And Environmental Conditions Associated With Physiological Variations Of Southwestern United States Pines, Taylor Brewer

UNLV Theses, Dissertations, Professional Papers, and Capstones

Juvenile and adult conifers in the southwestern United States are vulnerable to a range of different abiotic and biotic factors, yet it is unclear how their stress tolerance varies across environments. Predicted increases in the frequency and intensity of disturbance as well as greater climate and weather variability across the region highlight the potential for differential physiological responses across tree species and populations. This thesis focuses on two physiologic mechanisms, hydraulic vulnerability and mortality, that could be altered by climate change in two broadly distributed southwestern United States conifers: ponderosa pine and pinyon pine.

In chapter 2, I measured the …


The Influence Of Bihemispheric Transcranial Direct Current Stimulation On Muscle Fatigue, Ananya Singh Chauhan May 2024

The Influence Of Bihemispheric Transcranial Direct Current Stimulation On Muscle Fatigue, Ananya Singh Chauhan

UNLV Theses, Dissertations, Professional Papers, and Capstones

Unilateral transcranial direct current stimulation (tDCS) using two electrodes placed over the primary motor cortex (M1) and the contralateral supraorbital (SO) region (M1-SO montage) has been shown to decrease the progression of muscle fatigue. The primary purpose was to determine the impact of bihemispheric tDCS (bi-tDCS) applied over the left and right M1s (bi-tDCS) on the time to task failure (TTF) of a precision-grip task. The study implemented a double-blind, randomized, SHAM-controlled, within-subjects design. A total of 20 participants performed two experimental sessions (bi-tDCS and SHAM conditions) separated by a one-week washout. During each experimental session, a fatiguing isometric contraction …


The Influence Of Bilateral Dual Source Transcranial Direct Current Stimulation On The Progression Of Muscle Fatigue, Eliza Clinton May 2024

The Influence Of Bilateral Dual Source Transcranial Direct Current Stimulation On The Progression Of Muscle Fatigue, Eliza Clinton

UNLV Theses, Dissertations, Professional Papers, and Capstones

Transcranial direct current stimulation (tDCS) applied unilaterally to the primary motor cortex (M1) can significantly prolong the time to task failure (TTF) of a fatiguing contraction. The primary purpose of the study was to examine the influence of bilateral dual source tDCS (dstDCS) applied over the left and right M1s (ds-tDCS) on the TTF of a precision grip task. This was accomplished through the utilization of a double-blind, randomized, SHAM-controlled, within-subjects design. Fourteen participants completed two experiments (ds-tDCS and SHAM stimulation conditions) with a seven-day washout period between sessions. Each experiment involved the performance of a sustained isometric fatiguing contraction …


Investigations Into The Relationship Between Menopause And Alzheimer’S Disease Pathology In A Mouse Model With Ovarian Follicle Depletion, Amanda M. Leisgang Osse May 2024

Investigations Into The Relationship Between Menopause And Alzheimer’S Disease Pathology In A Mouse Model With Ovarian Follicle Depletion, Amanda M. Leisgang Osse

UNLV Theses, Dissertations, Professional Papers, and Capstones

Alzheimer’s Disease (AD) currently affects about 6.9 million Americans, with over two-thirds of those individuals being women. Interestingly, changes in the brain indicative of AD coincide with the onset of menopause. Post-menopausal women have significantly higher levels of AD pathologies, including amyloid beta and hyperphosphorylated tau, than pre-menopausal women. To investigate the relationship between AD pathologies and menopause, we induced menopause-like state in an AD mouse model, APP/PS1, by treatment with 4-vinylcyclohexene diepoxide (VCD) to accelerate ovarian follicle depletion. To monitor the transition to menopause, vaginal lavages and cytology was performed to determine if mice reached anestrous. Both female APP/PS1 …


A Low Dose Of Electro-Psychedelic Treatment Increases Neuronal Dendritic Arborization And Filopodic Spine Density, Elaine Aquino Vasquez May 2024

A Low Dose Of Electro-Psychedelic Treatment Increases Neuronal Dendritic Arborization And Filopodic Spine Density, Elaine Aquino Vasquez

UNLV Theses, Dissertations, Professional Papers, and Capstones

Neuropsychiatric disorders remain a formidable challenge to the global healthcare system, necessitating innovative treatments to address their complex pathophysiology. Alternative therapeutic approaches, including electroconvulsive treatment (ECT) and psychedelics, have gained attention for their capacity to relieve a broad range of symptoms. ECT is a long-standing effective therapy for patients, especially treatment-resistant ones. Psychedelics, like psilocybin, can induce profound and sustained therapeutic effects. The limited understanding of their mechanisms of action, compounded by the negative stigma surrounding ECT and psilocybin, prevents them from being used as adjunct agents. ECT and psilocybin promote synaptic plasticity and modulate neural remodeling, yet their comparative …


Cerebral Venous Sinus Thrombosis (Cvst): A Retrospective Study, Nia Acharya May 2024

Cerebral Venous Sinus Thrombosis (Cvst): A Retrospective Study, Nia Acharya

Theses/Capstones/Creative Projects

This retrospective study investigates the long-term management of Cerebral Venous Sinus Thrombosis (CVST) in 51 patients over a 3-month follow-up. The analysis covers demographics, risk factors, CVST presentation, associated diseases, thrombophilia, laboratory results, and antithrombotic treatments. CVST, a rare thrombosis of dural/cerebral sinuses, poses life-threatening risks with an annual incidence aligning with literature, notably affecting young individuals. Underlying causes range from rare disorders to common triggers, complicating diagnosis, especially during pregnancy. Imaging techniques aid diagnosis, with systemic anticoagulation preferred despite bleeding risks. Noteworthy findings include a higher incidence in women, predominantly presenting with headaches. Two cases of vaccine-induced immune thrombotic …


Dean's Research Newsletter, May 2024, Neil W. Schluger May 2024

Dean's Research Newsletter, May 2024, Neil W. Schluger

SOM Dean's Research Newsletter

No abstract provided.


Macrophage Polarization And Colorectal Cancer Immune Checkpoint Protein Expression., Anne Macleod May 2024

Macrophage Polarization And Colorectal Cancer Immune Checkpoint Protein Expression., Anne Macleod

Electronic Theses and Dissertations

The majority of patients with colorectal cancer do not respond to treatment with immunotherapy. Immunotherapy requires the expression of cell surface immune checkpoint proteins (e.g. PDL1) to exert its effect. Most (>85%) of colorectal cancers do not express these proteins and this contributes in part to the poor prognosis and survival in patients with advanced disease. The patients in which immunotherapy is a potential treatment option, are a genetic subtype known as mismatch repair deficient, and have demonstrated an excellent response to anti-PD-1/PDL1 immunotherapy. A key feature of mismatch repair deficient (MMRd) cancers is their immune cell rich tumor …


Sleep Disturbances In Adults With Tsc: Influences Of Treatment And Clinical Features, Kirstin Risgaard May 2024

Sleep Disturbances In Adults With Tsc: Influences Of Treatment And Clinical Features, Kirstin Risgaard

Dissertations and Theses (Open Access)

Tuberous sclerosis complex (TSC) is a rare genetic condition caused by pathogenic variants in the TSC1 or TSC2 genes. TSC is characterized by a multisystem, neurocutaneous phenotype including skin lesions, hamartomas, and epilepsy. Additionally, TSC can present with an array of behavioral, psychiatric, academic, psychosocial, intellectual, or neuropsychological difficulties comprehensively known as TAND, or TSC-associated neuropsychiatric disorders. Sleep disorders are a common feature of TAND; however, they are not well characterized in the adult TSC population. Likewise, little is known about how clinical features of the condition and commonly prescribed medications impact sleep. Therefore, this study aimed to determine the …


Editorial: Gene-Based Renaming Of Human Diseases, Ali J Marian May 2024

Editorial: Gene-Based Renaming Of Human Diseases, Ali J Marian

The Brown Foundation: Institute of Molecular Medicine

No abstract provided.


The Constitutively Active Form Of A Key Cholesterol Synthesis Enzyme Is Lipid Droplet-Localized And Upregulated In Endometrial Cancer Tissues, Hudson W Coates, Tina B Nguyen, Ximing Du, Ellen M Olzomer, Rhonda Farrell, Frances L Byrne, Hongyuan Yang, Andrew J Brown May 2024

The Constitutively Active Form Of A Key Cholesterol Synthesis Enzyme Is Lipid Droplet-Localized And Upregulated In Endometrial Cancer Tissues, Hudson W Coates, Tina B Nguyen, Ximing Du, Ellen M Olzomer, Rhonda Farrell, Frances L Byrne, Hongyuan Yang, Andrew J Brown

Faculty, Staff and Student Publications

Cholesterol is essential for both normal cell viability and cancer cell proliferation. Aberrant activity of squalene monooxygenase (SM, also known as squalene epoxidase), the rate-limiting enzyme of the committed cholesterol synthesis pathway, is accordingly implicated in a growing list of cancers. We previously reported that hypoxia triggers the truncation of SM to a constitutively active form, thus preserving sterol synthesis during oxygen shortfalls. Here, we show SM truncation is upregulated and correlates with the magnitude of hypoxia in endometrial cancer tissues, supporting the in vivo relevance of our earlier work. To further investigate the pathophysiological consequences of SM truncation, we …


Profiling The Activity Of The Para-Caspase Malt1 In B-Cell Acute Lymphoblastic Leukemia For Potential Targeted Therapeutic Application, Firas M Safa, Terri Rasmussen, Lorena Fontan, Min Xia, Ari Melnick, Adrian Wiestner, Patricia Lobelle-Rich, Jan A Burger, Yara Mouawad, Hana Safah, Erik K Flemington, Nakhle S Saba May 2024

Profiling The Activity Of The Para-Caspase Malt1 In B-Cell Acute Lymphoblastic Leukemia For Potential Targeted Therapeutic Application, Firas M Safa, Terri Rasmussen, Lorena Fontan, Min Xia, Ari Melnick, Adrian Wiestner, Patricia Lobelle-Rich, Jan A Burger, Yara Mouawad, Hana Safah, Erik K Flemington, Nakhle S Saba

Faculty, Staff and Student Publications

B-cell acute lymphoblastic leukemia (B-ALL) remains a hard-to-treat disease with a poor prognosis in adults. Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a para-caspase required for B-cell receptor (BCR)-mediated NF-κB activation. Inhibition of MALT1 in preclinical models has proven efficacious in many B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma and diffuse large B-cell lymphoma. We sought to examine the role of MALT1 in B-ALL and determine the biological consequences of its inhibition. Targeting MALT1 with both Z-VRPR-fmk and MI-2 efficiently kills B-ALL cells independent of the cell-of-origin (pro, pre, mature) or the presence of the Philadelphia …


Dlk-Mapk Signaling Coupled With Dna Damage Promotes Intrinsic Neurotoxicity Associated With Non-Mutated Tau, Sanming Li, Ethan R Roy, Yanyu Wang, Trent Watkins, Wei Cao May 2024

Dlk-Mapk Signaling Coupled With Dna Damage Promotes Intrinsic Neurotoxicity Associated With Non-Mutated Tau, Sanming Li, Ethan R Roy, Yanyu Wang, Trent Watkins, Wei Cao

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is the most prevalent form of neurodegeneration. Despite the well-established link between tau aggregation and clinical progression, the major pathways driven by this protein to intrinsically damage neurons are incompletely understood. To model AD-relevant neurodegeneration driven by tau, we overexpressed non-mutated human tau in primary mouse neurons and observed substantial axonal degeneration and cell death, a process accompanied by activated caspase 3. Mechanistically, we detected deformation of the nuclear envelope and increased DNA damage response in tau-expressing neurons. Gene profiling analysis further revealed significant alterations in the mitogen-activated protein kinase (MAPK) pathway; moreover, inhibitors of dual leucine …


The Intrinsic Substrate Specificity Of The Human Tyrosine Kinome, Tomer M Yaron-Barir, Brian A Joughin, Emily M Huntsman, Alexander Kerelsky, Daniel M Cizin, Benjamin M Cohen, Amit Regev, Junho Song, Neil Vasan, Ting-Yu Lin, Jose M Orozco, Christina Schoenherr, Cari Sagum, Mark T Bedford, R Max Wynn, Shih-Chia Tso, David T Chuang, Lei Li, Shawn S-C Li, Pau Creixell, Konstantin Krismer, Mina Takegami, Harin Lee, Bin Zhang, Jingyi Lu, Ian Cossentino, Sean D Landry, Mohamed Uduman, John Blenis, Olivier Elemento, Margaret C Frame, Peter V Hornbeck, Lewis C Cantley, Benjamin E Turk, Michael B Yaffe, Jared L Johnson May 2024

The Intrinsic Substrate Specificity Of The Human Tyrosine Kinome, Tomer M Yaron-Barir, Brian A Joughin, Emily M Huntsman, Alexander Kerelsky, Daniel M Cizin, Benjamin M Cohen, Amit Regev, Junho Song, Neil Vasan, Ting-Yu Lin, Jose M Orozco, Christina Schoenherr, Cari Sagum, Mark T Bedford, R Max Wynn, Shih-Chia Tso, David T Chuang, Lei Li, Shawn S-C Li, Pau Creixell, Konstantin Krismer, Mina Takegami, Harin Lee, Bin Zhang, Jingyi Lu, Ian Cossentino, Sean D Landry, Mohamed Uduman, John Blenis, Olivier Elemento, Margaret C Frame, Peter V Hornbeck, Lewis C Cantley, Benjamin E Turk, Michael B Yaffe, Jared L Johnson

Faculty, Staff and Student Publications

Phosphorylation of proteins on tyrosine (Tyr) residues evolved in metazoan organisms as a mechanism of coordinating tissue growth1. Multicellular eukaryotes typically have more than 50 distinct protein Tyr kinases that catalyse the phosphorylation of thousands of Tyr residues throughout the proteome1-3. How a given Tyr kinase can phosphorylate a specific subset of proteins at unique Tyr sites is only partially understood4-7. Here we used combinatorial peptide arrays to profile the substrate sequence specificity of all human Tyr kinases. Globally, the Tyr kinases demonstrate considerable diversity in optimal patterns of residues surrounding the site of phosphorylation, revealing the functional organization of …


Enhanced Ctla-4 Blockade Anti-Tumor Immunity With Apg-157 Combination In A Murine Head And Neck Cancer, Daniel Sanghoon Shin, Saroj Basak, Mysore S Veena, Begoña Comin-Anduix, Arjun Bhattacharya, Tien S Dong, Albert Ko, Philip Han, Jonathan Jacobs, Neda A Moatamed, Luis Avila, Matteo Pellegrini, Marilene Wang, Eri S Srivatsan May 2024

Enhanced Ctla-4 Blockade Anti-Tumor Immunity With Apg-157 Combination In A Murine Head And Neck Cancer, Daniel Sanghoon Shin, Saroj Basak, Mysore S Veena, Begoña Comin-Anduix, Arjun Bhattacharya, Tien S Dong, Albert Ko, Philip Han, Jonathan Jacobs, Neda A Moatamed, Luis Avila, Matteo Pellegrini, Marilene Wang, Eri S Srivatsan

Faculty, Staff and Student Publications

BACKGROUND: A phase I clinical study for patients with locally advanced H&N cancer with a new class of botanical drug APG-157 provided hints of potential synergy with immunotherapy. We sought to evaluate the efficacy of the combination of APG-157 and immune checkpoint inhibitors.

METHODS: CCL23, UM-SCC1 (human), and SCCVII (HPV-), MEER (HPV+) (murine) H&N cancer cell lines were utilized for in vitro and in vivo studies. We measured tumor growth by treating the mice with APG-157, anti-PD-1, and anti-CTLA-4 antibody combinations (8 groups). The tumor microenvironments were assessed by multi-color flow cytometry, immunohistochemistry, and RNA-seq analysis. Fecal microbiome was analyzed …


Mechanical Venous Thrombectomy For Deep Venous Thrombosis In Cancer Patients: A Single-Center Retrospective Study, Riya M Patel, Koustav Pal, Syed Hadi Ahmed, Joshua D Kuban, Milan Patel, Ketan Shah, Peiman Habibollahi, Zeyad Metwalli, Varshana Gurusamy, Sanjay Gupta, Cristhiam M Rojas-Hernandez, Vahid Afshar-Kharghan, Michael H Kroll, Rahul A Sheth May 2024

Mechanical Venous Thrombectomy For Deep Venous Thrombosis In Cancer Patients: A Single-Center Retrospective Study, Riya M Patel, Koustav Pal, Syed Hadi Ahmed, Joshua D Kuban, Milan Patel, Ketan Shah, Peiman Habibollahi, Zeyad Metwalli, Varshana Gurusamy, Sanjay Gupta, Cristhiam M Rojas-Hernandez, Vahid Afshar-Kharghan, Michael H Kroll, Rahul A Sheth

Faculty, Staff and Student Publications

PURPOSE: Venous thromboembolism (VTE) is a major contributor to the mortality of cancer patients. Mechanical thrombectomy (MT) is an endovascular technique that physically removes a thrombus without thrombolytics. The purpose of this study was to evaluate safety, efficacy, and clinical outcomes following MT for lower extremity DVT in cancer patients.

METHODS: This single-center, retrospective study evaluated outcomes following MT of lower extremity DVT in cancer patients from November 2019 to May 2023. The primary outcome measure was clinical success, defined as a decrease in Villalta score by at least 2 points following the intervention. Secondary outcomes included repeat intervention-free survival …


Modeling Acute Myocardial Infarction And Cardiac Fibrosis Using Human Induced Pluripotent Stem Cell-Derived Multi-Cellular Heart Organoids, Myeongjin Song, Da Bin Choi, Jeong Suk Im, Ye Na Song, Ji Hyun Kim, Hanbyeol Lee, Jieun An, Ami Kim, Hwan Choi, Joon-Chul Kim, Choongseong Han, Young Keul Jeon, Sung Joon Kim, Dong-Hun Woo May 2024

Modeling Acute Myocardial Infarction And Cardiac Fibrosis Using Human Induced Pluripotent Stem Cell-Derived Multi-Cellular Heart Organoids, Myeongjin Song, Da Bin Choi, Jeong Suk Im, Ye Na Song, Ji Hyun Kim, Hanbyeol Lee, Jieun An, Ami Kim, Hwan Choi, Joon-Chul Kim, Choongseong Han, Young Keul Jeon, Sung Joon Kim, Dong-Hun Woo

Faculty, Staff and Student Publications

Heart disease involves irreversible myocardial injury that leads to high morbidity and mortality rates. Numerous cell-based cardiac in vitro models have been proposed as complementary approaches to non-clinical animal research. However, most of these approaches struggle to accurately replicate adult human heart conditions, such as myocardial infarction and ventricular remodeling pathology. The intricate interplay between various cell types within the adult heart, including cardiomyocytes, fibroblasts, and endothelial cells, contributes to the complexity of most heart diseases. Consequently, the mechanisms behind heart disease induction cannot be attributed to a single-cell type. Thus, the use of multi-cellular models becomes essential for creating …


Mapping Recommendations Towards An Asian Code Against Cancer (Acac) As Part Of The World Code Against Cancer Framework: An Asian National Cancer Centers Alliance (Ancca) Initiative, Sok King Ong, Sarah K Abe, Gillian Li Gek Phua, Harindra Jayasekara, Kayo Togawa, Laureline Gatellier, Jeongseon Kim, Yawei Zhang, Siti Zuhrini Kahan, Siti Norbayah Yusof, Jong Soo Han, C S Pramesh, Manju Sengar, Abhishek Shankar, Clarito Cairo, Suleeporn Sangrajran, Erdenekhuu Nansalmaa, Tseveen Badamsuren, Tashi Dendup, Kinley Tshering, Jie He, R Soeko Werdi Nindito D, Azmi Ritana, Jeong Soo Im, Eun Young Park, Giang Nguyen Huong, Tran Thi Thanh Huong, Mohammed Biglari, Aasim Yusuf, Kishore Kumar Pradhananga, Champadeng Vongdala, Muhammad Taufiq Bin Jaafar, Nor Saleha Ibrahim Tamin, Yi Yi Myint, Kyaw Kan Kaung, Md Shafiur Rahman, Eshani Fernando, Beauta Rath, Babu Sukumaran, William Yk Hwang, Carolina Espina, Joachim Schüz, Manami Inoue, Tomohiro Matsuda May 2024

Mapping Recommendations Towards An Asian Code Against Cancer (Acac) As Part Of The World Code Against Cancer Framework: An Asian National Cancer Centers Alliance (Ancca) Initiative, Sok King Ong, Sarah K Abe, Gillian Li Gek Phua, Harindra Jayasekara, Kayo Togawa, Laureline Gatellier, Jeongseon Kim, Yawei Zhang, Siti Zuhrini Kahan, Siti Norbayah Yusof, Jong Soo Han, C S Pramesh, Manju Sengar, Abhishek Shankar, Clarito Cairo, Suleeporn Sangrajran, Erdenekhuu Nansalmaa, Tseveen Badamsuren, Tashi Dendup, Kinley Tshering, Jie He, R Soeko Werdi Nindito D, Azmi Ritana, Jeong Soo Im, Eun Young Park, Giang Nguyen Huong, Tran Thi Thanh Huong, Mohammed Biglari, Aasim Yusuf, Kishore Kumar Pradhananga, Champadeng Vongdala, Muhammad Taufiq Bin Jaafar, Nor Saleha Ibrahim Tamin, Yi Yi Myint, Kyaw Kan Kaung, Md Shafiur Rahman, Eshani Fernando, Beauta Rath, Babu Sukumaran, William Yk Hwang, Carolina Espina, Joachim Schüz, Manami Inoue, Tomohiro Matsuda

Faculty, Staff and Student Publications

This paper outlines the process undertaken by Asian National Cancer Centers Alliance (ANCCA) members in working towards an Asian Code Against Cancer (ACAC). The process involves: (i) identification of the criteria for selecting the existing set of national recommendations for ACAC (ii) compilation of existing national codes or recommendations on cancer prevention (iii) reviewing the scientific evidence on cancer risk factors in Asia and (iv) establishment of one or more ACAC under the World Code Against Cancer Framework. A matrix of national codes or key recommendations against cancer in ANCCA member countries is presented. These include taking actions to prevent …