Recent Submissions

  • PD-L1 regulation by Dual Oxygenase 2 (DUOX2), a Reactive Oxygen Species (ROS) producing enzyme in gastric cancers.

    Martins, Mariana B.; Carrier, France (2024-04-05)
    Immune checkpoint inhibitors have shown outstanding activities in some cancers, but their efficacy is rather variable with limited long-term response in most patients while others do not respond well or even develop resistances. The oxidative state of the tumor and its microenvironment plays a critical role in this response and highlights the importance of better understanding the role of redox enzymes in response to immunotherapy. In fact, Reactive Oxygen Species (ROS) effectors can either up or down regulate PD-L1 expression depending on their targets and mechanisms of action. Our data indicate that DUOX2, an NADPH enzyme involved in the production of H2O2, is expressed in about forty percent of human gastric cancers and is significantly increased in esophageal cancers. Moreover, DUOX2 expression in human gastric and esophageal cancer cells corresponds to down regulation of the immune checkpoint PD-L1. Conversely, down regulation of DUOX2 increases PD-L1, HIF-1a and c-Myc expression in these cells. To better understand the role of DUOX2 in the production of ROS and how it interferes with the expressions of HIF-1a and PD-L1, we also evaluated its effects on the ROS scavenger glutathione (GSH) and the ROS generating Ceramide in cells expressing or not DUOX2. The down regulation of DUOX2 reduced by more than half Ceramide levels and significantly increased GSH levels. This is consistent with the known effect of H2O2 on Ceramide generation through sphingomyelin hydrolysis and H2O2 inhibitory effect on HIF-1a binding and accumulation of HIF-1a protein. Because HIF-1a is a known regulator of PD-L1, DUOX2 expression on some tumors could thus interfere with PD-L1 expression through generation of H2O2. Moreover, because HIF-1a and PD-L1 expression contribute to radio-resistance, DUOX2 expression could sensitize cancer cells to radiation therapy. On the other hand, tumors lacking DUOX2 expression would be expected to be more sensitive to immunotherapy targeting PD-1 and/or PD-L1. DUOX2 expression thus appears to hold significant potential as a valuable biomarker to guide therapeutic decisions regarding radiation or immuno- therapy
  • Oxidative Stress Relates to Negative Symptoms in a Gluten Sensitive Schizophrenia Subgroup

    Kelly, Deanna L.; Kim, Eunkyoung; Redwood, Sidney; Eaton, William W.; Vyas, Gopal; Adams, Heather A.; Harrington, Valeria; Roche, Daniel; Cihakova, Daniela; Talor, Monica V.; et al. (2024-04-03)
  • Utilization of Pseudomonas Eradication Protocols Amongst Lung Transplant Centers

    Saharia, Kapil; Baddley, John; Heil, Emily; Prakash, Katya; Charles, D.; Reed, R.; Eberlein, M. (2024-04-11)
  • Chronic Alcohol Dampens Bidirectional Claustrocortical Signaling

    Wulff, Andreas; Sheats, Samuel H.; Douglass, Eliza A.; Mathur, Brian N. (Brian Neil) (2024-02-10)
  • Early Substance Use and Co-Morbid Risk Factors on Developmental Trajectories of Brain and Cognitive Measures

    Rodriguez Rivera, Pedro J.; Isaiah, Amal; Cloak, Christine; Chang, Linda, M.D.; Ernst, Thomas, Ph.D. (2024-03-04)
  • Self-Reported Barriers to Healthy Eating and Exercise in Older Veterans with Dysmobility

    Serra, Monica; Parker, Elizabeth; Addison, Odessa; Friedman, Ben; Kilpela, Lisa S. (2024-02-15)
  • Novel Use of LymphaTouch® to Treat Peripheral Facial Nerve Palsy: A Case Study

    Barth, Jodi; Guise, Abigail M.; Horn, Linda B. (2024-02-15)
  • Elder Abuse in Family Settings: Findings from Western Nepal

    Shrestha, Aman; Kafle, Bharat; Bhattarai, Preeti; Bhattarai, Pratik; Saruna, Ghimire (2024-02-22)
  • Door in- Door out Times: A Comprehensive Stroke Center Review

    Schrier, Chad; Palmisano, Caitlin; Phipps, Michael, M.D. (2024-02-07)
  • On vs. Off-hours Arrival to Groin Time: Identifying Gaps in a Comprehensive Stroke Center

    Schrier, Chad; Palmisano, Caitlin; Phipps, Michael, M.D. (2024-02-08)
  • Effects of Nanodysferlins on Recovery of Voltage-Induced SR Calcium Release after Osmotic Shock in Muscle Fibers from Dysferlin-null mice

    Lukyanenko, Valeriy; Muriel, Joaquin M.; Bloch, Robert J. (2024-02-10)
    Earlier we showed using shock injury (OSI) that dysferlin modulates the coupling of excitation to Ca2+ release skeletal myofibers (Kerr et al., PNAS, 2013; Lukyanenko et al., Front. Physiol., 2022). Here we studied dysferlin-null A/J mouse FDB myofibers expressing fluorescent variants of nanodysferlins, created by the Sutton and Hirsch laboratories, that are missing different combinations of C2 domains, to assess their abilities to target t-tubules and to support normal Ca2+ signaling. cDNAs encoding nanodysferlins (reduced to 3 or 4 C2 domains plus the Fer/DysF domains) were provided by Drs. Hirsch and Sutton via the Jain Foundation. They were tagged at their N-terminus with Venus and electroporated into A/J FDB muscles. Expression of all four nanodysferlins was poor. When they were detected by confocal microscopy, they located in longitudinal membrane structures overlying the Z-disks typical of a compartment of the ER, not in the punctate structures typical of t-tubules. Nanodysferlins 364, 365, and 431 supported normal Ca2+ transient before OSI but behaved like untreated A/J fibers after OSI. Nanodysferlin 430 reduced the original amplitude of Ca2+ transients by ~20%, but supported their full recovery after OSI. All the nanodysferlins failed to suppress Ca2+ waves typical of CICR in myofibers exposed to OSI. Nanodysferlins with an N-terminal Venus tag express poorly in cultured A/J myofibers, mislocalize to the ER and fail to support normal Ca2+ signaling, especially after OSI. Supported by the Jain Foundation, and NIH (RO1 AR064268)
  • Dual inhibition of CDK4/6 and IL-6 pathways as a novel therapeutic approach for triple-negative breast cancer cells

    Caroland, Kailey; Shi, Changyou; Lo, Hui-Wen; Lin, Jiayuh (2024-01-24)
    Triple-negative breast cancer (TNBC) is highly aggressive and associated with poor clinical outcomes. TNBC stands as a major cause of death among breast cancer patients and offers only a few therapeutic options. Abemaciclib, a cyclin dependent kinase 4/6 (CDK4/6) inhibitor, has received FDA approval for use in hormone receptor-positive, HER2-negative, and metastatic/advanced breast cancers. However, acquired resistance to CDK4/6 inhibitors in treating TNBC is becoming an increasing concern. Our recent results indicated that CDK4/6 inhibitors can induce IL-6 levels in TNBC cells, and increased IL-6 signaling could potentially compromise the efficacy of CDK4/6 inhibitors. In this study, abemaciclib was combined with an IL-6/GP130 inhibitor (bazedoxifene). We tested the effect of the combination on cell viability, migration, and invasion of human and mouse TNBC cells. Our data demonstrated that the bazedoxifene and abemaciclib combination synergistically inhibited TNBC cell viability, migration, and invasion in vitro. These results support dual inhibition of CDK4/6 and IL-6 as a novel therapeutic approach for TNBC.
  • Neuromuscular Junction Morphology as a Biomarker for Therapeutic Efficacy in Myasthenia Gravis

    Kadali, Sai Sri Kavya; Pinot, Kaylie; Shi, Gouli; Ward, Christopher, Ph.D. (2024-01-12)
    The neuromuscular junction (NMJ) is a complex synaptic structure linking the motor nerve to individual skeletal muscle fibers for the regulation of voluntary contraction[4]. Alterations in post-synaptic NMJ morphology are linked to muscle contractile deficits in various pathological conditions (e.g., muscular dystrophy, spinal muscular atrophy, traumatic nerve injury) as well as in aging. In autoimmune mediated Myasthenia Gravis (MG), NMJ morphology is altered by the immunologic degradation of the acetylcholine receptors (AchR’s) and the secondary effects of inflammation. Our work is focused on (1) developing NMJ morphology as a biomarker for the progression of muscle dysfunction in a rat model of MG and (2) determining if clinically effective anti-complement strategies in MG act to preserve NMJ structure. To this end we have established an image analysis pipeline in Nikon Elements to quantify pre- and post-synaptic morphology of the NMJ (bungarotoxin labeled AchR’s) and motor nerve/presynaptic structure (SV2 and neurofilament) in cryosectioned muscle samples. Using this strategy, we have begun to quantitate the change in an experimental rat model of MG and the impact of a clinically effective anti-complement strategy to mitigate these changes.
  • Role of KDM3A and EZH2 in Regulation of Glutamine Metabolism and Prostate Cancer Progression

    Khadka, Sudeep; Jeon, Hee-Young; Pornour, Majid; Ryu, Hyunju; Qi, Jianfei (2024-01-12)
    Epigenetic dysregulation is a hallmark of various cancers, including prostate cancer (PCa), and contributes to disease development and progression. KDM3A is a histone 3 lysine 9 (H3K9) demethylase that removes the repressive H3K9 methylation marks and promotes gene expression. EZH2, a catalytic subunit of Polycomb Repressive Complex 2 (PRC2), induces H3K27 trimethylation repressive marks to inhibit gene expression (canonical activity). In contrast to the repressive role of PRC2, we found that it interacts with KDM3A to promote transcription of selective genes such as GLUL (non-canonical activity). GLUL catalyzes de-novo glutamine synthesis that converts ammonia and glutamate to glutamine. Glutamine metabolism yields α-Ketoglutarate, an essential molecule for the tricarboxylic acid cycle (TCA). Additionally, it plays a crucial role in the synthesis of various macromolecules, including nucleotides, proteins, and hexosamine. Cancer cells including PCa cells are mostly addicted to glutamine and switch to glutamine metabolism for proliferation and survival. We aim to investigate the mechanism of transcriptional regulation of GLUL and glutamine metabolism in PCa progression due to KDM3A and PRC2 complex interaction, primarily focusing on the non-canonical role of PRC2 complex
  • A Preliminary Analysis of Social and Emotional Loneliness in an Aging Population of San Vito de Coto Brus, Costa Rica

    Leahy, NIcholas; Rallo, Melissa; Konduru, Hima; Wan, Christine; Pedersen, Lilliana; Bailey, Shania; Vetack, Alexis; Mora, Wendel; Gupta, Shailvi; Faerron Guzman, Carlos (2023-11-29)
  • Inhibition of GPR68 ameliorates acute lung injury in mice induced by endotoxin and mechanical ventilation

    Ke, Yunbo; Karki, Pratap; Williams, Charles H. (Charles Houston); Li, Yue; Birukov, Konstantin G.; Hong, Charles C., 1967-; Birukova, Anna A. (2023-12-01)
  • How to Create a Composite Equity Indicator for Transportation Safety

    Vesselinov, Roumen; Kaushik, Kartik; Kufera, Joseph A.; Auman, Kimberly M.; Bhagat, Komal (2024-01-05)

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