Medicine and Health Sciences Commons^™

Multistate Mumps Outbreak Originating From Asymptomatic Transmission At A Nebraska Wedding — Six States, August–October 2019, Matthew Donahue, Blake Hendrickson, Derek Julian, Nicholas Hill, Julie Rother, Samir Koirala, Joshua L. Clayton, Thomas Safranek, Bryan Buss

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In August 2019, 30 attendees at a Nebraska wedding developed mumps after being exposed to one asymptomatic index patient who was fully vaccinated according to Advisory Committee on Immunization Practices (ACIP) recommendations (1), resulting in a multistate outbreak. A public health investigation and response revealed epidemiologic links that extended from the index patient through secondary, tertiary, and quaternary patients and culminated in a measles-mumpsrubella (MMR) booster vaccination campaign in the local community where approximately half of the patients resided.

On The Inadequacy Of Species Distribution Models For Modelling The Spread Of Sars-Cov-2: Response To Araújo And Naimi, Joseph D. Chipperfield, Blas M. Benito, Robert B. O'Hara, Richard J. Telford, Colin J. Carlson

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The ongoing pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing significant damage to public health and economic livelihoods, and is putting significant strains on healthcare services globally. This unfolding emergency has prompted the preparation and dissemination of the article “Spread of SARS-CoV-2 Coronavirus likely to be constrained by climate” by Araújo and Naimi (2020). The authors present the results of an ensemble forecast made from a suite of species distribution models (SDMs), where they attempt to predict the suitability of the climate for the spread of SARS-CoV-2 over the coming months. They argue that climate is …

Meeting Overview: Interferon Lambda - Disease Impact And Therapeutic Potential, Thomas R. O'Brien, Howard A. Young, Raymond P. Donnelly, Ludmila Prokunina-Olsson

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A meeting entitled, "Interferon Lambda: Disease Impact and Translational Potential," was held on the campus of the National Institutes of Health in Bethesda, Maryland, on October 25-26, 2018. To our knowledge, this was the first meeting that focused exclusively on interferon lambda (IFN-λ). The meeting's purpose was to enhance interdisciplinary communication and promote new collaborations. The gathering brought together an international group of scientists from a wide range of disciplines. Sessions included: IFN-λ Biology, Therapy and Genetic Variation; IFN-λ and Hepatitis C Virus Infection; IFN-λ in Other Infections; and IFN-λ - Hepatic Fibrosis and Cancer. The next meeting on IFN-λ …

Post–Modern Epidemiology: When Methods Meet Matter, George Davey Smith

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In the last third of the 20th century, etiological epidemiology within academia in high-income countries shifted its primary concern from attempting to tackle the apparent epidemic of noncommunicable diseases to an increasing focus on developing statistical and causal inference methodologies. This move was mutually constitutive with the failure of applied epidemiology to make major progress, with many of the advances in understanding the causes of noncommunicable diseases coming from outside the discipline, while ironically revealing the infectious origins of several major conditions. Conversely, there were many examples of epidemiologic studies promoting ineffective interventions and little evident attempt to account for …

Durvalumab In Combination With Olaparib In Patients With Relapsed Sclc: Results From A Phase Ii Study, Anish Thomas, Rasa Vilimas, Christopher Trindade, Rebecca Erwin-Cohen, Nitin Roper, Liqiang Xi, Venkatesh Krishnasamy, Elliot Levy, Andy Mammen, Samantha Nichols, Yuanbin Chen, Vamsidhar Velcheti, Faye Yin, Eva Szabo, Yves Pommier, Seth M. Steinberg, Jane B. Trepel, Mark Raffeld, Howard A. Young, Javed Khan, Stephen Hewitt, Jung Min Lee

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Purpose: Despite high tumor mutationburden, immune checkpoint blockade has limited efficacy in SCLC. We hypothesized that poly (ADP-ribose) polymerase inhibition could render SCLC more susceptible to immune checkpoint blockade. Methods: A single-arm, phase II trial (NCT02484404) enrolled patients with relapsed SCLC who received durvalumab, 1500 mg every 4 weeks, and olaparib, 300 mg twice a day. The primary outcome was objective response rate. Correlative studies included mandatory collection of pretreatment and during-treatment biopsy specimens, which were assessed to define SCLC immunephenotypes: desert (CD8-positive T-cell prevalence low), excluded (CD8-positive T cells in stroma immediately adjacent/within tumor), and inflamed (CD8-positive T cells …

Ion Gresser 1928-2019, Jan Vilcek, Howard A. Young

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Ion Gresser, a virologist who transformed understanding of the roles of interferons, may be best remembered for showing that in mice, interferon-α (IFN-α) can produce acute and chronic disease. At the time Gresser began these studies, interferon was considered to be a selective antiviral substance, harmless to uninfected cells and organisms, and there was no indication that cytokines would play a role in pathogenesis. That belief was shattered with the 1975 Nature publication with the simple title “Lethality of interferon preparations for newborn mice.” Gresser subsequently demonstrated that antibodies to IFN-α can protect young mice from death caused by infection …

Ifn-Γ: A Cytokine At The Right Time, Is In The Right Place, J. Daniel Burke, Howard A. Young

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Interferon gamma has long been studied as a critical mediator of tumor immunity. In recent years, the complexity of cellular interactions that take place in the tumor microenvironment has become better appreciated in the context of immunotherapy. While checkpoint inhibitors have dramatically improved remission rates in cancer treatment, IFN-Γ and related effectors continue to be identified as strong predictors of treatment success. In this review, we provide an overview of the multiple immunosuppressive barriers that IFN-Γ has to overcome to eliminate tumors, and potential avenues for modulating the immune response in favor of tumor rejection.

Report On The 2018 Cancer, Autoimmunity, And Immunology Conference, Colleen S. Curran, Connie L. Sommers, Howard A. Young, Katarzyna Bourcier, Marie Mancini, Elad Sharon

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With the increased use of cancer immunotherapy, a number of immune-related adverse events (irAEs) are being identified. These irAEs can be compared with known autoimmune disorders in similar tissues, with important similarities and differences. Understanding the etiology of irAEs may bring to light concepts applicable to immune responses in cancer, autoimmunity, and infectious disease. This immunobiology is especially relevant to cancer patients with preexisting allogeneic transplants or autoimmune disease who are undergoing cancer immunotherapy. To address these facets of cancer immunotherapy, academic leaders from these various disciplines discussed current irAE basic and clinical research, irAE diagnosis and management, and the …

Critical Role Of Post-Transcriptional Regulation For Ifn-Γ In Tumor-Infiltrating T Cells, Fiamma Salerno, Aurelie Guislain, Julian J. Freen-Van Heeren, Benoit P. Nicolet, Howard A. Young, Monika C. Wolkers

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Protective T cell responses against tumors require the production of Interferon gamma (IFN-γ). However, tumor-infiltrating T cells (TILs) gradually lose their capacity to produce IFN-γ and therefore fail to clear malignant cells. Dissecting the underlying mechanisms that block cytokine production is thus key for improving T cell products. Here we show that although TILs express substantial levels of Ifng mRNA, post-transcriptional mechanisms impede the production of IFN-γ protein due to loss of mRNA stability. CD28 triggering, but not PD1 blocking antibodies, effectively restores the stability of Ifng mRNA. Intriguingly, TILs devoid of AU-rich elements within the 3ʹuntranslated region maintain stabilized …

Thymic Expression Of Il-4 And Il-15 After Systemic Inflammatory Or Infectious Th1 Disease Processes Induce The Acquisition Of"Innate" Characteristics During Cd8 + T Cell Development, Natalia S. Baez, Fabio Cerbán, Constanza Savid-Frontera, Deborah L. Hodge, Jimena Tosello, Eva Acosta-Rodriguez, Laura Almada, Adriana Gruppi, Maria Estefania Viano, Howard A. Young, Maria Cecilia Rodriguez-Galan

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Innate CD8 + T cells express a memory-like phenotype and demonstrate a strong cytotoxic capacity that is critical during the early phase of the host response to certain bacterial and viral infections. These cells arise in the thymus and depend on IL-4 and IL-15 for their development. Even though innate CD8 + T cells exist in the thymus of WT mice in low numbers, they are highly enriched in KO mice that lack certain kinases, leading to an increase in IL-4 production by thymic NKT cells. Our work describes that in C57BL/6 WT mice undergoing a Th1 biased infectious disease, …

Partners In Crime: Fledgling Tumors Hijack Inflammation, Balamurugan Kuppusamy, Howard A. Young

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While inflammation is a normal physiological response after tissue injury, the chemicals/mediators that are released by the damaged tissue can be toxic to the cells. This underlying inflammation increases the likelihood of cellular DNA damage and aberrant cell growth (Kiraly and others 2015). In this scenario, inflammation functions as a ‘‘behind-curtain factor’’ for many disorders. Cancer has long been known to be closely tethered to inflammation. Widespread evidence shows that inflammatory diseases such as colitis, pancreatitis, and hepatitis make their respective organs highly susceptible to eventual cancer development (Shalapour and Karin 2015). However, other studies have shown that in due …

Translational Repression Of Pre-Formed Cytokine-Encoding Mrna Prevents Chronic Activation Of Memory T Cells, Fiamma Salerno, Sander Engels, Maartje Van Den Biggelaar, Floris P.J. Van Alphen, Aurelie Guislain, Wanqi Zhao, Deborah L. Hodge, Sarah E. Bell, Jan Paul Medema, Marieke Von Lindern, Martin Turner, Howard A. Young, Monika C. Wolkers

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Memory T cells are critical for the immune response to recurring infections. Their instantaneous reactivity to pathogens is empowered by the persistent expression of cytokine-encoding mRNAs. How the translation of proteins from pre-formed cytokine-encoding mRNAs is prevented in the absence of infection has remained unclear. Here we found that protein production in memory T cells was blocked via a 3′ untranslated region (3′ UTR)-mediated process. Germline deletion of AU-rich elements (AREs) in the Ifng-3′ UTR led to chronic cytokine production in memory T cells. This aberrant protein production did not result from increased expression and/or half-life of the mRNA. Instead, …

Interferon-Gamma Impairs Maintenance And Alters Hematopoietic Support Of Bone Marrow Mesenchymal Stromal Cells, Marieke Goedhart, Anne S. Cornelissen, Carlijn Kuijk, Sulima Geerman, Marion Kleijer, Jaap D. Van Buul, Stephan Huveneers, Marc H.G.P. Raaijmakers, Howard A. Young, Monika C. Wolkers, Carlijn Voermans, Martijn A. Nolte

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Bone marrow (BM) mesenchymal stromal cells (MSCs) provide microenvironmental support to hematopoietic stem and progenitor cells (HSPCs). Culture-expanded MSCs are interesting candidates for cellular therapies due to their immunosuppressive and regenerative potential which can be further enhanced by pretreatment with interferon-gamma (IFN-γ). However, it remains unknown whether IFN-γ can also influence hematopoietic support by BM-MSCs. In this study, we elucidate the impact of IFN-γ on the hematopoietic support of BM-MSCs. We found that IFN-γ increases expression of interleukin (IL)-6 and stem cell factor by human BM-MSCs. IFN-γ-treated BM-MSCs drive HSPCs toward myeloid commitment in vitro, but impair subsequent differentiation of …

Tipsheet: Student Mental Health And Resources, Unl Office Of The Executive Vice Chancellor

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Stress, depression, anxiety, alcohol abuse, eating disorders, and other mental health challenges affect at least 1 in 5 college students*. Faculty can be an important source of support for UNL students. Here are some strategies for supporting student mental health:

1. Communicate the importance of mental health. Mental health is just as important as physical health. When someone breaks a leg they go to the hospital. Mental illness is the same thing. If someone is feeling depressed they should seek treatment. Normalize mental health by talking about getting support if you notice your students struggling with stress, depression, anxiety, etc. …

The Interplay Of Type I And Type Ii Interferons In Murine Autoimmune Cholangitis As A Basis For Sex-Biased Autoimmunity, Heekyong R. Bae, Deborah L. Hodge, Guo Xiang Yang, Patrick S.C. Leung, Sathi Babu Chodisetti, Julio C. Valencia, Michael Sanford, John M. Fenimore, Ziaur S.M. Rahman, Koichi Tsuneyama, Gary L. Norman, M E. Gershwin, Howard A. Young

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We have reported on a murine model of autoimmune cholangitis, generated by altering the AU-rich element (ARE) by deletion of the interferon gamma (IFN-γ) 3' untranslated region (coined ARE-Del−/−), that has striking similarities to human primary biliary cholangitis (PBC) with female predominance. Previously, we suggested that the sex bias of autoimmune cholangitis was secondary to intense and sustained type I and II IFN signaling. Based on this thesis, and to define the mechanisms that lead to portal inflammation, we specifically addressed the hypothesis that type I IFNs are the driver of this disease. To accomplish these goals, we crossed ARE-Del−/− …

Therapeutic And Immunological Interventions In Primary Biliary Cholangitis: From Mouse Models To Humans, Atsushi Tanaka, Patrick S.C. Leung, Howard A. Young, M. Eric Gershwin

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Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that predominantly affects women in their fifth and sixth decades. The diagnostic hallmarks of PBC are detection of anti-mitochondrial antibodies (AMAs) and chronic non-suppurative destructive cholangitis (CNSDC) of small- and medium-sized intrahepatic bile ducts in liver histological examination [1, 2]. A significant amount of data suggests that immunological activity against small biliary epithelial cells (BECs), found histologically as portal inflammation, leads to clinical disease. In PBC, as with other autoimmune diseases, both genetic and environmental factors contribute to the development of pathology [3–8]. The first-line therapy of PBC is ursodeoxycholic …

Current Prospects Of Type Ii Interferon Γ Signaling & Autoimmunity, Daniel S. Green, Howard A. Young, Julio C. Valencia

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Interferon γ (IFNγ) is a pleiotropic protein secreted by immune cells. IFNγ signals through the IFNγ receptor, a protein complex that mediates downstream signaling events. Studies into IFNγ signaling have provided insight into the general concepts of receptor signaling, receptor internalization, regulation of distinct signaling pathways, and transcriptional regulation. Although IFNγ is the central mediator of the adaptive immune response to pathogens, it has been shown to be involved in several non-infectious physiological processes. This review will provide an introduction into IFNγ signaling biology and the functional roles of IFNγ in the autoimmune response.

Rapid And Rigorous Il-17a Production By A Distinct Subpopulation Of Effector Memory T Lymphocytes Constitutes A Novel Mechanism Of Toxic Shock Syndrome Immunopathology, Peter A. Szabo, Ankur Goswami, Delfina M. Mazzuca, Kyoungok Kim, David B. O'Gorman, David A. Hess, Ian D. Welch, Howard A. Young, Bhagirath Singh, John K. Mccormick, S. M.Mansour Haeryfar

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Toxic shock syndrome (TSS) is caused by staphylococcal and streptococcal superantigens (SAgs) that provoke a swift hyperinflammatory response typified by a cytokine storm. The precipitous decline in the host's clinical status and the lack of targeted therapies for TSS emphasize the need to identify key players of the storm's initial wave. Using a humanized mouse model of TSS and human cells, we herein demonstrate that SAgs elicit in vitro and in vivo IL-17A responses within hours. SAg-triggered human IL-17A production was characterized by remarkably high mRNA stability for this cytokine. A distinct subpopulation of CD4+ effector memory T (TEM) cells …

Th1 Differentiation Drives The Accumulation Of Intravascular, Non-Protective Cd4 T Cells During Tuberculosis, Michelle A. Sallin, Shunsuke Sakai, Keith D. Kauffman, Howard A. Young, Jinfang Zhu, Daniel L. Barber

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Recent data indicate that the differentiation state of Th1 cells determines their protective capacity against tuberculosis. Therefore, we examined the role of Th1-polarizing factors in the generation of protective and non-protective subsets of Mtb-specific Th1 cells. We find that IL-12/23p40 promotes Th1 cell expansion and maturation beyond the CD73+CXCR3+T-betdim stage, and T-bet prevents deviation of Th1 cells into Th17 cells. Nevertheless, IL- 12/23p40 and T-bet are also essential for the production of a prominent subset of intravascular CX3CR1+KLRG1+ Th1 cells that persists poorly and can neither migrate into the lung parenchyma nor control Mtb growth. Furthermore, T-bet suppresses development of …

Toward Solving The Etiological Mystery Of Primary Biliary Cholangitis, Atsushi Tanaka, Patrick S.C. Leung, Howard A. Young, M. Eric Gershwin

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Primary biliary cholangitis (PBC) is considered a model autoimmune disease due to its signature anti-mitochondrial antibody (AMA) autoantibody, female predominance, and relatively specific portal infiltration and cholestasis. The identification and cloning of the major mitochondrial autoantigens recognized by AMA have served as an immunologic platform to identify the earliest events involved in loss of tolerance. Despite the relatively high concordance rate in identical twins, genome-wide association studies have not proven clinically useful and have led to suggestions of epigenetic events. To understand the natural history and etiology of PBC, several murine models have been developed, including spontaneous models, models induced …

Regulation Of Ifn-Γ Expression, John Fenimore, Howard A. Young

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Interferon gamma, referred to here as IFN- γ, is a major component in immunological cell signaling and is a critical regulatory protein for overall immune system function. First discovered in 1965 (Wheelock Science 149: (3681)310–311, 1965), IFN- γ is the only Type II interferon identified. Its expression is both positively and negatively controlled by different factors. In this chapter, we will review the transcriptional and post-transcriptional control of IFN-γ expression. In the transcriptional control part, the regular activators and suppressors are summarized, we will also focus on the epigenetic control, such as chromosome access, DNA methylation, and histone acetylation. The …

Chronic Expression Of Interferon-Gamma Leads To Murine Autoimmune Cholangitis With A Female Predominance, Heekyong R. Bae, Patrick S.C. Leung, Koichi Tsuneyama, Julio C. Valencia, Deborah L. Hodge, Seohyun Kim, Tim Back, Megan Karwan, Anand S. Merchant, Nobuyuki Baba, Dechun Feng, Ogyi Park, Bin Gao, Guo Xiang Yang, M. Eric Gershwin, Howard A. Young

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In most autoimmune diseases the serologic hallmarks of disease precede clinical pathology by years. Therefore, the use of animal models in defining early disease events becomes critical. We took advantage of a “designer” mouse with dysregulation of interferon gamma (IFNγ) characterized by prolonged and chronic expression of IFNγ through deletion of the IFNγ 3′-untranslated region adenylate uridylate-rich element (ARE). The ARE-Del-/- mice develop primary biliary cholangitis (PBC) with a female predominance that mimics human PBC that is characterized by up-regulation of total bile acids, spontaneous production of anti-mitochondrial antibodies, and portal duct inflammation. Transfer of CD4 T cells from ARE-Del-/- …

United States Health Care Reform Progress To Date And Next Steps, Barack H. Obama

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IMPORTANCE The Affordable Care Act is the most important health care legislation enacted in the United States since the creation of Medicare and Medicaid in 1965. The law implemented comprehensive reforms designed to improve the accessibility, affordability, and quality of health care.

OBJECTIVES To review the factors influencing the decision to pursue health reform, summarize evidence on the effects of the law to date, recommend actions that could improve the health care system, and identify general lessons for public policy from the Affordable Care Act.

EVIDENCE Analysis of publicly available data, data obtained from government agencies, and published research findings. …

Cd4 T Cell-Derived Ifn-Γ Plays A Minimal Role In Control Of Pulmonary Mycobacterium Tuberculosis Infection And Must Be Actively Repressed By Pd-1 To Prevent Lethal Disease, Shunsuke Sakai, Keith D. Kauffman, Michelle A. Sallin, Arlene H. Sharpe, Howard A. Young, Vitaly V. Ganusov, Daniel L. Barber

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IFN-γ–producing CD4 T cells are required for protection against Mycobacterium tuberculosis (Mtb) infection, but the extent to which IFN-γ contributes to overall CD4 T cell-mediated protection remains unclear. Furthermore, it is not known if increasing IFN-γ production by CD4 T cells is desirable in Mtb infection. Here we show that IFN-γ accounts for only ~30% of CD4 T cell-dependent cumulative bacterial control in the lungs over the first six weeks of infection, but >80% of control in the spleen. Moreover, increasing the IFN-γ–producing capacity of CD4 T cells by ~2 fold exacerbates lung infection and leads to the early death …

Aging Converts Innate B1a Cells Into Potent Cd8+ T Cell Inducers, Catalina Lee-Chang, Monica Bodogai, Kanako Moritoh, Xin Chen, Robert Wersto, Ranjan Sen, Howard A. Young, Michael Croft, Luigi Ferrucci, Arya Biragyn

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B cell dysregulation in aging is thought to mostly occur in conventional B2 cells without affecting innate B1 cells. Elderly humans and mice also accumulate 4-1BBL+ MHC class-IHi CD86Hi B cells of unknown origin. In this article, we report that these cells, termed 4BL cells, are activated murine and possibly human B1a cells. The activation is mediated by aging human monocytes and murine peritoneal macrophages. They induce expression and activation of 4-1BBL and IFN-gR1 on B1a cells to subsequently upregulate membrane TNF-α and CD86. As a result, activated B1a/4BL cells induce expression of granzyme B in CD8+ T cells by …

Surface Display Of Glycosylated Tyrosinase Related Protein-2 (Trp-2) Tumour Antigen On Lactococcus Lactis, Jeevanathan Kalyanasundram, Suet Lin Chia, Adelene Ai Lian Song, Abdul Rahim Raha, Howard A. Young, Khatijah Yusoff

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Background: The exploitation of the surface display system of food and commensal lactic acid bacteria (LAB) for bacterial, viral, or protozoan antigen delivery has received strong interest recently. The Generally Regarded as Safe (GRAS) status of the Lactococcus lactis coupled with a non-recombinant strategy of in-trans surface display, provide a safe platform for therapeutic drug and vaccine development. However, production of therapeutic proteins fused with cell-wall anchoring motifs is predominantly limited to prokaryotic expression systems. This presents a major disadvantage in the surface display system particularly when glycosylation has been recently identified to significantly enhance epitope presentation. In this study, …

Architecture Of High-Affinity Unnatural-Base Dna Aptamers Toward Pharmaceutical Applications, Ken Ichiro Matsunaga, Michiko Kimoto, Charlotte Hanson, Michael Sanford, Howard A. Young, Ichiro Hirao

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We present a remodeling method for high-affinity unnatural-base DNA aptamers to augment their thermal stability and nuclease resistance, for use as drug candidates targeting specific proteins. Introducing a unique mini-hairpin DNA provides robust stability to unnatural-base DNA aptamers generated by SELEX using genetic alphabet expansion, without reducing their high affinity. By this method, >80% of the remodeled DNA aptamer targeting interferon-γ (KD of 33 pM) survived in human serum at 37 °C after 3 days under our experimental conditions, and sustainably inhibited the biological activity of interferon-γ.

Impact Of Dietary Components On Nk And Treg Cell Function For Cancer Prevention, Young S. Kim, Thomas J. Sayers, Nancy H. Colburn, John A. Milner, Howard A. Young

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An important characteristic of cancer is that the disease can overcome the surveillance of the immune system. A possible explanation for this resistance arises from the ability of tumor cells to block the tumoricidal activity of host immune cells such as natural killer (NK) cells by inducing the localized accumulation of regulatory T (Treg) cells. Evidence exists that components in commonly consumed foods including vitamins A, D, and E, water-soluble constituents of mushrooms, polyphenolics in fruits and vegetables, and n-3 fatty acids in fish oil can modulate NK cell activities, Treg cell properties, and the interactions between those two cell …

Does The Microbiota Play A Role In The Pathogenesis Of Autoimmune Diseases?, Mairi H. Mclean, Dario Dieguez, Lindsey M. Miller, Howard A. Young

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The microbiota of the human metaorganism is not a mere bystander. These microbes have coevolved with us and are pivotal to normal development and homoeostasis. Dysbiosis of the GI microbiota is associated with many disease susceptibilities, including obesity, malignancy, liver disease and GI pathology such as IBD. It is clear that there is direct and indirect crosstalk between this microbial community and host immune response. However, the precise mechanism of this microbial influence in disease pathogenesis remains elusive and is now a major research focus. There is emerging literature on the role of the microbiota in the pathogenesis of autoimmune …

Nos Inhibition Modulates Immune Polarization And Improves Radiation-Induced Tumor Growth Delay, Lisa A. Ridnour, Robert Y.S. Cheng, Jonathan M. Weiss, Sukhbir Kaur, David R. Soto-Pantoja, Debashree Basudhar, Julie L. Heinecke, C. Andrew Stewart, William Degraff, Anastasia L. Sowers, Angela Thetford, Aparna H. Kesarwala, David D. Roberts, Howard A. Young, James B. Mitchell, Giorgio Trinchieri, Robert H. Wiltrout, David A. Wink

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Nitric oxide synthases (NOS) are important mediators of progrowth signaling in tumor cells, as they regulate angiogenesis, immune response, and immune-mediated wound healing. Ionizing radiation (IR) is also an immune modulator and inducer of wound response. We hypothesized that radiation therapeutic efficacy could be improved by targeting NOS following tumor irradiation. Herein, we show enhanced radiation-induced (10 Gy) tumor growth delay in a syngeneic model (C3H) but not immunosuppressed (Nu/Nu) squamous cell carcinoma tumor-bearing mice treated post-IR with the constitutive NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME). These results suggest a requirement of T cells for improved radiation tumor response. In …