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Medical Sciences

T cells targeting neuromyelitis optica autoantigen aquaporin-4 can cause paralysis and visual system injury

Author: Andrés Cruz-Herranz, Sharon A. Sagan, Raymond A. Sobel, Ari J. Green, Scott S. Zamvil

Manuscript ID: JNSCI#17-0425


Aquaporin-4 (AQP4)-specific antibodies are instrumental in promoting central nervous system (CNS) tissue injury in neuromyelitis optica (NMO), yet evidence indicates that AQP4-specific T cells also have a pivotal role in NMO pathogenesis. Although considerable effort has been devoted to creation of animal models to study how AQP4-specific T cells and antibodies may cooperate in development of both clinical and histologic opticospinal inflammatory disease, the initial attempts were unsuccessful.  Recently, it was discovered that T cells from AQP4-deficient (AQP4-/-) mice recognize distinct AQP4 epitopes that were not identified previously in wild-type (WT) mice, and that donor Th17 cells from AQP4-/- mice that target those novel epitopes could cause paralysis and visual system dysfunction associated with opticospinal inflammation in WT recipient mice. These observations indicate that the pathogenic AQP4-specific T cell repertoire is normally controlled by negative selection. Here, we describe the advances leading to development of an animal model for aquaporin-targeted CNS autoimmunity (ATCA).  This new model provides a foundation to investigate immune mechanisms that may participate in NMO pathogenesis and should permit preclinical testing of agents considered for treatment of NMO.


Medical Sciences

Vancomycin in the treatment of Primary Sclerosing Cholangitis: A Review

Author: Sukhpreet Singh, Kusum K. Kharbanda

Manuscript ID: JNSCI#17-0419


Primary sclerosing cholangitis (PSC) is a disease of the bile ducts that causes inflammation and destruction of the intra- and/or extra-hepatic bile ducts. It is also a progressive disorder that leads to fibrosis and liver failure and also increases risk of malignancy. PSC is a heterogeneous disease that is often associated with inflammatory bowel disease (IBD), mainly ulcerative colitis (UC). As of now, there is no established medical therapy for PSC and a majority of patients will eventually require liver transplantation. PSC is the fifth leading cause for liver transplantation, but transplantation does not guarantee a cure since there is a 20% chance of disease recurrence in the graft. At present the mainstay of therapy is ursodeoxycholic acid (UDCA) which has largely been studied in various randomised control trials but has failed to alter the long-term outcome and natural course of the disease. Pathogenesis of PSC is still not clearly understood but recent advances in understanding the pathogenesis have paved way for trial of new therapeutic agents. Here in this review article, we present information gathered from published case reports/series and randomised control trials on the relationship between the microbiota and PSC pathogenesis with a purpose of understanding whether vancomycin is a potential effective pharmacotherapy for patients with this disease.



Tumor-Draining Lymph Nodes Contain Immunodominant Peptide-Specific T Cells Which Demonstrate Efficacy In Murine Models Of Adoptive Immunotherapy

Author: Kevin Choong, John Ammori, Khaled Hamzeh, Hallie Graor, Julian Kim

Manuscript ID: JNSCI#17-0414


Background:  The purpose of this study was to determine whether tumor draining lymph nodes (TDLNs) contain the necessary components to process and present tumor-rejection antigens. The secondary objective was to determine whether short term ex vivo culture of TDLNs could generate peptide-reactive T cells with specific anti-tumor effector function in vivo.

Methods:  4T1 and RENCA cancer cell lines were transfected with an expression plasmid containing HER2. These cell lines were then inoculated into the mammary fat pads of BALB/c mice to generate TDLNs. The antigen-experienced CD62Llow T cell subpopulation of TDLNs was isolated and activated ex vivo with anti-CD3 and expanded in interleukin (IL)-2 prior to determining in vitro and  in vivo activity.

Results:  Of nine HER2 nonameric peptides synthesized using the SYFPIETHI prediction model, culture activated cells derived from TDLNs from HER2-bearing 4T1 cells (4T1.2) secreted significant levels of interferon-g in response to the highest affinity peptide TYLPTNASL. Furthermore, culture-activated cells derived from 4T1.2 TDLNs secreted significant levels of interferon-g when co-cultured with either 4T1.2 or HER2-transfected RENCA cells, but not RENCA transfected with control plasmid. Additionally, adoptive transfer of culture activated cells derived from 4T1.2 TDLNs cured mice bearing 4T1, 4T1.2 and RENCA-HER2 but not RENCA transfected with control plasmid.

Conclusions:  Short-term culture of TDLNs ex vivo results in generation of peptide-reactive T cells which can be expanded and cure mice bearing HER2 transfected tumors in vivo. These results provide proof-of-concept that TDLNs have the capacity to process and present tumor-rejection antigens, specific to an individual patient’s tumor.


Medical Sciences

Adiponectin and its Hydrolase-Activated Receptor

Author: Ankit X. Sharma, William L. Holland

Manuscript ID: JNSCI#17-0407


The relevance of adiponectin to insulin sensitivity has been elucidated over the last two decades. As a promoter of ceramide degradation, it works through its cognate receptors, AdipoR1 and AdipoR2, to alter bioactive sphingolipid species. Adiponectin diminishes the accumulation of ceramide, a lipid metabolite which can play a causal role in obesity-induced insulin resistance. Concurrently, adiponectin stimulates the production of sphingosine-1-phosphate (S1P), a cytoprotective molecule that accentuates adiponectin’s positive metabolic effects. This review focuses on recent work that solidifies knowledge of the adiponectin signaling pathway, gives new insight into some notable characteristics of adiponectin’s receptors, and most importantly, affirms adiponectin receptor agonism as a viable therapeutic tool to combat elevated ceramide levels and improve insulin sensitivity in obese patients with type 2 diabetes.



The Effects of Sex on Fatigue-Induced Changes in Electromechanical Efficiency and Torque

Author: Ethan C. Hill, Terry J. Housh, Cory M. Smith, Richard J. Schmidt, and Glen O. Johnson

Manuscript ID: JNSCI#17-0405


Electromechanical efficiency (efficiencyE-M) has been used to detect changes in neuromuscular function and track decreases in torque production as a result of muscle fatigue.  No previous investigations, however, have applied efficiencyE-M to examine sex-specific decreases in torque as a result of fatigue.   Therefore, the purpose of the present investigation was to examine sex differences from the fatigue-induced effects of repeated, submaximal, concentric forearm flexion muscle actions on pretest versus posttest measurements of concentric peak torque, electromyographic (EMG) amplitude, mechanomyographic (MMG) amplitude, and efficiencyE-M (MMG amplitude ÷ EMG amplitude).  Eleven men and eleven women performed 50 consecutive submaximal (65% of concentric peak torque), concentric muscle actions of the forearm flexors at 60°·s-1.  There were decreases in pretest versus posttest concentric peak torque for both the men (30.5%) and women (22.3%) as a result of the fatiguing exercise bout, but the decrease was greater for the men.  From pretest to posttest, however, efficiencyE-M increased when assessed during the peak torque muscle actions for both the men and women.  During the fatiguing exercise bout, torque output remained unchanged at 65% of concentric peak torque, while efficiencyE-M decreased for both the men and women, but the decrease was greater for the men than women.  Thus, efficiencyE-M did not track torque production during the submaximal fatiguing protocol or during the pretest versus posttest peak torque muscle actions.


Medical Sciences

Diabetes and Cardioplegia

Author: Brittany A Potz, Laura A Scrimgeour, Jun Feng, Frank W Sellke

Manuscript ID: JNSCI#17-0331


Cardiac surgery with cardiopulmonary bypass and cardioplegic arrest is associated injury to the vasculature and microcirculation leading to coronary microvascular dysfunction, permeability changes and cardiac dysfunction.    In the setting of cardiopulmonary bypass with cardioplegia, poorly-controlled diabetes is associated with significant changes in endothelium-dependent and independent vascular dysfunction, vascular reactivity, vascular permeability, protein expression, cell death, coronary/peripheral microcirculation and reduced vasomotor tone leading to hypotension and impaired endothelial function. The gene expression profiles after cardiopulmonary bypass with cardioplegic arrest is quantitatively and qualitatively different in patients with diabetes. Gene expression profiling capitalizing on the differences between patients with and without diabetes is a good place to identify potential medical targets.


Medical Sciences

Neurothekeoma: Review of the Literature and Case Presentation

Author: Jacquelynn P. Tran, Stefanos Boukovalas, Ramon T. Li, Alexis L. Boson, Jillian M. McLaughlin, Eric L. Cole

Manuscript ID: JNSCI#17-0330


Neurothekeomas are rare, benign cutaneous tumors often found on the head, neck, and upper extremities. They were first described in 1980 and since then, several cases have been reported in the literature. The purpose of this study is to review the current literature and: (1) summarize the common presentation of neurothekeomas, including gross and microscopic features, (2) describe microscopic variations, including myxoid, cellular and mixed presentation, and (3) summarize treatment options and risk factors for recurrence. We present a case of neurothekeoma on the nasal ala of an 8-year-old girl that we encountered at our institution.

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