Geneva Foundation

Geneva, WA, United States

Geneva Foundation

Geneva, WA, United States
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Videnovic M.,University of Belgrade | Opsenica D.M.,University of Belgrade | Burnett J.C.,Leidos Inc. | Gomba L.,U.S. Army | And 9 more authors.
Journal of Medicinal Chemistry | Year: 2014

Significantly more potent second generation 4-amino-7-chloroquinoline (4,7-ACQ) based inhibitors of the botulinum neurotoxin serotype A (BoNT/A) light chain were synthesized. Introducing an amino group at the C(3) position of the cholate component markedly increased potency (IC50 values for such derivatives ranged from 0.81 to 2.27 μM). Two additional subclasses were prepared: bis(steroidal)-4,7-ACQ derivatives and bis(4,7-ACQ)cholate derivatives; both classes provided inhibitors with nanomolar-range potencies (e.g., the Ki of compound 67 is 0.10 μM). During BoNT/A challenge using primary neurons, select derivatives protected SNAP-25 by up to 89%. Docking simulations were performed to rationalize the compounds' in vitro potencies. In addition to specific residue contacts, coordination of the enzyme's catalytic zinc and expulsion of the enzyme's catalytic water were a consistent theme. With respect to antimalarial activity, the compounds provided better IC90 activities against chloroquine resistant (CQR) malaria than CQ, and seven compounds were more active than mefloquine against CQR strain W2. © 2014 American Chemical Society.

PubMed | 779th Medical Group, Geneva Foundation, WellMed Medical Management, 424 Carnation Lane and Point Loma Nazarene University
Type: Journal Article | Journal: Military medicine | Year: 2016

To gain better understanding of the military medics (Navy Independent Duty Corpsman, Air Force Independent Duty Medical Technician, and Army Health Care Specialist, experiences providing health care for women in the deployed or ship setting.The researchers used an exploratory, descriptive design informed by ethnography. A total of 86 individuals participated in the focus group and individual interviews.Three themes were identified: Training Fidelity, Advocate Leader, and The Challenges of Providing Patient Care.Experience in austere settings has convinced a number of medics they need additional womens health care topics in every facet of their training. They further suggested such training should be provided in stepwise fashion, beginning with initial, technical training courses and continuing through medical skills sustainment platforms. They were especially interested in basic womens health concerns. Topics suggested included vaginal infections, urinary tract infections, and birth control management.Although the advancement of women in the military continues to make strides-it is clear the availability of quality womens health care that women feel comfortable accessing may be its defining limitation. Medics are an excellent conduit for reinforcing these healthy messages and providing first-line treatment to deployed military women.

PubMed | U.S. Army, Midwestern University, Ohio Wesleyan University, University of Texas Health Science Center at San Antonio and 2 more.
Type: Journal Article | Journal: American journal of disaster medicine | Year: 2017

Compare vasopressin, amiodarone, and epinephrine administration by sternal intraosseous (SIO), tibial intraosseous (TIO), and intravenous (IV) routes in a swine model of cardiac arrest.Prospective, randomized, between subjects, experimental design.Laboratory.Male Yorkshire-cross swine (N = 35), seven per group.Swine were randomized to SIO, TIO, IV, cardiopulmonary resuscitation (CPR) with defibrillation, or CPR-only groups. Ventricular fibrillation (VF) was induced under general anesthesia. Mechanical CPR began 2 minutes postarrest. Vasopressin (40 U) was administered to the SIO, TIO, and IV groups 4 minutes postarrest. Defibrillation was performed and amiodarone (300 mg) was administered 6 minutes postarrest. Defibrillation was repeated, and epinephrine (1 mg) was administered 10 minutes postarrest. Defibrillation was repeated every 2 minutes and epinephrine repeated every 4 minutes until return of spontaneous circulation (ROSC) or 26 postarrest minutes elapsed.Rate of ROSC, time to ROSC, and odds of ROSC.There were no significant differences in rate of ROSC between the SIO and TIO (p = 0.22) or IV groups (p = 1.0). Time to ROSC was five times less in the SIO group than the TIO group (p = 0.003) but not compared to IV (p = 0.125). Time to ROSC in the IV group was significantly less than the TIO group (p = 0.04). Odds of ROSC for the SIO group were five times higher compared to the TIO group but same as IV. Odds of ROSC in the IV group were higher than the TIO group.There was a statistically significant delay in the time to ROSC and a clinically significant difference in odds of ROSC when resuscitative drugs, including lipophilic amiodarone, were administered by the TIO route compared to the SIO and IV routes in a swine model of sudden cardiac arrest. Further investigations are warranted to isolate the mechanism behind these findings.

Kiris E.,Geneva Foundation | Kiris E.,U.S. Army | Kiris E.,Frederick National Laboratory for Cancer Research | Kota K.P.,Perkin Elmer Corporation | And 6 more authors.
Expert Review of Molecular Diagnostics | Year: 2014

Botulinum neurotoxins (BoNTs) are exceptionally potent inhibitors of neurotransmission, causing muscle paralysis and respiratory failure associated with the disease botulism. Currently, no drugs are available to counter intracellular BoNT poisoning. To develop effective medical treatments, cell-based assays provide a valuable system to identify novel inhibitors in a time- and cost-efficient manner. Consequently, cell-based systems including immortalized cells, primary neurons and stem cell-derived neurons have been established. Stem cell-derived neurons are highly sensitive to BoNT intoxication and represent an ideal model to study the biological effects of BoNTs. Robust immunoassays are used to quantify BoNT activity and play a central role during inhibitor screening. In this review, we examine recent progress in physiologically relevant cell-based assays and high-throughput screening approaches for the identification of both direct and indirect BoNT inhibitors. © 2014 Informa UK, Ltd.

Ying T.,Fudan University | Ying T.,U.S. National Cancer Institute | Feng Y.,U.S. National Cancer Institute | Wang Y.,U.S. National Cancer Institute | And 3 more authors.
mAbs | Year: 2014

The IgG1 Fc is a dimeric protein that mediates important antibody effector functions by interacting with Fcg receptors (FcgRs) and the neonatal Fc receptor (FcRn). Here, we report the discovery of a monomeric IgG1 Fc (mFc) that bound to FcgRI with very high affinity, but not to FcgRIIIa, in contrast to wild-type (dimeric) Fc. The binding of mFc to FcRn was the same as that of dimeric Fc. To test whether the high-affinity binding to FcgRI can be used for targeting of toxins, a fusion protein of mFc with a 38 kDa Pseudomonas exotoxin A fragment (PE38), was generated. This fusion protein killed FcgRI-positive macrophage-like U937 cells but not FcgRI-negative cells, and mFc or PE38 alone had no killing activity. The lack of binding to FcgRIIIa resulted in the absence of Fc-mediated cytotoxicity of a scFv-mFc fusion protein targeting mesothelin. The pharmacokinetics of mFc in mice was very similar to that of dimeric Fc. The mFc's unique FcgRs binding pattern and related functionality, combined with its small size, monovalency and the preservation of FcRn binding which results in relatively long half-life in vivo, suggests that mFc has great potential as a component of therapeutics targeting inflammation mediated by activated macrophages overexpressing FcgRI and related diseases, including cancer. © 2014 Taylor & Francis Group, LLC.

Shear D.A.,U.S. Army | Lu X.-C.M.,U.S. Army | Bombard M.C.,U.S. Army | Bombard M.C.,Geneva Foundation | And 6 more authors.
Journal of Neurotrauma | Year: 2010

Traumatic brain injury (TBI) produces a wide range of motor and cognitive changes. While some neurological symptoms may respond to therapeutic intervention during the initial recovery period, others may persist for many years after the initial insult, and often have a devastating impact on quality of life for the TBI victim. The aim of the current study was to develop neurobehavioral testing parameters designed to provide a longitudinal assessment of neurofunctional deficits in a rodent model of penetrating ballistic-like brain injury (PBBI). We report here a series of experiments in which unilateral frontal PBBI was induced in rats, and motor/cognitive abilities were assessed using a battery of tests ranging from 30 min to 10 weeks post-injury. The results showed that PBBI produced consistent and significant (1) neurological deficits (neuroscore examination: 30 min to 10 weeks post-PBBI), (2) sensorimotor dysfunction in the contralateral forelimb (forelimb asymmetry task: 7 and 21 days), (3) motor dysfunction (balance beam task: 3-7 days; and fixed-speed rotarod task: 3-28 days), and (4) spatial learning deficits in the Morris water maze (MWM) task out to 10 weeks post-injury. Overall, the results of this study demonstrate that PBBI produces enduring motor and cognitive deficits, and identifies the optimal task and testing parameters for facilitating longitudinal screening of promising therapeutic interventions in this brain injury model. Copyright 2010, Mary Ann Liebert, Inc.

Kane C.D.,Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc | Kane C.D.,U.S. Army | Nuss J.E.,U.S. Army | Nuss J.E.,Geneva Foundation | Bavari S.,U.S. Army
Expert Opinion on Therapeutic Patents | Year: 2015

Introduction: Botulinum neurotoxins (BoNTs) are among the most toxic of known biological molecules and function as acetylcholine release inhibitors and neuromuscular blocking agents. Paradoxically, these properties also make them valuable therapeutic agents for the treatment of movement disorders, urological conditions and hypersecretory disorders. Greater understanding of their molecular mechanism of action and advances in protein engineering has led to significant efforts to improve and expand their function with a view towards broadening their therapeutic potential.Areas covered: Searches of Espacenet and Google Patent have revealed a number of patents related to BoNTs. This review will focus on novel therapeutic uses and formulations disclosed during 2012-2014. The seven patents discussed will include nanoformulations of FDA-Approved BoNTs, additional BoNT subtypes and novel BoNT variants and chimeras created through protein engineering. Supporting patents and related publications are also briefly discussed.Expert opinion: The clinical and commercial success of BoNTs has prompted investigation into novel BoNTs or BoNT-mediated chimeras with promising in vitro results. Distinct strategies including the use of nanoformulations and targeted delivery have been implemented to identify new indication and improved functionality. Greater understanding of their systemic exposure, efficacy and safety profiles will be required for further development. © 2015 Informa UK, Ltd.

Nelson J.T.,University of Texas Health Science Center at San Antonio | Tepe V.,Geneva Foundation
Brain Stimulation | Year: 2015

Background: Modern neuromodulatory techniques for military applications have been explored for the past decade, with an intent to optimize operator performance and, ultimately, to improve overall military effectiveness. In light of potential military applications, some researchers have voiced concern about national security agency involvement in this area of research, and possible exploitation of research findings to support military objectives. The aim of this article is to examine the U.S. Department of Defense's interest in and application of neuromodulation. Methods: We explored articles, cases, and historical context to identify critical considerations of debate concerning dual use (i.e., national security and civilian) technologies, specifically focusing on non-invasive brain stimulation (NIBS). Discussion: We review the background and recent examples of DoD-sponsored neuromodulation research, framed in the more general context of research that aims to optimize and/or rehabilitate human performance. We propose that concerns about military exploitation of neuromodulatory science and technology are not unique, but rather are part of a larger philosophic debate pertaining to military application of human performance science and technology. We consider unique aspects of the Department of Defense research enterprise - which includes programs crucial to the advancement of military medicine - and why it is well-situated to fund and perform such research. We conclude that debate concerning DoD investment in human performance research must recognize the significant potential for dual use (civilian, medical) benefit as well as the need for civilian scientific insight and influence. Military interests in the health and performance of service members provide research funding and impetus to dual use applications that will benefit the civilian community. © 2015 Elsevier Inc. All rights reserved.

Kiris E.,Geneva Foundation | Kiris E.,U.S. Army | Kiris E.,Frederick National Laboratory for Cancer Research | Burnett J.C.,Leidos Inc. | And 3 more authors.
Current Topics in Medicinal Chemistry | Year: 2014

Botulinum neurotoxins (BoNTs) are endopeptidases that target motor neurons and block acetylcholine neurotransmitter release. This action results in the muscle paralysis that defines the disease botulism. To date, there are no FDA-approved therapeutics to treat BoNT-mediated paralysis after intoxication of the motor neuron. Importantly, the rationale for pursuing treatments to counter these toxins is driven by their potential misuse. Current drug discovery efforts have mainly focused on small molecules, peptides, and peptidomimetics that can directly and competitively inhibit BoNT light chain proteolytic activity. Although this is a rational approach, direct inhibition of the Zn2+ metalloprotease activity has been elusive as demonstrated by the dearth of candidates undergoing clinical evaluation. Therefore, broadening the scope of viable targets beyond that of active site protease inhibitors represents an additional strategy that could move the field closer to the clinic. Here we review the rationale, and discuss the outcomes of earlier approaches and highlight potential new targets for BoNT inhibition. These include BoNT uptake and processing inhibitors, enzymatic inhibitors, and modulators of neuronal processes associated with toxin clearance, neurotransmitter potentiation, and other pathways geared towards neuronal recovery and repair. © 2014 Bentham Science Publishers

Lynch S.M.,Idaho State University | DeHart D.D.,University of South Carolina | Belknap J.E.,University of Colorado at Boulder | Green B.L.,Georgetown University | And 3 more authors.
Psychiatric Services | Year: 2014

Objectives: This multisite study aimed to answer the following research questions about women in urban and rural jails. First, what is the current and lifetime prevalence of serious mental illness (major depressive disorder, bipolar disorder, and psychotic spectrum disorders) of women in jail? Second, what level of impairment is associated with their serious mental illness? Third, what is the proportion of incarcerated women with serious mental illness who also have posttraumatic stress disorder (PTSD), a substance use disorder, or both? Methods: Participants were 491 women randomly sampled in jails in Colorado, Idaho, South Carolina, and the metropolitan area of Washington, D.C. Structured interviews assessed lifetime and 12-month prevalence of disorders and level of impairment. Results: Forty-three percent of participants met lifetime criteria for a serious mental illness, and 32% met 12-month criteria; among the latter, 45% endorsed severe functional impairment. Fifty-three percentmet criteria for ever having PTSD. Almost one in three (29%) met criteria for a serious mental illness and PTSD, 38% for a serious mental illness and a cooccurring substance use disorder, and about one in four (26%) for all three in their lifetime. Conclusions: The prevalence of serious mental illness and its co-occurrence with substance use disorders and PTSD in this multisite sample suggest the critical need for comprehensive assessment of mental health at the point of women's entry into the criminal justice system and the necessity for more programs that offer alternatives to incarceration and that can address the complexity of female offenders' treatment needs.

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