Understanding disparities in clinical trials for Native Hawaiian men

Understanding low rates of participation by minority populations in clinical trials is critical for reducing and eliminating disparities. We examined beliefs and attitudes of Native Hawaiian men related to illness and cancer to better understand their rates of participation in clinical trials. We conducted face-to-face interviews with Native Hawaiian key informants throughout the State of Hawai‘i using quota sampling methods to obtain a range of perspectives about attitudes towards health care seeking to provide insight into low clinical trials participation. Interviews were audio-taped, transcribed, and independently coded by researchers. Thematic analysis guided the extraction of relevant data from the discussions. Key informants (N=16) suggested the following beliefs and attitudes regarding clinical trials participation: 1) mistrust in the healthcare system, 2) external locus of control, 3) gender norms, and 4) the customary pono (righteousness, to make right) practice towards family/community to model and maintain good health, including participation in cancer clinical trials. Native Hawaiian men in this study expressed hesitation in the benefits of formalized health care. Many men described experiences of racism, inequity, and injustice associated their interactions with health care providers. These encounters were factors that influenced their healthcare practices and beliefs towards maintaining health and longevity

CoastalImageLib: An open- source Python package for creating common coastal image products

CoastalImageLib is a Python library that produces common coastal image products intended for quantitative analysis of coastal environments. This library contains functions to georectify and merge multiple oblique camera views, produce statistical image products for a given set of images, and create subsampled pixel instruments for use in bathymetric inversion, surface current estimation, run-up calculations, and other quantitative analyses. This package intends to be an open-source broadly generalizable front end to future coastal imaging applications, ultimately expanding user accessibility to optical remote sensing of coastal environments. This package was developed and tested on data collected from the Argus Tower, a 43 m tall observation structure in Duck, North Carolina at the US Army Engineer Research and Development Center’s Field Research Facility that holds six stationary cameras which collect twice-hourly coastal image products. Thus, CoastalImageLib also contains functions designed to interface with the file storage and collection system implemented at the Argus Tower

Structural analysis of the role of the (β)3 subunit of the (α)V(β)3 integrin in IGF-I signaling

The disintegrin echistatin inhibits ligand occupancy of the (α)V(β)3 integrin and reduces Insulin-like growth factor I (IGF-I) stimulated migration, DNA synthesis, and receptor autophosphorylation in smooth muscle cells. This suggests that ligand occupancy of the (α)V(β)3 receptor is required for full activation of the IGF-I receptor. Transfection of the full-length (β)3 subunit into CHO cells that have no endogenous (β)3 and do not migrate in response to IGF-I was sufficient for IGF-I to stimulate migration of these anchorage dependent cells. In contrast, transfection of either of two truncated mutant forms of (β)3 (terminating at W(715) or E(731)) or a mutant with substitutions for Tyr(747) Tyr(759) (YY) into either CHO or into porcine smooth muscle cells did not restore the capacity of these cells to migrate across a surface in response to IGF-I. This effect was not due to loss of IGF-I receptor autophosphorylation since the response of the receptor to IGF-I was similar in cells expressing either the full-length or any of the mutant forms of the (β)3 subunit. Echistatin reduced IGF-I receptor phosphorylation in cells expressing the full-length or the YY mutant forms of (β)3 subunit, but it had no effect in cells expressing either of two truncated forms of (β)3. A cell-permeable peptide homologous to the C-terminal region of the (β)3 subunit (amino acids 747–762) reduced IGF-I stimulated migration and receptor autophosphorylation of non-transfected porcine smooth muscle cells. These results demonstrate that the full-length (β)3 with intact tyrosines at positions 747 and 759 is required for CHO cells to migrate in response to IGF-I. Furthermore, a region of critical amino acids between residues 742–762 is required for echistatin to induce its regulatory effect on receptor phosphorylation. Since the IGF-I receptor does not bind to (α)V(β)3 the results suggest that specific but distinct regions of the (β)3 subunit interact with intermediary proteins to facilitate IGF-I stimulated cell migration and echistatin induced inhibition of IGF-I signal transduction

Disruption of the association of integrin-associated protein (IAP) with tyrosine phosphatase non-receptor type substrate-1 (SHPS)-1 inhibits pathophysiological changes in retinal endothelial function in a rat model of diabetes

Our studies have shown that the association between integrin-associated protein (IAP) and SHPS-1 regulates the response of cells including osteoclasts, osteoblasts, smooth muscle and retinal endothelial cells to Insulin-like growth factor-I (IGF-I). The aims of this study were to determine whether the regulation of IGF-I responsiveness by IAP/SHPS-1 association is a generalized response of endothelial cells, to identify the mechanism by which IAP/SHPS-1 association contributes to changes in endothelial cell responses to IGF-I and to determine whether inhibiting their association alters pathophysiologic changes that occur in vivo

Hyperglycemia Enhances IGF-I-Stimulated Src Activation via Increasing Nox4-Derived Reactive Oxygen Species in a PKC -Dependent Manner in Vascular Smooth Muscle Cells

IGF-I–stimulated sarcoma viral oncogene (Src) activation during hyperglycemia is required for propagating downstream signaling. The aim of the current study was to determine the mechanism by which hyperglycemia enhances IGF-I–stimulated Src activation and the role of NADPH oxidase 4 (Nox4) and protein kinase C ζ (PKCζ) in mediating this response in vascular smooth muscle cells (VSMCs). Nox4 expression was analyzed in VSMCs exposed to hyperglycemia. The role of Nox4-derived reactive oxygen species (ROS) in IGF-I–stimulated Src activation was investigated via knockdown of Nox4. Different isoforms of PKC were screened to investigate their role in hyperglycemia-induced Nox4. The oxidation of Src was shown to be a prerequisite for its activation in response to IGF-I during hyperglycemia. Hyperglycemia induced Nox4, but not Nox1, and p22 phagocyte oxidase (p22phox) expression and IGF-I stimulated Nox4/p22phox complex formation, leading to increased ROS generation. Knockdown of Nox4 prevented ROS generation and impaired the oxidation and activation of Src in response to IGF-I, whereas knockdown of Nox1 had no effect. PKCζ was shown to mediate the hyperglycemia-induced increase in Nox4 expression. The key observations in cultured VSMCs were confirmed in the diabetic mice. Nox4-derived ROS is responsible for the enhancing effect of hyperglycemia on IGF-I–stimulated Src activation, which in turn amplifies IGF-I–linked downstream signaling and biological actions

Insulin-Like Growth Factor (IGF) Binding Protein 2 Functions Coordinately with Receptor Protein Tyrosine Phosphatase and the IGF-I Receptor To Regulate IGF-I-Stimulated Signaling

Insulin-like growth factor I (IGF-I) is a mitogen for vascular smooth muscle cells (VSMC) and has been implicated in the development and progression of atherosclerosis. IGF binding proteins (IGFBPs) modify IGF-I actions independently of IGF binding, but a receptor-based mechanism by which they function has not been elucidated. We investigated the role of IGFBP-2 and receptor protein tyrosine phosphatase β (RPTPβ) in regulating IGF-I signaling and cellular proliferation. IGFBP-2 bound RPTPβ, which led to its dimerization and inactivation. This enhanced PTEN tyrosine phosphorylation and inhibited PTEN activity. Utilization of substrate trapping and phosphatase-dead mutants showed that RPTPβ bound specifically to PTEN and dephosphorylated it. IGFBP-2 knockdown led to decreased PTEN tyrosine phosphorylation and decreased AKT Ser473 activation. IGFBP-2 enhanced IGF-I-stimulated VSMC migration and proliferation. Analysis of aortas obtained from IGFBP-2−/− mice showed that RPTPβ was activated, and this was associated with inhibition of IGF-I stimulated AKT Ser473 phosphorylation and VSMC proliferation. These changes were rescued following administration of IGFBP-2. These findings present a novel mechanism for coordinate regulation of IGFBP-2 and IGF-I signaling functions that lead to stimulation of VSMC proliferation. The results have important implications for understanding how IGFBPs modulate the cellular response to IGF-I

Innate Immune Cell Recovery Is Positively Regulated by NLRP12 during Emergency Hematopoiesis

With enhanced concerns of terrorist attacks, dual exposure to radiation and thermal combined injury (RCI) has become a real threat with devastating immunosuppression. NLRP12, a member of the NOD-like receptor family, is expressed in myeloid and bone marrow cells and has been implicated as a checkpoint regulator of inflammatory cytokines as well as an inflammasome activator. We show that NLRP12 has a profound impact on hematopoietic recovery during RCI by serving as a checkpoint of TNF signaling and preventing hematopoietic apoptosis. Using a mouse model of RCI, increased NLRP12 expression was detected in target tissues. Nlrp12−/− mice exhibited significantly greater mortality, inability to fight bacterial infection, heightened levels of pro-inflammatory cytokines, overt granulocyte/monocyte progenitor cell apoptosis and failure to reconstitute peripheral myeloid populations. Anti-TNF antibody administration improved peripheral immune recovery. These data suggest that NLRP12 is essential for survival after RCI by regulating myelopoiesis and immune reconstitution

Incidence and Symptoms of High Altitude Illness in South Pole Workers: Antarctic Study of Altitude Physiology (ASAP)

Introduction Each year, the US Antarctic Program rapidly transports scientists and support personnel from sea level (SL) to the South Pole (SP, 2835 m) providing a unique natural laboratory to quantify the incidence of acute mountain sickness (AMS), patterns of altitude related symptoms and the field effectiveness of acetazolamide in a highly controlled setting. We hypothesized that the combination of rapid ascent (3 hr), accentuated hypobarism (relative to altitude), cold, and immediate exertion would increase altitude illness risk. Methods Medically screened adults (N = 246, age = 37 ± 11 yr, 30% female, BMI = 26 ± 4 kg/m 2 ) were recruited. All underwent SL and SP physiological evaluation, completed Lake Louise symptom questionnaires (LLSQ, to define AMS), and answered additional symptom related questions (eg, exertional dyspnea, mental status, cough, edema and general health), during the 1st week at altitude. Acetazolamide, while not mandatory, was used by 40% of participants. Results At SP, the barometric pressure resulted in physiological altitudes that approached 3400 m, while T ° C averaged -42, humidity 0.03%. Arterial oxygen saturation averaged 89% ± 3%. Overall, 52% developed LLSQ defined AMS. The most common symptoms reported were exertional dyspnea-(87%), sleeping difficulty-(74%), headache-(66%), fatigue-(65%), and dizziness/lightheadedness-(46%). Symptom severity peaked on days 1-2, yet in >20% exertional dyspnea, fatigue and sleep problems persisted through day 7. AMS incidence was similar between those using acetazolamide and those abstaining (51 vs. 52%, P = 0.87). Those who used acetazolamide tended to be older, have less altitude experience, worse symptoms on previous exposures, and less SP experience. Conclusion The incidence of AMS at SP tended to be higher than previously reports in other geographic locations at similar altitudes. Thus, the SP constitutes a more intense altitude exposure than might be expected considering physical altitude alone. Many symptoms persist, possibly due to extremely cold, arid conditions and the benefits of acetazolamide appeared negligible, though it may have prevented more severe symptoms in higher risk subjects

Characterization of the Basal and mTOR-Dependent Acute Pulmonary and Systemic Immune Response in a Murine Model of Combined Burn and Inhalation Injury

Severe burn injury leads to a cascade of local and systemic immune responses that trigger an extreme state of immune dysfunction, leaving the patient highly susceptible to acute and chronic infection. When combined with inhalation injury, burn patients have higher mortality and a greater chance of developing secondary respiratory complications including infection. No animal model of combined burn and inhalation injury (B+I) exists that accurately mirrors the human clinical picture, nor are there any effective immunotherapies or predictive models of the risk of immune dysfunction. Our earlier work showed that the mechanistic/mammalian target of rapamycin (mTOR) pathway is activated early after burn injury, and its chemical blockade at injury reduced subsequent chronic bacterial susceptibility. It is unclear if mTOR plays a role in the exacerbated immune dysfunction seen after B+I injury. We aimed to: (1) characterize a novel murine model of B+I injury, and (2) investigate the role of mTOR in the immune response after B+I injury. Pulmonary and systemic immune responses to B+I were characterized in the absence or presence of mTOR inhibition at the time of injury. Data describe a murine model of B+I with inhalation-specific immune phenotypes and implicate mTOR in the acute immune dysfunction observed

Interplay between TCR Affinity and Necessity of Coreceptor Ligation: High-Affinity Peptide-MHC/TCR Interaction Overcomes Lack of CD8 Engagement

CD8 engagement is believed to be a critical event in the activation of naive T cells. In this communication, we address the effects of peptide-MHC (pMHC)/TCR affinity on the necessity of CD8 engagement in T cell activation of primary naive cells. Using two peptides with different measured avidities for the same pMHC-TCR complex, we compared biochemical affinity of pMHC/TCR and the cell surface binding avidity of pMHC/TCR with and without CD8 engagement. We compared early signaling events and later functional activity of naive T cells in the same manner. Although early signaling events are altered, we find that high-affinity pMHC/TCR interactions can overcome the need for CD8 engagement for proliferation and CTL function. An integrated signal over time allows T cell activation with a high-affinity ligand in the absence of CD8 engagement