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BackgroundNutritional rehabilitation during severe acute malnutrition (SAM) aims to quickly restore a healthy body weight, but rapid weight gain has been associated with later cardiovascular risk. We hypothesized that faster weight gain during SAM rehabilitation and post-hospitalization is associated with liver fat in adult survivors.MethodJamaican adult survivors of childhood SAM underwent abdominal CT scan to estimate liver fat as mean liver attenuation (MLA) and liver spleen ratio (L/S). Birth weight (BW) and anthropometry measured during, and post-hospitalization were abstracted from admission records.ResultsWe studied 42 marasmus survivors (MRs) and 40 kwashiorkor survivors (KWs). MRs had a lower mean BW (SD) 2.5 (0.8) vs 3.0 (0.7) kg; p=0.01) and were more wasted (p

The NIH Toolbox Cognitive Battery (NIHTB-CB) was developed as a common-metric, computerized cognitive screener for research. Although extensively normed and validated in Americans of different ethnicities, there is little data on how generalizable such results would be when used outside of the United States. The objective of this study was to assess measurement invariance (MI) of the NIHTB-CB across Jamaican and African-American samples and determine appropriateness of comparisons across groups. Multi-group confirmatory factor analyses using a single-factor model were conducted using five tests of fluid cognitive abilities from the NIHTB-CB, which assess working memory, episodic memory, processing speed, and executive function. MI was tested sequentially for configural, metric and scalar invariance. 125 Jamaican and 154 American adults of African descent were included. The Jamaican mean age was 31.6 ± 8.6 years (57% males) compared to 43.5 ± 15.5 years (25% males) for the African-American group. The Jamaicans had on average 11.3 ± 2.7 years of education compared to 13.9 ± 2.6 years for the African-Americans. We found metric and configural invariance across both samples but not scalar invariance. These findings suggest that the single factor emerging from the NIHTB-CB measures the same construct, i.e. fluid cognitive ability, in both groups and hence the battery is appropriate for assessments within cultures. However, lack of scalar invariance indicates that direct cross-cultural comparisons of performance levels should be interpreted with caution, also suggesting that U.S. normative standards are not generalizable to the Jamaican population.

BackgroundNutritional rehabilitation during severe malnutrition (SM) aims to quickly restore a healthy body weight, but rapid weight gain has been associated with later cardiovascular risk. We hypothesized that faster weight gain during SM rehabilitation and post-hospitalization is associated with liver fat in adult survivors.MethodAdult survivors of childhood SM underwent abdominal CT scan to estimate liver fat as mean liver attenuation (MLA) and liver spleen ratio (L/S). Birth weight (BW) and anthropometry measured during, and post-hospitalization were abstracted from admission records.ResultsWe studied 42 marasmus survivors (Ms) and 40 kwashiorkor survivors (Ks). Ms had a lower mean BW (SD) 2.5 (0.8) vs 3.0 (0.7) kg; p=0.01) and were more wasted (pp=0.03) than Ks on admission to hospital. Ms and Ks had similar rates of rehabilitation weight gain, which was inversely associated with MLA among all survivors of SM (r=-0.246, p=0.029), but only in Ms when assessed by diagnosis (r= -0.449, p=0.004). The association between rehabilitation weight gain and adult liver fat in Ms was not altered by BW, admission wasting or stunting. In Ks, post-hospitalization height gain was inversely associated with MLA (difference = -0.64, 95%CI: -0.64 to -0.13; p=0.006).ConclusionsFaster rehabilitation weight gain is associated with liver fat in adult survivors of childhood severe malnutrition. The finding that birth weight did not influence these outcomes may reflect the timing of the nutritional insult in utero. Target weight gain during nutritional rehabilitation may need to be lowered to optimize long-term outcomes in these children.

BackgroundNutritional rehabilitation during severe malnutrition (SM) aims to rapidly restore body size and minimize poor short-term outcomes. We hypothesized that too rapid weight gain during and after treatment might however predispose to cardiometabolic risk in adult life.MethodsWeight and height during hospitalization and one year post-hospitalization were abstracted from hospital records of children who survived SM. Six definitions of post-malnutrition weight gain/growth were analysed as continuous variables, quintiles and latent classes in age-sex and minimum weight-for-age z-scores-adjusted regression models against adult anthropometry, body composition (DEXA), blood pressure, blood glucose, insulin, and lipids.Results60% of 278 participants were male, mean (SD) age 28.2 (7.7) years, mean (SD) BMI 23.6 (5.2) kg/m2. Mean admission age for SM was 10.9 months (range 0.3-36.3 months) and 207/270 (77%) were wasted (weight-for-height z-score12.9 g/kg/day was associated with higher adult BMI (difference=0.5kg/m2, 95%CI: 0.1-0.9,p= 0.02), waist circumference (difference=1.4cm, 95%CI: 0.4-2.4,p=0.005), fat mass (difference = 1.1kg, 95%CI: 0.2-2,p=0.02), fat mass index (difference=0.32, 95%CI: -0.0001-0,p=0.05), and android fat mass (difference=0.09 kg, 95%CI: 0.01-0.2,p=0.03). Rehabilitation (g/month) and post-hospitalization (g/kg/month) weight gain were associated with greater lean mass (difference = 0.7 kg, 95% CI: 0.1, 1.3,p= 0.02) (difference=1.3kg, 95% CI: 0.3-2.4,p=0.015) respectively.ConclusionRehabilitation weight gain exceeding 13g/kg/day was associated with adult adiposity in young, normal-weight adult SM survivors. This raises questions around existing malnutrition weight gain targets and warrants further studies exploring optimal post-malnutrition growth.

Context and Objectives: Ischaemic stroke (IS) causes disability and uses massive public health resources. Cumulative disability from recurrence may be reduced with cardiometabolic risk reduction strategies e.g., lowering blood pressure (BP). We hypothesized that intensive exercise plus best available care in adults with recent IS improves fitness, glucose metabolism, muscle protein synthesis in paretic limbs compared to controls. BP changes were compared between intervention (INT) and controls (CON). Research Design and Setting: A randomised, interventional clinical trial conducted in Jamaican adults subjects: We investigate 103 adults with recent IS and residual weakness. Forty-nine subjects (24 women: mean age 61.5; 25 men: mean age 63.8) received task-oriented exercise training (TEXT) plus best available care. Fifty-four subjects (23 women: mean age 60.2; 31 men: mean age 61.3) received best care, including exercise advice. Measurements: We measured baseline, 3-month and 6-month BP. Results: After recent IS, TEXT plus best available care reduced systolic BP by 21 mmHg and diastolic by 12 mmHg compared to controls, independent of medication adherence, body composition; stroke severity. Men in the TEXT group had increased lean mass (P < 0.007), VO2 max (P = 0.03); 6-minute walk distance (P = 0.003). Leg press on paretic (P = 0.004) and non-paretic (P < 0.001) increased with TEXT vs CON over 6 months, in both sexes (P-values for sex difference > 0.2). Time-to-chair-rise decreased in both sexes who received intervention vs controls (P

e14552 Background: Recent advances in the field of cancer immunology have highlighted the importance of the immune system for eliminating tumors. Numerous studies have shown that tumor-infiltrating immune cells such as antigen-presenting cells (APCs), T cells, and natural killer (NK) cells play critical roles in tumor control. However, the inflammatory anti-tumor immune response is counteracted by the induction of immune regulatory mechanisms within the tumor microenvironment (TME). These findings have led to the development of immune-targeted therapies, which are aimed at activating anti-tumor immune signaling pathways and enhancing anti-tumor immune function. While immunotherapies, have revolutionized the treatment of several solid tumors and leukemias, at best response rates remain low at 25%-30%, and a portion of patients eventually develop resistance to therapy leading to disease progression and mortality. Methods: We have previously reported the potent effects of 3-4 daily intravenous infusions of immune modifying poly(lactic- co-glycolic acid) (PLGA) nanoparticles, ONP-302, free from drugs or other bioactive agents, for the amelioration of acute inflammatory diseases by targeting myeloid cells. The present studies describe a novel use for ONP-302 nanoparticles, employing an altered dosing scheme to reprogram myeloid cells resulting in significant enhancement of tumor immunity. The efficacy of ONP-302 nanoparticles at inducing an anti-tumor immune response was evaluated using syngeneic mouse tumor models. Results: ONP-302 infusion decreased tumor growth via the activation of the cGAS/STING pathway within myeloid cells, and subsequently increased NK cell activation via an IL-15-dependent mechanism. Additionally, ONP-302 treatment increased PD-1/PD-L1 expression in the tumor microenvironment, thereby allowing for functionality of anti-PD-1 for treatment in the B16.F10 melanoma tumor model which is normally unresponsive to monotherapy with anti-PD-1. Conclusions: These findings indicate that ONP-302 allows for tumor control via reprogramming myeloid cells via activation of the STING/IL-15/NK cell mechanism, as well as increasing anti-PD-1 response rates.

e14553 Background: The tumor microenvironment (TME) plays a crucial role in tumor growth and progression and has a significant influence on response to therapy. The TME consists of myeloid-derived cells, stroma (e.g. fibroblasts and extracellular matrix (ECM)), and the vasculature that together support tumor growth and progression. Studies in animal models and in humans show that myeloid- derived cells such as myeloid derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) engage in activities that support tumor growth and progression. These cells also promote immune suppression in the TME that blunts the efficacy of the anti-cancer drugs and immune-targeted therapies such as immune checkpoint inhibitors. In addition to MDSCs, cancer-associated fibroblasts (CAFs) in the TME support tumor progression via production of pro-tumor and pro-angiogenic growth-factors, remodeling of the ECM via production of proteases, and suppression of anti-tumor immune function. CAF abundance in the TME is a negative prognostic factor for several solid tumors and is associated with negative outcomes and poor response to immune-targeted therapies like immune checkpoint inhibitors. ONP-302 nanoparticles fabricated from biodegradable poly (lactic-co-glycolic acid)(PLGA) polymer have been previously described in the literature for the treatment of acute inflammatory conditions via immuno-modulatory effects on myeloid derived cells. Here, we evaluated the efficacy of ONP-302 nanoparticles at inhibiting tumor growth via targeted inhibition of myeloid-derived cells and reshaping of the TME. Methods: ONP-302 anti-tumor efficacy was evaluated in syngeneic mouse tumor models using both immunocompetent and immunodeficient mice. We examined the effect of ONP-302 treatment tumor growth kinetics and effects on the major cellular constituents of the TME such as myeloid-derived cells and CAFs. Results: Therapeutic treatment with ONP-302 in vivo resulted in a marked delay in tumor growth in three different syngeneic tumor models in immunocompetent mice. ONP- 302 efficacy persisted with depletion of CD8+ T cells in immunocompetent mice and also was effective in immune deficient mice. We found ONP-302 treatment caused a gene expression shift in TAMs toward the pro-inflammatory M1 type and substantially inhibited the expression of genes associated with the pro-tumorigenic function of CAFs. ONP-302 also induced apoptosis in CAFs in the TME. Conclusions: Our data indicate that the slowing of tumor growth after ONP-302 treatment is due to disruptions in known signaling pathways involving TAMs and CAFs, pathways typically supporting tumor growth. These data taken in concert indicate the activity of ONP-302 is pleotropic and affects multiple pathways.

Type 1 diabetes (T1D) is an autoimmune disease characterized by inflammatory lesions within islets (insulitis) and β cell loss which is associated T cell and B cell responses specific for pancreatic islet β cell proteins. Data show that treatment with poly(lactide-co-glycolide) (PLGA) nanoparticles (i.e. TIMP/COUR’s CNP) containing a single diabetogenic peptide blocks T1D induced by transfer of CD4+ BDC2.5 or CD8+ NY8.3 TCR transgenic T cells to NOD-scid mice. In contrast, Ag-specific tolerance approaches targeting single β-islet cell protein epitopes, e.g. GAD65 or Insulin, have failed to achieve efficacy in both wildtype NOD mice and clinical trials. The possibility exists that T1D initiation and progression is due to activation of T cell populations specific for multiple diabetogenic epitopes. To test this hypothesis, recombinant Chormogranin A, GAD65, and Insulin proteins were encapsulated within CNPs to assess Treg/Tr1 cell induction, inhibition of Ag-specific T cell responses, and blockade of T1D in NOD mice. While treatment of NOD mice with CNPs containing a single protein inhibited the corresponding Ag-specific T cell response, the inhibition of T1D development only occurred if all three diabetogenic proteins were included within the CNPs (CNP-T1D). CNP-T1D-induced blockade of T1D was characterized by Treg/Tr1 cell induction and a significant decrease in both peri-insulitis and immune cell infiltration into pancreatic islets. We have recently published that CNP treatment is both safe and induces Ag-specific tolerance in Phase I/IIa celiac disease clinical trials. Therefore, utilization of this technology including multiple diabetogenic proteins is a promising Ag-specific tolerance approach to T1D treatment.

Older people exhibit dysregulated innate immunity to respiratory viral infections, including influenza and SARS-CoV-2, to increase morbidity and mortality. Nanoparticles are a potential practical therapeutic that could divert exaggerated innate immune responses away from the lungs during viral infection. However, such therapeutics have not been examined for effectiveness during respiratory viral infection, particular in aged hosts. Here, we employed a highly lethal model of influenza viral infection in vulnerable aged mice to examine the ability of biodegradable, cargo-free nanoparticles, designated ONP-302, to resolve innate immune dysfunction and improve outcomes during infection. We administered ONP-302 via intravenous injection to aged mice at day 3 post-infection when the hyperinflammatory innate immune response is already established. We found that ONP-302 treatment diverted tissue-damaging inflammatory monocytes from the lungs to the spleen without impacting viral clearance or reducing chemo-attractive signals in the infected lung. Importantly, cargo-free nanoparticles reduced lung damage and histological lung inflammation and improved gas exchange and, ultimately, the clinical outcomes in influenza-infected aged mice. ONP-302 improves outcomes in influenza-infected, vulnerable, aged mice. Thus, our study provides vital fundamental information concerning a practical therapeutic which, if translated clinically, could improve disease outcomes for vulnerable older patients suffering from respiratory viral infections. Supported by COUR Pharmaceuticals

There are many autoimmune diseases where pathologic self T cells are the underlying cause of disease symptoms and progression. T cells are found at the site of tissue destruction, resulting not only in the exacerbation of disease, but also the release of self-epitopes in the context of inflammation resulting in the activation of additional T cell populations perpetuating disease. Published data have shown treatment with antigen-containing biodegradablepoly(lactide-co-glycolide) (PLGA) nanoparticles, i.e. tolerogenic immune-modifying particles (TIMP), is both safe and induces antigen-specific tolerance in mouse models of autoimmunity and allergy, as well as in a celiac disease Phase I/IIa clinical trial. This study further investigated the role and mechanism of TIMP-induced tolerance. The present data show that TIMP treatment modulated T cells specific for spread epitopes associated with disease progression, but not encapsulated within the TIMP, i.e. tissue-specific bystander suppression. The PLP139–151 TCR transgenic model systems was utilized to determine the cellular and molecular mechanisms driving antigen specific tolerance mediated by tolerogenic nanoparticle treatment. These data show antigen-specific TIMP treatment induced both FoxP3+ iTregs and IL-10+ Tr1 regulatory phenotypes within the antigen-specific T cell populations in both naïve mice and mice pre-primed with antigen/CFA. Additionally, both functional Tregs and IL-10 are required for TIMP-induced tolerance. Treatment thus activates various antigen-specific Treg subsets capable of regulating responses to disease-relevant autoepitopes not encapsulated within the TIMP via release of immunoregulatory cytokines within the inflammatory site. Supported by funding provided by Cour Pharmaceuticals Development, Inc.

Angiotensin-converting enzyme inhibitor (ACE-I) therapy reduces complications of acute myocardial infarction (MI) even when the therapy is started very early after an acute event. This study sought to determine whether administration of ACE-I therapy prior to acute MI is related to subsequent patient morbidity and mortality.Chart review of 318 consecutive patients admitted between September 1995 and December 1996 with a diagnosis of acute MI. Outcome data were compared between patient groups receiving ACE-I therapy prior to infarction and those who were not.Sixty-four patients (20%) were receiving prior ACE-I therapy. They experienced smaller MIs, as determined by peak creatine kinase elevation (1066 +/- 134 vs. 1510 +/- 95 IU; p0.05), and fewer Q-wave infarctions (p0.05) than did patients who were not receiving prior treatment. The severity of coronary artery disease, defined by an angiographic score, was similar for the two groups. Mortality rates, including patients resuscitated from ventricular fibrillation, were similar within the first 72 hours of admission (3% vs. 2%; p = NS), but patients receiving prior ACE-I therapy showed a greater long-term in-hospital mortality rate (14% vs. 5%; p0.05) related to more heart failure deaths. Multivariate logistic regression analysis identified age, treatment with digoxin prior to acute MI, and left ventricular ejection fraction after infarction, but not ACE-I therapy taken prior to infarction, as significant independent predictors of mortality and combined morbidity and mortality.In a group of patients experiencing an acute MI, those receiving prior ACE-I therapy were more likely to sustain fewer transmural MIs and smaller infarcts. Chronic ACE-I therapy may have cardioprotective effects during acute myocardial ischemia.

Her2 is a receptor tyrosine kinase that is overexpressed in approximately 20-30% of human breast cancers and affects clinical prognosis and outcome of these cancers. Treatment of Her2-positive breast cancer with the monoclonal antibody, trastuzumab, has improved the outcomes and prognosis for patients with this breast cancer subtype. However, development of resistance to trastuzumab is a major clinical problem in metastatic Her2-positive breast cancer. Many of the known mechanisms of trastuzumab resistance cause changes in protein phosphorylation patterns and therefore we have employed quantitative phosphoproteomics to further study trastuzumab resistance. Quantitative phosphoproteomics is a powerful method to comparatively identify phosphorylated proteins between different samples. Using electrospray tandem-mass spectrometry coupled with immunoaffinity purification and titanium dioxide (TiO2) phosphoenrichment, we wanted to identify differentially phosphorylated proteins in a pair of trastuzumab sensitive and resistant cells. We used stable isotope labeling of amino acids in cell culture (SILAC) to obtain quantitative information on the proteins identified by mass spectrometry. We have obtained quantitative data on two trastuzumab sensitive and resistant pairs of Her2 overexpressing human breast cancer cell lines (BT474 and SKBR3). 275 proteins were identified in the phosphoenriched fraction from the SKBR3 pair with 83 proteins reporting a ratio. 769 proteins were identified in the phosphoenriched fraction from the BT474 pair with 683 proteins reporting a ratio. Treatment of the trastuzumab resistant cells with Her2 siRNA drastically resulted in cell death indicating the sustained dependence of these cells on Her2 despite the resistance to Her2 targeted therapy. RNAi experiments, in combination with trastuzumab exposure, of candidate proteins expressing an increase in phosphorylation will be tested further to determine if trastuzumab resistance can be reversed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5126. doi:10.1158/1538-7445.AM2011-5126

To the Editor: The January 27 Case Record (Case 3-2000)1 concerned a patient who had systemic amyloidosis, AL type, with restrictive cardiomyopathy and multiple organ involvement. I wish to draw at...

To investigate the positive predictive value (PPV) of urinary vanillylmandelic acid (VMA) testing in the diagnosis of phaeochromocytoma and to describe the features associated with phaeochromocytoma at the University Hospital of the West Indies (UHWI).There were 551 VMA tests performed from January 2003 to June 2009 and 122 tests in 85 patients were elevated (ieor = 35 micromol/24 hr). The study patients were categorized as: (i) 'surgical' (5 patients who underwent surgery) or (ii) 'non-surgical' (remaining 80 patients). Forty medical charts (out of 85) were reviewed using a standardized data extraction form.The median age for patients in the non-surgical group (with charts reviewed, n = 35) was 36 years (range 9-70) and the median VMA was 43 micromol/24 hr (IQR 38-51). Of these patients, 83% had one or no symptom typical of phaeochromocytoma. In the surgical group the median VMA was 58 micromol/24 hr (IQR 44-101); phaeochromocytoma was confirmed histologically in 3 patients, all of whom had several symptoms typical of catecholamine excess. VMA testing had a PPV of 8%, specificity of 79% and sensitivity of 100%.VMA testing at UHWI has poor specificity and high sensitivity. These results contrast with international data showing that VMA testing is poorly sensitive but highly specific. The use of assays with higher specificity (eg plasma or urinary metanephrines) may represent a more cost-effective approach to biochemical screening at UHWI.

To assess the frequency of youth onset Type 2 diabetes mellitus (T2D) in Jamaica and the characteristics of youth with this form of diabetes.Patients from two major referral hospitals, diagnosed with diabetes before age 25 years and6 years prior to the study, were evaluated. Classification was based on the presence of GAD-65 and IA-2 diabetes autoantibodies (AB), fasting (FCP) and stimulated C-peptide (SCP) measurements, serum leptin and clinical phenotype as follows: (i) Type IA diabetes--AB+, (ii) Type lB diabetes--AB- and FCP230 pmol/l and/or SCP660pmol/l, (iii) Type 2 diabetes - AB- and FCP500 pmol/L and or SCP 2 1160 pmol/l (iv) Untypeable diabetes--AB- and FCP 230-500 pmol/l and or SCP 660-1160 pmol/l and (v) Lipoatrophic diabetes--clinical phenotype and serum leptin.Fifty-eight participants (21M, 37F, age 20-8 years, duration of diabetes 2.6-2 years) were enrolled in the study. Using the classification criteria, Type 1 diabetes was the most common form of diabetes: 18 (31%) Type 1A, 18 (31%) Type IB. Overall 22% (13 patients) had T2D. Patients with T2D were more likely to be female, older at diagnosis, obese and have a higher blood pressure when compared to those with Type 1 diabetes. In logistic regression analysis, age of diabetes onset, gender BMI, systolic and diastolic blood pressure were significantly associated with T2D. Obesity measured by BMI was the strongest predictor of T2D.While Type 1 diabetes was the predominant form of diabetes in this study, a significant proportion of Jamaicans with youth onset diabetes may have T2D. Obesity is the strongest clinical predictor of Type 2 diabetes in the young diabetic patient.