Bone metabolism and incretin hormones following glucose ingestion in young adults with pancreatic insufficient cystic fibrosis

BACKGROUND: Gut-derived incretin hormones, including glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1), regulate post-prandial glucose metabolism by promoting insulin production. GIP, GLP-1, and insulin contribute to the acute bone anti-resorptive effect of macronutrient ingestion by modifying bone turnover. Cystic fibrosis (CF) is associated with exocrine pancreatic insufficiency (PI), which perturbs the incretin response. Cross-talk between the gut and bone ( gut-bone axis ) has not yet been studied in PI-CF. The objectives of this study were to assess changes in biomarkers of bone metabolism during oral glucose tolerance testing (OGTT) and to test associations between incretins and biomarkers of bone metabolism in individuals with PI-CF. METHODS: We performed a secondary analysis of previously acquired blood specimens from multi-sample OGTT from individuals with PI-CF ages 14-30 years (n = 23). Changes in insulin, incretins, and biomarkers of bone resorption (C-terminal telopeptide of type 1 collagen [CTX]) and formation (procollagen type I RESULTS: CTX decreased by 32% by min 120 of OGTT (P \u3c 0.001), but P1NP was unchanged. Increases in GIP from 0 to 30 mins (rho = -0.48, P = 0.03) and decreases in GIP from 30 to 120 mins (rho = 0.62, P = 0.002) correlated with decreases in CTX from mins 0-120. Changes in GLP-1 and insulin were not correlated with changes in CTX, and changes in incretins and insulin were not correlated with changes in P1NP. CONCLUSIONS: Intact GIP response was correlated with the bone anti-resorptive effect of glucose ingestion, represented by a decrease in CTX. Since incretin hormones might contribute to development of diabetes and bone disease in CF, the gut-bone axis warrants further attention in CF during the years surrounding peak bone mass attainment

Associations among osteocalcin, leptin and metabolic health in children ages 9-13 years in the United States

BACKGROUND: This study aimed to investigate the relationships among osteocalcin, leptin and metabolic health outcomes in children ages 9-13 years. METHODS: This was a cross-sectional analysis of baseline data from 161 boys and 157 girls (ages 9-13 years) who previously participated in a double-blinded randomized placebo controlled trial of vitamin D supplementation. Relationships among fasting serum total osteocalcin (tOC), undercarboxylated osteocalcin (ucOC), leptin, and metabolic health outcomes were analyzed. RESULTS: Approximately 52% of study participants were obese based on percent body fat cutoffs (>25% for boys and >32% for girls) and about 5% had fasting serum glucose within the prediabetic range (i.e. 100 to 125 mg/dL). Serum tOC was not correlated with leptin, glucose, insulin, HOMA-IR, or HOMA-β after adjusting for percent body fat. However, serum ucOC negatively correlated with leptin (partial r = -0.16; p = 0.04) and glucose (partial r = -0.16; p = 0.04) after adjustment for percent body fat. Leptin was a positive predictor of insulin, glucose, HOMA-IR, and HOMA-β after adjusting for age, sex and percent body fat (all p < 0.001). CONCLUSIONS: These data depict an inverse relationship between leptin and various metabolic health outcomes in children. However, the notion that tOC or ucOC link fat with energy metabolism in healthy children was not supported

Insulin Resistance and the IGF-I-Cortical Bone Relationship in Children Ages 9-13 Years

IGF-I is a pivotal hormone in pediatric musculoskeletal development. Although recent data suggest that the role of IGF-I in total body lean mass and total body bone mass accrual may be compromised in children with insulin resistance, cortical bone geometric outcomes have not been studied in this context. Therefore, we explored the influence of insulin resistance on the relationship between IGF-I and cortical bone in children. A secondary aim was to examine the influence of insulin resistance on the lean mass-dependent relationship between IGF-I and cortical bone. Children were otherwise healthy, early adolescent black and white boys and girls (ages 9 to 13 years) and were classified as having high (n = 147) or normal (n = 168) insulin resistance based on the homeostasis model assessment of insulin resistance (HOMA-IR). Cortical bone at the tibia diaphysis (66% site) and total body fat-free soft tissue mass (FFST) were measured by peripheral quantitative computed tomography (pQCT) and dual-energy X-ray absorptiometry (DXA), respectively. IGF-I, insulin, and glucose were measured in fasting sera and HOMA-IR was calculated. Children with high HOMA-IR had greater unadjusted IGF-I (p < 0.001). HOMA-IR was a negative predictor of cortical bone mineral content, cortical bone area (Ct.Ar), and polar strength strain index (pSSI; all p ≤ 0.01) after adjusting for race, sex, age, maturation, fat mass, and FFST. IGF-I was a positive predictor of most musculoskeletal endpoints (all p < 0.05) after adjusting for race, sex, age, and maturation. However, these relationships were moderated by HOMA-IR (pInteraction < 0.05). FFST positively correlated with most cortical bone outcomes (all p < 0.05). Path analyses demonstrated a positive relationship between IGF-I and Ct.Ar via FFST in the total cohort (βIndirect Effect = 0.321, p < 0.001). However, this relationship was moderated in the children with high (βIndirect Effect = 0.200, p < 0.001) versus normal (βIndirect Effect = 0.408, p < 0.001) HOMA-IR. These data implicate insulin resistance as a potential suppressor of IGF-I-dependent cortical bone development, though prospective studies are needed

Mechanisms Suppressing Superheavy Element Yields in Cold Fusion Reactions

Superheavy elements are formed in fusion reactions which are hindered by fast nonequilibrium processes. To quantify these, mass-angle distributions and cross sections have been measured, at beam energies from below-barrier to 25% above, for the reactions of 48Ca,50Ti, and 54Cr with 208 Pb. Moving from 48Ca to 54Cr leads to a drastic fall in the symmetric fission yield, which is reflected in the measured mass-angle distribution by the presence of competing fast nonequilibrium deep inelastic and quasifission processes. These are responsible for reduction of the compound nucleus formation probablity PCN (as measured by the symmetric-peaked fission cross section), by a factor of 2.5 for 50Ti and 15 for 54Cr in comparison to 48 Ca. The energy dependence of PCN indicates that cold fusion reactions (involving 208Pb) are not driven by a diffusion process.The authors acknowledge the Australian Research Council for support through Discovery Grants No. DP140101337, No. DP160101254, No. DP170102318, No. FL110100098, and No. DE140100784. Financial support from the NCRIS HIA capability for operation of the Heavy Ion Accelerator Facility is acknowledged. The authors acknowledge the support of the German Academic Exchange Service (DAAD) via funds of the German Federal Ministry of Education and Research (BMBF)

Strategies and Practices in Off-Label Marketing of Pharmaceuticals: A Retrospective Analysis of Whistleblower Complaints

Aaron Kesselheim and colleagues analyzed unsealed whistleblower complaints against pharmaceutical companies filed in US federal fraud cases that contained allegations of off-label marketing, and develop a taxonomy of the various off-label practices

Impact of complex NOTCH1 mutations on survival in paediatric T-cell leukaemia

<p>Abstract</p> <p>Background</p> <p>Molecular alterations occur frequently in T-ALL and the potential impact of those abnormalities on outcome is still controversial. The current study aimed to test whether <it>NOTCH1 </it>mutations and additional molecular abnormalities would impact T-ALL outcome in a series of 138 T-ALL paediatric cases.</p> <p>Methods</p> <p>T-ALL subtypes, status of <it>SIL-TAL1 </it>fusion, ectopic expression of <it>TLX3</it>, and mutations in <it>FBXW7</it>, <it>KRAS</it>, <it>PTEN </it>and <it>NOTCH1 </it>were assessed as overall survival (OS) and event-free survival (EFS) prognostic factors. OS and EFS were determined using the Kaplan-Meier method and compared using the log-rank test.</p> <p>Results</p> <p>The frequencies of mutations were 43.5% for <it>NOTCH1</it>, while <it>FBXW7</it>, <it>KRAS </it>and <it>PTEN </it>exhibited frequencies of 19.1%, 9.5% and 9.4%, respectively. In 78.3% of cases, the coexistence of <it>NOTCH1 </it>mutations and other molecular alterations was observed. In multivariate analysis no statistical association was revealed between <it>NOTCH1 </it>mutations and any other variable analyzed. The mean length of the follow-up was 68.4 months and the OS was 50.7%. <it>SIL-TAL1 </it>was identified as an adverse prognostic factor. <it>NOTCH1 </it>mutation status was not associated with outcome, while the presence of <it>NOTCH1 </it>complex mutations (indels) were associated with a longer overall survival (<it>p </it>= 0.031) than point mutations.</p> <p>Conclusion</p> <p><it>NOTCH1 </it>mutations alone or in combination with <it>FBXW7 </it>did not impact T-ALL prognosis. Nevertheless, complex <it>NOTCH1 </it>mutations appear to have a positive impact on OS and the <it>SIL-TAL1 </it>fusion was validated as a negative prognostic marker in our series of T-ALL.</p

Cytokine and Protein Markers of Leprosy Reactions in Skin and Nerves: Baseline Results for the North Indian INFIR Cohort

Leprosy affects skin and peripheral nerves. Although we have effective antibiotics to treat the mycobacterial infection, a key part of the disease process is the accompanying inflammation. This can worsen after starting antibacterial treatment with episodes of immune mediated inflammation, so called ‘reactions’. These reactions are associated with worsening of the nerve damage. We recruited a cohort of 303 newly diagnosed leprosy patients in North India with the aim of understanding and defining the pathological processes better. We took skin and nerve biopsies from patients and examined them to define which molecules and mediators of inflammation were present. We found high levels of the cytokines Tumour Necrosis Factor alpha, Transforming Growth Factor beta and inducible Nitric Oxide Synthase in biopsies from patients with reactions. We also found high levels of bacteria and inflammation in the nerves. These experiments tell us that we need to determine which other molecules are present and to explore ways of switching off the production of these pro-inflammatory molecules

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival