Metabolic labelling of cholesteryl glucosides in Helicobacter pylori reveals how the uptake of human lipids enhances bacterial virulence.

Helicobacter pylori infects approximately half of the human population and is the main cause of various gastric diseases. This pathogen is auxotrophic for cholesterol, which it converts upon uptake to various cholesteryl α-glucoside derivatives, including cholesteryl 6'-acyl and 6'-phosphatidyl α-glucosides (CAGs and CPGs). Owing to a lack of sensitive analytical methods, it is not known if CAGs and CPGs play distinct physiological roles or how the acyl chain component affects function. Herein we established a metabolite-labelling method for characterising these derivatives qualitatively and quantitatively with a femtomolar detection limit. The development generated an MS/MS database of CGds, allowing for profiling of all the cholesterol-derived metabolites. The subsequent analysis led to the unprecedented information that these bacteria acquire phospholipids from the membrane of epithelial cells for CAG biosynthesis. The resulting increase in longer or/and unsaturated CAG acyl chains helps to promote lipid raft formation and thus delivery of the virulence factor CagA into the host cell, supporting the idea that the host/pathogen interplay enhances bacterial virulence. These findings demonstrate an important connection between the chain length of CAGs and the bacterial pathogenicity

A Comparison of Food-grade Folium mori Extract and 1-Deoxynojirimycin for Glycemic Control and Renal Function in Streptozotocin-induced Diabetic Rats

ABSTRACTFolium mori (桑葉 Sāng Yè, leaf of Morus alba L.; FM) is known to possess hypoglycemic effects, and 1-deoxynojirimycin (1-DNJ) has been proposed as an important functional compound in FM. However, the hypoglycemic activity of purified 1-DNJ has been rarely studied. It is also not known how FM and 1-DNJ affect the development of DM nephropathy. This study compared the antidiabetic effect of a commercial FM product with that of purified 1-DNJ in streptozotocin-induced diabetic rats. Seven days after induction, the diabetic rats were gavaged with FM (1, 3, 10, and 30mg/kg/day), 1-DNJ (30mg/kg/day), or vehicle (distilled deionized water; 2ml/kg/day) for 7days. All doses of FM ameliorated fasting and post-prandial blood glucose concomitantly with an increase in peripheral and pancreatic levels of insulin and improved homeostasis model assessment (HOMA-IR) in diabetic rats in a dose-dependent manner. Increased thiobarbituric acid reactive substances (TBARS) and nitrate/nitrite levels in the kidney, liver, and muscle of diabetic rats were reversed by all doses of FM. The renal function of the diabetic rats was normalized by all doses of FM, while blood pressure changes were reversed by FM at doses of 3mg/kg and above. Moreover, most of the above-mentioned parameters were improved by FM at doses of 3mg/kg and above to a similar extent as that of 1-DNJ. The results showed superior antidiabetic potential of the commercial FM product for glycemic control and protection against the development of diabetic nephropathy

Sequence Variants of ADIPOQ

Diabetes is a serious global health problem. Large-scale genome-wide association studies identified loci for type 2 diabetes mellitus (T2DM), including adiponectin (ADIPOQ) gene and transcription factor 7-like 2 (TCF7L2), but few studies clarified the effect of genetic polymorphisms of ADIPOQ and TCF7L2 on risk of T2DM. We attempted to elucidate association between T2DM and polymorphic variations of both in Taiwan’s Chinese Han population, with our retrospective case-control study genotyping single nucleotide polymorphisms (SNPs) in ADIPOQ and TCF7L2 genes both in 149 T2DM patients and in 139 healthy controls from Taiwan. Statistical analysis gauged association of these polymorphisms with risk of T2DM to show ADIPOQ rs1501299 polymorphism variations strongly correlated with T2DM risk (P=0.042), with rs2241766 polymorphism being not associated with T2DM (P=0.967). However, both polymorphisms rs7903146 and rs12255372 of TCF7L2 were rarely detected in Taiwanese people. This study avers that ADIPOQ rs1501299 polymorphism contributes to risk of T2DM in the Taiwanese population

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

Monte Carlo Determined Self-Shielded Groupwise Cross-Sections for the Activation Foil Stack Applied in the Epithermal Neutron Spectrum Adjustment

Activation foils, stacked in a package, together with a spectrum adjustment code are generally the means to characterize the neutron spectrum of a BNCT epithermal neutron beam. When using foil stacks, the phenomenon of neutron scattering is appreciably enhanced, especially in an epithermal neutron beam, as compared to a thermal neutron field. Contrary to the conventional idea of the self-shielding effect, self-shielding correction factors in most of the foils in the stack are larger than one. This paper demonstrates a way to correct the complex self-shielding effect using groupwise cross-sections adjusted for self-shielding, as calculated by the Monte Carlo neutron transport code, MCNP. This methodology can solve the perturbation problems caused by the foil stack applied in an epithermal neutron beam. In this study, the adjusted spectrum of the HB11 epithermal neutron beam, dedicated for BNCT research in at Petten in The Netherlands, is utilized and two adjusted spectra are presented with and without the self-shielding correction. The difference between the spectra is highly significant and demonstrates that the self-shielding correction cannot be ignored.JRC.F.4-Safety of future nuclear reactor

Neutron Spectra Measurement and Comparison of the HFR and THOR BNCT Beams

This paper aims to measure the spectra of HB11 (HFR) and the THOR BNCT beams by multiple activation foils. The self-shielding corrections were made with the aid of MCNP calculations. The initial spectra were adjusted by a sophisticated process named coarse-scaling adjustment using SAND-EX, which can adjust a given coarse-group spectrum into a fine-group structure, i.e. 640 groups, with excellent continuity. The epithermal neutron flux of the THOR beam is about three times of HB11. The thermal neutron flux, boron and gold reaction rates along the central axis of a PMMA phantom are calculated for both adjusted spectra for comparison.JRC.F.4-Safety of future nuclear reactor

Neutron spectra measurement and comparison of the HFR and THOR BNCT beams

This paper aims to measure the spectra of HB11 (high flux reactor, HFR) and the Tsing Hua open-pool reactor (THOR) boron neutron capture therapy (BNCT) beams by multiple activation foils. The selfshielding corrections were made with the aid of MCNP calculations. The initial spectra were adjusted by a sophisticated process named coarse-scaling adjustment using SAND-EX, which can adjust a given coarse-group spectrum into a fine-group structure, i.e. 640 groups, with excellent continuity. The epithermal neutron flux of the THOR beam is about three times of HB11. The thermal neutron flux, boron and gold reaction rates along the central axis of a PMMA phantom are calculated for both adjusted spectra for comparison.JRC.F.4-Nuclear Reactor Integrity Assessment and Knowledge Managemen

Coarse-Scaling Adjustment of Fine-group Neutron Spectra for Epithermal Neutron Beams in BNCT using Multiple Activation Detectors

In order to provide an improved and reliable neutron source description for treatment planning in boron neutron capture therapy (BNCT), a spectrum adjustment procedure named coarse-scaling adjustment has been developed and applied to the neutron spectrum measurements of both the Tsing Hua Open-pool Reactor (THOR) epithermal neutron beam in Taiwan and the High Flux Reactor (HFR) in The Netherlands, using multiple activation detectors. The coarse-scaling adjustment utilizes a similar idea as the well-known two-foil method, which adjusts the thermal and epithermal neutron fluxes according to the Maxwellian distribution for thermal neutrons and 1/E distribution over the epithermal neutron energy region. The coarse-scaling adjustment can effectively suppress the number of oscillations appearing in the adjusted spectrum and provide better smoothness. This paper also presents a sophisticated 9-step process utilizing twice the coarse-scaling adjustment which can adjust a given coarse-group spectrum into a fine-group structure, i.e. 640 groups, with satisfactory continuity and excellently matched reaction rates between measurements and calculation. The spectrum adjustment algorithm applied in this study is the same as the well-known SAND-II.JRC.F.4-Safety of future nuclear reactor