Combination Treatment with Sublethal Ionizing Radiation and the Proteasome Inhibitor, Bortezomib, Enhances Death-Receptor Mediated Apoptosis and Anti-Tumor Immune Attack

Sub-lethal doses of radiation can modulate gene expression, making tumor cells more susceptible to T-cell-mediated immune attack. Proteasome inhibitors demonstrate broad anti-tumor activity in clinical and pre-clinical cancer models. Here, we use a combination treatment of proteasome inhibition and irradiation to further induce immunomodulation of tumor cells that could enhance tumor-specific immune responses. We investigate the effects of the 26S proteasome inhibitor, bortezomib, alone or in combination with radiotherapy, on the expression of immunogenic genes in normal colon and colorectal cancer cell lines. We examined cells for changes in the expression of several death receptors (DR4, DR5 and Fas) commonly used by T cells for killing of target cells. Our results indicate that the combination treatment resulted in increased cell surface expression of death receptors by increasing their transcript levels. The combination treatment further increases the sensitivity of carcinoma cells to apoptosis through FAS and TRAIL receptors but does not change the sensitivity of normal non-malignant epithelial cells. Furthermore, the combination treatment significantly enhances tumor cell killing by tumor specific CD8+ T cells. This study suggests that combining radiotherapy and proteasome inhibition may simultaneously enhance tumor immunogenicity and the induction of antitumor immunity by enhancing tumor-specific T-cell activity

Influence of Portland Cement Class on the Corrosion Rate of Steel Reinforcement in Cement Mortar Caused by Penetrating Chloride and Sulfate from the Environment

U ovom je radu ispitivan utjecaj klase portland-cementa na brzinu korozije čelične armature u cementnom mortu, uzrokovane prodiranjem klorida ili sulfata iz okoliša u već očvrsli cementni mort. Za ispitivanja su upotrijebljene tri klase portland-cementa, PC 35, PC 45 i PC 55. Radi navedenih ispitivanja cilindrični uzorci od cementnog morta s čeličnom armaturom u sredini tretirani su šest mjeseci na sobnoj temperaturi u sljedećim otopinama: w(SO42-) = 2,1 % i w(Cl-) = 5 %. Za ispitivanje brzine korozije čelične armature u cementnom mortu primijenjene su elektrokemijske tehnike potenciostatske polarizacije, i to tehnika ekstrapolacije Tafelovih krivulja i tehnika potenciodinamičke polarizacije. Ispitivanje je provedeno na potenciostatu/ galvanostatu Princeton Applied Research 263A-2, programskim paketom PowerCORR®. Rezultati obje primijenjene tehnike pokazuju da su korozijski najaktivnije čelične armature u uzorcima pripremanim od cementa klase PC 35 u obje tretirane otopine, dok su korozijski najstabilnije čelične armature u uzorcima pripremanim od cementa klase PC 55. Rezultate provedenih istra?ivanja treba smatrati preliminarnima. Radi davanja preporuka za gradnju armiranobetonskih konstrukcija u morskom okolišu, potrebno je provesti ispitivanja utjecaja sulfata na beton i armaturu, na betonskim i armiranobetonskim uzorcima.The influence of portland cement class on the corrosion rate of steel reinforcement in cement mortar caused by penetrating chloride or sulfate from the environment in already hardened cement mortar is investigated in this paper. Three classes of portland cement have been used for the tests, PC 35, PC 45 and PC 55. Cylindrical samples of cement mortar with steel reinfor- cement in the middle were treated 6 months at room temperature in the following solutions: w(SO42-) = 2.1 % and w(Cl-) = 5 %. Two techniques have been used for testing corrosion rate of steel reinforcement in cement mortar: Tafel extrapolation technique and potentiodynamic polarization technique. Investigations were conducted by potentiostat/galvanostat Princeton Applied Research 263A-2 with the software PowerCORR®. The results of both techniques indi-cate the most active corrosion of steel reinforcement in the samples prepared from cement PC 35 in both treated solutions, while the lowest corrosion of the steel reinforcement was observed in cement samples prepared from cement PC 55. This conclusion was drawn by analyzing the results shown in Figs. 1–4. Comparing corrosion current density of samples, working electrodes, Figs. 1 and 2, Table 2, the results show the most stable corrosion of steel reinforcement in samples prepared from cement PC 55, and the most active corrosion in samples prepared from ce- ment PC 35. The most active corrosion in samples prepared from cement PC 35 is evident from the positions of the open circuit potentials whose values are less for samples prepared from cement PC 35 in both the treated solution, Figs. 1 and 2, Table 2. Comparison of the anodic polarization curves of the working electrodes in both the treated solutions, Figs. 3 and 4, also shows that the intensity of corrosion is the largest for the working electrodes prepared from cement PC 35 and the smallest for the working electrodes prepared from cement PC 55. Investigation results should be considered as preliminary. To make the recommendations for the construction of reinforced concrete structures in the maritime environment the impact of sulphates on concrete and steel bars should be investigated

The Compartmentalisation of Phosphorylated Free Oligosaccharides in Cells from a CDG Ig Patient Reveals a Novel ER-to-Cytosol Translocation Process

BACKGROUND: Biosynthesis of the dolichol linked oligosaccharide (DLO) required for protein N-glycosylation starts on the cytoplasmic face of the ER to give Man(5)GlcNAc(2)-PP-dolichol, which then flips into the ER for further glycosylation yielding mature DLO (Glc(3)Man(9)GlcNAc(2)-PP-dolichol). After transfer of Glc(3)Man(9)GlcNAc(2) onto protein, dolichol-PP is recycled to dolichol-P and reused for DLO biosynthesis. Because de novo dolichol synthesis is slow, dolichol recycling is rate limiting for protein glycosylation. Immature DLO intermediates may also be recycled by pyrophosphatase-mediated cleavage to yield dolichol-P and phosphorylated oligosaccharides (fOSGN2-P). Here, we examine fOSGN2-P generation in cells from patients with type I Congenital Disorders of Glycosylation (CDG I) in which defects in the dolichol cycle cause accumulation of immature DLO intermediates and protein hypoglycosylation. METHODS AND PRINCIPAL FINDINGS: In EBV-transformed lymphoblastoid cells from CDG I patients and normal subjects a correlation exists between the quantities of metabolically radiolabeled fOSGN2-P and truncated DLO intermediates only when these two classes of compounds possess 7 or less hexose residues. Larger fOSGN2-P were difficult to detect despite an abundance of more fully mannosylated and glucosylated DLO. When CDG Ig cells, which accumulate Man(7)GlcNAc(2)-PP-dolichol, are permeabilised so that vesicular transport and protein synthesis are abolished, the DLO pool required for Man(7)GlcNAc(2)-P generation could be depleted by adding exogenous glycosylation acceptor peptide. Under conditions where a glycotripeptide and neutral free oligosaccharides remain predominantly in the lumen of the ER, Man(7)GlcNAc(2)-P appears in the cytosol without detectable generation of ER luminal Man(7)GlcNAc(2)-P. CONCLUSIONS AND SIGNIFICANCE: The DLO pools required for N-glycosylation and fOSGN2-P generation are functionally linked and this substantiates the hypothesis that pyrophosphatase-mediated cleavage of DLO intermediates yields recyclable dolichol-P. The kinetics of cytosolic fOSGN2-P generation from a luminally-generated DLO intermediate demonstrate the presence of a previously undetected ER-to-cytosol translocation process for either fOSGN2-P or DLO

Unusual trivial trauma may end with extrusion of a well-functioning penile prosthesis: a case report

<p>Abstract</p> <p>Background</p> <p>Diabetes mellitus (DM) is the most common indication for insertion of a penile prosthesis and is a risk factor for infection of such prostheses.</p> <p>Case presentation</p> <p>Two patients presented with infected prostheses following unusual trivial penile trauma. Both patients underwent exploration and removal of the prostheses with uneventful recovery.</p> <p>Conclusion</p> <p>Appropriate sizing of the prosthesis should be taken into account to ensure good concealment and avoid easy exposure of the penis to unexpected trauma. Use of the newly designed antibiotic-coated prostheses appears preferable. As soon as signs of prosthesis infection appeared, extrusion of the device should be expedited.</p

Hyperhomocysteinemia is independently associated with albuminuria in the population-based CoLaus study

<p>Abstract</p> <p>Background</p> <p>Increased serum levels of homocysteine and uric acid have each been associated with cardiovascular risk. We analyzed whether homocysteine and uric acid were associated with glomerular filtration rate (GFR) and albuminuria independently of each other. We also investigated the association of <it>MTHFR </it>polymorphisms related to homocysteine with albuminuria to get further insight into causality.</p> <p>Methods</p> <p>This was a cross-sectional population-based study in Caucasians (<it>n </it>= 5913). Hyperhomocysteinemia was defined as total serum homocysteine ≥ 15 μmol/L. Albuminuria was defined as urinary albumin-to-creatinine ratio > 30 mg/g.</p> <p>Results</p> <p>Uric acid was associated positively with homocysteine (r = 0.246 in men and r = 0.287 in women, <it>P </it>< 0.001). The prevalence of albuminuria increased across increasing homocysteine categories (from 6.4% to 17.3% in subjects with normal GFR and from 3.5% to 14.5% in those with reduced GFR, <it>P </it>for trend < 0.005). Hyperhomocysteinemia (OR = 2.22, 95% confidence interval: 1.60-3.08, <it>P </it>< 0.001) and elevated serum uric acid (OR = 1.27, 1.08-1.50, per 100 μmol/L, <it>P </it>= 0.004) were significantly associated with albuminuria, independently of hypertension and type 2 diabetes. The 2-fold higher risk of albuminuria associated with hyperhomocysteinemia was similar to the risk associated with hypertension or diabetes. <it>MTHFR </it>alleles related to higher homocysteine were associated with increased risk of albuminuria.</p> <p>Conclusions</p> <p>In the general adult population, elevated serum homocysteine and uric acid were associated with albuminuria independently of each other and of renal function.</p

Homocysteine, vitamin B12 and folate levels in premature coronary artery disease

BACKGROUND: Hyperhomocysteinemia is known as an independent risk factor of atherosclerosis, but the probable role of hyperhomocysteinemia in premature Coronary Artery Disease (CAD) is not well studied. The aim of this study was to assess the role of hyperhomocysteinemia, folate and Vitamin B12 deficiency in the development of premature CAD. METHODS: We performed an analytical case-control study on 294 individuals under 45 years (225 males and 69 females) who were admitted for selective coronary angiography to two centers in Tehran. RESULTS: After considering the exclusion criteria, a total number of 225 individuals were enrolled of which 43.1% had CAD. The mean age of participants was 39.9 +/- 4.3 years (40.1 +/- 4.2 years in males and 39.4 +/- 4.8 years in females). Compared to the control group, the level of homocysteine measured in the plasma of the male participants was significantly high (14.9 +/- 1.2 versus 20.3 +/- 1.9 micromol/lit, P = 0.01). However there was no significant difference in homocysteine level of females with and without CAD (11.8 +/- 1.3 versus 11.5 ± 1.1 micromol/lit, P = 0.87). Mean plasma level of folic acid and vitamin B12 in the study group were 6.3 +/- 0.2 and 282.5 +/- 9.1 respectively. Based on these findings, 10.7% of the study group had folate deficiency while 26.6% had Vitamin B12 deficiency. Logistic regression analysis for evaluating independent CAD risk factors showed hyperhomocysteinemia as an independent risk factor for premature CAD in males (OR = 2.54 0.95% CI 1.23 to 5.22, P = 0.01). Study for the underlying causes of hyperhomocysteinemia showed that male gender and Vitamin B12 deficiency had significant influence on incidence of hyperhomocysteinemia. CONCLUSION: We may conclude that hyperhomocysteinemia is an independent risk factor for CAD in young patients (bellow 45 years old) – especially in men -and vitamin B12 deficiency is a preventable cause of hyperhomocysteinemia

Metabolite profiling reveals new insights into the regulation of serum urate in humans

Albrecht E, Waldenberger M, Krumsiek J, et al. Metabolite profiling reveals new insights into the regulation of serum urate in humans. Metabolomics. 2013;10(1):141-151.Serum urate, the final breakdown product of purine metabolism, is causally involved in the pathogenesis of gout, and implicated in cardiovascular disease and type 2 diabetes. Serum urate levels highly differ between men and women; however the underlying biological processes in its regulation are still not completely understood and are assumed to result from a complex interplay between genetic, environmental and lifestyle factors. In order to describe the metabolic vicinity of serum urate, we analyzed 355 metabolites in 1,764 individuals of the population-based KORA F4 study and constructed a metabolite network around serum urate using Gaussian Graphical Modeling in a hypothesis-free approach. We subsequently investigated the effect of sex and urate lowering medication on all 38 metabolites assigned to the network. Within the resulting network three main clusters could be detected around urate, including the well-known pathway of purine metabolism, as well as several dipeptides, a group of essential amino acids, and a group of steroids. Of the 38 assigned metabolites, 25 showed strong differences between sexes. Association with uricostatic medication intake was not only confined to purine metabolism but seen for seven metabolites within the network. Our findings highlight pathways that are important in the regulation of serum urate and suggest that dipeptides, amino acids, and steroid hormones are playing a role in its regulation. The findings might have an impact on the development of specific targets in the treatment and prevention of hyperuricemia