Withaferin A Inhibits Prostate Carcinogenesis in a PTEN-deficient Mouse Model of Prostate Cancer

Publication date: June 2017
Source:Neoplasia, Volume 19, Issue 6
Author(s): Jim Moselhy, Suman Suman, Mohammed Alghamdi, Balaji Chandarasekharan, Trinath P Das, Alatassi Houda, Murali Ankem, Chendil Damodaran
We recently demonstrated that AKT activation plays a role in prostate cancer progression and inhibits the pro-apoptotic function of FOXO3a and Par-4. AKT inhibition and Par-4 induction suppressed prostate cancer progression in preclinical models. Here, we investigate the chemopreventive effect of the phytonutrient Withaferin A (WA) on AKT-driven prostate tumorigenesis in a Pten conditional knockout (Pten-KO) mouse model of prostate cancer. Oral WA treatment was carried out at two different doses (3 and 5 mg/kg) and compared to vehicle over 45 weeks. Oral administration of WA for 45 weeks effectively inhibited primary tumor growth in comparison to vehicle controls. Pathological analysis showed the complete absence of metastatic lesions in organs from WA-treated mice, whereas discrete metastasis to the lungs was observed in control tumors. Immunohistochemical analysis revealed the down-regulation of pAKT expression and epithelial-to-mesenchymal transition markers, such as β-catenin and N-cadherin, in WA-treated tumors in comparison to controls. This result corroborates our previous findings from both cell culture and xenograft models of prostate cancer. Our findings demonstrate that the daily administration of a phytonutrient that targets AKT activation provides a safe and effective treatment for prostate cancer in a mouse model with strong potential for translation to human disease.



http://ift.tt/2qdmof3

Enhanced air dispersion modelling at a typical Chinese nuclear power plant site: Coupling RIMPUFF with two advanced diagnostic wind models

Publication date: September 2017
Source:Journal of Environmental Radioactivity, Volumes 175–176
Author(s): Yun Liu, Hong Li, Sida Sun, Sheng Fang
An enhanced air dispersion modelling scheme is proposed to cope with the building layout and complex terrain of a typical Chinese nuclear power plant (NPP) site. In this modelling, the California Meteorological Model (CALMET) and the Stationary Wind Fit and Turbulence (SWIFT) are coupled with the Risø Mesoscale PUFF model (RIMPUFF) for refined wind field calculation. The near-field diffusion coefficient correction scheme of the Atmospheric Relative Concentrations in the Building Wakes Computer Code (ARCON96) is adopted to characterize dispersion in building arrays. The proposed method is evaluated by a wind tunnel experiment that replicates the typical Chinese NPP site. For both wind speed/direction and air concentration, the enhanced modelling predictions agree well with the observations. The fraction of the predictions within a factor of 2 and 5 of observations exceeds 55% and 82% respectively in the building area and the complex terrain area. This demonstrates the feasibility of the new enhanced modelling for typical Chinese NPP sites.



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An evaluation of the TREC assay with regard to the integration of SCID screening into the Dutch newborn screening program

Publication date: Available online 6 May 2017
Source:Clinical Immunology
Author(s): Maartje Blom, Ingrid Pico-Knijnenburg, Marja Sijne-van Veen, Anita Boelen, Robbert Bredius, Mirjam van der Burg, Peter Schielen
Newborn screening of severe combined immunodeficiency through the detection of T-cell receptor excision circles will provide the opportunity of treating before the occurrence of life-threatening infections. With the EnLite Neonatal TREC assay (PerkinElmer) and end-point PCR, 39 samples (3.0%) of 1295 heel prick cards of the Dutch newborn screening program required a retest after initial analysis. After retest, 21 samples (1.62%) gave TREC levels below cut-off. A significant reduction in TREC levels was observed in heel prick cards stored for three months (n=33) and one year (n=33). Preterm newborns (n=155) showed significantly lower TREC levels and a higher retest-rate than full-term newborns. Peripheral blood spots of 22 confirmed SCID patients and 17 primary immunodeficiency patients showed undetectable or low TREC-levels. These findings suggest that the EnLite Neonatal TREC assay is a suitable method for SCID-screening in the Netherlands, thereby providing guidance in the decisions concerning implementation into the Dutch program.



http://ift.tt/2qEY8SK

Recurrent respiratory tract infections (RRTI) in the elderly: A late onset mild immunodeficiency?

Publication date: Available online 6 May 2017
Source:Clinical Immunology
Author(s): Esther van de Vosse, Monique M. van Ostaijen-ten Dam, René Vermaire, Els M. Verhard, Jacqueline L. Waaijer, Jaap A. Bakker, Sandra T. Bernards, Hermann Eibel, Maarten J. van Tol, Jaap T. van Dissel, Margje H. Haverkamp
Elderly with late-onset recurrent respiratory tract infections (RRTI) often have specific anti-polysaccharide antibody deficiency (SPAD). We hypothesized that late-onset RRTI is caused by mild immunodeficiencies, such as SPAD, that remain hidden through adult life. We analyzed seventeen elderly RRTI patients and matched controls. We determined lymphocyte subsets, expression of BAFF receptors, serum immunoglobulins, complement pathways, Pneumovax-23 vaccination response and genetic variations in BAFFR and MBL2. Twelve patients (71%) and ten controls (59%) had SPAD. IgA was lower in patients than in controls, but other parameters did not differ. However, a high percentage of both patients (53%) and controls (65%) were MBL deficient, much more than in the general population. Often, MBL2 secretor genotypes did not match functional deficiency, suggesting that functional MBL deficiency can be an acquired condition. In conclusion, we found SPAD and MBL deficiency in many elderly, and conjecture that at least the latter arises with age.



http://ift.tt/2pj3nmo

An evaluation of the TREC assay with regard to the integration of SCID screening into the Dutch newborn screening program

Publication date: Available online 6 May 2017
Source:Clinical Immunology
Author(s): Maartje Blom, Ingrid Pico-Knijnenburg, Marja Sijne-van Veen, Anita Boelen, Robbert Bredius, Mirjam van der Burg, Peter Schielen
Newborn screening of severe combined immunodeficiency through the detection of T-cell receptor excision circles will provide the opportunity of treating before the occurrence of life-threatening infections. With the EnLite Neonatal TREC assay (PerkinElmer) and end-point PCR, 39 samples (3.0%) of 1295 heel prick cards of the Dutch newborn screening program required a retest after initial analysis. After retest, 21 samples (1.62%) gave TREC levels below cut-off. A significant reduction in TREC levels was observed in heel prick cards stored for three months (n=33) and one year (n=33). Preterm newborns (n=155) showed significantly lower TREC levels and a higher retest-rate than full-term newborns. Peripheral blood spots of 22 confirmed SCID patients and 17 primary immunodeficiency patients showed undetectable or low TREC-levels. These findings suggest that the EnLite Neonatal TREC assay is a suitable method for SCID-screening in the Netherlands, thereby providing guidance in the decisions concerning implementation into the Dutch program.



http://ift.tt/2qEY8SK

Recurrent respiratory tract infections (RRTI) in the elderly: A late onset mild immunodeficiency?

Publication date: Available online 6 May 2017
Source:Clinical Immunology
Author(s): Esther van de Vosse, Monique M. van Ostaijen-ten Dam, René Vermaire, Els M. Verhard, Jacqueline L. Waaijer, Jaap A. Bakker, Sandra T. Bernards, Hermann Eibel, Maarten J. van Tol, Jaap T. van Dissel, Margje H. Haverkamp
Elderly with late-onset recurrent respiratory tract infections (RRTI) often have specific anti-polysaccharide antibody deficiency (SPAD). We hypothesized that late-onset RRTI is caused by mild immunodeficiencies, such as SPAD, that remain hidden through adult life. We analyzed seventeen elderly RRTI patients and matched controls. We determined lymphocyte subsets, expression of BAFF receptors, serum immunoglobulins, complement pathways, Pneumovax-23 vaccination response and genetic variations in BAFFR and MBL2. Twelve patients (71%) and ten controls (59%) had SPAD. IgA was lower in patients than in controls, but other parameters did not differ. However, a high percentage of both patients (53%) and controls (65%) were MBL deficient, much more than in the general population. Often, MBL2 secretor genotypes did not match functional deficiency, suggesting that functional MBL deficiency can be an acquired condition. In conclusion, we found SPAD and MBL deficiency in many elderly, and conjecture that at least the latter arises with age.



http://ift.tt/2pj3nmo

Adaptive release of heparin from anticoagulant hydrogels triggered by different blood coagulation factors

Publication date: August 2017
Source:Biomaterials, Volume 135
Author(s): Manfred F. Maitz, Jan Zitzmann, Jasmin Hanke, Claudia Renneberg, Mikhail V. Tsurkan, Claudia Sperling, Uwe Freudenberg, Carsten Werner
Feedback-controlled anticoagulant hydrogels were formed by crosslinking the anticoagulant heparin with star-shaped poly(ethylene glycol) using peptide linkers, which are selectively cleaved by different activated blood coagulation factors acting as proteolytic enzymes. Various cleavable peptide units, differing either in their thrombin turnover rates or in their responsiveness to factors activated earlier in the course of blood coagulation, were used for the formation of the biohybrid materials. Release triggered by the early coagulation factors Xa (FXa) or FXIIa/kallikrein was shown to enhance the efficiency of the released anticoagulant. Furthermore, FXa-cleavable gels enabled a faster release of heparin, which was attributed to the lower affinity of the factor for heparin. Combining early and fast responses, FXa-cleavable gels were shown to provide anticoagulant protection of biomaterial surfaces at low levels of released heparin in human whole-blood incubation experiments. The results demonstrate the potential for employing biomolecular circuits in the design of functional biomaterials to tailor the adaptive delivery of bioactive molecules.



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