Type 1 diabetes is a polygenic disease that results in an autoimmune response directed against insulin-producing beta cells.
is a known high-risk type 1 diabetes associated gene expressed in both ...immune- and pancreatic beta cells, but how genes affect the development of autoimmune diabetes is largely unknown. We employed CRISPR/Cas9 technology to generate a functional knockout of
in human pluripotent stem cells (hPSC) followed by differentiating stem-cell-derived beta-like cells (sBC) and detailed phenotypical analyses. The differentiation efficiency of
knockout (PTPN2 KO) sBC is comparable to wild-type (WT) control sBC. Global transcriptomics and protein assays revealed the increased expression of HLA Class I molecules in PTPN2 KO sBC at a steady state and upon exposure to proinflammatory culture conditions, indicating a potential for the increased immune recognition of human beta cells upon differential
expression. sBC co-culture with autoreactive preproinsulin-reactive T cell transductants confirmed increased immune stimulations by PTPN2 KO sBC compared to WT sBC. Taken together, our results suggest that the dysregulation of
expression in human beta cell may prime autoimmune T cell reactivity and thereby contribute to the development of type 1 diabetes.
Melioidosis, caused by Burkholderia pseudomallei, requires intensive antimicrobial treatment. However, standardized antimicrobial susceptibility testing (AST) methodology based on modern principles ...for determining breakpoints and ascertaining performance of methods are lacking for B. pseudomallei. This study aimed to establish MIC and zone diameter distributions on which to set epidemiological cut-off (ECOFF) values for B. pseudomallei using standard EUCAST methodology for non-fastidious organisms.
Non-consecutive, non-duplicate clinical B. pseudomallei isolates (9–70 per centre) were tested at eight study centres against eight antimicrobials by broth microdilution (BMD) and the EUCAST disc diffusion method. Isolates without and with suspected resistance mechanisms were deliberately selected. The EUCAST Development Laboratory ensured the quality of study materials, and provided guidance on performance of the tests and interpretation of results. Aggregated results were analysed according to EUCAST recommendations to determine ECOFFs.
MIC and zone diameter distributions were generated using BMD and disc diffusion results obtained for 361 B. pseudomallei isolates. MIC and zone diameter ECOFFs (mg/L; mm) were determined for amoxicillin-clavulanic acid (8; 22), ceftazidime (8; 22), imipenem (2; 29), meropenem (2; 26), doxycycline (2; none), tetracycline (8; 23), chloramphenicol (8; 22) and trimethoprim-sulfamethoxazole (4; 28).
We have validated the use of standard BMD and disc diffusion methodology for AST of B. pseudomallei. The MIC and zone diameter distributions generated in this study allowed us to establish MIC and zone diameter ECOFFs for the antimicrobials studied. These ECOFFs served as background data for EUCAST to set clinical MIC and zone diameter breakpoints for B. pseudomallei.
We investigate both, experimentally and theoretically, commensurability oscillations in the low-field magnetoresistance of lateral superlattices with broken inversion symmetry. We find that ...pronounced minima develop in the resistivity when the flat band conditions of several relevant harmonics of the periodic potential nearly coincide.
The effect of particle and pore arrangement on sintering and densification of ultra-fine (∼130nm) Ce0.9Gd0.1O2−δ powder was evaluated. The common understanding that higher initial density of a ...ceramic network leads to a higher sintered density is not valid for fine powders, which have extremely good sinterability when there is a favourable particle packing. The effect of the applied stresses during forming (which produce different particle packing arrangements) was investigated by forging green bodies by different shaping techniques, including casting, and cold isostatic pressing. Samples formed with techniques that apply low levels of stress had a particle arrangement which significantly enhanced sintering at low temperature, compared to those prepared by high stress techniques. The sample geometry, heat treatment for organic removal and the initial density of the green body had a negligible effect on the final density when the ratio of the pore size to particle size was around 1.
Tumor-related methylated DNA and circulating tumor cells (CTC) in the peripheral blood might be of prognostic importance in breast cancer. Thus, the aim of our study was to examine free methylated ...DNA and CTC in the blood from breast cancer patients and to correlate it with clinicopathological features known to influence prognosis.
We prospectively obtained serum samples from 85 patients with breast cancer and 22 healthy volunteers. Sera were analysed by methylation specific PCR (MethyLight PCR) for five genes: adenomatous polyposis coli (APC), ras association domain family protein 1A (RASSF1A), estrogen receptor 1 (ESR1), CDKN2A (p16) and glutathione s-transferase pi 1 (GSTP1). Beta actin (ACTB) served as control. In parallel matched peripheral blood of 63 patients was used to assay for circulating tumor cells in the peripheral blood by a modified immunomagnetic AdnaTest BreastCancerSelect with PCR detection for EPCAM, MUC1, MGB1 and SPDEF.
A hypermethylation in the APC gene in 29% (25/85), in RASSF1A in 26% (22/85), in GSTP1 in 18% (14/76) and in ESR1 in 38% (32/85) of all breast cancer patients was detected. No hypermethylation of CDKN2A was found (0/25). Blood samples of patients were defined CTC positive by detecting the EPCAM 13% (8/63), MUC1 16% (10/63), MGB 9% (5/55), SPDEF 12% (7/58) and in 27% detecting one or more genes (15/55). A significant difference was seen in methylated APC DNA between cancer patients and healthy volunteers. Moreover, methylated APC, RASSF1 and CTC were significantly different in metastatic versus non-metastatic disease. In addition, the presence of methylated APC, RASSF1A and CTC correlated significantly with AJCC-staging (p = 0.001, p = 0.031 and 0.002, respectively). High incidences of methylations were found for the genes RASSF1 and ESR1 in healthy individuals (both 23% 5/22). Methylated GSTP1 was predominantly found in the serum of patients with large primaries (p = 0.023) and was highly significantly correlated with positive Her2/neu status (p = 0.003). Elevated serum CA15.3 was strongly correlated with methylated APC and CTC detection (both p = 0.000). Methylated ESR1 failed to exhibit significant correlations with any of the above mentioned parameters. The presence of CTC in peripheral blood was significantly associated with methylated APC (p = 0.012) and methylated GSTP1 (p = 0.001).
The detection of methylated APC and GSTP1 DNA in serum correlated with the presence of CTC in the blood of breast cancer patients. Both methylated DNA and CTC correlated with a more aggressive tumor biology and advanced disease.
Neurofibromatosis Gerber, P A; Antal, A S; Neumann, N J ...
European journal of medical research,
03/2009, Letnik:
14, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Neurofibromatosis (NF) is one of the most common genetic disorders. Inherited in an autosomal dominant fashion, this phacomatosis is classified into two genetically distinct subtypes characterized by ...multiple cutaneous lesions and tumors of the peripheral and central nervous system. Neurofibromatosis type 1 (NF1), also referred to as Recklinghausen's disease, affects about 1 in 3500 individuals and presents with a variety of characteristic abnormalities of the skin and the peripheral nervous system. Neurofibromatosis type 2 (NF2), previously termed central neurofibromatosis, is much more rare occurring in less than 1 in 25 000 individuals. Often first clinical signs of NF2 become apparent in the late teens with a sudden loss of hearing due to the development of bi- or unilateral vestibular schwannomas. In addition NF2 patients may suffer from further nervous tissue tumors such as meningiomas or gliomas. This review summarizes the characteristic features of the two forms of NF and outlines commonalities and distinctions between NF1 and NF2.
Insulin-like growth factor (IGF)-1, -2 and Insulin like growth factor binding proteins (IGFBP) are involved in the proliferation and differentiation of cells. It has never been evaluated, if the ...IGF-system can serve as a tumor marker in neoplasms.
In our prospective study 163 patients with colorectal cancer (22), prostate cancer (21), head and neck tumors (17), lymphomas (20), lung cancer (34) and other entities (49) were analysed for their IGF and IGFBP serum levels at the beginning and the end of radiotherapy and compared to 13 healthy people. Subgroups of patients with local tumor disease versus metastatic disease, primary and recurrent therapy and curative versus palliative therapy were compared.
The serum levels of IGF-2 were significantly elevated in patients with prostate and colorectal cancer. However, sensitivity and specificity were only 70%. IGFBP-2 serum levels were elevated in patients with head and neck tumors. Again sensitivity and specificity were only 73%. A difference between local disease and metastatic disease could not be found. A difference between IGF serum levels before and after radiotherapy could not be detected.
The IGF-system cannot serve as a new tumor marker. The detected differences are very small, sensitivity and specificity are too low. IGF measurement is not useful for the evaluation of the success of radiotherapy in malignancies.
BACKGROUND: Adjuvant aromatase inhibitors increase osteoporosis and fractures in patients with hormone receptor–positive breast cancer. We have previously reported outcomes of the ABCSG-18 (study 18 ...from the Austrian Breast & Colorectal Cancer Study Group) trial showing that adjuvant anti–receptor activator of nuclear factor-κB ligand denosumab treatment counteracts these adverse effects and may improve outcomes. We report here the final long-term outcomes. METHODS: ABCSG-18 is a prospective, double-blind, placebo-controlled, phase 3 trial in which 3425 postmenopausal patients with early hormone receptor–positive breast cancer receiving aromatase inhibitor therapy were randomly assigned in 58 trial centers to receive either denosumab 60 mg or placebo administered subcutaneously every 6 months. The primary end point was the time to first clinical fracture after randomization. Secondary disease outcome–related end points were disease-free survival (DFS), bone metastasis–free survival (BMFS), and overall survival (OS). RESULTS: For this final protocol-defined analysis, median follow-up is 8 years (interquartile range, 6 to 9.6 years). There were 309 versus 368 DFS events (hazard ratio, 0.83; 95% confidence interval CI, 0.71 to 0.97) in the denosumab versus the placebo group, respectively, resulting in an absolute 9-year DFS benefit of 3.5 percentage points (79.4 vs. 75.9%). Adjuvant denosumab improved BMFS by 2.5 percentage points (88.9 vs. 86.4%; hazard ratio, 0.81; 95% CI, 0.65 to 1.00) and OS by 1.0 percentage point (90.9 vs. 89.9%; hazard ratio, 0.80; 95% CI, 0.64 to 1.01). No new toxicities for this dose of adjuvant denosumab were observed. CONCLUSIONS: DFS, BMFS, and OS continued to show benefit in this final long-term analysis of ABCSG-18. There were no new toxicities. (Funded by Amgen; ClinicalTrials.gov number, NCT00556374.)
ß-Mannan and mannanase in poultry nutrition SHASTAK, Y.; ADER, P.; FEUERSTEIN, D. ...
World's Poultry Science Journal,
03/2015, Letnik:
71, Številka:
1
Book Review, Journal Article
Recenzirano
Dietary plant ß-mannans are one of the major anti-nutritional components in monogastric nutrition. The presence of ß-mannans in poultry diets has been associated with many negative features ranging ...from high intestinal viscosity and low nutrient digestibility to adverse effects on innate immune response and microbial proliferation in the gut. ß-Mannanase supplementation to the feed of domestic fowl is one of the strategies for optimisation of nutritional value of ß-mannan containing diets. Research has shown positive effects of ß-mannanase supplementation on performance and nutrient digestibility in poultry fed corn-soybean meal-based diets as well as diets containing guar meal, copra meal, and palm kernel meal. Such performance and nutrient digestibility improvements are the result of single or combined modes of action due to ß-mannanase addition. Particularly over the last decade, it has become increasingly clear that these modes of action might be very complex and versatile. The identification and understanding of the mechanisms by which ß-mannanase supplementation affects nutrient digestion, metabolism, overall performance and health of birds, is important for the optimisation and broadening of the application of this enzyme in avian nutrition. This paper reviews various modes of action by ß-mannanase supplementation in poultry. Additionally, significance of single modes of action under different conditions is also discussed.
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