Abstract In this case–control study the association between the PTPN22 1858T and CTLA-4 49G gene variants and T1D in Croatian population was examined. We found that distribution of PTPN22 C1858T and ...CTLA-4 A49G genotypes between T1D patient ( n = 102) and control ( n = 193) groups differ significantly ( p < 0.0001 and p = 0.012, respectively). Moreover, although the risk alleles of both SNPs are distributed more frequently in patients, the significant difference is observed only for PTPN22 1858T allele ( p < 0.0001). This is therefore the first evidence that analyzed gene variants contribute to T1D pathogenesis in Croatian population.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Type 1 Diabetes mellitus (T1DM) begins with aberrant inflammatory process followed by auto-destruction in genetically susceptible individuals. Therefore, we hypothesized that gain-of-function allelic ...variants TNF-α-238A, -308A and PTPN22 1858T could be associated not only with T1DM development but also with the clinical outcome in patients of Bosnia and Herzegovina. A total of 402 subjects were enrolled in the association study. SNPs were determined by PCR-RFLP. Data was analyzed by GraphPad Prism and Sigma Stat 3.5 software. Genotypes frequencies at TNF-α-238 and -308 loci were not statistically different between patients and controls. In contrast, distribution of genotypes at the 1858 position of PTPN22 was significantly different, due to higher frequency of gain-of-function gene variants in patients than controls. Moreover, long term glucose regulation (based on HbA1c level) was significantly worse in patients with the risk TNF-α-308A allele than in patients with non-risk (G) allele. However, patients with the risk allele of both genes (TNF-α-308A and PTPN22 1858T) had the worst glycemic control, suggesting that those two work synergistically. In conclusion, in a cohort from Bosnia and Herzegovina TNF-α-308A allele is significantly associated with the worse long-term glucose control, but PTPN22 1858T allele is significantly associated with diabetes development.
Natural silicate materials, including zeolite clinoptilolite, have been shown to exhibit diverse biological activities and have been used successfully as a vaccine adjuvant and for the treatment of ...diarrhea. We report a novel use of finely ground clinoptilolite as a potential adjuvant in anticancer therapy. Clinoptilolite treatment of mice and dogs suffering from a variety of tumor types led to improvement in the overall health status, prolongation of life-span, and decrease in tumors size. Local application of clinoptilolite to skin cancers of dogs effectively reduced tumor formation and growth. In addition, toxicology studies on mice and rats demonstrated that the treatment does not have negative effects. In vitro tissue culture studies showed that finely ground clinoptilolite inhibits protein kinase B (c-Akt), induces expression of p21WAF1/CIP1 and p27KIP1 tumor suppressor proteins, and blocks cell growth in several cancer cell lines. These data indicate that clinoptilolite treatment might affect cancer growth by attenuating survival signals and inducing tumor suppressor genes in treated cells.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Because of its quantitative character and capability for high-throughput screening,
H nuclear magnetic resonance (NMR) spectroscopy is used extensively in the profiling of biofluids such as urine and ...blood plasma. However, the narrow frequency bandwidth of
H NMR spectroscopy leads to a severe overlap of the spectra of components present in the complex mixtures such as biofluids. Therefore,
H NMR-based metabolomics analysis is focused on targeted studies related to concentrations of the small number of metabolites. Here, we propose a library-based approach to quantify proportions of overlapping metabolites from
H NMR mixture spectra. The method boils down to the linear non-negative least squares (NNLS) problem, whereas proportions of the pure components contained in the library stand for the unknowns. The method is validated on an estimation of the proportions of (
) the 78 pure spectra, presumably related to type 2 diabetes mellitus (T2DM), from their synthetic linear mixture; (
) metabolites present in 62
H NMR spectra of urine of subjects with T2DM and 62
H NMR spectra of urine of control subjects. In both cases, the in-house library of 210 pure component
H NMR spectra represented the design matrix in the related NNLS problem. The proposed method pinpoints 63 metabolites that in a statistically significant way discriminate the T2DM group from the control group and 46 metabolites discriminating control from the T2DM group. For several T2DM-discriminative metabolites, we prove their presence by independent analytical determination or by pointing out the corresponding findings in the published literature.
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IJS, KILJ, NUK, PNG, UL, UM
Due to its capability for high-throughput screening 1H nuclear magnetic resonance (NMR) spectroscopy is commonly used for metabolite research. The key problem in 1H NMR spectroscopy of multicomponent ...mixtures is overlapping of component signals and that is increasing with the number of components, their complexity and structural similarity. It makes metabolic profiling, that is carried out through matching acquired spectra with metabolites from the library, a hard problem. Here, we propose a method for nonlinear blind separation of highly correlated components spectra from a single 1H NMR mixture spectra. The method transforms a single nonlinear mixture into multiple high-dimensional reproducible kernel Hilbert Spaces (mRKHSs). Therein, highly correlated components are separated by sparseness constrained nonnegative matrix factorization in each induced RKHS. Afterwards, metabolites are identified through comparison of separated components with the library comprised of 160 pure components. Thereby, a significant number of them are expected to be related with diabetes type 2. Conceptually similar methodology for nonlinear blind separation of correlated components from two or more mixtures is presented in the Supplementary material. Single-mixture blind source separation is exemplified on: (i) annotation of five components spectra separated from one 1H NMR model mixture spectra; (ii) annotation of fifty five metabolites separated from one 1H NMR mixture spectra of urine of subjects with and without diabetes type 2. Arguably, it is for the first time a method for blind separation of a large number of components from a single nonlinear mixture has been proposed. Moreover, the proposed method pinpoints urinary creatine, glutamic acid and 5-hydroxyindoleacetic acid as the most prominent metabolites in samples from subjects with diabetes type 2, when compared to healthy controls.
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•Method for single-mixture nonlinear blind source separation.•Sparseness constrained factorization is performed in multiple kernel Hilbert spaces.•The method performs library-assisted annotation of separated components .•Demonstration on 1H NMR urinary spectra from diabetic patients and healthy controls.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
An aqueous aluminosilicate hydrogel having oxide molar composition: 4.72Na
2O
·
Al
2O
3
·
1.93SiO
2
·
254.86H
2O was treated in two ways: (1) the hydrogel (system S
NL) was heated at 80
°C until the ...entire amount of amorphous aluminosilicate precursor (gel) has been transformed to zeolite A, (2) the hydrogel was frozen in liquid air and freeze-dried; solid liophilizate was poured in an appropriate volume of water, and the obtained suspension (system S
L) was treated in the same way as the system S
NL. The drastic treatment of hydrogel did not substantially change the distribution of nuclei in the matrix of the amorphous aluminosilicate precursor (gel) established during its precipitation. The consequence is that, in accordance with the principles of the gel “memory” effect, the crystal size distributions of the crystalline end product (zeolite A) obtained from both the systems (S
NL and S
L) are almost the same. On the other hand, the above mentioned treatment of hydrogel changes the concentrations of aluminium and silicon in the liquid phase and caused that the rate of crystal growth is somewhat higher in system S
L than in system S
NL. Population balance analysis of the crystallization processes has shown that the difference of the kinetics of crystallization of zeolite A from the systems S
NL and S
L is in larger extent caused by the small difference in the crystal growth rate and in the smaller extent by the particulate processes determined by the specific number of nuclei
N
S and distribution of nuclei in the gel matrix.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
To assess whether alterations in the K-ras, p53, and DPC4 genes are present in pancreatitis, a potential precancerous condition that can progress to pancreatic adenocarcinoma. To investigate the ...alterations occurring at hot spots of K-ras (exon 1), p53 (exons 5 and 7), and DPC4 (exons 8, 10 and 11).
In 10 patients with acute and 22 with chronic pancreatitis, without pancreatic intraepithelial neoplasia (PanIN), DNA was isolated from paraffin embedded tissue samples. The extracted DNA was analyzed by polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP) analysis, single-strand conformation polymorphism (SSCP) analysis, and DNA sequencing.
In acute pancreatitis samples no mutations were found in any of the investigated genes. In 7 out of 22 samples of chronic pancreatitis nucleotide substitution at exon 1 of K-ras (five at codon 12 and two at codon 13) were found. No mutations in p53 (exons 5 and 7) were detected. Two samples had nucleotide substitutions at exons 8 and 11 of DPC4, introducing STOP signal and change in the amino acid sequence, respectively. One chronic pancreatitis sample displayed simultaneous mutations in K-ras (exon 1, codon 12) and DPC4 (exon 8, codon 358).
Mutations of K-ras and Dpc4 genes can accumulate already in non-malignant, inflammatory pancreatic tissue, suggesting its applicability in monitoring of further destruction of pancreatic tissue and progression into malignancy.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The aim of this study was to evaluate decontamination (absorption) efficacy of a preparation called Mineral Cationic Carrier (MCC) against skin contamination with sulphur mustard in vivo. MCC is a ...synthetic preparation with known ion exchange, absorption efficiency, and bioactive potential. CBA mice were applied increasing doses of sulphur mustard on their skin and MCC was administered immediately after skin contamination. The results have confirmed the decontamination efficacy of MCC preparation, corresponding to 8.4 times the LD50 of percutaneous sulphur mustard, and call for further investigation.
Our Institute's nuclear, biological, and chemical defense research team continuously investigates and develops preparations for skin decontamination against nerve agents. In this in vivo study, we ...evaluated skin decontamination efficacy against sarin by a synthetic preparation called Mineral Cationic Carrier (MCC®) with known ion exchange, absorption efficacy and bioactive potential. Mice were treated with increasing doses of sarin applied on their skin, and MCC® was administered immediately after contamination. The results showed that decontamination with MCC® could achieve therapeutic efficacy corresponding to 3 x LD50 of percutaneous sarin and call for further research.
Kožna dekontaminacija živčanoga bojnog otrova sarina s apsorpcijskim pripravkom u uvjetima in vivo
The purpose of this study was to examine the short-term effects of diet containing 0.1% (m/m) of acarbose in standard laboratory chow on specific liver enzyme activities: alanine aminotransferase ...(ALT) and aspartate aminotransferase (AST) in control and diabetic CBA mice. Diabetes was induced by intravenous injection of alloxan monohydrate in a dose of 75 mg kg(-1) mouse body mass seven days before the treatment with acarbose. There were four groups of CBA mice in the experiment: control (C) mice (n = 6) and diabetic (D) mice (n = 8) fed standard chow; control (C/A-100) mice (n = 8) and diabetic (D/A-100) mice (n = 8) fed standard chow containing 0.1% acarbose. Diabetes induced a decrease of the ALT catalytic activities to 69.6% of the control value. A similar level of decreased ALT catalytic activity was detected in the liver of control and diabetic mice fed chow containing 0.1% acarbose. No changes in the specific and total activities of AST in the liver of experimental groups were observed.
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