910 resultados para 730108 Cancer and related disorders
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This thesis is devoted to the study of the hyperfine properties in iron-based superconductors and the synthesis of these compounds and related phases. During this work polycrystalline chalcogenide samples with stoichiometry 1:1 (FeTe1-χSχ, FeSe1-x) and pnictide samples with stoichiometry 1:2:2 (BaFe2(As1-χPχ)2, EuFe2(As1-x Px)2) were synthesized by solid-state reaction methods in vacuum and in a protecting Ar atmosphere. In several cases post-annealing in oxygen atmosphere was employed. The purity and superconducting properties of the obtained samples were checked with X-ray diffraction, SQUID and resistivity measurements. For studies of the magnetic properties of the investigated samples Mössbauer spectroscopy was used. Using low-temperature measurements around Tc and various values of the source velocity the hyperfine interactions were obtained and the magnetic and structural properties in the normal and superconducting states could be studied. Mössbauer measurements together with XRD characterization were also used for the detection of impurity phases. DFT calculations were used for the theoretical study of Mössbauer parameters for pnictide-based ᴻsamples BaFe2(As1-xPx)2 and EuFe2(As1-xPx)2.
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Maintenance of thermal homeostasis in rats fed a high-fat diet (HFD) is associated with changes in their thermal balance. The thermodynamic relationship between heat dissipation and energy storage is altered by the ingestion of high-energy diet content. Observation of thermal registers of core temperature behavior, in humans and rodents, permits identification of some characteristics of time series, such as autoreference and stationarity that fit adequately to a stochastic analysis. To identify this change, we used, for the first time, a stochastic autoregressive model, the concepts of which match those associated with physiological systems involved and applied in male HFD rats compared with their appropriate standard food intake age-matched male controls (n=7 per group). By analyzing a recorded temperature time series, we were able to identify when thermal homeostasis would be affected by a new diet. The autoregressive time series model (AR model) was used to predict the occurrence of thermal homeostasis, and this model proved to be very effective in distinguishing such a physiological disorder. Thus, we infer from the results of our study that maximum entropy distribution as a means for stochastic characterization of temperature time series registers may be established as an important and early tool to aid in the diagnosis and prevention of metabolic diseases due to their ability to detect small variations in thermal profile.
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The central role of extracellular matrix (ECM) macromolecules in diseases such as cancer and atherosclerotic vascular diseases including diabetic macroangiopathy is indisputable. Decorin and hyaluronan (HA) represent vital ECM macromolecules in the microenvironment of cells and are centrally involved in human cancer and cardiovascular biology. In cancer, decorin is considered to play a tumor suppressive role. However, there is some discrepancy whether malignant cells express it. Regarding HA, its contribution to the development of atherosclerotic vascular diseases has been well established. Nevertheless, the precise role of HA in arterial narrowing associated with diabetes is not known. The present study focused on two vital ECM macromolecules, namely decorin and HA. First, decorin expression was studied in human tumorigenesis. Furthermore, the effect of adenovirus-mediated decorin transduction on selected cancer cell lines was investigated. The results invariably showed that cancer cells completely lacked decorin expression. The study also demonstrated that transducing cancer cells with decorin adenoviral vector markedly inhibited their malignant behavior. In line with this, a strong induction of decorin expression in normal human embryonic stem cells (hESCs), but not in abnormal hESCs was observed during their differentiation. Secondly, the significance of HA in the development of diabetic macroangiopathy in response to hyperglycemia was evaluated. Results showed that the synthesis of HA by vascular smooth muscle cells was significantly increased in response to high glucose concentration. This increase was associated with the diminished ability of the cells to contract collagen-rich matrix suggesting that HA participates in the disturbed vascular remodeling of diabetic patients. The results of this study support endeavours to develop novel ECM macromolecule -based therapies targeting cancer and cardiovascular diseases.
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Obesity and its co-morbidities, such as metabolic syndrome (MetS), non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes, have increased over the last few decades like an epidemic. So far the mechanisms of many metabolic diseases are not known in detail and currently there are not enough effective means to prevent and treat them. Several recent studies have shown that the unbalanced gut microbiota composition (GMC) and activity have an influence on the fat accumulation in the body. Further, it seems that the GMC of obese individuals differs from the lean. The aim of this study was to investigate whether there are differences between the GMC of metabolically impaired overweight/obese (MetS group), metabolically healthy overweight/obese and normal-weight individuals. In addition, the mechanisms by which the gut bacteria as well as their specific structures, such as flagellin (FLG) that stimulates the Toll-like receptor 5 (TLR5) affect metabolism, were investigated both in vivo and in vitro in human adipocytes and hepatocytes. The results of this study show that the abundance of certain gram-positive bacteria belonging to the Clostridial cluster XIV was higher in the MetS group subjects compared to their metabolically healthy overweight/obese and lean counterparts. Metabolically impaired subjects tended to also have a greater abundance of potentionally inflammatory Enterobacteria in their gut and thus seemed to have aberrant GMC. In addition, it was found that subjects with a high hepatic fat content (HHFC group) had less Faecalibacterium prausnitzii in their gut than individuals with low hepatic fat content. Further gene expression analysis revealed that the HHFC group also had increased inflammation cascades in their adipose tissue. Additionally, metabolically impaired individuals displayed an increased expression of FLG-recognizing TLR5 in adipose tissue, and the TLR5 expression levels associated positively both with liver fat content and insulin resistance in humans. These changes in the adipose tissue may further contribute to the impaired metabolism observed, such as insulin resistance and dyslipidemia. In vitro -studies showed that the FLG-induced TLR5 activation in adipocytes enhanced the hepatic fat accumulation by decreasing insulin signaling and mitochondrial functions and increasing triglyceride synthesis due to increased glycerol secretion from adipocytes. In conclusion, the findings of this study suggest that it may be possible that the novel prevention and personalized treatment strategies based on GM modulation will succesfully be developed for obesity and metabolic disorders in the future.
Resumo:
Camilla Pelo Collagen Binding Integrins and Cancer Testis Antigens in Prostate Cancer and Melanoma Department of Biochemistry, MediCity Research Laboratory, University of Turku, Finland Annales Universitatis Turkuensis, Painosalama Oy, Turku, Finland 2016 ABSTRACT Prostate cancer is the second most common cancer in men worldwide. The incidence of melanoma, in turn, is increasing faster than any other cancer incidences. In Finland, more than 5000 prostate cancer and 1200 new melanoma cases are diagnosed each year. One approach to further understand the cellular processes involved in prostate cancer and melanoma is to gain better knowledge about alterations in gene expression and their potential impact on the progression of the diseases. This thesis is focused on expression studies in two gene families; integrins and cancer testis antigens (CT antigens), in human prostate adenocarcinoma and advanced human melanoma. Integrins are heterodimeric transmembrane receptors which regulate many important cellular processes such as cell proliferation, migration and survival. CT antigens are frequently expressed in different types of cancers, but are only expressed in testis in healthy individuals. CT antigens are also highly immunogenic proteins. Due to the properties mentioned above, integrins and CT antigens can function as target molecules for the development of cancer diagnostics and drugs. One of the main purposes of this thesis was to study the expression of the four collagen binding integrins α1β1, α2β1, α10β1, α11β1 and the cancer testis antigen 16 (CT16) in cancer cell lines and human tissues of prostate cancer and metastatic melanoma. Additional aims included studies on the biological role of CT16 and the abundance of CT16 in sera of advanced melanoma patients. The prognostic and diagnostic significance of CT16 and the collagen binding integrins were also evaluated. Expression studies on collagen binding integrins and the CT antigen CT16 in melanoma and prostate cancer were limited and the biological role of CT16 was unknown. In this thesis, the expression levels of α2β1 and α11β1 were found to be significantly altered in prostate cancer tissues. Integrin α2β1 decreased gradually during disease progression while α11 was elevated in prostate carcinoma compared to healthy tissues. In advanced melanoma, enhanced levels of α2 were associated with a significant shorter overall survival in advanced melanoma. In this thesis, CT16 was identified as a frequently expressed melanoma CT antigen with an anti-apoptotic function. To conclude, this thesis presents α2β1 and CT16, as potential and promising biomarkers for advanced melanoma. This thesis reports also the first functional study of CT16. Keywords: Collagen binding integrins, α1β1, α2β1, α10β1, α11β1, Cancer Testis antigens, CT16, melanoma, prostate cancer, expression
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This research was directed towards the investigation and development of an aryne route to the syntheses of aporphi ne and dibenzopyrrocolinium (dibenzoindolizinium) alkaloids and to the stability of the latter under the conditions used for aryne formation. The work c an be divided into three main sections . i) - Synthesis of Glaucine 6-Bromo-3,4-dimethoxyphenylacetic acid, prepared by the action of bromine i n acetic acid on3,4-dimethoxyphenylacetic a cid, was converted into its acid chloride by t he action of thionyl chloride. This on treatment with 3,4- dimethoxyphenylethylamine pr ovided N-(3, 4-dimethoxyphenylethyl)- 2-(2-bromo-4,S-dimethoxyphenyl)-acetamide which on dehydration with phosphoryl chloride (Bischler Napieralski reaction) in dry benzene afforded l -(2-bromo-4,S-dimethoxybenzyl)- 3,4-dihydro-6,7-dimethoxyisoquinoline, isolated as hydrochl oride. A new method o f destroying the excess of phosphoryl chloride was developed which proved to be quite useful. Methylation of the dihydroisoquinoline'with methyl iodide in methanol , and subsequent reduction with sodium borohydride provided (±)-6-bromolaudanosine. Act ion of potassamide or sodamide in anhydrous liquid ammonia on (±)-6-bromolaudanosine yielded the corresponding amino derivative along with other products. Diazotization and ring closure of (±)-6-aminolaudanosine then a f forded (±)-glaucine which was isolated as methiodide. ii) - Intramolecular Capture of Aryne During Glaucine Synthesis, and Subsequent Reactions . This section deals with the by-products formed under the conditions of the aryne stage of t he glaucine synthesis. The crude product, obtained in the reaction of potassamide or sodamide in liquid ammonia on (±)-6-bromolaudanosine, was s eparated by chromatography, Three products were separated and identified. a ) - 5,6-Dimethoxy-2-( 3,4-dimethoxy-6-ethylphenyl)-lmethylindole. Two mechanisms are proposed for the formation of this interesting product. This compound also was prepared by the action of potassamide in l,iquid ammonia on 5,6 ,l2,l2atetrahydro- 2,3,9,lO-tetramethoxy-7-methyldibenz[b,g]indolizinium i odide . b) - 5,6-Dimethoxy-2-(3,4-dimethoxy-6-vinylphenyl)-lmethylindoline. Its formation represented a new method of Hofmann degradation . Further confirmation of structure was done by performing the normal Hofmann reaction on 5, 6,12,12a-tetrahydro -2/3,9,lO-tetramethoxy ~7-methyldibe nz[ b,g]indolizinium iodide. The indoline prepared i n this way was identical in all respects with that prepared above . c) - 1- (2-amino-4,5-dimethoxybenzyl ) -l,2,3,4-tetrahydro-2- methyl-6,7-dimethoxyisoquinoline, was converted t o glaucine as stated in section 1 . iii) - Attempt:,ed Sxnthesis of Liriodenine Piperonal was converted into 3,4-methylenedioxyinitrostyrene which on reduction with lithium aluminium hydride provided 3,4-methylenedioxyphenylethylamine. The method of extraction after the reduction was improved t o some extent. The amine on condensation with m-chlorophenylacetyl chloride, prepared by the action of oxalyl chloride on 3,4-methylenedioxyphenylacetic acid, provided N-[ ~ -(3,4-methylenedioxyphenyl)- e thyl)-3-chlorophenylacetamide. This on dehydration with phosphoryl chloride in dry benzene followed by air oxidation afforded l-(3-chlorobenzoyl)-6,7-methylenedioxyi soquinoline. This compound on r eaction with potassamide in liquid ammonia afforded a crude product from which. one product was separated by chromatography i n a pure condition . This yellow compound analysed as,c17Hl ON2021 and was t he main product i n the reaction ; a t entative structure is proposed. A second compound, not obtained in pure condition, was submitted to Pschorr reaction in the hope of obtaining liriodenine, but without success.
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Fungal metabolism of halogenated and related steroids was investigated. The fungi Aspergillus niger ATCC 9142, Curvularia lunata NRRL 2380 and Rhizopus stolonifer ATCC6227b were studied in this regard. 2l-Fluoro-, 2l-chloro, 2l-bromo- and 2l-methyl-pregn-4-ene-3,20diones were prepared and incubated with ~ niger (a C-2l-hydroxylator) in order to observe the effect of the C-2l substituent on the metabolism of these substrates. In all four cases, the C-2l substituent prevented any significant metabolism of these substrates. llB-Fluoropregn-4-ene-3,20-dione was prepared and incubated with C. lunata (an llB-hydroxylator) and ~ stolonifer (an lla-hydroxylator). With ~ lunata, the ll-fluoro- substituent prevent hydroxylation at the 11 position, but diverted it to a site remote from the fluorine atom. In contrast, with ~ stolonifer the llB-fluoro- substituent, although slowing the apparent rate of hydroxylation, did not prevent its occurrence at the 11a- position. llB-Hydroxypregn-4-ene-3,20-dione was also incubated with R. stolonifer. The llB-hydroxy-;group did not appear to have any significant effect on hydroxylation at the lla- position. The incubation of a substrate, unsaturated at a favoured site of hydroxylation with Rhizopus arrhizus ATCC 11145 provided a complex mixture of products; among them were both the a and S epoxides. The formation of these products is rationalized as arising because of the lack of regio- and stereospecificity of the hydroxylase enzyme(s) involved.
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Forty-five 12- and 13-year-old females attending Grade 7 in North York, Ontario were randomly selected from a group of 100 females who had volunteered to participate in a oneday hands-on workshop called It's Your Choice at Seneca College. The goals of this intervention were to broaden the career horizons of these students and to help them realize the need to continue mathematics and science through high school in order to keep occupational options unlimited. The young women were given a pre- and post-attitude survey to provide background information. In the month following participation in the workshop the students were interviewed in small groups (S students per group) to discover their perceptions of the impact of the workshop. The interviews revealed that participants felt that after the workshop their feelings of self-confidence increased, specifically with respect to working with their hands. Participants felt more aware of the usefulness and importance of the study of mathematics, science and technology, They also felt that It's Your Choice increased their interest in careers in these domains and helped them to see that these careers are viable choices for females. The interviews also revealed that many of the participants felt that in this society their roles and their choices were influenced and probably limited by the fact that they are female.
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In order to investigate the use of Fast Atom Bombardment Mass Spectrometry (FAB-MS) as a tool for structural characterization, two groups of complexes are analyzed. The first group is a set of ruthenium(II) coordination complexes containing bidentate polypyridyl ligands. The positive and negative ion FAB-MS spectra are found to be sufficient to allow for an almost complete characterization of the central metal atom, the ligands and the counter anions contained in the intact complex. An unusual observation of mUltiply charged ions in the positive ion FAB-MS spectra (i.e. [RUL 3 ]2+) is explained to be as a result of the oxidative quenching of the excited state of the doubly charged ion by the matrix, 3-nitrobenzyl alcohol. An analysis of a mixture shows that the technique is a good one for identifying components therein. A group of triptycene and related complexes containing Group V elements is also analyzed by FAB-MS and the results. in terms of relative abundances of fragment ions, are found to be consistent with known metal-carbon bond strengths.
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This work contains the results of a series of reduction studies on polyhalogenated aromatic compounds and related ethers using alkali metals in liquid ammonia. In general, polychlorobenzenes were reduced to t he parent aromatic hydrocarbon or to 1 ,4-cyc1ohexadiene, and dipheny1ethers were cleaved to the aroma tic hydrocarbon and a phenol. Chlorinated dipheny1ethers were r eductive1y dechlorinated in the process. For example, 4-chlorodipheny1- ether gave benzene and phenol. Pentach1orobenzene and certain tetrachlorobenzenes disproportionated to a fair degree during the reduction process if no added proton source was present. The disproportionation was attributed to a build-up of amide ion. Addition of ethanol completely suppressed the formation of any disproportionation products. In the reductions of certain dipheny1ethers , the reduction of one or both of the dipheny1ether rings occurred, along with the normal cleavage. This was more prevalent when lithium was the metal used . As a Sidelight, certain chloropheno1s were readily dechlorinated. In light of these results, the reductive detoxification of the chlorinated dibenzo-1,4-dioxins seems possible with alkali metals in l iquid ammonia.
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The work described in this thesis has been divided into seven sections. The first section involves the preparation of N'-acyl-N'-arylN- benzothiohydrazides by the acylation of N'-aryl-N-benzothiohydrazides and is followed by a brief discussion of their possible conformation in solution. The second section deals with the preparation of 1,3,4-thiadiazolium salts by the action of perchloric acid/acetic anhydride on N'-acylN'- aryl-N-benzothiohydrazides and also by the reaction of N'-arylN- benzothiohydrazides with nitriles in an acidic medium. The preparation of 2-methylthio-I,3,4-thiadiazolium methosulfate by methylating the corresponding thione is also described. The third section deals with the reaction of 2-phenyl- and 2-methyl-I,3,4-thiadiazolium salts with alcohols in the presence of base. The stability and spectra of these compounds are discussed. Treatment of the 2-methyl-I,3,4-thiadiazolium salt with base was found to give rise to a dimeric anhydrobase and evidence supporting its structure is given. The anhydrobase could be trapped by a variety of acylating and thioacylating agents before dimerization occurred. In the fourth section, the reaction of N'-acyl-N'-aryl-N-benzothiohydrazides with a variety of acid anhydrides is described. These compounds were found to be identical with those obtained by acylating the anhydrobase. The mass spectral fragmentation of these compounds is described and the anomolous product obtained upon thiobenzoylation of 3-methyl-l-phenyl-pyrazal-5-one is also discussed. The fifth section deals with thioacyl derivatives of the anhydrobase which were prepared by the action of phosphorus pentasulfide upon the oxygen analogues and also obtained as the major product of the reaction of thioacetic acid with compounds related to N'-aryl-N-benzothiohydrazides. The mass spectra and p.m.r. spectra of these compounds are discussed. In the sixth section, the reaction of the 2-methylthio-l,3,4- thiadiazolium salt with active methylene compounds to give acyl and diacyl derivatives of the anhydrobase is described. Some aspects of these compounds are discussed. The seventh section describes the synthesis of ncyanine~' type dyes incorporating the l,3,4-thiadiazole ring and their spectra are briefly discussed.
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Rates and products have been determined for the thermal decomposition of bis diphenyl methyl peroxide and diphenyl methyl tert* butyl peroxide at 110@~145@C* The decomposition was uniformly unimolecular with activation energies for the bis diphenyl methyl peroxide in tetrachloroethylene* toluene and nitrobenzene 26,6* 28*3f and 27 Kcals/mole respectively. Diphenyl methyl tert* butyl peroxide showed an activation energy of 38*6 Kcals/mole* About 80-90% of the products in the case of diphenyl methyl peroxide could be explained by the concerted process, this coupled with the negative entropies of activation obtained is a conclusive evidence for the reaction adopting a major concerted path* All the products in the case of diphenyl methyl peroxide could be explained by known reactions of alkoxy radicals* About 80-85% of tert butanol and benzophenone formed suggested far greater cage disproportionation than diffusing apart* Rates of bis triphenyl methyl peroxide have been determined in tetrachloroethylene at 100-120@C* The activation energy was found to be 31 Kcals/mole*
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This research was directed towards the investigation of the Smiles rearrangement in hydrazidic systems and the synthesis of related heterocyclic compounds. The work can be conveniently divided into two main sections. Section 1 of the thesis relates to the synthesis and examination of the O+N migration of phenoxy- derivatives of hydrazidic halides. In general, hydrazidic halides were found to react with 2-nitrophenol and 4-nitrophenol to give corresponding a-nitrophenoxy- compounds. These a-nitrophenoxy- compounds were found to rearrange in warm base to give the corresponding N-benzoyl compounds via a proposed five-membered transition state. Experiments conducted in styrene revealed no radical contribution to the rearrangement. Cross-over product analysis indicated the rearrangement as intramolecular and consistent with the Smiles rearrangement. The preparation of N-a-chlorobenzylidene-N'-2-nitrophenyl- -N'-(2,4-dibromophenyl)hydrazine from N-benzoyl-N'-2-nitrophenyl- N'-(2,4-dibromophenyl)hydrazine was accomplished using phosphorus oxychloride. Examination of this hydrazidic chloride indicated a marked decrease .in reactivity as compared to the N-a-chlorobenzylidene-N'-phenylhydrazine case. Section 2 concerns itself with the preparation of heterocyclic compounds using an analogy of the five-membered transition state present in the Smiles rearrangement of a substituted benzylidene derivatives A new preparation of 2,4-phenyl1,3,4- oxadiazol-S-one using N-benzoyl-N'-phenylhydrazine and ethyl thiochloroformate is reported. Two new preparations of N-a-thiobenzoyl-N'-(2,4-dibromophenylhydrazine are reported using sodium hydrosulfide in conjunction with N-a-bromobenzylidene-N'-(2,4-dibromophenyl)hydrazine in the first, and phosphorus pentasulfide with N-benzoylN'-( 2,4-dibromophenyl)hydrazine in the second. The latter is preferred due to the formation of a sulfide co-product in the former. Two preparations of 2-phenyl-4-(2,4-dibromophenyl)-1,3,4- thiadiazol-S-one are reported using N-thiobenzoyl-N'-(2,4-dibromophenyl) hydrazine and ethyl chloroformate and ethyl thiochloroformate Two rapid and easy preparations of 2-phenyl-4-(2,4-dibromophenyl)- 1,3,4-triazol-S-one are reported using ethyl chloroformate and ethyl thiochloroformate. Sodium cyanate in conjunction with a-aminobenzylidene-N'-(2,4-dibromophenyl)hydrazine also provided 2-phenyl-4-(2,4-dibromophenyl)-1,3,4-triazol-S-one Section 2 concludes with an examination of two possible mechanistic routes to the prepared heterocycles.
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The formation and the isolation of fluoroboron salts, (D2BF2+)(PF6-), (DD'BF2+)(PF6-) and (D3BF2+)(PF6-)2, have been carried out. 1,8-Diazabicyclo [5,4.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4,3,O]non-5-ene (DBN), extremely strong organic bases, were introduced into the fluoroboron cation systems and induced a complicated redistribution reaction in the D/BF3/BC13 systems. The result was the formation of all BFnCI4-n-, D.BFnCI3-n and fluoroboron cation species which were detected by 19p and 11B NMR spectrometry. The displacement reaction of CI- from these D.BFnCI3-n (n = 1 and 2) species by the second entering ligand is much faster than in other nitrogen donor containing systems which have been previously studied. Tetramethylguanidine, oxazolines and thiazolines can also produce similar reactions in D/BF3/BCI3 systems, but no significant BFnC4-n- species were observed. As well as influences of their basicity and their steric hindrance, N=C-R(X) (X = N, 0 or S) and N=C( X)2 (X = N or S) structures of ligands have significant effects on the fonnationof fluoroboron cations and the related NMR parameters. D3BF2+ and some D2BF2+ show the expected inertness, but (DBU)2BF2+ shows an interestingly high reactivity. (D2BF2+)(X-) formed from weak organic bases such as pyridine can react with stronger organic bases and form DD'BF2+ and D'2BF2+ in acetone or nitromethane. Fast atom bombardment mass spectrometry is doubly meaningful to this work. Firstly, FABMS can be directly applied to the complicated fluoroboron cation containing solution systems as an excellent complementary technique to multinuclear NMR. Secondly, the gas-phase ion substitution reaction of (D2BF2+)(PF6-) with the strong organic bases is successfully observed in a FABMS ion source when the B-N bond is not too strong in these cations.