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Objectives: If a woman is in a physiological post partum condition, there will be an increase in the production of free radicals in her body. This situation will be worse if the woman is undergoing pathological postpartum, the production of free radicals in her body will be even greater. This condition is known as "oxidative stress". Theoretical Framework: Doing Otaria exercise will affect the muscle's need for oxygen, which will increase, meaning it requires strong blood flow like the uterine muscles. By doing postpartum exercises, it will stimulate uterine contractions, so that uterine contractions will be better, the release of lochia will be smooth, which will affect the uterine involution process. Method: The design used in this research was Post Test Only Control Group Design or post test with experimental and control groups. The sample in this study was 20 respondents in the experimental group and 20 respondents in the control group. Results and conclusion: In postpartum mothers, there is an increase in lipid peroxidation products, especially 8-OhdG. The 8-OHdG is one of the product compounds of the lipid peroxide reaction which is also used as a marker of oxidative stress Implications of the research: Research implications: midwifery services, maternal and child health and the reduction of maternal and infant mortality rates are affected by this study. The potential for quality midwifery care in the postpartum period can benefit the health of mothers and their babies. This study allows for further research and collaboration in the future to further reduce maternal mortality in the post partum period.

Oxidative stress (OS) is a situation that occurs as a result of un-equilibrium between reactive oxygen species (ROS) formation and the antioxidant defence system. 8-hydroxy-2-deoxyguanosine (8-OHdG), an oxidized form of deoxyguanosine, is found in higher levels in aging oocytes. In this cross-sectional study, we aimed to evaluate the effect of 8-OHdG on the intracytoplasmic sperm injection (ICSI). Follicular fluid (FF) samples were taken after removing the oocyte for later analysis of 8-OHdG. The couples participants were categorized according to the cause of subfertility into three groups (female factor, malefactor, and unexplained infertility). Further division according to pregnancy state was done to evaluate the precise role of 8-OHdG on pregnancy state and ICSI outcome. Result : This study showed that the 8-OHdG levels significantly higher in non-pregnant women (p < 0.05). Correlation study showed that 8-OHdG level in follicular fluid is negatively correlating with the number of retrieved oocytes, metaphase two oocytes (MII), fertilized oocytes (2PN = two pronuclei), cleaved zygotes, good quality embryos, and the difference was statistically significant (p < 0.05). Conclusion: The study revealed that the 8-OHdG level in follicular fluid negatively influences ICSI outcome and it is higher in non-pregnant women.

Conventional DNA analysis techniques can hardly detect DNA damage in ruminant spermatozoa due to high DNA compaction in these cells. Furthermore, these techniques cannot discriminate whether the damage is due to oxidative stress. The main purpose of this study was to evaluate the efficacy of two techniques for determining DNA damage in ovine sperm when the source of that damage is oxidative stress. Semen samples from twenty Manchega rams (Ovis aries) were collected and cryopreserved. After thawing, the samples were subjected to different levels of oxidative stress, and DNA oxidation was quantified using an 8-hydroxy-2′-deoxyguanosine (8-OHdG) immunodetection assay and Sperm Chromatin Structure Assay (SCSA®). For this purpose, we evaluated five different concentrations of an oxidation solution (H2O2/FeSO4•7H2O) on ram sperm DNA. Our study with the 8-OHdG immunodetection assay shows that there are higher values for DNA oxidation in samples that were subjected to the highest oxidative stress (8 M H2O2/800 µM FeSO4•7H2O) and those that were not exposed to high oxidative stress, but these differences were not significant (p ≥ 0.05). The two SCSA® parameters considered, DNA fragmentation index (DFI %) and high DNA stainability (HDS %), showed significant differences between samples that were subjected to high concentrations of the oxidation agent and those that were not (p < 0.05). We can conclude that the 8-OHdG immunodetection assay and SCSA® detect DNA damage caused by oxidative stress in ovine sperm under high oxidative conditions; SCSA® is a more straightforward method with more accurate results. For these reasons, an oxidative-stress-specific assay such as 8-OHdG immunodetection is not needed to measure DNA damage caused by oxidative stress in ram sperm samples.

Background: Cytosolic glutathione S-transferases (GSTs) might affect both the development and the progression of renal cell carcinoma (RCC) due to their dual functionality. The aim of this study was to evaluate specific role of GST gene variants (GSTA1, GSTM1, GSTT1 and GSTP1) as determinants of risk in patients with renal cell carcinoma, independently or simultaneously with recognized RCC risk factors, as well as to discern whether phenotype changes reflect genotype-associated risk. Furthermore, we evaluated the effect of GST gene variants on postoperative prognosis in RCC patients. Special attention was paid to the most frequent type of RCC, clear renal cell carcinoma (ccRCC). Methods: GST genotypes were determined in 305 RCC patients and 326 matched-controls in whom overall survival was evaluated as well. The levels of benzo(a)pyrene diolepoxide (BPDE)-DNA adducts and 8-hydroxy-2′-deoxyguanosine (8-OHdG) were determined by ELISA method. The expression of GSTM1 and GSTP1 protein level, as well as the level of regulatory (ASK1, JNK1/2) and executor (Caspase-3) apoptotic molecules in ccRCC tissue samples were analyzed by method of immuniblot. The presence of GSTM1:ASK1/ GSTP1:JNK1/2 protein:protein interactions was determined by means of immunoprecipitation. Results: Significant association between GST genotype and risk of overall RCC and ccRCC development was found for GSTM1-null and GSTP1-variant genotypes, independently (p<0.05). Furthermore, 22% of all recruited ccRCC patients were carriers of combined GSTM1-null/GSTT1-active/GSTA1-low activity/GSTP1-variant genotype, exhibiting 9.32-fold elevated ccRCC risk compared to the reference genotype combination (p=0.041). Significant association between GST genotype and ccRCC risk in smokers was found only for the GSTP1 genotype, while GSTM1-null/GSTP1-variant/GSTA1 low-activity genotype combination was present in 94% of smokers with ccRCC, increasing the risk of ccRCC up to 7.57 (p=0.026)..., Uvod: Zbog uloga koje poseduju, citosolne glutation S-transferaze (GST) mogu biti značajne kako u nastanku, tako i u progresiji karcinoma bubrežnog parenhima (KBP). U ovoj studiji je ispitivana uloga pojedinih GST genskih varijanti (GSTA1, GSTM1, GSTT1 i GSTP1) u nastanku KBP, nezavisno ili udruženo sa poznatim faktorima rizika za nastanak ovog karcinoma, kao i moguća povezanost fenotipskih karakteristika tumora sa odgovarajućim genotipom. Pored toga, ispitivan je i potencijalni prognostički značaj polimorfne ekspresije GST proteina kod bolesnika sa KBP. Posebna pažnja je posvećena najučestalijem podtipu KBP, svetloćelijskom karcinomu bubrežnog parenhima (sKBP). Materijal i Metode: Polimorfizam GSTa je određivan kod 305 pacijenata sa KBP i kod 326 kontrola, uparenih po godinama i polu. Pored fenotipskih karakteristika tumora, u grupi pacijenata sa KPB je praćeno i preživljavanje. Nivoi benzo(a)piren diolepoksid (BPDE)-DNK-konjugata, kao i nivoi 8-hidroksi-2-deoksiguanozina (8-OHdG) su određivani ELISA metodom. Ekspresija GSTM1 i GSTP1 proteina, kao i ekspresija regulatornih (ASK1, JNK1/2) i egzekutornih (Caspaza 3) apoptotskih molekula u uzorcima tumorskog tkiva je analizirana metodom imunoblota. Prisustvo GSTM1:ASK1, odnosno GSTP1:JNK1/2 protein:proteinske interakcije je ispitivano metodom imunoprecipitacije. Rezultati: Uočen je značajan efekat GSTM1-nultog i GSTP1-varijantnog genotipa na rizik za nastanak KBP (p<0.05). Pored toga, 22% svih pacijenata sa sKBP su bili nosioci kombinovanog GSTM1-nultog/GSTT1-aktivnog/GSTA1-genotipa smanjene aktivnosti/GSTP1-varijantnog genotipa i bili su u 9.32 - puta većem riziku za nastanak sKBP u poređenju sa nosiocima referentnog genotipa (GSTM1-aktivni/GSTT1-nulti/GSTA1-aktivni/GSTP1-referentni genotip) (p=0.041). Uočen je efekat GSTP1-varijantnog genotipa na rizik za nastanak KBP kod pušača, dok je kombinacija GSTM1-nulti/GSTP1-varijantni/GSTA1-genotip smanjene aktivnosti bila prisutna u 94% pušača sa sKBP, povećavajući rizik o

Циљ: Циљ ове студије је био да се разјасни улога генског полиморфизма GSTO1 (rs4925) и GSTO2 (rs156697) у индивидуалној подложности за настанак карцинома прелазног епитела мокраћне бешике, заједно са њиховим модификујућим ефектом на укупно преживљавање и/или хемотерапију код ових болесника. Такође је испитивана и експресија GSTO1-1 у туморском и околном морфолошки неизмењеном епителу болесника са карциномом прелазног епитела мокраћне бешике. Mатеријал и методе: Полиморфизам GSTO1 и GSTO2 је одређиван анализом производа рестрикционе дигестије ДНК фрагмената насталих реакцијом ланчаног умножавања (PCR-RFLP). Предиктивна вредност различитих GSTO генотипова је процењивана Коксовим регресионим хазардним моделима, док су Каплан-Мајерове криве коришћене за за приказивање вероватноће испитиваних догађаја, а лог-ранк тест за утврђивање разлика у вероватноћи преживљавања. GSTO1-1 експресија је одређивана методом Вестерн блота и реакцијом ланчаног умножавања у реалном времену (RT-PCR), док је за испитивање укупне S-глутатионилације изведена електрофореза под нередукујућим условима. Концентрација укупног и оксидованог глутатиона је одређена спектрофотометријски. Концентрација интерлеукина-8 (IL-8) у цитосолу и уринарни 8-хидрокси-2′-деоксигуанозин (8-OHdG) су одређени методом ензимског имуноесеја. Резултати: Носиоци варијантног GSTO2*G/G генотипа су били под повећаним ризиком за настанак карцинома прелазног епитела мокраћне бешике (OR=2,6, 95% CI=1,2-5,8, p=0,041), који је био још израженији када је овај генотип био удружен са пушењем (OR-odds ratio =4,3, 95%CI-confidence interval =1,6-11,2, p=0,003). Даље, добијени резултати указују да су носиоци хаплотипа GSTO1*C/GSTO2*G (GSTO1 референтни алел/GSTO2 варијантни алел) под највећим ризиком за настанак карцинома мокраћне бешике (OR=2,8, 95%CI=1,5-5,2, p=0,002)..., Purpose: The aim of the study was to clarify the role of GSTO1 (rs4925) and GSTO2 (rs156697) genetic polymorphisms in individual susceptibility to transitional cell carcinoma (TCC) of urinary bladder, together with their modifying effect on the overall survival and/or chemotherapy treatment in these patients. We also examined the GSTO1 expression pattern in tumor and non-tumor tissue of TCC patients. Methods: GSTO1 and GSTO2 genotyping was performed by polymerase chain reaction– restriction fragment length polymorphism (PCR-RFLP). The effect of GSTOs polymorphisms on predicting mortality was analyzed by the Cox proportional hazard models, while Kaplan-Meier curves with log-rank tests were used to assess differences in survival probability. GSTO1-1 expression was determined by Western blot and real time-PCR, while for the total S-glutathionylation electrophoresis under non-reducing conditions was performed. The total and oxidized glutathione content was measured by an enzymatic recycling method. Tumor cytosolic interleukin-8 (IL-8) and urine 8-hydroxy-2′- deoxyguanosine (8-OHdG) concentrations were estimated by enzyme-linked immunosorbent assay (ELISA). Results: Carriers of the variant GSTO2*G/G genotype were at increased risk of TCC development (OR-odds ratio =2.6, 95% CI-confidence interval =1.2-5.8, p=0.041), which was more pronounced, when associated with smoking (OR=4.3, 95%CI=1.6-11.2, p=0.003). Furthermore, these results indicate that GSTO1*C/GSTO2*G (GSTO1 wild type/GSTO2 variant) haplotype carriers were at the highest risk for the TCC development (OR=2.8, 95%CI=1.5-5.2, p=0.002). Although urinary 8-OHdG in TCC patients was significantly higher than in controls, the effect of combined GSTO1/GSTO2 genotype on the extent of oxidative damage was not found. GSTO1*A/A or GSTO2*G/G variant genotypes were independent predictors of the higher risk of death among TCC patients (HR-hazard ratio =2.9, p=0.022; HR=3.9, p=0.001; respectively) and significantly influenced t

Циљ: Циљ ове студије је био да се разјасни улога генског полиморфизма GSTO1 (rs4925) и GSTO2 (rs156697) у индивидуалној подложности за настанак карцинома прелазног епитела мокраћне бешике, заједно са њиховим модификујућим ефектом на укупно преживљавање и/или хемотерапију код ових болесника. Такође је испитивана и експресија GSTO1-1 у туморском и околном морфолошки неизмењеном епителу болесника са карциномом прелазног епитела мокраћне бешике. Mатеријал и методе: Полиморфизам GSTO1 и GSTO2 је одређиван анализом производа рестрикционе дигестије ДНК фрагмената насталих реакцијом ланчаног умножавања (PCR-RFLP). Предиктивна вредност различитих GSTO генотипова је процењивана Коксовим регресионим хазардним моделима, док су Каплан-Мајерове криве коришћене за за приказивање вероватноће испитиваних догађаја, а лог-ранк тест за утврђивање разлика у вероватноћи преживљавања. GSTO1-1 експресија је одређивана методом Вестерн блота и реакцијом ланчаног умножавања у реалном времену (RT-PCR), док је за испитивање укупне S-глутатионилације изведена електрофореза под нередукујућим условима. Концентрација укупног и оксидованог глутатиона је одређена спектрофотометријски. Концентрација интерлеукина-8 (IL-8) у цитосолу и уринарни 8-хидрокси-2′-деоксигуанозин (8-OHdG) су одређени методом ензимског имуноесеја. Резултати: Носиоци варијантног GSTO2*G/G генотипа су били под повећаним ризиком за настанак карцинома прелазног епитела мокраћне бешике (OR=2,6, 95% CI=1,2-5,8, p=0,041), који је био још израженији када је овај генотип био удружен са пушењем (OR-odds ratio =4,3, 95%CI-confidence interval =1,6-11,2, p=0,003). Даље, добијени резултати указују да су носиоци хаплотипа GSTO1*C/GSTO2*G (GSTO1 референтни алел/GSTO2 варијантни алел) под највећим ризиком за настанак карцинома мокраћне бешике (OR=2,8, 95%CI=1,5-5,2, p=0,002)..., Purpose: The aim of the study was to clarify the role of GSTO1 (rs4925) and GSTO2 (rs156697) genetic polymorphisms in individual susceptibility to transitional cell carcinoma (TCC) of urinary bladder, together with their modifying effect on the overall survival and/or chemotherapy treatment in these patients. We also examined the GSTO1 expression pattern in tumor and non-tumor tissue of TCC patients. Methods: GSTO1 and GSTO2 genotyping was performed by polymerase chain reaction– restriction fragment length polymorphism (PCR-RFLP). The effect of GSTOs polymorphisms on predicting mortality was analyzed by the Cox proportional hazard models, while Kaplan-Meier curves with log-rank tests were used to assess differences in survival probability. GSTO1-1 expression was determined by Western blot and real time-PCR, while for the total S-glutathionylation electrophoresis under non-reducing conditions was performed. The total and oxidized glutathione content was measured by an enzymatic recycling method. Tumor cytosolic interleukin-8 (IL-8) and urine 8-hydroxy-2′- deoxyguanosine (8-OHdG) concentrations were estimated by enzyme-linked immunosorbent assay (ELISA). Results: Carriers of the variant GSTO2*G/G genotype were at increased risk of TCC development (OR-odds ratio =2.6, 95% CI-confidence interval =1.2-5.8, p=0.041), which was more pronounced, when associated with smoking (OR=4.3, 95%CI=1.6-11.2, p=0.003). Furthermore, these results indicate that GSTO1*C/GSTO2*G (GSTO1 wild type/GSTO2 variant) haplotype carriers were at the highest risk for the TCC development (OR=2.8, 95%CI=1.5-5.2, p=0.002). Although urinary 8-OHdG in TCC patients was significantly higher than in controls, the effect of combined GSTO1/GSTO2 genotype on the extent of oxidative damage was not found. GSTO1*A/A or GSTO2*G/G variant genotypes were independent predictors of the higher risk of death among TCC patients (HR-hazard ratio =2.9, p=0.022; HR=3.9, p=0.001; respectively) and significantly influenced t

Introduction: UVC may induce oxidative stress mediated by ROS. Pimpinella alpina Molk (PaM) have been utilized by aging male as rejuvenation remedy. Objective: To elucidate the PaM effect on oxidative stress biomarker in rats. Methods: 25 of Sprague-Dawley male rats were divided into 5 groups, PaM with a dosage of 50, 100, and 150 mg were administered during 15 days to evaluate the biomarker of oxidative stress following UVC irradiation for 30 minutes beforehand. The oxidative stress biomarkers were measured by TBARS and FRAP assay respectively. Results: Post Hoc analysis demonstrated that MDA and 8-OHdG concentration in PaM group were significantly lower (p < 0.001), otherwise the concentration of TAC in PaM group were significantly higher, p < 0.001. Conclusion: Administration of PaM with 50, 100, and 150 mg dosage capable of improving oxidative stress biomarker in Sprague-Dawley male rats.

It has been well established that air pollution is associated with health impacts. This study investigated the relationship between exposure to air pollutants and potential biomarkers of health effects. The research project was conducted in 2 separate study locations and cohorts. Study 1: An Evaluation of Children’s Exposures to Respirable Particulates, Environmental PM2.5, PAHs and Metal Compounds in The South West of Western Australia. A cross sectional study to evaluate the exposures of children (n=18), and controls (n=15) to respirable particulates PAHs and metal compounds in the South West of Australia during 2011. Ambient particulate matter (PM2.5) samples were found to be significantly higher in Collie as compared to Dalyellup. However, personal PM2.5 concentrations between locations were not significantly different and both PAH and heavy metals were below the levels of detection. Urinary levels of 1-hydroxypyrene (1-OHpy) were below the level of detection. Copper, selenium and nickel were present in urine samples and these were not significantly different between locations, nor was there any correlation with residential areas within study locations. Urinary nickel concentrations were higher than expected for nonoccupational cohorts and although statistically insignificant, mean values of urinary nickel were highest for homes using gas as a fuel source. These data endorse current views that the reconstruction of PM2.5 exposures and related respiratory health effects based simply on the mass of airborne particulate matter alone is not sufficient in providing an insight to the respiratory health of susceptible subgroups such as children. The presence of certain urinary heavy metals suggests possible accumulation in participants via alternative routes of entry, probably a dietary source. Studies that rely purely on data accrued from ambient PM2.5 mass, and/or general health data might not detect or underestimate significant relationships between certain componen

type:Departmental Bulletin Paper, [Abstract] Orthostatic dysregulation (OD), an autonomic imbalance manifesting dizziness upon standing up and vertigo as principal symptoms, is also considered to be a partly psychosomatic disorder because the condition is likely to be influenced by mental stress. Nephrotic syndrome (NS) can cause such stress in relation to recurrences, exacerbations, and vulnerability to infections. In this study we retrospectively investigated symptoms of depression in 7-to 15-year-old children with OD and NS using the Birleson Depression Self-Rating Scale for Children (DSRS-C). Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) was measured in NS patients as a urinary oxidative stress marker. In children with OD, DSRS-C scores were significantly higher than in a general population of elementary and junior high school students (P＝0.00030 for elementary and junior high school students combined; P＝0.0057 for junior high school students). In children with NS, DSRS-C scores were significantly lower than in the other elementary and junior high school students (P＝0.019). Urinary 8-OHdG did not correlate significantly with the number of NS recurrences, duration of illness, or incidence of recurrence. No NS-related variable was found to be significantly correlated with oxidative stress. School absence often persists in OD patients even after somatic symptoms have been improved by drug therapy such as midodrine hydrochloride treatment, suggesting that symptoms of depression may prolong school absence in those with OD. Since the DSRS-C can rapidly quantify the severity of depression, early administration is recommended for children with OD.

Ovarian cancer is the leading cause of death from gynaecological cancers in the Western world. Ovarian cancer comprises of tumours with distinct behaviour and individually different responses to chemotherapy, even within the same histology. Unfortunately, there are no molecular markers in clinical use to either distinguish between patients with better and worse prognosis or to predict individual chemosensitivity. The comprehension of the molecular effects of chemotherapeutic drugs is a prerequisite for finding predictive molecular factors for chemoresponse and prognosis. Some proteins in molecular pathways contributing to DNA damage response, angiogenesis and oxidative stress have been implicated in ovarian cancer prognosis. In this study, the responses in p53 pathway and among angiogenesis-related factors to chemotherapeutic drugs were analysed in ovarian cancer cell lines. In OVCAR-3 cells with mutated p53, cisplatin but not docetaxel induced p14ARF, an important regulator of p53, at mRNA and protein level. Cisplatin also significantly increased the mRNA expression of angiogenesis-related factors TSP-1, BMP-4, ET-1 and PlGF-2 while an equivalent dose of docetaxel had only minor effects. In clinical ovarian carcinomas, the expression of BMP-4, TSP-1 and CD105 as well as the marker of oxidative stress derived DNA damage, 8-OHdG, and peroxiredoxin antioxidants were analysed by immunohistochemistry. High expression of BMP-4 and cytoplasmic peroxiredoxin IV were associated with better prognosis, while high 8-OHdG expression associated with shorter survival. Explant cultures of fresh ovarian tumour tissue were used for the evaluation of individual responses of p53 and Hdm2 after in vitro treatments of the explant cultures by carboplatin or docetaxel. Major differences between the individual tumours were found, especially in the responses of p53 to carboplatin. The results of this study suggest, that BMP-4, 8-OHdG and peroxiredoxin IV may serve as prognostic mar, Tiivistelmä Munasarjasyöpä on suurinta kuolleisuutta aiheuttava gynekologinen syöpä läntisessä maailmassa. Munasarjakasvaimet eroavat toisistaan niin käyttäytymiseltään kuin yksilölliseltä sytostaattihoitovasteeltaan, jopa sama histologisen tyypin sisällä. Kliinisessä käytössä ei valitettavasti ole sellaisia molekulaarisia merkkiaineita, jotka erottaisivat toisistaan paremman ja huonomman ennusteen kasvaimet tai ennustaisivat yksilöllistä solunsalpaajaherkkyyttä. Hoitovastetta ja potilaan prognoosia ennustavien merkkiaineiden löytämisen edellytys on kemoterapian molekyylitason vaikutusten ymmärtäminen. DNA vaurion tunnistamiseen, angiogeneesiin ja oksidatiiviseen stressiin liittyvien vaikutusreittien joillakin proteiineilla on ehdotettu olevan ennusteellista merkitystä munasarjasyövässä. Tässä väitöskirjatyössä analysoitiin munasarjasyöpäsoluja käyttäen p53 vaikutusreitin ja eräiden angiogeneesiin liittyvien tekijöiden vasteita sytostaateille. Mutatoitunutta p53 proteiinia kantavissa OVCAR-3 soluissa sisplatiini, toisin kuin dosetakseli, indusoi p53 proteiinin tärkeää säätelijää, p14ARF:a sekä mRNA- että proteiinitasolla. Sisplatiini lisäsi merkittävästi myös usean angiogeneesiin liittyvän tekijän (TSP-1, BMP-4, ET-1 ja PlGF-2) mRNA:ta. Dosetakselin vaikutukset vastaavalla annoksella olivat vähäiset. Kliinisissä munasarjasyövissä BMP-4, TSP-1 ja CD105 sekä oksidatiivisen stressin aiheuttaman DNA-vaurion merkkiaineen, 8-OHdG:n sekä peroksiredoksiiniantioksidanttien ilmeneminen analysoitiin immunohistokemiallisesti. BMP-4:n ja sytoplasmisen peroksiredoksiini IV:n vahva ilmentyminen liittyivät parempaan ennusteeseen, kun taas 8-OHdG:n vahva ilmentyminen liittyi huonompaan elinajan ennusteeseen. Tuoreen munasarjasyöpäkudoksen eksplanttiviljelyn avulla selvitettiin p53 ja Hdm2 proteiinien vasteita syöpäkudoksen karboplatiini- tai dosetakseli-käsittelyille. Selkeitä yksilökohtaisia eroja havaittiin erityisesti karboplatiinin aiheuttamissa p53 vasteissa niin eri potilaiden

Ovarian cancer is the leading cause of death from gynaecological cancers in the Western world. Ovarian cancer comprises of tumours with distinct behaviour and individually different responses to chemotherapy, even within the same histology. Unfortunately, there are no molecular markers in clinical use to either distinguish between patients with better and worse prognosis or to predict individual chemosensitivity. The comprehension of the molecular effects of chemotherapeutic drugs is a prerequisite for finding predictive molecular factors for chemoresponse and prognosis. Some proteins in molecular pathways contributing to DNA damage response, angiogenesis and oxidative stress have been implicated in ovarian cancer prognosis. In this study, the responses in p53 pathway and among angiogenesis-related factors to chemotherapeutic drugs were analysed in ovarian cancer cell lines. In OVCAR-3 cells with mutated p53, cisplatin but not docetaxel induced p14ARF, an important regulator of p53, at mRNA and protein level. Cisplatin also significantly increased the mRNA expression of angiogenesis-related factors TSP-1, BMP-4, ET-1 and PlGF-2 while an equivalent dose of docetaxel had only minor effects. In clinical ovarian carcinomas, the expression of BMP-4, TSP-1 and CD105 as well as the marker of oxidative stress derived DNA damage, 8-OHdG, and peroxiredoxin antioxidants were analysed by immunohistochemistry. High expression of BMP-4 and cytoplasmic peroxiredoxin IV were associated with better prognosis, while high 8-OHdG expression associated with shorter survival. Explant cultures of fresh ovarian tumour tissue were used for the evaluation of individual responses of p53 and Hdm2 after in vitro treatments of the explant cultures by carboplatin or docetaxel. Major differences between the individual tumours were found, especially in the responses of p53 to carboplatin. The results of this study suggest, that BMP-4, 8-OHdG and peroxiredoxin IV may serve as prognostic mar, Tiivistelmä Munasarjasyöpä on suurinta kuolleisuutta aiheuttava gynekologinen syöpä läntisessä maailmassa. Munasarjakasvaimet eroavat toisistaan niin käyttäytymiseltään kuin yksilölliseltä sytostaattihoitovasteeltaan, jopa sama histologisen tyypin sisällä. Kliinisessä käytössä ei valitettavasti ole sellaisia molekulaarisia merkkiaineita, jotka erottaisivat toisistaan paremman ja huonomman ennusteen kasvaimet tai ennustaisivat yksilöllistä solunsalpaajaherkkyyttä. Hoitovastetta ja potilaan prognoosia ennustavien merkkiaineiden löytämisen edellytys on kemoterapian molekyylitason vaikutusten ymmärtäminen. DNA vaurion tunnistamiseen, angiogeneesiin ja oksidatiiviseen stressiin liittyvien vaikutusreittien joillakin proteiineilla on ehdotettu olevan ennusteellista merkitystä munasarjasyövässä. Tässä väitöskirjatyössä analysoitiin munasarjasyöpäsoluja käyttäen p53 vaikutusreitin ja eräiden angiogeneesiin liittyvien tekijöiden vasteita sytostaateille. Mutatoitunutta p53 proteiinia kantavissa OVCAR-3 soluissa sisplatiini, toisin kuin dosetakseli, indusoi p53 proteiinin tärkeää säätelijää, p14ARF:a sekä mRNA- että proteiinitasolla. Sisplatiini lisäsi merkittävästi myös usean angiogeneesiin liittyvän tekijän (TSP-1, BMP-4, ET-1 ja PlGF-2) mRNA:ta. Dosetakselin vaikutukset vastaavalla annoksella olivat vähäiset. Kliinisissä munasarjasyövissä BMP-4, TSP-1 ja CD105 sekä oksidatiivisen stressin aiheuttaman DNA-vaurion merkkiaineen, 8-OHdG:n sekä peroksiredoksiiniantioksidanttien ilmeneminen analysoitiin immunohistokemiallisesti. BMP-4:n ja sytoplasmisen peroksiredoksiini IV:n vahva ilmentyminen liittyivät parempaan ennusteeseen, kun taas 8-OHdG:n vahva ilmentyminen liittyi huonompaan elinajan ennusteeseen. Tuoreen munasarjasyöpäkudoksen eksplanttiviljelyn avulla selvitettiin p53 ja Hdm2 proteiinien vasteita syöpäkudoksen karboplatiini- tai dosetakseli-käsittelyille. Selkeitä yksilökohtaisia eroja havaittiin erityisesti karboplatiinin aiheuttamissa p53 vasteissa niin eri potilaiden

Exposure to arsenic (As), cadmium (Cd) and lead (Pb) may generate oxidative stress, which can be assessed by 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in urine, a sensitive marker of oxidatively damaged DNA. We have evaluated oxidative stress induced by mixed chronic exposure to As, Cd, Pb, as well as the influence of As metabolism and nutritional status, i.e. ferritin (Ft), selenium (Se), zinc (Zn), manganese (Mn) and body weight. 8-oxodG was measured in urine from 212 women in early pregnancy from Matlab, rural Bangladesh, using LC-MS/MS. Cd and Pb were analyzed in urine and erythrocytes, while Se, Mn and Zn were analyzed in erythrocytes, all by ICPMS. As and As metabolites were analyzed in urine by HPLC-ICPMS. Ferritin was analyzed in plasma by radioimmunoassay. Median concentration of 8-oxodG was 8.3 nmol/L (adjusted for specific gravity), range 1.2-43, corresponding to a median of 4.7 mug/g creatinine, range 1.8-32. 8-oxodG was positively associated with urinary Cd (ss=0.32, p<0.001), urinary As (ss=0.0007, p=0.001), fraction of the monomethylated arsenic metabolite (MMA) in urine (ss=0.0026, p=0.004) and plasma Ft (ss = 0.20, p<0.001). A joint effect was seen for U-Cd and U-As, but whether this effect was additive or multiplicative was difficult to discern.

On 26 April 1986 an accident occurred in the Chernobyl nuclear power plant resulting in the release of large amount of radionuclides. Almost five percent of the total released caesium-137 was deposited in Sweden. The incidence of malignancies in the most affected counties in Sweden was investigated in three epidemiological studies. In the first study the incidence of malignancies in children and adolescents was studied for the period 1978-1992. The parishes and their inhabitants were classified according to the ground deposition of caesium-137 on an analogue map provided be the Swedish Radiological Protection Authority. A continuous increase of brain tumour incidence observed during the time of the study had no clear relationship to the Chernobyl fallout. A somewhat decreased relative risk of ALL was observed in areas with increased deposition. Other malignancies showed no changes in incidence over time or with regard to the exposure of caesium-137. In study II and III we enlarged the study base by including adults. We improved the methodology by defining a cohort of subjects who lived in the same parish from 31 December 1985 to 31 December 1987. The inhabitants from seven counties were included. Parishes were classified the same way as in study I. Due to the large number of individuals six exposure categories could be created; <3, 3–29, 30–39, 40–59, 60–79, and 80–120 kBq caesium-137/m2. The inhabitants of the 117 non-affected parishes (<3 kBq/m2) served as reference. During the 1988-1996 followup, 22,409 malignancies were recorded. The MH-IRR in the fully adjusted model was 1.00 (reference), 1.05, 1.03, 1.08, 1.10 and 1.21, respectively. ERR was 0.11 per 100 kBq/m2 (95% CL 0.03;0.20). A more advanced method was used in Study III by ignoring the exposure classification for parishes, and instead matching the dwelling coordinate to a digital map of deposition of casesium-137. In spite of a more valid exposure classification the risk estimates were similar in st

On 26 April 1986 an accident occurred in the Chernobyl nuclear power plant resulting in the release of large amount of radionuclides. Almost five percent of the total released caesium-137 was deposited in Sweden. The incidence of malignancies in the most affected counties in Sweden was investigated in three epidemiological studies. In the first study the incidence of malignancies in children and adolescents was studied for the period 1978-1992. The parishes and their inhabitants were classified according to the ground deposition of caesium-137 on an analogue map provided be the Swedish Radiological Protection Authority. A continuous increase of brain tumour incidence observed during the time of the study had no clear relationship to the Chernobyl fallout. A somewhat decreased relative risk of ALL was observed in areas with increased deposition. Other malignancies showed no changes in incidence over time or with regard to the exposure of caesium-137. In study II and III we enlarged the study base by including adults. We improved the methodology by defining a cohort of subjects who lived in the same parish from 31 December 1985 to 31 December 1987. The inhabitants from seven counties were included. Parishes were classified the same way as in study I. Due to the large number of individuals six exposure categories could be created; <3, 3–29, 30–39, 40–59, 60–79, and 80–120 kBq caesium-137/m2. The inhabitants of the 117 non-affected parishes (<3 kBq/m2) served as reference. During the 1988-1996 followup, 22,409 malignancies were recorded. The MH-IRR in the fully adjusted model was 1.00 (reference), 1.05, 1.03, 1.08, 1.10 and 1.21, respectively. ERR was 0.11 per 100 kBq/m2 (95% CL 0.03;0.20). A more advanced method was used in Study III by ignoring the exposure classification for parishes, and instead matching the dwelling coordinate to a digital map of deposition of casesium-137. In spite of a more valid exposure classification the risk estimates were similar in st

On 26 April 1986 an accident occurred in the Chernobyl nuclear power plant resulting in the release of large amount of radionuclides. Almost five percent of the total released caesium-137 was deposited in Sweden. The incidence of malignancies in the most affected counties in Sweden was investigated in three epidemiological studies. In the first study the incidence of malignancies in children and adolescents was studied for the period 1978-1992. The parishes and their inhabitants were classified according to the ground deposition of caesium-137 on an analogue map provided be the Swedish Radiological Protection Authority. A continuous increase of brain tumour incidence observed during the time of the study had no clear relationship to the Chernobyl fallout. A somewhat decreased relative risk of ALL was observed in areas with increased deposition. Other malignancies showed no changes in incidence over time or with regard to the exposure of caesium-137. In study II and III we enlarged the study base by including adults. We improved the methodology by defining a cohort of subjects who lived in the same parish from 31 December 1985 to 31 December 1987. The inhabitants from seven counties were included. Parishes were classified the same way as in study I. Due to the large number of individuals six exposure categories could be created; <3, 3–29, 30–39, 40–59, 60–79, and 80–120 kBq caesium-137/m2. The inhabitants of the 117 non-affected parishes (<3 kBq/m2) served as reference. During the 1988-1996 followup, 22,409 malignancies were recorded. The MH-IRR in the fully adjusted model was 1.00 (reference), 1.05, 1.03, 1.08, 1.10 and 1.21, respectively. ERR was 0.11 per 100 kBq/m2 (95% CL 0.03;0.20). A more advanced method was used in Study III by ignoring the exposure classification for parishes, and instead matching the dwelling coordinate to a digital map of deposition of casesium-137. In spite of a more valid exposure classification the risk estimates were similar in st

On 26 April 1986 an accident occurred in the Chernobyl nuclear power plant resulting in the release of large amount of radionuclides. Almost five percent of the total released caesium-137 was deposited in Sweden. The incidence of malignancies in the most affected counties in Sweden was investigated in three epidemiological studies. In the first study the incidence of malignancies in children and adolescents was studied for the period 1978-1992. The parishes and their inhabitants were classified according to the ground deposition of caesium-137 on an analogue map provided be the Swedish Radiological Protection Authority. A continuous increase of brain tumour incidence observed during the time of the study had no clear relationship to the Chernobyl fallout. A somewhat decreased relative risk of ALL was observed in areas with increased deposition. Other malignancies showed no changes in incidence over time or with regard to the exposure of caesium-137. In study II and III we enlarged the study base by including adults. We improved the methodology by defining a cohort of subjects who lived in the same parish from 31 December 1985 to 31 December 1987. The inhabitants from seven counties were included. Parishes were classified the same way as in study I. Due to the large number of individuals six exposure categories could be created; <3, 3–29, 30–39, 40–59, 60–79, and 80–120 kBq caesium-137/m2. The inhabitants of the 117 non-affected parishes (<3 kBq/m2) served as reference. During the 1988-1996 followup, 22,409 malignancies were recorded. The MH-IRR in the fully adjusted model was 1.00 (reference), 1.05, 1.03, 1.08, 1.10 and 1.21, respectively. ERR was 0.11 per 100 kBq/m2 (95% CL 0.03;0.20). A more advanced method was used in Study III by ignoring the exposure classification for parishes, and instead matching the dwelling coordinate to a digital map of deposition of casesium-137. In spite of a more valid exposure classification the risk estimates were similar in st

On 26 April 1986 an accident occurred in the Chernobyl nuclear power plant resulting in the release of large amount of radionuclides. Almost five percent of the total released caesium-137 was deposited in Sweden. The incidence of malignancies in the most affected counties in Sweden was investigated in three epidemiological studies. In the first study the incidence of malignancies in children and adolescents was studied for the period 1978-1992. The parishes and their inhabitants were classified according to the ground deposition of caesium-137 on an analogue map provided be the Swedish Radiological Protection Authority. A continuous increase of brain tumour incidence observed during the time of the study had no clear relationship to the Chernobyl fallout. A somewhat decreased relative risk of ALL was observed in areas with increased deposition. Other malignancies showed no changes in incidence over time or with regard to the exposure of caesium-137. In study II and III we enlarged the study base by including adults. We improved the methodology by defining a cohort of subjects who lived in the same parish from 31 December 1985 to 31 December 1987. The inhabitants from seven counties were included. Parishes were classified the same way as in study I. Due to the large number of individuals six exposure categories could be created; <3, 3–29, 30–39, 40–59, 60–79, and 80–120 kBq caesium-137/m2. The inhabitants of the 117 non-affected parishes (<3 kBq/m2) served as reference. During the 1988-1996 followup, 22,409 malignancies were recorded. The MH-IRR in the fully adjusted model was 1.00 (reference), 1.05, 1.03, 1.08, 1.10 and 1.21, respectively. ERR was 0.11 per 100 kBq/m2 (95% CL 0.03;0.20). A more advanced method was used in Study III by ignoring the exposure classification for parishes, and instead matching the dwelling coordinate to a digital map of deposition of casesium-137. In spite of a more valid exposure classification the risk estimates were similar in st

Repeated injections of D-galactosamine hydrochloride (GalN) increase the survival rate of Long-Evans Cinnamon (LEC) rats, an animal model of Wilson’s disease. The aim of the present study was to investigate the mechanism of GalN for prevention of spontaneous lethal hepatic injury in LEC rats. MaleLEC rats were given a single subcutaneous injection of 300mg/kg of GalN or vehicle (0.9%NaCl) at 14weeks, and killed at 28 weeks of age. Next, 6-week-old male LEC rats were given weekly subcutaneous injections of 300 mg/kg of GalN or vehicle for 3 or 12 weeks, and their hepatic 8-hydroxydeoxy-2’-guanosine (8-OHdG), glutathione peroxidase (GPX), and catalase activities were measured. None of GalN-treated rats died of hepatic injury (0/12), whereas the mortality rate of control rats given 0.9% NaCl was 17% (2/12). GalN administration for 12 weeks decreased the hepatic 8-OHdG, and GalN administration for either 3 or 12weeks increased the glutathione peroxidase activity. GalN administration increased the serum level of alanine aminotransferase, and accelerated megalocytic degeneration of the hepatocytes. GalN treatment is effective in preventing lethal hepatitis in LEC rats and decrease of oxidative DNA damage by GalN plays an important role in increase of the survival rate.

Joint Research on Environmental Science and Technology for the Earth

Joint Research on Environmental Science and Technology for the Earth