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- Grankvist, Kjell, 1954-
(author)
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Mechanisms of alloxan diabetogenicity
- 1981
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Doctoral thesis (other academic/artistic)abstract
- Suspensions of pancreatic islet cells from ob/ob-mice were incubated with Trypan Blue. Microscope photometry showed that apparently viable cells excluded the dye completely, whereas the nuclei of non-viable cells accumulated Trypan Blue by a saturable process. Alloxan rapidly increased the permeability of the plasma membrane in mouse 3-cells; the exclusion of Trypan Blue is a valid and useful measure of islet cell viability following alloxan exposure.The diabetogenic action of alloxan may be mediated by hydroxyl radicals. In several biological systems hydroxyl radicals are formed by an iron-catalyzed reaction between superoxide anion radicals and hydrogen peroxide. To test whether this applies to alloxan diabetogenicity, the effects of superoxide dismutase, catalase, scavengers of hydroxyl radicals, and metal ion chelators were tested (a) in a cell-free radical-generating system and (b) on islets and islet-cells exposed to alloxan In vitro. The effect of longtime-circulating superoxide dismutase injected prior to alloxan was tested on mice in vivo.Luminol chemiluminescence was used to monitor alloxan-dependent radical production. Accumulation of 8^Rb+ and exclusion of Trypan Blue were used as cell viability criteria in isolated mouse islets and islet-cells. Blood glucose was determined to monitor the development of diabetes in living animals.Superoxide dismutase, catalase, scavengers of hydroxyl radicals, and metal ion chelators inhibited the alloxan-dependent chemiluminescence and decreased the toxic effects on Rb+ accumulation or Trypan Blue exclusion in islets and islet-cells. Superoxide dismutase, linked to polyethylene glycol and injected 12 hours before alloxan, largely prevented the development of alloxan diabetes.Alloxan toxicity _in vitro and in vivo seems to depend on the formation of superoxide radicals and hydrogen peroxide which in turn form the noxious hydroxyl radical via an iron-catalyzed Haber-Weiss reaction.As free radicals and hydrogen peroxide can be formed by other chemicals and during inflammation, and inflammation may accompany the outbreak of human diabetes, studies on the beneficiary effects of superoxide dismutase and other scavengers of free radicals in other forms of diabetes seem warranted.
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| 2. |
- Schock, Helena, 1984-, et al.
(author)
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Anti-Mullerian hormone and risk of invasive serous ovarian cancer
- 2014
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In: Cancer Causes and Control. - : Springer. - 0957-5243 .- 1573-7225. ; 25:5, s. 583-589
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Journal article (peer-reviewed)abstract
- Epithelial ovarian cancers either arise directly from Mullerian-type epithelium or acquire Mullerian characteristics in the course of neoplastic transformation. The anti-Mullerian hormone (AMH) causes regression of Mullerian structures during fetal development in males and has been shown to inhibit the growth of epithelial ovarian cancer. Therefore, we hypothesized that pre-diagnostic serum concentrations of AMH are inversely associated with risk of invasive serous ovarian cancer. A case-control study (107 cases, 208 controls) was nested within the population-based Finnish Maternity Cohort (1986-2007). The sample donated during the first trimester of the last pregnancy preceding cancer diagnosis of the case subjects was selected for the study. For each case, two controls, matched on age and date at sampling, as well as parity at sampling and at cancer diagnosis were selected. AMH was measured by a second-generation AMH ELISA. Conditional logistic regression was used to compute odds ratios (OR) and 95 % confidence intervals (CI) for invasive serous ovarian cancer associated with AMH concentrations. Overall AMH concentrations were not associated with risk of invasive serous ovarian cancer (OR 0.93; 95 % CI 0.49-1.77 for top vs. bottom tertile, P (trend) = 0.83). In women older than the median age at sampling (32.7 years), a doubling of AMH was associated with decreased risk (OR 0.69; 95 % CI 0.49-0.96), whereas an increased risk (OR 1.64; 95 % CI 1.06-2.54) was observed in younger women, P (homogeneity) = 0.002. In this first prospective investigation, risk of invasive serous ovarian cancer was not associated with pre-diagnostic AMH concentrations overall; however, the association may depend on age at AMH measurement.
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| 3. |
- Schock, Helena, 1984-, et al.
(author)
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Early pregnancy IGF-I and placental GH and risk of epithelial ovarian cancer : A nested case-control study
- 2015
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In: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 137:2, s. 439-447
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Journal article (peer-reviewed)abstract
- Insulin-like growth factor-I (IGF-I) signaling may promote ovarian tumor development by exerting mitotic, antiapoptotic and proangiogenic effects. During pregnancy, maternal production of IGF-I is regulated by placental growth hormone (GH). Parity is an established protective factor for ovarian cancer, however, no prior study has evaluated placental GH and IGF-I in pregnancy and epithelial ovarian cancer (EOC). Prior prospective studies on the association between IGF-I and EOC in nonpregnant populations were inconclusive and did not address associations in subtypes of EOC. Among members of the Finnish Maternity Cohort and the Northern Sweden Maternity Cohort, we identified 1,045 EOC cases, diagnosed after recruitment (1975-2008) and before March 2011 and 2,658 individually matched controls. Placental GH and IGF-I were measured in serum from the last pregnancy before EOC diagnosis or selection as control. We used conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for tertiles and a doubling of hormone concentrations. Higher IGF-I was associated with a nonsignificant decrease in risk for invasive [ORT3 vs. T1 : 0.79 (0.62-1.02); ptrend = 0.07] and endometrioid tumors [ORT3 vs. T1 : 0.55 (0.28-1.07); ptrend = 0.07]. The protective association between higher IGF-I levels and risk of invasive EOC was stronger in analyses limited to women aged <55 years at diagnosis [ORT3 vs. T1 : 0.74 (0.57-0.96); ptrend = 0.03]. Our study provides the first data on placental GH and IGF-I in pregnancy and EOC risk overall and by subtype. Our data suggest higher IGF-I levels in pregnancy may be associated with lower risk of invasive and endometrioid EOC.
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| 4. |
- Schock, Helena, 1984-, et al.
(author)
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Early pregnancy sex steroids and maternal risk of epithelial ovarian cancer
- 2014
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In: Endocrine-Related Cancer. - : Society for Endocrinology. - 1351-0088 .- 1479-6821. ; 21:6, s. 831-844
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Journal article (peer-reviewed)abstract
- Well-established associations between reproductive characteristics and epithelial ovarian cancer (EOC) support an involvement of sex steroid hormones in the etiology of EOC. Limited previous studies have evaluated circulating androgens and the risk of EOC, and estrogens and progesterone have been investigated in only one of the previous studies. Furthermore, there is little data on potential heterogeneity in the association between circulating hormones and EOC by histological subgroup. Therefore, we conducted a nested case-control study within the Finnish Maternity Cohort and the Northern Sweden Maternity Cohort to investigate the associations between circulating pre-diagnostic sex steroid concentrations and the histological subtypes of EOC. We identified 1052 EOC cases among cohort members diagnosed after recruitment (1975-2008) and before March 2011. Up to three controls were individually matched to each case (n=2694). Testosterone, androstenedione, 17-hydroxyprogesterone (17-OHP), progesterone, estradiol (E-2), and sex hormone-binding globulin levels were measured in serum samples collected during the last pregnancy before EOC diagnosis. We used conditional logistic regression to estimate odds ratios (ORs) and 95% CIs. Associations between hormones and EOC differed with respect to tumor histology and invasiveness. Sex steroid concentrations were not associated with invasive serous tumors; however, doubling of testosterone and 17-OHP concentration was associated with approximately 40% increased risk of borderline serous tumors. A doubling of androgen concentrations was associated with a 50% increased risk of mucinous tumors. The risk of endometrioid tumors increased with higher E-2 concentrations (OR: 1.89 (1.20-2.98)). This large prospective study in pregnant women supports a role of sex steroid hormones in the etiology of EOC arising in the ovaries.
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| 5. |
- Schock, Helena, 1984-, et al.
(author)
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Longitudinal Assessment of Pregnancy Hormones
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Other publication (other academic/artistic)abstract
- Evidence suggests that the hormonal milieu of pregnancy is an important determinant of subsequent cancer and other chronic diseases in both the mother and the offspring. How well a single blood specimen collected during a pregnancy characterizes exposure to these hormones throughout gestation, and also in subsequent pregnancies, is not well understood. We used serial serum samples from 71 pregnant women (25 primiparous, 25 biparous, and 21 with 2 consecutive pregnancies) with natural, complication-free pregnancies and a healthy offspring at term who participated in a population-based screening trial for congenital infections in Finland between January 1st, 1988 and June 30, 1989 and provided a blood sample in each trimester. Hormone levels were more strongly correlated between consecutive trimesters of a pregnancy than between the 1st and 3rd trimester (e.g. estradiol, 1st vs. 2nd and 2nd vs. 3rd trimester r=0.51 and r=0.60, p<0.01; 1st vs. 3rd trimester r=0.32, p<0.05). Concentrations of sRANKL remained stable throughout gestation, whereas estradiol, estrone, progesterone, testosterone, prolactin, and osteoprotegerin increased throughout pregnancy. First trimester hormone concentrations explained less of the variation in the third trimester on their own than second trimester hormone levels (e.g. estradiol R²T1=16% and R²T2=42%). Addition of maternal (e.g., smoking) and/or child characteristics (e.g., sex) improved the accuracy of the 3rd trimester estimates for some of the hormones. In conclusion, one hormone measurement in early pregnancy, in conjunction with maternal and fetal characteristics, permits estimation of 3rd trimester hormone concentrations.
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