There is growing evidence that some chemicals present in the environment have the capacity to inhibit, or potentially induce, aromatase activity. This study compared aromatase activities and ...isoform-specific mRNA expression in brain and ovary tissue from non-exposed fathead minnows representing three different ages and stages of reproductive activity, and from fathead minnows exposed to the aromatase inhibitor fadrozole for 7
d. The goal was to determine whether measures of a single aromatase endpoint in either brain or ovary tissue would be sufficient to understand and predict system-wide effects of endocrine disrupting chemicals on aromatase activity and transcript levels. Aromatase activity in the ovary, but not brain, varied significantly with age/reproductive category, with adults held in non-reproductive conditions showing significantly lower activity than juveniles and reproductively-active adults. Significant correlations between isoform-specific transcript levels and aromatase activity were observed for ovary tissue, but those relationships were not robust for all age/reproductive categories, nor were they sustained in fadrozole-treated fish. In vitro, fadrozole inhibited the aromatase activity of brain and ovary post-mitochondrial supernatants with similar potency (IC50s
=
8.82
±
1.58 and 6.93
±
0.80
μM for brain and ovary, respectively), despite large differences in the magnitude of activity. In vivo, fadrozole altered aromatase activity and isoform-specific transcript levels in both brain and ovary tissue, but concentration-response relationships were different for each tissue. Aromatase activity and P450aromB mRNA expression in brain showed a dose-dependent decrease at concentrations greater than 5.55
μg/L. In contrast, ovary activity showed an inverted U-shaped concentration-response consistent with the interplay between increased P450aromA transcript levels in ovary and competitive inhibition of the aromatase enzyme. As a whole, results of this study did not reveal any robust correlations between brain and ovary aromatase activity and/or isoform-specific mRNA expression. However, they were consistent with the current body of evidence related to teleost aromatase regulation, suggesting that increased understanding of the biology of aromatase may facilitate system-wide understanding of effects on aromatase based on relatively few measured endpoints.
Peritoneal metastasis from biliary carcinoma (PMC) is associated with poor prognosis when treated with chemotherapy.
To evaluate the impact on survival of cytoreductive surgery (CRS) and hyperthermic ...intraperitoneal chemotherapy (HIPEC), and compare with conventional palliative chemotherapy for patients with PMC.
A prospective multicenter international database was retrospectively searched to identify all patients with PMC treated with a potentially curative CRS/HIPEC (CRS/HIPEC group). The overall survival (OS) was compared to patients with PMC treated with palliative chemotherapy (systemic chemotherapy group). Survival was analyzed using Kaplan-Meier method and compared with Log-Rank test.
Between 1995 and 2015, 34 patients were included in the surgical group, and compared to 21 in the systemic chemotherapy group. In the surgical group, median peritoneal cancer index was 9 (range 3–26), macroscopically complete resection was obtained for 25 patients (73%). There was more gallbladder localization in the surgical group compared to the chemotherapy group (35% vs. 18%, p = 0.001). Median OS was 21.4 and 9.3 months for surgical and chemotherapy group, respectively (p=0.007). Three-year overall survival was 30% and 10% for surgical and chemotherapy group, respectively.
Treatment with CRS and HIPEC for biliary carcinoma with peritoneal metastasis is feasible and may provide survival benefit when compared to palliative chemotherapy.
African clawed frogs (
Xenopus laevis) were exposed to one of eight nominal waterborne concentrations including 0, 0.1, 1.0, 10, or 25
μg/L atrazine, 0.005% ethanol (EtOH), or 0.1
mg/L estradiol (E2) ...or dihydrotestosterone (DHT) containing 0.005% EtOH. Frogs were exposed from 72
h posthatch until 2–3 months postmetamorphosis via a 3-day static renewal exposure regimen. Atrazine at concentrations between 0.1 and 25
μg/L did not significantly affect mortality, growth, gonad development, laryngeal muscle size, or aromatase activity in juvenile
X. laevis. Male frogs exposed to 1.0
μg/L atrazine had lower E2 levels compared to controls, but this response was not consistent among other concentrations of atrazine. Male and female frogs exposed to DHT had larger laryngeal dilator muscle areas compared to controls. E2-exposed female frogs had decreased gonadal aromatase activity, and E2-exposed male frogs had statistically greater plasma concentrations of E2 compared to controls.
The extent of contamination of the Black Sea by selected organochlorine compounds has been assessed through the analysis of surficial sediments taken from throughout the region. Concentrations of ...HCHs at sites influenced by the Danube delta are among the highest recorded on a global basis (up to
40
ng
g
−1
dry wt). The ratio between the α- and γ-isomers was relatively low indicating contamination through the use of lindane. Concentrations of DDTs (
0.06–72
ng
g
−1
dry wt) and PCBs (
0.06–72
ng
g
−1
dry wt) were not especially high in comparison to levels reported from throughout the world. The DDE/DDT ratio was, however, low indicating fresh inputs and hence current usage of DDT within the Black Sea region.
The prognosis of decompensated cirrhosis resulting from chronic hepatitis B is poor, and the benefits of treatment with interferon are outweighed by serious side effects and by the risk of fatal ...exacerbation of disease activity. Lamivudine rapidly reduces hepatitis B virus (HBV)‐DNA in serum to undetectable levels. We have treated 35 patients with chronic hepatitis B and decompensated cirrhosis with lamivudine 100 mg or 150 mg orally once daily. Pretreatment, all were positive for HBV‐DNA in serum. Ten had Child‐Pugh class B and 25 had Child‐Pugh class C liver disease. Seven patients underwent liver transplantation within 6 months of treatment initiation, 5 patients died within 6 months, and 23 patients were treated for at least 6 months (mean = 19 months). In a majority of these 23 cases, there was a slow but marked improvement in liver function, which was most apparent after 9 months of treatment, with a decrease in serum bilirubin from 67 ± 13 to 30 ± 4 μmol/L (P< .05, baseline vs. 9 months), an increase in serum albumin from 27 ± 1 to 34 ± 1g/L (P< .05), and a decrease in Child‐Pugh score from 10.3 ± 0.4 to 7.5 ± 0.5(P< .05). Three patients developed resistance to lamivudine because of a mutation in the YMDD motif, but liver function did not deteriorate. We conclude that inhibition of viral replication with lamivudine results in a significant improvement of liver function in patients with decompensated HBV cirrhosis, but the long‐term benefits remain uncertain.
•Estrone exposure resulted in up-regulation of three genes in fish embryos.•Whole-mount in situ hybridization was applied to fathead minnow embryos and larvae.•Staining of estrogen-inducible genes ...was observed in the liver of fish larvae.•Whole-mount in situ hybridization is useful for early-life toxicological studies.
Early-life stage fish can be more sensitive to toxicants than adults, so delineating mechanisms of perturbation of biological pathways by chemicals during this life stage is crucial. Whole-mount in situ hybridization (WISH) paired with quantitative real-time polymerase chain reaction (QPCR) assays can enhance pathway-based analyses through determination of specific tissues where changes in gene expression are occurring. While WISH has frequently been used in zebrafish (Danio rerio), this technology has not previously been applied to fathead minnows (Pimephales promelas), another well-established small fish model species. The objective of the present study was to adapt WISH to fathead minnow embryos and larvae, and use the approach to evaluate the effects of estrone, an environmentally-relevant estrogen receptor (ER) agonist. Embryos were exposed via the water to 0, 18 or 1800ngestrone/L (0, 0.067 and 6.7nM) for 3 or 6 days in a solvent-free, flow-through test system. Relative transcript abundance of three estrogen-responsive genes, estrogen receptor-α (esr1), cytochrome P450-aromatase B (cyp19b), and vitellogenin (vtg) was examined in pooled whole embryos using QPCR, and the spatial distribution of up-regulated gene transcripts was examined in individual fish using WISH. After 3 days of exposure to 1800ngestrone/L, esr1 and cyp19b were significantly up-regulated, while vtg mRNA expression was not affected. After 6 days of exposure to 1800ngestrone/L, transcripts for all three genes were significantly up-regulated. Corresponding WISH assays revealed spatial distribution of esr1 and vtg in the liver region, an observation consistent with activation of the hepatic ER. This study clearly demonstrates the potential utility of WISH, in conjunction with QPCR, to examine the mechanistic basis of the effects of toxicants on early-life stage fathead minnows.
Purpose
Peritoneal carcinomatosis from appendiceal goblet cell carcinoma (A-GCC) is a rare and aggressive form of appendiceal tumor. Cytoreductive surgery (CRS) and hyperthermic intra peritoneal ...chemotherapy (HIPEC) was reported as an interesting alternative regarding survival compared to surgery without HIPEC and/or systemic chemotherapy. Our aim was to evaluate the impact of CRS and HIPEC for patients presenting A-GCC through an international registry.
Methods
A prospective multicenter international database was retrospectively searched to identify all patients with A-GCC tumor and peritoneal metastases who underwent CRS and HIPEC through the Peritoneal Surface Oncology Group International (PSOGI). The post-operative complications, long-term results, and principal prognostic factors were analyzed.
Results
The analysis included 83 patients. After a median follow-up of 47 months, the median overall survival (OS) was 34.6 months. The 3- and 5-year OS was 48.5% and 35.7%, respectively. Patients who underwent complete macroscopic CRS had a significantly better survival than those treated with incomplete CRS. The 5-year OS was 44% and 0% for patients who underwent complete, and incomplete CRS, respectively (HR 9.65,
p
< 0.001). Lymph node involvement and preoperative chemotherapy were also predictive of a worse prognosis. There were 3 postoperative deaths, and 30% of the patients had major complications.
Conclusion
CRS and HIPEC may increase long-term survival in selected patients with peritoneal metastases of A-GCC origin, especially when complete CRS is achieved. Ideally, randomized control trials or more retrospective data are needed to confirm CRS and HIPEC as the gold standard in this pathology.
High‐resolution mass spectrometry is advantageous for monitoring physiological impacts and contaminant biotransformation products in fish exposed to complex wastewater effluent. We evaluated this ...technique using skin mucus from male and female fathead minnows (Pimephales promelas) exposed to control water or treated wastewater effluent at 5, 20, and 100% levels for 21 d, using an on‐site, flow‐through system providing real‐time exposure. Both sex‐specific and non‐sex–specific responses were observed in the mucus metabolome, the latter suggesting the induction of general compensatory pathways for xenobiotic exposures. Altogether, 85 statistically significant treatment‐dependent metabolite changes were observed out of the 310 total endogenous metabolites that were detected (156 of the 310 were annotated). Partial least squares‐regression models revealed strong covariances between the mucus metabolomes and up‐regulated hepatic messenger ribonucleic acid (mRNA) transcripts reported previously for these same fish. These regression models suggest that mucus metabolomic changes reflected, in part, processes by which the fish biotransformed xenobiotics in the effluent. In keeping with this observation, we detected a phase II transformation product of bisphenol A in the skin mucus of male fish. Collectively, these findings demonstrate the utility of mucus as a minimally invasive matrix for simultaneously assessing exposures and effects of environmentally relevant mixtures of contaminants. Environ Toxicol Chem 2018;37:788–796. Published 2017 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.
Xenobiotic transformation pathways may be impacted by the exposure of fathead minnows to treated wastewater effluent, as reflected in fish skin mucus measured with high resolution mass spectrometry‐based metabolomics and identified in part with the mummichog program. Subsequent data mining resulted in the discovery of a phase II transformation product of bisphenol A in the skin mucus of male fish.
Purpose
Ovarian cancer is the most common deadly cancer of gynecologic origin. Patients often are diagnosed at advanced stage with peritoneal metastasis. There are many rare histologies of ovarian ...cancer; some have outcomes worse than serous ovarian cancer. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) can be considered for patients with recurrence. This study was designed to assess the impact of CRS and HIPEC on survival of patient with peritoneal metastasis from rare ovarian malignancy.
Methods
A prospective, multicentric, international database was retrospectively searched to identify all patients with rare ovarian tumor (mucinous, clear cells, endometrioid, small cell hypercalcemic, and other) and peritoneal metastasis who underwent CRS and HIPEC through the Peritoneal Surface Oncology Group International (PSOGI) and BIG-RENAPE working group. The postoperative complications, long-term results, and principal prognostic factors were analyzed.
Results
The analysis included 210 patients with a median follow-up of 43.5 months. Median overall survival (OS) was 69.3 months, and the 5-year OS was 57.7%. For mucinous tumors, median OS and DFS were not reached at 5 years. For granulosa tumors, median overall survival was not reached at 5 years, and median DFS was 34.6 months. Teratoma or germinal tumor showed median overall survival and DFS that were not reached at 5 years. Differences in OS were not statistically significant between histologies (
p
= 0.383), whereas differences in DFS were (
p
< 0.001).
Conclusions
CRS and HIPEC may increases long-term survival in selected patients with peritoneal metastasis from rare ovarian tumors especially in mucinous, granulosa, or teratoma histological subtypes.
Sediment and water samples collected from 32 locations in Ulsan Bay and adjacent inland areas were analyzed for polycyclic aromatic hydrocabons (PAHs), nonylphenol (NP), octylphenol (OP), bisphenol A ...(BPA), organochlorine (OC) pesticides (HCB, HCHs, CHLs, and DDTs), and polychlorinated biphenyls (PCBs) to characterize their spatial distribution and contamination status. PAHs were detected in nearly all sediment and water extracts from Ulsan Bay and its inland locations. The sedimentary PAH concentrations ranged from 17 to 3,100 ng/g on a dry weight basis (DW), which were predominated by two- and three-ring aromatic hydrocarbons in river and/or stream, and four- to six-ring compounds in Ulsan Bay sediment. Concentrations of PAHs in pore water samples were generally two or three orders magnitude less than those of corresponding sediment samples. Maximum concentrations of NP, OP, and BPA in sediments were 1,040, 120, and 54 ng/g DW, respectively. Concentrations of OP and BPA were, on average, 5- to 13-fold less than those of NP. PCB concentrations in sediment ranged from 1.4 to 77 ng/g DW, which were predominated by lower chlorinated congeners such as di- through pentachlorinated biphenyls. Among different OC pesticides analyzed, concentrations of DDTs were the greatest, ranging from 0.02 to 41.9 ng/g DW. NP concentrations were greater at inner locations proximal to municipal wastewater discharges into rivers and/or streams, whereas the concentrations of PCBs and PAHs were great near the sites of high industrial activities. Sediment-pore water partitioning coefficients correlated with those of reported Koc or Kow values for selected PAHs in Ulsan Bay, but these varied by an order of magnitude for stream and/or river sediments.
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