AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 5 2010
Pawel Mach
Citation Mach P, Blecharz P, Basta P, Marianowski P, Skret-Magierlo J, Kojs Z, Grabiec M, Wicherek L. Differences in the soluble HLA-G blood serum concentration levels in patients with ovarian cancer and ovarian and deep endometriosis. Am J Reprod Immunol 2010 Problem, The relationship between endometriosis and cancer has been widely discussed in the literature but is still not well clarified. Perhaps significantly, soluble human leukocyte antigen-G (sHLA-G) has been identified in the microenvironment of both ovarian cancer and endometrioma. The aim of this study has been to evaluate the sHLA-G levels in the blood sera of women with deep endometriosis and ovarian endometrioma over the course of the menstrual cycle and to compare to the levels of sHLA-G in the blood sera of women with ovarian cancer. Method of study, In our study, we examined the blood sera obtained from 123 patients operated on because of ovarian cancer (65 cases), ovarian endometrioma (30 cases), and deep endometriosis (28 cases). We decided to compare the levels of sHLA-G in patients with endometriosis to those found in patients with ovarian cancer with respect to the menstrual cycle phases. The sHLA-G concentration level was measured by enzyme-linked immunosorbent assay kit. Results, The level of sHLA-G concentration in the blood serum of patients with deep endometriosis fluctuates over the course of the menstrual cycle, and during the proliferative and secretory phases, it remains at a high level comparable to that found in patients with ovarian cancer. By contrast, the level of sHLA-G concentration in the blood serum of patients with ovarian endometrioma fluctuates minimally over the course of the different menstrual cycle phases and, as in patients with ovarian cancer, it remains at high level during the proliferative phase. Conclusion, sHLA-G blood serum concentration levels would seem to provide important information regarding the degree of immune system regulation disturbance in both ectopic endometrial cells and the cancer cell suppressive microenvironment. [source]

Association of CASP8 D302H polymorphism with reduced risk of aggressive prostate carcinoma

THE PROSTATE, Issue 6 2010
Jessica Lubahn
Abstract BACKGROUND Because of the dramatically different clinical course of aggressive and indolent prostate carcinoma (PCa), markers that distinguish between these phenotypes are of critical importance. Apoptosis is an important protective mechanism for unrestrained cellular growth and metastasis. Therefore, dysfunction in this pathway is a key step in cancer progression. As such, genetic variants in apoptosis genes are potential markers of aggressive PCa. Recent work in breast carcinoma has implicated the histidine variant of CASP8 D302H (rs1045485) as a protective risk allele. METHODS We tested the hypothesis that the H variant was protective for aggressive PCa in a pooled analysis of 796 aggressive cases and 2,060 controls. RESULTS The H allele was associated with a reduced risk of aggressive PCa (ORper allele,= 0.67, 95% CI: 0.54,0.83, Ptrend,=,0.0003). The results were similar for European-Americans (ORper allele,=,0.68; 95% CI: 0.54,0.86) and African-Americans (ORper allele,=,0.61; 95% CI: 0.34,1.10). We further determined from the full series of 1,160 cases and 1,166 controls in the Prostate, Lung, Colorectal, Ovarian (PLCO) population that the protective effect of the H allele tended to be limited to high-grade and advanced PCa (all cases ORper allele,=,0.94; 95% CI: 0.79,1.11; localized, low-grade disease ORper allele,=,0.98; 95% CI: 0.79,1.23; and aggressive disease ORper allele,=,0.73; 95% CI: 0.50,1.07). CONCLUSION These results suggest that histidine variant of CASP8 D302H is a protective allele for aggressive PCa with potential utility for identification of patients at differential risk for this clinically significant phenotype. Prostate 70: 646,653, 2010. © 2009 Wiley-Liss, Inc. [source]

Fertility preservation in young women with epithelial ovarian cancer

CANCER, Issue 18 2009
Jason D. Wright MD
Abstract BACKGROUND: Surgical management of ovarian cancer consists of hysterectomy with bilateral oophorectomy. In young women, this results in the loss of reproductive function and estrogen deprivation. In the current study, the authors examined the safety of fertility-conserving surgery in premenopausal women with epithelial ovarian cancers. METHODS: Women aged ,50 years with stage IA or IC epithelial ovarian cancer who were registered in the Surveillance, Epidemiology, and End Results database were examined. Patients who underwent bilateral oophorectomy were compared with those who underwent ovarian conservation. A second analysis examined uterine conservation versus hysterectomy. Multivariate Poisson regression models were developed to describe predictors of fertility preservation. Survival was examined using Cox proportional hazards models and the Kaplan-Meier method. RESULTS: In total, 1186 women, including 754 women (64%) who underwent bilateral oophorectomy and 432 women (36%) who underwent ovarian preservation, were identified. Younger age, later year of diagnosis, and residence in the eastern or western United States were associated with ovarian preservation (P < .05 for all). Women with endometrioid and clear cell histologies and stage IC disease were less likely to have ovarian conservation (P < .05). In a Cox model, ovarian preservation had no effect on survival (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.39-1.20). Young age, later year of diagnosis, residence in the eastern or western United States, single women, mucinous tumors, and patients with stage IA disease were more likely to have uterine preservation (P < .05 for all). In a multivariate model, uterine preservation had no effect on survival (HR, 0.87; 95% CI, 0.62-1.22). CONCLUSIONS: Ovarian and uterine-conserving surgery were safe in young women who had stage IA and IC epithelial ovarian cancer. Cancer 2009. © 2009 American Cancer Society. [source]

Medical treatment of hirsutism

DERMATOLOGIC THERAPY, Issue 5 2008
Ulrike Blume-Peytavi
ABSTRACT:, Hirsutism is usually the result of an underlying adrenal, ovarian, or central endocrine abnormality mainly due to polycystic ovary syndrome but may also be idiopathic or drug induced. The aim of medical treatment of hirsutism is to rectify any causal hormonal balance, slow down or stop excessive hair growth, and improve the aesthetic appearance of hirsutism, thereby positively affecting the patient's quality of life. Today, for the majority of women, a monotherapy with oral contraceptives that have antiandrogenic activity is recommended as a first-line treatment for hirsutism. Combining an oral contraceptive pill with an antiandrogen is recommended if clinical improvement of hirsutism is insufficient after 6,9 months' monotherapy. In women who present with hirsutism, hyperandrogenism, and insulin resistance, insulin sensitizers are effective for the hirsutism as well as the hyperinsulinemia, hyperandrogenism, and infertility but there is no convincing evidence that they are effective for hirsutism alone. Topical eflornithine is a medical therapy that can be a useful adjuvant for hirsutism when used in conjunction with systemic medications or with laser/photoepilation. [source]

Expression of AMH, SF1, and SOX9 in gonads of genetic female chickens during sex reversal induced by an aromatase inhibitor

DEVELOPMENTAL DYNAMICS, Issue 2 2001
Séverine Vaillant
Abstract Aromatase inhibitors administered prior to histological signs of gonadal sex differentiation can induce sex reversal of genetic female chickens. Under the effects of Fadrozole (CGS 16949A), a nonsteroidal aromatase inhibitor, the right gonad generally becomes a testis, and the left gonad a testis or an ovotestis. We have compared the expression pattern of the genes encoding AMH (the anti-Müllerian hormone), SF1 (steroidogenic factor 1), and SOX9 (a transcription factor related to SRY) in these sex-reversed gonads with that in control testes and ovaries, using in situ hybridization with riboprobes on gonadal sections. In control males, the three genes are expressed in Sertoli cells of testicular cords; however, only SOX9 is male specific, since as observed previously AMH and SF1 but not SOX9 are expressed in the control female gonads. In addition to testicular-like cords, sex-reversed gonads present many lacunae with a composite, thick and flat epithelium. We show that during embryonic and postnatal development, AMH, SF1 and SOX9 are expressed in the epithelium of testicular-like cords and in the thickened part but not in the flattened part of the epithelium of composite lacunae. AMH and SF1 but not SOX9 are expressed in follicular cells of ovotestes. Coexpression of the three genes, of which SOX9 is a specific Sertoli-cell marker, provides strong evidence for the transdifferentiation of ovarian into testicular epithelium in gonads of female chickens treated with Fadrozole. © 2001 Wiley-Liss, Inc. [source]

Diagnostic utility of mammaglobin and GCDFP-15 in the identification of metastatic breast carcinoma in fluid specimens

DIAGNOSTIC CYTOPATHOLOGY, Issue 7 2009
Z. Yan M.D.
Abstract Morphologic differentiation of breast carcinoma from nonmammary malignancies in fluid specimens can be a diagnostic challenge. Immunocytochemistry is often employed in the differential diagnosis. In this study, we evaluated the expression of mammoglobin (MGB1) in body-cavity fluid specimens and compared its efficacy as a marker for metastatic breast carcinomas with that of gross cystic disease fluid protein-15 (GCDFP-15). Cell blocks from 40 fluid specimens were immunostained with monoclonal antibodies against MGB1 and GCDFP-15. They included 15 breast carcinomas and 25 nonmammary carcinomas (10 lungs, 10 ovaries, 3 gastrointestinal tracts, 1 kidney, and 1 urinary bladder). Positivity was defined as the presence of cytoplasmic staining in 10% or more carcinoma cells. Thirteen (87%) and seven (47%) breast carcinomas showed positive staining with MGB1 and GCDFP-15, respectively. Three (12%) nonmammary carcinomas (2 ovarian and 1 colonic) showed positive MGB1 staining; one (3%) nonmammary carcinoma demonstrated positive GCDFP-15 staining. The differences of MGB1 and GCDFP-15 staining between breast and nonmammary carcinomas were statistically significant (P < 0.05). Both MGB1 and GCDFP-15 are specific markers for metastatic breast carcinomas in cell block fluid specimens (88 vs. 96%). However, MGB1 is more sensitive than GCDFP-15 as a marker for metastatic breast carcinoma (87 vs. 46%). Diagn. Cytopathol. 2009. © 2009 Wiley-Liss, Inc. [source]

Kallikrein 4 is expressed in malignant mesothelioma,Further evidence for the histogenetic link between mesothelial and epithelial cells

DIAGNOSTIC CYTOPATHOLOGY, Issue 2 2007
Ben Davidson M.D., Ph.D.
Abstract The objective of this study was to analyze Kallikrein 4 protein (hK4) expression in effusions and solid tumors of patients diagnosed with malignant mesothelioma (MM) and compare hK4 expression in MM with that in breast and ovarian adenocarcinomas. Sections from 65 MM (21 effusions, 44 solid tumors) and 63 breast carcinomas (28 effusions, 35 solid tumors) were stained for hK4 using immunohistochemistry. Results were compared with our previously published data for 284 ovarian carcinomas (181 effusions, 103 solid tumors). Expression of hK4 was detected in 26/65 (40%) MM and 52/63 (83%) breast carcinomas. Ovarian carcinoma showed staining values that were comparable to those in breast carcinoma (expression of hK4 in 144/181; 80% effusions and 85/103; 83% solid tumors). As opposed to our previous findings in ovarian carcinoma, hK4 expression was higher in solid tumors when compared with to effusions in both MM (P = 0.013) and breast carcinoma (P = 0.002). Comparative analysis of the three tumor types showed significantly higher expression in ovarian and breast adenocarcinomas when compared with MM (P < 0.001). In conclusion, hK4 is frequently expressed in MM, with higher levels detected in solid tumors, although its expression is more limited than in gynecological adenocarcinomas. The presence of hK4 in MM, a non-hormonally regulated tumor, provides further support to the histogenetic link between mesothelial and epithelial cells. Diagn. Cytopathol. 2007;35:80,84. © 2007 Wiley-Liss, Inc. [source]

The ,I/,III-tubulin isoforms and their complexes with antimitotic agents

FEBS JOURNAL, Issue 14 2006
Docking, molecular dynamics studies
Both microtubule destabilizer and stabilizer agents are important molecules in anticancer therapy. In particular, paclitaxel has been demonstrated to be effective for the treatment of ovarian, breast, and nonsmall cell lung carcinomas. It has been shown that emergence of resistance against this agent correlates with an increase in the relative abundance of tubulin isoform ,III and that the more recently discovered IDN5390 can be effectively used once resistance has emerged. In this paper, we analyze the binding modes of these antimitotic agents to type I and III isoforms of ,-tubulin by computational methods. Our results are able to provide a molecular explanation of the experimental data. Using the same protocol, we could also show that no preference for any of the two isoforms can be detected for epothilone A, a potentially very interesting drug for which no data about the emergence of resistance is currently available. Our analysis provides structural insights about the recognition mode and the stabilization mechanism of these antimitotic agents and provides useful suggestions for the design of more potent and selective antimitotic agents. [source]

Gemcitabine-induced severe pulmonary toxicity

FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2004
Fabrice Barlési
Abstract Gemcitabine is a relatively new deoxycytidine analog (2,,2,-difluorodeoxycytidine) with structural similarities to cytosine arabinoside (Ara-C). Activity of gemcitabine is demonstrated in the treatment of many solid tumors, like pancreas, ovarian and nonsmall cell lung cancer (NSCLC). Although gemcitabine is considered as a drug with a good safety profile, cases of gemcitabine-induced severe pulmonary toxicity (GISPT) were reported as for Ara-C. We performed a systematic review of reported cases on the GISPT. Twenty-nine clinical trials especially interesting NSCLC patients (21) and 21 reported cases recording 40 patients were analyzed. The incidence of the GISPT varies from 0 to 5%. The clinical presentation is a subacute clinical syndrome and is frequently nonspecific. The predominant radiographic pattern on chest X-ray are reticulo-nodular interstitial infiltrates. It was postulated that the physio-pathological mechanism of the GISPT was an inflammatory reaction of the alveolar capillary wall cytokine-mediated, which created an abnormal permeability of its membrane. After the differential diagnosis were ruled out, the discontinuation of the drug and the early initiation of steroids and diuretics are the most frequently performed treatments. Under these conditions, the outcome was favorable in a delay of few days generally for a majority of patients but 20% of patients died. Some risk factors, as a previous pulmonary disease or a previous thoracic irradiation, for the occurrence of the GISPT were proposed. GISPT is rare but sometimes fatal. Its a necessity to increase awareness about it to enhanced an early and suitable management of patients developing such a toxicity after gemcitabine administration. [source]

Cadherin 13 in cancer

GENES, CHROMOSOMES AND CANCER, Issue 9 2010
Alexandra V. Andreeva
We review the evidence suggesting the involvement of Cadherin 13 (CDH13, T-cadherin, H-cadherin) in various cancers. CDH13 is an atypical member of the cadherin family, devoid of a transmembrane domain and anchored to the exterior surface of the plasma membrane via a glycosylphosphatidylinositol anchor. CDH13 is thought to affect cellular behavior largely through its signaling properties. It is often down-regulated in cancerous cells. CDH13 down-regulation has been associated with poorer prognosis in various carcinomas, such as lung, ovarian, cervical and prostate cancer. CDH13 re-expression in most cancer cell lines inhibits cell proliferation and invasiveness, increases susceptibility to apoptosis, and reduces tumor growth in in vivo models. These properties suggest that CDH13 may represent a possible target for therapy in some cancers. At the same time, CDH13 is up-regulated in blood vessels growing through tumors and promotes tumor neovascularization. In contrast to most cancer cell lines, CDH13 overexpression in endothelial cells promotes their proliferation and migration, and has a pro-survival effect. We also discuss molecular mechanisms that may regulate CDH13 expression and underlie its roles in cancer. © 2010 Wiley-Liss, Inc. [source]

Statistical behavior of complex cancer karyotypes

GENES, CHROMOSOMES AND CANCER, Issue 4 2005
Mattias Höglund
Epithelial tumors commonly show complex and variable karyotypes that obscure the identification of general patterns of the karyotypic evolution. To overcome some of these problems, we previously systematically analyzed the accumulated cytogenetic data from individual tumor types by using various statistical means. In the present study, we compare previous results obtained for nine tumor types and perform several meta-analyses of data obtained from a number of epithelial tumors, including head and neck, kidney, bladder, breast, colorectal, ovarian, and lung cancer, as well as from malignant melanoma and Wilms tumor, with the specific aim of discovering common patterns of karyotypic evolution. We show that these tumors frequently develop through a hypo- or a hyperdiploid pathway and progress by an increasing number of alternative imbalances through at least two karyotypic phases, Phases I and II, and possibly through a third, Phase III. During Phase I, the karyotypes exhibited a power law distribution of both the number of changes per tumor and the frequency distribution at which bands were involved in breaks. At the transition from Phase I to Phase II/III, the observed power law distributions were lost, indicating a transition from an ordered and highly structured process to a disordered and chaotic pattern. The change in karyotypic orderliness at the transition from Phase I to Phase II/III was also shown by a drastic difference in karyotypic entropy. © 2005 Wiley-Liss, Inc. [source]

Germline mutations of the BRCA1-associated ring domain (BARD1) gene in breast and breast/ovarian families negative for BRCA1 and BRCA2 alterations

GENES, CHROMOSOMES AND CANCER, Issue 3 2002
Chiara Ghimenti
BARD1 (BRCA1-associated RING domain) was identified by yeast two-hybrid screening as a protein interacting with BRCA1. Somatic and germline mutations of BARD1 have been detected in sporadic breast, ovarian, and endometrial cancers. The present study represents the first description of BARD1 germline mutations in hereditary breast and breast/ovarian cancer patients. We analyzed the BARD1 gene in 40 families with hereditary breast and breast/ovarian cancer, tested negative for BRCA1 and BRCA2 mutations. A mutational analysis by PCR-SSCP on the coding region and the exon,intron splice boundaries of the BARD1 gene yielded four different germline mutations. A group of 20 patients diagnosed with sporadic breast cancer below the age of 40 was also examined and only one germline mutation was found. A study of loss of heterozygosity at the BARD1 locus in neoplastic tissues from patients with BARD1 germline mutations was carried out. In all cases, we were unable to find any evidence for allelic deletions. The involvement of BARD1 mutations in the susceptibility to hereditary breast and breast/ovarian cancer is discussed. [source]

UbcH10 expression in human lymphomas

HISTOPATHOLOGY, Issue 6 2009
Giancarlo Troncone
Aims:, The UbcH10 ubiquitin-conjugating enzyme plays a key role in regulating mitosis completion. We have previously reported that UbcH10 overexpression is associated with aggressive thyroid, ovarian and breast carcinomas. The aim of this study was to investigate UbcH10 expression in human lymphomas. Methods and results:, Cell lines and tissue samples of Hodgkin's lymphoma (HL) and of non-Hodgkin's lymphoma (NHL) were screened for UbcH10 expression at transcriptional and translational levels. UbcH10 expression was related to the grade of malignancy. In fact, it was low in indolent tumours and high in a variety of HL and NHL cell lines and in aggressive lymphomas. It was highest in Burkitt's lymphoma, as shown by quantitative real-time polymerase chain reaction and by tissue microarray immunohistochemistry. Flow cytometry of cell lines confirmed that UbcH10 expression is cell-cycle dependent, steadily increasing in S phase, peaking in G2/M phase and dramatically decreasing in G0/G1 phases. We also showed that UbcH10 plays a relevant role in lymphoid cell proliferation, since blocking of its synthesis by RNA interference inhibited cell growth. Conclusions:, Taken together, these results indicate that UbcH10 is a novel lymphoid proliferation marker encompassing the cell cycle window associated with exit from mitosis. Its overexpression in aggressive lymphomas suggests that UbcH10 could be a therapeutic target in this setting. [source]

Biomarker-assisted diagnosis of ovarian, cervical and pulmonary small cell carcinomas: the role of TTF-1, WT-1 and HPV analysis

HISTOPATHOLOGY, Issue 3 2007
J W Carlson
Aims:, Small cell carcinoma of the ovary, hypercalcaemic-type (SCCOH) is morphologically similar to small cell carcinomas from other sites. The aims of this study were to (i) determine if a biomarker panel would distinguish small cell carcinomas of the ovary, cervix (SCCCx) and lung (SCCLu) and (ii) potentially determine the histogenesis of SCCOH. Methods and results:, Nine ovarian small cell carcinomas (seven hypercalcaemic type; two pulmonary type), eight SCCCx and 22 SCCLu were immunostained for thyroid transcription factor (TTF)-1, WT-1, p16, cKIT and OCT3/4; a subset of cases were tested for human papillomavirus (HPV). WT-1 was diffusely positive in 6/7 SSCOH versus two of 33 other small cell carcinomas (P , 0.001). TTF-1 was diffusely positive in 20/22 SCCLu and 1/8 SCCCx, and negative in all SCCOH. p16 and cKIT demonstrated variable patterns of immunoreactivity in all cases. HPV was identified in 5/6 SCCCx; SCCOH and SCCLu were negative for HPV. Conclusions:, Combined staining with WT-1 and TTF-1 will distinguish SCCOH from SCCLu and SCCCx with a sensitivity of 86% and specificity of 97%. HPV is specific for tumours of cervical origin, but p16 immunohistochemistry is not useful for this purpose. The presence of diffuse WT-1 supports a Müllerian origin for SCCOH, whereas the absence of cKIT and OCT3/4 argues against a germ cell origin. [source]

Contribution of BRCA1 and BRCA2 mutations to inherited ovarian cancer,

HUMAN MUTATION, Issue 12 2007
Susan J. Ramus
Abstract A total of 283 epithelial ovarian cancer families from the United Kingdom (UK) and the United States (US) were screened for coding sequence changes and large genomic alterations (rearrangements and deletions) in the BRCA1 and BRCA2 genes. Deleterious BRCA1 mutations were identified in 104 families (37%) and BRCA2 mutations in 25 families (9%). Of the 104 BRCA1 mutations, 12 were large genomic alterations; thus this type of change represented 12% of all BRCA1 mutations. Six families carried a previously described exon 13 duplication, known to be a UK founder mutation. The remaining six BRCA1 genomic alterations were previously unreported and comprised five deletions and an amplification of exon 15. One of the 25 BRCA2 mutations identified was a large genomic deletion of exons 19,20. The prevalence of BRCA1/2 mutations correlated with the extent of ovarian and breast cancer in families. Of 37 families containing more than two ovarian cancer cases and at least one breast cancer case with diagnosis at less than 60 years of age, 30 (81%) had a BRCA1/2 mutation. The mutation prevalence was appreciably less in families without breast cancer; mutations were found in only 38 out of 141 families (27%) containing two ovarian cancer cases only, and in 37 out of 59 families (63%) containing three or more ovarian cancer cases. These data indicate that BRCA1 and BRCA2 are the major susceptibility genes for ovarian cancer but that other susceptibility genes may exist. Finally, it is likely that these data will be of clinical importance for individuals in families with a history of epithelial ovarian cancer, in providing accurate estimates of their disease risks. Hum Mutat 28(12), 1207,1215, 2007. © 2007 Wiley-Liss, Inc. [source]

The association of plasma androgen levels with breast, ovarian and endometrial cancer risk factors among postmenopausal women

INTERNATIONAL JOURNAL OF CANCER, Issue 1 2010
Kim N. Danforth
Abstract Although androgens may play an etiologic role in breast, ovarian and endometrial cancers, little is known about factors that influence circulating androgen levels. We conducted a cross-sectional analysis among 646 postmenopausal women in the Nurses' Health Study to examine associations between adult risk factors for cancer, including the Rosner/Colditz breast cancer risk score, and plasma levels of testosterone, free testosterone, androstenedione, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). All analyses were adjusted for age, laboratory batch and other cancer risk factors. Free testosterone levels were 79% higher among women with a body mass index of ,30 vs. <22 kg/m2 (p -trend <0.01) and 25% higher among women with a waist circumference of >89 vs. ,74 cm (p -trend = 0.02). Consuming >30 g of alcohol a day vs. none was associated with a 31% increase in DHEA and 59% increase in DHEAS levels (p -trend = 0.01 and <0.01, respectively). Smokers of ,25 cigarettes per day had 35% higher androstenedione and 44% higher testosterone levels than never smokers (p -value, F -test = 0.03 and 0.01, respectively). No significant associations were observed for height or time since menopause with any androgen. Testosterone and free testosterone levels were ,30% lower among women with a hysterectomy vs. without (both p -values < 0.01). Overall breast cancer risk was not associated with any of the androgens. Thus, several risk factors, including body size, alcohol intake, smoking and hysterectomy, were related to androgen levels among postmenopausal women, while others, including height and time since menopause, were not. Future studies are needed to clarify further which lifestyle factors modulate androgen levels. [source]

Low drug resistance to both platinum and taxane chemotherapy on an in vitro drug resistance assay predicts improved survival in patients with advanced epithelial ovarian, fallopian and peritoneal cancer

INTERNATIONAL JOURNAL OF CANCER, Issue 11 2009
Koji Matsuo
Abstract The objective of this study was to evaluate the role of an in vitro drug resistance assay to platinum and taxane in the management of advanced epithelial ovarian, fallopian and primary peritoneal cancer. All patients with FIGO Stage IIIc and IV who received postoperative chemotherapy with platinum and taxane for more than 4 courses after the initial cytoreductive surgery between 1995 and 2008 were evaluated. Patients who received neoadjuvant chemotherapy were not included. An in vitro drug resistance assay (EDR Assay, Oncotech, Tustin, CA) was used to determine drug resistance for each patient's tumor tissue. Level of drug resistance was described as extreme (EDR), intermediate (IDR), or low (LDR). Response to chemotherapy and survival were correlated to the EDR Assay. Of the 335 patients who underwent primary cytoreductive surgery, 173 cases met the criteria for statistical evaluation. The 58 patients (33.5%) whose tumors had LDR to both platinum and taxane had statistically improved progression-free survival and overall survival (OS) compared with the 115 patients (66.5%) who demonstrated IDR or EDR to platinum and/or taxane (5-year OS rates, 41.1% vs. 30.9%, p = 0.014). The 5-year OS rates for the 28 (16.2%) cases that had optimal cytoreduction with LDR to both platinum and taxane was significantly improved over the 62 (35.8%) cases that were suboptimally cytoreduced with IDR or EDR to platinum and/or taxane (54.1% vs. 20.4%, respectively, p < 0.001). In conclusion, LDR to both platinum and taxane chemotherapy, as determined by an in vitro drug resistance assay, independently predicts improved survival in patients with advanced epithelial ovarian, fallopian and peritoneal cancer, especially in those patients who undergo optimal primary cytoreduction. © 2009 UICC [source]

Co-twin control and cohort analyses of body mass index and height in relation to breast, prostate, ovarian, corpus uteri, colon and rectal cancer among Swedish and Finnish twins

INTERNATIONAL JOURNAL OF CANCER, Issue 4 2007
Ellen Lundqvist
Abstract Associations between anthropometric measures and cancer have been studied previously, but relatively few studies have had the opportunity to control for genetic and early shared environmental factors. In this study, we analyzed 2 twin cohorts from Sweden born 1886,1925 (n = 21,870) and 1926,1958 (n = 30,279) and 1 from Finland born 1880,1958 (n = 25,882) including in total 78,031 twins, and studied the association between BMI and height and risk of prostate, breast, ovarian, corpus uteri, colon and rectal cancer. The cohorts were both analyzed through a co-twin control method and as traditional cohorts. In co-twin control analyses, older obese (BMI , 30 kg/m2) subjects (median age 56 years at baseline) were at higher risk of cancer of the corpus uteri (OR = 3.0; 95% CI 0.9,10.6), colon (OR = 1.9; 95% CI 0.8,4.5) and breast (OR = 2.5; 95% CI 1.3,4.2). For younger obese women (median age 30 years at baseline), an inverse tendency was observed for breast cancer (OR = 0.6; 95% CI 0.3,1.5, p for trend = 0.05). The tallest women had an increased risk of breast (OR = 1.8; 95% CI 1.3,2.7) and ovarian cancer (OR = 1.7; 95% CI 0.8,3.5). No consistent associations were found for prostate cancer either for BMI or height. There are some suggestions in our study that uncontrolled genetic or early shared environmental factors may affect risk estimates in studies of anthropometric measures and cancer risk, but do not explain observations of increased cancer risks related to BMI or height. © 2007 Wiley-Liss, Inc. [source]

Dietary acrylamide and human cancer

INTERNATIONAL JOURNAL OF CANCER, Issue 2 2006
Claudio Pelucchi
Abstract Low levels of acrylamide have been found in several foods cooked at high temperatures. While there is sufficient evidence for the carcinogenicity of acrylamide in experimental animals, the few epidemiologic studies conducted to date on occupational and dietary exposure to acrylamide have found no consistent evidence of association with human cancer risk. Using data from an integrated network of Italian and Swiss hospital-based case-control studies, we analyzed the relation between dietary acrylamide intake and cancers of the oral cavity and pharynx (749 cases, 1,772 controls), esophagus (395 cases, 1,066 controls), large bowel (1,394 cases of colon, 886 cases of rectal cancer, 4,765 controls), larynx (527 cases, 1,297 controls), breast (2,900 cases, 3,122 controls), ovary (1,031 cases, 2,411 controls) and prostate (1,294 cases, 1,451 controls). All the studies included incident, histologically confirmed cancer cases and controls admitted to the same network of hospitals for acute nonneoplastic conditions. We calculated odds ratios (ORs) using multivariate logistic regression models, adjusted for energy intake and other major covariates of interest. The ORs for the highest versus the lowest quintile of acrylamide intake were 1.12 (95% CI = 0.76,1.66) for cancer of the oral cavity/pharynx, 1.10 (95% CI = 0.65,1.86) for esophageal, 0.97 (95% CI = 0.80,1.18) for colorectal, 1.23 (95% CI = 0.80,1.90) for laryngeal, 1.06 (95% CI = 0.88,1.28) for breast, 0.97 (95% CI = 0.73,1.31) for ovarian and 0.92 (95% CI = 0.69,1.23) for prostate cancer. None of the trend in risk was significant. This uniquely large and comprehensive data set does not show any consistent association between intake of acrylamide and the risk of breast and several other common cancers. © 2005 Wiley-Liss, Inc. [source]

Anti-tumor efficacy of the nucleoside analog 1-(2-deoxy-2-fluoro-4-thio-,-D-arabinofuranosyl) cytosine (4,-thio-FAC) in human pancreatic and ovarian tumor xenograft models

INTERNATIONAL JOURNAL OF CANCER, Issue 6 2005
Deborah A. Zajchowski
Abstract 1-(2-Deoxy-2-fluoro-4-thio-,- D -arabinofuranosyl) cytosine (4,-thio-FAC) is a deoxycytidine analog that has been shown previously to have impressive anti-proliferative and cytotoxic effects in vitro and in vivo toward colorectal and gastric tumors. In our present studies, the pharmacokinetic behavior in nude mice and the effectiveness of 4,-thio-FAC against human pancreatic and ovarian tumor growth were assessed in comparison with standard chemotherapeutic agents. Potent in vitro anti-proliferative effects were observed against pancreatic (Capan-1, MIA-PaCa-2, BxPC-3) and ovarian (SK-OV-3, OVCAR-3, ES-2) cancer cell lines with IC50 of 0.01,0.2 ,M. In vivo anti-tumor activity was evaluated in nude mice bearing subcutaneously (s.c.) implanted human pancreatic tumor xenografts or intraperitoneally (i.p.) disseminated human ovarian xenografted tumors. Oral daily administration of 4,-thio-FAC for 8,10 days significantly inhibited the growth of gemcitabine-resistant BxPC-3 pancreatic tumors and induced regression of gemcitabine-refractory Capan-1 tumors. 4,-Thio-FAC was also a highly effective inhibitor of ovarian peritoneal carcinomatosis. In the SK-OV-3 and ES-2 ovarian cancer models, 4,-thio-FAC prolonged survival to a greater extent than that observed with gemcitabine. Furthermore, the superiority of 4,-thio-FAC to carboplatin and paclitaxel was demonstrated in the ES-2 clear cell ovarian carcinoma model. Studies provide evidence that 4,-thio-FAC is a promising new alternative to gemcitabine and other chemotherapeutic drugs in the treatment of a variety of tumor indications, including pancreatic and ovarian carcinoma. © 2004 Wiley-Liss, Inc. [source]

Small interfering RNA (siRNA) inhibits the expression of the Her2/neu gene, upregulates HLA class I and induces apoptosis of Her2/neu positive tumor cell lines

INTERNATIONAL JOURNAL OF CANCER, Issue 1 2004
Aniruddha Choudhury
Abstract Silencing of a specific mRNA using double stranded RNA oligonucleotides represents one of the newest technologies for suppressing a specific gene product. Small interfering RNA (siRNA) are 21 nucleotides long, double stranded RNA fragments that are identical in sequence to the target mRNA. We designed 3 such siRNA against the Her2/neu (HER2) gene. The HER2 gene is known to play an important role in the oncogenesis of several types of cancers, such as breast, ovarian, colon and gastric cancers. Introduction of the siRNA into HER2 positive tumor lines in vitro greatly reduced the cell surface expression of the HER2 protein. Concurrently, a range of effects on cell physiology, such as growth inhibition or apoptosis, was observed. The expression of HLA class I was observed to be upregulated when HER2 was silenced with siRNA. Treatment of SKBr3 and MCF7/HER2 tumor cell lines with the HER2 siRNA resulted in growth arrest of cells in the late G1/S-phase. Our results suggest that siRNA may be an effective method of abrogating the effect of HER2 in tumorigenesis. © 2003 Wiley-Liss, Inc. [source]

Aspects of the reproductive biology and breeding management of Asian and African elephants Elephas maximus and Loxodonta africana

INTERNATIONAL ZOO YEARBOOK, Issue 1 2006
T. B. HILDEBRANDT
Elephants possess many unique qualities, including some that relate directly to their reproductive biology. Thus, comparative studies on elephants provide valuable information to the growing biological database for extant mammals. Left undisturbed, Asian Elephas maximus and African Loxodonta Africana elephants reproduce well in the wild. It is ironic then that most captive populations face possible,extinction'because of historically poor reproductive performance. Some of the problems with breeding elephants in captivity are logistical but others, like ovarian and uterine pathologies and bull infertility, have management-related aetiology. Through advances in endocrine monitoring and ultrasound imaging techniques, we are beginning to understand some of the complex mechanisms controlling reproductive function in elephants. Several reproductive characteristics appear to be unique to the taxon, such as luteal steroidogenic function, follicular development patterns, pituitary gonadotrophin secretion, a 22 month-long gestation and musth (in ,,). One example is the,double LH surge'occurring 3 weeks apart during the follicular or non-luteal phase of the cycle, with only the second surge inducing ovulation. These qualities have at times both enhanced and hampered efforts to understand and control reproduction. We have learned that techniques developed for domestic or laboratory species are not always directly applicable to elephants. However, the recent success of artificial insemination based on new ultrasound and endocrine methodology offers hope that establishing selfsustaining populations is possible. This paper reviews our current knowledge of elephant reproduction and how it is being used to aid species conservation for maximal reproductive efficiency and enhancement of genetic management. [source]

Steroidogenic gene expression in H295R cells and the human adrenal gland: adrenotoxic effects of lindane in vitro

JOURNAL OF APPLIED TOXICOLOGY, Issue 6 2006
Agneta Oskarsson
Abstract The focus on the refinement, reduction and replacement of animal use in toxicity testing requires the development of cell-based systems that mimic the effects of xenobiotics in human tissues. The human adrenocortical carcinoma cell line, H295R, has been proposed as a model for studies on adrenal steroidogenesis and its disruption. In this study, expression profiles for nine adrenal steroidogenic genes were characterized in H295R cells using real-time RT-PCR. Treatment with forskolin increased cortisol secretion and stimulated transcription of all the steroidogenic genes except SULT2A1. The transcript profile from H295R cells in the presence and absence of forskolin was compared with the transcript profile from human adrenal glands. The gene expression pattern observed in the forskolin-treated H295R cells was more similar to that in the human adrenal gland, than the expression pattern in untreated cells. To examine H295R cells as a possible in vitro system for the assessment of adrenal disruption using molecular endpoints, the insecticide lindane (, -hexachlorocyclohexane) was used. In vivo, lindane has been shown to inhibit testicular, ovarian and adrenal steroidogenesis. It was demonstrated that lindane reduced cortisol secretion, downregulated the expression of a subset of the genes encoding steroidogenic enzymes and repressed transcriptional activation of the steroidogenic acute regulatory protein (StAR) gene promoter. Thus the H295R cell line provides a good in vitro system for the analysis of the human adrenal steroidogenic pathway at the level of hormone production and gene expression. This in vitro test can be used for the rapid detection of adrenal endocrine disruption and as a tool for mechanistic studies. Copyright © 2006 John Wiley & Sons, Ltd. [source]

Two-generation reproductive toxicity study of inhaled tertiary amyl methyl ether (TAME) vapor in CD® rats

JOURNAL OF APPLIED TOXICOLOGY, Issue 6 2003
R. W. Tyl
Abstract Under Of,ce of Prevention, Pesticides and Toxic Substances draft guidelines, CD® weanling F0 rats (30 of each gender per group) inhaled tertiary amyl methyl ether vapor at 0, 250, 1500 or 3000 ppm 5 days a week and 6 h a day for 10 weeks, with vaginal cytology evaluated for weeks 8,10. The F0 animals then produced F1 offspring, with exposure 7 days a week from mating through to lactation. During the F1 prebreed exposure period, vaginal patency, preputial separation (PPS) and vaginal cytology were evaluated. The F1 animals were mated, with F2 anogenital distance measured on postnatal day zero. At F2 weaning 30 of each gender per group were selected for postwean retention, with no exposures, through vaginal patency and PPS. Body weights, feed consumption and clinical signs were recorded throughout the study. Adult F0 and F1 systemic toxicity was present at 1500 and 3000 ppm. Minor adult male reproductive toxicity was present at 3000 ppm. There were no adult effects on vaginal cyclicity, estrous cycle length, mating, fertility, pregnancy, gestational length or ovarian and uterine weights. There were no treatment-related gross or histopathologic ,ndings in parental male or female systemic or reproductive organs. The F1 and F2 offspring toxicity was present at 1500 and 3000 ppm. The no-observable-adverse-effect level for adult systemic and offspring toxicity was 250 ppm and 1500 ppm for male reproductive toxicity (females at >3000 ppm). Copyright © 2003 John Wiley & Sons, Ltd. [source]

Coronary Artery Bypass Surgery in Patients with Malignancy: A Single-Center Study with Comparison to Patients Without Malignancy

JOURNAL OF CARDIAC SURGERY, Issue 2 2009
Nezihi Kucukarslan M.D.
In this study, we compared the outcome of coronary artery bypass graft (CABG) in such patients with those without malignancy. Methods: The patients were selected from those who had undergone coronary artery bypass surgery in the last decade. The study group (group I) included the patients with malignancy in remission. The control group comprised those patients who were selected randomly from those without any malignancy. The patients were retospectively examined with regard to preoperative, operative, and postoperative data from personal files, computerized recording system, and operation reports. Results: Group I included 48 patients (age 48 to 69; 29 male) while group II included 50 patients (age = 38 to 73; 35 male). In group I, comorbidity rates were: renal dysfunction in 12 (25%), obstructive lung disease 10 (21%), congestive failure in four (8%) patients. The malignancy rates were: lung in 15 (31%), breast in 10 (21%), stomach in five (10%), colon in four (8%), renal in one (2%), Hodgkin's lyphoma in three (6%), leukemia in two (4%), ovarian in three (6%), and prostate in five (10%) patients. In group II, the comorbidity rates were: diabetes mellitus 18 (36%), renal dysfunction in five (10%) and obstructive lung disease in 13 (26%) patients. In group I, chemotherapy and radiotherapy were performed in 38 and 34 patients, respectively. In groups I and II, the CABG was elective in 47 (98%) and in 45 patients (90%); the off-pump surgery was performed in 27 (56%) and 12 (24%) patients, respectively. The total duration of bypass was 37 ± 6 minutes and 44 ± 5 minutes; the duration of aortic clamp was 26 ± 4 and 29 ± 7 minutes, respectively, in groups I and II. Posoperative complication rates were: infection in 12 (25%), bleeding in eight (17%), acute renal insufficiency in eight (17%), prolonged air escape in five (10%), and prolonged entubation in 17 (35%) patients in group I and atrial fibrillation in 11 (22%) patients in group II. Mortality rates in both groups were two (4%). Conclusion: CABG in patients with comorbid malignancy is as safe as the other patients. In patients with full remission of malignancy, the surgeons should be encouraged about the safety of CABG. [source]

Lipophilic but not hydrophilic statins selectively induce cell death in gynaecological cancers expressing high levels of HMGCoA reductase

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 5 2010
S. Kato
Abstract Recent reports have suggested that statins induce cell death in certain epithelial cancers and that patients taking statins to reduce cholesterol levels possess lower cancer incidence. However, little is known about the mechanisms of action of different statins or the effects of these statins in gynaecological malignancies. The apoptotic potential of two lipophilic statins (lovastatin and simvastatin) and one hydrophilic statin (pravastatin) was assessed in cancer cell lines (ovarian, endometrial and cervical) and primary cultured cancerous and normal tissues. Cell viability was studied by MTS assays and apoptosis was confirmed by Western blotting of PARP and flow cytometry. The expressions of key apoptotic cascade proteins were analysed. Our results demonstrate that both lovastatin and simvastatin, but not pravastatin, selectively induced cell death in dose- and time-dependent manner in ovarian, endometrial and cervical cancers. Little or no toxicity was observed with any statin on normal cells. Lipophilic statins induced activation of caspase-8 and -9; BID cleavage, cytochrome C release and PARP cleavage. Statin-sensitive cancers expressed high levels of HMG-CoA reductase compared with resistant cultures. The effect of lipophilic statins was dependent on inhibition of enzymatic activity of HMG-CoA reductase since mevalonate pre-incubation almost completely abrogated the apoptotic effect. Moreover, the apoptotic effect involved the inhibition of synthesis of geranylgeranyl pyrophosphate rather than farnesyl pyrophosphate. In conclusion, lipophilic but not hydrophilic statins induce cell death through activation of extrinsic and intrinsic apoptotic cascades in cancerous cells from the human female genital tract, which express high levels of HMG-CoA reductase. These results promote further investigation in the use of lipophilic statins as anticancer agents in gynaecological malignancies. [source]

DNA methylation and histone modification regulate silencing of OPG during tumor progression,

JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2009
Tung-Ying Lu
Abstract The identification of molecules that are down-regulated in malignant phenotype is important for understanding tumor biology and their role in tumor suppression. We compared the expression profile of four normal nasal mucosal (NNM) epithelia and a series of nasopharyngeal cancinoma (NPC) cell lines using cDNA microarray and confirmed the actual expression of the selected genes, and found osteoprotegerin (OPG) to be ubiquitously deficient in NPC cells. We also found OPG to be down-regulated in various cancer cell lines, including oral, cervical, ovarian, lung, breast, pancreas, colon, renal, prostate cancer, and hepatoma. Administration of recombinant OPG (rOPG) brought about a reduction in cancer cell growth through apoptotic mechanism. We generated eleven monoclonal antibodies (MAbs) against OPG to study OPG's expression and biological functions in cancer cells. OPG was detected in the tumor stromal regions, but not in the cancer cell per se in surgical specimens of liver cancer. Quantitative reverse transcription-polymerase chain reaction (Q-RT-PCR) revealed that OPG was down-regulated in NPC tissues compared with normal nasal polyp (NNP) tissues. In addition, we showed OPG silencing to be associated with promoter methylation as well as histone modifications. In OPG-silenced cancer cell lines, the OPG gene promoter CpG dinucleotides were highly methylated. Compared to normal cells, silenced OPG gene in cancer cells were found to have reduced histone 3 lysine 4 tri-methylation (H3K4me3) and increased histone 3 lysine 27 tri-methylation (H3K27me3). Taken together, these results suggest that OPG silencing in carcinoma cancer cells occurs through epigenetic repression. J. Cell. Biochem. 108: 315,325, 2009. © 2009 Wiley-Liss, Inc. [source]

Age and size compositions, growth and reproductive biology of the breaksea cod Epinephelides armatus, a gonochoristic serranid

JOURNAL OF FISH BIOLOGY, Issue 5 2007
S. E Moore
Details of the reproductive biology, size and age compositions and growth of the breaksea cod Epinephelides armatus, the sole representative of Epinephelides, were obtained by collecting monthly samples of a wide total length (LT) range of individuals from coastal marine waters at 31,32° S on the lower west coast of Australia. Although the modal LT class of females (250,299 mm) was markedly less than that of males (400,449 mm), the modal ages of the two sexes were similar, i.e. 4 v. 5 years, respectively. The similarity in the age compositions and the histological demonstration that the gonads of all E. armatus consist solely of either ovarian or testicular tissues demonstrate that this species is gonochoristic, which is highly unusual for an anthiinine serranid. The absence of a central, membrane-lined ,ovarian' lumen in the testes of juveniles would account for adult testes containing neither this ovarian remnant nor the peripherally located sperm sinuses that are found in the mature testes of almost all other serranids. The results demonstrate that E. armatus exhibits a very unusual pattern of sexual development for a serranid. The spawning period of E. armatus lasts for c. 9 months, which is long for a species in temperate Western Australian waters, but comparable with that of many other relatively small serranids elsewhere. Females grow slower than males, attaining LT at 3, 5 and 10 years of c. 200, 285 and 420 mm, respectively, compared with c. 215, 315 and 450 mm, respectively. Females, however, attain maturity at a greater LT and older age than males. [source]

Comparison of the efficiency and sensitivity of virus isolation and molecular methods for routine diagnosis of infectious haematopoietic necrosis virus and infectious pancreatic necrosis virus

JOURNAL OF FISH DISEASES, Issue 2 2002
-Maganja, D Barli
Infectious haematopoietic necrosis virus (IHNV) and infectious pancreatic necrosis virus (IPNV) are widely distributed fish pathogens in Europe. A reverse transcriptase,polymerase chain reaction (RT,PCR) assay was developed for the detection of both viruses as an alternative method to virus assay in cell culture. Oligonucleotide primers corresponding to highly conserved regions of glycoprotein G-gene sequences were used for IHNV. For the detection of IPNV the VP2-coding region was selected for RT,PCR amplification. Products of the expected size were amplified from total ribonucleic acid (RNA) extracts of infected cells. The optimized RT,PCR methods successfully detected viral RNA from ovarian and seminal fluids and other organs. To enhance the sensitivity and specificity of RT,PCR, a semi-nested PCR assay was tested using additional specific inner primers for reamplification of products obtained by RT,PCR. Because of the possibility of template carry-over contamination, a closed one step RT,PCR method was tested. This technically simplified approach was then combined with the PCR,enzyme linked immunosorbent assay (ELISA) method for the detection of amplification products and verification using specific biotinylated probes. The test provides an additional tool for the detection of IHNV and IPNV which is rapidly and easily performed and is highly sensitive, especially for the detection of IHNV in fish samples coinfected with IPNV. The PCR,ELISA method for the detection of RT,PCR products enables the screening of large numbers of samples and offers the possibility for automatisation of diagnostic work. [source]

Noradrenaline Involvement in the Negative-Feedback Effects of Ovarian Steroids on Luteinising Hormone Secretion

JOURNAL OF NEUROENDOCRINOLOGY, Issue 10 2009
C. V. V. Helena
Noradrenaline has been shown to modulate the ovarian-steroid feedback on luteinising-hormone (LH) release. However, despite the high amount of evidence accumulated over many years, the role of noradrenaline in LH regulation is still not clearly understood. The present study aimed to further investigate the involvement of noradrenaline in the negative-feedback effect of oestradiol and progesterone on basal LH secretion. In experiment 1, ovariectomised (OVX) rats received a single injection of oil, oestradiol, or progesterone at 09.00,10.00 h and were decapitated 30 or 60 min later. Levels of noradrenaline and its metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), were determined in microdissections of the preoptic area (POA) and medial basal hypothalamus-median eminence (MBH-ME) and correlated with LH secretion. Basal LH levels were decreased 30 and 60 min after oestradiol or progesterone injection, and this hormonal response was significantly correlated with a reduction in POA MHPG levels, which reflect noradrenaline release. In addition, noradrenaline levels in the POA were increased, whereas noradrenaline turnover (MHPG/noradrenaline ratio) was decreased 60 min after the injection of both hormones. No effect was found in the MBH-ME. In experiment 2, i.c.v. administration of noradrenaline (60 nmol), performed 15 min before oestradiol or progesterone injection in jugular vein-cannulated OVX rats, completely prevented the ovarian steroid-induced inhibition of LH secretion. The data obtained provide direct evidence that LH secretion in OVX rats is positively regulated by basal noradrenergic activity in the POA, and its reduction appears to play a role in the negative-feedback effect of ovarian steroids on LH secretion in vivo. [source]