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Supplementary Table S2.

Supplementary Methods.

Purpose: Ovarian clear cell adenocarcinoma (OCCA) is an uncommon histotype that is generally refractory to platinum-based chemotherapy. We analyze here the most comprehensive gene expression and copy number data sets, to date, to identify potential therapeutic targets of OCCA.Experimental Design: Gene expression and DNA copy number were carried out using primary human OCCA tumor samples, and findings were confirmed by immunohistochemistry on tissue microarrays. Circulating interleukin (IL) 6 levels were measured in serum from patients with OCCA or high-grade serous cancers and related to progression-free and overall survival. Two patients were treated with sunitinib, and their therapeutic responses were measured clinically and by positron emission tomography.Results: We find specific overexpression of the IL6-STAT3-HIF (interleukin 6-signal transducer and activator of transcription 3-hypoxia induced factor) pathway in OCCA tumors compared with high-grade serous cancers. Expression of PTHLH and high levels of circulating IL6 in OCCA patients may explain the frequent occurrence of hypercalcemia of malignancy and thromboembolic events in OCCA. We describe amplification of several receptor tyrosine kinases, most notably MET, suggesting other potential therapeutic targets. We report sustained clinical and functional imaging responses in two OCCA patients with chemotherapy-resistant disease who were treated with sunitinib, thus showing significant parallels with renal clear cell cancer.Conclusions: Our findings highlight important therapeutic targets in OCCA, suggest that more extensive clinical trials with sunitinib in OCCA are warranted, and provide significant impetus to the growing realization that OCCA is molecularly and clinically distinct to other forms of ovarian cancer. Clin Cancer Res; 17(8); 2538–48. ©2011 AACR.

Supplementary Figures S1-S5.

Supplementary Tables S1-S6, Supplementary References. Supplementary Table S1. Characteristics of included studies; S2. Complete-case analysis of ten years estimated hazard ratios (HR) for all cause death in patients with ovarian cancer. S3. Complete-case analysis of ten years estimated subhazard ratios (SHR) for ovarian cancer death in patients with ovarian cancer. S4. Ten years estimated subhazard ratios (SHR) for ovarian cancer death in patients with ovarian cancer (with multiple imputation for missing grade and stage). S5. Complete-case analysis of ten years estimated hazard ratios (HR) for all cause death in patients with high grade serous ovarian cancer. S6. Ten years estimated hazard ratios (HR) for all cause death in patients with high grade serous ovarian cancer (with multiple imputation for missing stage).

Specific sleep disorders have been linked to disease progression in different cancers. We hypothesised sleep symptom clusters would differ between cancer types. The aim of this study was to compare sleep symptom clusters in post-treatment melanoma, breast and endometrial cancer patients. Data were collected from 124 breast cancer patients (1 male, 60 ± 15 years, 28.1 ± 6.6 kg/msup2/sup), 82 endometrial cancer patients (64.0 ± 12.5 years, 33.5 ± 10.4 kg/msup2/sup) and 112 melanoma patients (59 male, 65.0 ± 18.0 years, 29.1 ± 6.6 kg/msup2/sup). All patients completed validated questionnaires to assess sleep symptoms, including the Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), and Functional Outcomes of Sleep Questionnaire-10 (FOSQ-10). Snoring, tiredness, observed apneas, age, BMI, and gender data were also collected. Binary values (PSQI, ISI, FOSQ), or continuous variables for sleepiness (ESS) and perceived sleep quality (PSQI), were created and sleep symptom clusters were identified and compared across cancer cohorts. Four distinct sleep symptom clusters were identified: minimally symptomatic (n = 152, 47.7%); insomnia-predominant (n = 87, 24.9%); very sleepy with upper airway symptoms (n = 51, 16.3%), and severely symptomatic with severe dysfunction (n = 34, 11.1%). Breast cancer patients were significantly more likely to be in the insomnia predominant or severely symptomatic with severe dysfunction clusters, whereas melanoma patients were more likely to be minimally symptomatic or sleepy with upper airway symptoms (p lt;0.0001). Endometrial cancer patients were equally distributed across symptom clusters. Sleep symptom clusters vary across cancer patients. A more personalised approach to the management of sleep-related symptoms in these patients may improve the long term quality of life and survival.

Most women with ovarian cancer have a poor prognosis, but studies have reported an association between statin use and improved survival. We investigated the potential survival benefit of statins in women with ovarian cancer using data from the Ovarian cancer Prognosis and Lifestyle study, a prospective study of Australian women aged 18 to 79 years, diagnosed with ovarian cancer from 2012 to 2015 and followed for 5 to 8 years. We obtained information from patient-completed questionnaires and medical records. We defined exposure based on prediagnosis use, as most women used statins continuously (prediagnosis and postdiagnosis) and few started using statins postdiagnosis. We measured survival from date of first treatment (surgery or neoadjuvant chemotherapy) until date of death or last follow-up. We used Cox regression to calculate hazard ratios (HR) and 95% confidence intervals (CI), adjusting for potential confounders. To reduce bias due to confounding by indication, we also applied inverse probability of treatment weighting (IPTW). Of 955 eligible women, 21% reported statin use before diagnosis. Statin users had a slightly better survival (HR = 0.90, 95% CI = 0.70-1.15) that was driven by lipophilic statin use (HR = 0.82, 95% CI = 0.61-1.11), with no association for hydrophilic statins (HR = 1.04, 95% CI = 0.72-1.49). The IPTW model weighted to all women with ovarian cancer also suggested a possible reduction in mortality associated with lipophilic statins (HR = 0.80, 95% CI = 0.54-1.21). In analyses restricted to women with hyperlipidaemia, the HRs were further from the null. Our findings are consistent with previous evidence, suggesting that lipophilic statins might improve ovarian cancer survival. Further investigation, in larger cohorts, or preferably in a randomised trial, is required.

PurposeThe known EOC susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes.MethodsWe sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases verses controls were further examined in an independent set of 14,146 EOC cases and 28,661 controls from the ovarian cancer association consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics.ResultsThe odds ratios (OR) associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 – 5.68; P = 0.00068), 1.99 for POLK (95% CI 1.15 – 3.43; P = 0.014), and 4.07 for SLX4 (95% CI 1.34-12.4; P = 0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 −1.00, P=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive.ConclusionsWe have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes.We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics.The ORs associated for high-grade serous ovarian cancer were 3.01 forWe have found strong evidence that carriers of

Objective: To evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival. Patients and Methods: We conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong). Results: Expression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P

Identifying single nucleotide polymorphisms (SNPs) that influence chemotherapy disposition may help to personalize cancer treatment and limit toxicity. Genome-wide approaches are unbiased, compared with candidate gene studies, but usually require large cohorts. As most chemotherapy is given cyclically multiple blood sampling is required to adequately define drug disposition, limiting patient recruitment. We found that carboplatin and paclitaxel disposition are stable phenotypes in ovarian cancer patients and tested a genome-wide association study (GWAS) design to identify SNPs associated with chemotherapy disposition. We found highly significant SNPs in ABCC2, a known carboplatin transporter, associated with carboplatin clearance (asymptotic P = 5.2 × 106, empirical P = 1.4 × 10−5), indicating biological plausibility. We also identified novel SNPs associated with paclitaxel disposition, including rs17130142 with genome-wide significance (asymptotic P = 2.0 × 10−9, empirical P = 1.3 × 10−7). Although requiring further validation, our work demonstrated that GWAS of chemotherapeutic drug disposition can be effective, even in relatively small cohorts, and can be adopted in drug development and treatment programs.

A 68-year-old man with hypertension, dyslipidemia, chronic kidney disease, and history of hemorrhagic stroke was admitted to our hospital because of atrial fibrillation (AF). After transesophageal echocardiography (TEE) that excluded the presence of left atrial appendage (LAA) thrombus, he underwent electrical cardioversion with sinus rhythm restoration. Nevertheless, he presented at 1-month follow-up visit with atrial fibrillation. Due to the history of hemorrhagic stroke and the subsequent contraindication to anticoagulation therapy, he was identified as a candidate to percutaneous closure of LAA. TEE was performed before the procedure to rule out the presence of LAA thrombus and to assess the dimensions and the morphology of the LAA. The procedure was performed under general anesthesia and TEE guidance. After transseptal puncture of the fossa ovalis, a 22-mm Amplatzer Cardiac Plug (ACP) (AGA, St. Jude Medical) device was advanced in the LAA through a dedicated delivery system (12-Fr Amplatzer TorqVue 45 × 45 Delivery Sheath – AGA, St. Jude Medical). Once the correct implanting zone was localized, the device was released under fluoroscopic and echocardiographic guidance. A check for pericardial effusion at the end of the procedure was done by transthoracic echo (TTE). The patient was discharged the day after the procedure with long-term therapy with a daily 100-mg aspirin and 75-mg clopidogrel for 3 months. Endocarditis antibiotic prophylaxis was also recommended for at least 6 months (Figs. 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, and 19.9).

Post-myocardial infarction ventricular septal rupture (VSR) is one of the most serious complications occurring in patients with ST elevation myocardial infarction. Although surgical repair with concurrent coronary artery bypass grafting (CABG) is considered the treatment of choice, it carries a very high morbidity and mortality rates. For this reason, surgical approach to all patients might not be reasonable, in particular when patients are critically ill or with multiple comorbidities. Percutaneous interventional approach appears to be safe and effective in patients with a chronic VSR or treated for a residual shunt after initial surgical closure. Immediate primary transcatheter closure in acute setting may also be considered an alternative and effective strategy in selected patients ensuring greater effectiveness and fewer complications compared to surgery. The timing of surgical or percutaneous intervention is critical: the presence of cardiogenic shock and closure in the acute phase after VSR diagnosis are important risk factors of mortality. Due to the high mortality rate, the use of percutaneous occluders has been investigated as an alternative approach. The treatment with dedicated device is in general successful with few procedure-related complications. This strategy is a less invasive alternative to surgical approach; however it needs to be applied on a case-by-case basis.

Contains fulltext : 174140.pdf (Publisher’s version ) (Closed access) PURPOSE: Survival following ovarian cancer diagnosis is generally low; understanding factors related to prognosis could be important to optimize treatment. The role of previously diagnosed comorbidities and use of medications for those conditions in relation to prognosis for ovarian cancer patients has not been studied extensively, particularly according to histological subtype. METHODS: Using pooled data from fifteen studies participating in the Ovarian Cancer Association Consortium, we examined the associations between history of hypertension, heart disease, diabetes, and medications taken for these conditions and overall survival (OS) and progression-free survival (PFS) among patients diagnosed with invasive epithelial ovarian carcinoma. We used Cox proportional hazards regression models adjusted for age and stage to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) overall and within strata of histological subtypes. RESULTS: History of diabetes was associated with increased risk of mortality (n = 7,674; HR = 1.12; 95% CI = 1.01-1.25). No significant mortality associations were observed for hypertension (n = 6,482; HR = 0.95; 95% CI = 0.88-1.02) or heart disease (n = 4,252; HR = 1.05; 95% CI = 0.87-1.27). No association of these comorbidities was found with PFS in the overall study population. However, among patients with endometrioid tumors, hypertension was associated with lower risk of progression (n = 339, HR = 0.54; 95% CI = 0.35-0.84). Comorbidity was not associated with OS or PFS for any of the other histological subtypes. Ever use of beta blockers, oral antidiabetic medications, and insulin was associated with increased mortality, HR = 1.20; 95% CI = 1.03-1.40, HR = 1.28; 95% CI = 1.05-1.55, and HR = 1.63; 95% CI = 1.20-2.20, respectively. Ever use of diuretics was inversely associated with mortality, HR = 0.71; 95% CI = 0.53-0.94. CONCLUSIONS: Histories of hypertension, diabetes, and use of diuretics, beta blockers, insulin, and oral antidiabetic medications may influence the survival of ovarian cancer patients. Understanding mechanisms for these observations could provide insight regarding treatment.

The progesterone receptor (PR) is a critical mediator of progesterone action in the female reproductive system. Expressed in the human as two proteins, PRA and PRB, the receptor is a ligand-activated nuclear transcription factor that regulates transcription by interaction with protein cofactors and binding to specific response elements in target genes. We previously reported that PR was located in discrete subnuclear foci in human endometrium. In this study, we investigated the role of ligand in the formation of PR foci and their association with transcriptional activity. PR foci were detected in mouse uterus and normal human breast tissues and were more abundant when circulating progesterone was high. In human malignant tissues, PR foci were aberrant: foci were larger in endometrial cancers than in normal endometrium, and in breast cancers hormone-dependence was decreased. Chromatin disruption also increased foci size and decreased ligand dependence, suggesting that altered nuclear architecture may contribute to the aberrant PR foci observed in endometrial and breast cancers. In breast cancer cells, movement of PR into foci required exposure to ligand and was blocked by transcriptional inhibitors and by prolonged inhibition of proteasomal degradation. Foci contained PR dimers, and fluorescence resonance energy transfer demonstrated that PR foci contained the highest concentration of receptor dimers in the nucleus. PR in foci colocalized with transcription factors and nascent RNA transcripts only in the presence of ligand, and inhibition of coactivator recruitment inhibited PR foci formation. The demonstration that focal distribution of PR within the nucleus is associated with transcription suggests a link between the subnuclear distribution of PR and its transcriptional activity that is likely to be important for normal cellular function of PR.

Background: Vitamin D status might be associated with cancer survival. Survival after ovarian cancer is poor, but the association with vitamin D has rarely been examined. Objective: We evaluated the association between serum 25-hydroxyvitamin D [25(OH)D], a marker of vitamin D status, and ovarian cancer survival. Design: Participants were women with invasive ovarian cancer diagnosed between 2002 and 2005 who participated in the Australian Ovarian Cancer Study. Serum samples, collected at diagnosis (n = 670) or after completion of primary treatment and before recurrence (n = 336), were assayed for 25(OH)D. Sociodemographic, dietary, and lifestyle data came from questionnaires self-completed at recruitment, and clinical and survival data were from medical records, supplemented by linkage to the Australian National Death Index (October 2011). Cox proportional hazards regression was used to estimate HRs and 95% CIs for the association between circulating 25(OH)D and survival. Results: Overall, 59% of the women died during follow-up, with 95% of deaths resulting from ovarian cancer. Circulating 25(OH)D concentrations (mean: 44 nmol/L) were significantly associated with age, state of residence, season of blood collection, and body mass index but not with tumor histology, stage or grade, or comorbidities. Higher 25(OH)D concentrations at diagnosis were significantly associated with longer survival (adjusted HR: 0.93; 95% CI: 0.88, 0.99 per 10 nmol/L), but there was no significant association with progression-free survival or for 25(OH)D measured after primary treatment. Conclusions: In our cohort, higher serum 25(OH)D concentrations at diagnosis were associated with longer survival among women with ovarian cancer. If confirmed in other studies, this suggests that vitamin D status at diagnosis may be an independent predictor of prognosis. Furthermore, if the association is found to be causal, improving vitamin D status may improve ovarian cancer survival rates.

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology. ispartof: Nature communications vol:5 pages:4999- ispartof: location:England status: published

Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-κB (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P < 2.5 × 10−5). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41–2.35; P = 4.13 × 10−6] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56–0.82; P = 2.33 × 10−5). Other associations of note included TNF receptor–associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77–0.92; P = 6.49 × 10−5) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26–0.73; P = 4.56 × 10−4). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies. Cancer Epidemiol Biomarkers Prev; 23(7); 1421–7. ©2014 AACR.

This study assesses regional coronary flow reserve using adenosine thallium-201 scintigraphy early and 6 months after angiographically successful percutaneous transluminal coronary angioplasty (PTCA) or stent implantation. Seventeen consecutive men with a significant isolated left anterior descending coronary artery stenosis were scheduled for repeat coronary angiography and adenosine-planar thallium-201 scintigraphy within 24 hours and 6 months after successful PTCA (n = 8) or stent implantation (n = 9). After background subtraction, left ventricular segmental uptake was semiquantitatively assessed on thallium images. The perfusion defect severity was scored from 0 (normal) to 3. Coronary angiograms were analyzed using an automated edge contour detection computer analysis system. Data are expressed as mean value +/- 1 SD, and proportions as percentage. The residual narrowing was 17 +/- 8% after PTCA and 9 +/- 2% after stent implantation (p = 0.02). Twenty-four hours after the procedure, hypoperfused segments were detected in all patients (100%) and in 4 patients (44%) (p = 0.05), respectively. The total number of hypoperfused segments was greater after PTCA than after stent implantation (16 [40%] vs 7 [16%], p = 0.001, respectively) as was the perfusion defect severity (4.4 +/- 3.1 vs 1 +/- 1.2, p = 0.006). Six months after the procedure, 3 of the 5 patients who had undergone PTCA without restenosis still had reversible perfusion defects. None of the stent-treated patients had restenosis or reversible perfusion defects (p = 0.05). Among PTCA-treated patients without restenosis, the total number of hypoperfused segments and the perfusion defect severity were 9 of 25 (36%) and 0.8 +/- 0.8, respectively. Thus, a regional reduction in coronary flow reserve, occasionally observed early after successful stent implantation, is probably due to a transient alteration of small coronary vessels, as was also supported by the absence of perfusion defects 6 months after the procedure. The more severe impairment of regional coronary flow reserve observed early after successful PTCA is probably also due to angiographic underestimation of the residual stenosis, as suggested also by the persistence of reversible perfusion defects 6 months after the procedure in a few patients.

Hypertriglyceridemia is a common metabolic disorder with a major inherited component. In some individuals the condition is suspected to occur as a result of overproduction of apolipoprotein (apo)CIII, a major constituent of triglyceride-rich lipoproteins. Population studies have established an association with the apoCIII gene but the identify of the causal mutation remains unknown. In the present study we have examined a series of six 5' polymorphic nucleotides (G-935 to A, C-641 to A, G-630 to A, deletion of T-625, C-482 to T, and T-455 to C) that lie within the promoter region of the apoCIII gene for evidence of possible involvement in disease susceptibility. The polymorphic nucleotides at positions -455 and -482 reside within a negative insulin-response element. We show, in a community-based sample of 503 school children, that a DNA polymorphism (S2 allele) within the 3'-noncoding region of the apoCIII gene was associated with elevated apoCIII and triglyceride levels, but that the polymorphic nucleotides of the promoter were not. In addition, no obvious effect of any extended apoCIII promoter haplotype on plasma apoCIII or triglyceride levels, over and above that conferred by the presence of the S2 polymorphic nucleotide, was detected. These results demonstrate that none of the 5' apoCIII polymorphisms can account for the association of the apoCIII gene locus with hypertriglyceridemia and, moreover, owing to linkage disequilibrium, raise the possibility that the region conferring susceptibility maps downstream, rather than upstream, of the apoCIII gene promoter sequences.

To assess whether inflammatory markers predict atherosclerotic disease activity after carotid treatment in patients with severe carotid stenosis and nonsignificant coronary artery disease undergoing carotid stenting.From March 1, 2004, to September 30, 2005, a total of 55 consecutive patients (mean ± SD age, 69±8.3 years; 26 men) with severe carotid stenosis and nonsignificant coronary artery disease were treated with carotid stent implantation. Patients were followed up for a period of 5 years for the occurrence of cardiovascular events.A significant correlation between quantitative analysis of debris entrapped in the filters and inflammatory markers was found. Moreover, the number of particles per filter, the total particles area, and the mean particle axis per filter were significantly higher in patients with clinical events at the follow-up compared with patients without events (87 vs 32, P=.006; 50,118.7 vs 17,782, P=.002; 33.9 vs 30.2, P=.03). At 5-year follow-up we recorded cardiovascular or neurologic events in 11 of the 55 patients (20%). Higher preprocedural levels of high-sensitivity C-reactive protein, interleukin 6 soluble receptor, and interleukin 6 were significantly associated with clinical events at follow-up (P.001, P=.05, and P=.02, respectively). In particular high-sensitivity C-reactive protein measured at 24 and 48 hours after carotid stenting showed a significant correlation with clinical events (P=.001). Also preprocedural intracellular adhesion molecule 1 and circulating vascular cell adhesion molecule 1 blood concentrations were significantly correlated with a worse prognosis at follow-up (P=.04 and P=.03, respectively).In patients with severe carotid stenosis and nonsignificant coronary artery disease, inflammation is associated with atherosclerotic disease activity and a worse prognosis. Interleukin 6, interleukin 6 soluble receptor, intracellular adhesion molecule 1, vascular cell adhesion molecule 1, and high-sensitivity C-reactive protein levels at baseline and 24 and 48 hours after carotid stenting are predictive of neurologic and cardiovascular events at follow-up.

Foraminiferal assemblages in the coastal pools system from Oliveri-Tindari (North-eastern Sicily).Benthic foraminiferal assemblages from the Oliveri-Tindari lagoon (Messina, Italy), located on the Tyrrhenian coast of Sicily, have been studied.Results of grain size analyses showed that the silt fraction is predominant in almost all pools, except for the Marinello and Mergolo pools, whose sediment can be classified as silty clays.Optical microscopy examination revealed that size fractions higher than 63µm include both terrigenous and biogenic components (mostly Foraminifera).Based on micropaleontological study, the fauna consisted of 55 foraminiferal species belonging to 26 genera. The benthic foraminiferal assemblages included eurytherme and euryhaline taxa (Miliolids, Peneroplids and Ammonias), that are characteristic of sandy substratum and warm shallow waters or brackish environments. The foraminiferal assemblages also seemed to be diversified in relation to the grain-size.An estimation of the species diversity was performed using different parameters.Statistic diversity indexes showed that the two most ancient pools (Marinello and Mergolo) are considerably less rich in species than the other ones (Nuovo, Porto Vecchio, Fondo Porto, Verde). The observed stability of the foraminiferal assemblages confirmed they are reliable indicators of average environmental conditions of coastal ponds as highly dynamic environments, at least in the short-middle temporal scale.

Purpose: Ovarian clear cell adenocarcinoma (OCCA) is an uncommon histotype that is generally refractory to platinum-based chemotherapy. We analyze here the most comprehensive gene expression and copy number data sets, to date, to identify potential therapeutic targets of OCCA. Experimental Design: Gene expression and DNA copy number were carried out using primary human OCCA tumor samples, and findings were confirmed by immunohistochemistry on tissue microarrays. Circulating interleukin (IL) 6 levels were measured in serum from patients with OCCA or high-grade serous cancers and related to progression-free and overall survival. Two patients were treated with sunitinib, and their therapeutic responses were measured clinically and by positron emission tomography. Results: We find specific overexpression of the IL6-STAT3-HIF (interleukin 6-signal transducer and activator of transcription 3-hypoxia induced factor) pathway in OCCA tumors compared with high-grade serous cancers. Expression of PTHLH and high levels of circulating IL6 in OCCA patients may explain the frequent occurrence of hypercalcemia of malignancy and thromboembolic events in OCCA. We describe amplification of several receptor tyrosine kinases, most notably MET, suggesting other potential therapeutic targets. We report sustained clinical and functional imaging responses in two OCCA patients with chemotherapy-resistant disease who were treated with sunitinib, thus showing significant parallels with renal clear cell cancer. Conclusions: Our findings highlight important therapeutic targets in OCCA, suggest that more extensive clinical trials with sunitinib in OCCA are warranted, and provide significant impetus to the growing realization that OCCA is molecularly and clinically distinct to other forms of ovarian cancer. Clin Cancer Res; 17(8); 2538–48. ©2011 AACR.

Grain-size, mineralogical and chemical analyses were carried out on fine fraction of sediments collected in the Gulfs of Patti and Milazzo, two borderland basins in the Southern Tyrrhenian extending offshore the northeastern Sicilian coast. Results of granulometric analyses on size fractions smaller than 63 μm showed that the investigated samples can be classified mainly as clayey silts. The coarse fractions (>63 μm), examined by optical microscopy, consist of a terrigenous component, representing in some samples about 98–99% of the total sediment, and by a biogenic component. This latter is mainly made up of benthic Foraminifera. The mineralogical composition of the fine fraction, determined by X-Ray diffractometry, is represented by muscovite, quartz, clay minerals, carbonates (calcite) and, in some samples, by calcium and sodium-rich plagioclases. The method of saturation with K and Mg, followed by ethylene glycol solvation and heating, are used for a qualitative determination of the clay minerals. Clay mineralogical composition is characterized by the dominance of clinochlore and illite, with minor amounts of smectite (especially montmorillonite) and vermiculite. The chemical data reflect the main mineralogical composition showing a uniform quantitative composition, with high Al 2 O 3 and SiO 2 values and very few variations in the relative abundance of the other components. The Cr/Th, Th/Sc, Th/Co and La/Sc ratios suggest a felsic nature of the source rocks. Finally the geochemical parameters such as V/Cr, U/Th, Ni/Co and Cu/Zn ratios indicate that examined sediments were deposited under oxic environments.

Purpose: An assay for the single-nucleotide polymorphism (SNP), rs61764370, has recently been commercially marketed as a clinical test to aid ovarian cancer risk evaluation in women with family histories of the disease. rs67164370 is in a 3′-UTR miRNA binding site of the KRAS oncogene and is a candidate for epithelial ovarian cancer (EOC) susceptibility. However, only one published article, analyzing fewer than 1,000 subjects in total, has examined this association. Experimental Design: Risk association was evaluated in 8,669 cases of invasive EOC and 10,012 controls from 19 studies participating in the Ovarian Cancer Association Consortium, and in 683 cases and 2,044 controls carrying BRCA1 mutations from studies in the Consortium of Investigators of Modifiers of BRCA1/2. Prognosis association was also examined in a subset of five studies with progression-free survival (PFS) data and 18 studies with all-cause mortality data. Results: No evidence of association was observed between genotype and risk of unselected EOC (OR = 1.02, 95% CI: 0.95–1.10), serous EOC (OR = 1.08, 95% CI: 0.98–1.18), familial EOC (OR = 1.09, 95% CI: 0.78–1.54), or among women carrying deleterious mutations in BRCA1 (OR = 1.09, 95% CI: 0.88–1.36). There was little evidence for association with survival time among unselected cases (HR = 1.10, 95% CI: 0.99–1.22), among serous cases (HR = 1.12, 95% CI = 0.99–1.28), or with PFS in 540 cases treated with carboplatin and paclitaxel (HR = 1.18, 95% CI: 0.93–1.52). Conclusions: These data exclude the possibility of an association between rs61764370 and a clinically significant risk of ovarian cancer or of familial ovarian cancer. Use of this SNP for ovarian cancer clinical risk prediction, therefore, seems unwarranted. Clin Cancer Res; 17(11); 3742–50. ©2011 AACR.

The role of Frank-Starling law of the heart in determining the increase in cardiac output during exercise in humans is still controversial (e.g., the mechanisms responsible for the enhancement of left ventricular [LV] filling during the shortened diastolic interval). Ten weight lifters, 12 swimmers and 12 sedentary subjects who underwent maximal upright bicycle exercise testing were studied. First-pass radionuclide angiography was performed both at rest and at peak exercise using a multicrystal gamma camera. Compared with resting values, heart rate and cardiac index at peak exercise increased by 101 +/- 16 beats/min (p less than 0.001) and 6.7 +/- 2.8 liters/min/m2 (p less than 0.001) in weight lifters, by 96 +/- 9 beats/min (p less than 0.001) and 9.5 +/- 2 liters/min/m2 (p less than 0.001) in swimmers, and by 103 +/- 9 beats/min (p less than 0.001) and 7.3 +/- 1.8 liters/min/m2 (p less than 0.001) in sedentary subjects. Stroke volume increased by 20.5 +/- 9.8 ml/m2 (p less than 0.001) in swimmers only. End-diastolic volume at peak exercise did not change in weight lifters and in swimmers; it decreased by 8.2 +/- 8.6 ml/m2 (p less than 0.01) in sedentary subjects. A significant correlation was found between the decrease in end-systolic volume and the increase in peak rapid filling rate at peak exercise in all 3 groups (r = 0.65, p less than 0.05 in weight lifters; r = 0.59, p less than 0.05 in swimmers; r = 0.67, p less than 0.05 in sedentary subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective BRCA1 mutations predispose to cancer in hormone responsive tissues. A predominance of estrogen receptor (ER)-negative breast cancers in BRCA1 mutation carriers and potential interactions between ERα and BRCA1 suggest a link between hormones and BRCA1. However, the expression pattern of ERα and other hormone receptors in BRCA1-associated ovarian cancer was unknown. Methods Twenty-two BRCA1-associated ovarian cancer cases were matched with sporadic cases (no family history of ovarian or breast cancer) for FIGO stage, grade, histologic subtype, and patient age and hormone receptor expression was measured immunohistochemically. Results ERα expression was similar in BRCA1-associated ovarian cancer compared with matched sporadic counterparts, in contrast with previous findings in BRCA1-linked breast cancer. There was also no significant difference in expression of progesterone receptors and androgen receptor between the matched cases in the two groups. However, differences were noted in the relative expression of receptor isotypes, in particular, levels of ERα and ERβ were positively correlated in sporadic tumors but inversely related in BRCA1-associated tumors. Conclusion Similar hormone receptor expression in BRCA1-associated ovarian cancer and matched sporadic counterparts may be further evidence that at least a proportion of sporadic ovarian tumors and BRCA1-associated tumors develop through similar pathways.

Primary and acquired chemotherapy resistance remains a major challenge in the treatment of epithelial ovarian cancer and there are currently few targeted treatments that improve clinical outcome. We screened for genes that could potentially be targeted to sensitise, or re-sensitise, ovarian cancer cells to chemotherapy and identified a novel candidate, Ankyrin Repeat Domain 1 (ANKRD1), not previously described in ovarian cancer. ANKRD1 is a putative transcription factor with roles in muscle development, inflammation and response to cell stress. ANKRD1 is a target of TGF-β/Wnt signalling, and is also a binding partner of Titin (TTN) which been identified as a candidate with a high probability of carrying ‘driver’ mutations in ovarian cancer. ANKRD1 was expressed in serous ovarian cancer samples and higher tumor levels were found in patients with worse outcome (overall survival, p=0.013), (Scurr et al, Clin Cancer Res 2008; 14: 6924-32). In this study we showed that ANKRD1 levels decrease in response to cisplatin, in concert with induction of PARP cleavage and apoptosis in human ovarian cancer cell lines, COLO316, PEO14 and OAW42. We showed that decreasing ANKRD1 expression using siRNA (ON-TARGETplus Human ANKRD1 siRNA) increased cisplatin-induced apoptosis. Increased cisplatin sensitivity was associated with endoplasmic reticulum (ER) stress, evidenced by induction of GRP78, GADD153 and increased intracellular Ca2+ release. We have screened drug libraries (Prestwick library) for agents that sensitise ovarian cancer cell lines to platins, via an ANKRD1 related mechanism, and have identified several potential candidate molecules. Taken together, these results suggest that ANKRD1 plays a significant role in the regulation of apoptosis in human ovarian cancer cells, and is a potential molecular target to enhance sensitivity of ovarian cancer to chemotherapy. Citation Format: Ying Lei, Beric Ross Henderson, Catherine Emmanuel, Paul Harnett, Anna de Fazio. Chemo-sensitisation in epithelial ovarian cancer cell lines by targeting Ankyrin Repeat Domain 1 (ANKRD1). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4616. doi:10.1158/1538-7445.AM2014-4616

We performed a multi-stage genome-wide association study (GWAS) for drug response in ovarian cancer. We selected 313 chemotherapy treated patients from the Australian Ovarian Cancer Study (AOCS). Patients were treated with paclitaxel/carboplatin and the trait of interest was Progression Free Survival (PFS). We maximized power for a fixed genotyping budget by genotyping individuals from the tails of the distribution: 94 with good survival and 94 with poor survival, taking into account extent of residual disease following surgery. Patients were genotyped on Illumina HumanOmni1-Quad arrays (1140419 loci).Two further cohorts with measures of PFS and whole genome data available; 134 ovarian patients from the Mayo clinic (genotyped on Illumina HumanHap 610 arrays, 620901 loci) and 68 patients from The Cancer Genome Atlas ovarian cancer set (genotyped on Illumina Human1M arrays, 1199187 loci) were meta-analyzed with the AOCS set (stage 1). We have imputed all the stage 1 samples with reference of the 1000 Genome data to allow more direct comparison of SNPs not common to all of the arrays used (up to 6 million SNPs with good imputation quality). Based on the chemotherapy treatment received by each patient, we assigned the patients into primary and secondary analysis, with primary analysis using a more strictly defined treatment subgroup. We followed up the stage 1 findings by genotyping 26 SNPs in more than 3,000 samples collected from 8 study sites of Ovarian Cancer Association Consortium (OCAC). These 26 SNPs were mainly genotyped SNPs, chosen from 23 distinct regions showing the strongest association with chemotherapy response from either primary or secondary analysis. 2 SNPs showed nominal significance in the replication sample (chr 12: rs1861932, chr 22: rs708444). We are currently genotyping more regions to seek replication of the initial findings. In summary, we sought to identify genes that underlie individual differences in chemoresistance. In the future, typing variations in these genes will be important for personalizing drug regimes for patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4679. doi:10.1158/1538-7445.AM2011-4679

Prolactin receptor and oestrogen receptor are co-ordinately expressed in human breast cancer cell lines and in human breast tumour biopsies, leading to the suggestion that the expression of these receptors may be coupled. To examine this hypothesis, T-47D and MCF-7 human breast cancer cells were treated with sodium butyrate, a known modulator of oestrogen receptor levels, and the changes in oestrogen and prolactin receptor mRNA and binding activity were measured. In both cell lines treatment with 0.3-10 mM sodium butyrate resulted in a parallel decrease in prolactin and oestrogen receptor mRNA levels and binding activity. In T-47D cells, where the effect was transient, mRNA levels of both receptors recovered in parallel. These data indicated that oestrogen receptor and prolactin receptor gene expression is modulated in parallel by sodium butyrate and supported the hypothesis that the expression of these two receptors is coupled.

Objectives. The aim of this study was to compare risk factors for coronary atherosclerosis in children with a family history of unheralded myocardial infarction or uncomplicated stable angina. Background. In patients with unheralded myocardial infarction, coronary atherosclerosis might have a greater tendency to cause acute coronary occlusion than in patients with uncomplicated stable angina, suggesting the possibility of different risk factors in these two groups of patients. Methods. Serum lipid levels were compared in children with a family history of unheralded myocardial infarction (236 children) or uncomplicated stable angina (48 children) or no family history of ischemic heart disease (613 children). Results. Mean (± 1 SD) total serum cholesterol was higher in children with a family history of myocardial infarction than in control subjects (161 ± 28 vs. 154 ± 25 mg%, p < 0.01). In children with a family history of stable angina, mean total serum cholesterol (159 ± 25 mg%) was similar to that in children with family history of myocardial infarction. High density lipoprotein cholesterol and apolipoprotein A-I were higher in children with family history of stable angina than in children with family history of myocardial infarction and control subjects (69 ± 18 vs. 61 ± 13 and 60 ± 13 mg%, p < 0.01; 143 ± 23 vs. 130 ± 18 and 129 ± 18 mg%, p < 0.01, respectively). in children with a family history of myocardial infarction, the low density/high density lipoprotein cholesterol ratio was significantly higher than in control subjects (1.53 ± 0.64 vs. 1.44 ± 0.56, p < 0.05). Conversely, in children with a family history of stable angina, this ratio (1.24 ± 0.51) was significantly lower (p < 0.05) than in control subjects. Conclusions. Risk factors for coronary athersclerosis in children with a family history of unheralded myocardial infraction are different from those in children with a family history of uncomplicated stable angina. Higher levels of apolipoprotein A-I early in life might reduce the risk of acute coronary syndromes.