Expression Profiling of Ovarian Cancer: markers and targets for therapy

Ovarian cancer is the leading cause of death from gynecological cancer in the Western world. The initial response of the primary tumor to taxane and platinum-based chemotherapy is high, however 20% of patients never achieve a clinical response and the majority of the patients will relapse and eventually die of drug-resistant disease. Chapter 1 includes a general overview of ovarian cancer, its epidemiology, histology, typing and the different therapies. The major drawback in the treatment of ovarian cancer is late detection and therapy failure due to intrinsic and acquired chemotherapy resistance and several mechanisms involved in the platinum-based chemotherapy resistance are described. Furthermore, the importance of expression profiling (mRNA or protein) in the search for tumor markers suitable for early detection of ovarian cancer, response prediction, progression monitoring and identification of targets for therapy is discussed. Chapter 2A The expression profiling of 24 ovarian carcinomas led to the discovery of a discriminating 69-gene signature from which a predictive nine-gene set was extracted. The nine-gene set predicted the resistance in an independent validation set (n=72) with a sensitivity of 89% (95% CI: 0.68-1.09) and a specificity of 59% (95% CI: 0.47-0.71)(OR=0.09, p=0.026). The predictive nine-gene set consists of the following genes, FN1, TOP2A, LBR, ASS, COL3A1, STK6, SGPP1, ITGAE and PCNA. Interestingly, three of these nine genes are already direct or indirect targets for therapy, i.e. topoisomerase 2A (TOP2A), serine/threonine kinase 6 (STK6) and argininosuccinate synthetase (ASS). The predictive power of the nine-gene set needs to be further validated in larger independent multicenter study before this model can be implemented in the clinical practice. Chapter 2B In their â?~letter to the editorâ?T, Gevaert et al. suggest that in clinical practice, a higher specificity would have been more successful assuming that patients predicted not to respond are given a different treatment not containing platinum drugs. We agree that the predictive gene signature needs further validation before implementation in the clinical practice can be advised. However, it is was not our intention to withhold platinum treatment from patients predicted not to respond, but to tailor the treatment based on the expression profile. An overexpression of TOP2A indicates that adding a TOP2A inhibitor, like etoposide, to the conventional platinum treatment, might proof to be beneficial for the patient. Chapter 2C Underexpression of one of the nine genes from the predictive gene set, i.e. Argininosuccinate synthetase (ASS) was associated with platinum-based chemotherapy resistance. To determine if this observed association was functional, ASS was downregulated with siRNA in three ovarian cancer cell lines that were relatively sensitive to cisplatin. For all three cell lines, this did not result in a reduced response to cisplatin measured with an MTT assay. However, due to differences between cell lines and carcinomas, we cannot exclude that ASS might still play a role in platinum-based chemotherapy resistance in ovarian cancer patients. Chapter 3 One of the nine genes of the predictive gene set i.e. proliferating cell nuclear antigen (PCNA), is involved in the DNA mismatch repair (MMR). In vitro, a relationship between MMR deficiency and platinum-drug resistance was suThe full text of this item cannot yet be made available, due to a publisher's embarg

A numerical study of infinitely renormalizable area-preserving maps

It has been shown in (Gaidashev et al, 2010) and (Gaidashev et al, 2011) that infinitely renormalizable area-preserving maps admit invariant Cantor sets with a maximal Lyapunov exponent equal to zero. Furthermore, the dynamics on these Cantor sets for any two infinitely renormalizable maps is conjugated by a transformation that extends to a differentiable function whose derivative is Holder continuous of exponent alpha>0. In this paper we investigate numerically the specific value of alpha. We also present numerical evidence that the normalized derivative cocycle with the base dynamics in the Cantor set is ergodic. Finally, we compute renormalization eigenvalues to a high accuracy to support a conjecture that the renormalization spectrum is real

Clinical outcome comparison of Grade Group 1 and Grade Group 2 prostate cancer with and without cribriform architecture at the time of radical prostatectomy

Aims: Invasive cribriform and intraductal carcinoma are associated with aggressive disease in Grade Group 2 (GG2) prostate cancer patients. However, the characteristics and clinical outcome of patients with GG2 prostate cancer without cribriform architecture (GG2−) as compared with those with Grade Group 1 (GG1) prostate cancer are unknown. The aim of this study was to investigate the clinical and pathological characteristics of GG1 and GG2− prostate cancer in radical prostatectomy specimens. Methods and results: We reviewed 835 radical prostatectomy specimens for Grade Group, pT stage, surgical margin status, and the presence of cribriform architecture. Biochemical recurrence-free survival and metastasis were used as clinical outcomes. GG1 prostate cancer was seen in 207 patients, and GG2 prostate cancer was seen in 420 patients, of whom 228 (54%) showed cribriform architecture (GG2+) and 192 (46%) did not. GG2− patients had higher prostate-specific antigen levels (9.4 ng/ml versus 7.0 ng/ml; P < 0.001), more often had extraprostatic extension (36% versus 11%; P < 0.001) and had more positive surgical margins (27% versus 17%; P = 0.01) than GG1 patients. GG2− patients ha

Khinchin theorem and anomalous diffusion

A recent paper [M. H. Lee, Phys. Rev. Lett. 98, 190601 (2007)] has called attention to the fact that irreversibility is a broader concept than ergodicity, and that therefore the Khinchin theorem [A. I. Khinchin, Mathematical Foundations of Statistical Mechanics (Dover, New York) 1949] may fail in some systems. In this Letter we show that for all ranges of normal and anomalous diffusion described by a Generalized Langevin Equation the Khinchin theorem holds.Comment: 4 pages, 3 figure

No elliptic islands for the universal area-preserving map

A renormalization approach has been used in \cite{EKW1} and \cite{EKW2} to prove the existence of a \textit{universal area-preserving map}, a map with hyperbolic orbits of all binary periods. The existence of a horseshoe, with positive Hausdorff dimension, in its domain was demonstrated in \cite{GJ1}. In this paper the coexistence problem is studied, and a computer-aided proof is given that no elliptic islands with period less than 20 exist in the domain. It is also shown that less than 1.5% of the measure of the domain consists of elliptic islands. This is proven by showing that the measure of initial conditions that escape to infinity is at least 98.5% of the measure of the domain, and we conjecture that the escaping set has full measure. This is highly unexpected, since generically it is believed that for conservative systems hyperbolicity and ellipticity coexist

miR-634 restores drug sensitivity in resistant ovarian cancer cells by targeting the Ras-MAPK pathway

Background: Drug resistance hampers the efficient treatment of malignancies, including advanced stage ovarian cancer, which has a 5-year survival rate of only 30 %. The molecular processes underlying resistance have been extensively studied, however, not much is known about the involvement of microRNAs. Methods: Differentially expressed microRNAs between cisplatin sensitive and resistant cancer cell line pairs were determined using microarrays. Mimics were used to study the role of microRNAs in drug sensitivity of ovarian cancer cell lines and patient derived tumor cells. Luciferase reporter constructs were used to establish regulation of target genes by microRNAs. Results: MiR-634 downregulation was associated with cisplatin resistance. Overexpression of miR-634 affected cell cycle progression and enhanced apoptosis in ovarian cancer cells. miR-634 resensitized resistant ovarian cancer cell lines and patient derived drug resistant tumor cells to cisplatin. Similarly, miR-634 enhanced the response to carboplatin and doxorubicin, but not to paclitaxel. The cell cycle regulator CCND1, and Ras-MAPK pathway components GRB2, ERK2 and RSK2 were directly repressed by miR-634 overexpression. Repression of the Ras-MAPK pathway using a MEK inhibitor phenocopied the miR-634 effects on viability and chemosensitivity. Conclusion:miR-634 levels determine chemosensitivity in ovarian cancer cells. We identify miR-634 as a therapeutic candidate to resensitize chemotherapy resistant ovarian tumors

The VEGF pathway and the AKT/mTOR/p70S6K1 signalling pathway in human epithelial ovarian cancer

Vascular endothelial growth factor (VEGF)-A inhibitors exhibit unseen high responses and toxicity in recurrent epithelial ovarian cancer suggesting an important role for the VEGF/VEGFR pathway. We studied the correlation of VEGF signalling and AKT/mTOR signalling. Using a tissue microarray of clinical samples (N=86), tumour cell immunohistochemical staining of AKT/mTOR downstream targets, pS6 and p4E-BP1, together with tumour cell staining of VEGF-A and pVEGFR2 were semi-quantified. A correlation was found between the marker for VEGFR2 activation (pVEGFR2) and a downstream target of AKT/mTOR signalling (pS6) (R=0.29; P=0.002). Additional gene expression analysis in an independent cDNA microarray dataset (N=24) showed a negative correlation (R=−0.73, P<0.0001) between the RPS6 and the VEGFR2 gene, which is consistent as the gene expression and phosphorylation of S6 is inversely regulated. An activated tumour cell VEGFR2/AKT/mTOR pathway was associated with increased incidence of ascites (χ2, P=0.002) and reduced overall survival of cisplatin–taxane-based patients with serous histology (N=32, log-rank test, P=0.04). These data propose that VEGF-A signalling acts on tumour cells as a stimulator of the AKT/mTOR pathway. Although VEGF-A inhibitors are classified as anti-angiogenic drugs, these data suggest that the working mechanism has an important additional modality of targeting the tumour cells directly

Prostate Cancer Patients Under Active Surveillance with a Suspicious Magnetic Resonance Imaging Finding Are at Increased Risk of Needing Treatment: Results of the Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) Consortium

Background: The inclusion criterion for active surveillance (AS) is low- or intermediate-risk prostate cancer. The predictive value of the presence of a suspicious lesion at magnetic resonance imaging (MRI) at the time of inclusion is insufficiently known. Objective: To evaluate the percentage of patients needing active treatment stratified by the presence or absence of a suspicious lesion at baseline MRI. Design, setting, and participants: A retrospective analysis of the data from the multicentric AS GAP3 Consortium database was conducted. The inclusion criteria were men with grade group (GG) 1 or GG 2 prostate cancer combined with prostate-specific antigen <20 ng/ml. We selected a subgroup of patients who had MRI at baseline and for whom MRI results and targeted biopsies were used for AS eligibility. Suspicious MRI was defined as an MRI lesion with Prostate Imaging Reporting and Data System (PI-RADS)/Likert ≥3 and for which targeted biopsies did not exclude the patient for AS. Outcome measurements and statistical analysis: The primary outcome was treatment free survival (FS). The secondary outcomes were histological GG progression FS and continuation of AS (discontinuation FS). Results and limitations: The study cohort included 2119 patients (1035 men with nonsuspicious MRI and 1084 with suspicious MRI) with a median follow-up of 23 (12–43) mo. For the whole cohort, 3-yr treatment FS was 71% (95% confidence interval [CI]: 69–74). For nonsuspicious MRI and suspicious MRI groups, 3-yr treatment FS rates were, respectively, 80% (95% CI: 77–83) and 63% (95% CI: 59–66). Active treatment (hazard ratio [HR] = 2.0, p < 0.001), grade progression (HR = 1.9, p < 0.001), and discontinuation of AS (HR = 1.7, p < 0.001) were significantly higher in the suspicious MRI group than in the nonsuspicious MRI group. Conclusions: The risks of switching to treatment, histological progression, and AS discontinuation are higher in cases of suspicious MRI at inclusion. Patient summary: Among men with low- or intermediate-risk prostate cancer who choose active surveillance, those with suspicious magnetic resonance imaging (MRI) at the time of inclusion in active surveillance are more likely to show switch to treatment than men with nonsuspicious MRI

Ovarian cancer cell line panel (OCCP): Clinical importance of in vitro morphological subtypes

Epithelial ovarian cancer is a highly heterogeneous disease and remains the most lethal gynaecological malignancy in the Western world. Therapeutic approaches need to account for inter-patient and intra-tumoural heterogeneity and detailed characterization of in vitro models representing the different histological a