Christoph Grimm

Interleukin-1 and interleukin-6 gene polymorphisms and the risk of breast cancer in Caucasian women

Purpose: Genetic polymorphisms of cytokine-encoding genes are known to predispose to malignant disease. Interleukin (IL)-1 and IL-6 are crucially involved in breast carcinogenesis. Whether polymorphisms of the genes encoding IL-1 (IL1) and IL-6 (IL6) also influence breast cancer risk is unknown. Experimental Design: In the present case-control study, we ascertained three polymorphisms of the IL1 gene cluster [−889 C/T polymorphism of the IL1α gene (IL1A), −511 C/T polymorphism of the IL1β promoter (IL1B promoter), a polymorphism of IL1β exon 5 (IL1B exon 5)], an 86-bp repeat in intron 2 of the IL1 receptor antagonist gene (IL1RN), and the −174 G/C polymorphism of the IL6 gene (IL6) in 269 patients with breast cancer and 227 healthy controls using PCR and pyrosequencing. Results: Polymorphisms within the IL1 gene cluster and the respective haplotypes were not associated with the presence and the phenotype of breast cancer. The IL6 polymorphism was significantly associated with breast cancer. Odds ratios for women with one or two high-risk alleles versus women homozygous for the low-risk allele were 1.5 (95% confidence interval, 1.04-2.3; P = 0.04) and 2.0 (95% confidence interval, 1.1-3.6; P = 0.02), respectively. No association was ascertained between presence of the IL6 polymorphism and various clinicopathologic variables. Conclusions: Although polymorphisms within the IL1 gene cluster do not seem to influence breast cancer risk or phenotype, presence of the −174C IL6 allele increases the risk of breast cancer in Caucasian women in a dose-dependent fashion.

Monocyte Chemoattractant Protein-1 Serum Levels in Patients with Breast Cancer

The chemokine monocyte chemoattractant protein (MCP)-1 is thought to be involved in breast carcinogenesis. We evaluated MCP-1 serum levels in patients with breast cancer (n = 135), ductal carcinoma in situ (DCIS) I–III (n = 30), benign breast lesions (n = 143) and in healthy women (n = 27). We determined the value of MCP-1 serum levels as a differentiation marker between malignant, preinvasive and benign breast diseases and as a predictive marker for the biological phenotype of breast carcinoma. Median (range) MCP-1 serum levels in patients with breast cancer, DCIS I–III, benign breast lesions and healthy women were 200 (57–692) pg/ml, 194 (58–525) pg/ml, 174 (39–529) pg/ml and 175 (67–425) pg/ml, respectively. No differences were ascertained between the patient groups. In patients with breast cancer, increased MCP-1 serum levels were correlated with advanced tumor stage (p = 0.04) and lymph node involvement (p = 0.04). We were not able to establish MCP-1 as a differentiation marker between malignant and benign breast diseases. Our data might indicate that MCP-1 influences breast carcinogenesis by facilitating tumor growth and metastatic spread, thus altering the biological phenotype of the disease.

Plasma Fibrinogen Levels and Prognosis in Patients with Ovarian Cancer: A Multicenter Study

INTRODUCTION To evaluate pretherapeutic plasma fibrinogen levels as a prognostic parameter in patients with epithelial ovarian cancer (EOC). Materials and Methods. In the present multicenter study, pretherapeutic plasma fibrinogen levels were evaluated in 422 patients with EOC. Plasma fibrinogen levels were correlated with clinicopathological parameters and patient survival. RESULTS The mean (standard deviation) pretherapeutic plasma fibrinogen level was 450.0 (150.1) mg/dl. Elevated plasma fibrinogen levels were associated with advanced tumor stage (p = .01) and the presence of a postoperative residual tumor mass (p < .001), but not with histological grade (p = .1) and histological type (p = .8). In a multivariate Cox regression model, tumor stage (p < .001 and p < .001), postoperative residual tumor mass (p = .001 and p = .008), and plasma fibrinogen level (p < .001 and p = .002), but not histological type (p = .8 and p = .2), patient age (p = .9 and p = .9), and serum cancer antigen 125 (p = 0.2 and p = 0.3) and C-reactive protein (p = .2 and p = .3) levels, were associated with disease-free and overall survival, respectively. Histological grade was associated with overall but not with disease-free survival (p = .01 and p = .8), respectively. CONCLUSIONS Pretherapeutic plasma fibrinogen levels can be used as an independent prognostic parameter in patients with EOC.

SystemC-AMS Requirements, Design Objectives and Rationale

This paper presents and discusses the foundations on which the analog and mixed-signal extensions of SystemC, named SystemC-AMS, will be developed. First, requirements from targeted application domains are identified. These are then used to derive design objectives and related rationales. Finally, some preliminary seed work is presented and the outline of the analog and mixed-signal extensions development work is given.

Genetic polymorphisms associated with thrombophilia and vascular disease in women with unexplained late intrauterine fetal death: a multicenter study.

Objective: We determined whether gene polymorphisms associated with thrombophilia and vascular disease as etiologic factors were involved in the pathogenesis of pregnancy-associated complications. Methods: We conducted a multicenter case-control study in which we studied 94 women with late unexplained intrauterine fetal death (IUFD) and 94 healthy women with at least one uncomplicated full-term pregnancy and no history of IUFD. We obtained blood samples from all subjects and analyzed their DNA for 12 common polymorphisms of thrombophilic and vascular genes (factor V Leiden, factor V H1299R, prothrombin G20210A, factor XIII V34L, MTHFR C677T, MTHFR A1298C, betafibrinogen-455 G to A, PAI-1 4G/5G, GPIIIa L33P, HFE C282Y, apolipoprotein B R3500Q, and apolipoprotein E2/E3/E4). Results: We found no significant association between any of the polymorphisms investigated and IUFD. Subgroup analyses involving various combinations of polymorphisms and in which gestational age and fetal weight were corrected for also showed no significant results. Conclusions: Our data represent the largest study to date with respect to thrombophilic and vascular gene polymorphisms in IUFD. In accordance with others, we challenge the importance of thrombophilic and vascular gene polymorphisms in the pathogenesis of this condition.

Towards analog and mixed-signal SOC design with systemC-AMS

Systems-on-Chip (SoCs) are heterogeneous by nature as they may integrate digital, analog, RF hardware as well as software components or non electrical parts such as sensors or actuators. The increasing level of complexity for designing SoCs in a reasonable amount of time and resources asks, among other capabilities, for powerful modeling and simulation means. SystemC is emerging as a de facto standard for digital system design, but is still lacking a standard support of continuous-time and mixed discrete-event/continuous-time systems. This paper presents the first elements of extensions to SystemC, called SystemC-AMS, that are proposed to fill the gap.

Treatment of cervical intraepithelial neoplasia with topical imiquimod: a randomized controlled trial.

OBJECTIVE: Alternatives to surgical therapy are needed for the treatment of high-grade cervical intraepithelial neoplasia (CIN 2–3). We aimed to estimate the efficacy of a treatment with imiquimod, a topical immune-response modulator, in patients with CIN 2–3. MATERIALS AND METHODS: Fifty-nine patients with untreated CIN 2–3 were randomly allocated to a 16-week treatment with self-applied vaginal suppositories containing either imiquimod or placebo. The main outcome was efficacy, defined as histologic regression to CIN 1 or less after treatment. Secondary outcomes were complete histologic remission, human papillomavirus (HPV) clearance, and tolerability. Assuming a two-sided 5% significance level and a power of 80%, a sample size of 24 patients per group was calculated to detect a 35% absolute increase in CIN 2–3 regression. RESULTS: Histologic regression was observed in 73% of patients in the imiquimod group compared with 39% in the placebo group (P=.009). Complete histologic remission was higher in the imiquimod group (47%) compared with the placebo group (14%) (P=.008). At baseline, all patients tested positive for high-risk HPV. Human papillomavirus clearance rates were increased in the imiquimod group (60%) compared with the placebo group (14%) (P<.001). In patients with HPV-16 infection, complete remission rates were 47% in the imiquimod group compared with 0% in the placebo group (P=.003). Microinvasive cancer was observed in three of 59 (5% [1–14%]) patients, all within the placebo group. Topical imiquimod treatment was well tolerated, and no high-grade side effects were observed. CONCLUSION: Topical imiquimod is an efficacious and feasible treatment for patients with CIN 2–3. CLINCAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00941252. LEVEL OF EVIDENCE: I

Extending SystemC to support mixed discrete-continuous system modeling and simulation

Systems on chip are more and more heterogeneous and include software, analog/RF and digital hardware, and non-electronic components, such as sensors or actuators. The design and verification of such systems require appropriate modeling means to deal with the increasing complexity and to achieve efficient simulation. SystemC, a set of C++ classes and methods, provides a modeling and simulation framework that supports digital (discrete) hardware and software systems from abstract specifications to register transfer level models. We propose a way to extend the capabilities of SystemC to support mixed discrete-continuous systems by implementing a synchronous dataflow (SDF) model of computation (MoC). The SDF MoC is used to embed continuous-time behavior in SDF modules and to support synchronization with the existing SystemC kernel. The paper presents an overview of the architecture and the syntax of the proposed extensions and gives modeling examples with simulation results.

Analog and mixed signal modelling with SystemC-AMS

SystemC is likely to become more and more important for the design of digital circuits from the specification down to the RT-level. Complex systems often contain analog components. This paper introduces concepts for the extension of the SystemC methodology for the specification and design of analog and mixed signal systems. The concepts are illustrated on a telecommunication system including digital hardware and software, analog filter and an analog environment.

p16INK4a expression in invasive vulvar squamous cell carcinoma.

p16INK4a, a member of the INK4a family of cyclin-dependent kinase inhibitors, is known as a negative regulator of cell cycle progression and differentiation. Although p16INK4a has been shown to be a promising biomarker for the detection of cervical intraepithelial neoplasia, few data have been published on vulvar cancer. Using immunohistochemistry, we evaluated the expression of p16INK4a in 80 cases of invasive vulvar squamous cell carcinoma. Results were correlated with clinicopathologic parameters and survival data to determine the prognostic significance of p16INK4a in vulvar cancer. p16INK4a expression was detected in 34 of 80 (43%) cases of invasive vulvar squamous cell carcinoma. The expression was localized to the cytoplasm and the nuclei of the tumor cells. Correlations between p16INK4a expression status and any clinicopathologic variables failed to be of statistical significance. In a univariate analysis, groin lymph node status, tumor stage, and tumor grade were associated with disease-free and overall survival, respectively. Patients positive for p16INK4a expression showed a significantly longer disease-free and overall survival by univariate analysis. p16INK4a expression was not associated with survival in a multivariate Cox-regression model. Our data add on those published in the literature and suggest that p16INK4a may be of prognostic significance in invasive vulvar squamous cell carcinoma.