Search

Background: The prognostic relevance of the amount of extraprostatic cancer spread in nerves in prostate cancer patients is not well established., Methods: Eighty-eight patients were included in our study with pT3a pN0 M0 R0 prostate cancer treated with retropubic prostatectomy. Eighty-seven of them showed perineural invasion, 54 were confined to the prostate, 33 showed cancer spread in extraprostatic nerves, which was quantified by counting each transverse section of nerves infiltrated by cancer in totally embedded specimens. Biochemical relapse was established by serum PSA levels of ≥0.2 ng/ml as well as PSA ≥ 0.4 ng/ml and higher according to the EAU guidelines., Results: Extraprostatic but not intraprostatic perineural infiltration was significantly more often found in tumors of higher Gleason score. Intraprostatic number of infiltrated nerves (NIN) correlated with extraprostatic NIN. There was no association between extraprostatic or intraprostatic NIN and Gleason score, lymphatic, or blood vessel invasion. Extraprostatic neural infiltration in ≤10 nerves extended relapse free survival in univariate analysis for PSA 0.2 and 0.4 ng/ml (P = 0.002 and P < 0.000001, respectively) and remained significant in multivariate analysis for PSA 0.4 ng/ml (P = 0.039)., Conclusions: High amount of extraprostatic NIN correlates with tumor progression and seems to be an independent prognostic parameter., (Copyright © 2011 Wiley Periodicals, Inc.)

Recognition of pathogens by the innate immune system requires proteins that detect conserved molecular patterns. Nucleic acids are recognized by cytoplasmic sensors as well as by endosomal Toll-like receptors (TLRs). It has become evident that TLRs require additional proteins to be activated by their respective ligands. In this study, we show that CD14 (cluster of differentiation 14) constitutively interacts with the MyD88-dependent TLR7 and TLR9. CD14 was necessary for TLR7- and TLR9-dependent induction of proinflammatory cytokines in vitro and for TLR9-dependent innate immune responses in mice. CD14 associated with TLR9 stimulatory DNA in precipitation experiments and confocal imaging. The absence of CD14 led to reduced nucleic acid uptake in macrophages. Additionally, CD14 played a role in the stimulation of TLRs by viruses. Using various types of vesicular stomatitis virus, we showed that CD14 is dispensable for viral uptake but is required for the triggering of TLR-dependent cytokine responses. These data show that CD14 has a dual role in nucleic acid-mediated TLR activation: it promotes the selective uptake of nucleic acids, and it acts as a coreceptor for endosomal TLR activation.

Over 1 billion people are estimated to be overweight, placing them at risk for diabetes, cardiovascular disease, and cancer. We performed a systems-level genetic dissection of adiposity regulation using genome-wide RNAi screening in adult Drosophila. As a follow-up, the resulting approximately 500 candidate obesity genes were functionally classified using muscle-, oenocyte-, fat-body-, and neuronal-specific knockdown in vivo and revealed hedgehog signaling as the top-scoring fat-body-specific pathway. To extrapolate these findings into mammals, we generated fat-specific hedgehog-activation mutant mice. Intriguingly, these mice displayed near total loss of white, but not brown, fat compartments. Mechanistically, activation of hedgehog signaling irreversibly blocked differentiation of white adipocytes through direct, coordinate modulation of early adipogenic factors. These findings identify a role for hedgehog signaling in white/brown adipocyte determination and link in vivo RNAi-based scanning of the Drosophila genome to regulation of adipocyte cell fate in mammals.

Introduction: Accumulating evidence has demonstrated an association between periodontal infectious agents, such as Porphyromonas gingivalis, and vascular disease. Tissue factor (TF) and its specific tissue factor pathway inhibitor (TFPI) are produced by vascular cells and are important regulators of the coagulation cascade., Materials and Methods: To assess the role of P. gingivalis in atherothrombosis, we infected primary human aortic smooth muscle cells (HASMC) with either P. gingivalis 381, its non-invasive mutant DPG3, or heat-killed P. gingivalis 381. Levels and activity of TF and TFPI were measured 8 and 24 hours after infection in cell extracts and cell culture supernatants., Results: P. gingivalis 381 did not affect total TF antigen or TF activity in HASMC, but it significantly suppressed TFPI levels and activity compared to uninfected control cells, and those infected with the non-invasive mutant strain or the heat-killed bacteria. Further, P. gingivalis' LPS (up to a concentration of 5 microg/ml) failed to induce prothrombotic effects in HASMC, suggesting a significant role for the ability of whole viable bacteria to invade this cell type., Conclusion: These data demonstrate for the first time that infection with a periodontal pathogen induces a prothrombotic response in HASMC.

Objective: The aim of this study was to investigate the prognostic relevance of lymphangiogenesis and lymphovascular invasion in a large cohort of breast cancer patients., Introduction: Invasion of tumor cells into blood and lymphatic vessels is one of the critical steps for metastasis. The presence or absence of lymph node metastasis is one of the main decision criteria for further therapy. One shortcoming of previous morphologic studies was the lack of specific markers that could exact discriminate between blood and lymphatic vessels. The aim of this study was to evaluate the prognostic relevance of lymphangiogenesis and lymphovascular invasion in breast cancer patients., Methods: We investigated 374 tissue specimens of patients suffering from invasive breast cancer by immunostaining for the lymphatic endothelial specific marker podoplanin. Lymphangiogenesis, quantified by evaluating the lymphatic microvessels density (LMVD), and lymphovascular invasion (LVI) were correlated with various clinical parameters and prognostic relevance., Results: LMVD correlated significantly with LVI (P = 0.001). LVI was associated significantly with a higher risk for developing lymph-node metastasis (P = 0.004). Calculating the prognostic relevance, LVI presented as an independent prognostic parameter for disease free as well as overall survival (P = 0.001, and P = 0.001, respectively)., Conclusion: Our data provide evidence that the biologic system of lymphangiogenesis constitutes a potential new target for development of anti-breast cancer therapeutic concepts. Our results further suggest that young, premenopausal patients with low differentiated breast tumors and high LMVD and LVI would, in particular, benefit from lymphangiogenesis-associated therapeutic strategies.

Id-1 is an important regulator of cellular growth and differentiation and controls malignant progression of breast cancer cells. The aim of our study was to assess the clinical impact of Id-1 expression in breast cancer, i.e., its potential impact on prognosis and prediction of treatment response. Id-1 protein expression was determined immunohistochemically in 191 patients with lymph-node negative breast cancer, and univariate and multivariate survival analysis was carried out. Fifteen (7.9%) specimens showed strong expression, 75 (39.3%) moderate, 55 (28.8%) weak expression and 46 (24.1%) cases no expression of Id-1. Patients with strong or moderate Id-1 expression had a significant shorter overall (p = 0.003, Cox regression) and disease-free survival (p = 0.01, Cox regression) compared to those with absent or low expression. Progesterone receptor density was significantly higher in breast cancers with absent/low Id-1 expression compared to those with moderate/strong expression (p < 0.001, t-test). Id-1 expression was significantly stronger in cases positive for p16(INK4a) expression compared to those negative for p16 (p = 0.049, Mann-Whitney test). The influence of Id-1 on clinical outcome seems much stronger in patients with negative estrogen receptor status compared to those with positive status, who received receptor antagonists as adjuvant therapy in most cases. Overexpression of Id-1 protein represents a strong independent prognostic marker in node negative breast cancer, and future therapies inhibiting Id-1 expression might be beneficial for these patients. Our results also suggest that due to the apparent interaction of Id-1 with the steroid-receptor system in breast cancer, hormonal therapies might influence Id-1 expression and its impact on clinical outcome., (Copyright 2003 Wiley-Liss, Inc.)