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Background: Matrix metalloproteinases (MMPs) are involved in the degradation of protein components of the extracellular matrix and thus play an important role in tumor invasion and metastasis. Their expression is related to the progression of gynecological cancers (e.g. endometrial, cervical or ovarian carcinoma). In this study we investigated the expression pattern of the 23 MMPs, currently known in humans, in different gynecological cancer cell lines. Methods: In total, cell lines from three endometrium carcinomas (Ishikawa, HEC-1-A, AN3 CA), three cervical carcinomas (HeLa, Caski, SiHa), three chorioncarcinomas (JEG, JAR, BeWo), two ovarian cancers (BG-1, OAW-42) and one teratocarcinoma (PA-1) were examined. The expression of MMPs was analyzed by RT-PCR, Western blot and gelatin zymography. Results: We demonstrated that the cell lines examined can constitutively express a wide variety of MMPs on mRNA and protein level. While MMP-2, -11, -14 and -24 were widely expressed, no expression was seen for MMP-12, -16, -20, -25, -26, -27 in any of the cell lines. A broad range of 16 MMPs could be found in the PA1 cells and thus this cell line could be used as a positive control for general MMP experiments. While the three cervical cancer cell lines expressed 10-14 different MMPs, the median expression in endometrial and choriocarcinoma cells was 7 different enzymes. The two investigated ovarian cancer cell lines showed a distinctive difference in the number of expressed MMPs (2 vs. 10). Conclusions: Ishikawa, Caski, OAW-42 and BeWo cell lines could be the best choice for all future experiments on MMP regulation and their role in endometrial, cervical, ovarian or choriocarcinoma development, whereas the teratocarcinoma cell line PA1 could be used as a positive control for general MMP experiments.
The Marketing Effect
(2010)
Over the last years, evidence has accumulated suggesting that by systematically reducing the amount of dietary carbohydrates (CHOs) one could suppress, or at least delay, the emergence of cancer, and that proliferation of already existing tumor cells could be slowed down. This hypothesis is supported by the association between modern chronic diseases like the metabolic syndrome and the risk of developing or dying from cancer. CHOs or glucose, to which more complex carbohydrates are ultimately digested, can have direct and indirect effects on tumor cell proliferation: first, contrary to normal cells, most malignant cells depend on steady glucose availability in the blood for their energy and biomass generating demands and are not able to metabolize significant amounts of fatty acids or ketone bodies due to mitochondrial dysfunction. Second, high insulin and insulin-like growth factor (IGF)-1 levels resulting from chronic ingestion of CHO-rich Western diet meals, can directly promote tumor cell proliferation via the insulin/IGF1 signaling pathway. Third, ketone bodies that are elevated when insulin and blood glucose levels are low, have been found to negatively affect proliferation of different malignant cells in vitro or not to be usable by tumor cells for metabolic demands, and a multitude of mouse models have shown antitumorigenic properties of very low CHO ketogenic diets. In addition, many cancer patients exhibit an altered glucose metabolism characterized by insulin resistance and may profit from an increased protein and fat intake. In this review, we address the possible beneficial effects of low CHO diets on cancer prevention and treatment. Emphasis will be placed on the role of insulin and IGF1 signaling in tumorigenesis as well as altered dietary needs of cancer patients.
Background: Tumor patients exhibit an increased peripheral demand of fatty acids and protein. Contrarily, tumors utilize glucose as their main source of energy supply. Thus, a diet supplying the cancer patient with sufficient fat and protein for his demands while restricting the carbohydrates (CHO) tumors thrive on, could be a helpful strategy in improving the patients’ situation. A ketogenic diet (KD) fulfills these requirements. Therefore, we performed a pilot study to investigate the feasibility of a KD and its influence on the quality of life of patients with advanced metastatic tumors. Methods: Sixteen patients with advanced metastatic tumors and no conventional therapeutic options participated in the study. The patients were instructed to follow a KD (less than 70 g CHO per day) with normal groceries and were provided with a supply of food additives to mix a protein/fat shake to simplify the 3-month intervention period. Quality of life [assessed by EORTC QLQ-C30 (version 2)], serum and general health parameters were determined at baseline, after every two weeks of follow-up, or after drop out. The effect of dietary change on metabolism was monitored daily by measuring urinary ketone bodies. Results: One patient did not tolerate the diet and dropped out within 3 days. Among those who tolerated the diet, two patients died early, one stopped after 2 weeks due to personal reasons, one felt unable to stick to the diet after 4 weeks, one stopped after 6 and two stopped after 7 and 8 weeks due to progress of the disease, one had to discontinue after 6 weeks to resume chemotherapy and five completed the 3 month intervention period. These five and the one who resumed chemotherapy after 6 weeks report an improved emotional functioning and less insomnia, while several other parameters of quality of life remained stable or worsened, reflecting their very advanced disease. Except for temporary constipation and fatigue, we found no severe adverse side effects, especially no changes in cholesterol or blood lipids. Conclusions: These pilot data suggest that a KD is suitable for even advanced cancer patients. It has no severe side effects and might improve aspects of quality of life and blood parameters in some patients with advanced metastatic tumors.
Glioblastomas are characterized by an aggressive local growth pattern, a marked degree of invasiveness and poor prognosis. Tumor invasiveness is facilitated by the increased activity of proteolytic enzymes which are involved in destruction of the extracellular matrix of the surrounding healthy brain tissue. Elevated levels of matrix metalloproteinases (MMPs) were found in glioblastoma (GBM) cell-lines, as well as in GBM biopsies as compared with low-grade astrocytoma (LGA) and normal brain samples, indicating a role in malignant progression. A careful review of the available literature revealed that both the expression and role of several of the 23 human MMP proteins is controversely discussed and for some there are no data available at all. We therefore screened a panel of 15 LGA and 15 GBM biopsy samples for those MMPs for which there is either no, very limited or even contradictory data available. Hence, this is the first complete compilation of the expression pattern of all 23 human MMPs in astrocytic tumors. This study will support a better understanding of the specific expression patterns and interaction of proteolytic enzymes in malignant human glioma and may provide additional starting points for targeted patient therapy.
Breast cancer is the most common cancer among women worldwide. Every year, nearly 1.4 million new cases of breast cancer are diagnosed, and about 450.000 women die of the disease. Approximately 15-25% of breast cancer cases exhibit increased quantities of the trans-membrane receptor tyrosine kinase human epidermal growth factor receptor 2 (HER2) on the tumor cell surface. Previous studies showed that blockade of this HER2 proto-oncogene with the antibody trastuzumab substantially improved the overall survival of patients with this aggressive type of breast cancer. Recruitment of natural killer (NK) cells and subsequent induction of antibody-dependent cell-mediated cytotoxicity (ADCC) contributed to this beneficial effect. We hypothesized that antibody binding to HER2-positive breast cancer cells and thus ADCC might be further improved by synergistically applying two different HER2-specific antibodies, trastuzumab and pertuzumab. We found that tumor cell killing via ADCC was increased when the combination of trastuzumab, pertuzumab, and NK cells was applied to HER2-positive breast cancer cells, as compared to the extent of ADCC induced by a single antibody. Furthermore, a subset of \(CD44^{high}CD24^{low}HER2^{low}\) cells, which possessed characteristics of cancer stem cells, could be targeted more efficiently by the combination of two HER2-specific antibodies compared to the efficiency of one antibody. These in vitro results demonstrated the immunotherapeutic benefit achieved by the combined application of trastuzumab and pertuzumab. These findings are consistent with the positive results of the clinical studies, CLEOPATRA and NEOSPHERE, conducted with patients that had HER2-positive breast cancer. Compared to a single antibody treatment, the combined application of trastuzumab and pertuzumab showed a stronger ADCC effect and improved the targeting of breast cancer stem cells.
Candida albicans and Candida dubliniensis are pathogenic fungi that are highly related but differ in virulence and in some phenotypic traits. During in vitro growth on certain nutrient-poor media, C. albicans and C. dubliniensis are the only yeast species which are able to produce chlamydospores, large thick-walled cells of unknown function. Interestingly, only C. dubliniensis forms pseudohyphae with abundant chlamydospores when grown on Staib medium, while C. albicans grows exclusively as a budding yeast. In order to further our understanding of chlamydospore development and assembly, we compared the global transcriptional profile of both species during growth in liquid Staib medium by RNA sequencing. We also included a C. albicans mutant in our study which lacks the morphogenetic transcriptional repressor Nrg1. This strain, which is characterized by its constitutive pseudohyphal growth, specifically produces masses of chlamydospores in Staib medium, similar to C. dubliniensis. This comparative approach identified a set of putatively chlamydospore-related genes. Two of the homologous C. albicans and C. dubliniensis genes (CSP1 and CSP2) which were most strongly upregulated during chlamydospore development were analysed in more detail. By use of the green fluorescent protein as a reporter, the encoded putative cell wall related proteins were found to exclusively localize to C. albicans and C. dubliniensis chlamydospores. Our findings uncover the first chlamydospore specific markers in Candida species and provide novel insights in the complex morphogenetic development of these important fungal pathogens.
Background: Ketogenic diets (KDs) have gained some popularity not only as effective weight-loss diets and treatment options for several diseases, but also among healthy and physically active individuals for various reasons. However, data on the effects of ketosis in the latter group of individuals are scarce. We therefore collected pilot data on the physiological response to a self-prescribed ketogenic diet lasting 5-7 weeks in a small cohort of healthy and physically active individuals. Methods: Twelve subjects (7 males, 5 females, age 24-60 years) who followed moderate to intensive exercise routines underwent blood testing, bioelectrical impedance analysis (BIA) and spiroergometry during an incremental treadmill test. On the next day, they went on a self-prescribed KD for a median of 38 days (range 35-50 days), after which the same tests were performed again. Ketosis was self-monitored by urinary ketone strips. Subjective feeling during the diet was assessed by a questionnaire after the intervention. Due to the small and heterogenous sample, the results are interpreted in the context of the already existing literature. Results: The KDs were tolerated well by the majority of individuals. Impaired recovery from exercise remained the most frequently reported side effect until the end of the study. Most blood parameters remained stable during the intervention. However, there were significant elevations of total and LDL cholesterol concentrations (p<0.01) and a trend towards increased HDL-cholesterol (p=0.05). The drastic reduction of carbohydrates had no statistically significant influence on running performance judged by the time to exhaustion, VO2max and respiratory compensation points. BIA measurements showed significant increases in phase angle (p=0.01) indicating improvements of body composition with an estimated decrease of 3.4 kg of fat mass (p=0.002) and gain of 1.3 kg of fat free mass. We discuss the validity of these estimates taking into account a possibly altered hydration status due to the KD. Conclusions: Active healthy individuals will probably experience no major problems during a short term KD lasting several weeks. The drastically reduced carbohydrate content of the diet seems to be no limiting factor for running performance. In addition, improvements in body composition can be expected. While most biochemical parameters are not influenced by the diet, there seems to be an impact on the blood lipid profile that could be considered problematic with respect to cardiovascular disease risk. However, the predictive role of cholesterol levels alone in individuals undergoing regular physical activity remains to be elucidated.
Background
The epidural route is still considered the gold standard for labour analgesia, although it is not without serious consequences when incorrect placement goes unrecognized, e.g. in case of intravascular, intrathecal and subdural placements. Until now there has not been a viable alternative to epidural analgesia especially in view of the neonatal outcome and the need for respiratory support when long-acting opioids are used via the parenteral route. Pethidine and meptazinol are far from ideal having been described as providing rather sedation than analgesia, affecting the cardiotocograph (CTG), causing fetal acidosis and having active metabolites with prolonged half-lives especially in the neonate. Despite these obvious shortcomings, intramuscular and intravenously administered pethidine and comparable substances are still frequently used in delivery units.
Since the end of the 90ths remifentanil administered in a patient-controlled mode (PCA) had been reported as a useful alternative for labour analgesia in those women who either don’t want, can’t have or don’t need epidural analgesia.
Discussion
In view of the need for conversion to central neuraxial blocks and the analgesic effect remifentanil has been demonstrated to be superior to pethidine. Despite being less effective in terms of the resulting pain scores, clinical studies suggest that the satisfaction with analgesia may be comparable to that obtained with epidural analgesia. Owing to this fact, remifentanil has gained a place in modern labour analgesia in many institutions.
However, the fact that remifentanil may cause harm should not be forgotten when the use of this potent mu-agonist is considered for the use in labouring women. In the setting of one-to-one midwifery care, appropriate monitoring and providing that enough experience exists with this potent opioid and the treatment of potential complications, remifentanil PCA is a useful option in addition to epidural analgesia and other central neuraxial blocks. Already described serious consequences should remind us not refer to remifentanil PCA as a “poor man’s epidural” and to safely administer remifentanil with an appropriate indication.
Summary
Therefore, the authors conclude that economic considerations and potential cost-savings in conjunction with remifentanil PCA may not be appropriate main endpoints when studying this valuable method for labour analgesia.