Cystatin C Is Downregulated in Prostate Cancer and Modulates Invasion of Prostate Cancer Cells via MAPK/Erk and Androgen Receptor Pathways

Cystatin C is believed to prevent tumor progression by inhibiting the activities of a family of lysosomal cysteine proteases. However, little is known about the precise mechanism of cystatin C function in prostate cancer. In the present study, we examined the expression of cystatin C and its association with matrix metalloproteinases 2 (MMP2) and androgen receptor (AR) in a tissue microarray comparing benign and malignant specimens from 448 patients who underwent radical prostatectomy for localized prostate cancer. Cystatin C expression was significantly lower in cancer specimens than in benign tissues (p<0.001) and there was a statistically significant inverse correlation between expression of cystatin C and MMP2 (rs2 = −0.056, p = 0.05). There was a clear trend that patients with decreased level of cystatin C had lower overall survival. Targeted inhibition of cystatin C using specific siRNA resulted in an increased invasiveness of PC3 cells, whereas induction of cystatin C overexpression greatly reduced invasion rate of PC3 in vitro. The effect of cystatin C on modulating the PC3 cell invasion was provoked by Erk2 inhibitor that specifically inhibited MAPK/Erk2 activity. This suggests that cystatin C may mediate tumor cell invasion by modulating the activity of MAPK/Erk cascades. Consistent with our immunohistochemical findings that patients with low expression of cystatin C and high expression of androgen receptor (AR) tend to have worse overall survival than patients with high expression of cystatin C and high AR expression, induced overexpression of AR in PC3 cells expressing cystatin C siRNA greatly enhanced the invasiveness of PC3 cells. This suggests that there may be a crosstalk between cystatin C and AR-mediated pathways. Our study uncovers a novel role for cystatin C and its associated cellular pathways in prostate cancer invasion and metastasis

Consumption-based greenhouse gas emissions accounting with capital stock change highlights dynamics of fast-developing countries.

Traditional consumption-based greenhouse gas emissions accounting attributed the gap between consumption-based and production-based emissions to international trade. Yet few attempts have analyzed the temporal deviation between current emissions and future consumption, which can be explained through changes in capital stock. Here we develop a dynamic model to incorporate capital stock change in consumption-based accounting. The new model is applied using global data for 1995-2009. Our results show that global emissions embodied in consumption determined by the new model are smaller than those obtained from the traditional model. The emissions embodied in global capital stock increased steadily during the period. However, capital plays very different roles in shaping consumption-based emissions for economies with different development characteristics. As a result, the dynamic model yields similar consumption-based emissions estimation for many developed countries comparing with the traditional model, but it highlights the dynamics of fast-developing countries

CYSTATIN C AND NEUROENDOCRINE DIFFERENTIATION IN THE MALE REPRODUCTIVE SYSTEM AND IN PROSTATE CANCER

Cystatins are endogenous protease inhibitors that regulate the proteolytic activities of family C1 (papain-like) cysteine proteases, such as human cathepsins B, H, K, L, and S. Cystatin C shows the fastest inhibition and the highest affinity of all cystatins towards lysosomal cysteine proteases in general and is widespread in human tissues and body fluids. Alterations in the balance between the cysteine proteases and the cystatins have been associated with cancer cell invasion and metastasis. Neuroendocrine cells, containing growth stimulatory hormones, are found in various degrees in the vast majority of prostatic adenocarcinomas, and neuroendocrine differentiation has been correlated with tumor progression and resistance to hormonal therapy. Recent immunohistochemical studies suggest that there may be a relationship between cystatin C and the neuroendocrine system. The aim of this thesis was to examine cystatin C and neuroendocrine differentiation in the male genital tract and in prostate cancer. RESULTS AND CONCLUSIONS: 1. Cystatin C is highly expressed and widely distributed in benign tissues throughout the male genital tract, indicating that cystatin C is an important local protease inhibitor in these tissues. 2. Cystatin C is produced by prostate cancer cells in vivo and in vitro. 3. The expression of cystatin C is altered in prostate cancer relative to that in benign prostatic tissues, and there is an association between increased cathepsin B / cystatin C ratio and cancer progression and advanced disease. 4. The number of prostatic neuroendocrine cells increases during hormonal treatment, indicating that androgen-deprivation therapy enhances the selection and progression of androgen-independent neuroendocrine tumor cells. 5. Our finding of scattered, strongly cystatin C-positive neuroendocrine-like cells in prostate cancer tissues suggests that cystatin C may be a useful tissue marker for neuroendocrine differentiation in prostate cancer

Influence of standard heparin or low molecular weight heparin on healing of abdominal wounds and colonic anastomoses in rats

The influence of standard heparin or low molecular weight (LMW) heparin on healing of abdominal wounds and colonic anastomoses was studied in rats. Subcutaneous injection of 1 XaI U/g b.w. of standard or LMW-heparin or 0.5 ml physiologic saline was given 12 hours preoperatively and daily for 3 or 7 days postoperatively. Breaking strength of the abdominal wound and the anastomosis was measured, as were haemoglobin and albumin in serum. Hydroxyproline as a measure of collagen and tissue dry weight was determined in standardized segments of colonic wall adjacent to the anastomosis. Except for significant increase in breaking strength of the anastomosis after 7-day injection of LMW heparin, no differences in the parameters of wound healing were found after 3 or 7 days. In rats receiving standard heparin there was increased bleeding tendency (reduced haemoglobin) compared with the LMW-heparin group and the controls. The administered heparin thus did not negatively influence healing, and standard and LMW-heparin did not differ in this respect

Men’s Perception of Being Invited for Prostate Cancer Testing and the Information About Its Pros and Cons—A Survey from Two Population-based Testing Programmes

Background: There is no national screening programme for prostate cancer in Sweden. Instead, population-based organised prostate cancer testing (OPT) projects are introduced to make information and testing more equal and effective. Objective: To evaluate men’s perception of being invited to OPT and of the information in the invitation letter, and whether their perception is influenced by educational level. Design, setting, and participants: A questionnaire was sent out to men invited to OPT in 2020: 600 50-yr-old men in Region Västra Götaland and 1000 50-, 56-, and 62-yr-old men in Region Skåne. Outcome measurements and statistical analysis: Responses were evaluated on a Likert scale. The chi-square test was used to compare proportions. Results and limitations: A total of 534 men (34%) responded. Almost all considered the OPT concept as very good (84%) or good (13%). Among men not previously undergone a prostate-specific antigen (PSA) test, a larger proportion with nonacademic (53%) than with academic education (41%) responded that the text about disadvantages was very clear (p = 0.03). A similar difference was observed for the text about advantages (68% vs 58%, p = 0.09). There was no association between education and searching for more information elsewhere. The low response rate is the main limitation. Conclusions: Almost all responding men evaluating the invitation letter for OPT were positive about making a personal decision regarding whether or not to have a PSA test. Most were content with the brief information. Men with academic education were somewhat less likely to find the information very clear. This shows a need for further research about how best to describe the advantages and disadvantages of prostate cancer testing. Patient summary: Almost all men who responded to a questionnaire to evaluate the invitation letter for organised prostate cancer testing were positive about the opportunity to make a personal decision regarding whether or not to have a prostate-specific antigen test

Implementation of the measure of case discussion complexity to guide selection of prostate cancer patients for multidisciplinary team meetings

Background: Multidisciplinary team meetings (MDTMs) provide an integrated team approach to ensure individualized and evidence-based treatment recommendations and best expert advice in cancer care. A growing number of patients and more complex treatment options challenge MDTM resources and evoke needs for case prioritization. In this process, decision aids could provide streamlining and standardize evaluation of case complexity. We applied the recently developed Measure of Case Discussion Complexity, MeDiC, instrument with the aim to validate its performance in another healthcare setting and diagnostic area as a means to provide cases for full MDTM discussions. Methods: The 26-item MeDiC instrument evaluates case complexity and was applied to 364 men with newly diagnosed prostate cancer in Sweden. MeDiC scores were generated from individual-level health data and were correlated with clinicopathological parameters, healthcare setting, and the observed clinical case selection for MDTMs. Results: Application of the MeDiC instrument was feasible with rapid scoring based on available clinical data. Patients with high-risk prostate cancers had significantly higher MeDiC scores than patients with low or intermediate-risk cancers. In the total study, population affected lymph nodes and metastatic disease significantly influenced MDTM referral, whereas comorbidities and age did not predict MDTM referral. When individual patient MeDiC scores were compared to the clinical MDTM case selection, advanced stage, T3/T4 tumors, involved lymph nodes, presence of metastases and significant physical comorbidity were identified as key MDTM predictive factors. Conclusions: Application of the MeDiC instrument in prostate cancer may be used to streamline case selection for MDTMs in cancer care and may complement clinical case selection