Pim-selective inhibitor DHPCC-9 reveals Pim kinases as potent stimulators of cancer cell migration and invasion

Conclusions: Altogether, our data indicate that DHPCC-9 is not only a powerful tool to investigate physiological effects of the oncogenic Pim family kinases, but also an attractive molecule for drug development to inhibit invasiveness of Pim-overexpressing cancer cells

Dairy consumption and cardiometabolic diseases: systematic review and updated meta-analyses of prospective cohort studies

Purpose of Review Dairy products contain both beneficial and harmful nutrients in relation to cardiometabolic diseases. Here, we provide the latest scientific evidence regarding the relationship between dairy products and cardiometabolic diseases by reviewing the literature and updating meta-analyses of observational studies. Recent Findings We updated our previous meta-analyses of cohort studies on type 2 diabetes, coronary heart disease (CHD), and stroke with nine studies and confirmed previous results. Total dairy and low-fat dairy (per 200 g/d) were inversely associated with a 3–4% lower risk of diabetes. Yogurt was non-linearly inversely associatedwith diabetes (RR = 0.86, 95%CI: 0.83–0.90 at 80 g/ d). Total dairy and milk were not associated with CHD (RR~1.0). An increment of 200 g of daily milk intake was associated with an 8% lower risk of stroke. Summary The latest scientific evidence confirmed neutral or beneficial associations between dairy products and risk of cardiometabolic diseases

Medical theses as part of the scientific training in basic medical and dental education: experiences from Finland

<p>Abstract</p> <p>Background</p> <p>Teaching the principles of scientific research in a comprehensive way is important at medical and dental schools. In many countries medical and dental training is not complete until the candidate has presented a diploma thesis. The objective of this study was to evaluate the nature, quality, publication pattern and visibility of Finnish medical diploma theses.</p> <p>Methods</p> <p>A total of 256 diploma theses presented at the University of Oulu from 2001 to 2003 were analysed. Using a standardised questionnaire, we extracted several characteristics from each thesis. We used the name of the student to assess whether the thesis resulted in a scientific publication indexed in medical article databases. The number of citations received by each published thesis was also recorded.</p> <p>Results</p> <p>A high proportion of the theses (69.5%) were essentially statistical in character, often combined with an extensive literature review or the development of a laboratory method. Most of them were supervised by clinical departments (55.9%). Only 61 theses (23.8%) had been published in indexed scientific journals. Theses in the fields of biomedicine and diagnostics were published in more widely cited journals. The median number of citations received per year was 2.7 and the range from 0 to 14.7.</p> <p>Conclusion</p> <p>The theses were seldom written according to the principles of scientific communication and the proportion of actually published was small. The visibility of these theses and their dissemination to the scientific community should be improved.</p

Zoledronic acid treatment impairs protein geranyl-geranylation for biological effects in prostatic cells

BACKGROUND: Nitrogen-containing bisphosphonates (N-BPs) have been designed to inhibit osteoclast-mediated bone resorption. However, it is now accepted that part of their anti-tumor activities is related to interference with the mevalonate pathway. METHODS: We investigated the effects of zoledronic acid (ZOL), on cell proliferation and protein isoprenylation in two tumoral (LnCAP, PC-3,), and one normal established (PNT1-A) prostatic cell line. To assess if inhibition of geranyl-geranylation by ZOL impairs the biological activity of RhoA GTPase, we studied the LPA-induced formation of stress fibers. The inhibitory effect of ZOL on geranyl geranyl transferase I was checked biochemically. Activity of ZOL on cholesterol biosynthesis was determined by measuring the incorporation of (14)C mevalonate in cholesterol. RESULTS: ZOL induced dose-dependent inhibition of proliferation of all the three cell lines although it appeared more efficient on the untransformed PNT1A. Whatever the cell line, 20 μM ZOL-induced inhibition was reversed by geranyl-geraniol (GGOH) but neither by farnesol nor mevalonate. After 48 hours treatment of cells with 20 μM ZOL, geranyl-geranylation of Rap1A was abolished whereas farnesylation of HDJ-2 was unaffected. Inhibition of Rap1A geranyl-geranylation by ZOL was rescued by GGOH and not by FOH. Indeed, as observed with treatment by a geranyl-geranyl transferase inhibitor, treatment of PNT1-A cells with 20 μM ZOL prevented the LPA-induced formation of stress fibers. We checked that in vitro ZOL did not inhibit geranyl-geranyl-transferase I. ZOL strongly inhibited cholesterol biosynthesis up to 24 hours but at 48 hours 90% of this biosynthesis was rescued. CONCLUSION: Although zoledronic acid is currently the most efficient bisphosphonate in metastatic prostate cancer management, its mechanism of action in prostatic cells remains unclear. We suggest in this work that although in first intention ZOL inhibits FPPsynthase its main biological actitivity is directed against protein Geranylgeranylation

Invasive characteristics of human prostatic epithelial cells: understanding the metastatic process

Prostate cancer has a predilection to metastasise to the bone marrow stroma (BMS) by an as yet uncharacterised mechanism. We have defined a series of coculture models of invasion, which simulate the blood/BMS boundary and allow the elucidation of the signalling and mechanics of trans-endothelial migration within the complex bone marrow environment. Confocal microscopy shows that prostate epithelial cells bind specifically to bone marrow endothelial-to-endothelial cell junctions and initiate endothelial cell retraction. Trans-endothelial migration proceeds via an epithelial cell pseudopodial process, with complete epithelial migration occurring after 232±43 min. Stromal-derived factor-1 (SDF-1)/CXCR4 signalling induced PC-3 to invade across a basement membrane although the level of invasion was 3.5-fold less than invasion towards BMS (P=0.0007) or bone marrow endothelial cells (P=0.004). Maximal SDF-1 signalling of invasion was completely inhibited by 10 μM of the SDF-1 inhibitor T140. However, 10 μM T140 only reduced invasion towards BMS and bone marrow endothelial cells by 59% (P=0.001) and 29% (P=0.011), respectively. This study highlights the need to examine the potential roles of signalling molecules and/or inhibitors, not just in single-cell models but in coculture models that mimic the complex environment of the bone marrow

Alendronate decreases orthotopic PC-3 prostate tumor growth and metastasis to prostate-draining lymph nodes in nude mice

<p>Abstract</p> <p>Background</p> <p>Metastatic prostate cancer is associated with a high morbidity and mortality but the spreading mechanisms are still poorly understood. The aminobisphosphonate alendronate, used to reduce bone loss, has also been shown to inhibit the invasion and migration of prostate cancer cells <it>in vitro</it>. We used a modified orthotopic PC-3 nude mouse tumor model of human prostate cancer to study whether alendronate affects prostate tumor growth and metastasis.</p> <p>Methods</p> <p>PC-3 cells (5 × 10⁵) were implanted in the prostates of nude mice and the mice were treated with alendronate (0.5 mg/kg/day in PBS, s.c.) or vehicle for 4 weeks. After sacrifice, the sizes of tumor-bearing prostates were measured and the tumors and prostate-draining regional iliac and sacral lymph nodes were excised for studies on markers of proliferation, apoptosis, angiogenesis and lymphangiogenesis, using histomorphometry and immunohistochemistry.</p> <p>Results</p> <p>Tumor occurrence in the prostate was 73% in the alendronate-treated group and 81% in the control group. Mean tumor size (218 mm³, range: 96–485 mm³, <it>n </it>= 11) in the alendronate-treated mice was 41% of that in the control mice (513 mm³, range: 209–1350 mm³, <it>n </it>= 13) (<it>p </it>< 0.05). In the iliac and sacral lymph nodes of alendronate-treated mice, the proportion of metastatic area was only about 10% of that in control mice (<it>p </it>< 0.001). Immunohistochemical staining of tumor sections showed that alendronate treatment caused a marked decrease in the number of CD34-positive endothelial cells in tumors (<it>p </it>< 0.001) and an increase in that of ISEL positive apoptotic cells in tumors as well as in lymph node metastases (<it>p </it>< 0.05) compared with those in the vehicle-treated mice. The density of m-LYVE-1-stained lymphatic capillaries was not changed.</p> <p>Conclusion</p> <p>Our results demonstrate that alendronate treatment opposes growth of orthotopic PC-3 tumors and decreases tumor metastasis to prostate-draining lymph nodes. This effect could be at least partly explained by decreased angiogenesis and increased apoptosis. The results suggest that bisphosphonates have anti-tumoral and anti-invasive effects on primary prostate cancer.</p

MicroRNA-125b Induces Metastasis by Targeting STARD13 in MCF-7 and MDA-MB-231 Breast Cancer Cells

MicroRNAs (miRNAs) are a class of small noncoding RNAs that regulate gene expression by targeting mRNAs to trigger either translation repression or mRNA degradation. miR-125b is down-regulated in human breast cancer cells compared with the normal ones except highly metastatic tumor cells MDA-MB-231. However, few functional studies were designed to investigate metastatic potential of miR-125b. In this study, the effects of miR-125b on metastasis in human breast cancer cells were studied, and the targets of miR-125b were also explored. Transwell migration assay, cell wound healing assay, adhesion assay and nude mice model of metastasis were utilized to investigate the effects of miR-125b on metastasis potential in vitro and in vivo. In addition, it was implied STARD13 (DLC2) was a direct target of miR-125b by Target-Scan analysis, luciferase reporter assay and western blot. Furthermore, activation of STARD13 was identified responsible for metastasis induced by miR-125b through a siRNA targeting STARD13. qRT-PCR, immunofluorescent assay and western blot was used to observe the variation of Vimentin and α-SMA in breast cancer cells. In summary, our study provided new insights into the function of miR-125b during the metastasis of breat cancer cells and also suggested the role of miR-125b in pro-metastasis by targeting STARD13

Clinical and Organizational Factors Related to the Reduction of Mechanical Restraint Application in an Acute Ward: An 8-Year Retrospective Analysis

Background: The purpose of this study was to describe the frequency of mechanical restraint use in an acute psychiatric ward and to analyze which variables may have significantly influenced the use of this procedure. Methods: This retrospective study was conducted in the Servizio Psichiatrico di Diagnosi e Cura (SPDC) of Modena Centro. The following variables of our sample, represented by all restrained patients admitted from 1-1-2005 to 31-12-2012, were analyzed: age, gender, nationality, psychiatric diagnoses, organic comorbidity, state and duration of admission, motivation and duration of restraints, nursing shift and hospitalization day of restraint, number of patients admitted at the time of restraint and institutional changes during the observation period. The above variables were statistically compared with those of all other non-restrained patients admitted to our ward in the same period. Results: Mechanical restraints were primarily used as a safety procedure to manage aggressive behavior of male patients, during the first days of hospitalization and night shifts. Neurocognitive disorders, organic comorbidity, compulsory state and long duration of admission were statistically significantly related to the increase of restraint use (p<.001, multivariate logistic regression). Institutional changes, especially more restricted guidelines concerning restraint application, were statistically significantly related to restraint use reduction (p<.001, chi2 test, multivariate logistic regression). Conclusion: The data obtained highlight that mechanical restraint use was influenced not only by clinical factors, but mainly by staff and policy factors, which have permitted a gradual but significant reduction in the use of this procedure through a multidimensional approach

Team climate, intention to leave and turnover among hospital employees: Prospective cohort study

<p>Abstract</p> <p>Background</p> <p>In hospitals, the costs of employee turnover are substantial and intentions to leave among staff may manifest as lowered performance. We examined whether team climate, as indicated by clear and shared goals, participation, task orientation and support for innovation, predicts intention to leave the job and actual turnover among hospital employees.</p> <p>Methods</p> <p>Prospective study with baseline and follow-up surveys (2–4 years apart). The participants were 6,441 (785 men, 5,656 women) hospital employees under the age of 55 at the time of follow-up survey. Logistic regression with generalized estimating equations was used as an analysis method to include both individual and work unit level predictors in the models.</p> <p>Results</p> <p>Among stayers with no intention to leave at baseline, lower self-reported team climate predicted higher likelihood of having intentions to leave at follow-up (odds ratio per 1 standard deviation decrease in team climate was 1.6, 95% confidence interval 1.4–1.8). Lower co-worker assessed team climate at follow-up was also association with such intentions (odds ratio 1.8, 95% confidence interval 1.4–2.4). Among all participants, the likelihood of actually quitting the job was higher for those with poor self-reported team climate at baseline. This association disappeared after adjustment for intention to leave at baseline suggesting that such intentions may explain the greater turnover rate among employees with low team climate.</p> <p>Conclusion</p> <p>Improving team climate may reduce intentions to leave and turnover among hospital employees.</p