Telomerase gene therapy ameliorates the effects of neurodegeneration associated to short telomeres in mice

Neurodegenerative diseases associated with old age such as Alzheimer's disease present major problems for society, and they currently have no cure. The telomere protective caps at the ends of chromosomes shorten with age, and when they become critically short, they can induce a persistent DNA damage response at chromosome ends, triggering secondary cellular responses such as cell death and cellular senescence. Mice and humans with very short telomeres owing to telomerase deficiencies have an earlier onset of pathologies associated with loss of the regenerative capacity of tissues. However, the effects of short telomeres in very low proliferative tissues such as the brain have not been thoroughly investigated. Here, we describe a mouse model of neurodegeneration owing to presence of short telomeres in the brain as the consequence of telomerase deficiency. Interestingly, we find similar signs of neurodegeneration in very old mice as the consequence of physiological mouse aging. Next, we demonstrate that delivery of telomerase gene therapy to the brain of these mice results in amelioration of some of these neurodegeneration phenotypes. These findings suggest that short telomeres contribute to neurodegeneration diseases with aging and that telomerase activation may have a therapeutic value in these diseases

Prevalence of the most frequent BRCA1 mutations in Polish population

The purpose of our study was to establish the frequency and distribution of the four most common BRCA1 mutations in Polish general population and in a series of breast cancer patients. Analysis of the population frequency of 5382insC (c.5266dupC), 300T >G (p.181T >G), 185delAG (c.68_69delAG) and 3819del5 (c.3700_3704del5) mutations of the BRCA1 gene were performed on a group of respectively 16,849, 13,462, 12,485 and 3923 anonymous samples collected at birth in seven Polish provinces. The patient group consisted of 1845 consecutive female breast cancer cases. The most frequent BRCA1 mutation in the general population was 5382insC found in 29 out of 16,849 samples (0.17%). 300T >G and 3819del5 mutations were found in respectively 11 of 13,462 (0.08%) and four of 3923 (0.1%) samples. The population prevalence for combined Polish founder 5382insC and 300T >G mutations was 0.25% (1/400). The frequencies of 5382insC and 300T >G carriers among consecutive breast cancer cases were, respectively, 1.9% (35/1845) and 1.2% (18/1486). Comparing these data with the population frequency, we calculated the relative risk of breast cancer for 5382insC mutation at OR = 17 and for 300T >G mutation at OR = 26. Our results, based on large population studies, show high frequencies of founder 5382insC and 300T >G BRCA1 mutations in Polish general population. Carriage of one of these mutations is connected with a very high relative risk of breast cancer

Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations

Women with mutations of the genes BRCA1 or BRCA2 are at increased risk of ovarian cancer. Oral contraceptives protect against ovarian cancer in general, but it is not known whether they protect against the disease in carriers of these mutations. We obtained self-reported lifetime histories of oral contraceptive use from 451 women who carried mutations of BRCA1 or BRCA2. We used conditional logistic regression to estimate the odds ratios associated with oral contraceptive use, comparing the histories of 147 women with ovarian cancer (cases) to those of 304 women without ovarian cancer (controls) who were matched to cases on year of birth, country of residence and gene (BRCA1 vs BRCA2). Reference ages for controls had to exceed the ages at diagnosis of their matched cases. After adjusting for parity, the odds-ratio for ovarian cancer associated with use of oral contraceptives for at least 1 year was 0.85 (95 percent confidence interval, 0.53-1.36). The risk decreased by 5% (1-9%) with each year of use (P for trend=0.01). Use for 6 or more years was associated with an odds-ratio of 0.62 (0.35-1.09). These data support the hypothesis that long-term oral contraceptive use reduces the risk of ovarian cancer among women who carry mutations of BRCA1 or BRCA2

Ovarian cancer histology-specific incidence trends in Canada 1969–1993: age-period-cohort analyses

This study examined histology-specific incidence trends of ovarian cancer in Canada, 1969–1993. The impact of age, period and cohort effects on these trends were studied by means of age-period-cohort analysis. Age-standardized incidence rates of serous, endometrioid, clear cell and germ cell tumours increased significantly and the rates of sex cord-stromal and other classified epithelial ovarian tumours decreased considerably. The rates of mucinous and NOS/unclassified tumours remained unchanged. Cohort effect has a major impact on incidence trends of serous, endometrioid, germ cell, sex cord-stromal and other classified epithelial ovarian tumours but no meaningful impact on trends of mucinous, clear cell, or NOS/unclassified ovarian tumours. Various cohort patterns by histology subtypes were observed: the risk of developing serious tumours increased markedly among birth cohorts of 1895–1930, stabilized thereafter and decreased among young cohorts of 1950–1960; the risk of germ cell tumours increased significantly among young cohorts of 1965–1980; and the risk of sex cord-stromal tumours dropped constantly among cohorts 1910–1950. Various period patterns by histology subtypes observed in this study suggested changes in histology classification criteria over the period. Further studies need to consider the various etiologies and the classification criteria changes according to histology subtypes. © 1999 Cancer Research Campaig

Elevated Oestrogen Receptor Splice Variant ERαΔ5 Expression in Tumour-adjacent Hormone-responsive Tissue

Susceptibility to prostate or endometrial cancer is linked with obesity, a state of oestrogen excess. Oestrogen receptor (ER) splice variants may be responsible for the tissue-level of ER activity. Such micro-environmental regulation may modulate cancer initiation and/or progression mechanisms. Real-time reverse transcriptase (RT) polymerase chain reaction (PCR) was used to quantitatively assess the levels of four ER splice variants (ERαΔ3, ERαΔ5, ERβ2 and ERβ5), plus the full-length parent isoforms ERα and ERβ1, in high-risk [tumour-adjacent prostate (n = 10) or endometrial cancer (n = 9)] vs. low-risk [benign prostate (n = 12) or endometrium (n = 9)], as well as a comparison of UK (n = 12) vs. Indian (n = 15) benign prostate. All three tissue groups expressed the ER splice variants at similar levels, apart from ERαΔ5. This splice variant was markedly raised in all of the tumour-adjacent prostate samples compared to benign tissues. Immunofluorescence analysis for ERβ2 in prostate tissue demonstrated that such splice variants are present in comparable, if not greater, amounts as the parent full-length isoform. This small pilot study demonstrates the ubiquitous nature of ER splice variants in these tissue sites and suggests that ERαΔ5 may be involved in progression of prostate adenocarcinoma

Effect of Myostatin Depletion on Weight Gain, Hyperglycemia, and Hepatic Steatosis during Five Months of High-Fat Feeding in Mice

The marked hypermuscularity in mice with constitutive myostatin deficiency reduces fat accumulation and hyperglycemia induced by high-fat feeding, but it is unclear whether the smaller increase in muscle mass caused by postdevelopmental loss of myostatin activity has beneficial metabolic effects during high-fat feeding. We therefore examined how postdevelopmental myostatin knockout influenced effects of high-fat feeding. Male mice with ubiquitous expression of tamoxifen-inducible Cre recombinase were fed tamoxifen for 2 weeks at 4 months of age. This depleted myostatin in mice with floxed myostatin genes, but not in control mice with normal myostatin genes. Some mice were fed a high-fat diet (60% of energy) for 22 weeks, starting 2 weeks after cessation of tamoxifen feeding. Myostatin depletion increased skeletal muscle mass ∼30%. Hypermuscular mice had ∼50% less weight gain than control mice over the first 8 weeks of high-fat feeding. During the subsequent 3 months of high-fat feeding, additional weight gain was similar in control and myostatin-deficient mice. After 5 months of high-fat feeding, the mass of epididymal and retroperitoneal fat pads was similar in control and myostatin-deficient mice even though myostatin depletion reduced the weight gain attributable to the high-fat diet (mean weight with high-fat diet minus mean weight with low-fat diet: 19.9 g in control mice, 14.1 g in myostatin-deficient mice). Myostatin depletion did not alter fasting blood glucose levels after 3 or 5 months of high-fat feeding, but reduced glucose levels measured 90 min after intraperitoneal glucose injection. Myostatin depletion also attenuated hepatic steatosis and accumulation of fat in muscle tissue. We conclude that blocking myostatin signaling after maturity can attenuate some of the adverse effects of a high-fat diet

Ovarian cysts in women receiving tamoxifen for breast cancer

Tamoxifen is a nonsteroidal anti-oestrogen with gynaecological side-effects. Only recently, ovarian cyst formation during tamoxifen treatment has been reported. The present study aimed to evaluate patient-related parameters that determine ovarian cyst formation in women using tamoxifen for breast cancer. A cross-sectional study was performed in 142 breast cancer patients using tamoxifen. Forty-five patients were also examined prior to tamoxifen treatment. Gynaecological assessment, transvaginal ultrasonography (TVU) and serum oestradiol (E2) and follicle stimulating hormone (FSH) analysis were performed. Follow-up assessments were performed twice a year. Uni- or bilateral ovarian cysts were detected by TVU in 24 tamoxifen-using patients and in one patient before tamoxifen treatment. Multiple regression analysis showed that cyst development is related (multiple R = 0.73) to high E2 (P < 0.001), younger age (P < 0.001) and absence of high-dose chemotherapy (P = 0.007). Patients with ovarian cysts had higher serum E2 levels compared to patients without cysts (1.95 vs 0.05 nmol l−1; P < 0.001). All patients after high-dose chemotherapy or older than 50 years had E2 < 0.10 nmol l−1 and/or amenorrhoea > 1 year and did not develop ovarian cysts. Patients still having a menstrual cycle during tamoxifen had a high chance (81%) of developing ovarian cysts. Breast cancer patients receiving tamoxifen only develop ovarian cysts if their ovaries are able to respond to FSH stimulation as shown by E2 production. © 1999 Cancer Research Campaig

Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and -independent downregulation of specificity proteins (Sp) transcription factors

<p>Abstract</p> <p>Background</p> <p>Betulinic acid (BA) inhibits growth of several cancer cell lines and tumors and the effects of BA have been attributed to its mitochondriotoxicity and inhibition of multiple pro-oncogenic factors. Previous studies show that BA induces proteasome-dependent degradation of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 in prostate cancer cells and this study focused on the mechanism of action of BA in colon cancer cells.</p> <p>Methods</p> <p>The effects of BA on colon cancer cell proliferation and apoptosis and tumor growth <it>in vivo </it>were determined using standardized assays. The effects of BA on Sp proteins and Sp-regulated gene products were analyzed by western blots, and real time PCR was used to determine microRNA-27a (miR-27a) and ZBTB10 mRNA expression.</p> <p>Results</p> <p>BA inhibited growth and induced apoptosis in RKO and SW480 colon cancer cells and inhibited tumor growth in athymic nude mice bearing RKO cells as xenograft. BA also decreased expression of Sp1, Sp3 and Sp4 transcription factors which are overexpressed in colon cancer cells and decreased levels of several Sp-regulated genes including survivin, vascular endothelial growth factor, p65 sub-unit of NFκB, epidermal growth factor receptor, cyclin D1, and pituitary tumor transforming gene-1. The mechanism of action of BA was dependent on cell context, since BA induced proteasome-dependent and proteasome-independent downregulation of Sp1, Sp3 and Sp4 in SW480 and RKO cells, respectively. In RKO cells, the mechanism of BA-induced repression of Sp1, Sp3 and Sp4 was due to induction of reactive oxygen species (ROS), ROS-mediated repression of microRNA-27a, and induction of the Sp repressor gene ZBTB10.</p> <p>Conclusions</p> <p>These results suggest that the anticancer activity of BA in colon cancer cells is due, in part, to downregulation of Sp1, Sp3 and Sp4 transcription factors; however, the mechanism of this response is cell context-dependent.</p

A Canvas for Establishing Global Software Development Collaborations

Jufo-id:80620There is an increasing need and interest for organizations to collaborate with internal and external partners on a global scale for creating software-based products and services. Potential risks and different strategies need to be addressed when setting up such collaborations. Aspects such as cultural and social features, coordination, infrastructure, organizational change processes, or communication issues need to be con- sidered. Although there are already experiences available with respect to setting up global collaborations, they mainly focus on specific areas. It is dicult for companies to quickly assess if they have considered all rele- vant aspects. An overall aid that guides companies in systematically setting up global collaborations is widely missing. In this paper we present a study based on the snowballing method as a systematic approach to literature review. Based on this literature review and inputs from indus- try we investigated what aspects and practices need to be considered when establishing global software development collaborations and how to prioritize them. Based on that we created activity roadmaps that aggregate existing experiences. Reported experiences were structured into nine main aspects each containing extracted successful practices for set- ting up global software development collaborations. As a result we came up with an initial version of a canvas that is proposed as guidance for companies for setting up global collaborations in the software development domain.Peer reviewe