Twenty Years of Drilling the Deepest Hole in Ice

No abstract available. doi:10.2204/iodp.sd.11.05.2011</a

Cholesterol nucleation time in gallbladder bile of patients with solitary or multiple cholesterol gallstones

Patients with multiple cholesterol gallbladder stones have been found to be at a higher risk for the recurrence of gallstones after successful nonsurgical treatment than those with a solitary stone. Cholesterol gallstone recurrence, like primary gallstone formation, probably involves a triple defect with supersaturation, abnormally rapid nucleation of cholesterol in bile and altered gallbladder motor function. We investigated whether the increased recurrence rate of patients with multiple stones might be caused by more rapid nucleation. Therefore the time required for cholesterol monohydrate crystals to appear in ultracentrifuged bile of patients with solitary (n = 71) or multiple (n = 42) cholesterol gallstones was determined. The cholesterol nucleation time was significantly (p 4 days) nucleation time. However, no difference in the cholesterol saturation index was found between the bile samples from patients with solitary stones and the bile samples from patients with multiple stones (1.55 ± 0.65 vs. 1.54 ± 0.59, mean ± S.D., respectively). The more rapid cholesterol nucleation in gallbladder bile may, therefore, be the major risk factor causing the higher percentage of stone recurrence in patients with multiple cholesterol stones as compared with patients with solitary cholesterol stones

Transcription factors NRF2 and HSF1 have opposing functions in autophagy

Abstract Autophagy plays a critical role in the maintenance of cellular homeostasis by degrading proteins, lipids and organelles. Autophagy is activated in response to stress, but its regulation in the context of other stress response pathways, such as those mediated by heat shock factor 1 (HSF1) and nuclear factor-erythroid 2 p45-related factor 2 (NRF2), is not well understood. We found that the Michael acceptor bis(2-hydoxybenzylidene)acetone (HBB2), a dual activator of NRF2 and HSF1, protects against the development of UV irradiation-mediated cutaneous squamous cell carcinoma in mice. We further show that HBB2 is an inducer of autophagy. In cells, HBB2 increases the levels of the autophagy-cargo protein p62/sequestosome 1, and the lipidated form of microtubule-associated protein light chain 3 isoform B. Activation of autophagy by HBB2 is impaired in NRF2-deficient cells, which have reduced autophagic flux and low basal and induced levels of p62. Conversely, HSF1-deficient cells have increased autophagic flux under both basal as well as HBB2-induced conditions, accompanied by increased p62 levels. Our findings suggest that NRF2 and HSF1 have opposing roles during autophagy, and illustrate the existence of tight mechanistic links between the cellular stress responses

Expression of NAD(P)H quinone dehydrogenase 1 (NQO1) is increased in the endometrium of women with endometrial cancer and women with Polycystic Ovary Syndrome

OBJECTIVE: Women with a prior history of polycystic ovary syndrome (PCOS) have an increased risk of endometrial cancer (EC). AIM: To investigate whether the endometrium of women with PCOS possess gene expression changes similar to those found in EC. DESIGN AND METHODS: Patients with EC, PCOS and control women unaffected by either PCOS or EC were recruited into a cross-sectional study at the Nottingham University Hospital, UK. For RNA sequencing, representative individual endometrial biopsies were obtained from women with EC, PCOS and a woman unaffected by PCOS or EC. Expression of a subset of differentially expressed genes identified by RNA sequencing, including NAD(P)H quinone dehydrogenase 1 (NQO1), were validated by quantitative reverse transcriptase PCR validation (n=76) and in the cancer genome atlas UCEC (uterine corpus endometrioid carcinoma) RNA sequencing dataset (n=381). The expression of NQO1 was validated by immuno-histochemistry in EC samples from a separate cohort (n=91) comprised of consecutive patients who underwent hysterectomy at St Mary's Hospital, Manchester between 2011 and 2013. A further 6 postmenopausal women with histologically normal endometrium who underwent hysterectomy for genital prolapse were also included. Informed consent and local ethics approval was obtained for the study. RESULTS: We show for the first that that NQO1 expression is significantly increased in the endometrium of women with PCOS and EC. Immunohistochemistry confirms significantly increased NQO1 protein expression in EC relative to non-malignant endometrial tissue (p<0.0001). CONCLUSIONS: The results obtained here support a previously unrecognized molecular link between PCOS and EC involving NQO1

Clusterin inhibition using OGX-011 synergistically enhances zoledronic acid activity in osteosarcoma

Purpose: Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants new strategies still needed to improve overall patient survival. Among new therapeutic approaches, zoledronic acid (ZOL) represents a promising adjuvant molecule to chemotherapy to limit the osteolytic component of bone tumors. However, ZOL triggers the elevation of heat shock proteins (Hsp), including Hsp27 and clusterin (CLU), which could enhance tumor cell survival and treatment resistance. We hypothesized that targeting CLU using siRNA or the antisense drug, OGX-011, will suppress treatment-induced CLU induction and enhance ZOL-induced cell death in osteosarcoma (OS) cells. Methods: The combined effects of OGX-011 and ZOL were investigated in vitro on cell growth, viability, apoptosis and cell cycle repartition of ZOL-sensitive or -resistant human OS cell lines (SaOS2, U2OS, MG63 and MNNG/HOS). Results: In OS cell lines, ZOL increased levels of HSPs, especially CLU, in a dose- and time-dependent manner by mechanism including increased HSF1 transcription activity. The OS resistant cells to ZOL exhibited higher CLU expression level than the sensitive cells. Moreover, CLU overexpression protects OS sensitive cells to ZOL-induced cell death by modulating the MDR1 and farnesyl diphosphate synthase expression. OGX-011 suppressed treatment-induced increases in CLU and synergistically enhanced the activity of ZOL on cell growth and apoptosis. These biologic events were accompanied by decreased expression of HSPs, MDR1 and HSF1 transcriptional activity. In vivo, OGX-011, administered 3 times a week (IP, 20mg/kg), potentiated the effect of ZOL (s.c; 50µg/kg), significantly inhibiting tumor growth by 50% and prolonging survival in MNNG/HOS xenograft model compared to ZOL alone. Conclusion: These results indicate that ZOL-mediated induction of CLU can be attenuated by OGX-011, with synergistic effects on delaying progression of osteosarcoma

Cyclin E overexpression as a biomarker for combination treatment strategies in inflammatory breast cancer

Inflammatory breast cancer (IBC) is a virulent form of breast cancer, and novel treatment strategies are urgently needed. Immunohistochemical analysis of tumors from women with a clinical diagnosis of IBC (n = 147) and those with non-IBC breast cancer (n = 2510) revealed that, whereas in non-IBC cases cytoplasmic cyclin E was highly correlated with poor prognosis (P < 0.001), in IBC cases both nuclear and cytoplasmic cyclin E were indicative of poor prognosis. These results underscored the utility of the cyclin E/CDK2 complex as a novel target for treatment. Because IBC cell lines were highly sensitive to the CDK2 inhibitors dinaciclib and meriolin 5, we developed a high-throughput survival assay (HTSA) to design novel sequential combination strategies based on the presence of cyclin E and CDK2. Using a 14-cell-line panel, we found that dinaciclib potentiated the activity of DNA-damaging chemotherapies treated in a sequence of dinaciclib followed by chemotherapy, whereas this was not true for paclitaxel. We also identified a signature of DNA repair–related genes that are downregulated by dinaciclib, suggesting that global DNA repair is inhibited and that prolonged DNA damage leads to apoptosis. Taken together, our findings argue that CDK2-targeted combinations may be viable strategies in IBC worthy of future clinical investigation

The anti-rheumatic drug, leflunomide, synergizes with MEK inhibition to suppress melanoma growth

Cutaneous melanoma, which develops from the pigment producing cells called melanocytes, is the most deadly form of skin cancer. Unlike the majority of other cancers, the incidence rates of melanoma are still on the rise and the treatment options currently available are being hindered by resistance, limited response rates and adverse toxicity. We have previously shown that an FDA approved drug leflunomide, used for rheumatoid arthritis (RA), also holds potential therapeutic value in treating melanoma especially if used in combination with the mutant BRAF inhibitor, vemurafenib. We have further characterized the function of leflunomide and show that the drug reduces the number of viable cells in both wild-type and BRAFV600E mutant melanoma cell lines. Further experiments have revealed leflunomide reduces cell proliferation and causes cells to arrest in G1 of the cell cycle. Cell death assays show leflunomide causes apoptosis at treatment concentrations of 25 and 50 μM. To determine if leflunomide could be used combinatorialy with other anti-melanoma drugs, it was tested in combination with the MEK inhibitor, selumetinib. This combination showed a synergistic effect in the cell lines tested. This drug combination led to an enhanced decrease in tumor size when tested in vivo compared to either drug alone, demonstrating its potential as a novel combinatorial therapy for melanoma

Comparison of the effect of raw and blanched-frozen broccoli on DNA damage in colonocytes

Consumption of cruciferous vegetables may protect against colorectal cancer. Cruciferous vegetables are rich in a number of bioactive constituents including polyphenols, vitamins and glucosinolates. Before consumption, cruciferous vegetables often undergo some form of processing that reduces their content of bioactive constituents and may determine whether they exert protective effects. The aim of this study was to compare the ability of raw and blanched-frozen broccoli to protect colonocytes against DNA damage, improve antioxidant status and induce xenobiotic metabolising enzymes (XME). Fifteen Landrace x Large White male pigs were divided into five age and weight matched sets (79 days, SD 3, and 34.7 kg, SD 3.9 respectively). Each set consisted of siblings to minimise genetic variation. Within each set, pigs received a cereal-based diet, unsupplemented (control) or supplemented with 600 g/d of raw or blanched-frozen broccoli for 12 d. The consumption of raw broccoli caused a significant 27% increase in DNA damage in colonocytes (P=0.03) relative to the control diet, whereas blanched-frozen broccoli had no significant effect. Both broccoli diets had no significant effect on plasma antioxidant status or hepatic and colonic XME. This study is the first to report that the consumption of raw broccoli can damage DNA in porcine colonocytes

Принципи діяльнісного підходу та самостійного навчання іноземних мов крізь призму поглядів чеських педагогів

The article focuses on the characteristics of the essence and the purpose of a «learning by doing» approach, the principle of the autonomy of learning foreign languages approach; the drawbacks of a «learning by doing» approach have been singled out; the analysis of the implementation recommendations by the Check scientists has been done.The purpose of the article is to characterize the principle of a «learning by doing» approach and the principle of an autonomous learning approach in the Check Republic. To achieve the purpose of the research certain tasks have been singled out: a). to describe the essence and of a «learning by doing» approach; b). to single out the drawbacks of a learning by doing» approach; c). to characterize the essence of the principle of an autonomous learning approach; d) to analyze the recommendations on the implementation of a «learning by doing» and an autonomous learning approach made by the Check and Danish scientists. The essence of a «learning by doing» approach may be characterized as an integral learning with an active pupil. A pupil acquires the knowledge of a foreign language by the help of his own activity to solve the tasks in a situation similar to a situation in a real life. A teacher and a pupil are involved in the process of a balanced cooperation. A pupil changes the role of a teacher and the latter becomes a partner, an advisor and an assistant. The essence of the autonomous learning approach focuses on a pupil with his abilities and individual peculiarities at the centre of a pedagogical activity.Key words: principle, «learning by doing» approach, autonomous foreign language learning approach, pedagogical activity, purpose of learning, recommendations.У статті схарактеризовано мету принципів діяльнісного підходу та самостійного навчання іноземних мов; з’ясовано сутність принципу діяльнісного підходу, яка полягає в цілісному навчанні з активним учнем: учень отримує нові знання за допомогою своєї власної діяльності для вирішення завдань в ситуації, які наближаються до ситуацій в позакласній реальності; учень змінює роль вчителя; виокремлено недоліки діяльнісного підходу до навчання іноземних мов: однобічність та небезпека потрапляння в крайнощі; здійснено аналіз рекомендацій чеських науковців щодо втілення принципу діяльнісного підходу до навчання: ментальна гігієна, ритмізація процесу навчання, обмін інформацією між вчителем і учнем , а також між учнями; з’ясовано сутність принципу самостійного навчання, яка полягає в допомозі вчитель повинен допомогти учневі прогресувати, культивуючи при цьому почуття незалежності, самобутності.Ключові слова: прицип, діяльнісний підхід, самостійне навчання, ціль навчання, рекомендації