Cancer incidence and mortality in people aged less than 75 years: Changes in Australia over the period 1987–2007

BackgroundAustralia has one of the highest rates of cancer incidence worldwide and, despite improving survival, cancer continues to be a major public health problem. Our aim was to provide simple summary measures of changes in cancer mortality and incidence in Australia so that progress and areas for improvement in cancer control can be identified.MethodsWe used national data on cancer deaths and newly registered cancer cases and compared expected and observed numbers of deaths and cases diagnosed in 2007. The expected numbers were obtained by applying 1987 age–sex specific rates (average of 1986–1988) directly to the 2007 population. The observed numbers of deaths and incident cases were calculated for 2007 (average of 2006–2008). We limited the analyses to people aged less than 75 years.ResultsThere was a 28% fall in cancer mortality (7827 fewer deaths in 2007 vs. 1987) and a 21% increase in new cancer diagnoses (13,012 more diagnosed cases in 2007). The greatest reductions in deaths were for cancers of the lung in males (?2259), bowel (?1797), breast (?773) and stomach (?577). Other notable falls were for cancers of the prostate (?295), cervix (?242) and non-Hodgkin lymphoma (?240). Only small or no changes occurred in mortality for cancers of the lung (female only), pancreas, brain and related, oesophagus and thyroid, with an increase in liver cancer (267). Cancer types that showed the greatest increase in incident cases were cancers of the prostate (10,245), breast (2736), other cancers (1353), melanoma (1138) and thyroid (1107), while falls were seen for cancers of the lung (?1705), bladder (?1110) and unknown primary (?904).ConclusionsThe reduction in mortality indicates that prevention strategies, improvements in cancer treatment, and screening programmes have made significant contributions to cancer control in Australia since 1987. The rise in incidence is partly due to diagnoses being brought forward by technological improvements and increased coverage of screening and early diagnostic testing.     

Lectin microarray profiling of metastatic breast cancers

Altered protein glycosylation compared with the disease-free state is a universal feature of cancer cells. It has long been established that distinct glycan structures are associated with specific forms of cancer, but far less is known about the complete array of glycans associated with certain tumors. The cancer glycome has great potential as a source of biomarkers, but progress in this field has been hindered by a lack of available techniques for the elucidation of disease-associated glycosylation. In the present study, lectin microarrays consisting of 45 lectins with different binding preferences covering N- and O-linked glycans were coupled with evanescent-field activated fluorescent detection in the glycomic analysis of primary breast tumors and the serum and urine of patients with metastatic breast cancer. A single 50 μm section of a primary breast tumor or <1 μL of breast cancer patient serum or urine was sufficient to detect glycosylation alterations associated with metastatic breast cancer, as inferred from lectin-binding patterns. The high-throughput, sensitive and relatively simple nature of the simultaneous analysis of N- and O-linked glycosylation following minimal sample preparation and without the need for protein deglycosylation makes the lectin microarray analysis described a valuable tool for discovery phase glycomic profiling.     

Calcium channels, transporters and exchangers in placenta: a review

Calcium (Ca2+) entry in cells is crucial for development and physiology of virtually all cell types. It acts as an intracellular (second) messenger to regulate a diverse array of cellular functions, from cell division and differentiation to cell death. Among candidates for Ca2+ entry in cells are-voltage-dependant Ca2+ channels (VDCCs), transient receptor potential (TRP)-related Ca2+ channels and store-operated Ca2+ (SOC) channels. Plasma membrane Ca2+-ATPases (PMCA) and Na+/Ca2+ exchanger (NCX) are mainly responsible for Ca2+ extrusion. These different Ca2+channels/transporters and exchangers exhibit specific distribution and physiological properties. During pregnancy, the syncytiotrophoblast layer of the human placenta transfers as much as 30 g of Ca2+ from the mother to the fetus, especially in late gestation where Ca2+ transport through different channels must increase in response to the demands of accelerating bone mineralization of the fetus. The identification and characterization of the different Ca2+ channels/transporters and exchangers on the brush-border membrane (BBM) facing the maternal circulation, and the basal plasma membrane (BPM) facing the fetal circulation; placental membrane of the syncytiotrophoblasts have been the focus of numerous studies. This review discusses current views in this field regarding localization and functions during transcellular Ca2+ entry and extrusion from cells particularly in the placenta.     

AQP1 gene expression is upregulated by arginine vasopressin and cyclic AMP agonists in trophoblast cells

Aquaporins (AQPs) are water channels that regulate water flow in many tissues. As AQP1 is a candidate to regulate placental fluid exchange, we sought to investigate the effect of arginine vasopressin (AVP) and cAMP agonists on AQP1 gene expression in first trimester-derived extravillous cytotrophoblasts (HTR-8/Svneo) and two highly proliferative carcinoma trophoblast-like cell lines but with a number of functional features of the syncytiotrophoblast namely; JAR and JEG-3 cells. Our data demonstrated that AVP (0.1 nM) significantly increased the expression of AQP1 mRNA at 10 h in HTR-8/SVneo and JEG-3 cells (P<0.05). Both SP-cAMP, a membrane-permeable and phosphodiesterase resistant cAMP, and forskolin, an adenylate cyclase stimulator significantly increased AQP1 mRNA expression in all cell lines after 2 h in a dose-dependent manner (P<0.05) with a parallel increase in protein expression. In the time course study, 5 microM of either SP-cAMP or forskolin significantly stimulated AQP1 mRNA expression after 2 h in HTR-8/SVneo cells and after 10 h in JAR and JEG-3 cells. AQP1 protein expression was highest after 20 h in both HTR-8/SVneo and JEG-3 cells (P<0.05). AVP-stimulated cAMP elevation was blocked in the presence of 9-(tetrahydro-2'-furyl) adenine (SQ22536) (100 microM), a cell-permeable adenylate cyclase inhibitor (P<0.05). These results indicate that in trophoblasts-like cells AQP1 gene expression is upregulated by both AVP and cAMP agonists. Furthermore, our data demonstrate that a cAMP-dependent pathway is responsible for the AVP effect on AQP1. Thus, modulation of AQP1 expression by maternal hormones may regulate invasion and fetal-placental-amnion water homeostasis during gestation.     

Evaluation of Phosphatidylinositol-4-Kinase IIIα as a Hepatitis C Virus Drug Target

Phosphatidylinositol-4-kinase IIIα (PI4KIIIα) is an essential host cell factor for hepatitis C virus (HCV) replication. An N-terminally truncated 130-kDa form was used to reconstitute an in vitro biochemical lipid kinase assay that was optimized for small-molecule compound screening and identified potent and specific inhibitors. Cell culture studies with PI4KIIIα inhibitors demonstrated that the kinase activity was essential for HCV RNA replication. Two PI4KIIIα inhibitors were used to select cell lines harboring HCV replicon mutants with a 20-fold loss in sensitivity to the compounds. Reverse genetic mapping isolated an NS4B-NS5A segment that rescued HCV RNA replication in PIK4IIIα-deficient cells. HCV RNA replication occurs on specialized membranous webs, and this study with PIK4IIIα inhibitor-resistant mutants provides a genetic link between NS4B/NS5A functions and PI4-phosphate lipid metabolism. A comprehensive assessment of PI4KIIIα as a drug target included its evaluation for pharmacologic intervention in vivo through conditional transgenic murine lines that mimic target-specific inhibition in adult mice. Homozygotes that induce a knockout of the kinase domain or knock in a single amino acid substitution, kinase-defective PI4KIIIα, displayed a lethal phenotype with a fairly widespread mucosal epithelial degeneration of the gastrointestinal tract. This essential host physiologic role raises doubt about the pursuit of PI4KIIIα inhibitors for treatment of chronic HCV infection.     

A novel strategy for delivering Niemann-Pick type C2 proteins across the blood–brain barrier using the brain endothelial-specific AAV-BR1 virus

Treating central nervous system (CNS) diseases is complicated by the incapability of numerous therapeutics to cross the blood–brain barrier (BBB), mainly composed of brain endothelial cells (BECs). Genetically modifying BECs into protein factories that supply the CNS with recombinant proteins is a promising approach to overcome this hindrance, especially in genetic diseases, like Niemann Pick disease type C2 (NPC2), where both CNS and peripheral cells are affected. Here, we investigated the potential of the BEC-specific adeno-associated viral vector (AAV-BR1) encoding NPC2 for expression and secretion from primary BECs cultured in an in vitro BBB model with mixed glial cells, and in healthy BALB/c mice. Transduced primary BECs had significantly increased NPC2 gene expression and secreted NPC2 after viral transduction, which significantly reversed cholesterol deposition in NPC2 deficient fibroblasts. Mice receiving an intravenous injection with AAV-BR1-NCP2-eGFP were sacrificed 8 weeks later and examined for its biodistribution and transgene expression of eGFP and NPC2. AAV-BR1-NPC2-eGFP was distributed mainly to the brain and lightly to the heart and lung, but did not label other organs including the liver. eGFP expression was primarily found in BECs throughout the brain but occasionally also in neurons suggesting transport of the vector across the BBB, a phenomenon also confirmed in vitro. NPC2 gene expression was up-regulated in the brain, and recombinant NPC2 protein expression was observed in both transduced brain capillaries and neurons. Our findings show that AAV-BR1 transduction of BECs is possible and that it may denote a promising strategy for future treatment of NPC2.

     

Use of Menopausal Hormone Therapy and Bioidentical Hormone Therapy in Australian Women 50 to 69 Years of Age: Results from a National,Cross-Sectional Study

Menopausal Hormone Therapy (MHT) use in Australia fell by 55% from 2001 to 2005, following the release of large-scale findings on its risks and benefits. Comprehensive national data, including information on overall prevalence of MHT use as well as information on duration of use in Australia have not been reported since the 2004–5 National Health Survey, when 11% of women aged 45+ years were estimated to be current MHT users. No national data are available on prevalence of use of “bioidentical” hormone therapy (BHT). The objective of this study was to determine recent prevalence of MHT and BHT use. A cross-sectional, national, age-stratified, population survey was conducted in 2013. Eligible women, aged 50–69 years, resident in Australia were randomly sampled in 5-year age groups from the Medicare enrolment database (Australia’s universal health scheme). The response rate was 22% based on return of completed questionnaires, and analyses were restricted to 4,389 women within the specified age range. The estimated population-weighted prevalence of current use of MHT was 13% (95%CI 12–14), which was broadly similar to the previously reported national figures in 2004–5, suggesting that the use of MHT in Australia has largely stabilised over the past decade. A total of 39% and 20% of current-users with an intact uterus reported use of oestrogen-progestagen MHT and oestrogen-only MHT, respectively, whereas 77% of hysterectomised current-users used oestrogen-only MHT. Almost three-quarters of current-users [population-weighted prevalence 9% (95%CI 8–10)] had used MHT for ≥5 years. In regard to BHT, estimated population-weighted prevalence of ever use was 6% (95%CI 6–7) and 2% (95%CI 2–3) for current use. The population-weighted prevalence of MHT and BHT combined, in current users in their fifties and sixties was 15% (95%CI 14–16). These data provide a recent national “snapshot” of Australian women’s use of both conventional MHT and of BHT.     

The relative contributions of biological and abiotic processes to carbon dynamics in subarctic sea ice

Knowledge on the relative effects of biological activity and precipitation/dissolution of calcium carbonate (CaCO₃) in influencing the air-ice CO₂ exchange in sea-ice-covered season is currently lacking. Furthermore, the spatial and temporal occurrence of CaCO₃ and other biogeochemical parameters in sea ice are still not well described. Here we investigated autotrophic and heterotrophic activity as well as the precipitation/dissolution of CaCO₃ in subarctic sea ice in South West Greenland. Integrated over the entire ice season (71 days), the sea ice was net autotrophic with a net carbon fixation of 56 mg C m^?2, derived from a sea-ice-related gross primary production of 153 mg C m^?2 and a bacterial carbon demand of 97 mg C m^?2. Primary production contributed only marginally to the TCO₂ depletion of the sea ice (7–25 %), which was mainly controlled by physical export by brine drainage and CaCO₃ precipitation. The net biological production could only explain 4 % of this sea-ice-driven CO₂ uptake. Abiotic processes contributed to an air-sea CO₂ uptake of 1.5 mmol m^?2 sea ice day^?1, and dissolution of CaCO₃ increased the air-sea CO₂ uptake by 36 % compared to a theoretical estimate of melting CaCO₃-free sea ice. There was a considerable spatial and temporal variability of CaCO₃ and the other biogeochemical parameters measured (dissolved organic and inorganic nutrients).