Smoking accelerates pancreatic cancer progression by promoting differentiation of MDSCs and inducing HB-EGF expression in macrophages.

Smoking is an established risk factor for pancreatic cancer (PC), but late diagnosis limits the evaluation of its mechanistic role in the progression of PC. We used a well-established genetically engineered mouse model (LSL-K-ras(G12D)) of PC to elucidate the role of smoking during initiation and development of pancreatic intraepithelial neoplasia (PanIN). The 10-week-old floxed mice (K-ras(G12D); Pdx-1cre) and their control unfloxed (LSL-K-ras(G12D)) littermates were exposed to cigarette smoke (total suspended particles: 150 mg/m(3)) for 20 weeks. Smoke exposure significantly accelerated the development of PanIN lesions in the floxed mice, which correlated with tenfold increase in the expression of cytokeratin19. The systemic accumulation of myeloid-derived suppressor cells (MDSCs) decreased significantly in floxed mice compared with unfloxed controls (P<0.01) after the smoke exposure with the concurrent increase in the macrophage (P<0.05) and dendritic cell (DCs) (P<0.01) population. Further, smoking-induced inflammation (IFN-γ, CXCL2; P<0.05) was accompanied by enhanced activation of pancreatic stellate cells and elevated levels of serum retinoic acid-binding protein 4, indicating increased bioavailability of retinoic acid which contributes to differentiation of MDSCs to tumor-associated macrophages (TAMs) and DCs. TAMs predominantly contribute to the increased expression of heparin-binding epidermal growth factor-like growth factor (EGFR ligand) in pre-neoplastic lesions in smoke-exposed floxed mice that facilitate acinar-to-ductal metaplasia (ADM). Further, smoke exposure also resulted in partial suppression of the immune system early during PC progression. Overall, the present study provides a novel mechanism of smoking-induced increase in ADM in the presence of constitutively active K-ras mutation.

Unbiased analysis of pancreatic cancer radiation resistance reveals cholesterol biosynthesis as a novel target for radiosensitisation.

BACKGROUND: Despite its promise as a highly useful therapy for pancreatic cancer (PC), the addition of external beam radiation therapy to PC treatment has shown varying success in clinical trials. Understanding PC radioresistance and discovery of methods to sensitise PC to radiation will increase patient survival and improve quality of life. In this study, we identified PC radioresistance-associated pathways using global, unbiased techniques. METHODS: Radioresistant cells were generated by sequential irradiation and recovery, and global genome cDNA microarray analysis was performed to identify differentially expressed genes in radiosensitive and radioresistant cells. Ingenuity pathway analysis was performed to discover cellular pathways and functions associated with differential radioresponse and identify potential small-molecule inhibitors for radiosensitisation. The expression of FDPS, one of the most differentially expressed genes, was determined in human PC tissues by IHC and the impact of its pharmacological inhibition with zoledronic acid (ZOL, Zometa) on radiosensitivity was determined by colony-forming assays. The radiosensitising effect of Zol in vivo was determined using allograft transplantation mouse model. RESULTS: Microarray analysis indicated that 11 genes (FDPS, ACAT2, AG2, CLDN7, DHCR7, ELFN2, FASN, SC4MOL, SIX6, SLC12A2, and SQLE) were consistently associated with radioresistance in the cell lines, a majority of which are involved in cholesterol biosynthesis. We demonstrated that knockdown of farnesyl diphosphate synthase (FDPS), a branchpoint enzyme of the cholesterol synthesis pathway, radiosensitised PC cells. FDPS was significantly overexpressed in human PC tumour tissues compared with healthy pancreas samples. Also, pharmacologic inhibition of FDPS by ZOL radiosensitised PC cell lines, with a radiation enhancement ratio between 1.26 and 1.5. Further, ZOL treatment resulted in radiosensitisation of PC tumours in an allograft mouse model. CONCLUSIONS: Unbiased pathway analysis of radioresistance allowed for the discovery of novel pathways associated with resistance to ionising radiation in PC. Specifically, our analysis indicates the importance of the cholesterol synthesis pathway in PC radioresistance. Further, a novel radiosensitiser, ZOL, showed promising results and warrants further study into the universality of these findings in PC, as well as the true potential of this drug as a clinical radiosensitiser.

[Early screening criteria for children at risk of overweight]. / Critères de repérage précoce des enfants à risque de développer un surpoids.

BACKGROUND: Health professionals who monitor the growth of children are also involved in the early detection of overweight. Appropriate tools are required for this purpose. OBJECTIVE: The study sought to identify predictive markers of the development of subsequent overweight using a simple set of criteria. METHODS: A consecutive cohort was composed of 1424 grade 4 children in Aquitaine, France, aged 8-9 years. Body mass index (BMI) was calculated during school health assessments at 8-9 years of age. Data from previous assessments at 3-4 and 5-6 years of age were also collected. RESULTS: Of the 189/1424 children (13.9 %) who were overweight according to the French national cut off for children aged 8-9 years, 67 (33.8 %) were already overweight at 3-4 years and 107 (54.1 %) at 5-6 years. Of the 134 (9.4 %) who were overweight at 5-6 years, 43.3 % were already overweight at 3-4 years and 79.9 % were overweight at 8-9 years. On the other hand, 76 of these 134 children (56.7 %) were not overweight at 3-4 years, so they had become overweight between the two assessments. The combination of the criterion "overweight at 3-4 years or 5-6 years" and "increase in BMI>1kg/m(2) between 3-4 years and 5-6 years" appears to be the best predictor of the risk of overweight at 8-9 years, with good sensitivity (75.3 %) and specificity (87.9 %). CONCLUSION: A predictive tool based on BMI changes between ages 3-4 years and 5-6 years could be used for the early detection of the risk of developing overweight and obesity. The tool is easy to use, especially for health care in schools. Furthermore, the present findings confirm the value of following up and managing children who are already overweight between the ages of 3 and 6 years.

Selective coral mortality associated with outbreaks of Acanthaster planci L. in Bootless Bay, Papua New Guinea.

Population outbreaks of crown-of-thorns sea star (Acanthaster planci L.) remain one of the most significant biological disturbances on tropical coral reefs although the increasing attention given to other threats has greatly limited recent progress in understanding the cause and consequences of this phenomenon. In September 2005 dramatic increases in the abundance of A. planci were observed on reefs within Bootless Bay, Central Province, Papua New Guinea, where few crown-of-thorns have previously been reported. Densities of A. planci peaked at 162 sea stars per hectare and caused extensive coral mortality. This outbreak killed upwards of 55% of live corals, reducing overall coral cover from 42.4% in 2005 down to just 19.1% in March 2006. Declines in coral cover were largely driven by widespread mortality of Acropora spp. which dominated reef assemblages prior to the outbreak. The extensive depletion of Acropora spp. greatly altered the coral composition as well as the physical structure of reef habitats. In the absence of any other major disturbances these coral communities are likely to quickly recover, but this outbreak highlights the ongoing contribution of A. planci to degradation of coral reef environments.

Population variables and life-history characteristics of the alligator pipefish Syngnathoides biaculeatus, in Papua New Guinea.

Population structure and life-history variables of the widely distributed alligator pipefish Syngnathoides biaculeatus were characterized in Bootless Bay, Papua New Guinea over the course of 11 months. There was little evidence of seasonality with four focal populations showing no significant change in abundance. Similarly, the sex ratio remained 1:1 for all but 1 month. Reproductive males carrying eggs (148-278 mm in total length, L(T)) were found in all months. Brood size was significantly, positively related to male L(T) for newly laid broods only. Maximum observed brood size was 351 and mean +/-s.d. brood size was 238 +/- 57 for newly laid broods. Juveniles and males showed no change in mean L(T) over the year while slightly smaller females were captured in November 2006 and September 2007. Males were significantly longer than females so von Bertalanffy growth coefficients were estimated separately for each sex: males L(infinity)= 285 mm, K = 0.82 year(-1) and females L(infinity)= 261 mm, K = 1.10 year(-1). These estimates suggest that this species grows rapidly and has a short-life span. In the context of growing concern about overexploitation of syngnathids, a rapid growth rate combined with year round reproductive activity suggests that the tropical S. biaculeatus may be relatively resilient with regard to fishing pressure.

An automated clinic management system for a family planning network.

The medical information, financial, and logistic aspects of a comprehensive computer-based Appointment, Registration, Information System, and Evaluation (ARISE) are analyzed for the management of a family planning program serving 30,000 patients annually. An overview of the existing computer system network is presented with descriptions of the interactive master patient index, the batch appointment process, the management statistics package, and Department of Health, Education, and Welfare (HEW) reporting. Emphasis is placed on the financial management control system which includes 1) procedures for third-party submission of claims for payment, in particular Titles IVA, XX, and XIX (Social Security Act), together with discussion of related administrative requirements; 2) technics of auditing data integrity including systematic sampling of collected data; and 3) the process of billing and receipts collection. Methodology and implementation aspects of ARISE may have wide applicability to other family planning and similarly structured clinical programs.