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Anti-vascular endothelial growth factor (VEGF) therapy has demonstrated efficacy in treating human metastatic cancers, but therapeutic resistance is a practical limitation and most tumors eventually become unresponsive. To identify microenvironmental factors underlying the resistance of cancer to antiangiogenesis therapy, we conducted genomic analyses of intraperitoneal ovarian tumors in which adaptive resistance to anti-VEGF therapy (B20 antibody) developed. We found that expression of the microseminoprotein, prostate-associated (MSMP) gene was substantially upregulated in resistant compared with control tumors. MSMP secretion from cancer cells was induced by hypoxia, triggering MAPK signaling in endothelial cells to promote tube formation in vitro. Recruitment of the transcriptional repressor CCCTC-binding factor (CTCF) to the MSMP enhancer region was decreased by histone acetylation under hypoxic conditions in cancer cells. MSMP siRNA, delivered in vivo using the DOPC nanoliposomes, restored tumor sensitivity to anti-VEGF therapy. In ovarian cancer patients treated with bevacizumab, serum MSMP concentration increased significantly only in non-responders. These findings imply that MSMP inhibition combined with the use of antiangiogenesis drugs may be a new strategy to overcome resistance to antiangiogenesis therapy.

Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCAmutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma.

Cardiovascular disease (CVD) is rapidly becoming an important public health problem in sub-Saharan Africa, yet the response so far is often minimal and inadequate. While there is, undoubtedly, a 'double burden of disease' (persisting infectious diseases co-existing with emerging non-communicable disease), this is hardly reflected in current health planning, possibly due to a limited appreciation of the changing pattern of CVD and CVD risk factor exposure. In a situation where there are also considerable budget constraints and well-established infectious disease priorities, it is difficult to implement effective interventions for prevention or treatment of CVD. Yet such planning is urgently needed and a template for a comprehensive programme, adaptable to local situations, is presented here. The first step is to raise awareness and create evidence-based commitment among policy-makers, which could lead to the establishment of a multi-sectoral CVD unit at national level. Programmes need to focus on prevention of modifiable risk factors at population level, involving a wide range of institutions and individuals. Recommended strategies include decentralizing the design and implementation of programmes, with appropriate standardized surveillance of major risk factors, all complemented by operational, epidemiological and basic research.

Numerical solutions to the ambient edge problem associated with narrow helical grooves are presented. It is shown that the computed value of edge correction, Δcorr, holds a parabolic relation with the mesh size. The final converged solutions are, therefore, obtained by extrapolating numerical results obtained at different mesh sizes. For extreme cases, the numerical solutions are in total agreement with the analytical solutions obtained by Elrod [1, 2]. Complete maps for the edge correction as a function of groove geometry are presented.

The utility of parallel analysis techniques (as employed by the ORNL GeMSAEC Photometric Analyzer) for the determination of sulfur dioxide has been evaluated. The results of the study emphasize the advantage of parallel analysis for systems involving unstable reagents and/or absorbing moieties.

The ORNL GeMSAEC Photometric Analyzer is described briefly. The use of a small computer with this instrument, for data acquisition and handling and for automatic printout of the analytical results, is also described. The determination of orthophosphate by the molybdenum-blue procedure has been utilized in a statistical evaluation of the GeMSAEC system, and the results are presented. This study illustrates the considerations that are important in designing procedures for the GeMSAEC type of analyzer, and the advantages that accrue.

Mice immunized to Hymenolepis nana were exposed to 950, 1150, 1350 or 1450 R x-radiation, then injected with syngeneic marrow from non-immune donors. Other immunized mice were exposed to 700 R but were not given marrow. To test for persistence of immunity, the mice were challenged with H. nana eggs. Parasite larvae (cysticercoids) developed in only 3 (1 or 2 cysticercoids each) of 40 immunized-unirradiated control mice challenged with eggs. Cysticercoids developed on egg challenge in all unimmunized control mice.There was no difference in cysticercoid counts between immunized-un-irradiated controls and either the 700 R group or the mice exposed to 1150 R and given 40 × 106 marrow cells 1 day later. A small number of cysticercoids developed in most of the mice exposed to 1350 or 1450 R and given 40 × 106 marrow cells 1 day after irradiation. Cysticercoids also developed in most of a 950 R group given 0·5 × 106 marrow cells 1 day after irradiation and 40 × 106 cells 20 days later; the cysticercoid counts were not different from those in similarly immunized and irradiated mice given only 0·5 × 106 cells. Thus, no benefit was derived from the second injection of marrow (40 × 106 cells) delayed until 21 days after irradiation. In contrast, in immunized mice given 40 × 106 marrow cells 4 days after 950 R, cysticercoid counts were not different from those in immunized-unirradiated controls.The role of transplanted syngeneic marrow in promoting persistence of immunity acquired before irradiation is discussed.

Two dynamic methods are compared for integrating the Reynolds equation as applied to determining the axial dynamics of a spool bearing. It is shown that very sensitive phase shifts in the numerical schemes can badly falsify the dynamics and thus care is needed in interpreting results using classical methods. Second order temporal accuracy can alleviate these problems and one such scheme is presented with excellent phase properties that is just as computationally efficient per time step as any of the first order accurate schemes.