The role of cholesterol metabolism and cholesterol transport in carcinogenesis: a review of scientific findings, relevant to future cancer therapeutics

While the unique metabolic activities of malignant tissues as potential targets for cancer therapeutics has been the subject of several recent reviews, the role of cholesterol metabolism in this context is yet to be fully explored. Cholesterol is an essential component of mammalian cell membranes as well as a precursor of bile acids and steroid hormones. The hypothesis that cancer cells need excess cholesterol and intermediates of the cholesterol biosynthesis pathway to maintain a high level of proliferation is well accepted, however the mechanisms by which malignant cells and tissues reprogram cholesterol synthesis, uptake and efflux are yet to be fully elucidated as potential therapeutic targets. High and low density plasma lipoproteins are the likely major suppliers of cholesterol to cancer cells and tumors, potentially via receptor mediated mechanisms. This review is primarily focused on the role(s) of lipoproteins in carcinogenesis, and their future roles as drug delivery vehicles for targeted cancer chemotherapy

Evidence for a novel functional role of cannabinoid CB2 receptors in the thalamus of neuropathic rats

Cannabinoid CB1 receptors have analgesic effects in models of neuropathic pain, but can also produce psychoactive side-effects. A supraspinal location of CB2 receptors has recently been described. CB2 agonists are also antinociceptive, although the functional role of supraspinal CB2 receptors in the control of nociception is unknown. Herein, we provide evidence that CB2 receptors in the thalamus play a functional role in the modulation of responses of neurons in the ventral posterior nucleus (VPL) of the thalamus in neuropathic, but not sham-operated, rats. Spontaneous and mechanically evoked activity of VPL neurons was recorded with a multichannel electrode array in anaesthetized spinal nerve-ligated (SNL) rats and compared to sham-operated rats. Intra-VPL administration of the CB2 agonist JWH-133 (30 ng in 500 nL) significantly reduced spontaneous (P < 0.05), non-noxious (P < 0.001) and noxious (P < 0.01) mechanically evoked responses of VPL neurons in SNL rats, but not in sham-operated rats. Inhibitory effects of JWH-133 on spontaneous (P < 0.01) and noxious-evoked (P < 0.001) responses of neurons were blocked by the CB2 antagonist SR144528. Local administration of SR144528 alone did not alter spontaneous or evoked responses of VPL neurons, but increased burst activity of VPL neurons in SNL rats. There were, however, no differences in levels of the endocannabinoids anandamide and 2AG in the thalamus of SNL and sham-operated rats. These data suggest that supraspinal CB2 receptors in the thalamus may contribute to the modulation of neuropathic pain responses

Pre-main-sequence population in NGC 1893 region

In this paper we continued our efforts to understand the star formation scenario in and around the young cluster NGC 1893. We used a sample of the young stellar sources (YSOs) identified on the basis of multiwavelength data (optical, near-infrared (NIR), mid-infrared (MIR) and X-ray) to study the nature of YSOs associated with the region. The identified YSOs show an age spread of ~ 5 Myr. The YSOs located near the nebulae at the periphery of the cluster are relatively younger in comparison to those located within the cluster region. The present results are in accordance with those obtained by us in previous studies. Other main results from the present study are: 1) the fraction of disk bearing stars increases towards the periphery of the cluster; 2) there is an evidence supporting the notion that the mechanisms for disk dispersal operate less efficiently for low-mass stars; 3) the sample of Class II sources is found to be relatively older in comparison to that of Class III sources. A comparison of various properties of YSOs in the NGC 1893 region with those in the Tr 37/ IC 1396 region is also discussed.Comment: Accepted for publication in New Astronom

Palaeoproterozoic magnesite: lithological and isotopic evidence for playa/sabkha environments

Magnesite forms a series of 1- to 15-m-thick beds within the approximate to2.0 Ga (Palaeoproterozoic) Tulomozerskaya Formation, NW Fennoscandian Shield, Russia. Drillcore material together with natural exposures reveal that the 680-m-thick formation is composed of a stromatolite-dolomite-'red bed' sequence formed in a complex combination of shallow-marine and non-marine, evaporitic environments. Dolomite-collapse breccia, stromatolitic and micritic dolostones and sparry allochemical dolostones are the principal rocks hosting the magnesite beds. All dolomite lithologies are marked by delta C-13 values from +7.1 parts per thousand to +11.6 parts per thousand (V-PDB) and delta O-18 ranging from 17.4 parts per thousand to 26.3 parts per thousand (V-SMOW). Magnesite occurs in different forms: finely laminated micritic; stromatolitic magnesite; and structureless micritic, crystalline and coarsely crystalline magnesite. All varieties exhibit anomalously high delta C-13 values ranging from +9.0 parts per thousand to +11.6 parts per thousand and delta O-18 values of 20.0-25.7 parts per thousand. Laminated and structureless micritic magnesite forms as a secondary phase replacing dolomite during early diagenesis, and replaced dolomite before the major phase of burial. Crystalline and coarsely crystalline magnesite replacing micritic magnesite formed late in the diagenetic/metamorphic history. Magnesite apparently precipitated from sea water-derived brine, diluted by meteoric fluids. Magnesitization was accomplished under evaporitic conditions (sabkha to playa lake environment) proposed to be similar to the Coorong or Lake Walyungup coastal playa magnesite. Magnesite and host dolostones formed in evaporative and partly restricted environments; consequently, extremely high delta C-13 values reflect a combined contribution from both global and local carbon reservoirs. A C- 13-rich global carbon reservoir (delta C-13 at around +5 parts per thousand) is related to the perturbation of the carbon cycle at 2.0 Ga, whereas the local enhancement in C-13 (up to +12 parts per thousand) is associated with evaporative and restricted environments with high bioproductivity

Treatment for inclusion body myositis

Background Inclusion body myositis (IBM) is a late‐onset inflammatory muscle disease (myopathy) associated with progressive proximal and distal limb muscle atrophy and weakness. Treatment options have attempted to target inflammatory and atrophic features of this condition (for example with immunosuppressive and immunomodulating drugs, anabolic steroids, and antioxidant treatments), although as yet there is no known effective treatment for reversing or minimising the progression of inclusion body myositis. In this review we have considered the benefits, adverse effects, and costs of treatment in targeting cardinal effects of the condition, namely muscle atrophy, weakness, and functional impairment. Objectives To assess the effects of treatment for IBM. Search methods On 7 October 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register for Controlled Trials (CENTRAL), MEDLINE, and EMBASE. Additionally in November 2014 we searched clinical trials registries for ongoing or completed but unpublished trials. Selection criteria We considered randomised or quasi‐randomised trials, including cross‐over trials, of treatment for IBM in adults compared to placebo or any other treatment for inclusion in the review. We specifically excluded people with familial IBM and hereditary inclusion body myopathy, but we included people who had connective tissue and autoimmune diseases associated with IBM, which may or may not be identified in trials. We did not include studies of exercise therapy or dysphagia management, which are topics of other Cochrane systematic reviews. Data collection and analysis We used standard Cochrane methodological procedures. Main results The review included 10 trials (249 participants) using different treatment regimens. Seven of the 10 trials assessed single agents, and 3 assessed combined agents. Many of the studies did not present adequate data for the reporting of the primary outcome of the review, which was the percentage change in muscle strength score at six months. Pooled data from two trials of interferon beta‐1a (n = 58) identified no important difference in normalised manual muscle strength sum scores from baseline to six months (mean difference (MD) ‐0.06, 95% CI ‐0.15 to 0.03) between IFN beta‐1a and placebo (moderate‐quality evidence). A single trial of methotrexate (MTX) (n = 44) provided moderate‐quality evidence that MTX did not arrest or slow disease progression, based on reported percentage change in manual muscle strength sum scores at 12 months. None of the fully published trials were adequately powered to detect a treatment effect. We assessed six of the nine fully published trials as providing very low‐quality evidence in relation to the primary outcome measure. Three trials (n = 78) compared intravenous immunoglobulin (combined in one trial with prednisone) to a placebo, but we were unable to perform meta‐analysis because of variations in study analysis and presentation of trial data, with no access to the primary data for re‐analysis. Other comparisons were also reported in single trials. An open trial of anti‐T lymphocyte immunoglobulin (ATG) combined with MTX versus MTX provided very low‐quality evidence in favour of the combined therapy, based on percentage change in quantitative muscle strength sum scores at 12 months (MD 12.50%, 95% CI 2.43 to 22.57). Data from trials of oxandrolone versus placebo, azathioprine (AZA) combined with MTX versus MTX, and arimoclomol versus placebo did not allow us to report either normalised or percentage change in muscle strength sum scores. A complete analysis of the effects of arimoclomol is pending data publication. Studies of simvastatin and bimagrumab (BYM338) are ongoing. All analysed trials reported adverse events. Only 1 of the 10 trials interpreted these for statistical significance. None of the trials included prespecified criteria for significant adverse events. Authors' conclusions Trials of interferon beta‐1a and MTX provided moderate‐quality evidence of having no effect on the progression of IBM. Overall trial design limitations including risk of bias, low numbers of participants, and short duration make it difficult to say whether or not any of the drug treatments included in this review were effective. An open trial of ATG combined with MTX versus MTX provided very low‐quality evidence in favour of the combined therapy based on the percentage change data given. We were unable to draw conclusions from trials of IVIg, oxandrolone, and AZA plus MTX versus MTX. We need more randomised controlled trials that are larger, of longer duration, and that use fully validated, standardised, and responsive outcome measures

Chemostratigraphy of Neoproterozoic carbonates: implications for 'blind dating'

The delta C-13(carb) and Sr-87/Sr-86 secular variations in Neoproteozoic seawater have been used for the purpose of 'isotope stratigraphy' but there are a number of problems that can preclude its routine use. In particular, it cannot be used with confidence for 'blind dating'. The compilation of isotopic data on carbonate rocks reveals a high level of inconsistency between various carbon isotope age curves constructed for Neoproteozoic seawater, caused by a relatively high frequency of both global and local delta C-13(carb) fluctuations combined with few reliable age determinations. Further complication is caused by the unresolved problem as to whether two or four glaciations, and associated negative delta C-13(carb) excursions, can be reliably documented. Carbon isotope stratigraphy cannot be used alone for geological correlation and 'blind dating'. Strontium isotope stratigraphy is a more reliable and precise tool for stratigraphic correlations and indirect age determinations. Combining strontium and carbon isotope stratigraphy, several discrete ages within the 590-544 Myr interval, and two age-groups at 660-610 and 740-690 Myr can be resolved

Lacustrine stromatolites: Useful structures for environmental interpretation – an example from the Miocene Ebro Basin

The significance of stromatolites as depositional environmental indicators and the underlying causes of lamination in the lacustrine realm are poorly understood. Stromatolites in a ca 600 m thick Miocene succession in the Ebro Basin are good candidates to shed light on these issues because they are intimately related to other lacustrine carbonate and sulphate facies, grew under variable environmental conditions and show distinct lamination patterns. These stromatolites are associated with wave-related, clastic-carbonate laminated limestones. Both facies consist of calcite and variable amounts of dolomite. Thin planar stromatolites (up to 10 cm thick and less than 6 m long) occurred in very shallow water. These stromatolites represented first biological colonization after: (i) subaerial exposure in the palustrine environment (i.e. at the beginning of deepening cycles); or (ii) erosion due to surge action, then coating very irregular surfaces on laminated limestones (i.e. through shallowing or deepening cycles). Sometimes they are associated with evaporative pumping. Stratiform stromatolites (10 to 30 cm high and tens of metres long) and domed stromatolites (10 to 30 cm high and long) developed in deeper settings, between the surge periods that produced hummocky cross-stratification and horizontal lamination offshore. Changes in stromatolite lamina shape, and thus in the growth forms through time, can be attributed to changes in water depth, whereas variations in lamina continuity are linked to water energy and sediment supply. Growth of the stromatolites resulted from in situ calcite precipitation and capture of minor amounts of fine-grained carbonate particles. Based on texture, four types of simple laminae are distinguished. The simple micrite and microsparite laminae can be grouped into light and dark composite laminae, which represent, respectively, high and low Precipitation/Evaporation ratio periods. Different lamination patterns provide new ideas for the interpretation of microbial laminations as a function of variations in climate-dependent parameters (primarily the Precipitation/Evaporation ratio) over variable timescales