New Selective Estrogen Receptor Modulators (SERMs) in Development

Selective estrogen receptor modulators (SERMs) or estrogen agonists/antagonists have shown promise in osteoporosis in that they have the potential to reduce the risk of fracture, and also reduce the risk of breast cancer. SERMs maybe classified according to their core structure, which is typically a variation of the 17 beta-estradiol template and subclassified according to the side chain at the helix 12 affector region. The best known are the triphenylethylenes such as tamoxifen, used in the management of breast cancer. However, the clinical application of this class of SERMs has been limited due to endometrial stimulation. A second class is the benzothiophenes such as raloxifene and arzoxifene, which have skeletal benefit with little, if any, uterine stimulation. Indole-based SERMs such as bazedoxifene have a 2-phenyl ring system that serves as a core binding unit. Other classes include benzopyrans and naphthalenes (eg, lasofoxifene). In this review article, I will discuss raloxifene and three new SERMs—arzoxifene, bazedoxifene, and lasofoxifene—that have been recently studied. I will discuss their effect on bone, breast, and the cardiovascular system, as well as on safety

Future possibilities in the prevention of breast cancer: Breast cancer prevention trials

The available results from breast cancer chemoprevention trials are reviewed. Four trials using tamoxifen have been performed, of which three have reported efficacy results. A fifth trial using raloxifene has also been reported. The largest tamoxifen trial showed approximately 50% reduction in breast cancer incidence in the short term, but the two smaller trials did not find any reduction. Greater agreement exists for side effects; incidences of thromboembolic disease and endometrial cancers are raised approximately threefold when tamoxifen is used for 5 years. The possible reasons for the discrepancy in breast cancer reduction are explored. A review of trial parameters does not clearly explain this difference, and a meta-analysis indicates that all results are compatible with a 40% reduction in short-term incidence. Several important questions remain regarding the clinical implications of this result, including the effect on mortality, the appropriate risk groups for chemoprevention and the long-term effects on incidence. Continued follow up of these trials is crucial for resolving these issues

Determining Atlantic Ocean province contrasts and variations

The Atlantic Meridional Transect (AMT) series of twenty-five cruises over the past twenty years has produced a rich depth-resolved biogeochemical in situ data resource consisting of a wealth of core variables. These multiple core datasets, key to the operation of AMT, such as temperature, salinity, oxygen and inorganic nutrients, are often only used as ancillary measurements for contextualising hypothesis-driven process studies. In this paper these core in situ variables, alongside data drawn from satellite Earth Observation (EO) and modelling, have been analysed to determine characteristic oceanic province variations encountered over the last twenty years on the AMT through the Atlantic Ocean. The EO and modelling analysis shows the variations of key environmental variables in each province, such as surface currents, the net heat flux and subsequent large scale biological responses, such as primary production. The in situ core dataset analysis allows the variation in features such as the tropical oxygen minimum zone to be quantified as well as showing clear contrasts between the provinces in nutrient stoichiometry. Such observations and relationships can be used within basin scale biogeochemical models to set realistic variation ranges

Bone loss and the aromatase inhibitors

The increasing use of systemic adjuvant therapies has considerably improved the prognosis from early breast cancer. However, some of these therapies affect bone metabolism, resulting in osteoporosis. Aromatase inhibitors lower circulating oestrogen levels to almost unrecordable levels in postmenopausal women, predisposing them to bone loss with an increase in fracture risk. Ongoing clinical trials are favouring the use of the aromatase inhibitors over tamoxifen and this may advocate greater use of these drugs in the future. Strategies for the identification and management of treatment-induced bone loss are currently being defined

Limiting esophageal temperature in radiofrequency ablation of left atrial tachyarrhythmias results in low incidence of thermal esophageal lesions

<p>Abstract</p> <p>Background</p> <p>Atrio-esophageal fistula formation following radiofrequency ablation of left atrial tachyarrhythmias is a rare but devastating complication. Esophageal injuries are believed to be precursors of fistula formation and reported to occur in up to 47% of patients. This study investigates the incidence of esophageal lesions when real time esophageal temperature monitoring and temperature limitation is used.</p> <p>Methods</p> <p>184 consecutive patients underwent open irrigated radiofrequency ablation of left atrial tachyarrhythmias. An esophageal temperature probe consisting of three independent thermocouples was used for temperature monitoring. A temperature limit of 40°C was defined to interrupt energy delivery. All patients underwent esophageal endoscopy the next day.</p> <p>Results</p> <p>Endoscopy revealed ulcer formation in 3/184 patients (1.6%). No patient developed atrio-esophageal fistula. Patient and disease characteristics had no influence on ulcer formation. The temperature threshold of 40°C was reached in 157/184 patients. A temperature overshoot after cessation of energy delivery was observed frequently. The mean maximal temperature was 40.8°C. Using a multiple regression analysis creating a box lesion that implies superior- and inferior lines at the posterior wall connecting the right and left encircling was an independent predictor of temperature. Six month follow-up showed an overall success rate of 78% documented as sinus rhythm in seven-day holter ECG.</p> <p>Conclusion</p> <p>Limitation of esophageal temperature to 40°C is associated with the lowest incidence of esophageal lesion formation published so far. This approach may contribute to increase the safety profile of radiofrequency ablation in the left atrium.</p

Targeted antitumour therapy – future perspectives

The advent of targeted therapy presents an unprecedented opportunity for advances in the treatment of cancer. A key challenge will be to translate the undoubted promise of targeted agents into tangible clinical benefits. Achieving this goal is likely to be dependent upon a number of factors. These include continued research to improve our understanding of the heterogeneity and complexity of the tumour microenvironment; refinement of clinical trial design to incorporate nontraditional end points such as the optimum biological dose and health-related quality of life; and the use of technological advancements in proteomics, genomics and biomarker development to better predict tumour types and patient subsets that may be particularly responsive to treatment, as well as enable a more accurate assessment of drug effect at the molecular level. In summary, the future success of targeted agents will require an integrated multidisciplinary approach involving all stakeholders

Improved Constraints on Sterile Neutrino Mixing from Disappearance Searches in the MINOS, MINOS+, Daya Bay, and Bugey-3 Experiments.

Searches for electron antineutrino, muon neutrino, and muon antineutrino disappearance driven by sterile neutrino mixing have been carried out by the Daya Bay and MINOS+ collaborations. This Letter presents the combined results of these searches, along with exclusion results from the Bugey-3 reactor experiment, framed in a minimally extended four-neutrino scenario. Significantly improved constraints on the θ_{μe} mixing angle are derived that constitute the most constraining limits to date over five orders of magnitude in the mass-squared splitting Δm_{41}^{2}, excluding the 90%&nbsp;C.L. sterile-neutrino parameter space allowed by the LSND and MiniBooNE observations at 90%&nbsp;CL_{s} for Δm_{41}^{2}&lt;13  eV^{2}. Furthermore, the LSND and MiniBooNE 99%&nbsp;C.L. allowed regions are excluded at 99% CL_{s} for Δm_{41}^{2}&lt;1.6 eV^{2}

Vitamin E deficiency and risk of equine motor neuron disease

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