Detecting the orientation of magnetic fields in galaxy clusters

Clusters of galaxies, filled with hot magnetized plasma, are the largest bound objects in existence and an important touchstone in understanding the formation of structures in our Universe. In such clusters, thermal conduction follows field lines, so magnetic fields strongly shape the cluster's thermal history; that some have not since cooled and collapsed is a mystery. In a seemingly unrelated puzzle, recent observations of Virgo cluster spiral galaxies imply ridges of strong, coherent magnetic fields offset from their centre. Here we demonstrate, using three-dimensional magnetohydrodynamical simulations, that such ridges are easily explained by galaxies sweeping up field lines as they orbit inside the cluster. This magnetic drape is then lit up with cosmic rays from the galaxies' stars, generating coherent polarized emission at the galaxies' leading edges. This immediately presents a technique for probing local orientations and characteristic length scales of cluster magnetic fields. The first application of this technique, mapping the field of the Virgo cluster, gives a startling result: outside a central region, the magnetic field is preferentially oriented radially as predicted by the magnetothermal instability. Our results strongly suggest a mechanism for maintaining some clusters in a 'non-cooling-core' state.Comment: 48 pages, 21 figures, revised version to match published article in Nature Physics, high-resolution version available at http://www.cita.utoronto.ca/~pfrommer/Publications/pfrommer-dursi.pd

Potential antitumor effects of nitrogen-containing bisphosphonate in hormone receptor negative breast cancer patients with bone metastases

<p>Abstract</p> <p>Background</p> <p>This retrospective study evaluated, according to hormone receptor status, the antitumor effects of bisphosphonate especially on survival and disease progression in breast cancer patients with metastatic bone disease.</p> <p>Methods</p> <p>Of 317 patients with initial bone metastasis and known breast cancer subtypes, 230 patients (72.6%) had hormone receptor (HR) positive tumors, and 87 patients (27.4%) had HR negative tumors. We assessed the primary outcome of overall survival (OS), after adjusting for other factors, comparing a group that received bisphosphonates (BPs) with a group that did not receive it.</p> <p>Results</p> <p>87.8% of HR positive and 69.0% of HR negative patients received BPs with a median number of 17.7 cycles. Although BPs treatment made no survival benefit in HR positive group, HR negative patients showed a significant prolonged survival when they received BPs treatment (hazard ratio = 0.56 [95% CI 0.34 to 0.91], <it>P </it>= 0.019). In multivariate analysis, disease free interval > 2 years (<it>P </it>= 0.036), a sum of metastatic sites < 3 (<it>P </it>= 0.034), and BP treatments (<it>P </it>= 0.007) were significant factors for survival in HR negative patients.</p> <p>Conclusion</p> <p>Bisphosphonate treatment can result in a survival benefit in metastatic breast cancer patients with HR negative tumors.</p

Fast and reliable pricing of American options with local volatility

We present globally convergent multigrid methods for the nonsymmetric obstacle problems as arising from the discretization of Black—Scholes models of American options with local volatilities and discrete data. No tuning or regularization parameters occur. Our approach relies on symmetrization by transformation and data recovery by superconvergence

The role of bisphosphonates in breast cancer: The present and future role of bisphosphonates in the management of patients with breast cancer

At least 25% of patients with breast cancer develop skeletal metastases, with bone the site of disease producing the greatest morbidity. It is apparent that the bisphosphonates present an important component of the treatment strategy. They are now the treatment of choice in tumour-induced hypercalcaemia, and they can reduce bone pain and skeletal complications such as pathological fractures. In addition, bisphosphonates are being increasingly evaluated in the prevention of bone metastases and to prevent and treat cancer therapy-induced osteoporosis. Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of bisphosphonate

Outcome following surgery for colorectal cancer: analysis by hospital after adjustment for case-mix and deprivation

Outcome, adjusted for case-mix and deprivation, in 3200 patients undergoing resection for colorectal cancer in 11 hospitals in Central Scotland between 1991 and 1994 was studied. There were significant differences among individual hospitals in the proportion of elderly (P<0.001) and deprived (P<0.0001) patients, the mode (P=0.007) and stage (P<0.0001) at presentation, and the proportion of patients who underwent apparently curative resection (P<0.001). There were no significant differences in postoperative mortality. Cancer-specific survival at 5 years following apparently curative resection varied from 59 to 76%; cancer-specific survival at 2 years following palliative resection varied from 22 to 44%. The corresponding hazard ratios, adjusted for the above prognostic factors, for patients undergoing apparently curative resection varied among hospitals from 0.58 to 1.32; and the ratios for palliative resection varied from 0.73 to 1.26. This study demonstrates that, after adjustment for variations in case-mix and deprivation, significant differences in outcome among hospitals following resection for colorectal cancer persist

Mutations in protocadherin 15 and cadherin 23 affect tip links and mechanotransduction in mammalian sensory hair cells

Immunocytochemical studies have shown that protocadherin-15 (PCDH15) and cadherin-23 (CDH23) are associated with tip links, structures thought to gate the mechanotransducer channels of hair cells in the sensory epithelia of the inner ear. The present report describes functional and structural analyses of hair cells from Pcdh15av3J (av3J), Pcdh15av6J (av6J) and Cdh23v2J (v2J) mice. The av3J and v2J mice carry point mutations that are predicted to introduce premature stop codons in the transcripts for Pcdh15 and Cdh23, respectively, and av6J mice have an in-frame deletion predicted to remove most of the 9th cadherin ectodomain from PCDH15. Severe disruption of hair-bundle morphology is observed throughout the early-postnatal cochlea in av3J/av3J and v2J/v2J mice. In contrast, only mild-to-moderate bundle disruption is evident in the av6J/av6J mice. Hair cells from av3J/av3J mice are unaffected by aminoglycosides and fail to load with [3H]-gentamicin or FM1-43, compounds that permeate the hair cell's mechanotransducer channels. In contrast, hair cells from av6J/av6J mice load with both FM1-43 and [3H]-gentamicin, and are aminoglycoside sensitive. Transducer currents can be recorded from hair cells of all three mutants but are reduced in amplitude in all mutants and have abnormal directional sensitivity in the av3J/av3J and v2J/v2J mutants. Scanning electron microscopy of early postnatal cochlear hair cells reveals tip-link like links in av6J/av6J mice, substantially reduced numbers of links in the av3J/av3J mice and virtually none in the v2J/v2J mice. Analysis of mature vestibular hair bundles reveals an absence of tip links in the av3J/av3J and v2J/v2J mice and a reduction in av6J/av6J mice. These results therefore provide genetic evidence consistent with PCDH15 and CDH23 being part of the tip-link complex and necessary for normal mechanotransduction

HPV16 oncogene expression levels during early cervical carcinogenesis are determined by the balance of epigenetic chromatin modifications at the integrated virus genome.

In cervical squamous cell carcinomas, high-risk human papillomavirus (HRHPV) DNA is usually integrated into host chromosomes. Multiple integration events are thought to be present within the cells of a polyclonal premalignant lesion and the features that underpin clonal selection of one particular integrant remain poorly understood. We previously used the W12 model system to generate a panel of cervical keratinocyte clones, derived from cells of a low-grade premalignant lesion naturally infected with the major HRHPV type, HPV16. The cells were isolated regardless of their selective advantage and differed only by the site of HPV16 integration into the host genome. We used this resource to test the hypothesis that levels of HPV16 E6/E7 oncogene expression in premalignant cells are regulated epigenetically. We performed a comprehensive analysis of the epigenetic landscape of the integrated HPV16 DNA in selected clones, in which levels of virus oncogene expression per DNA template varied ~6.6-fold. Across the cells examined, higher levels of virus expression per template were associated with more open chromatin at the HPV16 long control region, together with greater loading of chromatin remodelling enzymes and lower nucleosome occupancy. There were higher levels of histone post-translational modification hallmarks of transcriptionally active chromatin and lower levels of repressive hallmarks. There was greater abundance of the active/elongating form of the RNA polymerase-II enzyme (RNAPII-Ser2P), together with CDK9, the component of positive transcription elongation factor b complex responsible for Ser2 phosphorylation. The changes observed were functionally significant, as cells with higher HPV16 expression per template showed greater sensitivity to depletion and/or inhibition of histone acetyltransferases and CDK9 and less sensitivity to histone deacetylase inhibition. We conclude that virus gene expression per template following HPV16 integration is determined through multiple layers of epigenetic regulation, which are likely to contribute to selection of individual cells during cervical carcinogenesis.This work was supported by Cancer Research UK (Programme Grant A13080); the Medical Research Council; The Pathological Society of Great Britain and Ireland (E.L.A.K.); and the Agency for Science, Technology and Research, Singapore (Q.Y.A).This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/onc.2016.

An open cohort study of bone metastasis incidence following surgery in breast cancer patients

Background: To help design clinical trials of adjuvant bisphosphonate therapy for breast cancer, the temporal incidence of bone metastasis was investigated in a cohort of patients. We have tried to draw the criteria to use adjuvant bisphosphonate.Methods: Consecutive breast cancer patients undergoing surgery between 1988 and 1998 (5459 patients) were followed up regarding bone metastasis until December 2006. Patients characteristics at the time of surgery were analyzed by Cox method, with bone metastasis as events. Patient groups were assigned according to Cox analysis, and were judged either to require the adjuvant bisphosphonate or not, using the tentative criteria: high risk (>3% person-year), medium risk (1-3%), and low risk (3% per person-year, patients with stage I <1% per person-year, andthose with stages II were between 1 and 3%. Further analysis with histology in stage II patients showed that stage IIB with high risk histology also had a high incidence (3% person year), whereas stage IIA with medium risk histology were <1%.Conclusions: Bone metastasis incidence remained constant for many years. Using pN, T, and histopathology, patients could be classified into high, medium, and low risk groups

Meta-analysis of clodronate and breast cancer survival

Clinical trials have reported conflicting results on whether oral clodronate therapy improves survival in breast cancer patients. This study was undertaken to evaluate further the effect of oral clodronate therapy on overall survival, bone metastasis-free survival and nonskeletal metastasis-free survival among breast cancer patients. An extensive literature search was undertaken for the period 1966 to July 2006 to identify clinical trials examining survival in breast cancer patients who received 2 or 3 years of oral clodronate therapy at 1600 mg day−1 compared with those without therapy. Meta-analyses were carried out separately for patients diagnosed with advanced breast cancer and early breast cancer. Our meta-analysis found no evidence of any statistically significant difference in overall survival, bone metastasis-free survival or nonskeletal metastasis-free survival in advanced breast cancer patients receiving clodronate therapy or early breast cancer patients receiving adjuvant clodronate treatment compared with those who did not receive any active treatment