Breast MRI and tumour biology predict axillary lymph node response to neoadjuvant chemotherapy for breast cancer

Background: In patients who have had axillary nodal metastasis diagnosed prior to neoadjuvant chemotherapy for breast cancer, there is little consensus on how to manage the axilla subsequently. The aim of this study was to explore whether a combination of breast magnetic resonance imaging (MRI) assessed response and primary tumour pathology factors could identify a subset of patients that might be spared axillary node clearance.Methods: A retrospective data analysis was performed of patients with core biopsy-proven axillary nodal metastasis prior to commencement of neoadjuvant chemotherapy (NAC) who had subsequent axillary node clearance (ANC) at definitive breast surgery. Breast tumour and axillary response at MRI before, during and on completion of NAC, core biopsy tumour grade, tumour type and immunophenotype were correlated with pathological response in the breast and the number of metastatic nodes in the ANC specimens.Results: Of 87 consecutive patients with MRI at baseline, interim and after neoadjuvant chemotherapy who underwent ANC at time of breast surgery, 33 (38%) had no residual macrometastatic axillary disease, 28 (32%) had 1–2 metastatic nodes and 26 (30%) had more than 2 metastatic nodes. Factors that predicted axillary nodal complete response were MRI complete response in the breast (p < 0.0001), HER2 positivity (p = 0.02) and non-lobular tumour type (p = 0.015).Conclusion: MRI assessment of breast tumour response to NAC and core biopsy factors are predictive of response in axillary nodes, and can be used to guide decision making regarding appropriate axillary surgery

Zoledronic acid renders human M1 and M2 macrophages susceptible to Vδ2(+) γδ T cell cytotoxicity in a perforin-dependent manner.

Vδ2(+) T cells are a subpopulation of γδ T cells in humans that are cytotoxic towards cells which accumulate isopentenyl pyrophosphate. The nitrogen-containing bisphosphonate, zoledronic acid (ZA), can induce tumour cell lines to accumulate isopentenyl pyrophosphate, thus rendering them more susceptible to Vδ2(+) T cell cytotoxicity. However, little is known about whether ZA renders other, non-malignant cell types susceptible. In this study we focussed on macrophages (Mϕs), as these cells have been shown to take up ZA. We differentiated peripheral blood monocytes from healthy donors into Mϕs and then treated them with IFN-γ or IL-4 to generate M1 and M2 Mϕs, respectively. We characterised these Mϕs based on their phenotype and cytokine production and then tested whether ZA rendered them susceptible to Vδ2(+) T cell cytotoxicity. Consistent with the literature, IFN-γ-treated Mϕs expressed higher levels of the M1 markers CD64 and IL-12p70, whereas IL-4-treated Mϕs expressed higher levels of the M2 markers CD206 and chemokine (C-C motif) ligand 18. When treated with ZA, both M1 and M2 Mϕs became susceptible to Vδ2(+) T cell cytotoxicity. Vδ2(+) T cells expressed perforin and degranulated in response to ZA-treated Mϕs as shown by mobilisation of CD107a and CD107b to the cell surface. Furthermore, cytotoxicity towards ZA-treated Mϕs was sensitive-at least in part-to the perforin inhibitor concanamycin A. These findings suggest that ZA can render M1 and M2 Mϕs susceptible to Vδ2(+) T cell cytotoxicity in a perforin-dependent manner, which has important implications regarding the use of ZA in cancer immunotherapy

Search for R-parity-violating supersymmetry in events with four or more leptons in sqrt(s) =7 TeV pp collisions with the ATLAS detector

A search for new phenomena in final states with four or more leptons (electrons or muons) is presented. The analysis is based on 4.7 fb−1 of $\sqrt{s}=7\;\mathrm{TeV}$ proton-proton collisions delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in two signal regions: one that requires moderate values of missing transverse momentum and another that requires large effective mass. The results are interpreted in a simplified model of R-parity-violating supersymmetry in which a 95% CL exclusion region is set for charged wino masses up to 540 GeV. In an R-parity-violating MSUGRA/CMSSM model, values of m 1/2 up to 820 GeV are excluded for 10 < tan β < 40

The perceptions of social responsibility for community resilience to flooding: the impact of past experience, age, gender and ethnicity

Community resilience to flooding depends, to a large extent, on the participation of community members to take more responsibility for enhancing their own resilience. The perception of social responsibility (SR) which is argued to be one of the antecedents influencing individual’s willingness to undertake resilient behaviours can significantly contribute to community resilience through individual and collective actions. Understanding of factors influencing the perceptions of SR of individuals within community might help with developing strategies to increase the perceptions of SR. This research explores perceptions of SR in relation to flooding for householders and local businesses and establishes their relationships with experience of flooding and demographic factors of age, gender and ethnicity. The data were obtained via a questionnaire survey of three communities in Birmingham and one community in South East London, UK, three with experience of flooding and one without. A total of 414 responses were received and used in the multiple regression analysis. The analysis identified ‘experience of flooding’, ‘age’ and ‘South Asian’ ethnic group as significant variables, suggesting that older individuals from South Asian ethnic groups with previous experience of flooding are likely to be more socially responsible than others without these attributes

Towards a framework for attention cueing in instructional animations: Guidelines for research and design

This paper examines the transferability of successful cueing approaches from text and static visualization research to animations. Theories of visual attention and learning as well as empirical evidence for the instructional effectiveness of attention cueing are reviewed and, based on Mayer’s theory of multimedia learning, a framework was developed for classifying three functions for cueing: (1) selection—cues guide attention to specific locations, (2) organization—cues emphasize structure, and (3) integration—cues explicate relations between and within elements. The framework was used to structure the discussion of studies on cueing in animations. It is concluded that attentional cues may facilitate the selection of information in animations and sometimes improve learning, whereas organizational and relational cueing requires more consideration on how to enhance understanding. Consequently, it is suggested to develop cues that work in animations rather than borrowing effective cues from static representations. Guidelines for future research on attention cueing in animations are presented

Cross-tolerance to abiotic stresses in halophytes: Application for phytoremediation of organic pollutants

International audienceHalopytes are plants able to tolerate high salt concentrations but no clear definition was retained for them. In literature, there are more studies that showed salt-enhanced tolerance to other abiotic stresses compared to investigations that found enhanced salt tolerance by other abiotic stresses in halophytes. The phenomenon by which a plant resistance to a stress induces resistance to another is referred to as cross-tolerance. In this work, we reviewed cross-tolerance in halophytes at the physiological, biochemical, and molecular levels. A special attention was accorded to the cross-tolerance between salinity and organic pollutants that could allow halophytes a higher potential of xenobiotic phytoremediation in comparison with glycophytes

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Analgesic management of an eight-year-old Springer Spaniel after amputation of a thoracic limb

Analgesic agents were administered perioperatively to an eight-year-old Springer Spaniel undergoing amputation of its right thoracic limb. The amputation was carried out due to a painful, infiltrative and poorly differentiated sarcoma involving the nerves of the brachial plexus. A combination of pre-emptive and multimodal perioperative analgesic strategies was used; including intravenous (IV) infusions of fentanyl, morphine, lidocaine and ketamine

Selective C-Rel Activation via Malt1 Controls Anti-Fungal TH-17 Immunity by Dectin-1 and Dectin-2

C-type lectins dectin-1 and dectin-2 on dendritic cells elicit protective immunity against fungal infections through induction of TH1 and TH-17 cellular responses. Fungal recognition by dectin-1 on human dendritic cells engages the CARD9-Bcl10-Malt1 module to activate NF-κB. Here we demonstrate that Malt1 recruitment is pivotal to TH-17 immunity by selective activation of NF-κB subunit c-Rel, which induces expression of TH-17-polarizing cytokines IL-1β and IL-23p19. Malt1 inhibition abrogates c-Rel activation and TH-17 immunity to Candida species. We found that Malt1-mediated activation of c-Rel is similarly essential to induction of TH-17-polarizing cytokines by dectin-2. Whereas dectin-1 activates all NF-κB subunits, dectin-2 selectively activates c-Rel, signifying a specialized TH-17-enhancing function for dectin-2 in anti-fungal immunity by human dendritic cells. Thus, dectin-1 and dectin-2 control adaptive TH-17 immunity to fungi via Malt1-dependent activation of c-Rel