Bisphosphonates have been studied in randomised trials in early breast cancer to investigate their ability to prevent cancer treatment-induced bone loss (CTIBL) and reduce the risk of disease ...recurrence and metastasis. Treatment benefits have been reported but bisphosphonates do not currently have regulatory approval for either of these potential indications. This consensus paper provides a review of the evidence and offers guidance to breast cancer clinicians on the use of bisphosphonates in early breast cancer. Using the nominal group methodology for consensus, a systematic review of the literature was augmented by a workshop held in October 2014 for breast cancer and bone specialists to present and debate the available pre-clinical and clinical evidence for the use of adjuvant bisphosphonates. This was followed by a questionnaire to all members of the writing committee to identify areas of consensus. The panel recommended that bisphosphonates should be considered as part of routine clinical practice for the prevention of CTIBL in all patients with a T score of <-2.0 or ≥2 clinical risk factors for fracture. Compelling evidence from a meta-analysis of trial data of >18 000 patients supports clinically significant benefits of bisphosphonates on the development of bone metastases and breast cancer mortality in post-menopausal women or those receiving ovarian suppression therapy. Therefore, the panel recommends that bisphosphonates (either intravenous zoledronic acid or oral clodronate) are considered as part of the adjuvant breast cancer treatment in this population and the potential benefits and risks discussed with relevant patients.
•This paper proposes equivalent models of active distribution networks (ADN).•Equivalent models allow TSOs to expand the system observability.•The proposed model is able to take into account the ...prior knowledge of an ADN.•The model can be easily adapted to different configurations of the ADN.•The approach is validated by a simulation study on a Benchmark MV Active Network.
This paper proposes a methodology for the identification of equivalent models of active distribution networks. Due to the increasing installation of distributed generation plants, distribution networks are acquiring an “active” role in the management of the overall power system. In this context, equivalent modeling is becoming essential for allowing transmission system operators to expand the system observability and improve the interoperability with distribution system operators. The present paper proposes a nonlinear model and an identification procedure able to take into account the prior knowledge of a given active distribution network. The result is an equivalent model, which can be easily adapted for reproducing the dynamical behavior of the network with different configurations. The proposed approach is validated through a simulation study on a Benchmark Medium Voltage Active Network.
Tumor phenotype may change during breast cancer progression. This study evaluates the prognostic impact of receptor discordance between paired primaries and recurrences.
One hundred and thirty-nine ...patients underwent histological sampling of suspected breast cancer recurrence. All the pathology assessments ER, PgR and human epidermal growth factor receptor 2 (HER2) on both primaries and confirmed recurrences were performed at the same laboratory.
A breast cancer recurrence was confirmed in 119 cases. Rates of discordance were 13.4%, 39% and 11.8% for ER, PgR and HER2, respectively. Ninety-two patients maintained the same tumor phenotype i.e. the same hormone receptors (HR) and HER2 status, whereas 27 (22.7%) changed during progression. The loss of HR positivity and the loss of HER2 positivity resulted in a worse post-recurrence survival (P=0.01 and P=0.008, respectively) and overall survival (OS; P=0.06 and P=0.0002, respectively), compared with the corresponding concordant-positive cases. Tumor phenotype discordance was associated with worse post-recurrence and OS (P=0.006 and P=0.002, respectively); those cases who turned into triple-negative experienced the poorest outcome, respect to the concordant group (P=0.001, OS).
We demonstrated for the first time an impact on OS of phenotype discordance between primary breast cancer and relapse. Among discordant cases, receptor loss resulted in the main determinant of poorer outcome.
This paper describes the comparison and parameterization process of dynamic battery models for cell and system simulation. Three commonly used equivalent circuit battery models are parameterized ...using a numeric optimization method and basic electrical tests with a lithium-ion polymer battery cell. The maximum model performance is investigated, and the parameterized models are compared regarding the parameterization effort and the model accuracy. For the model with the best tradeoff between the parametrization effort and the model accuracy, a reasonable simplification of the parameterization process is presented. This model is parameterized with the simplified parameterization process and, finally, validated by using a current profile obtained from an electric vehicle simulation performing a real-life driving cycle.
Emerging literature data are showing that a change in human epidermal growth factor receptor (HER2) status adversely affects breast cancer patient's prognosis. The aim of this study was to evaluate ...the prognostic impact of HER2 loss in patients with HER2-positive disease treated with neoadjuvant therapy with or without anti-HER2 agents.
One hundred and seven consecutive HER2-positive patients were identified from a prospectively maintained database. The first cohort includes 40 patients treated with chemotherapy (CT) alone. The second cohort includes 67 patients treated with neoadjuvant CT plus anti-HER2 agents (trastuzumab and/or lapatinib). HER2 expression was evaluated by immunihistochemistry or fluorescence in situ hybridization on pretreatment core biopsy and on surgical specimen after therapy.
The rates of pathologic complete response (pCR) and breast-conserving surgery were higher in the CT + anti-HER2 cohort. A loss of HER2 expression was observed in 40% of the patients with residual disease after CT alone versus 14.7% of the patients after CT + anti-HER2 agents (P = 0.019). Patients not achieving a pCR have a significant increase in the risk of relapse when compared with those achieving a pCR (hazard ratio HR 9.55, P = 0.028). Patients with HER2 loss tended to have a higher risk of relapse as comparing to patients with maintained HER2 positivity (HR 2.41, P = 0.063).
The pCR is confirmed as a powerful predictor of long-term outcome. The rate of HER2 loss is higher in patients receiving neoadjuvant CT without anti-HER2 agents. HER2 status on residual disease after preoperative therapy can be helpful in selecting patients at different risk of relapse, to be included in prospective trial exploring further adjuvant therapy.
Cultured species of aquatic animals span more than five phyla. Animal welfare attention is directed towards the vertebrates because of the their neural complexity, and is currently focused on the ...finfish because of the size and visibility of that segment of the aquaculture industry. The characteristics of the aquatic environment and their impact on the animal have forced growers to develop cultural practices designed to control and minimize animal stress. This was not done as a result of social awareness, but out of necessity to keep fish alive and healthy; and managing stress is a principal key in ensuring animal welfare. Aquatic farmers are aware of the consequences of fish stress, but have limited knowledge of the basic biological principles of animal stress and have little exposure to the linkages between these concepts and the issues critical to animal welfare. Although the industry has many tools available for monitoring and preventing stress, not all growers have had exposure to the information that is available or know of its value when addressing issues of animal welfare.
Management of small cell lung cancer (SCLC) has not changed over the last decades. In more recent years, alterations of DNA repair machinery and other molecular pathways have been identified in SCLC ...and preclinical data suggest that dysregulation of these pathways might offer new therapeutic opportunities.While immune checkpoint inhibitors (ICIs) have had a major impact on the clinical outcome of several solid tumors, including non-small cell lung cancer, the potential role of ICIs is currently under investigation in SCLC and some promising data are available. However, several clinical and biological hurdles have to be overcome and predictive markers are still eagerly needed. Knowledge of molecular pathways specifically involved in SCLC growth and treatment resistance is essential for a more rational planning of new combinations including ICIs.The present manuscript summarizes the current clinical evidence on immunotherapy in SCLC, describes the molecular bases underlying treatment resistance and discusses the potentialities and the rationale of different therapeutic combinations.
Atmospheric tides and associated dynamics during two major boreal sudden stratospheric warmings (SSWs) have been investigated. The evolutionary Lomb Scargle and wavelet spectral analysis of specular ...meteor radar (SMR)‐derived hourly winds reveal evidence of non‐linear interactions between the semidiurnal solar tide and the quasi‐20‐day wave (Q20dw) during SSWs. The zonal wavenumber (ZWN) diagnosis indicates possible non‐linear interaction between the dominant semidiurnal migrating tide (SW2) and zonally symmetric 20‐day wave (20dw0) component, producing the secondary waves. The non‐linear interaction between the ZWN 2 component of stationary planetary wave (SPW2) and westward propagating 20‐day wave (20dwW2) in the stratosphere seems crucial to produce the 20dw0. As observed in the SMR‐derived wind spectra, the excited 20dw0 possibly interacts non‐linearly with SW2 to generate secondary waves. Therefore, the present study provides the first observational evidence of a two‐step non‐linear interaction associated with zonally symmetric planetary waves during major SSWs.
Plain Language Summary
The sun‐synchronous semidiurnal tide (SW2) is a major wave in the middle and high latitude mesosphere and lower thermosphere (MLT). Sudden stratospheric warming (SSW) is a polar winter hemispheric event characterized by enhanced planetary wave (PW) activity. Non‐linear interaction between the two waves produces secondary waves whose frequencies are sum and difference of the primary waves. Further, the secondary waves, having a frequency closely spaced to the tidal frequency, beat with the tide, resulting in modulation of the tidal amplitude by the PW's period due to the non‐linear interaction. The spectral analysis of specular meteor radar‐derived hourly winds supports this notion, and hence provides evidence for non‐linear interactions in the MLT. The dominant PW involved in the interaction is found to be zonally symmetric. The non‐linear interaction between the stationary PW and propagating PW in the stratosphere plays an important role in forcing the zonally symmetric component, that can reach MLT altitudes. Furthermore, non‐linear interaction between SW2 and the zonally symmetric PW produces the observed secondary waves in the MLT in the form of side bands in radar spectra. Overall, the present study provides the first observational evidence of a two‐step non‐linear interaction during SSWs.
Key Points
Spectral analysis on meteor radar winds provides evidence of non‐linear interaction between semidiurnal tide and quasi‐20‐day wave
Possible role of zonal wavenumber 2 stationary planetary wave in forcing zonally symmetric 20‐day wave in the stratosphere
First observational evidence of two‐step non‐linear interaction associated with zonally symmetric planetary waves during major sudden stratospheric warmings
The prognosis of small-cell lung cancer (SCLC) is dismal and new effective therapies are needed. Immunotherapy looks promising, but no molecular predictive markers are currently available, and data ...on immune microenvironment are very limited.
We retrospectively analysed 104 SCLC cases. Immunohistochemistry evaluation of PD-L1 was performed both on tumour cells (TCs) and on tumour-infiltrating immune cells (TIICs) by using anti-PD-L1 22C3 antibody (DAKO) and categorised by using 1% as cut-off point. Tumour-infiltrating lymphocytes (TILs) were characterised by using anti-CD8 and anti-FOXP3 antibodies. Semi-quantitative score was used and categorised as positive versus negative/low. The relation of molecular markers with prognosis and with clinical variables was evaluated.
The analysis included 66 stage I–III patients (48 surgically resected, 18 treated with radical-intent chemoradiotherapy) and 38 metastatic cases. In the overall study population, PD-L1 was expressed on TCs and TIICs in 25% and 40% of cases, respectively. The proportion of PD-L1-positive cases was significantly higher in stage I–III versus metastatic patients (32% versus 13%, p: 0.034 for TCs; 51.5% versus 21% for TIICs, p: 0.002). CD8- and FOXP3-positive TILs were present in 59% and 72% of samples, respectively. The presence of FOXP3-TILs was associated with improved prognosis among non-metastatic patients, with a hazard ratio for survival of 0.32 (95% confidence interval CI: 0.16–0.7, p: 0.006) for univariate analysis, and 0.37 (95% CI: 0.17–0.81, p: 0.013) for multivariate analysis.
Immune contexture of SCLC may differ according to stage. The presence of FOXP3-positive TILs is a potential prognostic marker for stage I–III SCLCs and warrants further investigation.
•The study depicts distribution of PD-L1 expression in small-cell lung cancer (SCLC) according to stage.•The study characterises tumour-infiltrating lymphocytes (TILs) in SCLC.•Independent positive prognostic impact of FOXP3-TILs is shown in stage I–III SCLCs.
Aim
The aim of this study was to investigate the effects of 4 consecutive simulated night shifts on glucose homeostasis, mitochondrial function and central and peripheral rhythmicities compared with ...a simulated day shift schedule.
Methods
Seventeen healthy adults (8M:9F) matched for sleep, physical activity and dietary/fat intake participated in this study (night shift work n = 9; day shift work n = 8). Glucose tolerance and insulin sensitivity before and after 4 nights of shift work were measured by an intravenous glucose tolerance test and a hyperinsulinaemic euglycaemic clamp respectively. Muscles biopsies were obtained to determine insulin signalling and mitochondrial function. Central and peripheral rhythmicities were assessed by measuring salivary melatonin and expression of circadian genes from hair samples respectively.
Results
Fasting plasma glucose increased (4.4 ± 0.1 vs. 4.6 ± 0.1 mmol L−1; P = .001) and insulin sensitivity decreased (25 ± 7%, P < .05) following the night shift, with no changes following the day shift. Night shift work had no effect on skeletal muscle protein expression (PGC1α, UCP3, TFAM and mitochondria Complex II‐V) or insulin‐stimulated pAkt Ser473, pTBC1D4Ser318 and pTBC1D4Thr642. Importantly, the metabolic changes after simulated night shifts occurred despite no changes in the timing of melatonin rhythmicity or hair follicle cell clock gene expression across the wake period (Per3, Per1, Nr1d1 and Nr1d2).
Conclusion
Only 4 days of simulated night shift work in healthy adults is sufficient to reduce insulin sensitivity which would be expected to increase the risk of T2D.
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