Activation of EGFR, HER2 and HER3 by neurotensin/neurotensin receptor 1 renders breast tumors aggressive yet highly responsive to lapatinib and metformin in mice

A present challenge in breast oncology research is to identify therapeutical targets which could impact tumor progression. Neurotensin (NTS) and its high affinity receptor (NTSR1) are up regulated in 20% of breast cancers, and NTSR1 overexpression was shown to predict a poor prognosis for 5 year overall survival in invasive breast carcinomas. Interactions between NTS and NTSR1 induce pro-oncogenic biological effects associated with neoplastic processes and tumor progression. Here, we depict the cellular mechanisms activated by NTS, and contributing to breast cancer cell aggressiveness. We show that neurotensin (NTS) and its high affinity receptor (NTSR1) contribute to the enhancement of experimental tumor growth and metastasis emergence in an experimental mice model. This effect ensued following EGFR, HER2, and HER3 over-expression and autocrine activation and was associated with an increase of metalloproteinase MMP9, HB-EGF and Neuregulin 2 in the culture media. EGFR over expression ensued in a more intense response to EGF on cellular migration and invasion. Accordingly, lapatinib, an EGFR/HER2 tyrosine kinase inhibitor, as well as metformin, reduced the tumor growth of cells overexpressing NTS and NTSR1. All cellular effects, such as adherence, migration, invasion, altered by NTS/NTSR1 were abolished by a specific NTSR1 antagonist. A strong statistical correlation between NTS-NTSR1-and HER3 (p< 0.0001) as well as NTS-NTSR1-and HER3-HER2 (p< 0.001) expression was found in human breast tumors. Expression of NTS/NTSR1 on breast tumoral cells creates a cellular context associated with cancer aggressiveness by enhancing epidermal growth factor receptor activity. We propose the use of labeled NTS/NTSR1 complexes to enlarge the population eligible for therapy targeting HERs tyrosine kinase inhibitor or HER2 overexpression

Module design and fault diagnosis in electric vehicle batteries

Systems integration issues, such as electrical and thermal design and management of full battery packs - often containing hundreds of cells - have been rarely explored in the academic literature. In this paper we discuss the design and construction of a 9 kWh battery pack for a motorsports application. The pack contained 504 lithium cells arranged into 2 sidepods, each containing 3 modules, with each module in a 12P7S configuration. This paper focuses particularly on testing the full battery pack and diagnosing subsequent problems related to cells being connected in parallel. We demonstrate how a full vehicle test can be used to identify malfunctioning strings of cells for further investigation. After individual cell testing it was concluded that a single high inter-cell contact resistance was causing currents to flow unevenly within the pack, leading to cells being unequally worked. This is supported by a Matlab/Simulink model of one battery module, including contact resistances. Over time the unequal current flowing through cells can lead to significant differences in cells' state of charge and open circuit voltages, large currents flowing between cells even when the load is disconnected, cells discharging and aging more quickly than others, and jeopardise capacity and lifetime of the pack

The design and impact of in-situ and operando thermal sensing for smart energy storage

Lithium-ion is increasingly the technology of choice for battery-powered systems. Current cell performance monitoring, which relies on measurements of full cell voltage and sporadic surface temperature, does not provide a reliable information on the true internal battery state. Here, we address this issue by transforming off the shelf cells into smart systems by embedding flexible distributed sensors for long-term in-situ and operando thermodynamic data collection. Our approach, which enables the monitoring of the true battery state, does not impact its performance. In particular, our results show that this unprecedented methodology can be used to optimise the performance and map the safety limits of lithium-ion cells. We find that the cell core temperature is consistently and significantly higher than the surface temperature, and reveal a breach of safety limits during a rapid discharge test. We also demonstrate an application of a current considerably higher than the manufacturers’ specification, enabling a significant decrease in charging time, without compromising the cell’s thermal stability. Consequently, this work on cell instrumentation methodology has the potential to facilitate significant advances in battery technology

Combining lapatinib and pertuzumab to overcome lapatinib resistance due to NRG1-mediated signalling in HER2-amplified breast cancer.

Acquired resistance to lapatinib, an inhibitor of EGFR and HER2 kinases, is common. We found that reactivation of EGFR, HER2 and HER3 occurred within 24 hours of lapatinib treatment after their initial dephosphorylation. This was associated with increased expression of NRG1 in cells treated with lapatinib. Exogenous NRG1 partially rescued breast cancer cells from growth inhibition by lapatinib. In addition, both parental and lapatinib-resistant breast cancer cells were sensitive to SGP1, which inhibits binding of NRG1 and other HER3 ligands. Addition of pertuzumab to lapatinib further inhibited NRG1-induced signalling, which was not fully inhibited by either drug alone. In animal model, a combination of pertuzumab to lapatinib induced a greater tumor regression than either lapatinib or pertuzumab monotherapy. This novel combination treatment may provide a promising strategy in clinical HER2-targeted therapy and may inhibit a subset of lapatinib-resistant breast cancer, although the group of patients that will respond to this therapy requires further stratification

The Neurotensin Receptor-1 Pathway Contributes to Human Ductal Breast Cancer Progression

BACKGROUND: The neurotensin (NTS) and its specific high affinity G protein coupled receptor, the NT1 receptor (NTSR1), are considered to be a good candidate for one of the factors implicated in neoplastic progression. In breast cancer cells, functionally expressed NT1 receptor coordinates a series of transforming functions including cellular migration and invasion. METHODS AND RESULTS: we investigated the expression of NTS and NTSR1 in normal human breast tissue and in invasive ductal breast carcinomas (IDCs) by immunohistochemistry and RT-PCR. NTS is expressed and up-regulated by estrogen in normal epithelial breast cells. NTS is also found expressed in the ductal and invasive components of IDCs. The high expression of NTSR1 is associated with the SBR grade, the size of the tumor, and the number of metastatic lymph nodes. Furthermore, the NTSR1 high expression is an independent factor of prognosis associated with the death of patients. CONCLUSION: these data support the activation of neurotensinergic deleterious pathways in breast cancer progression

A lumped thermal model of lithium-ion battery cells considering radiative heat transfer

Thermal management plays a critical role in battery operations to improve safety and prolong battery life, especially in high power applications such as electric vehicles. A lumped parameter (LP) battery thermal model (BTM) is usually preferred for real-time thermal management due to its simple structure and ease of implementation. Considering the time-varying model parameters (e.g., the varying convective heat dissipation coefficient under different cooling conditions), an online parameter estimation scheme is needed to improve modelling accuracy. In this paper, a new formulation of adaptive LP BTM is proposed. Unlike the conventional LP BTMs that only consider convection heat transfer, the radiative heat transfer is also considered in the proposed model to better approximate the physical heat dissipation process, which leads to an improved modelling accuracy. On the other hand, the radiative heat transfer introduces nonlinearity to the BTM and poses challenge to online parameter estimation. To tackle this problem, the simplified refined instrumental variable approach is proposed for real-time parameter estimation by reformulating the nonlinear model equations into a linear-in-the-parameter manner. Finally, test data are collected using a Li ion battery. The experimental results have verified the accuracy of the proposed BTM and the effectiveness of the proposed online parameter estimation algorithm