Choosing the right cell line for breast cancer research

Breast cancer is a complex and heterogeneous disease. Gene expression profiling has contributed significantly to our understanding of this heterogeneity at a molecular level, refining taxonomy based on simple measures such as histological type, tumour grade, lymph node status and the presence of predictive markers like oestrogen receptor and human epidermal growth factor receptor 2 (HER2) to a more sophisticated classification comprising luminal A, luminal B, basal-like, HER2-positive and normal subgroups. In the laboratory, breast cancer is often modelled using established cell lines. In the present review we discuss some of the issues surrounding the use of breast cancer cell lines as experimental models, in light of these revised clinical classifications, and put forward suggestions for improving their use in translational breast cancer research

The Role of the Medial Prefrontal Cortex in Regulating Social Familiarity-Induced Anxiolysis

Overcoming specific fears and subsequent anxiety can be greatly enhanced by the presence of familiar social partners, but the neural circuitry that controls this phenomenon remains unclear. To overcome this, the social interaction (SI) habituation test was developed in this lab to systematically investigate the effects of social familiarity on anxiety-like behavior in rats. Here, we show that social familiarity selectively reduced anxiety-like behaviors induced by an ethological anxiogenic stimulus. The anxiolytic effect of social familiarity could be elicited over multiple training sessions and was specific to both the presence of the anxiogenic stimulus and the familiar social partner. In addition, socially familiar conspecifics served as a safety signal, as anxiety-like responses returned in the absence of the familiar partner. The expression of the social familiarity-induced anxiolysis (SFiA) appears dependent on the prefrontal cortex (PFC), an area associated with cortical regulation of fear and anxiety behaviors. Inhibition of the PFC, with bilateral injections of the GABAA agonist muscimol, selectively blocked the expression of SFiA while having no effect on SI with a novel partner. Finally, the effect of D-cycloserine, a cognitive enhancer that clinically enhances behavioral treatments for anxiety, was investigated with SFiA. D-cycloserine, when paired with familiarity training sessions, selectively enhanced the rate at which SFiA was acquired. Collectively, these outcomes suggest that the PFC has a pivotal role in SFiA, a complex behavior involving the integration of social cues of familiarity with contextual and emotional information to regulate anxiety-like behavior

Development of a Multivalent Subunit Vaccine against Tularemia Using Tobacco Mosaic Virus (TMV) Based Delivery System

Francisella tularensisis a facultative intracellular pathogen, and is the causative agent of a fatal human disease known as tularemia. F. tularensis is classified as a Category A Biothreat agent by the CDC based on its use in bioweapon programs by several countries in the past and its potential to be used as an agent of bioterrorism. No licensed vaccine is currently available for prevention of tularemia. In this study, we used a novel approach for development of a multivalent subunit vaccine against tularemia by using an efficient tobacco mosaic virus (TMV) based delivery platform. The multivalent subunit vaccine was formulated to contain a combination of F. tularensis protective antigens: OmpA-like protein (OmpA), chaperone protein DnaK and lipoprotein Tul4 from the highly virulent F. tularensisSchuS4 strain. Two different vaccine formulations and immunization schedules were used. The immunized mice were challenged with lethal (10xLD100) doses of F. tularensisLVS on day 28 of the primary immunization and observed daily for morbidity and mortality. Results from this study demonstrate that TMV can be used as a carrier for effective delivery of multiple F. tularensisantigens. TMV-conjugate vaccine formulations are safe and multiple doses can be administered without causing any adverse reactions in immunized mice. Immunization with TMV-conjugated F. tularensisproteins induced a strong humoral immune response and protected mice against respiratory challenges with very high doses of F. tularensis LVS. This study provides a proof-of-concept that TMV can serve as a suitable platform for simultaneous delivery of multiple protective antigens of F. tularensis. Refinement of vaccine formulations coupled with TMV-targeting strategies developed in this study will provide a platform for development of an effective tularemia subunit vaccine as well as a vaccination approach that may broadly be applicable to many other bacterial pathogens

The impacts of climate change on the winter water cycle of the western Himalaya

Some 180 million people depend on the Indus River as a key water resource, fed largely by precipitation falling over the western Himalaya. However, the projected response of western Himalayan precipitation to climate change is currently not well constrained: CMIP5 GCMs project a reduced frequency and vorticity of synoptic-scale systems impacting the area, but such systems would exist in a considerably moister atmosphere. In this study, a convection-permitting (4 km horizontal resolution) setup of the Weather Research and Forecasting (WRF) model is used to examine 40 cases of these synoptic-scale systems, known as western disturbances (WDs), as they interact with the western Himalaya. In addition to a present-day control run, three experiments are performed by perturbing the boundary and initial conditions to reflect pre-industrial, RCP4.5 and RCP8.5 background climates respectively. It is found that in spite of the weakening intensity of WDs, net precipitation associated with them in future climate scenarios increases significantly; conversely there is no net change in precipitation between the pre-industrial and control experiments despite a significant conversion of snowfall in the pre-industrial experiment to rainfall in the control experiment, consistent with the changes seen in historical observations. This shift from snowfall to rainfall has profound consequences on water resource management in the Indus Valley, where irrigation is dependent on spring meltwater. Flux decomposition shows that the increase in future precipitation follows directly from the projected moistening of the tropical atmosphere (which increases the moisture flux incident on the western Himalaya by 28%) overpowering the weakened dynamics (which decreases it by 20%). Changes to extreme rainfall events are also examined: it is found that such events may increase significantly in frequency in both future scenarios examined. Two-hour maxima rainfall events that currently occur in 1-in-8 WDs are projected to increase tenfold in frequency in the RCP8.5 scenario; more prolonged (one-week maxima) events are projected to increase fiftyfold