Faculty Bibliography

Treatment protocols for breast cancer depend predominantly on receptor status with respect to estrogen (estrogen receptor alpha), progesterone (progesterone receptor) and human epidermal growth factor [human epidermal growth factor receptor 2 (HER2)]. The presence of one or more of these receptors suggests that a treatment targeting these pathways might be effective, while the absence of, or in the case of HER2, lack of overexpression of, all of these receptors, termed triple negative breast cancer (TNBC), indicates a need for the more toxic chemotherapy. In an effort to develop targeted therapies for TNBC, it will be necessary to differentiate among specific TNBC subtypes. The subset of TNBC that expresses androgen receptor (AR) has been determined to express genes consistent with a luminal subtype and therefore may be amenable to therapies targeting either AR, itself, or other pathways typical of a luminal subtype. Recent investigations of the AR signal pathway within breast cancer lead to AR as a significant target for breast cancer therapy with several clinical trials currently in progress. The subclass of TNBC that lacks AR, which we have termed quadruple negative breast cancer (QNBC) currently lacks a defined targetable pathway. Unlike AR-positive TNBC, QNBC predominantly exhibits a basal-like molecular subtype. Several subtypes and related pathway proteins are preferentially expressed in QNBC that may serve as effective targets for treatment, such as ACSL4, SKP2 and EGFR. ACSL4 expression has been demonstrated to be inversely correlated with expression of hormone/growth factor receptors and may thus serve as a biomarker for QNBC as well as a target for therapy. In the following review we summarize some of the current efforts to develop alternatives to chemotherapy for TNBC and QNBC.

With advanced aging, there is a decline in innate cardiovascular function. This decline is not general in nature. Instead, specific changes occur that impact the basic cardiovascular function, which include alterations in biochemical pathways and ion channel function. This review focuses on a particular ion channel that couple the latter two processes, namely the KATP channel, which opening is promoted by alterations in intracellular energy metabolism. We show that the intrinsic properties of the KATP channel changes with advanced aging and argue that the channel can be further modulated by biochemical changes. The importance is widespread, given the ubiquitous nature of the KATP channel in the cardiovascular system where it can regulate processes as diverse as cardiac function, blood flow and protection mechanisms against superimposed stress, such as cardiac ischemia. We highlight questions that remain to be answered before the KATP channel can be considered as a viable target for therapeutic intervention.

The temporal transcription factor Kruppel has a dual role in the development of neurons.

OBJECTIVE: Temporal lobe epilepsy (TLE) is one of the most common forms of epilepsy. Unfortunately, the clinical outcomes of TLE cannot be determined based only on current diagnostic modalities. A better understanding of white matter (WM) connectivity changes in TLE may aid the identification of network abnormalities associated with TLE and the phenotypic characterisation of the disease. METHODS: We implemented a novel approach for characterising microstructural changes along WM pathways using diffusional kurtosis imaging (DKI). Along-the-tract measures were compared for 32 subjects with left TLE and 36 age-matched and gender-matched controls along the left and right fimbria-fornix (FF), parahippocampal WM bundle (PWMB), arcuate fasciculus (AF), inferior longitudinal fasciculus (ILF), uncinate fasciculus (UF) and cingulum bundle (CB). Limbic pathways were investigated in relation to seizure burden and control with antiepileptic drugs. RESULTS: By evaluating measures along each tract, it was possible to identify abnormalities localised to specific tract subregions. Compared with healthy controls, subjects with TLE demonstrated pathological changes in circumscribed regions of the FF, PWMB, UF, AF and ILF. Several of these abnormalities were detected only by kurtosis-based and not by diffusivity-based measures. Structural WM changes correlated with seizure burden in the bilateral PWMB and cingulum. CONCLUSIONS: DKI improves the characterisation of network abnormalities associated with TLE by revealing connectivity abnormalities that are not disclosed by other modalities. Since TLE is a neuronal network disorder, DKI may be well suited to fully assess structural network abnormalities related to epilepsy and thus serve as a tool for phenotypic characterisation of epilepsy.

We investigated vestibular function and otolith size (OS) in larvae of white seabass Atractoscion nobilis exposed to high partial pressure of CO2 (pCO(2)) The context for our study is the increasing concentration of CO2 in seawater that is causing ocean acidification (OA). The utricular otoliths are aragonitic structures in the inner ear of fish that act to detect orientation and acceleration. Stimulation of the utricular otoliths during head movement results in a behavioral response called the vestibulo-ocular reflex (VOR). The VOR is a compensatory eye rotation that serves to maintain a stable image during movement. VOR is characterized by gain (ratio of eye amplitude to head amplitude) and phase shift (temporal synchrony). We hypothesized that elevated pCO(2) would increase OS and affect the VOR. We found that the sagittae and lapilli of young larvae reared at 2500 mu atm pCO(2) (treatment) were 14 to 20% and 37 to 39% larger in area, respectively, than those of larvae reared at 400 mu atm pCO(2) (control). The mean gain of treatment larvae (0.39 +/- 0.05, n = 28) was not statistically different from that of control larvae (0.30 +/- 0.03, n = 20), although there was a tendency for treatment larvae to have a larger gain. Phase shift was unchanged. Our lack of detection of a significant effect of elevated pCO(2) on the VOR may be a result of the low turbulence conditions of the experiments, large natural variation in otolith size, calibration of the VOR or mechanism of acid-base regulation of white seabass larvae.

Functional magnetic resonance imaging (fMRI) without an explicit task, i.e., resting state fMRI, of individuals with Attention-Deficit/Hyperactivity Disorder (ADHD) is growing rapidly. Early studies were unaware of the vulnerability of this method to even minor degrees of head motion, a major concern in the field. Recent efforts are implementing various strategies to address this source of artifact along with a growing set of analytical tools. Availability of the ADHD-200 Consortium dataset, a large-scale multi-site repository, is facilitating increasingly sophisticated approaches. In parallel, investigators are beginning to explicitly test the replicability of published findings. In this narrative review, we sketch out broad, overarching hypotheses being entertained while noting methodological uncertainties. Current hypotheses implicate the interplay of default, cognitive control (frontoparietal) and attention (dorsal, ventral, salience) networks in ADHD; functional connectivities of reward-related and amygdala-related circuits are also supported as substrates for dimensional aspects of ADHD. Before these can be further specified and definitively tested, we assert the field must take on the challenge of mapping the "topography" of the analytical space, i.e., determining the sensitivities of results to variations in acquisition, analysis, demographic and phenotypic parameters. Doing so with openly available datasets will provide the needed foundation for delineating typical and atypical developmental trajectories of brain structure and function in neurodevelopmental disorders including ADHD when applied to large-scale multi-site prospective longitudinal studies such as the forthcoming Adolescent Brain Cognitive Development study.

Brain activation studies in humans have shown the dynamic nature of neuronal N-acetylaspartate (NAA) and N-acetylaspartylglutamate (NAAG) based on changes in their MRS signals in response to stimulation. These studies demonstrated that upon visual stimulation there was a focal increase in cerebral blood flow (CBF) and a decrease in NAA or in the total of NAA and NAAG signals in the visual cortex, and that these changes were reversed upon cessation of stimulation. In the present study we have developed an animal model in order to explore the relationships between brain stimulation, neuronal activity, CBF and NAA. We use "designer receptor exclusively activated by designer drugs" (DREADDs) technology for site-specific neural activation, a local field potential electrophysiological method for measurement of changes in the rate of neuronal activity, functional MRS for measurement of changes in NAA and a blood oxygenation level-dependent (BOLD) MR technique for evaluating changes in CBF. We show that stimulation of the rat prefrontal cortex using DREADDs results in the following: (i) an increase in level of neuronal activity; (ii) an increase in BOLD and (iii) a decrease in the NAA signal. These findings show for the first time the tightly coupled relationships between stimulation, neuron activity, CBF and NAA dynamics in brain, and also provide the first demonstration of the novel inverse stimulation-NAA phenomenon in an animal model.

Fever is a highly conserved systemic response to infection dating back over 600 million years. Although conferring a survival benefit, fever can negatively impact the function of excitable tissues, such as the heart, producing cardiac arrhythmias. Here we show that mice lacking fibroblast growth factor homologous factor 2 (FHF2) have normal cardiac rhythm at baseline, but increasing core body temperature by as little as 3 degrees C causes coved-type ST elevations and progressive conduction failure that is fully reversible upon return to normothermia. FHF2-deficient cardiomyocytes generate action potentials upon current injection at 25 degrees C but are unexcitable at 40 degrees C. The absence of FHF2 accelerates the rate of closed-state and open-state sodium channel inactivation, which synergizes with temperature-dependent enhancement of inactivation rate to severely suppress cardiac sodium currents at elevated temperatures. Our experimental and computational results identify an essential role for FHF2 in dictating myocardial excitability and conduction that safeguards against temperature-sensitive conduction failure.

This Matters Arising Response paper addresses the Sultan et al. (2016) Matters Arising paper, published concurrently in Neuron. Clonally related excitatory neurons maintain a coherent relationship following their specification and migration. Whether cortical interneurons behave similarly is a fundamental question in developmental neuroscience. In Mayer et al. (2015), we reported that sibling interneurons disperse over several millimeters, across functional and anatomical boundaries. This finding demonstrated that clonality is not predictive of an interneuron's ultimate circuit specificity. Comparing the distribution of interneurons published in Mayer et al. to a random computer simulation, Sultan et al. suggest that clonally related interneurons are "not randomly dispersed." We argue that this comparison provides no insight into the influence of clonality on interneuron development because the entire population of cortical interneurons is "not randomly dispersed" in vivo. We find that the majority of cortical interneurons are similarly distributed whether or not they share a lineal relationship. Thus, at present there is no compelling evidence that clonality influences the position or function of interneurons.

In Alzheimer's disease, soluble tau accumulates and deposits as neurofibrillary tangles (NFTs). However, a precise toxic mechanism of tau is not well understood. We hypothesized that overexpression of wild-type tau downregulates brain-derived neurotrophic factor (BDNF), a neurotrophic peptide essential for learning and memory. Two transgenic mouse models of human tau expression and human tau (hTau40)-transfected human neuroblastoma (SH-SY5Y) cells were used to examine the effect of excess or pathologically modified wild-type human tau on BDNF expression. Both transgenic mouse models, with or without NFTs, as well as hTau40-SH-SY5Y cells significantly downregulated BDNF messenger RNA compared with controls. Similarly, transgenic mice overexpressing amyloid-beta (Abeta) significantly downregulated BDNF expression. However, when crossed with tau knockout mice, the resulting animals exhibited BDNF levels that were not statistically different from wild-type mice. These results demonstrate that excess or pathologically modified wild-type human tau downregulates BDNF and that neither a mutation in tau nor the presence of NFTs is required for toxicity. Moreover, our findings suggest that tau at least partially mediates Abeta-induced BDNF downregulation. Therefore, Alzheimer's disease treatments targeting Abeta alone may not be effective without considering the impact of tau pathology on neurotrophic pathways.