Slepian functions and their use in signal estimation and spectral analysis

It is a well-known fact that mathematical functions that are timelimited (or spacelimited) cannot be simultaneously bandlimited (in frequency). Yet the finite precision of measurement and computation unavoidably bandlimits our observation and modeling scientific data, and we often only have access to, or are only interested in, a study area that is temporally or spatially bounded. In the geosciences we may be interested in spectrally modeling a time series defined only on a certain interval, or we may want to characterize a specific geographical area observed using an effectively bandlimited measurement device. It is clear that analyzing and representing scientific data of this kind will be facilitated if a basis of functions can be found that are "spatiospectrally" concentrated, i.e. "localized" in both domains at the same time. Here, we give a theoretical overview of one particular approach to this "concentration" problem, as originally proposed for time series by Slepian and coworkers, in the 1960s. We show how this framework leads to practical algorithms and statistically performant methods for the analysis of signals and their power spectra in one and two dimensions, and on the surface of a sphere.Comment: Submitted to the Handbook of Geomathematics, edited by Willi Freeden, Zuhair M. Nashed and Thomas Sonar, and to be published by Springer Verla

Behavioural Effects of Using Sulfasalazine to Inhibit Glutamate Released by Cancer Cells: A Novel target for Cancer-Induced Depression

Despite the lack of robust evidence of effectiveness, current treatment options for cancer-induced depression (CID) are limited to those developed for non-cancer related depression. Here, anhedonia-like and coping behaviours were assessed in female BALB/c mice inoculated with 4T1 mammary carcinoma cells. The behavioural effects of orally administered sulfasalazine (SSZ), a system xc- inhibitor, were compared with fluoxetine (FLX). FLX and SSZ prevented the development of anhedonia-like behaviour on the sucrose preference test (SPT) and passive coping behaviour on the forced swim test (FST). The SSZ metabolites 5-aminosalicylic acid (5-ASA) and sulfapyridine (SP) exerted an effect on the SPT but not on the FST. Although 5-ASA is a known anti-inflammatory agent, neither treatment with SSZ nor 5-ASA/SP prevented tumour-induced increases in serum levels of interleukin-1β (IL-1β) and IL-6, which are indicated in depressive disorders. Thus, the observed antidepressant-like effect of SSZ may primarily be attributable to the intact form of the drug, which inhibits system xc-. This study represents the first attempt at targeting cancer cells as a therapeutic strategy for CID, rather than targeting downstream effects of tumour burden on the central nervous system. In doing so, we have also begun to characterize the molecular pathways of CID

Scalar and vector Slepian functions, spherical signal estimation and spectral analysis

It is a well-known fact that mathematical functions that are timelimited (or spacelimited) cannot be simultaneously bandlimited (in frequency). Yet the finite precision of measurement and computation unavoidably bandlimits our observation and modeling scientific data, and we often only have access to, or are only interested in, a study area that is temporally or spatially bounded. In the geosciences we may be interested in spectrally modeling a time series defined only on a certain interval, or we may want to characterize a specific geographical area observed using an effectively bandlimited measurement device. It is clear that analyzing and representing scientific data of this kind will be facilitated if a basis of functions can be found that are "spatiospectrally" concentrated, i.e. "localized" in both domains at the same time. Here, we give a theoretical overview of one particular approach to this "concentration" problem, as originally proposed for time series by Slepian and coworkers, in the 1960s. We show how this framework leads to practical algorithms and statistically performant methods for the analysis of signals and their power spectra in one and two dimensions, and, particularly for applications in the geosciences, for scalar and vectorial signals defined on the surface of a unit sphere.Comment: Submitted to the 2nd Edition of the Handbook of Geomathematics, edited by Willi Freeden, Zuhair M. Nashed and Thomas Sonar, and to be published by Springer Verlag. This is a slightly modified but expanded version of the paper arxiv:0909.5368 that appeared in the 1st Edition of the Handbook, when it was called: Slepian functions and their use in signal estimation and spectral analysi

Future therapeutic targets in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. Without adequate treatment, patients with RA will develop joint deformity and progressive functional impairment. With the implementation of treat-to-target strategies and availability of biologic therapies, the outcomes for patients with RA have significantly improved. However, the unmet need in the treatment of RA remains high as some patients do not respond sufficiently to the currently available agents, remission is not always achieved and refractory disease is not uncommon. With better understanding of the pathophysiology of RA, new therapeutic approaches are emerging. Apart from more selective Janus kinase inhibition, there is a great interest in the granulocyte macrophage-colony stimulating factor pathway, Bruton's tyrosine kinase pathway, phosphoinositide-3-kinase pathway, neural stimulation and dendritic cell-based therapeutics. In this review, we will discuss the therapeutic potential of these novel approaches

Abstract P3-03-13: Chronic inhibition of signal transducer and activator of transcription 3/5 in treatment-resistant human breast cancer cell subtypes: Convergence on the reactive oxyten species/SUMOylation pathway and its effects on xCT expression and system xc- activity

Abstract Pharmacologically targeting activated signal transducer and activator of transcription 3 (STAT3) and/or STAT5 has been an active area of cancer research. The cystine/glutamate antiporter system xc- contributes to redox balance and export of intracellularly produced glutamate in response to up-regulated glutaminolysis in aggressive breast cancer cells. We have previously shown that blocking STAT3/5 using the novel small molecule inhibitor SH-4-54, designed to target the SH2 domains of both proteins, increases expression of xCT, which encodes the active component of system xc-, thereby increasing antiporter activity in human breast cancer cells. The current investigation demonstrates that chronic treatment with SH-4-54, followed by clonal selection of treatment-resistant MDA-MB-231 and T47D breast cancer cells, elicits distinct subtype-dependent effects. xCT mRNA and protein levels, glutamate release, and cystine uptake are decreased relative to untreated passage-matched controls in the triple-negative MDA-MB-231 SH-4-54-resistant clones, with the inverse occurring in estrogen-responsive T47D cells. This “ying-yang” effect is linked with a shifted balance between phosphorylated STAT3 and STAT5, intracellular levels of reactive oxygen species (ROS), STAT5 SUMOylation/de-SUMOylation, and the expression of STAT3/5 target genes (assessed by NextGeneration RNA sequencing). STAT5 emerged as a definitive negative transcriptional regulator of xCT, while STAT3 activation was coupled with increased system xc- activity. Specifically, inhibiting constitutive STAT3 phosphorylation in MDA-MB-231 cells induces ROS, thereby affecting the SUMO pathway by favoring de-SUMOylation and STAT5 phosphorylation. Activated STAT5 is then able to serve as a repressor by binding to its recognition sequence within the xCT promoter, reducing xCT expression and thereby destabilizing an important redox balancing mechanism by limiting cystine uptake through system xc-. In contrast, in ERα-positive cells that initially respond to STAT5-mediated signaling, STAT3 becomes activated and xCT expression is up-regulated in response to chronic SH-4-54 treatment, potentially leading to a more aggressive cancer subtype. Further destabilizing the cellular redox status may therefore be critical to produce clinically meaningful outcomes linked to chronic treatment with potent STAT3/5 inhibitors like SH-4-54. We assessed this notion by treating SH-4-54-resistant MDA-MB-231 clones with specific ROS-inducing reagents, including capsazepine, bleomycin, and paclitaxel, which produced different effects on cell viability. We propose that careful classification of a patient's breast cancer subtype is central to therapeutically targeting STAT3/5 as a means of treating breast cancer, particularly given that xCT is emerging as an important biomarker of aggressive cancers. Citation Format: Linher-Melville K, Nashed MG, Ungard R, Haftchenary S, Gunning PT, Singh G. Chronic inhibition of signal transducer and activator of transcription 3/5 in treatment-resistant human breast cancer cell subtypes: Convergence on the reactive oxyten species/SUMOylation pathway and its effects on xCT expression and system xc- activity [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-03-13.</jats:p