The prognostic effect of DDX3 upregulation in distant breast cancer metastases

Metastatic breast cancer remains one of the leading causes of death in women and identification of novel treatment targets is therefore warranted. Functional studies showed that the RNA helicase DDX3 promotes metastasis, but DDX3 expression was never studied in patient samples of metastatic cancer. In order to validate previous functional studies and to evaluate DDX3 as a potential therapeutic target, we investigated DDX3 expression in paired samples of primary and metastatic breast cancer. Samples from 79 breast cancer patients with distant metastases at various anatomical sites were immunohistochemically stained for DDX3. Both cytoplasmic and nuclear DDX3 expression were compared between primary and metastatic tumors. In addition, the correlation between DDX3 expression and overall survival was assessed. Upregulation of cytoplasmic (28%; OR 3.7; p?=?0.002) was common in breast cancer metastases, especially in triple negative (TN) and high grade cases. High cytoplasmic DDX3 levels were most frequent in brain lesions (65%) and significantly correlated with high mitotic activity and triple negative subtype. In addition, worse overall survival was observed for patients with high DDX3 expression in the metastasis (HR 1.79, p?=?0.039). Overall, we conclude that DDX3 expression is upregulated in distant breast cancer metastases, especially in the brain and in TN cases. In addition, high metastatic DDX3 expression correlates with worse survival, implying that DDX3 is a potential therapeutic target in metastatic breast cancer, in particular in the clinically important group of TN patients.     

Immediate effects of foot orthoses on pain during functional tasks in people with patellofemoral osteoarthritis: A cross-over,proof-of-concept study

Background

The purpose of the study was to determine whether prefabricated foot orthoses immediately reduce pain during functional tasks in people with patellofemoral osteoarthritis, compared to flat insoles and shoes alone.

Power‐law dynamics in neuronal and behavioral data introduce spurious correlations

Relating behavioral and neuroimaging measures is essential to understanding human brain function. Often, this is achieved by computing a correlation between behavioral measures, e.g., reaction times, and neurophysiological recordings, e.g., prestimulus EEG alpha‐power, on a single‐trial‐basis. This approach treats individual trials as independent measurements and ignores the fact that data are acquired in a temporal order. It has already been shown that behavioral measures as well as neurophysiological recordings display power‐law dynamics, which implies that trials are not in fact independent. Critically, computing the correlation coefficient between two measures exhibiting long‐range temporal dependencies may introduce spurious correlations, thus leading to erroneous conclusions about the relationship between brain activity and behavioral measures. Here, we address data‐analytic pitfalls which may arise when long‐range temporal dependencies in neural as well as behavioral measures are ignored. We quantify the influence of temporal dependencies of neural and behavioral measures on the observed correlations through simulations. Results are further supported in analysis of real EEG data recorded in a simple reaction time task, where the aim is to predict the latency of responses on the basis of prestimulus alpha oscillations. We show that it is possible to "predict" reaction times from one subject on the basis of EEG activity recorded in another subject simply owing to the fact that both measures display power‐law dynamics. The same is true when correlating EEG activity obtained from different subjects. A surrogate‐data procedure is described which correctly tests for the presence of correlation while controlling for the effect of power‐law dynamics. Hum Brain Mapp 36:2901–2914, 2015. © 2015 Wiley Periodicals, Inc.     

Brain volumetric changes and cognitive ageing during the eighth decade of life

Later‐life changes in brain tissue volumes—decreases in the volume of healthy grey and white matter and increases in the volume of white matter hyperintensities (WMH)—are strong candidates to explain some of the variation in ageing‐related cognitive decline. We assessed fluid intelligence, memory, processing speed, and brain volumes (from structural MRI) at mean age 73 years, and at mean age 76 in a narrow‐age sample of older individuals (n = 657 with brain volumetric data at the initial wave, n = 465 at follow‐up). We used latent variable modeling to extract error‐free cognitive levels and slopes. Initial levels of cognitive ability were predictive of subsequent brain tissue volume changes. Initial brain volumes were not predictive of subsequent cognitive changes. Brain volume changes, especially increases in WMH, were associated with declines in each of the cognitive abilities. All statistically significant results were modest in size (absolute r‐values ranged from 0.114 to 0.334). These results build a comprehensive picture of macrostructural brain volume changes and declines in important cognitive faculties during the eighth decade of life. Hum Brain Mapp 36:4910–4925, 2015. © 2015 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc     

The stability of coping strategies in older adults with osteoarthritis and the ability of these strategies to predict changes in depression,disability, and pain

Objectives: Given the chronically painful, incurable nature of osteoarthritis, effective cognitive and behavioral coping strategies may be critical for older adults with the disease. Little is known about how and why coping changes over time, nor about stability of coping strategies in persons with osteoarthritis. The aims of this work were to examine the structure of coping in older adults with osteoarthritis, the association of coping strategies with well-being, the stability of coping over time, and its association with changes in well-being over the same period.

Method: In a cross-sectional study, 199 older adults with osteoarthritis of the knee were assessed at baseline and two-years’ follow-up. Items from two coping scales were factor analyzed, and Pearson's correlations and paired-samples t-tests assessed relative and absolute stability of the resultant coping strategies. CFA assessed the stability of the factor structure itself. Ordinary least-squares regression analyses examined the impact of change in coping on well-being.

Results: A five-factor coping solution emerged: stoicism, refocusing, problem-solving, wishful-thinking, and emotion-focused coping. The factor structure showed stability over the two-year period. Absolute stability of strategies varied, indicating that change in coping styles was possible.

Conclusion: Changes in coping style predicts future well-being; however, coping remains malleable with age and maladaptive strategies can be effectively targeted. Greater knowledge of the utility or maladaptive nature of a given strategy may help guide decisions about interventions for patients with osteoarthritis and encourage more adaptive coping styles.     

The new DSM-5 diagnosis of mild neurocognitive disorder and its relation to research in mild cognitive impairment

The Diagnostic Statistical Manual-5 (DSM-5) has included a category named the neurocognitive disorder which was formally known in DSM-IV as ‘dementia, delirium, amnestic, and other cognitive disorders’. The DSM-5 distinguishes between ‘mild’ and ‘major’ neurocognitive disorders. Major neurocognitive disorder replaces the DSM-IV's term ‘dementia or other debilitating conditions’. A pivotal addition is ‘mild neurocognitive disorder (mNCD)’ defined by a noticeable decrement in cognitive functioning that goes beyond normal changes seen in aging. It is a disorder that may progress to dementia – importantly, it may not.

Presently, our understanding of mNCD is derived from research on mild cognitive impairment (MCI). Whereas there is currently no clear treatment for mNCD, many experimental therapies now and into the future will focus upon secondary prevention, namely decreasing the risk of progression to major NCD. In this article, we will focus on mNCD by reviewing the relevant literature on MCI. We will review the research on the incidence and prevalence of MCI, conversion rates from MCI to dementia, risk factors for conversion of MCI to dementia, comorbidity of MCI with other neuropsychiatric disorders (NPS), and the development of treatment strategies for neuropsychiatric disorders in MCI.

The presence of NPS is common among individuals with MCI and is an important risk for progression to dementia. However, there has been little research on effective treatments for NPS in MCI. Clinicians and investigators must determine if the treatment of the NPS in mNCD will improve quality of life and help reduce the progression of the cognitive impairment.     

Rab14 Regulates Maturation of Macrophage Phagosomes Containing the Fungal Pathogen Candida albicans and Outcome of the Host-Pathogen Interaction

Avoidance of innate immune defense is an important mechanism contributing to the pathogenicity of microorganisms. The fungal pathogen Candida albicans undergoes morphogenetic switching from the yeast to the filamentous hyphal form following phagocytosis by macrophages, facilitating its escape from the phagosome, which can result in host cell lysis. We show that the intracellular host trafficking GTPase Rab14 plays an important role in protecting macrophages from lysis mediated by C. albicans hyphae. Live-cell imaging of macrophages expressing green fluorescent protein (GFP)-tagged Rab14 or dominant negative Rab14, or with small interfering RNA (siRNA)-mediated knockdown of Rab14, revealed the temporal dynamics of this protein and its influence on the maturation of macrophage phagosomes following the engulfment of C. albicans cells. Phagosomes containing live C. albicans cells became transiently Rab14 positive within 2 min following engulfment. The duration of Rab14 retention on phagosomes was prolonged for hyphal cargo and was directly proportional to hyphal length. Interference with endogenous Rab14 did not affect the migration of macrophages toward C. albicans cells, the rate of engulfment, the overall uptake of fungal cells, or early phagosome processing. However, Rab14 depletion delayed the acquisition of the late phagosome maturation markers LAMP1 and lysosomal cathepsin, indicating delayed formation of a fully bioactive lysosome. This was associated with a significant increase in the level of macrophage killing by C. albicans. Therefore, Rab14 activity promotes phagosome maturation during C. albicans infection but is dysregulated on the phagosome in the presence of the invasive hyphal form, which favors fungal survival and escape.     

Multifunctional cytomegalovirus (CMV)-specific CD8+ T cells are not restricted by telomere-related senescence in young or old adults

Antigen-specific multifunctional T cells that secrete interferon-γ, interleukin-2 and tumour necrosis factor-α simultaneously after activation are important for the control of many infections. It is unclear if these CD8⁺ T cells are at an early or late stage of differentiation and whether telomere erosion restricts their replicative capacity. We developed a multi-parameter flow cytometric method for investigating the relationship between differentiation (CD45RA and CD27 surface phenotype), function (cytokine production) and replicative capacity (telomere length) in individual cytomegalovirus (CMV) antigen-specific CD8⁺ T cells. This involves surface and intracellular cell staining coupled to fluorescence in situ hybridization to detect telomeres (flow-FISH). The end-stage/senescent CD8⁺ CD45RA⁺ CD27⁻ T-cell subset increases significantly during ageing and this is exaggerated in CMV immune-responsive subjects. However, these end-stage cells do not have the shortest telomeres, implicating additional non-telomere-related mechanisms in inducing their senescence. The telomere lengths in total and CMV (NLV)-specific CD8⁺ T cells in all four subsets defined by CD45RA and CD27 expression were significantly shorter in old compared with young individuals in both a Caucasian and an Asian cohort. Following stimulation by anti-CD3 or NLV peptide, similar proportions of triple-cytokine-producing cells are found in CD8⁺ T cells at all stages of differentiation in both age groups. Furthermore, these multi-functional cells had intermediate telomere lengths compared with cells producing only one or two cytokines after activation. Therefore, global and CMV (NLV)-specific CD8⁺ T cells that secrete interferon-γ, interleukin-2 and tumour necrosis factor-α are at an intermediate stage of differentiation and are not restricted by excessive telomere erosion.