Blood-brain barrier (BBB) dysfunction is an integral feature of neurological disorders and involves the action of multiple proinflammatory cytokines on the microvascular endothelial cells lining ...cerebral capillaries. There is still however, considerable ambiguity throughout the scientific literature regarding the mechanistic role(s) of cytokines in this context, thereby warranting a comprehensive in vitro investigation into how different cytokines may cause dysregulation of adherens and tight junctions leading to BBB permeabilization.
The present study employs human brain microvascular endothelial cells (HBMvECs) to compare/contrast the effects of TNF-α and IL-6 on BBB characteristics ranging from the expression of interendothelial junction proteins (VE-cadherin, occludin and claudin-5) to endothelial monolayer permeability. The contribution of cytokine-induced NADPH oxidase activation to altered barrier phenotype was also investigated.
In response to treatment with either TNF-α or IL-6 (0-100 ng/ml, 0-24 hrs), our studies consistently demonstrated significant dose- and time-dependent decreases in the expression of all interendothelial junction proteins examined, in parallel with dose- and time-dependent increases in ROS generation and HBMvEC permeability. Increased expression and co-association of gp91 and p47, pivotal NADPH oxidase subunits, was also observed in response to either cytokine. Finally, cytokine-dependent effects on junctional protein expression, ROS generation and endothelial permeability could all be attenuated to a comparable extent using a range of antioxidant strategies, which included ROS depleting agents (superoxide dismutase, catalase, N-acetylcysteine, apocynin) and targeted NADPH oxidase blockade (gp91 and p47 siRNA, NSC23766).
A timely and wide-ranging investigation comparing the permeabilizing actions of TNF-α and IL-6 in HBMvECs is presented, in which we demonstrate how either cytokine can similarly downregulate the expression of interendothelial adherens and tight junction proteins leading to elevation of paracellular permeability. The cytokine-dependent activation of NADPH oxidase leading to ROS generation was also confirmed to be responsible in-part for these events.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Heparan sulfate is found on the surface of most cell types, as well as in basement membranes and extracellular matrices. Its strong anionic properties and highly variable structure enable this ...glycosaminoglycan to provide binding sites for numerous protein ligands, including many soluble mediators of the immune system, and may promote or inhibit their activity. The formation of ligand binding sites on heparan sulfate (HS) occurs in a tissue‐ and context‐specific fashion through the action of several families of enzymes, most of which have multiple isoforms with subtly different specificities. Changes in the expression levels of these biosynthetic enzymes occur in response to inflammatory stimuli, resulting in structurally different HS and acquisition or loss of binding sites for immune mediators. In this review, we discuss the multiple roles for HS in regulating immune responses, and the evidence for inflammation‐associated changes to HS structure.
Review of the established and emerging roles of heparan sulfate as an immune regulator through binding inflammatory ligands in the microenvironment and on cell surfaces.
With the shift to de-escalation of therapy for some breast cancers and fewer surgical excisions for high-risk lesions identified on breast imaging studies at one end of the spectrum, and the greater ...use of neoadjuvant systemic therapy at the other end, pathologists are ever more critical in guiding management decisions for women with breast disease following core needle biopsy. One important consequence of this shift in management paradigms is the elimination of the opportunity for a “second-look” with the excision specimen to confirm or refine the diagnosis rendered on core needle biopsy. Thus, not only is there the imperative for accuracy and precision of core needle biopsy diagnoses, increasingly it is the only opportunity for that diagnosis.
Older adults are at risk for loneliness, and interventions to promote social connectedness are needed to directly address this problem. The nature of interventions aimed to affect the distinct, ...subjective concepts of loneliness/social connectedness has not been clearly described. The purpose of this review was to map the literature on interventions and strategies to affect loneliness/social connectedness for older adults.
A comprehensive scoping review was conducted. Six electronic databases were searched from inception in July 2015, resulting in 5530 unique records. Standardized inclusion/exclusion criteria were applied, resulting in a set of 44 studies (reported in 54 articles) for further analysis. Data were extracted to describe the interventions and strategies, and the context of the included studies. Analytic techniques included calculating frequencies, manifest content analysis and meta-summary.
Interventions were described or evaluated in 39 studies, and five studies described strategies to affect loneliness/social connectedness of older adults or their caregivers in a qualitative descriptive study. The studies were often conducted in the United States (38.6%) among community dwelling (54.5%), cognitively intact (31.8%), and female-majority (86.4%) samples. Few focused on non-white participants (4.5%). Strategies described most often were engaging in purposeful activity and maintaining contact with one's social network. Of nine intervention types identified, the most frequently described were One-to-One Personal Contact and Group Activity. Authors held divergent views of why the same type of intervention might impact social connectedness, but social contact was the most frequently conceptualized influencing factor targeted, both within and across intervention types.
Research to test the divergent theories of why interventions work is needed to advance understanding of intervention mechanisms. Innovative conceptualizations of intervention targets are needed, such as purposeful activity, that move beyond the current focus on the objective social network as a way to promote social connectedness for older adults.
Quasicrystals possess long-range order but lack the translational symmetry of crystalline solids. In solid state physics, periodicity is one of the fundamental properties that prescribes the ...electronic band structure in crystals. In the absence of periodicity and the presence of quasicrystalline order, the ways that electronic states change remain a mystery. Scanning tunnelling microscopy and atomic manipulation can be used to assemble a two-dimensional quasicrystalline structure mapped upon the Penrose tiling. Here, carbon monoxide molecules are arranged on the surface of Cu(111) one at a time to form the potential landscape that mimics the ionic potential of atoms in natural materials by constraining the electrons in the two-dimensional surface state of Cu(111). The real-space images reveal the presence of the quasiperiodic order in the electronic wave functions and the Fourier analysis of our results links the energy of the resonant states to the local vertex structure of the quasicrystal.
The human HDAC (histone deacetylase) family, a well-validated anticancer target, plays a key role in the control of gene expression through regulation of transcription. While HDACs can be subdivided ...into three main classes, the class I, class II and class III HDACs (sirtuins), it is presently unclear whether inhibiting multiple HDACs using pan-HDAC inhibitors, or targeting specific isoforms that show aberrant levels in tumours, will prove more effective as an anticancer strategy in the clinic. To address the above issues, we have tested a number of clinically relevant HDACis (HDAC inhibitors) against a panel of rhHDAC (recombinant human HDAC) isoforms. Eight rhHDACs were expressed using a baculoviral system, and a Fluor de Lystrade mark (Biomol International) HDAC assay was optimized for each purified isoform. The potency and selectivity of ten HDACs on class I isoforms (rhHDAC1, rhHDAC2, rhHDAC3 and rhHDAC8) and class II HDAC isoforms (rhHDAC4, rhHDAC6, rhHDAC7 and rhHDAC9) was determined. MS-275 was HDAC1-selective, MGCD0103 was HDAC1- and HDAC2-selective, apicidin was HDAC2- and HDAC3-selective and valproic acid was a specific inhibitor of class I HDACs. The hydroxamic acid-derived compounds (trichostatin A, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat) were potent pan-HDAC inhibitors. The growth-inhibitory effect of the HDACis on HeLa cells showed that both pan-HDAC and class-I-specific inhibitors inhibited cell growth. The results also showed that both pan-HDAC and class-I-specific inhibitor treatment resulted in increased acetylation of histones, but only pan-HDAC inhibitor treatment resulted in increased tubulin acetylation, which is in agreement with their activity towards the HDAC6 isoform.
Epidemiologic data suggest that parity increases risk of hormone receptor-negative breast cancer and that breastfeeding attenuates this association. Prospective data, particularly on the joint ...effects of higher parity and breastfeeding, are limited.
We investigated parity, breastfeeding, and breast cancer risk by hormone-receptor (estrogen (ER) and progesterone receptor (PR)) and molecular subtypes (luminal A, luminal B, HER2-enriched, and basal-like) in the Nurses' Health Study (NHS; 1976-2012) and NHSII (1989-2013). A total of 12,452 (ER+ n = 8235; ER- n = 1978) breast cancers were diagnosed among 199,514 women. We used Cox proportional hazards models, adjusted for breast cancer risk factors, to calculate hazard ratios (HR) and 95% confidence intervals (CI).
Parous women had lower risk of ER+ breast cancer (vs. nulliparous, HR = 0.82 0.77-0.88); no association was observed for ER- disease (0.98 0.84-1.13; P
= 0.03). Among parous women, breastfeeding was associated with lower risk of ER- (vs. never 0.82 0.74-0.91), but not ER+, disease (0.99 0.94-1.05; P
< 0.001). Compared to nulliparous women, higher parity was inversely associated with luminal B breast cancer regardless of breastfeeding (≥ 3 children: ever breastfed, 0.78 0.62-0.98; never breastfed, 0.76 0.58-1.00) and luminal A disease only among women who had breastfed (≥ 3 children, 0.84 0.71-0.99). Basal-like breast cancer risk was suggestively higher among women with higher parity who never breastfed; associations were null among those who ever breastfed.
This study provides evidence that breastfeeding is inversely associated with hormone receptor-negative breast cancers, representing an accessible and cost-effective risk-reduction strategy for aggressive disease subtypes.
The co‐involvement of tumour necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6) during blood‐brain barrier (BBB) injury has been reported in various models of neuroinflammation, although the precise ...functional interplay between these archetypal proinflammatory cytokines remains largely undefined within this context. In the current paper, we tested the hypothesis that TNF‐α‐mediated BBB disruption is measurably attributable in‐part to induction of microvascular endothelial IL‐6 production. In initial experiments, we observed that treatment of human brain microvascular endothelial cells (HBMvECs) with TNF‐α (0–100 ng/mL, 0–24 h) robustly elicited both time‐ and dose‐dependent induction of IL‐6 expression and release, as well as expression of the IL‐6 family receptor, GP130. Further experiments demonstrated that the TNF‐α‐dependent generation of reactive oxygen species, down‐regulation of adherens/tight junction proteins, and concomitant elevation of HBMvEC permeability, were all significantly attenuated by blockade of IL‐6 signalling using either an anti‐IL‐6 neutralizing antibody or an IL‐6 siRNA. Based on these observations, we conclude that TNF‐α treatment of HBMvECs in vitro activates IL‐6 production and signalling, events that were shown to synergize with TNF‐α actions to elicit HBMvEC permeabilization. These novel findings offer a constructive insight into the specific contribution of downstream cytokine induction to the injurious actions of TNF‐α at the BBB microvascular endothelium interface.
The co‐involvement of tumour necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6) during blood–brain barrier (BBB) injury has been widely reported. Using human brain microvascular endothelial cells (HBMvEC), we show that TNF‐α‐mediated BBB disruption is measurably attributable in‐part to induction of endothelial IL‐6 production and signalling. We demonstrate that the TNF‐α‐dependent generation of reactive oxygen species (ROS), down‐regulation of interendothelial junctions, and concomitant elevation of HBMvEC permeability, could be significantly attenuated by using either an IL‐6 neutralizing antibody or an IL‐6‐specific siRNA. These findings provide insight into the complex nature of proinflammatory cytokine injury at the BBB microvascular endothelium interface.
The co‐involvement of tumour necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6) during blood–brain barrier (BBB) injury has been widely reported. Using human brain microvascular endothelial cells (HBMvEC), we show that TNF‐α‐mediated BBB disruption is measurably attributable in‐part to induction of endothelial IL‐6 production and signalling. We demonstrate that the TNF‐α‐dependent generation of reactive oxygen species (ROS), down‐regulation of interendothelial junctions, and concomitant elevation of HBMvEC permeability, could be significantly attenuated by using either an IL‐6 neutralizing antibody or an IL‐6‐specific siRNA. These findings provide insight into the complex nature of proinflammatory cytokine injury at the BBB microvascular endothelium interface.
* Context.--Breast pathology has many mimics and diagnostic pitfalls. Evaluation of malignant breast lesions, particularly in the biopsy setting, can be especially challenging, with diagnostic errors ...having significant management implications. Objective.--To discuss the pitfalls encountered when evaluating ductal carcinoma in situ and invasive breast carcinomas, providing histologic clues and guidance for appropriate use and interpretation of immunohistochemistry to aid in the correct diagnosis. Data Sources.--Data were obtained from review of pertinent literature of ductal carcinoma in situ and invasive breast carcinomas and from the experience of the authors as practicing breast pathologists. Conclusions.--Awareness of the pitfalls in diagnosing breast cancers is important when creating a differential diagnosis for each breast lesion evaluated. This review will cover some of these scenarios to aid in the diagnostic process.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
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