Lupus and Sjögren’s syndrome distinct disease endotypes clustered based on activity scores and immune profiles

Background: Sjögren’s syndrome (SS) is a chronic autoimmune disorder affecting approximately 0.1–0.4% of the general population with a female-to-male ratio of 9:1 usually diagnosed in the fourth and fifth decades of life [1]. Clinically, SS is typified by ocular and oral dryness developed as a consequence of the autoimmune process. It may occur either alone, as primary (p)SS, or secondary to other autoimmune disease, often rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) or systemic sclerosis, secondary (s)SS. Objectives: 1) Identify the peripheral B and T cells abnormalities in patients with pSS, secondary SS associated with systemic lupus erythematosus (SLE) and SLE alone in comparison to healthy donors. 2) Correlate immune phenotypes with clinical features and serological parameters. 3) Identify distinct patients’ endotypes relevant for therapeutic strategies. Methods: Blood samples, clinical and laboratory parameters from 28 patients with pSS, 32 SLE, 15 SS/SLE and age/sex-matched HC were obtained. Immunophenotyping and lipid-raft analyses were performed by flow-cytometry. Results: There were distinct CD19+ B cells, and CD4+ and CD8+ T cell subpopulations observed in pSS, SLE and SS/SLE patients compared to healthy donors. SS/SLE have the most striking B cell phenotype abnormalities than patients with pSS or SLE (increased Bm2 cells and decreased early and late Bm5 cells).There were significant positive and negative correlations of immune cells with clinical parameters in pSS, SLE and SS/SLE patients. The fold-change of memory B cells was significantly reduced in all disease groups with comparison to healthy controls. Fold-change of CD8+ T responder cells were significantly reduced in all diseases, and similarly, CD4+ naïve T cells in SLE and SS/SLE. A highly significant increase in CD4+ T regulatory was observed in pSS. Hierarchical clustering of immune cells in patients yielded 5 distinct endotypes, with clustering reflected in patients with similar disease activity scores. Conclusions: This is the first comprehensive immunophenotype analysis performed patients with pSS, SLE and SS/SLE. We identified significant reduction in memory B cells fold-changed in all disease groups, reduction in CD4+ naïve T cells in SLE and SS/SLE and reduction in T responders in all disease CD8+ in comparison to healthy donors. The most significant T cell abnormalities were found in patients with SLE, however a significant correlation between lipid raft expression as marker of cell activation and disease activity score (ESSDAI) was found only in pSS patients. The five distinct disease endotype clustering showed distinct immune profile in patients with overlapping autoimmune conditions which is particularly relevant for stratification of therapy

Application of a Common Data Model (CDM) to rank the paediatric user and prescription prevalence of 15 different drug classes in South Korea, Hong Kong, Taiwan, Japan and Australia: an observational, descriptive study

Objective: To measure the paediatric user and prescription prevalence in inpatient and ambulatory settings in South Korea, Hong Kong, Taiwan, Japan and Australia by age and gender. A further objective was to list the most commonly used drugs per drug class, per country. Design and setting: Hospital inpatient and insurance paediatric healthcare data from the following databases were used to conduct this descriptive drug utilisation study: (i) the South Korean Ajou University School of Medicine database; (ii) the Hong Kong Clinical Data Analysis and Reporting System; (iii) the Japan Medical Data Center; (iv) Taiwan’s National Health Insurance Research Database and (v) the Australian Pharmaceutical Benefits Scheme. Country-specific data were transformed into the Observational Medical Outcomes Partnership Common Data Model. Patients: Children (≤18 years) with at least 1 day of observation in any of the respective databases from January 2009 until December 2013 were included. Main outcome measures: For each drug class, we assessed the per-protocol overall user and prescription prevalence rates (per 1000 persons) per country and setting. Results: Our study population comprised 1 574 524 children (52.9% male). The highest proportion of dispensings was recorded in the youngest age category (<2 years) for inpatients (45.1%) with a relatively high user prevalence of analgesics and antibiotics. Adrenergics, antihistamines, mucolytics and corticosteroids were used in 10%–15% of patients. For ambulatory patients, the highest proportion of dispensings was recorded in the middle age category (2–11 years, 67.1%) with antibiotics the most dispensed drug overall. Conclusions: Country-specific paediatric drug utilisation patterns were described, ranked and compared between four East Asian countries and Australia. The widespread use of mucolytics in East Asia warrants further investigation

Attention deficit hyperactivity symptoms predict problematic mobile phone use

Attention-deficit-hyperactivity disorder (ADHD) is the most commonly diagnosed childhood disorder characterised by inattention, hyperactivity/impulsivity, or both. Some of the key traits of ADHD have previously been linked to addictive and problematic behaviours. The aim of the present study was to examine the relationship between problematic mobile phone use, smartphone addiction risk and ADHD symptoms in an adult population. A sample of 273 healthy adult volunteers completed the Adult ADHD Self-Report Scale (ASRS), the Mobile Phone Problem Usage Scale (MPPUS), and the Smartphone Addiction Scale (SAS). A significant positive correlation was found between the ASRS and both scales. More specifically, inattention symptoms and age predicted smartphone addiction risk and problematic mobile phone use. Our results suggest that there is a positive relationship between ADHD traits and problematic mobile phone use. In particular, younger adults with higher level of inattention symptoms could be at higher risk of developing smartphone addiction. The implication of our findings for theoretical frameworks of problematic mobile phone use and clinical practice are discussed

CD44s and CD44v6 Expression in Head and Neck Epithelia

Background: CD44 splice variants are long-known as being associated with cell transformation. Recently, the standard form of CD44 (CD44s) was shown to be part of the signature of cancer stem cells (CSCs) in colon, breast, and in head and neck squamous cell carcinomas (HNSCC). This is somewhat in contradiction to previous reports on the expression of CD44s in HNSCC. The aim of the present study was to clarify the actual pattern of CD44 expression in head and neck epithelia. Methods: Expression of CD44s and CD44v6 was analysed by immunohistochemistry with specific antibodies in primary head and neck tissues. Scoring of all specimens followed a two-parameters system, which implemented percentages of positive cells and staining intensities from − to +++ (score = %×intensity; resulting max. score 300). In addition, cell surface expression of CD44s and CD44v6 was assessed in lymphocytes and HNSCC. Results: In normal epithelia CD44s and CD44v6 were expressed in 60–95% and 50–80% of cells and yielded mean scores with a standard error of a mean (SEM) of 249.5±14.5 and 198±11.13, respectively. In oral leukoplakia and in moderately differentiated carcinomas CD44s and CD44v6 levels were slightly increased (278.9±7.16 and 242±11.7; 291.8±5.88 and 287.3±6.88). Carcinomas in situ displayed unchanged levels of both proteins whereas poorly differentiated carcinomas consistently expressed diminished CD44s and CD44v6 levels. Lymphocytes and HNSCC lines strongly expressed CD44s but not CD44v6. Conclusion: CD44s and CD44v6 expression does not distinguish normal from benign or malignant epithelia of the head and neck. CD44s and CD44v6 were abundantly present in the great majority of cells in head and neck tissues, including carcinomas. Hence, the value of CD44s as a marker for the definition of a small subset of cells (i.e. less than 10%) representing head and neck cancer stem cells may need revision

Mass Size Distribution and Chemical Composition of the Surface Layer of Summer and Winter Airborne Particles in Zabrze, Poland

Mass size distributions of ambient aerosol were measured in Zabrze, a heavily industrialized city of Poland, during a summer and a winter season. The chemical analyses of the surface layer of PM10, PM2.5 and PM1 in this area were also performed by X-ray photoelectron spectroscopy (XPS). Results suggested that the influence of an atmospheric aerosol on the health condition of Zabrze residents can be distinctly stronger in winter than in summer because of both: higher concentration level of particulate matter (PM) and higher contribution of fine particles in winter season compared to summer. In Zabrze in June (summer) PM10 and PM2.5 reached about 20 and 14 μg/m3, respectively, while in December (winter) 57 and 51 μg/m3, respectively. The XPS analysis showed that elemental carbon is the major surface component of studied airborne particles representing about 78%–80% (atomic mass) of all detected elements

Coordinated optimization of visual cortical maps (II) Numerical studies

It is an attractive hypothesis that the spatial structure of visual cortical architecture can be explained by the coordinated optimization of multiple visual cortical maps representing orientation preference (OP), ocular dominance (OD), spatial frequency, or direction preference. In part (I) of this study we defined a class of analytically tractable coordinated optimization models and solved representative examples in which a spatially complex organization of the orientation preference map is induced by inter-map interactions. We found that attractor solutions near symmetry breaking threshold predict a highly ordered map layout and require a substantial OD bias for OP pinwheel stabilization. Here we examine in numerical simulations whether such models exhibit biologically more realistic spatially irregular solutions at a finite distance from threshold and when transients towards attractor states are considered. We also examine whether model behavior qualitatively changes when the spatial periodicities of the two maps are detuned and when considering more than 2 feature dimensions. Our numerical results support the view that neither minimal energy states nor intermediate transient states of our coordinated optimization models successfully explain the spatially irregular architecture of the visual cortex. We discuss several alternative scenarios and additional factors that may improve the agreement between model solutions and biological observations.Comment: 55 pages, 11 figures. arXiv admin note: substantial text overlap with arXiv:1102.335

Impact of Protein Stability, Cellular Localization, and Abundance on Proteomic Detection of Tumor-Derived Proteins in Plasma

Tumor-derived, circulating proteins are potentially useful as biomarkers for detection of cancer, for monitoring of disease progression, regression and recurrence, and for assessment of therapeutic response. Here we interrogated how a protein's stability, cellular localization, and abundance affect its observability in blood by mass-spectrometry-based proteomics techniques. We performed proteomic profiling on tumors and plasma from two different xenograft mouse models. A statistical analysis of this data revealed protein properties indicative of the detection level in plasma. Though 20% of the proteins identified in plasma were tumor-derived, only 5% of the proteins observed in the tumor tissue were found in plasma. Both intracellular and extracellular tumor proteins were observed in plasma; however, after normalizing for tumor abundance, extracellular proteins were seven times more likely to be detected. Although proteins that were more abundant in the tumor were also more likely to be observed in plasma, the relationship was nonlinear: Doubling the spectral count increased detection rate by only 50%. Many secreted proteins, even those with relatively low spectral count, were observed in plasma, but few low abundance intracellular proteins were observed. Proteins predicted to be stable by dipeptide composition were significantly more likely to be identified in plasma than less stable proteins. The number of tryptic peptides in a protein was not significantly related to the chance of a protein being observed in plasma. Quantitative comparison of large versus small tumors revealed that the abundance of proteins in plasma as measured by spectral count was associated with the tumor size, but the relationship was not one-to-one; a 3-fold decrease in tumor size resulted in a 16-fold decrease in protein abundance in plasma. This study provides quantitative support for a tumor-derived marker prioritization strategy that favors secreted and stable proteins over all but the most abundant intracellular proteins

COMP-Angiopoietin-1 Recovers Molecular Biomarkers of Neuropathy and Improves Vascularisation in Sciatic Nerve of ob/ob Mice

mice. mice displayed regeneration of small-diameter endoneural microvessels. Effects of COMP-Ang-1 corresponded to increased phosphorylation of Akt and p38 MAPK upon Tie-2 receptor. mice suggesting COMP-Ang-1 as novel treatment option to improve morphologic and protein expression changes associated with diabetic neuropathy

SMI of Bcl-2 TW-37 is active across a spectrum of B-cell tumors irrespective of their proliferative and differentiation status

The Bcl-2 family of proteins is critical to the life and death of malignant B-lymphocytes. Interfering with their activity using small-molecule inhibitors (SMI) is being explored as a new therapeutic strategy for treating B-cell tumors. We evaluated the efficacy of TW-37, a non-peptidic SMI of Bcl-2 against a range spectrum of human B-cell lines, fresh patient samples and animal xenograft models. Multiple cytochemical and molecular approaches such as acridine orange/ethidium bromide assay for apoptosis, co-immunoprecipitation of complexes and western blot analysis, caspase luminescent activity assay and apoptotic DNA fragmentation assay were used to demonstrate the effect of TW-37 on different B-cell lines, patient derived samples, as well as in animal xenograft models. Nanomolar concentrations of TW-37 were able to induce apoptosis in both fresh samples and established cell lines with IC50 in most cases of 165–320 nM. Apoptosis was independent of proliferative status or pathological classification of B-cell tumor. TW-37 was able to block Bim-Bcl-XL and Bim-Mcl-1 heterodimerization and induced apoptosis via activation of caspases -9, -3, PARP and DNA fragmentation. TW-37 administered to tumor-bearing SCID mice led to significant tumor growth inhibition (T/C), tumor growth delay (T-C) and Log10kill, when used at its maximum tolerated dose (40 mg/kg × 3 days) via tail vein. TW-37 failed to induce changes in the Bcl-2 proteins levels suggesting that assessment of baseline Bcl-2 family proteins can be used to predict response to the drug. These findings indicate activity of TW-37 across the spectrum of human B-cell tumors and support the concept of targeting the Bcl-2 system as a therapeutic strategy regardless of the stage of B-cell differentiation

Evidence That Gene Activation and Silencing during Stem Cell Differentiation Requires a Transcriptionally Paused Intermediate State

A surprising portion of both mammalian and Drosophila genomes are transcriptionally paused, undergoing initiation without elongation. We tested the hypothesis that transcriptional pausing is an obligate transition state between definitive activation and silencing as human embryonic stem cells (hESCs) change state from pluripotency to mesoderm. Chromatin immunoprecipitation for trimethyl lysine 4 on histone H3 (ChIP-Chip) was used to analyze transcriptional initiation, and 3′ transcript arrays were used to determine transcript elongation. Pluripotent and mesodermal cells had equivalent fractions of the genome in active and paused transcriptional states (∼48% each), with ∼4% definitively silenced (neither initiation nor elongation). Differentiation to mesoderm changed the transcriptional state of 12% of the genome, with roughly equal numbers of genes moving toward activation or silencing. Interestingly, almost all loci (98–99%) changing transcriptional state do so either by entering or exiting the paused state. A majority of these transitions involve either loss of initiation, as genes specifying alternate lineages are archived, or gain of initiation, in anticipation of future full-length expression. The addition of chromatin dynamics permitted much earlier predictions of final cell fate compared to sole use of conventional transcript arrays. These findings indicate that the paused state may be the major transition state for genes changing expression during differentiation, and implicate control of transcriptional elongation as a key checkpoint in lineage specification