Loneliness, Depression, and Inflammation: Evidence from the Multi-Ethnic Study of Atherosclerosis

Objective Both objective and subjective aspects of social isolation have been associated with alterations in immune markers relevant to multiple chronic diseases among older adults. However, these associations may be confounded by health status, and it is unclear whether these social factors are associated with immune functioning among relatively healthy adults. The goal of this study was to examine the associations between perceived loneliness and circulating levels of inflammatory markers among a diverse sample of adults. Methods Data come from a subset of the Multi-Ethnic Study of Atherosclerosis (n = 441). Loneliness was measured by three items derived from the UCLA Loneliness Scale. The association between loneliness and C-reactive protein (CRP) and fibrinogen was assessed using multivariable linear regression analyses. Models were adjusted for demographic and health characteristics. Results Approximately 50% of participants reported that they hardly ever felt lonely and 17.2% felt highly lonely. Individuals who were unmarried/unpartnered or with higher depressive symptoms were more likely to report being highly lonely. There was no relationship between perceived loneliness and ln(CRP) (β = -0.051, p = 0.239) adjusting for demographic and health characteristics. Loneliness was inversely associated with ln(fibrinogen) (β = -0.091, p = 0.040), although the absolute magnitude of this relationship was small. Conclusion These results indicate that loneliness is not positively associated with fibrinogen or CRP among relatively healthy middle-aged adults

Competing with stationary prediction strategies

In this paper we introduce the class of stationary prediction strategies and construct a prediction algorithm that asymptotically performs as well as the best continuous stationary strategy. We make mild compactness assumptions but no stochastic assumptions about the environment. In particular, no assumption of stationarity is made about the environment, and the stationarity of the considered strategies only means that they do not depend explicitly on time; we argue that it is natural to consider only stationary strategies even for highly non-stationary environments.Comment: 20 page

Role of extracellular vesicle-based cell-to-cell communication in multiple myeloma progression

Multiple myeloma (MM) progression closely depends on the bidirectional crosstalk between tumor cells and the surrounding microenvironment, which leads to the creation of a tumor supportive niche. Extracellular vesicles (EVs) have emerged as key players in the pathological interplay between the malignant clone and near/distal bone marrow (BM) cells through their biologically active cargo. Here, we describe the role of EVs derived from MM and BM cells in reprogramming the tumor microenvironment and in fostering bone disease, angiogenesis, immunosuppression, drug resistance, and, ultimately, tumor progression. We also examine the emerging role of EVs as new therapeutic agents for the treatment of MM, and their potential use as clinical biomarkers for early diagnosis, disease classification, and therapy monitoring

Redox-dependent dimerization of p38 alpha mitogen-activated protein kinase with mitogen-activated protein kinase kinase 3

The kinase p38α MAPK (p38α) plays a pivotal role in many biological processes. p38α is activated by canonical upstream kinases that phosphorylate the activation region. The purpose of our study was to determine whether such activation may depend on redox-sensing cysteines within p38α. p38α was activated and formed a disulfide-bound heterodimer with MAP2K3 (MKK3) in rat cardiomyocytes and isolated hearts exposed to H2O2 This disulfide heterodimer was sensitive to reduction by mercaptoethanol and was enhanced by the thioredoxin-reductase inhibitor auranofin. We predicted that Cys-119 or Cys-162 of p38α, close to the known MKK3 docking domain, were relevant for these redox characteristics. The C119S mutation decreased whereas the C162S mutation increased the dimer formation, suggesting that these two Cys residues act as vicinal thiols, consistent with C119S/C162S being incapable of sensing H2O2 Similarly, disulfide heterodimer formation was abolished in H9C2 cells expressing both MKK3 and p38α C119S/C162S and subjected to simulated ischemia and reperfusion. However, the p38α C119S/C162S mutants did not exhibit appreciable alteration in activating dual phosphorylation. In contrast, the anti-inflammatory agent 10-nitro-oleic acid (NO2-OA), a component of the Mediterranean diet, reduced p38α activation and covalently modified Cys-119/Cys-162, probably obstructing MKK3 access. Moreover, NO2-OA reduced the dephosphorylation of p38α by hematopoietic tyrosine phosphatase (HePTP). Furthermore, steric obstruction of Cys-119/Cys-162 by NO2-OA pretreatment in Langendorff-perfused murine hearts prevented the p38-MKK3 disulfide dimer formation and attenuated H2O2-induced contractile dysfunction. Our findings suggest that cysteine residues within p38α act as redox sensors that can dynamically regulate the association between p38 and MKK3.</p

The Landscape of lncRNAs in Multiple Myeloma: Implications in the “Hallmarks of Cancer”, Clinical Perspectives and Therapeutic Opportunities

Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides that are not translated into proteins. Nowadays, lncRNAs are gaining importance as key regulators of gene expression and, consequently, of several biological functions in physiological and pathological conditions, including cancer. Here, we point out the role of lncRNAs in the pathogenesis of multiple myeloma (MM). We focus on their ability to regulate the biological processes identified as “hallmarks of cancer” that enable malignant cell transformation, early tumor onset and progression. The aberrant expression of lncRNAs in MM suggests their potential use as clinical biomarkers for diagnosis, patient stratification, and clinical management. Moreover, they represent ideal candidates for therapeutic targeting

Reasons for tooth extractions and related risk factors in adult patients: a cohort study

Background: The aimof this studywas to evaluate oral status, the reasons for tooth extractions and related risk factors in adult patients attending a hospital dental practice. Methods: 120 consecutive patients ranging from23 to 91 years in age (mean age of 63.3 - 15.8) having a total of 554 teeth extracted were included. Surveys about general health status were conducted and potential risk factors such as smoking, diabetes and age were investigated. Results: a total of 1795 teeth weremissing after extraction procedures and the mean number of remaining teeth after the extraction process was 16.8 ± 9.1 per patient. Caries (52.2%) was the most common reason for extraction along with periodontal disease (35.7%). Males were more prone to extractions, with 394 of the teeth extracted out of the total of 554 (71.1%). Male sex (β = 2.89; 95% CI 1.26, 4.53; p = 0.001) and smoking habit (β = 2.95; 95% CI 1.12, 4.79; p = 0.002) were related to a higher number of teeth extracted. Age (β = -0.24; 95% CI -0.31, -0.16; p &lt; 0.001) and diabetes (β = -4.47; 95% CI -7.61, -1.33; p = 0.006) were related to a higher number of missing teeth at evaluation time. Moreover, periodontal disease was more common as a reason of extraction among diabetic patients than among non-diabetic ones (p = 0.04). Conclusions: caries and periodontal disease were the most common causes of extraction in a relatively old study population: further screening strategies might be required for the early interception of caries and periodontal disease

Simrank: Rapid and sensitive general-purpose k-mer search tool

Terabyte-scale collections of string-encoded data are expected from consortia efforts such as the Human Microbiome Project (http://nihroadmap.nih.gov/hmp). Intra- and inter-project data similarity searches are enabled by rapid k-mer matching strategies. Software applications for sequence database partitioning, guide tree estimation, molecular classification and alignment acceleration have benefited from embedded k-mer searches as sub-routines. However, a rapid, general-purpose, open-source, flexible, stand-alone k-mer tool has not been available. Here we present a stand-alone utility, Simrank, which allows users to rapidly identify database strings the most similar to query strings. Performance testing of Simrank and related tools against DNA, RNA, protein and human-languages found Simrank 10X to 928X faster depending on the dataset. Simrank provides molecular ecologists with a high-throughput, open source choice for comparing large sequence sets to find similarity

Riflettanza di superfici vulcaniche:la campagna 2003 sul Monte Etna

The results obtained in Mt. Etna spectroradiometric field survey of June 2003 are presented and discussed. The goal of the survey was the analysis of the reflectance properties of the young pyroclastic deposits produced after the effusive activity of 2002-2003 and of the older lava flows. To achieve this goal, a template was created in order to organize the field data collected in a number of selected sites characterised by different surface materials. The results show that reflectance of pyroclastic flows is always very low and constant, besides grain size and composition of the flow. Pahoehoe units show higher reflectance values, even though the spectral characterisation of the older lava flows must take into account weathering products and vegetation coverage

Targeting angiogenesis in multiple myeloma by the VEGF and HGF blocking DARPin® protein MP0250: a preclinical study

The investigational drug MP0250 is a multi-specific DARPin® molecule that simultaneously binds and neutralizes VEGF and HGF with high specificity and affinity. Here we studied the antiangiogenic effects of the MP0250 in multiple myeloma (MM). In endothelial cells (EC) isolated from bone marrow (BM) of MM patients (MMEC) MP0250 reduces VEGFR2 and cMet phosphorylation and affects their downstream signaling cascades. MP0250 influences the secretory profile of MMEC and inhibits their in vitro angiogenic activities (spontaneous and chemotactic migration, adhesion, spreading and capillarogenesis). Compared to anti-VEGF or anti-HGF neutralizing mAbs, MP0250 strongly reduces capillary network formation and vessel-sprouting in a Matrigel angiogenesis assay. MP0250 potentiates the effect of bortezomib in the same in vitro setting. It significantly reduces the number of newly formed vessels in the choriollantoic membrane assay (CAM) and the Matrigel plug assay. In the syngeneic 5T33MM tumor model, MP0250 decreases the microvessel density (MVD) and the combination MP0250/bortezomib lowers the percentage of idiotype positive cells and the serum levels of M-protein. Overall results define MP0250 as a strong antiangiogenic agent with potential as a novel combination drug for treatment of MM patients

Loss of bacterial diversity during antibiotic treatment of intubated patients colonized with Pseudomonas aeruginosa

Management of airway infections caused by Pseudomonas aeruginosa is a serious clinical challenge, but little is known about the microbial ecology of airway infections in intubated patients. We analyzed bacterial diversity in endotracheal aspirates obtained from intubated patients colonized by P. aeruginosa by using 16S rRNA clone libraries and microarrays (PhyloChip) to determine changes in bacterial community compositions during antibiotic treatment. Bacterial 16S rRNA genes were absent from aspirates obtained from patients briefly intubated for elective surgery but were detected by PCR in samples from all patients intubated for longer periods. Sequencing of 16S rRNA clone libraries demonstrated the presence of many orally, nasally, and gastrointestinally associated bacteria, including known pathogens, in the lungs of patients colonized with P. aeruginosa. PhyloChip analysis detected the same organisms and many additional bacterial groups present at low abundance that were not detected in clone libraries. For each patient, both culture-independent methods showed that bacterial diversity decreased following the administration of antibiotics, and communities became dominated by a pulmonary pathogen. P. aeruginosa became the dominant species in six of seven patients studied, despite treatment of five of these six with antibiotics to which it was sensitive in vitro. Our data demonstrate that the loss of bacterial diversity under antibiotic selection is highly associated with the development of pneumonia in ventilated patients colonized with P. aeruginosa. Interestingly, PhyloChip analysis demonstrated reciprocal changes in abundance between P. aeruginosa and the class Bacilli, suggesting that these groups may compete for a similar ecological niche and suggesting possible mechanisms through which the loss of microbial diversity may directly contribute to pathogen selection and persistence