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Παρασκευή, 20 Ιανουαρίου 2017

Editorial Board

Publication date: March 2017
Source:Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Volume 1864, Issue 3





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IJERPH, Vol. 14, Pages 99: Microbiological Contamination at Workplaces in a Combined Heat and Power (CHP) Station Processing Plant Biomass

The aim of the study was to evaluate the microbial contamination at a plant biomass processing thermal power station (CHP). We found 2.42 × 103 CFU/m3 of bacteria and 1.37 × 104 CFU/m3 of fungi in the air; 2.30 × 107 CFU/g of bacteria and 4.46 × 105 CFU/g of fungi in the biomass; and 1.61 × 102 CFU/cm2 bacteria and 2.39 × 101 CFU/cm2 fungi in filtering facepiece respirators (FFRs). Using culture methods, we found 8 genera of mesophilic bacteria and 7 of fungi in the air; 10 genera each of bacteria and fungi in the biomass; and 2 and 5, respectively, on the FFRs. Metagenomic analysis (Illumina MiSeq) revealed the presence of 46 bacterial and 5 fungal genera on the FFRs, including potential pathogens Candida tropicalis, Escherichia coli, Prevotella sp., Aspergillus sp., Penicillium sp.). The ability of microorganisms to create a biofilm on the FFRs was confirmed using scanning electron microscopy (SEM). We also identified secondary metabolites in the biomass and FFRs, including fumigaclavines, quinocitrinines, sterigmatocistin, and 3-nitropropionic acid, which may be toxic to humans. Due to the presence of potential pathogens and mycotoxins, the level of microbiological contamination at workplaces in CHPs should be monitored.

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Genes, Vol. 8, Pages 44: Tissue Non-Specific Genes and Pathways Associated with Diabetes: An Expression Meta-Analysis

We performed expression studies to identify tissue non-specific genes and pathways of diabetes by meta-analysis. We searched curated datasets of the Gene Expression Omnibus (GEO) database and identified 13 and five expression studies of diabetes and insulin responses at various tissues, respectively. We tested differential gene expression by empirical Bayes-based linear method and investigated gene set expression association by knowledge-based enrichment analysis. Meta-analysis by different methods was applied to identify tissue non-specific genes and gene sets. We also proposed pathway mapping analysis to infer functions of the identified gene sets, and correlation and independent analysis to evaluate expression association profile of genes and gene sets between studies and tissues. Our analysis showed that PGRMC1 and HADH genes were significant over diabetes studies, while IRS1 and MPST genes were significant over insulin response studies, and joint analysis showed that HADH and MPST genes were significant over all combined data sets. The pathway analysis identified six significant gene sets over all studies. The KEGG pathway mapping indicated that the significant gene sets are related to diabetes pathogenesis. The results also presented that 12.8% and 59.0% pairwise studies had significantly correlated expression association for genes and gene sets, respectively; moreover, 12.8% pairwise studies had independent expression association for genes, but no studies were observed significantly different for expression association of gene sets. Our analysis indicated that there are both tissue specific and non-specific genes and pathways associated with diabetes pathogenesis. Compared to the gene expression, pathway association tends to be tissue non-specific, and a common pathway influencing diabetes development is activated through different genes at different tissues.

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Suppression of Neu1 sialidase delays the absorption of yolk sac in medaka (Oryzias latipes) accompanied with the accumulation of α2-3 sialo-glycoproteins

Publication date: Available online 20 January 2017
Source:Biochimie
Author(s): Sena Ryuzono, Ryo Takase, Yuko Kamada, Takanori Ikenaga, Petros Kingstone Chigwechokha, Masaharu Komatsu, Kazuhiro Shiozaki
Sialidase catalyzes the removal of sialic acids from glycoconjugates. Recently, medaka sialidase Neu1 has been cloned and its enzymatic properties were investigated. Although enzymatic properties of this sialidase, such as optimal pH and substrate specificity, exhibits high similarity with human NEU1, Neu1 physiological functions in fish are still unclear. Here, to understand Neu1 significance in medaka embryogenesis, sialidase translation knockdown was carried out with one-cell stage fertilized egg using morpholino oligo injection.Neu1 exhibited desialylation of α2-3 sialic acid linkage in vitro and lysosomal localization in medaka caudal fin primary cells. Chloroquine treatment, inhibitor of lysosomal enzymes, caused an accumulation of α2-3 sialo-glycoproteins in the primary cells. During the embryogenesis neu1 mRNA level was elevated until 3.5 day post fertilization (dpf) while an initial decrease of α2-3 sialo-glycoprotein was observed around the same developmental stage. Neu1 knockdown by morpholino oligo induced some abnormal phenotypes such as delay of yolk sacs absorption and small embryos. Sialidase-knockdown embryos also showed increase of heart rate in 5.5 and 6.5 dpf. Furthermore, about 37% decrease of hatching rate was observed in Neu1-MO treated embryos compared with control MO. Embryos showing severe phenotypes stopped embryogenesis at the late stage of development. Alteration of embryonic sialo-glycoproteins induced by morpholino injection was examined by lectin blotting to clarify the mechanism of abnormal development. As a result, degradation of several α2-3 sialo-glycoproteins was suppressed in Neu1-MO embryo, possibly induced by the interruption of lysosomal desialylation toward yolk glycoprotein. Our results suggest that medaka Neu1 could be crucial for embryonic development through the degradation of yolk sac nutrition.



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CD36 gene polymorphism is associated with Alzheimer’s disease

Publication date: Available online 20 January 2017
Source:Biochimie
Author(s): Omar Šerý, Jana Janoutová, Laura Ewerlingová, Alice Hálová, Jan Lochman, Vladimír Janout, Naim A. Khan, Vladimir J. Balcar
CD36 gene encodes a membrane glycoprotein (type B scavenger receptor) present on the surface of many types of cells and having multiple cellular functions ranging from angiogenesis to gustatory perception of fatty acids. Using a case control genetic association approach we have analyzed selected single nucleotide polymorphisms (SNP’s) in a total of 859 patients with Alzheimer’s disease (AD) and controls and have identified the allele T in rs3211893 polymorphism of CD36 gene as significantly increasing the risk of AD. Additionally we have investigated, in the same sample of control subjects and patients, SNP’s in ApoE gene and confirmed that the previously identified AD-associated SNP’s indeed increased the risk and decreased the age of onset of AD as reported by others earlier. Based on the current knowledge of CD36 biochemistry we propose that the AD risk-imparting variants of CD36 alter cholesterol homeostasis, oxidation stress or induce pathological inflammatory cascades. The SNP rs3211892 has previously been associated with heart disease and other conditions but the present study is the first to identify a significant association between variations in CD36 gene and the risk of Alzheimer’s disease.



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Plasma Kallikrein enhances platelet aggregation response by subthreshold doses of ADP

Publication date: Available online 20 January 2017
Source:Biochimie
Author(s): Tatiana F. Ottaiano, Sheila S. Andrade, Cleide de Oliveira, Mariana C.C. Silva, Marcus V. Buri, Maria A. Juliano, Manoel J.B.C. Girão, Misako U. Sampaio, Alvin H. Schmaier, Alexander Wlodawer, Francisco H.A. Maffei, Maria L.V. Oliva
Human plasma kallikrein (huPK) potentiates platelet responses to subthreshold doses of ADP, although huPK itself, does not induce platelet aggregation. In the present investigation, we observe that huPK pretreatment of platelets potentiates ADP-induced platelet activation by prior proteolysis of the G-protein-coupled receptor PAR-1. The potentiation of ADP-induced platelet activation by huPK is mediated by the integrin αIIbβ3 through interactions with the KGD/KGE sequence motif in huPK. Integrin αIIbβ3 is a cofactor for huPK binding to platelets to support PAR-1 hydrolysis that contributes to activation of the ADP signaling pathway. This activation pathway leads to phosphorylation of Src, AktS473, ERK1/2, and p38 MAPK, and to Ca2+ release. The effect of huPK is blocked by specific antagonists of PAR-1 (SCH 19197) and αIIbβ3 (abciximab) and by synthetic peptides comprising the KGD and KGE sequence motifs of huPK. Further, recombinant plasma kallikrein inhibitor, rBbKI, also blocks this entire mechanism. These results suggest a new function for huPK. Formation of plasma kallikrein lowers the threshold for ADP-induced platelet activation. The present observations are consistent with the notion that plasma kallikrein promotes vascular disease and thrombosis in the intravascular compartment and its inhibition may ameliorate cardiovascular disease and thrombosis.



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Incidence of Posttransplant Skin Cancer High in Organ Transplant Recipients

A multicenter study showed that an occurrence of posttransplant skin cancer was common among a group of organ transplant recipients. (Source: CancerNetwork)

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Pembrolizumab Offers Some Durable Responses in Advanced Urothelial Cancer

The PD-1 inhibitor pembrolizumab showed promising antitumor activity and acceptable safety in patients with advanced urothelial cancer, in a phase I trial. (Source: CancerNetwork)

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Endometrioid Ovarian Cancer Presents Earlier, Offers Better Survival Than Serous Carcinoma

Women with endometrioid ovarian cancer present at a younger age and with earlier stage disease than those with serous ovarian cancer, according to a new analysis. The earlier presentation resulted in better 5- and 10-year overall survival rates as well. (Source: CancerNetwork)

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IJMS, Vol. 18, Pages 213: Methylglyoxal-Mediated Stress Correlates with High Metabolic Activity and Promotes Tumor Growth in Colorectal Cancer

Cancer cells generally rely on aerobic glycolysis as a major source of energy. Methylglyoxal (MG), a dicarbonyl compound that is produced as a side product during glycolysis, is highly reactive and induces the formation of advanced glycation end-products that are implicated in several pathologies including cancer. All mammalian cells have an enzymatic defense against MG composed by glyoxalases GLO1 and GLO2 that converts MG to d-lactate. Colorectal cancer (CRC) is one of the most frequently occurring cancers with high morbidity and mortality. In this study, we used immunohistochemistry to examine the level of MG protein adducts, in a series of 102 CRC human tumors divided into four clinical stages. We consistently detected a high level of MG adducts and low GLO1 activity in high stage tumors compared to low stage ones suggesting a pro-tumor role for dicarbonyl stress. Accordingly, GLO1 depletion in CRC cells promoted tumor growth in vivo that was efficiently reversed using carnosine, a potent MG scavenger. Our study represents the first demonstration that MG adducts accumulation is a consistent feature of high stage CRC tumors. Our data point to MG production and detoxification levels as an important molecular link between exacerbated glycolytic activity and CRC progression.

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Survival of acute monocytic leukemia cells is driven by fatty acid oxidation-mediated activation of AMPK in bone marrow adipocytes

Leukemia cells in the bone marrow (BM) must meet the biochemical demands of increased cell proliferation by continually adapting to fluctuations in nutrient and oxygen availability. Thus, targeting metabolic abnormalities in leukemia cells located in the BM may provide an effective therapeutic strategy. In this study, we report the discovery of a metabolic role for BM adipocytes in supporting the growth of leukemic blasts. Preventing nutrient starvation-induced apoptosis of leukemic cells by BM adipocytes, as well as the metabolic and molecular mechanisms involved in this process, were investigated using various analytical techniques. In acute monocytic leukemia (AMoL) cells, the prevention of spontaneous apoptosis by BM adipocytes was associated with an increase in fatty acid β-oxidation (FAO) along with upregulation of PPARγ, FABP4, CD36, and BCL2 genes. Co-culture of AMoL cells with BM adipocyte increased adiponectin receptor gene expression and its downstream target stress response kinase AMPK, p38 MAPK with autophagy activation, and upregulated antiapoptotic chaperone heat shock proteins. Inhibition of FAO disrupted in these co-cultures metabolic homeostasis, increased reactive oxygen species production, induced the integrated stress response mediator ATF4, and increased apoptosis in AMoL. Our results suggest that BM adipocytes support AMoL cell survival by regulating their metabolic energy balance. Further, they rationalize disruption of FAO in BM adipocytes as a novel therapeutic strategy for AMoL therapy.

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A transposon-based analysis reveals RASA1 is involved in triple negative breast cancer

RAS genes are mutated in 20% of human tumors, but these mutations are very rare in breast cancer. Here we used a mouse model to generate tumors upon activation of a mutagenic T2Onc2 transposon via expression of a transposase driven by the keratin K5 promoter in a p53+/- background. These animals mainly developed mammary tumors, most of which had transposon insertions in one of two RASGAP genes, neurofibromin1 (NF1) and RAS p21 protein activator (Rasa1). Immunohistochemical analysis of a collection of human breast tumors confirmed that low expression of RASA1 is frequent in basal (triple-negative) and ER-negative tumors. Bioinformatic analysis of human breast tumors in the TCGA database showed that although RASA1 mutations are rare, allelic loss is frequent, particularly in basal tumors (80%) and in association with TP53 mutation. Inactivation of RASA1 in MCF10A cells resulted in the appearance of a malignant phenotype in the context of mutated p53. Our results suggest that alterations in the Ras pathway due to the loss of negative regulators of RAS may be a common event in basal breast cancer.

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SDHD promoter mutations ablate GABP transcription factor binding in melanoma

SDHD encodes subunit D of the succinate dehydrogenase complex, an integral membrane protein. Across cancer types, recurrent SDHD promoter mutations were reported to occur exclusively in melanomas, at a frequency of 4-5%. These mutations are predicted to disrupt consensus ETS-transcription factor binding sites and are correlated with both reduced SDHD gene expression and poor prognosis. However, the consequence of these mutations on SDHD expression in melanoma is still unclear. Here, we found that expression of SDHD in melanoma correlated with the expression of multiple ETS-transcription factors, particularly in SDHD promoter wild-type samples. Consistent with the predicted loss of ETS-transcription factor binding, we observed that recurrent hotspot mutations resulted in decreased luciferase activity in reporter assays. Furthermore, we demonstrated specific GABPA and GABPB1 binding to probes containing the wild-type promoter sequences, with binding disrupted by the SDHD hotspot promoter mutations in both quantitative mass spectrometry and band-shift experiments. Finally, using siRNA-mediated knockdown across multiple melanoma cell lines, we determined that loss of GABPA resulted in reduced SDHD expression at both RNA and protein levels. These data are consistent with a key role for GABPA/B1 as the critical ETS-transcription factors deregulating SDHD expression in the context of highly recurrent promoter mutations in melanoma, and warrant a detailed search for other recurrent promoter mutations that create or disrupt GABPA consensus sequences.

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Fibrinolytic enzyme co-therapy improves tumor perfusion and therapeutic efficacy of anticancer nanomedicine

Elevated interstitial fluid pressure and solid stress within tumors contribute to poor intratumoral distribution of nanomedicine. In this study, we hypothesized that the presence of fibrin in tumor extracellular matrix contributes to hindered intratumoral distribution of nanocarriers and that this can be overcome through the use of a fibrinolytic enzyme such as tissue plasminogen activator (tPA). Analysis of fibrin expression in human tumor biopsies showed significant fibrin staining in nearly all tumor types evaluated. However, staining was heterogeneous across and within tumor types. We determined the effect of fibrin on the diffusion, intratumoral distribution, and therapeutic efficacy of nanocarriers. Diffusivity of nanocarriers in fibrin matrices was limited and could be improved significantly by co-incubation with tPA. In vivo, co-administration of tPA improved the anticancer efficacy of nanoparticle-encapsulated paclitaxel in subcutaneous syngeneic mouse melanoma and orthotopic xenograft lung cancer models. Furthermore, treatment with tPA led to decompression of blood vessels and improved tumor perfusion. Co-treatment with tPA resulted in greater intratumoral penetration of a model nanocarrier (Doxil®), leading to enhanced availability of the drug in the tumor core. Fibrinolytics such as tPA are already approved for other indications. Fibrinolytic co-therapy is therefore a rapidly translatable strategy for improving therapeutic effectiveness of anticancer nanomedicine.

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Prostate cancer patients with late radiation toxicity exhibit reduced expression of genes involved in DNA double strand break repair and homologous recombination.

Severe late damage to normal tissue is a major limitation of cancer radiotherapy in prostate cancer patients. In a recent retrospective study, late radiation toxicity was found to relate to a decreased decay of γ-H2AX foci and reduced induction of DNA double strand break repair genes. Here we report evidence of prognostic utility in prostate cancer for γ-H2AX foci decay ratios and gene expression profiles derived from ex vivo-irradiated patient lymphocytes. Patients were followed ≥2 years after radiotherapy. Clinical characteristics were assembled and toxicity was recorded using the Common Terminology Criteria (CTCAE) v4.0. No clinical factor was correlated with late radiation toxicity. The γ-H2AX foci decay ratio correlated negatively with toxicity grade, with a significant difference between grad ≥3 and grade 0 patients (p=0.02). A threshold foci decay ratio, determined in our retrospective study, correctly classified 23 of 28 patients with grade ≥3 toxicity (sensitivity 82%) and 9 of 14 patients with grade 0 toxicity (specificity 64%). Induction of homologous recombination (HR) repair genes was reduced with increasing toxicity grade. The difference in fold induction of the HR gene set was most pronounced between grade 0 and grade ≥3 toxicity (p=0.008). Notably, reduced responsiveness of HR repair genes to irradiation and inefficient double strand break repair correlated with severe late radiation toxicity. Using a decay ratio classifier, we correctly classified 82% of patients with grade ≥3 toxicity, suggesting a prognostic biomarker for cancer patients with a genetically enhanced risk for late radiation toxicity to normal tissues after radiotherapy.

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Somatic ephrin receptor mutations are associated with metastasis in primary colorectal cancer

The contribution of somatic mutations to metastasis of colorectal cancers (CRC) is currently unknown. To find mutations involved in the CRC metastatic process, we performed deep mutational analysis of 676 genes in 107 stages II-IV primary CRC, of which half had metastasized. The mutation prevalence in the ephrin (Eph) family of tyrosine kinase receptors was ten-fold higher in primary tumors of metastatic CRC than in non-metastatic cases and preferentially occurred in stage III and IV tumours. Mutational analyses in situ confirmed expression of mutant Eph receptors. To enable functional studies of EphB1 mutations, we demonstrated that DLD-1 CRC cells expressing EphB1 form aggregates upon co-culture with ephrin-B1 expressing cells. When mutations in the fibronectin type III and kinase domains of EphB1 were compared to wild-type EphB1 in DLD-1 CRC cells, they decreased ephrin-B1 induced compartmentalization. These observations provide a mechanistic link between EphB receptor mutations and metastasis in CRC.

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RelB expression determines the differential effects of ascorbic acid in normal and cancer cells

Cancer cells typically experience higher oxidative stress than normal cells, such that elevating pro-oxidant levels can trigger cancer cell death. Although pre-exposure to mild oxidative agents will sensitize cancer cells to radiation, this pre-exposure may also activate the adaptive stress defense system in normal cells. Ascorbic acid (AA) is a prototype redox modulator that when infused intravenously appears to kill cancers without injury to normal tissues; however, the mechanisms involved remain elusive. In this study, we show how AA kills cancer cells and sensitizes prostate cancer to radiation therapy, while also conferring protection upon normal prostate epithelial cells against radiation-induced injury. We found that the NF-κB transcription factor RelB is a pivotal determinant in the differential radiosensitization effects of AA in prostate cancer cells and normal prostate epithelial cells. Mechanistically, high ROS concentrations suppress RelB in cancer cells. RelB suppression decreases expression of the sirtuin SIRT3 and the powerful antioxidant MnSOD, which in turn increases oxidative and metabolic stresses in prostate cancer cells. In contrast, AA enhances RelB expression in normal cells, improving antioxidant and metabolic defenses against radiation injury. In addition to showing how RelB mediates the differential effects of AA on cancer and normal tissue radiosensitivities, our work also provides a proof of concept for the existence of redox modulators that can improve the efficacy of radiotherapy while protecting against normal tissue injury in cancer settings.

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Constitutive NOTCH3 signaling promotes the growth of basal breast cancers

Notch ligands signal through one of four receptors on neighboring cells to mediate cell-cell communication and control cell fate, proliferation and survival. Although aberrant Notch activation has been implicated in numerous malignancies, including breast cancer, the importance of individual receptors in distinct breast cancer subtypes and the mechanisms of receptor activation remain unclear. Using a novel antibody to detect active NOTCH3, we report here that NOTCH3 signals constitutively in a panel of basal breast cancer cell lines and in more than one-third of basal tumors. Selective inhibition of individual ligands revealed that this signal does not require canonical ligand induction. A NOTCH3 antagonist antibody inhibited growth of basal lines whereas a NOTCH3 agonist antibody enhanced the transformed phenotype in vitro and in tumor xenografts. Transcriptomic analyses generated a Notch gene signature that included Notch pathway components, the oncogene c-Myc, and the mammary stem cell regulator Id4. This signature drove clustering of breast cancer cell lines and tumors into the common subtypes and correlated with the basal classification. Our results highlight an unexpected ligand-independent induction mechanism and suggest that constitutive NOTCH3 signaling can drive an oncogenic program in a subset of basal breast cancers.

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Biomarker based PET Imaging of Diffuse Intrinsic Pontine Glioma in Mouse Models

Diffuse intrinsic pontine glioma (DIPG) is a childhood brainstem tumor with a universally poor prognosis. Here, we characterize on a positron emission tomography (PET) probe for imaging DIPG in vivo. In human histological tissues, the probes target, poly(ADP)ribose polymerase 1 (PARP1), was highly expressed in DIPG compared to normal brain. PET imaging allowed for the sensitive detection of DIPG in a genetically engineered mouse model (GEMM), and probe uptake correlated to histologically determined tumor infiltration. Imaging with the sister fluorescence agent revealed that uptake was confined to proliferating, PARP1 expressing cells. Comparison to other imaging technologies revealed remarkable accuracy of our biomarker approach. We subsequently demonstrated that serial imaging of DIPG in mouse models enables monitoring of tumor growth, as shown in modeling of tumor progression. Overall, this validated method for quantifying DIPG burden would serve useful in monitoring treatment response in early phase clinical trials.

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Differential PI3K{delta} signaling in CD4+ T cell subsets enables selective targeting of T regulatory cells to enhance cancer immunotherapy

To modulate T cell function for cancer therapy one challenge is to selectively attenuate regulatory but not conventional CD4+ T cell subsets (Treg and Tconv). In this study we show how a functional dichotomy in Class IA PI3K isoforms in these two subsets of CD4+ T cells be exploited to target Treg while leaving Tconv intact. Studies employing isoform-specific PI3K inhibitors and a PI3Kδ-deficient mouse strain revealed that PI3Kα and PI3Kβ were functionally redundant with PI3Kδ in Tconv. Conversely, PI3Kδ was functionally critical in Treg, acting there to control TCR signaling, cell proliferation and survival. Notably, in a murine model of lung cancer, co-administration of a PI3Kδ-specific inhibitor with a tumor-specific vaccine decreased numbers of suppressive Treg and increased numbers of vaccine-induced CD8 T-cells within the tumor microenvironment, eliciting potent anti-tumor efficacy. Overall, our results offer a mechanistic rationale to employ PI3Kδ inhibitors to selectively target Treg and improve cancer immunotherapy.

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Bone metastasis of prostate cancer can be therapeutically targeted at the TBX2-WNT signaling axis

Identification of factors that mediate visceral and bone metastatic spread and subsequent bone remodeling events is highly relevant to successful therapeutic intervention in advanced human prostate cancer (PCa). TBX2, a T-box family transcription factor that negatively regulates cell cycle inhibitor p21, plays critical roles during embryonic development, and recent studies have highlighted its role in cancer. Here we report that TBX2 is overexpressed in human PCa specimens and bone metastases from xenograft mouse models of human PCa. Blocking endogenous TBX2 expression in PC3 and ARCaPM PCa cell models using a dominant negative construct resulted in decreased tumor cell proliferation, colony formation, and invasion in vitro. Blocking endogenous TBX2 in human PCa mouse xenografts decreased invasion and abrogation of bone and soft tissue metastasis. Furthermore, blocking endogenous TBX2 in PCa cells dramatically reduced bone colonizing capability through reduced tumor cell growth and bone remodeling in an intra-tibial mouse model. TBX2 acted in trans by promoting transcription of the canonical WNT (WNT3A) promoter. Genetically rescuing WNT3A levels in PCa cells with endogenously blocked TBX2 partially restored the TBX2-induced PCa metastatic capability in mice. Conversely, WNT3A neutralizing antibodies or WNT antagonist SFRP-2 blocked TBX2 induced invasion. Our findings highlight TBX2 as a novel therapeutic target upstream of WNT3A, where WNT3A antagonists could be novel agents for the treatment of metastasis and for skeletal complications in PCa patients.

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Two-pore channel function is crucial for migration of invasive cancer cells

Metastatic invasion is the major cause of cancer-related deaths. In this study, we introduce two-pore channels (TPC), a recently described class of NAADP- and PI(3,5)P2-sensitive Ca2+-permeable cation channels in the endolysosomal system of cells, as candidate targets for the treatment of invasive cancers. Inhibition of the channel abrogated migration of metastatic cancer cells in vitro. Silencing or pharmacological inhibition of the two-pore channel TPC2 reduced lung metastasis of mammary mouse cancer cells. Disrupting TPC function halted trafficking of β1-integrin leading to its accumulation in EEA1-positive early endosomes. As a consequence, invasive cancer cells were no longer able to form leading edges which are required for adequate migration. Our findings link TPC to cancer cell migration and provide a preclinical proof of concept for their candidacy as targets to treat metastatic cancers.

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FLT3 and JAK2 mutations in acute myeloid leukemia promote inter-chromosomal homologous recombination and the potential for copy neutral loss of heterozygosity (CN-LOH)

Acquired copy neutral loss-of-heterozygosity (CN-LOH) is a frequent occurrence in myeloid malignancies and is often associated with resistance to standard therapeutic modalities and poor survival. Here we show that constitutive signaling driven by mutated FLT3 and JAK2 confers inter-chromosomal homologous recombination (iHR), a precedent for CN-LOH. Using a targeted recombination assay, we determined significant iHR activity in internal tandem duplication FLT3 (FLT3-ITD) and JAK2V617F mutated cells. Sister chromatid exchanges, a surrogate measure of iHR, was significantly elevated in primary FLT3-ITD normal karyotype acute myeloid leukemia (NK-AML) compared to wild type FLT3 NK-AML. Homologous recombination (HR) was harmonized to S phase of the cell cycle to repair broken chromatids and prevent iHR. Increased HR activity in G0 arrested primary FLT3-ITD NK-AML in contrast to wild-type FLT3 NK-AML. Cells expressing mutated FLT3-ITD demonstrated a relative increase in mutation frequency as detected by thymidine kinase (TK) gene mutation assay. Moreover, resistance was associated with CN-LOH at the TK locus. Treatment of FLT3-ITD and JAK2V617F mutant cells with the antioxidant N-acetylcysteine diminished reactive oxygen species (ROS), restoring iHR and HR levels. Our findings show that mutated FLT3-ITD and JAK2 augment ROS production and HR, shifting the cellular milieu towards illegitimate recombination events such as iHR and CN-LOH. Therapeutic reduction of ROS may thus prevent leukemic progression and relapse in myeloid malignancies.

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Biomarker dynamics in B-cell lymphoma: a longitudinal prospective study of plasma samples up to 25 years before diagnosis

The B-cell activation markers CXCL13, sCD23, sCD27, and sCD30 are associated with future lymphoma risk. However, a lack of information about the individual dynamics of marker-disease association hampers interpretation. In this study, we identified 170 individuals who had donated two pre-diagnostic blood samples before B-cell lymphoma diagnosis, along with 170 matched cancer-free controls from the Northern Sweden Health and Disease Study. Lymphoma risk associations were investigated by subtype and marker levels measured at baseline, at the time of the repeated sample, and with the rate of change in the marker level. Notably, we observed strong associations between CXCL13, sCD23, sCD27, and sCD30 and lymphoma risk in blood samples collected 15 to 25 years before diagnosis. B-cell activation marker levels increased among future lymphoma cases over time, while remaining stable among controls. Associations between slope and risk were strongest for indolent lymphoma subtypes. We noted a marked association of sCD23 with chronic lymphocytic leukemia (ORSlope = 28, Ptrend = 7.279 x 10-10). Among aggressive lymphomas, the association between diffuse large B-cell lymphoma risk and slope was restricted to CXCL13. B-cell activation seemed to play a role in B-cell lymphoma development at early stages across different subtypes. Further, B-cell activation presented differential trajectories in future lymphoma patients, mainly driven by indolent subtypes. Our results suggest a utility of these markers in predicting the presence of early occult disease and/or the screening and monitoring of indolent lymphoma in individual patients.

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Urocortin suppresses endometrial cancer cell migration via CRFR2 and its system components are differentially modulated by estrogen

Abstract

Urocortin (UCN1) peptide shares structural and functional homology with corticotropin-releasing factor (CRF). UCN1 is significantly reduced in endometrial adenocarcinoma compared to healthy controls. However, there are no data which evaluate the effects of UCN1 in the endometrium, or how it is modulated. We used proliferation and transwell assays to determine the effect of UCN1 on the proliferation and migration of Ishikawa and HEC1A cells. We also determined the expression levels of UCN1 and its receptors produced by estrogen receptor agonists, and the effect of UCN1 on estrogen receptor expression, using quantitative polymerase chain reaction. UCN1 suppressed migration of endometrial cancer cells in vitro. This effect appears to be specific to CRF receptor 2 (CRFR2), as selective antagonism of CRFR2 but not CRFR1 completely eliminated suppression of migration. Activation of ERA reduced UCN1 expression, but only had a small effect on the expression of CRFR1. However, expression of CRFR2 was more notably reduced at both the mRNA and protein levels by activation of ERB. UCN1 in turn reduced both ERA and ERB expression, as assessed by real-time quantitative PCR. We demonstrate that UCN1 significantly suppresses the migration of endometrial cancer cells but has no effect on their proliferation. Thus, loss of UCN1 in endometrial cancer may promote invasion and metastatic spread. There is a complex relationship between the UCN1 system and estrogen receptors, which may provide insights into endometrial carcinogenesis, a disease known to be driven by estrogen excess.

Thumbnail image of graphical abstract

In this study, we have shown that urocortin 1 (UCN1) significantly suppresses migration of endometrial cancer cells, via CRFR2. It has previously been shown that UCN1 expression is significantly reduced in endometrial cancer and therefore loss of UCN1 may promote cancer invasion and metastasis. We have also demonstrated that UCN1 expression is differentially regulated by estrogen receptor activation, suggesting that the loss of UCN1 seen in endometrial cancer is secondary to estrogen excess.



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Genetic predictors of long-term graft function in kidney and pancreas transplant patients

<span class="paragraphSection">Kidney and pancreas transplantation have helped transform the lives of people with end-stage renal failure and individuals with type 1 diabetes who have poor glycaemic control/severe secondary complications, respectively. Despite an improvement in immunosuppressive regimes, operative techniques and decreased initial rejection rates, there has been little improvement in long-term graft survival rates over the past decade. Whilst limited progress has been made in establishing clinical markers of graft function, several genetic markers of long-term graft function have been identified. These genetic markers have the potential to (i) assist in selecting marginal donor organs for transplantation, (ii) provide better understanding of the mechanisms behind graft loss enabling identification of new, or repurposing, current treatments to extend graft function and (iii) provide a window of opportunity to identify and treat individuals before graft failure has occurred. This review will discuss the different genetic variants screened for a role in predicting transplant longevity, examine their findings and limitations and introduce where the future of genetic research within the transplantation field lies.</span>

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IJERPH, Vol. 14, Pages 104: The Basic Act for Suicide Prevention: Effects on Longitudinal Trend in Deliberate Self-Harm with Reference to National Suicide Data for 1996–2014

A suicide prevention strategy was launched in Japan in 2006 to address the high suicide rate, which had increased considerably since 1998. The national strategy from 2007 involved the enhancement of psychiatric treatment services at emergency medical facilities and supportive observation by individuals close to patients. The national suicide rate has decreased gradually since 2008; however, national information regarding the number of patients who had engaged in deliberate self-harm was absent. Therefore, the present study examined the longitudinal trend in hospital admissions due to deliberate self-harm in Japan. Data from the National Patient Survey between 1996 and 2014—a nationally representative cross-sectional survey of inpatient care every 3 years—were used. Data for 13,014 patients were included in the estimation of the number of hospital admissions due to deliberate self-harm. The results show that the estimated number of admissions due to deliberate self-harm increased from 2078 in September 1996 to 3189 in September 2008, when the national number of suicide cases peaked, and decreased to 1783 in 2014. Approximately half of the patients were admitted to hospital because of self-harm via means other than drug poisoning, which had a high mortality rate (5.6%). The proportion of patients receiving public assistance was higher in those who had engaged in deliberate self-harm (8.5%) relative to that observed in the general population. Overall, the trend in deliberate self-harm was synchronous with the number of suicide cases over time. As economic poverty has been associated with suicidal ideation and behavior and some recipients of public assistance tend to abuse psychotropic medication, the public assistance program should provide mental health support for recipients of social benefit schemes.

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The impact of a panel of 18 SNPs on breast cancer risk in women attending a UK familial screening clinic: a case-control study

Background

Breast cancer familial risk clinics offer screening and preventive strategies. While BRCA1/BRCA2 genetic testing provides important risk information for some women, panels of more common breast cancer risk genetic variants may have relevance to greater numbers of women with familial risk.

Methods

Three polygenic risk scores (PRS) based on 18 SNPs were investigated in a case–control study of women attending a familial risk clinic. PRS were derived from published general European population allele ORs and frequencies (18-SNPs (SNP18)). In women with BRCA1/BRCA2 mutations, 3 SNPs/13 SNPs, respectively, generated the PRS estimates. In total, 364 incident breast cancer cases (112 with BRCA1/2 mutations) were matched with 1605 controls (691 BRCA1/2) by age last mammogram and BRCA1/2 genetic test result. 87 women with cancer before attendance were also considered. Logistic regression was used to measure PRS performance through ORs per IQR and calibration of the observed to expected (O/E) logarithm relative risk when unadjusted and adjusted for phenotypic risk factors assessed by the Tyrer-Cuzick (TC) model.

Results

SNP18 was predictive for non-carriers of BRCA1/2 mutations (IQR OR 1.55, 95% CI 1.29 to 1.87, O/E 96%). Findings were unaffected by adjustment from TC (IQR OR 1.56, 95% CI 1.29 to 1.89) or when prior cancers were included (IQR OR 1.55, 95% CI 1.30 to 1.87). There was some evidence to support polygenic scores with weights for individuals with BRCA1/2 mutations (BRCA1 IQR OR 1.44, 95% CI 1.17 to 1.76; BRCA2 IQ OR 1.44, 95% CI 0.90 to 2.31).

Conclusions

PRS may be used to refine risk assessment for women at increased familial risk who test negative/have low likelihood of BRCA1/2 mutations. They may alter the recommended prevention strategy for many women attending family history clinics.



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De novo mtDNA point mutations are common and have a low recurrence risk

Background

Severe, disease-causing germline mitochondrial (mt)DNA mutations are maternally inherited or arise de novo. Strategies to prevent transmission are generally available, but depend on recurrence risks, ranging from high/unpredictable for many familial mtDNA point mutations to very low for sporadic, large-scale single mtDNA deletions. Comprehensive data are lacking for de novo mtDNA point mutations, often leading to misconceptions and incorrect counselling regarding recurrence risk and reproductive options. We aim to study the relevance and recurrence risk of apparently de novo mtDNA point mutations.

Methods

Systematic study of prenatal diagnosis (PND) and recurrence of mtDNA point mutations in families with de novo cases, including new and published data. ‘De novo’ based on the absence of the mutation in multiple (postmitotic) maternal tissues is preferred, but mutations absent in maternal blood only were also included.

Results

In our series of 105 index patients (33 children and 72 adults) with (likely) pathogenic mtDNA point mutations, the de novo frequency was 24.6%, the majority being paediatric. PND was performed in subsequent pregnancies of mothers of four de novo cases. A fifth mother opted for preimplantation genetic diagnosis because of a coexisting Mendelian genetic disorder. The mtDNA mutation was absent in all four prenatal samples and all 11 oocytes/embryos tested. A literature survey revealed 137 de novo cases, but PND was only performed for 9 (including 1 unpublished) mothers. In one, recurrence occurred in two subsequent pregnancies, presumably due to germline mosaicism.

Conclusions

De novo mtDNA point mutations are a common cause of mtDNA disease. Recurrence risk is low. This is relevant for genetic counselling, particularly for reproductive options. PND can be offered for reassurance.



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De novo missense variants in HECW2 are associated with neurodevelopmental delay and hypotonia

Background

The causes of intellectual disability (ID) are diverse and de novo mutations are increasingly recognised to account for a significant proportion of ID.

Methods and results

In this study, we performed whole exome sequencing on a large cohort of patients with ID or neurodevelopmental delay and identified four novel de novo predicted deleterious missense variants in HECW2 in six probands with ID/developmental delay and hypotonia. Other common features include seizures, strabismus, nystagmus, cortical visual impairment and dysmorphic facial features. HECW2 is an ubiquitin ligase that stabilises p73, a crucial mediator of neurodevelopment and neurogenesis.

Conclusion

This study implicates pathogenic genetic variants in HECW2 as potential causes of neurodevelopmental disorders in humans.



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Risk assessment of maternally inherited SDHD paraganglioma and phaeochromocytoma

Background

Germline mutations in the SDHD tumour suppressor gene (11q23.1) predispose to phaeochromocytomas and paragangliomas (PPGL) mainly on a paternal transmission. However, PPGL have been recently reported in three carriers of a maternally inherited SDHD mutation.

Objective

To assess the risk of PPGL occurrence on maternal transmission of SDHD mutation.

Methods

Pedigrees of 80 SDHD-related families have been reviewed. 35 asymptomatic subjects carrying a maternally transmitted SDHD mutation were identified. 20 of them accepted to benefit from a PPGL imaging screening.

Results

A unique histologically proven biochemically negative phaeochromocytoma has been diagnosed in a 35-year-old woman. Molecular investigations carried out on tumour tissue revealed that the loss of heterozygosity encompassed the paternally derived q arm and the maternally derived p arm of chromosome 11.

Conclusions

This study demonstrates that the risk of developing PPGL for a subject carrying a germline SDHD mutation on the maternal allele remains a rare scenario but does exist. Our data suggest an adjustment of current genetic counselling and clinical care recommendations for at-risk subjects. A targeted familial genetic test should be proposed from the age of 18 years to every subject having a mother carrying a germline SDHD mutation and a first medical workup, including imaging, should be recommended to SDHD-positive mutation carriers.



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High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing

Background

Intellectual disability is a very complex condition where more than 600 genes have been reported. Due to this extraordinary heterogeneity, a large proportion of patients remain without a specific diagnosis and genetic counselling. The need for new methodological strategies in order to detect a greater number of mutations in multiple genes is therefore crucial.

Methods

In this work, we screened a large panel of 1256 genes (646 pathogenic, 610 candidate) by next-generation sequencing to determine the molecular aetiology of syndromic intellectual disability. A total of 92 patients, negative for previous genetic analyses, were studied together with their parents. Clinically relevant variants were validated by conventional sequencing.

Results

A definitive diagnosis was achieved in 29 families by testing the 646 known pathogenic genes. Mutations were found in 25 different genes, where only the genes KMT2D, KMT2A and MED13L were found mutated in more than one patient. A preponderance of de novo mutations was noted even among the X linked conditions. Additionally, seven de novo probably pathogenic mutations were found in the candidate genes AGO1, JARID2, SIN3B, FBXO11, MAP3K7, HDAC2 and SMARCC2. Altogether, this means a diagnostic yield of 39% of the cases (95% CI 30% to 49%).

Conclusions

The developed panel proved to be efficient and suitable for the genetic diagnosis of syndromic intellectual disability in a clinical setting. Next-generation sequencing has the potential for high-throughput identification of genetic variations, although the challenges of an adequate clinical interpretation of these variants and the knowledge on further unknown genes causing intellectual disability remain to be solved.



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Targeted massively parallel sequencing and histological assessment of skeletal muscles for the molecular diagnosis of inherited muscle disorders

Background

Inherited skeletal muscle diseases are genetically heterogeneous diseases caused by mutations in more than 150 genes. This has made it challenging to establish a high-throughput screening method for identifying causative gene mutations in clinical practice.

Aim

In the present study, we developed a useful method for screening gene mutations associated with the pathogenesis of skeletal muscle diseases.

Methods

We established four target gene panels, each covering all exonic and flanking regions of genes involved in the pathogenesis of the following muscle diseases: (1) muscular dystrophy (MD), (2) congenital myopathy/congenital myasthenic syndrome, (3) metabolic myopathy and (4) myopathy with protein aggregations/rimmed vacuoles. We assigned one panel to each patient based on the results of clinical and histological analyses of biopsied muscle samples and performed high-throughput sequencing by using Ion PGM next-generation sequencer. We also performed protein analysis to confirm defective proteins in patients with major muscular dystrophies. Further, we performed muscle-derived cDNA analysis to identify splice-site mutations.

Results

We identified possible causative gene mutations in 33% of patients (62/188) included in this study. Our results showed that the MD panel was the most useful, with a diagnostic rate of 46.2%.

Conclusions

Thus, we developed a high-throughput sequencing technique for diagnosing inherited muscle diseases. The use of this technique along with histological and protein analyses may be useful and cost-effective for screening mutations in patients with inherited skeletal muscle diseases.



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Genetics of idiopathic pulmonary fibrosis: from mechanistic pathways to personalised medicine

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and ultimately fatal disorder for which there is no cure. While the disease is by definition idiopathic, accumulating evidence, including familial aggregation of cases and the occurrence of pulmonary fibrosis in the context of a number of rare genetic disorders, indicates that genetic factors contribute significantly to the pathogenesis of IPF. Several disease-associated genetic variants, both rare and common, have been identified in familial and sporadic IPF. While the full clinical implications of these genetic associations remain to be elucidated, observational studies suggest that genotype influences the development of the disease and its outcome. Available data indicate that genetics has the potential to identify individuals at risk of IPF, classify patients more precisely, clarify the key pathways involved in disease pathogenesis and eventually develop more effective targeted therapies. Considerable research is required before a comprehensive disease fingerprint of IPF can be delivered. Nevertheless, the application of rapidly evolving molecular biology and genomic technologies combined with appropriate bioinformatic methodology offers an unprecedented and realistic opportunity to achieve this goal.



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The cerebellum and embodied semantics: evidence from a case of genetic ataxia due to STUB1 mutations

Abundant research on lexicosemantic processing indicates that damage to movement-related regions (the motor and premotor cortices, Broca's area and the basal ganglia1) distinctively impairs processing of action verbs, that is, verbs denoting bodily motion. Moreover, such deficits could be hereditary,2 suggesting an association with genetic factors. We, thus, hypothesised that genetically based deterioration of other motor regions could involve similar impairments. In particular, through a combination of structural and functional MRI (fMRI) with genetic and behavioural analysis, this case study indicates that distinctive action-verb deficits can also be linked to genetic mutations affecting the cerebellum, a key motor hub implicated in balance, posture and movement coordination. Accordingly, in line with the embodied cognition framework, our data illuminate a potential functional specialisation of the cerebellum within the lexicosemantic domain.

To test our hypothesis, we profited from access to a unique case of genetic ataxia and assessed...



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Homozygous and compound heterozygous mutations in the FBN1 gene: unexpected findings in molecular diagnosis of Marfan syndrome

Background

Marfan syndrome (MFS) is an autosomal-dominant connective tissue disorder usually associated with heterozygous mutations in the gene encoding fibrillin-1 (FBN1). Homozygous and compound heterozygous cases are rare events and have been associated with a clinical severe presentation.

Objectives

Report unexpected findings of homozygosity and compound heterozygosity in the course of molecular diagnosis of heterozygous MFS and compare the findings with published cases.

Methods and results

In the context of molecular diagnosis of heterozygous MFS, systematic sequencing of the FBN1 gene was performed in 2500 probands referred nationwide. 1400 probands carried a heterozygous mutation in this gene. Unexpectedly, among them four homozygous cases (0.29%) and five compound heterozygous cases (0.36%) were identified (total: 0.64%). Interestingly, none of these cases carried two premature termination codon mutations in the FBN1 gene. Clinical features for these carriers and their families were gathered and compared. There was a large spectrum of severity of the disease in probands carrying two mutated FBN1 alleles, but none of them presented extremely severe manifestations of MFS in any system compared with carriers of only one mutated FBN1 allele. This observation is not in line with the severe clinical features reported in the literature for four homozygous and three compound heterozygous probands.

Conclusion

Homozygotes and compound heterozygotes were unexpectedly identified in the course of molecular diagnosis of MFS. Contrary to previous reports, the presence of two mutated alleles was not associated with severe forms of MFS. Although homozygosity and compound heterozygosity are rarely found in molecular diagnosis, they should not be overlooked, especially among consanguineous families. However, no predictive evaluation of severity should be provided.



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The performance of deleteriousness prediction scores for rare non-protein-changing single nucleotide variants in human genes

In recent years, whole genome sequencing has increasingly been used as a replacement of whole exome sequencing for identifying causal variants of human diseases. In response to this trend, several ‘genome-level’ deleteriousness prediction scores have been proposed to implement the scores designed specifically for missense or splicing variants. The aim of this study was to investigate the prediction accuracy of those genome-level scores for rare non-protein-changing single nucleotide variants (npcSNVs) in and near human genes. We compared 15 genome-level deleteriousness prediction scores and eight conservation scores using receiver operating characteristic (ROC) and area under curve (AUC). We found that fathmm-MKL coding score1 was the best score for npcSNVs (AUC=0.875), outperforming other genome-level deleteriousness prediction scores and conservation scores.

As the cost of whole genome and exome sequencing has reduced considerably, clinical use of sequencing data is becoming more popular. Even though more candidate SNVs were identified and...



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First report of mesalamine (5-aminosalicylic acid) as the causative agent in a case of acute generalized exanthamous pustulosis. Rocci, Erin; Park, Kelly; Hutchens, Kelli; Winterfield, Laura

Acute generalized exanthamous pustulosis (AGEP)is a rare eruption of non-follicular sterile pustuleson a diffuse background of erythema and edema,commonly associated with fever and leukocytosis.Antibiotics are implicated in most cases; however,other drugs have been reported to cause AGEP. Wereport a case of a 73-year-old man with a historyof ulcerative colitis who presented with a diffusepustular rash, renal failure, elevated liver functiontests, and leukocytosis with neutrophilia. A week priorto admission, the patient was started on mesalamineto treat colitis. Upon admission, a workup includinga skin biopsy was performed and was consistentwith AGEP. Mesalamine was discontinued, and thepatient’s skin eruption, renal function, liver functiontests, and leukocytosis subsequently improved.Mesalamine has an unknown mechanism of action.However, it is thought to be an anti-inflammatoryagent that blocks the production of leukotrienesand prostaglandins and is an immunosuppressantthat increases the release of adenosine...

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Eruptive collagenoma in a child. António, Ana Marta; Alves, João; Barreiros, Hugo; Bártolo, Elvira

Eruptive collagenoma is a rare entity, with unknownetiology, considered to be a type of connective tissuenevus composed of collagen. It is usually reported inyoung adults occurring predominantly on the trunkand extremities. Systemic findings and family historyof a similar condition are not typically associated andthe prognosis is excellent. There are few pediatric casesreported in literature. Herein we report an uncommoncase of eruptive collagenoma in a 12-year-old childand present a brief review of the literature.

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Cutaneous manifestations of disseminated gonococcemia. Beatrous, Surget V; Grisoli, Stratton B; de la Bretonne, Jr, Gaston A; Matherne, Ryan J

Background: Sexually transmitted infections, includingurogenital gonorrheal infection, are a growing healthconcern in the United States. Nearly 50% of cervicalinfections are asymptomatic. If left undiagnosedand untreated, there is a risk of disseminatedinfection. Purpose: To describe an 18-year-old womanpresenting with disseminated gonococcal infectionconfirmed by blood cultures, skin biopsy, and urinegonococcal probe. We also describe the presentation,diagnosis, and treatment of disseminated gonococcalinfection, including discussion of the variousmorphologies of cutaneous lesions that have beenreported in the literature. Materials and Methods: Thefeatures of a woman with disseminated gonococcalinfection are presented. Using PubMed, the termscutaneous, disseminated, gonococcal, gonorrhea,infection, lesions, manifestations, pustules, skin, andsystemic were searched. Relevant citations wereutilized and discussed. Results: Hemorrhagic pustules,petechiae, and purpuric lesions developed in a youngwoman with fever ...

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Job Recruitment - Novy. School of Medicine, UC Davis

The University of California Davis, School of Medicine, Department of Dermatology is recruiting for a full-time position at the Associate or Full Professor level in the Clinical X Series or Health Sciences Clinical Professor (HSCP) Series. The successful candidate is nominated to be the holder of the Frederick G. Novy, Jr. M.D Endowed Professorship. Appointees to the ClinX series are expected to conduct independent research. Both series require significant participation in teaching and University/public service.

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Apremilast for treatment of recurrent erythema multiforme. Chen, Tinley; Levitt, Jacob; Geller, Lauren

Recurrent erythema multiforme with oralinvolvement is therapeutically challenging.Apremilast has been used with success in resolvingthe oral aphthae of Behçet disease, prompting theuse of the drug in patients with oral erosions fromerythema multiforme. Three patients with oralerythema multiforme were given apremilast at dosesof 30-60mg daily. Complete clearance of the lesionswere observed in all three patients, including thoserefractory to other standard therapies. Apremilast maypresent an effective option for recurrent erythemamultiforme for patients who have failed trials antiviraland immunosuppressive therapies.

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Pregnancy-associated morphea: a case report and literature review. Pham, Anh Khow; Srivastava, Bhaskar; Deng, April

Morphea, also known as localized scleroderma, is arare fibrosing disorder of the skin, the pathogenesisof which is incompletely understood. It is thought,however, to involve interplay of genetic dispositionand triggering environmental factors, such asinfections and autoimmunity. Pregnancy as a potentialtrigger has only been reported in four cases. Herein,we present a patient who developed morphea of thebreasts during pregnancy, which rapidly resolvedwith a normal delivery. Our patient was distinct fromsome of the reported patients because her conditionwas tightly correlated with her pregnancy, as judgingby rapid resolution after delivery. In addition, therewas no apparent infection, history of autoimmunity,or development of autoimmunity during or afterpregnancy. Although the pathogenesis of pregnancyassociatedmorphea is largely unknown, we exploredpotential mechanisms of this condition, which mayinvolve mechanical injury, “microchimerism,” andshifts in intrapartum hormones, such as TGF-β.

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Gabapentin-induced aquagenic wrinkling of the palms. Emiroglu, Nazan; Cengiz, Fatma P; Su, Ozlem; Onsun, Nahide

Aquagenic keratoderma (AK) or aquagenic wrinklingis a rare palmoplantar skin disease. It is sporadic orhereditary condition. It appears in childhood or youngadulthood and it is seen as multiple asymptomaticsmall shiny papules on the peripheral margin ofpalms and/or soles after submersion in water. Thepathogenesis and etiology of ASA remains unclear.Drugs sometimes trigger AK. Herein, we present thecase of a 29-year-old man who had begun treatmentwith gabapentin three weeks before the onset of hiscutaneous symptoms.

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YouTube as a source of health information: Analysis of sun protection and skin cancer prevention related issues. Ruppert, Linda; Køster, Brian; Siegert, Anna Maria; Cop, Christian; Boyers, Lindsay; Karimkhani, Chante; Winston, Helena; Mounessa, Jessica; Dellavalle, Robert P; Reinau, Daphne; Diepgen, Thomas; Surber, Christian

Although social media ubiquitously supplementstraditional information sources such as newspapers,magazines, radio, and television, investigation of onlinehealth information related to sun protection and skincancer prevention has been scarce and largely limitedto English language sources. Using the search terms“sun protection,” “sunscreen,” “skin cancer prevention,”“tanning bed” and “vitamin D,” we investigated 281YouTube videos presented in 6 languages: English,German, French, Spanish, Swedish, and Danish. Foreach video, we used a four-sectioned checklist toassess general information, popularity, expert drivenmeasures, and heuristic driven measures. Differencesbetween languages were detected: English languagevideos were most frequently viewed (median numberof views: 5488 compared to 248 -1591 in otherlanguages). Approximately 60% of videos revealednegative effects of solar ultraviolet (UV)-exposure.The majority of videos (75%) targeted adults. Videoson tanning beds and sunscreen contained false ormisleading i...

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Certolizumab-induced guttate psoriasiform dermatitis. Fischer, Ryan; DaCunha, Matthew; Rajpara, Anand

Certolizumab is a TNF inhibitor that has showngreat efficacy in chronic inflammatory diseases. Wereport a patient exhibiting a novel adverse effect ofcertolizumab: drug-induced guttate psoriasiformeruption. A review of the mechanism of psoriasiformdrug eruptions is also included.

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Second degree burn to mustard powder. Tartar, Danielle M; Sharon, Victoria R

Mustard seeds and powder are commonly used inhomeopathic and traditional medicines, in whichthey are believed to have both anti-microbial andanti-inflammatory properties. They are thereforeutilized in the treatment of conditions ranging fromarthritis to respiratory congestion. Herein, we presenta patient with a second degree burn who usedmustard powder in the form of a mustard plasterto treat chest congestion. She experienced seconddegree burn wounds to the lower neck and chest, andrecovery with complete re-epithelialization followingtopical silver sulfadiazine, liberal emollient therapy,and triamcinolone ointment. This case highlightsthe potential danger of inappropriate use of topicalhomeopathic remedies such as mustard powder anddetails a successful treatment regimen.

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Unna boot central gauze technique for chronic venous leg ulcers. Gao, Anne L; Cole, Justin G; Stoecker, William V

Background: Venous leg ulcers generally take manyweeks to heal. Novel therapies that shorten healingtime and require less complex care are needed.Purpose: The purpose of this report is to presenta pilot study for a new method that can result ina faster healing time for venous leg ulcers usinginexpensive materials. Methods: A central-gauzeprotocol was developed as described here. A three-ply gauze sponge was placed in the center of theulcer, allowing a peripheral 3-5 mm rim of ulcer toremain exposed. Saline solution was applied to thegauze sponge. A 3-layer Unna boot was applied overthe ulcer with short-stretch compression. This noveltechnique exposed only a peripheral rim of the ulcerto the zinc oxide paste, allowing the central portionof the ulcer to drain through the saline-soaked gauze.The ulcer was photographed at each clinic visit andthe wound area was estimated by finding the bestfitellipse for the ulcer area and computing the areaof the ellipse by a standard formula. Results: Threepatients with small v...

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Cutaneous leishmaniasis mimicking squamous cell carcinoma. Oetken, Tara; Hiscox, Bryan; Orengo, Ida; Rosen, Theodore

A 41-year-old man from Cuero, Texas with a nonhealinglesion on his left cheek was referred to ourclinic for removal of a squamous cell carcinoma. Thepatient first noticed a “pimple” on his left cheek 3-4months prior to presentation. When the lesion beganto grow he presented to his primary care physician anda biopsy was taken, showing “atypical squamous cellproliferation.” Mohs surgery was performed and thenodule was removed with no evidence of malignancyseen on histopathology. Upon review of the surgicalbiopsies by consulting pathologists, the diagnosis ofleishmaniasis was established and later confirmed bythe Center for Disease Control and Prevention (CDC)as Leishmania mexicana. The patient was referred toinfectious disease specialists for further management.

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Metastatic neuroendocrine carcinoma in the skin. Garcia, Andres; Mays, Steven; Silapunt, Sirunya

Cutaneous metastases secondary to neuroendocrinetumors are rare. Herein we report a case of a 75-yearoldwoman who presented with a rare cutaneousmetastatic disease. She was previously diagnosed withmetastatic neuroendocrine carcinoma of unknownprimary, with metastases to liver, lung, and bone.Biopsy of the skin lesion demonstrated archetypicalpathology and positive immunohistochemicalstaining for chromogranin A and synaptophysin. Thepatient started palliative chemo-radiation therapyand passed away soon after.

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Healthcare reform literacy among academic dermatologists: What we know and don’t know about the Affordable Care Act. Raphael, Brian A; Chen, Suephy; Stoff, Benjamin

Importance: There have been no attempts to determinethe understanding of the Affordable Care Act (ACA)among dermatologists. Objective: Assess knowledgeof the ACA among academic dermatologists. Design:A 21-item survey was administered to membersof the Association of Professors of Dermatology(APD). The items assessed knowledge and opinionsof the ACA, and demographics of the participants.Multivariate regressions were conducted todetermine associations between variables.Participants: Members of the Association of Professorsof Dermatology. Main Measure: Knowledge of theACA. Results: One hundred and eight out of 368 APDmembers completed the survey (29.3%). Ninetysixpercent of responders practice in an academicsetting. Only 36 (33.3%) rated their knowledge of theACA as good/great, whereas 67 (62%) believed thatthe ACA will change their practice. The mean numberof knowledge questions correctly answered was 4.5out of 7 (64.3%). Dermatologists who reported thattheir knowledge of the bill was good/great (p=0.04)and proc...

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Classic Kaposi sarcoma in an HIV-negative Han Chinese man: a case report. Mitre, Victoria; Applebaum, Danielle S; Potenziani, Silvia; Hsu, Sylvia

Kaposi sarcoma (KS) is a multifocal angioproliferativetumor of endothelial origin. Despite nearly identicalclinical and histopathologic presentations, KS isclassified into four distinct varieties: classic/sporadic,AIDS-associated, African/endemic, and iatrogenic. Allsubtypes are invariably linked to human herpesvirus-8(HHV-8) and show a male predilection. Classic Kaposisarcoma is exceedingly rare in the Asian populationand its incidence varies by region and ethnic grouppredominance. A study in the Xinjiang region of Chinafound that only 1% of classic KS cases occurred inpatients belonging to the Han Chinese ethnic group,which formulates 84% of the Taiwanese population.Therefore, classic KS is extremely rare in Taiwan, withvery few reports describing the manifestations ofdisease in this population. We report a case of animmunocompetent 68-year-old HIV-negative HanChinese man born and raised in Taiwan with classicKaposi sarcoma on his trunk and extremities.

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Successful treatment of recalcitrant discoid lupus erythematosus with ustekinumab. Romero-Maté, Alberto; García-Donoso, Carmen; Hernández-Núñez, Almudena; Martínez-Morán, Cristina; Moreno-Torres, Amalia; Borbujo-Martínez, Jesús

We report a 52-year old woman with a 28-year historyof disfiguring facial discoid lupus erythematosus(DLE), persistent despite both classical therapiesand rituximab. Ustekinumab 45 mg was started incombination with methotrexate and intralesionalcorticosteroids. Methotrexate and intralesionalcorticosteroids were withdrawn 30 months later andustekinumab maintained as monotherapy. Fortyeight months later stable improvement was achievedwithout side effects. Only nine patients with cutaneouslupus erythematosus (CLE) treated with ustekinumabhave been reported to date. Ustekinumab could be apromising alternative in severe and recalcitrant casesof CLE. Possibly, the Th17-inflammation pathway isplaying a role in these patients.

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Malignant syphilis: ostraceous, ulceronecrotic lesions in a patient with human immunodeficiency virus. Mohan, Girish C; Ali, Robert A; Isache, Carmen L; Sharma, Rohit K; Perniciaro, Charles

We present a 36-year-old HIV-positive man with a sixweek history of spreading, ulcerative, and necroticcutaneous lesions. Laboratory and histopathologicexamination revealed syphilis. This case of malignantsyphilis, also known as lues maligna, is an uncommonvariant of this sexually transmitted infection. This casehighlights the importance of including malignantsyphilis in the differential diagnosis of patientspresenting with a disseminated ulcerative andnecrotic rash, especially in individuals with HIV.

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Job Recruitment - Dermatologists & Mohs Surgeon. School of Medicine, UC David

The University of California, Davis, School of Medicine, Department of Dermatology, is recruiting for four academic dermatologists in the Clinical X series or Health Sciences Clinical Professor (HSCP) series at the Assistant/Associate/Professor level based on experience and qualifications. Three of these positions are for general medical dermatologists, and one is for a fellowship-trained Mohs surgeon/procedural dermatologist. The appointments may be made up to 100%.

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Cutaneous T-cell lymphoma-associated Leser-Trélat sign: report and world literature review. Narala, Saisindhu; Cohen, Philip R

Background: The sign of Leser-Trélat is characterizedby the sudden appearance of seborrheic keratosesassociated with an underlying malignancy. Objectives:An elderly man who developed multiple new-onsetseborrheic keratoses temporally associated witha diagnosis of mycosis fungoides is described andlymphoma-associated Leser-Trélat sign is reviewed.Methods: Pubmed was used to search the followingterms: cutaneous T-cell lymphoma, Leser-Trélat,leukemia, lymphoma, mycosis fungoides, and Sézarysyndrome. Papers with these terms and referencescited within these papers were reviewed. Results:An 84-year-old man developed multiple seborrheickeratoses temporally associated with a diagnosisof mycosis fungoides is presented. He was treatedwith bexarotene and achieved clinical remission;the number of seborrheic keratoses also decreased.Lymphoma-associated Leser-Trélat sign has beenobserved not only with mycosis fungoides but alsoother lymphomas and leukemias. Conclusions: Thesign of Leser-Trélat is predominantly associated wi...

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Prevention of poison ivy dermatitis with oral homeopathic Rhus toxicodendron. Signore, Robert Joseph

Acute allergic contact dermatitis to poison ivy is acommon and miserable dermatosis which affectsmillions of Americans each year. Preventativemeasures, such as avoidance, protective clothing,barrier creams, soaps, and solvents often fail despiteour patients’ best attempts. Severe allergic reactionsto poison ivy are a significant source of decreasedemployee productivity owing to inability to work anda major health care expenditure. Patients may haveto leave their jobs and discontinue favorite outdoorrecreational activities as a result of severe urushiolsensitivity. Thus, a simple and effective method ofpreventing poison ivy dermatitis would be of greatbenefit to clinical dermatologists and their patients.Complementary and alternative medical practitionerscommonly prescribe homeopathic poison ivyproducts by mouth for the prevention of poisonivy dermatitis. Yet, conventional dermatologists aremostly unaware of this little known clinical pearl. Theauthor discusses two open studies and anecdotalexperience with adm...

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Surviving in isolation: genetic variation, bottlenecks and reproductive strategies in the Canarian endemic Limonium macrophyllum (Plumbaginaceae)

Abstract

Oceanic archipelagos are typically rich in endemic taxa, because they offer ideal conditions for diversification and speciation in isolation. One of the most remarkable evolutionary radiations on the Canary Islands comprises the 16 species included in Limonium subsection Nobiles, all of which are subject to diverse threats, and legally protected. Since many of them are single-island endemics limited to one or a few populations, there exists a risk that a loss of genetic variation might limit their long-term survival. In this study, we used eight newly developed microsatellite markers to characterize the levels of genetic variation and inbreeding in L. macrophyllum, a species endemic to the North-east of Tenerife that belongs to Limonium subsection Nobiles. We detected generally low levels of genetic variation over all populations (H T = 0.363), and substantial differentiation among populations (F ST = 0.188; R ST = 0.186) coupled with a negligible degree of inbreeding (F = 0.042). Obligate outcrossing may have maintained L. macrophyllum relatively unaffected by inbreeding despite the species’ limited dispersal ability and the genetic bottlenecks likely caused by a prolonged history of grazing. Although several factors still constitute a risk for the conservation of L. macrophyllum, the lack of inbreeding and the recent positive demographic trends observed in the populations of this species are factors that favour its future persistence.



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Phase I study of lurbinectedin, a synthetic tetrahydroisoquinoline that inhibits activated transcription, induces DNA single- and double-strand breaks, on a weekly × 2 every-3-week schedule

Summary

Background Lurbinectedin administered as a 1-h intravenous infusion every 3 weeks induces neutropenia, with the nadir usually occurring during the second week. This phase I study evaluated an alternative lurbinectedin dosing schedule consisting of a 1-h infusion on days 1 and 8 every 3 weeks. Patients and methods Twenty-one patients with advanced cancer received lurbinectedin using a standard cohort dose escalation design. Results Three dose levels of 3, 4, and 5 mg of lurbinectedin were explored. The recommended phase II dose was 5 mg, with 3 of 13 patients having dose-limiting toxicity (DLT), although grade 4 neutropenia occurred in 50% of patients. Other frequent toxicities were mild to moderate nausea and vomiting, fatigue, decreased appetite, stomatitis and asymptomatic creatinine and transaminase increases. No objective responses occurred, but prolonged stable disease was observed in 7 patients, including 3 with soft tissue sarcoma. Conclusion The recommended phase II dose of lurbinectedin is 5 mg, administered as a 1-h infusion on days 1 and 8 every 3 weeks. These data support further testing of this dose and schedule, particularly in soft tissue sarcoma.



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Efficacy and Mediation of a Theory-Based Physical Activity Intervention for African American Men Who Have Sex with Men: A Randomized Controlled Trial

Abstract

Background

Few trials have tested physical-activity interventions among sexual minorities, including African American men who have sex with men (MSM).

Purpose

We examined the efficacy and mediation of the Being Responsible for Ourselves (BRO) physical-activity intervention among African American MSM.

Method

African American MSM were randomized to the physical-activity intervention consisting of three 90-min one-on-one sessions or an attention-matched control intervention and completed pre-intervention, immediately post-intervention, and 6- and 12-month post-intervention audio computer-based surveys.

Results

Of the 595 participants, 503 completed the 12-month follow-up. Generalized estimating equation models revealed that the intervention increased self-reported physical activity compared with the control intervention, adjusted for pre-intervention physical activity. Mediation analyses suggested that the intervention increased reasoned action approach variables, subjective norm and self-efficacy, increasing intention immediately post-intervention, which increased physical activity during the follow-up period.

Conclusions

Interventions targeting reasoned action approach variables may contribute to efforts to increase African American MSM’s physical activity.

Clinical trial registration

The trial was registered with the ClinicalTrials.gov Identifier NCT02561286.



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Personality and Risk of Frailty: the English Longitudinal Study of Ageing

Abstract

Background

There is evidence that the personality traits conscientiousness, extraversion and neuroticism are associated with health behaviours and with risk of various health outcomes. We hypothesised that people who are lower in conscientiousness or extraversion or higher in neuroticism may be at greater risk of frailty in later life.

Methods

We used general linear models to examine the prospective relation between personality, assessed using the Midlife Development Inventory, and change in frailty, modelled by a frailty index, in 5314 men and women aged 60 to over 90 years from the English Longitudinal Study of Ageing.

Results

Men and women with higher levels of neuroticism or lower levels of extraversion or conscientiousness had an increased frailty index score at follow-up. After adjustment for potential confounding or mediating variables, including frailty index score at baseline, the frailty index score at follow-up—which potentially ranges from 0 to 1—was higher by 0.035 (95 % confidence interval 0.018, 0.052) for a standard deviation increase in neuroticism and lower by 0.061 (0.031, 0.091) or 0.045 (0.020, 0.071) for a standard deviation increase in extraversion or conscientiousness, respectively. There was some evidence that the association between extraversion and frailty may be due to reverse causation whereby poorer health affected responses to items in the personality inventory.

Conclusions

Higher levels of neuroticism or lower levels of conscientiousness or extraversion may be risk factors for the onset or progression of frailty. Future studies need to replicate these observations in other populations and explore the mechanisms underlying these associations.



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Need Satisfaction Moderates the Association Between Physical Activity and Affective States in Adults Aged 50+: an Activity-Triggered Ambulatory Assessment

Abstract

Background

Substantial evidence shows that physical activities of daily living are positively correlated with affective states in middle-aged and older adults. However, people’s physical activity decreases when they grow older, and conditions that enhance older individuals’ physical activities of daily living are not well understood.

Purpose

This study investigated need satisfaction (competence, relatedness, and autonomy) and its moderating effect on the within-subject relation between physical activities of daily living and three dimensions of affective states (valence, energetic arousal, and calmness) based on an ambulatory assessment that used activity-triggered e-diaries.

Method

The physical activities of daily living of 68 adults aged 50+ (mean age = 60.1 ± 7.1) were measured objectively for three consecutive days, and need satisfaction and affective states were assessed as a function of the amount of physical activity during the preceding 10 min before the affect measurement (in activity-triggered e-diaries). Hierarchical multilevel analyses were performed.

Results

Need satisfaction was significantly and positively correlated with the three dimensions of affective states. Further, physical activities of daily living were significantly associated with energetic arousal and calmness, but not valence. However, when physical activities of daily living were more autonomously regulated, the association of physical activities of daily living and valence became significant and positive.

Conclusion

The findings regarding the significant moderating effects of need satisfaction are crucial for interventions aiming to improve the health-enhancing effects of physical activity in adults aged 50+. Positive feelings owing to physical activities in daily living depend on the extent that psychological needs are satisfied.



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Perceived Weight Discrimination and 10-Year Risk of Allostatic Load Among US Adults

Abstract

Background

Discrimination promotes multisystem physiological dysregulation termed allostatic load, which predicts morbidity and mortality. It remains unclear whether weight-related discrimination influences allostatic load.

Purpose

The aim of this study was to prospectively examine 10-year associations between weight discrimination, allostatic load, and its components among adults 25–75 years in the Midlife Development in the US Biomarker Substudy.

Methods

Participants with information on weight discrimination were analyzed (n=986). At both timepoints, participants self-reported the frequency of perceived weight discrimination across nine scenarios as “never/rarely” (scored as 0), “sometimes” (1), or “often” (2). The two scores were averaged and then dichotomized as “experienced” versus “not experienced” discrimination. High allostatic load was defined as having ≥3 out of 7 dysregulated systems (cardiovascular, sympathetic/parasympathetic nervous systems, hypothalamic pituitary axis, inflammatory, lipid/metabolic, and glucose metabolism), which collectively included 24 biomarkers. Relative risks (RR) were estimated from multivariate models adjusted for sociodemographic and health characteristics, other forms of discrimination, and BMI.

Results

Over 41% of the sample had obesity, and 6% reported weight discrimination at follow-up. In multivariable-adjusted analyses, individuals who experienced (versus did not experience) weight discrimination had twice the risk of high allostatic load (RR, 2.07; 95 % CI, 1.21; 3.55 for baseline discrimination; 2.16, 95 % CI, 1.39; 3.36 for long-term discrimination). Weight discrimination was associated with lipid/metabolic dysregulation (1.56; 95 % CI 1.02, 2.40), glucose metabolism (1.99; 95 % CI 1.34, 2.95), and inflammation (1.76; 95 % CI 1.22, 2.54), but no other systems.

Conclusions

Perceived weight discrimination doubles the 10-year risk of high allostatic load. Eliminating weight stigma may reduce physiological dysregulation, improving obesity-related morbidity and mortality.



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The Impact of Interventions that Integrate Accelerometers on Physical Activity and Weight Loss: A Systematic Review

Abstract

Background

Regular physical activity is important for improving and maintaining health, but sedentary behavior is difficult to change. Providing objective, real-time feedback on physical activity with wearable motion-sensing technologies (activity monitors) may be a promising, scalable strategy to increase physical activity or decrease weight.

Purpose

We synthesized the literature on the use of wearable activity monitors for improving physical activity and weight-related outcomes and evaluated moderating factors that may have an impact on effectiveness.

Methods

We searched five databases from January 2000 to January 2015 for peer-reviewed, English-language randomized controlled trials among adults. Random-effects models were used to produce standardized mean differences (SMDs) for physical activity outcomes and mean differences (MDs) for weight outcomes. Heterogeneity was measured with I 2.

Results

Fourteen trials (2972 total participants) met eligibility criteria; accelerometers were used in all trials. Twelve trials examined accelerometer interventions for increasing physical activity. A small significant effect was found for increasing physical activity (SMD 0.26; 95 % CI 0.04 to 0.49; I 2 = 64.7 %). Intervention duration was the only moderator found to significantly explain high heterogeneity for physical activity. Eleven trials examined the effects of accelerometer interventions on weight. Pooled estimates showed a small significant effect for weight loss (MD −1.65 kg; 95 % CI −3.03 to −0.28; I 2= 81 %), and no moderators were significant.

Conclusions

Accelerometers demonstrated small positive effects on physical activity and weight loss. The small sample sizes with moderate to high heterogeneity in the current studies limit the conclusions that may be drawn. Future studies should focus on how best to integrate accelerometers with other strategies to increase physical activity and weight loss.



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Barriers to HIV Medication Adherence as a Function of Regimen Simplification

Abstract

Background

Barriers to HIV medication adherence may differ by levels of dosing schedules.

Purpose

The current study examined adherence barriers associated with medication regimen complexity and simplification.

Methods

A total of 755 people living with HIV currently taking anti-retroviral therapy were recruited from community services in Atlanta, Georgia. Participants completed audio-computer-assisted self-interviews that assessed demographic and behavioral characteristics, provided their HIV viral load obtained from their health care provider, and completed unannounced phone-based pill counts to monitor medication adherence over 1 month.

Results

Participants taking a single-tablet regimen (STR) were more likely to be adherent than those taking multi-tablets in a single-dose regimen (single-dose MTR) and those taking multi-tablets in a multi-dose regimen (multi-dose MTR), with no difference between the latter two. Regarding barriers to adherence, individuals taking STR were least likely to report scheduling issues and confusion as reasons for missing doses, but they were equally likely to report multiple lifestyle and logistical barriers to adherence.

Conclusions

Adherence interventions may need tailoring to address barriers that are specific to dosing regimens.



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Predictors of Smoking Cessation and Relapse in Cancer Patients and Effect on Psychological Variables: an 18-Month Observational Study

Abstract

Background

Although cancer patients are generally strongly advised to quit smoking in order to improve treatment efficacy and survival, up to 68 % of patients who were smokers at the time of cancer diagnosis continue smoking. Psychological factors such as depression and anxiety are likely to be associated with smoking behavior following a cancer diagnosis, but the empirical evidence is scarce.

Purpose

This observational study aimed at estimating smoking cessation rates and assessing the effect of smoking cessation on psychological symptoms, as well as the predictive role of the same psychological variables on smoking cessation and smoking relapse following cancer surgery.

Methods

As part of a larger prospective, epidemiological study, smokers (n = 175) with a first diagnosis of nonmetastatic cancer completed the Hospital Anxiety and Depression Scale, the Insomnia Severity Index, and the Fear of Cancer Recurrence Inventory. Quitters (n = 55) and pair-matched nonquitters (n = 55) were compared on each symptom at pre-quitting, post-quitting, and at a 4-month follow-up. Predictors of smoking cessation and smoking relapse, including psychological variables, were also investigated.

Results

Fifty-five patients (31.4 %) stopped smoking at least on one occasion during the study. Of the 55 quitters, 27 (49.1 %) experienced a relapse. At pre-quitting, quitters had significantly higher levels of anxiety (p = .03) and fear of cancer recurrence (p = .01) than nonquitters, symptoms that significantly diminished at post-quitting and 4 months later in this subgroup of patients. Having breast cancer significantly predicted smoking cessation (relative risk [RR] = 3.08), while depressive symptoms were a significant predictor of smoking relapse (RR = 1.07).

Conclusions

This study highlights the importance of psychological symptoms in predicting tobacco cessation and relapse among individuals with cancer. Our findings suggest that breast cancer patients are more inclined to stop smoking than patients with other cancers, but future studies should attempt to delineate the effect on smoking cessation of gender and other demographics that characterize this subgroup. This study also suggests that a particular attention should be paid to the early management of depressive symptoms in order to prevent smoking relapse.



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Using Integrative Data Analysis to Examine Changes in Alcohol Use and Changes in Sexual Risk Behavior Across Four Samples of STI Clinic Patients

Abstract

Background

Patients in sexually transmitted infection (STI) clinics report high levels of alcohol use, which are associated with risky sexual behavior. However, no studies have examined how changes in alcohol use relate to changes in sexual risk behavior.

Purpose

We used parallel process latent growth modeling to explore how changes in alcohol use related to changes in sexual behavior across four samples of clinic patients.

Methods

Patients participating in HIV prevention trials from urban clinics in the Northeastern and Midwestern USA (N = 3761, 59 % male, 72 % Black) completed measures at 3-month intervals over 9–12 months. Integrative data analysis was used to create composite measures of alcohol use across samples. Sexual risk measures were counts of partners and unprotected sex acts. Parallel process models tested whether alcohol use changes were correlated with changes in the number of partners and unprotected sex.

Results

Growth models with good fit showed decreases that slowed over time in sexual risk behaviors and alcohol use. Parallel process models showed positive correlations between levels of (rs = 0.17–0.40, ps < 0.001) and changes in (rs = 0.21–0.80, ps < 0.05) alcohol use and number of sexual partners across studies. There were strong associations between levels of (rs = 0.25–0.43, ps < 0.001) and changes in (rs = 0.24–0.57, ps < 0.01) alcohol use and unprotected sex in one study recruiting hazardous drinkers.

Conclusions

Across four samples of clinic patients, reductions in alcohol use were associated with reductions in the number of sexual partners. HIV prevention interventions may be strengthened by addressing alcohol use.



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Relationship between IL-27 and coronary arterial lesions in children with Kawasaki disease

Abstract

Kawasaki disease (KD) arises due to the disorder of the inflammation response and faulty immune regulation. Interleukin-27 (IL-27) is a novel cytokine with both pro-inflammatory and anti-inflammatory effects. This study investigated the relationship between serum levels of IL-27, Interleukin-17A (IL-17A), Interleukin-10 (IL-10), Interleukin-6 (IL-6), Interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and coronary artery lesions (CALs) in patients with KD. We obtained blood samples from 81 children with KD before intravenous immunoglobulin (IVIG) therapy. Levels of IL-27, IL-17A, IL-10, IL-6, IL-1β and TNF-α were measured in 251 cases, including 4 groups: the normal control group, NC (n = 90), febrile control, FC (n = 80), KD without coronary arteries (n = 41) and KD with coronary arterial lesions (n = 40). White blood cells counts (WBC), red blood cells counts (RBC), hemoglobin, C-reactive protein (CRP), erythrocyte sedimentation rate and procalcitonin (PCT) were tested in all subjects. Levels of IL-27, IL-10, IL-17A, IL-6, IL-1β and TNF-α were significantly elevated, and RBC and hemoglobin significantly decreased in the group of KD group compared with febrile and control groups. IL-27, IL-6, IL-1β and TNF-α serum levels are even higher in KD children with CALs. There was positive relationship between serum levels of IL-27 and WBC, CRP, PCT, IL-10, IL-17A, IL-6 and TNF-α in children with KD. The up-regulation of IL-27 may be closely linked to up-regulation of systemic pro-inflammatory markers in acute KD. Morover, IL-27 may be involved in the development of CALs in acute KD.



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Use of LDL receptor-targeting peptide vectors for in vitro and in vivo cargo transport across the blood-brain barrier [Research]

The blood-brain barrier (BBB) prevents the entry of many drugs into the brain and, thus, is a major obstacle in the treatment of CNS diseases. There is some evidence that the LDL receptor (LDLR) is expressed at the BBB and may participate in the transport of endogenous ligands from blood to brain, a process referred to as receptor-mediated transcytosis. We previously described a family of peptide vectors that were developed to target the LDLR. In the present study, in vitro BBB models that were derived from either wild-type and LDLR knockout animals (ldlr–/–) were used to validate the specific LDLR-dependent transcytosis of LDL via a nondegradative route. We next showed that LDLR-targeting peptide vectors, whether in fusion or chemically conjugated to an Ab Fc fragment, promote binding to apical LDLR and transendothelial transfer of the Fc fragment across BBB monolayers via the same route as LDL. Finally, we demonstrated in vivo that LDLR significantly contributes to the brain uptake of vectorized Fc. We thus provide further evidence that LDLR is a relevant receptor for CNS drug delivery via receptor-mediated transcytosis and that the peptide vectors we developed have the potential to transport drugs, including proteins or Ab based, across the BBB.—Molino, Y., David, M., Varini, K., Jabès, F., Gaudin, N., Fortoul, A., Bakloul, K., Masse, M., Bernard, A., Drobecq, L., Lécorché, P., Temsamani, J., Jacquot, G., Khrestchatisky, M. Use of LDL receptor–targeting peptide vectors for in vitro and in vivo cargo transport across the blood-brain barrier.



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Robust Gold Nanoparticle Sheets by Ligand Cross-Linking at the Air–Water Interface

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.6b05563
ancac3?d=yIl2AUoC8zA


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Geographic heterogeneity in the prevalence of human papillomavirus in head and neck cancer

Abstract

Human papillomavirus (HPV) causes oropharyngeal squamous cell carcinoma (OPSCC), although strongly divergent results have been reported regarding the prevalence of HPV16 in different countries, whether this represents important differences in etiology remains unclear. Applying rigorous protocols for sample processing, we centrally evaluated 1420 head and neck tumors (533 oropharynx, 395 oral cavity and 482 larynx) from studies conducted in the US, Europe and Brazil for mucosal HPV DNA and p16INK4a expression to evaluate regional heterogeneity in the proportion of HPV16-associated OPSCC and other head and neck cancer, and to assess covariates associated with the risk of HPV16-positive OPSCC. While majority of OPSCC in the US (60%) were HPV16-positive, this proportion was 31% in Europe and only 4% in Brazil (p<0.01). Similar differences were observed for other head and neck tumors, ranging from 7% in the US and 5% in Europe, to 0% in South America. The odds of HPV16-positive OPSCC declined with increasing pack years of smoking (OR: 0.75; 95% CI: 0.64 -0.87) and drink years of alcohol use (OR: 0.64; 95% CI: 0.54-0.76). These results suggest that while the contribution of HPV16 is substantial for the oropharynx, it remains limited for oral cavity and laryngeal cancers. This article is protected by copyright. All rights reserved.



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