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Τρίτη, 24 Ιανουαρίου 2017

The Complexities of Using an Umbrella in New York City

Who yields to whom in the meeting of umbrellas on a city sidewalk?

-- Read more on ScientificAmerican.com
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The Complexities of Using an Umbrella in New York City

Who yields to whom in the meeting of umbrellas on a city sidewalk?

-- Read more on ScientificAmerican.com
feed?d=yIl2AUoC8zA feed?d=qj6IDK7rITs feed?d=l6gmwiTKsz0 feed?i=SFBc1qyGnXQ:WVjzmjYS6XU:gIN9vFwOq feed?d=ZC7T4KBF6Nw feed?d=I9og5sOYxJI feed?d=QXVau8BzmBE


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Pine Tree Tapping in Siberia with Special Reference to Alcohol Consumption

The post Pine Tree Tapping in Siberia with Special Reference to Alcohol Consumption appeared first on Welcome to Avens.



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Understanding the Role of Structural Integrity and Differential Expression of Integrin Profiling to Identify Potential Therapeutic Targets in Breast Cancer

Abstract

Breast cancer is found to be the most prevalent neoplasm in women worldwide. Despite the function of physically tethering cells to the matrix, transmembrane protein integrins are crucially involved in diverse cellular functions such as cell differentiation, proliferation, invasion, migration and metastasis. Dysregulation of integrins and their interactions with the cells and their microenvironment can trigger several signalling cues that determine the cell fate decision. In this review we spotlight all pre-existing integrin molecules, their structure, molecular interactions motifs, and function through several cross talks with kinase receptors. We also discuss the role of these integrins as potential prognostic and therapeutic targets and also in the regulation of breast cancer cells differentiation. Understanding of integrin structure and their motifs for ligand interactions in this context will enable the development of new therapeutic approaches to sensitize the tumours and their microenvironment to conventional therapy and overall suppress their metastatic phenotype. This article is protected by copyright. All rights reserved



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Genes, Vol. 8, Pages 48: Primary Cilia as a Possible Link between Left-Right Asymmetry and Neurodevelopmental Diseases

Cilia have multiple functions in the development of the entire organism, and participate in the development and functioning of the central nervous system. In the last decade, studies have shown that they are implicated in the development of the visceral left-right asymmetry in different vertebrates. At the same time, some neuropsychiatric disorders, such as schizophrenia, autism, bipolar disorder, and dyslexia, are known to be associated with lateralization failure. In this review, we consider possible links in the mechanisms of determination of visceral asymmetry and brain lateralization, through cilia. We review the functions of seven genes associated with both cilia, and with neurodevelopmental diseases, keeping in mind their possible role in the establishment of the left-right brain asymmetry.

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Bacteriaphobia

Bacteriaphobia: An abnormal and persistent fear of germs. Sufferers from bacteriaphobia experience undue anxiety even though they realize that most germs are not pathogens (disease-causing germs). To avoid germs, they may repeat cleaning rituals, such as washing their hands or face.

"Bacteriaphobia" is derived from the Greek "bacterion" (staff) and "phobos" (fear). The Greek word for "staff" was chosen because some bacteria (bacilli) are rod-shaped, like a staff.

Alternate spelling: Bacteriophobia. Alternate name: Bacillophobia. Also referred to as germaphobia, germaphobe, or germophobe.



MedTerms (TM) is the Medical Dictionary of MedicineNet.com.
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Effect of Systemic Insulin Treatment on Diabetic Wound Healing

Abstract

This study investigates if different diabetic treatment regimens affects diabetic foot ulcer healing. From January 2013 to December 2014, 107 diabetic foot ulcers in 85 patients were followed until wound healing, amputation or development of a non-healing ulcer at the last follow-up visit. Demographic data, diabetic treatment regimens, presence of peripheral vascular disease, wound characteristics and outcome were collected. Non-healing wound was defined as major or minor amputation or those who didn't have complete healing until the last observation. Median age was 60.0 years (range: 31.1-90.1) and 58 cases (68.2%) were males. Twenty-four cases reached a complete healing (healing rate: 22.4%). Median follow-up period in subjects with classified as having chronic wounds was 6.0 months (range: 0.7-21.8). Insulin treatment was a part of diabetes management in 52 (61.2%) cases. Insulin therapy significantly increased the wound healing rate (30.3% [20/66 ulcers] vs. 9.8% [4/41 ulcers]) (P=0.013). In multivariate random-effect logistic regression model, adjusting for age, gender, smoking status, type of diabetes, hypertension, chronic kidney disease, peripheral arterial disease, oral hypoglycemic use, wound infection, involved side, presence of Charcot's deformity, gangrene, osteomyelitis on x-ray, and serum hemoglobin A1C levels, insulin treatment was associated with a higher chance of complete healing (beta±SE: 15.2±6.1, P=0.013). Systemic insulin treatment can improve wound healing in diabetic ulcers after adjusting for multiple confounding covariates. This article is protected by copyright. All rights reserved.



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Sulforaphane suppresses cell growth and collagen expression of keloid fibroblasts

Abstract

Keloids are fibroproliferative diseases characterized by the accumulation of an extracellular matrix including collagen. Various growth factors, or cytokines, and their receptors are overexpressed in keloids, and they are expected to be therapy targets. Sulforaphane, a dietary isothiocyanate, has recently shown anti-tumor, anti-inflammatory and anti-fibrotic properties. In this study, we found that sulforaphane inhibited cell growth and reduced collagen at the mRNA and protein levels in keloid fibroblasts. Moreover, sulforaphane markedly suppressed the expression of IL-6, α-SMA, and inhibited Stat3 and Smad3 signaling pathways in keloid fibroblast KF112 cells. Sulforaphane induced G2/M cell-cycle arrest with the induction of p21 in KF112 cells. In addition, sulforaphane also inhibited cell growth and suppressed the expression of collagen in keloid fibroblasts under a coculture with peripheral blood mononuclear cells. Furthermore, sulforaphane also suppressed IL-6, Stat3 and Smad3 signaling in the coculture system. This study suggests that sulforaphane may be a novel keloid treatment. This article is protected by copyright. All rights reserved.



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Non-Animal Models of Wound Healing in Cutaneous Repair: In Silico, In Vitro, Ex Vivo And In Vivo Models Of Wounds And Scars In Human Skin

Abstract

Tissue repair models are essential in order to explore the pathogenesis of wound healing and scar formation, identify new drug targets/biomarkers and to test new therapeutics. However, no animal model is an exact replicate of the clinical situation in man as in addition to differences in the healing of animal skin; the response to novel therapeutics can be variable when compared to human skin. The aim of this review is to evaluate currently available non-animal wound repair models in human skin, including: in silico, in vitro, ex vivo, and in vivo. The appropriate use of these models is extremely relevant to wound-healing research as it enables improved understanding of the basic mechanisms present in the wound-healing cascade and aid in discovering better means to regulate them for enhanced healing or prevention of abnormal scarring. The advantage of in silico models is that they can be used as a first in virtue screening tool to predict the effect of a drug/stimulus on cells/tissues and help plan experimental research/clinical trial studies but remain theoretical until validated. In vitro models allow direct quantitative examination of an effect on specific cell types alone without incorporating other tissue-matrix components, which limits their utility. Ex vivo models enable immediate and short-term evaluation of a particular effect on cells and its surrounding tissue components compared with in vivo models that provide direct analysis of a stimulus in the living human subject before/during/after exposure to a stimulus. Despite clear advantages, there remains a lack of standardisation in design, evaluation and follow-up, for acute/chronic wounds and scars in all models. In conclusion, ideal models of wound-healing research are desirable and should mimic not only the structure plus cellular and molecular interactions, of wound types in human skin. Future models may also include organ/skin-on-a-chip with potential application in wound-healing research. This article is protected by copyright. All rights reserved.



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Traumatologie der Nase

Zusammenfassung

Die Nase als prominentestes Element des Gesichtes wird überdurchschnittlich oft traumatisiert. Eine exakte Beurteilung einer traumatisierten Nase, eine angemessene Diagnostik und die Entscheidung zu einer adäquaten Frühbehandlung tragen dazu bei, bleibende Formstörungen zu verhindern. Die gesamte Palette der bekannten Techniken der Rhinoplastik ermöglicht weitreichende Korrekturmaßnahmen. In die Planung intensiver Korrekturmaßnahmen sollten technische Varianten wie mehrfache Osteotomien und die Abtragung überschüssiger Knochensequester oder Narben einbezogen werden. Außerdem ist die Auswahl eines geeigneten Materials zur Auffüllung von Defekten wichtig.



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A Pilot Randomized, Controlled Study of Nanocrystalline Silver, Manuka Honey, and Conventional Dressing in Healing Diabetic Foot Ulcer

Nanocrystalline silver (nAg) and Manuka honey (MH) dressing have increasing popularity for treating diabetic foot ulcer (DFU). This study was an open-label randomized controlled trial with three parallel groups’ design in examining the preliminary effectiveness of nAg against MH and conventional dressing in healing DFU in terms of ulcer healing, ulcer infection, and inflammation. 31 participants (11 in the nAg group, 10 in the MH group, and 10 in the convention group) diagnosed with type 2 diabetes were enrolled. Wound cleaning, debridement, and topical dressing application were performed according to the group allocation in each visit at weeks 1, 2, 3, 4, 6, 8, 10, and 12. The results found that the proportions of complete ulcer healing were 81.8%, 50%, and 40% in the nAg, MH, and conventional groups, respectively. The ulcer size reduction rate was potentially higher in the nAg group (97.45%) than the MH group (86.21%) and the conventional group (75.17%). In bacteriology, nAg showed a greater rate of microorganism reduction although it was not significant. To conclude, nAg alginate was potentially superior to MH and conventional dressing in healing diabetic foot ulcer in terms of ulcer size reduction rate.

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Photoluminescence Enhancement of Titanate Nanotubes by Insertion of Rare Earth Ions in Their Interlayer Spaces

The optical properties of titanate nanotubes (TiNts) intercalated with rare earths (RE) ions were intensively investigated in this study. To prepare the nanomaterials, sodium titanate nanotubes (Na-TiNts) were submitted to ion exchange reactions with different rare earth elements (RE: Pr3+, Er3+, Nd3+, and Yb3+). To the best of our knowledge, it is the first time that these RE-TiNts were synthesized. All samples were characterized by Raman spectroscopy, X-ray powder diffraction (XRD), transmission electron microscopy (TEM), and energy dispersive X-ray spectroscopy (EDS). Furthermore, the optical properties were examined using photoluminescence spectroscopy (PL) and UV-Vis-NIR absorption spectroscopy. The PL intensity (visible range) of the RE-TiNt samples showed a strong dependence when the temperature was decreased down to 20 K. This PL enhancement probably was promoted by electronic modifications in titanate layer band gap and/or interface charge transfers due to RE ions intercalation.

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Cytokine Imbalance as a Common Mechanism in Both Psoriasis and Rheumatoid Arthritis

Psoriasis (PS) and rheumatoid arthritis (RA) are immune-mediated inflammatory diseases. Previous studies showed that these two diseases had a common pathogenesis, but the precise molecular mechanism remains unclear. In this study, RNA sequencing of peripheral blood mononuclear cells was employed to explore both the differentially expressed genes (DEGs) of 10 PS and 10 RA patients compared with those of 10 healthy volunteers and the shared DEGs between these two diseases. Bioinformatics network analysis was used to reveal the connections among the shared DEGs and the corresponding molecular mechanism. In total, 120 and 212 DEGs were identified in PS and RA, respectively, and 31 shared DEGs were identified. Bioinformatics analysis indicated that the cytokine imbalance relevant to key molecules (such as extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase (MAPK), tumor necrosis factor (TNF), colony-stimulating factor 3 (CSF3), interleukin- (IL-) 6, and interferon gene (IFNG)) and canonical signaling pathways (such as the complement system, antigen presentation, macropinocytosis signaling, nuclear factor-kappa B (NF-κB) signaling, and IL-17 signaling) was responsible for the common comprehensive mechanism of PS and RA. Our findings provide a better understanding of the pathogenesis of PS and RA, suggesting potential strategies for treating and preventing both diseases. This study may also provide a new paradigm for illuminating the common pathogenesis of different diseases.

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Optimization Models and Algorithms for Operation and Control with Advanced Information Technologies



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Gut Microbiota in a Rat Oral Sensitization Model: Effect of a Cocoa-Enriched Diet

Increasing evidence is emerging suggesting a relation between dietary compounds, microbiota, and the susceptibility to allergic diseases, particularly food allergy. Cocoa, a source of antioxidant polyphenols, has shown effects on gut microbiota and the ability to promote tolerance in an oral sensitization model. Taking these facts into consideration, the aim of the present study was to establish the influence of an oral sensitization model, both alone and together with a cocoa-enriched diet, on gut microbiota. Lewis rats were orally sensitized and fed with either a standard or 10% cocoa diet. Faecal microbiota was analysed through metagenomics study. Intestinal IgA concentration was also determined. Oral sensitization produced few changes in intestinal microbiota, but in those rats fed a cocoa diet significant modifications appeared. Decreased bacteria from the Firmicutes and Proteobacteria phyla and a higher percentage of bacteria belonging to the Tenericutes and Cyanobacteria phyla were observed. In conclusion, a cocoa diet is able to modify the microbiota bacterial pattern in orally sensitized animals. As cocoa inhibits the synthesis of specific antibodies and also intestinal IgA, those changes in microbiota pattern, particularly those of the Proteobacteria phylum, might be partially responsible for the tolerogenic effect of cocoa.

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Physical activity and survival of colorectal cancer patients: Population-based study from Germany

Abstract

Increasing evidence shows physical activity to be associated with improved colorectal cancer (CRC) prognosis. However, large-scale prospective patient cohorts, comprehensively ascertaining physical activity, comprehensively considering potential variation by CRC stage and considering specific outcome measures, are sparse. Therefore, we aimed to evaluate the association of lifetime and latest prediagnostic leisure time physical activity with relevant prognostic outcomes in a large population-based cohort of CRC patients. 3,121 patients, diagnosed with CRC in 2003-2010 (median age: 69 years), were interviewed on socio-demographic and lifestyle factors, medication, and comorbidities. Cancer recurrence, vital status, and cause of death were documented over a median follow-up time of 4.8 years. Associations between lifetime and latest prediagnostic leisure time physical activity and overall, CRC-specific, recurrence-free, and disease-free survival were evaluated with Cox regression. Latest but not lifetime leisure time physical activity [in metabolic task hours per week (MET-h/wk)] was associated with decreased overall and CRC-specific mortality (>56.2 vs. ≤13.2 MET-h/wk: adjusted hazard ratio (aHR)Overall/latest=0.75; 95% confidence interval (CI)= 0.61-0.91; aHRCRC-specific/latest=0.81; 95%CI=0.64-1.02). In particular lifetime and latest walking, were associated with decreased mortality (>20 vs. 0-10 MET-h/wk of walking: aHROverall/latest=0.66; 95%CI=0.56-0.77; aHRCRC-specific/latest=0.72; 95%CI=0.60-0.87; aHROverall/lifetime=0.78; 95%CI=0.66-0.93; aHRCRC-specific/lifetime=0.71; 95%CI=0.58-0.86). Associations were particularly pronounced for lifetime walking in metastatic (stage IV) and for latest walking in nonmetastatic disease patients.

Prediagnostic physical activity was associated with improved CRC prognosis. Associations might be restricted to certain activities or depend on (non)metastatic disease state. Further optimization of activity recommendations and increase of recommendation adherence may help to improve patients' prognosis. This article is protected by copyright. All rights reserved.



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The effect of medications which cause inflammation of the gastro-oesophageal tract on cancer risk: A nested case-control study of routine Scottish data

Abstract

Bisphosphonate, tetracycline and spironolactone use has been shown to increase gastro-oesophageal inflammation, an accepted risk factor for cancer. However, evidence on the effect of these medications on gastro-oesophageal cancer risk are mixed or missing entirely. Therefore, we conducted a nested case-control study using the Primary Care Clinical Information Unit Research (PCCIUR) database from Scotland. Cases with oesophageal or gastric cancer between 1999 and 2011 were matched to up to five controls based on age, gender, year of diagnosis and general practice. Medication use was ascertained using electronic prescribing records. Conditional logistic regression was used to calculate odds ratios (ORs) for the association between medication use and cancer risk after adjustment for comorbidities and other medication use.

A similar proportion of gastro-oesophageal cancer cases received bisphosphonates (3.9% vs. 3.5%), tetracycline (6.0% vs. 6.0%) and spironolactone (1.4% vs. 1.1%) compared with the controls. The adjusted ORs for the association between gastro-oesophageal cancer and bisphosphonates, tetracycline and spironolactone were 1.05 (95% CI: 0.85, 1.31), 0.99 (95% CI: 0.84, 1.17) and 1.04 (95% CI: 0.73, 1.49). Further analysis revealed bisphosphonates were associated with increased oesophageal cancer risk (1.34, 95% CI: 1.03, 1.74) but reduced gastric cancer risk (0.71, 95% CI: 0.49, 1.03), although there was no obvious dose-response relationship. Overall, there is little evidence that that the use of bisphosphonate, tetracycline or spironolactone is associated with increased risk of gastro-oesophageal cancer. Our findings should reassure GPs and patients that these widely-used medications are safe with respect to gastro-oesophageal cancer risk. This article is protected by copyright. All rights reserved.



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Cervical cancer incidence after screening with HPV, cytology, and visual methods: 18-year follow-up of the Guanacaste cohort

Abstract

Testing negative for human papillomavirus (HPV) predicts long-term reassurance against invasive cervical cancer (ICC). To provide realistic estimates of effectiveness for new screening programs, we studied ICC risk after a 7-year repeated multi-method screening effort. In 1993-94, 10,049 women aged 18-97 were enrolled into a population-based cohort study of cervical HPV in Guanacaste, Costa Rica. Women were screened at different intervals according to enrollment results. Each visit (mean 3.2, 90% attendance) included split-sample conventional, automated, and liquid-based cytology; visual inspection; cervicography; and PCR-based HPV testing. Abnormal screening led to colposcopy and excisional treatment as appropriate during the study. Referral to colposcopy for HPV in the absence of other findings was introduced only at the last visit. Population-based Costa Rica Cancer Registry linkage identified cohort women diagnosed with ICC in the 18 years following cohort enrollment. The ICC cumulative risk was 0.4% (n=38); 18 were diagnosed with ICC after study participation. Of these, 9 were missed at the screening step (negative screening or below the referral threshold, refused screening or colposcopy), 5 attended colposcopy but were not diagnosed as CIN2+, and 4 were treated for CIN2/3 but progressed to ICC nonetheless. Decreasing age-standardized ICC rates for the 1993-2011 period were observed in Guanacaste; cohort women showed additional 31% ICC incidence reduction with apparent downstaging of cancers that occurred. ICC risk following negative HPV testing in the optimal age range 30-50 was extremely low. Real-life screening effectiveness following introduction is lower than the potential near-complete efficacy predicted by HPV natural history. This article is protected by copyright. All rights reserved.



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Oncotype Dx recurrence score among BRCA1/2 germline mutation carriers with hormone receptors positive breast cancer

Abstract

Gene expression assays are widely used to predict risk of recurrence in early breast cancer (BC). We report the 21-gene expression assay (Oncotype Dx) recurrence score (RS) distribution of 27 BRCA carriers with estrogen receptor (ER) positive BCs, identified at Hadassah Medical Center, combined with 2 previous studies. Treatment decision and outcomes of the 27 BRCA carriers were compared with an Israeli cohort of 1594 patients published recently. We found Oncotype Dx RS low (<18), intermediate (18-30), and high (>30) among 12 (21.4%), 23 (41.1%) and 21 (37.5%) of 56 BRCA1 carriers compared with 15 (17.2%), 49 (56.3%) and 23 (26.4%) of 87 BRCA2 carriers (p=0.2). The corresponding distribution in a population of 82,434 women published by Genomic Health was 53.4%, 36.3% and 10.3% for low, intermediate and high RS (p< 0.001 for BRCA1 and BRCA2). Treatment decision regarding chemotherapy according to RS was similar in BRCA1, BRCA2 and the control group. Two of 27 carriers had distant recurrence: a BRCA1 carrier with RS of 18 and a BRCA2 carrier with RS of 22; both have an excellent response to chemotherapy. We found an approximately 3 fold increased rate of high RS among BRCA1 and 2 carriers with ER positive BC compared with the general BC population. These data might indicate that hormone positive BC in BRCA carriers are molecularly unique. The surprisingly good response to chemotherapy in the metastatic setting in 2 patients may suggest that the predictive value of low-intermediate RS in carriers merits further studies. This article is protected by copyright. All rights reserved.



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Dopamine receptor type 2 (DRD2) and somatostatin receptor type 2 (SSTR2) agonists are effective in inhibiting proliferation of progenitor/stem-like cells isolated from non functioning pituitary tumors

Abstract

The role of progenitor/stem cells in pituitary tumorigenesis, resistance to pharmacological treatments and tumor recurrence is still unclear. This study investigated the presence of progenitor/stem cells in non-functioning pituitary tumors (NFPTs) and tested the efficacy of dopamine receptor type 2 (DRD2) and somatostatin receptor type 2 (SSTR2) agonists to inhibit their in vitro proliferation.

We found that 70% of 46 NFPTs formed spheres co-expressing stem cell markers, transcription factors (DAX1, SF1, ERG1) and gonadotropins. Analysis of tumor behavior showed that spheres formation was associated with tumor invasiveness (OR= 3,96; IC: 1.05-14.88, p=0.036). The in vitro reduction of cell proliferation by DRD2 and SSTR2 agonists (31±17% and 35±13% inhibition, respectively, p<0.01 vs basal) occurring in about a half of NFPTs cells was conserved in the corresponding spheres. Accordingly, these drugs increased cyclin-dependent kinase inhibitor p27 and decreased cyclin D3 expression in spheres.

In conclusion, we provided further evidence for the existence of cells with a progenitor/stem cells-like phenotype in the majority of NFPTs, particularly in those with invasive behavior, and demonstrated that the antiproliferative effects of dopaminergic and somatostatinergic drugs were maintained in progenitor/stem-like cells. This article is protected by copyright. All rights reserved.



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Immunohistochemical Detection of Lymph Node-DTCs in Patients with Node-Negative HNSCC

Abstract

This study was performed to systematically assess the prevalence, topography and prognostic impact of disseminated tumor cells (DTCs) in lymph nodes (LN) of patients with primary, regional and distant metastasis-free head and neck squamous cell carcinoma (HNSCC) who underwent resection with elective neck dissection.

From the routinely processed resection specimen, we could prospectively analyze a total of 1.137 exactly mapped LNs of 50 pN0-HNSCC patients, classified as tumor free by routine histopathology. Three immunohistochemistry (IHC) assays using antibodies directed against CK5/14, a broad spectrum of CKs (1-8, 10, 14-16, and 19), and CD44v6, respectively, were applied on 4.190 LN sections to detect DTCs. The IHC results were correlated with clinico-pathologic parameters and clinical follow-up data.

We detected seven micrometastases (MM) in five patients and 31 DTCs in 12 patients. Overall, 15 (30%) patients were positive for DTCs or MMs. Strikingly, the anatomical distribution of LN affected with DTCs was not random, but was dependent on the lateralization of the primary tumor and clustered significantly most proximal to the primary tumor. None of the investigated patients developed loco-regional lymphatic or distant metastasis during the mean follow-up period of 71 months.

Our results reveal clinically occult tumor cell dissemination as an early and frequent event in HNSCC. Considering that higher rates of recurrences in therapeutic lymph node dissection concepts have been reported than in elective neck dissection strategies, our DTC-data support to perform elective neck dissections, since they appear to be effective in preventing loco-regional lymphatic recurrence from LN DTCs or MMs. This article is protected by copyright. All rights reserved.



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Alcohol and Lung Cancer Risk Among Never Smokers: A Pooled Analysis from the International Lung Cancer Consortium and the SYNERGY Study

Abstract

It is not clear whether alcohol consumption is associated with lung cancer risk. The relationship is likely confounded by smoking, complicating the interpretation of previous studies. We examined the association of alcohol consumption and lung cancer risk in a large pooled international sample, minimizing potential confounding of tobacco consumption by restricting analyses to never smokers. Our study included 22 case-control and cohort studies with a total of 2548 never-smoking lung cancer patients and 9362 never-smoking controls from North America, Europe and Asia within the International Lung Cancer Consortium (ILCCO) and SYNERGY Consortium. Alcohol consumption was categorized into amounts consumed (grams per day) and also modelled as a continuous variable using restricted cubic splines for potential non-linearity. Analyses by histologic sub-type were included. Associations by type of alcohol consumed (wine, beer and liquor) were also investigated. Alcohol consumption was inversely associated with lung cancer risk with evidence most strongly supporting lower risk for light and moderate drinkers relative to non-drinkers (>0-4.9g per day: OR=0.80, 95% CI=0.70-0.90; 5-9.9g per day: OR=0.82, 95% CI=0.69-0.99; 10-19.9g per day: OR=0.79, 95% CI=0.65-0.96). Inverse associations were found for consumption of wine and liquor, but not beer. The results indicate that alcohol consumption is inversely associated with lung cancer risk, particularly among subjects with low to moderate consumption levels, and among wine and liquor drinkers, but not beer drinkers. Although our results should have no relevant bias from the confounding effect of smoking we cannot preclude that confounding by other factors contributed to the observed associations. Confounding in relation to the non-drinker reference category may be of particular importance. This article is protected by copyright. All rights reserved.



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Modelling gesture use and early language development in autism spectrum disorder

Abstract

Background

Nonverbal communication abilities, including gesture use, are impaired in autism spectrum disorder (ASD). However, little is known about how common gestures may influence or be influenced by other areas of development.

Aims

To examine the relationships between gesture, fine motor and language in young children with ASD compared with a comparison group using multiple measures and methods in a structural equation modelling framework.

Methods & Procedures

Participants included 110 children with ASD and a non-ASD comparison group of 87 children (that included children with developmental delays (DD) or typical development (TD)), from 12 to 48 months of age. A construct of gesture use as measured by the Communication and Symbolic Behavior Scales—Developmental Profile Caregiver Questionnaire (CQ) and the Autism Diagnostic Observation Schedule (ADOS), as well as fine motor from the Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales—II (VABS-II) was examined using second-order confirmatory factor analysis (CFA). A series of structural equation models then examined concurrent relationships between the aforementioned latent gesture construct and expressive and receptive language. A series of hierarchical regression analyses was run in a subsample of 36 children with ASD with longitudinal data to determine how gesture factor scores predicted later language outcomes.

Outcomes & Results

Across study groups, the gesture CFA model with indicators of gesture use from both the CQ (parent-reported) and ADOS (direct observation), and measures of fine motor provided good fit with all indicators significantly and strongly loading onto one gesture factor. This model of gesture use, controlling for age, was found to correlate strongly with concurrent expressive and receptive language. The correlations between gestures and concurrent language were similar in magnitude in both the ASD and non-ASD groups. In the longitudinal subsample of children with ASD, gestures at time 1 predicted later receptive (but not expressive) language outcomes on the VABS-II, after controlling for nonverbal cognition, ASD severity, age and time 1 language.

Conclusions & Implications

This study extends research on the relationship between nonverbal communication and language by supporting the idea of an underlying construct of gesture use that includes fine motor ability and relates to language in young children with ASD. This further supports theories espousing developmental influences of motor and nonverbal communication strategies as important in early language learning.



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Generalization and maintenance of treatment gains in primary progressive aphasia (PPA): a systematic review

Abstract

Background

Cognitive–linguistic treatments and interventions targeting communication have been developed within the context of primary progressive aphasia (PPA), however knowledge about the scope of generalization and maintenance of therapy gains considering PPA subtypes remains scarce and awaits systematic investigation.

Aims

To analyse the effects of semantic therapy on generalization and maintenance of treatment outcomes in individuals with PPA, considering its different subtypes.

Methods & Procedures

Central, PubMed, Medline, Web of Knowledge and Scopus were used to retrieve articles of interest. A total of 25 non-randomized studies published between 2000 and 2016 met the eligibility criteria and therefore were included in this study.

Main Contribution

This systematic review provides evidence-based information for clinical practice in PPA. Generalization and maintenance effects post-treatment for each PPA variant are analysed and discussed. Several factors are described as important to maximize the scope for generalization and maintenance of treatment gains.

Conclusions & Implications

Generalization is particularly hard to achieve in the semantic variant, as in the face of degraded semantic knowledge learning is rigid and context dependent. In contrast, non-fluent and logopenic variants offer better scope for generalization. Maintenance patterns do not seem to be influenced by PPA subtype, but rather by other factors such as continued practice, treatment length and frequency of sessions. In the future, clinicians should consider the PPA subtype when planning the treatment protocol.



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Speech production in 3-year-old internationally adopted children with unilateral cleft lip and palate

Abstract

Background

In the last decade, a large number of children with cleft lip and palate have been adopted to Sweden. A majority of the children were born in China and they usually arrive in Sweden with an unoperated palate. There is currently a lack of knowledge regarding speech and articulation development in this group of children, who also have to deal with a late first language switch.

Aims

To study consonant proficiency in 3-year-old internationally adopted children with unilateral cleft lip and palate (UCLP) compared with peers with UCLP born in Sweden. Also to study the type and frequency of consonant errors and to perceptually compare velopharyngeal competence between the groups.

Methods & Procedures

Thirty-two children born between 2006 and 2010 with UCLP participated in the study—14 adopted from China and 18 children born in Sweden. Both groups were treated by the same cleft palate team. Audio recordings at 3 years of age were perceptually analysed by blinded listeners. Consonant proficiency was measured via per cent consonants correct adjusted for age (PCC-A), per cent correct manners (PCM) and per cent correct places (PCP). The prevalence of audible nasal air leakage and velopharyngeal competence were judged and compared between groups. The type and frequencies of consonant errors related to place and manner of articulation were also analysed.

Outcomes & Results

The internationally adopted children had significantly fewer correct consonants compared with the Swedish-born children. This was true for PCC-A, PCP and PCM. This group also had significantly higher prevalence of glottal stops/fricatives and deleted target consonants more often. Also the internationally adopted children had a higher prevalence of incompetent velopharyngeal function. The only outcome variable with similar results in the groups was audible nasal air leakage.

Conclusions & Implications

The present study indicated that there were significant differences regarding consonant proficiency and velopharyngeal competence between internationally adopted children with a UCLP and their Swedish-born peers with UCLP at the age of 3 years. Internationally adopted children with UCLP should be considered an at risk group for a higher prevalence of speech difficulties than non-adoptees. Thus, it is particularly important to follow this group of children over time. Longitudinal studies of speech and language development in internationally adopted children with UCLP are needed.



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Depupylase Dop requires Inorganic Phosphate in the Active Site for Catalysis [Protein Synthesis and Degradation]

Analogous to eukaryotic ubiquitination, proteins in actinobacteria can be post-translationally modified in a process referred to as pupylation, the covalent attachment of prokaryotic ubiquitin-like protein Pup to lysine side chains of the target protein via an isopeptide bond. Like in eukaryotes, an opposing activity counteracts the modification by specific cleavage of the isopeptide bond formed with Pup. However, the enzymes involved in pupylation and depupylation have evolved independently of ubiquitination and are related to the family of ATP-binding and hydrolyzing carboxylate-amine ligases of the glutamine synthetase type. Furthermore, the Pup ligase PafA and the depupylase Dop share close structural and sequence homology and have a common evolutionary history despite catalyzing opposing reactions. Here, we investigate the role played by the nucleotide in the active site of the depupylase Dop using a combination of biochemical experiments and X-ray crystallographic studies. We show that, although Dop does not turn over ATP stoichiometrically, the active site nucleotide species in Dop is ADP and inorganic phosphate rather than ATP, and that non-hydrolyzable analogs of ATP cannot support the enzymatic reaction. This finding suggests that the catalytic mechanism is more similar to the mechanism of the ligase PafA than previously thought and likely involves the transient formation of a phosphorylated Pup-intermediate. Evidence is presented for a mechanism where the inorganic phosphate acts as the nucleophilic species in amide bond cleavage and implications for Dop function are discussed.

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MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-beta [Cell Biology]

Nephrotoxicity is a major adverse effect of cisplatin-mediated chemotherapy in cancer patients. The pathogenesis of cisplatin-induced nephrotoxicity remains largely unclear, making it difficult to design effective renoprotective approaches. Here, we have examined the role of microRNAs (miRNAs) in cisplatin-induced nephrotoxicity. We show that cisplatin nephrotoxicity was not affected by overall depletion of both beneficial and detrimental miRNAs from kidney proximal tubular cells in mice in which the miRNA-generating enzyme Dicer had been conditionally knocked out. To identify miRNAs involved in cisplatin nephrotoxicity, we used microarray analysis to profile miRNA expression and identified 47 up- regulated microRNAs and 20 down-regulated microRNAs in kidney cortical tissues. One up-regulated miRNA was miR-375, whose expression was also induced in cisplatin-treated renal tubular cells. Interestingly, inhibition of miR-375 decreased cisplatin-induced apoptosis, suggesting that miR-375 is a cell-damaging or pro-apoptotic agent. Blockade of p53 or NF-κB attenuated cisplatin-induced miR-375 expression, supporting a role of p53 and NF-κB in miR-375 induction. We also identified hepatocyte nuclear factor 1 homeobox B (Hnf-1β) as a key downstream target of miR-375. Of note, we further demonstrated that Hnf-1β protected renal cells against cisplatin-induced apoptosis. Together, these results suggest that upon cisplatin exposure, p53 and NF-κB collaboratively induce miR-375 expression, which, in turn, represses Hnf-1β activity, resulting in renal tubular cell apoptosis and nephrotoxicity.

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In vivo Modelling of the Pathogenic Effect of Copper Transporter Mutations that cause Menkes and Wilson Disease, Motor Neuropathy and Susceptibility to Alzheimer's Disease [Metabolism]

Copper is an essential biometal and several inherited diseases are directly associated with a disruption to normal copper homeostasis. The best characterised are the copper deficiency and toxicity disorders Menkes and Wilson disease, caused by mutations in the p-Type Cu-ATPase genes ATP7A and ATP7B respectively. Missense mutations in the C-terminal portion of ATP7A have also been shown to cause Distal Motor Neuropathy while polymorphisms in ATP7B are associated with increased risk of Alzheimer's disease. We have generated a single, in vivo model for studying multiple pathogenic mutations in ATP7 proteins, using Drosophila melanogaster, which has a single orthologue of ATP7A and ATP7B. Four pathogenic ATP7A mutations and two ATP7B mutations were introduced into a genomic ATP7 rescue construct containing an in-frame C-terminal GFP tag. Analysis of the wild type ATP7:GFP transgene confirmed that ATP7 is expressed at the basolateral membrane of larval midgut copper cells and that the transgene can rescue a normally early-lethal ATP7 deletion allele to adulthood. Analysis of the gATP7:GFP transgenes containing pathogenic mutations showed that the function of ATP7 was affected, to varying degrees, by all six of the mutations investigated in this study. Of particular interest, the ATP7BK832R Alzheimer's disease susceptibility allele was found, for the first time, to be a loss of function allele. This in vivo system allows us to assess the severity of individual ATP7A/B mutations in an invariant genetic background and has the potential to be used to screen for therapeutic compounds able to restore function to faulty copper transport proteins.

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Flavonoids suppress Pseudomonas aeruginosa virulence through allosteric inhibition of quorum-sensing receptors [Gene Regulation]

Quorum sensing is a process of cell-cell communication that bacteria use to regulate collective behaviors. Quorum sensing depends on the production, detection, and group-wide response to extracellular signal molecules called autoinducers. In many bacterial species, quorum sensing controls virulence factor production. Thus, disrupting quorum sensing is considered a promising strategy to combat bacterial pathogenicity. Several members of a family of naturally-produced plant metabolites called flavonoids inhibit Pseudomonas aeruginosa biofilm formation by an unknown mechanism. Here, we explore this family of molecules further and we demonstrate that flavonoids specifically inhibit quorum sensing via antagonism of the autoinducer-binding receptors, LasR and RhlR. Structure-activity relationship analyses demonstrate that the presence of two hydroxyl moieties in the flavone A-ring backbone are essential for potent inhibition of LasR/RhlR. Biochemical analyses reveal that the flavonoids function non-competitively to prevent LasR/RhlR DNA-binding. Administration of the flavonoids to P. aeruginosa alters transcription of quorum-sensing-controlled target promoters and suppresses virulence factor production, confirming their potential as anti-infectives that do not function by traditional bacteriocidal or bacteriostatic mechanisms.

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Nectin-like 4 complexes with Choline Transporter-Like protein-1, and regulates Schwann cell choline homeostasis and lipid biogenesis in vitro [Lipids]

Nectin-like 4 (Necl4, Cadm4) is a Schwann cell-specific cell adhesion molecule that promotes axo-glial interactions. In vitro and in vivo studies have shown that Necl4 is necessary for proper peripheral nerve myelination. However the molecular mechanisms that are regulated by Necl4 and affect peripheral myelination currently remain unclear. We used an in vitro approach to start identifying some of the mechanisms that could explain Necl4 function. Using mass spectrometry and Western blot techniques, we have identified Choline Transporter-Like 1 (CTL1) as a putative complexing partner with Necl4. We show that intracellular choline levels are significantly elevated in Necl4-deficient Schwann cells. The analysis of extracellular d9-choline uptake revealed a deficit in the amount of d9-choline found inside Necl4-deficient Schwann cells, suggestive of either reduced transport capabilities or increased metabolization of transported choline. An extensive lipidomic screen of choline derivatives showed that total phosphatidylcholine and phosphatidylinositol (but not diacylglycerol or sphingomyelin) are significantly elevated in Necl4-deficient Schwann cells, particularly specific subspecies of phosphatidylcholine carrying very long polyunsaturaed fatty acid chains. Finally, CTL1-deficient Schwann cells are significantly impaired in their ability to myelinate neurites in vitro. To our knowledge, this is the first demonstration of a bona fide cell adhesion molecule, Necl4, regulating choline homeostasis and lipid biogenesis. Phosphatidylcholines are major myelin phospholipids, and several phosphorylated phosphatidylinositols species are known to regulate key aspects of peripheral myelination. Furthermore the biophysical properties imparted to plasma membranes are regulated by fatty acid chain profiles. It will be therefore important to translate these in vitro observations to in vivo studies of Necl4 and CTL1-deficient mice.

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Increased Dynamics of Tricarboxylic Acid Cycle and Glutamate Synthesis in Obese Adipose Tissue: In vivo Metabolic Turnover Analysis [Metabolism]

Obesity locates upstream of various metabolic disorders. However, little is known about abnormalities in metabolic change of obese adipose tissue. Here, we use static metabolic analysis and in vivo metabolic turn over analysis to assess metabolic dynamics in obese mice. The static metabolic analyses showed that glutamate and constitutive metabolites of tricarboxylic acid (TCA) cycle were increased in white adipose tissue (WAT) of ob/ob and diet-induced obesity (DIO) mice, but not in liver or skeletal muscle of these obese mice. Moreover, in vivo metabolic turnover analyses demonstrated that glucose-derived these metabolites were dynamically and specifically produced in obese WAT, compared to lean WAT. Glutamate rise in obese WAT was associated with downregulation of GLAST, a major glutamate transporter for adipocytes, and low uptake of glutamate into adipose tissue. In adipocytes, glutamate treatment reduced adiponectin secretion and insulin-mediated glucose uptake and phosphorylation of Akt. These data suggest that high intra-adipocytes glutamate level potentially relates to adipocyte dysfunction in obesity. The study provides novel insight of metabolic dysfunction in obesity through comprehensive application of in vivo metabolic turnover analysis in two obese animal models.

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Selective ablation of tumor suppressors in parafollicular C cells elicits medullary thyroid carcinoma [Signal Transduction]

Among the four different types of thyroid cancer, treatment of medullary thyroid carcinoma poses a major challenge due to its propensity of early metastasis. To further investigate the molecular mechanisms of medullary thyroid carcinoma and discover candidates for targeted therapies, we developed a new mouse model of medullary thyroid carcinoma based on our CGRPCreER mouse line. This system enables gene manipulation in parafollicular C cells in the thyroid, the purported cells of origin of medullary thyroid carcinoma. Selective inactivation of tumor suppressors, such as p53, Rb and Pten, in mature parafollicular C cells via an inducible Cre recombinase from CGRPCreER led to development of murine medullary thyroid carcinoma. Loss of Pten accelerated p53/Rb-induced medullary thyroid carcinoma, indicating interactions between pathways controlled by tumor suppressors. Moreover, labeling differentiated parafollicular C cells by CGRPCreER allows us to follow their fate during malignant transformation to medullary thyroid tumor. Our findings support a model in which mutational events in differentiated parafollicular C cells result in medullary thyroid carcinoma. Through expression analysis including RNA-Seq, we uncovered major signaling pathways and networks that are perturbed following the removal of tumor suppressors. Taken together, these studies not only increase our molecular understanding of medullary thyroid carcinoma but also offer new candidates for designing targeted therapies or other treatment modalities.

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Ectopic expression of mouse melanopsin in Drosophila photoreceptors reveals fast response kinetics and persistent dark excitation [Neurobiology]

The intrinsically photosensitive retinal ganglion cells (ipRGC) initiate non-image forming light-dependent activities and express the melanopsin (OPN4) photopigment. Several features of ipRGC photosensitivity are characteristic of fly photoreceptors. However, the light-response kinetics of ipRGC is much slower due to unknown reasons. Here we used transgenic Drosophila, in which the mouse OPN4 replaced the native Rh1 photopigment of Drosophila R1-6 photoreceptors, resulting in deformed rhabdomeric structure. Immunocytochemistry revealed OPN4 expression at the base of the rhabdomeres, mainly at the rhabdomeral stalk. Measurements of the Early Receptor Current (ERC), a linear manifestation of photopigment activation indicated large expression of OPN4 in the plasma membrane. Comparing the ERC amplitude and action spectra between wild type (WT) and the Opn4-expressing Drosophila, further indicated that large quantities of a blue absorbing photopigment were expressed, having a dark-stable blue intermediate state. Strikingly, the light induced current (LIC) of the Opn4-expressing fly photoreceptors was ~130 folds faster than that of ipRGC. Furthermore, intense white flash induced small amplitude prolonged dark current composed of discrete unitary currents similar to the Drosophila single photon responses. The induction of prolonged dark currents by intense blue light could be suppressed by a following intense green light, suggesting induction and suppression of Prolonged Depolarizing Afterpotential (PDA). This is the first demonstration of heterologous functional expression of mammalian Opn4 in the genetically emendable Drosophila photoreceptors. Moreover, the fast Opn4-induced ionic current relative to that of mouse ipRGC, indicates that the slow light-response of ipRGC does not arise from an intrinsic property of melanopsin.

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Will Computers Replace Radiologists? - Medscape


Medscape

Will Computers Replace Radiologists?
Medscape
I recently told a radiology resident who demolished the worklist, "You're a machine." He beamed with pride. Imitation is the highest form of flattery. But the machine, not content in being imitated, wants to encroach on our turf. CT could scarcely have ...



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A systematic review: differentiation of stem cells into functional pericytes [Review]

Pericytes are an integral cellular component of vascular structures. Numerous studies have investigated various stem cell types as potential sources of pericytes for application in cell-based therapy. The diverse stem cell types and variable experimental protocols of these studies make it imperative to evaluate the relevant scientific literature on the basis of a unified standard. The purpose of this systematic review is to rigorously evaluate the relevant scientific literature for conclusive evidence that stem cells can differentiate into functional pericytes. An online literature search was conducted up to July 2016. Eligible papers were evaluated on 4 pertinent criteria: 1) appropriate controls, 2) markers to confirm pericyte phenotype, 3) techniques for assessing pericyte functionality, and 4) differentiation efficiency of the protocol. Our search yielded 20 eligible studies (from 2006 to 2016), 12 of which were published in the last 5 yr. Of these 20 articles, only 1 had positive control, and 5 papers evaluated differentiation efficiency. The most commonly used pericyte markers were neuron-glial antigen 2, platelet-derived growth factor receptor-β, and α-smooth muscle actin. Three articles were associated with adipose stem cells, 4 with mesenchymal stem cells, and 7 with pluripotent stem cells, whereas the remaining 6 articles were based on other miscellaneous stem cell types. Stem cells can serve as a potential source of pericytes, but there should be standardized guidelines in future studies for assessing pericyte differentiation.—Xu, J., Gong, T., Heng, B. C., Zhang, C. F. A systematic review: differentiation of stem cells into functional pericytes.



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Misdirection of endosomal trafficking mediated by herpes simplex virus-encoded glycoprotein B [Research]

Herpes simplex virus (HSV)–encoded glycoprotein B (gB) is the most abundant protein in the viral envelope and promotes fusion of the virus with the cellular membrane. In the present study, we found that gB impacts on the major histocompatibility complex (MHC)-II pathway of antigen presentation by fostering homotypic fusion of early endosomes and trapping MHC-II molecules in these altered endosomes. By using an overexpression approach, we demonstrated that transient expression of gB induces giant vesicles of early endosomal origin, which contained Rab5, early endosomal antigen 1 (EEA1), large amounts of MHC-II molecules [human leukocyte antigen (HLA)-DR, and HLA-DM] but no CD63. In HSV-1–infected and stably transfected cell lines that expressed lower amounts of gB, giant endosomes were not observed, but strongly increased amounts of HLA-DR and HLA-DM were found in EEA1+ early endosomes. We used these giant vesicles as a model system and revealed that gB interacts with Rab5 and EEA1, and that gB-induced homotypic fusion of early endosomes to giant endosomes requires phosphatidylinositol 3-phosphate, the activity of soluble N-ethylmaleimide-sensitive factor attachment protein receptors, and the cytosolic gB sequence 889YTQVPN894. We conclude that gB expression alters trafficking of molecules of the HLA-II processing pathway, which leads to increased retention of MHC-II molecules in early endosomal compartments, thereby intercepting antigen presentation.—Niazy, N., Temme, S., Bocuk, D., Giesen, C., König, A., Temme, N., Ziegfeld, A., Gregers, T. F., Bakke, O., Lang, T., Eis-Hübinger, A. M., Koch, N. Misdirection of endosomal trafficking mediated by herpes simplex virus–encoded glycoprotein B.



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Differential expression of human {gamma}-tubulin isotypes during neuronal development and oxidative stress points to a {gamma}-tubulin-2 prosurvival function [Research]

-Tubulins are highly conserved members of the tubulin superfamily essential for microtubule nucleation. Humans possess 2 -tubulin genes. It is thought that -tubulin-1 represents a ubiquitous isotype, whereas -tubulin-2 is found predominantly in the brain, where it may be endowed with divergent functions beyond microtubule nucleation. The molecular basis of the purported functional differences between -tubulins is unknown. We report discrimination of human -tubulins according to their electrophoretic and immunochemical properties. In vitro mutagenesis revealed that the differences in electrophoretic mobility originate in the C-terminal regions of the -tubulins. Using epitope mapping, we discovered mouse monoclonal antibodies that can discriminate between human -tubulin isotypes. Real time quantitative RT-PCR and 2-dimensional-PAGE showed that -tubulin-1 is the dominant isotype in fetal neurons. Although -tubulin-2 accumulates in the adult brain, -tubulin-1 remains the major isotype in various brain regions. Localization of -tubulin-1 in mature neurons was confirmed by immunohistochemistry and immunofluorescence microscopy on clinical samples and tissue microarrays. Differentiation of SH-SY5Y human neuroblastoma cells by all-trans retinoic acid, or oxidative stress induced by mitochondrial inhibitors, resulted in upregulation of -tubulin-2, whereas the expression of -tubulin-1 was unchanged. Fractionation experiments and immunoelectron microscopy revealed an association of -tubulins with mitochondrial membranes. These data indicate that in the face of predominant -tubulin-1 expression, the accumulation of -tubulin-2 in mature neurons and neuroblastoma cells during oxidative stress may denote a prosurvival role of -tubulin-2 in neurons.—Dráberová, E., Sulimenko, V., Vinopal, S., Sulimenko, T., Sládková, V., D'Agostino, L., Sobol, M., Hozák P., Křen, L., Katsetos, C. D., Dráber, P. Differential expression of human -tubulin isotypes during neuronal development and oxidative stress points to -tubulin-2 prosurvival function.



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Combined Biomarker Expression May Be Significant Driver of Tumorogenisis in Colorectum

Using immunohistochemistry to measure the expression of certain target enzymes —cox-2 and 15-prostaglandin dehydrogenase (15-PGDH)—in premalignant colorectal adenomas, researchers were able to get significant predictive and prognostic information in patients treated with the cox-2 inhibitor celecoxib for prevention of colorectal adenomas. (Source: CancerNetwork)

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Addition of Vemurafenib to Irinotecan/Cetuximab Delayed Progression in BRAF-Mutated mCRC

The addition of the BRAF inhibitor vemurafenib to irinotecan and cetuximab prolonged progression-free survival and resulted in a higher disease control rate than treatment with irinotecan and cetuximab alone in patients with BRAF-mutant metastatic colorectal cancer. (Source: CancerNetwork)

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Nivolumab New Standard for Previously Treated MSI-H Metastatic CRC

The immune checkpoint inhibitor nivolumab showed durable responses and disease control in a group of heavily pretreated patients with DNA mismatch repair deficient/microsatellite instability high (MSI-H) metastatic colorectal cancer. (Source: CancerNetwork)

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Quantifying Queensland patients with cancer health service usage and costs: study protocol

Introduction

The overall mortality rate for cancer has declined in Australia. However, socioeconomic inequalities exist and the out-of-pocket costs incurred by patients in Australia are high compared with some European countries. There is currently no readily available data set to provide a systematic means of measuring the out-of-pocket costs incurred by patients with cancer within Australia. The primary aim of the project is to quantify the direct out-of-pocket healthcare expenditure of individuals in the state of Queensland, who are diagnosed with cancer.

Methods and analysis

This project will build Australia's first model (called CancerCostMod) of out-of-pocket healthcare expenditure of patients with cancer using administrative data from Queensland Cancer Registry, for all individuals diagnosed with any cancer in Queensland between 1 July 2011 and 30 June 2012, linked to their Admitted Patient Data Collection, Emergency Department Information System, Medicare Benefits Schedule and Pharmaceutical Benefits Scheme records from 1 July 2011 to 30 June 2015. No identifiable information will be provided to the authors. The project will use a combination of linear and logistic regression modelling, Cox proportional hazards modelling and machine learning to identify differences in survival, total health system expenditure, total out-of-pocket expenditure and high out-of-pocket cost patients, adjusting for demographic and clinical confounders, and income group, Indigenous status and geographic location. Results will be analysed separately for different types of cancer.

Ethics and dissemination

Human Research Ethics approval has been obtained from the Townsville Hospital and Health Service Human Research Ethics Committee (HREC/16/QTHS/110) and James Cook University Human Research Ethics Committee (H6678). Permission to waive consent has been sought from Queensland Health under the Public Health Act 2005.



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Anaesthesia modalities during laser photocoagulation for retinopathy of prematurity: a retrospective, longitudinal study

Objectives

Laser photocoagulation surgery is a routine treatment for threshold retinopathy of prematurity (ROP). However, little is known about which anaesthesia protocols provide efficient pain control while minimising exposure risk to vulnerable infants. In this study, therefore, we assessed the efficacy and tolerability of multiple anaesthesia techniques used on premature infants during laser therapy.

Design and main outcome measures

Anaesthesia modalities consisted of topical eye drops anaesthesia, general anaesthesia and intravenous fentanyl sedation with mechanical ventilation. Laser treatment efficacy and detailed operative information were retrospectively and consecutively analysed. Cardiorespiratory stability was assessed and compared. The Neonatal Pain Agitation and Sedation Scale (N-PASS) was used to evaluate tolerability in infants that underwent intravenous fentanyl sedation.

Results

97 cases of prematurity were included in this study. In 94/97 (96.9%) cases, vascular proliferation regressed. In the topical anaesthesia groups, the ophthalmologist needed 12–16 min more to complete the treatment. During the 3 postoperative days, topical anaesthesia demonstrated the greatest instability; 4/31 (12.90%) infants in this group suffered from life threatening events requiring resuscitation. The only instability observed in general anaesthesia and fentanyl sedation was attributed to difficulty in extubating within 24 hours after surgery. During laser therapy, the N-PASS score increased to 1.8 in the fentanyl sedation group.

Conclusions

Topical anaesthesia was associated with more cardiorespiratory instability during ROP laser treatment. While general anaesthesia and fentanyl sedation had similar postoperative cardiorespiratory results, the latter demonstrated acceptable pain stress control. However, the difficulty of weaning off mechanical ventilation in some cases after surgery needs to be addressed in future studies.



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Citizenship status and engagement in HIV care: an observational cohort study to assess the association between reporting a national ID number and retention in public-sector HIV care in Johannesburg, South Africa

Objective

In many resource-limited settings, people from rural areas migrate to urban hubs in search of work. Thus, urban public-sector HIV clinics in South Africa (SA) often cater to both local residents and patients from other provinces and/or countries. The objective of this analysis was to compare programmatic treatment outcomes by citizenship status in an urban clinic in SA.

Setting

An urban public-sector HIV treatment facility in Johannesburg, SA.

Participants

We included all antiretroviral therapy (ART)-naïve, non-pregnant patients who initiated standard first-line treatment from January 2008 to December 2013. 12 219 patients were included and 59.5% were women.

Primary outcome measure

Patients were followed from ART initiation until death, transfer, loss to follow-up (LTF), or data set closure. We describe attrition (mortality and LTF) stratified by SA citizenship status (confirmed SA citizens (with national ID number), unconfirmed SA citizens (no ID), and foreign nationals) and model the risk of attrition using Cox proportional hazards regression.

Results

70% of included patients were confirmed SA citizens, 19% were unconfirmed SA citizens, and 11% were foreign nationals. Unconfirmed SA citizens were far more likely to die or become LTF than other patients. A similar proportion of foreign nationals (18.2%) and confirmed SA citizens (17.7%) had left care at 1 year compared with 47.0% of unconfirmed SA citizens (adjusted hazard ratio (aHR) unconfirmed SA vs confirmed SA: 2.68; 95% CI 2.42 to 2.97). By the end of follow-up, 75.5% of unconfirmed SA citizens had left care, approximately twice that of any other group.

Conclusions

Unconfirmed SA citizens were more likely to drop out of care after ART initiation than other patients. Further research is needed to determine whether this observed attrition is representative of migration and/or self-transfer to another HIV clinic as such high rates of attrition pose challenges for the success of the national ART programme.



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Survival prospects after acute myocardial infarction in the UK: a matched cohort study 1987-2011

Objectives

Estimate survival after acute myocardial infarction (AMI) in the general population aged 60 and over and the effect of recommended treatments.

Design

Cohort study in the UK with routinely collected data between January 1987 and March 2011.

Setting

310 general practices that contributed to The Health Improvement Network (THIN) database.

Participants

4 cohorts who reached the age of 60, 65, 70, or 75 years between 1987 and 2011 included 16 744, 43 528, 73 728, and 76 392 participants, respectively. Participants with a history of AMI were matched on sex, year of birth, and general practice to 3 controls each.

Outcome measures

The hazard of all-cause mortality associated with AMI was calculated by a multilevel Cox's proportional hazards regression, adjusted for sex, year of birth, socioeconomic status, angina, heart failure, other cardiovascular conditions, chronic kidney disease, diabetes, hypertension, hypercholesterolaemia, alcohol consumption, body mass index, smoking status, coronary revascularisation, prescription of β-blockers, ACE inhibitors, calcium-channel blockers, aspirin, or statins, and general practice.

Results

Compared with no history of AMI by age 60, 65, 70, or 75, having had 1 AMI was associated with an adjusted hazard of mortality of 1.80 (95% CI 1.60 to 2.02), 1.71 (1.59 to 1.84), 1.50 (1.42 to 1.59), or 1.45 (1.38 to 1.53), respectively, and having had multiple AMIs with a hazard of 1.92 (1.60 to 2.29), 1.87 (1.68 to 2.07), 1.66 (1.53 to 1.80), or 1.63 (1.51 to 1.76), respectively. Survival was better after statins (HR range across the 4 cohorts 0.74–0.81), β-blockers (0.79–0.85), or coronary revascularisation (in first 5 years) (0.72–0.80); unchanged after calcium-channel blockers (1.00–1.07); and worse after aspirin (1.05–1.10) or ACE inhibitors (1.10–1.25).

Conclusions

The hazard of death after AMI is less than reported by previous studies, and standard treatments of aspirin or ACE inhibitors prescription may be of little benefit or even cause harm.



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Sing Your Lungs Out--a community singing group for chronic obstructive pulmonary disease: a 1-year pilot study

Objective

Singing group participation may benefit patients with chronic obstructive pulmonary disease (COPD). Previous studies are limited by small numbers of participants and short duration of generally hospital-based singing group intervention. This study examines the feasibility of long-term participation in a community singing group for patients with COPD who had completed pulmonary rehabilitation (PR).

Methods

This was a feasibility cohort study. Patients with COPD who had completed PR and were enrolled in a weekly community exercise group were recruited to a new community-based singing group which met weekly for over 1 year. Measurements at baseline, 4 months and 1 year comprised comprehensive pulmonary function tests including lung volumes, 6 min walk test (6MWT), Clinical COPD Questionnaire (CCQ), Hospital Anxiety and Depression Scale (HADS) and hospital admission days for acute exacerbation of COPD (AECOPD) for 1 year before and after the first singing group session.

Findings

There were 28 participants with chronic lung disease recruited from 140 people approached. Five withdrew in the first month. 21 participants meeting Global Initiative for Chronic Obstructive Lung Disease criteria for COPD completed 4-month and 18 completed 1-year assessments. The mean attendance was 85%. For the prespecified primary outcome measure, total HADS score, difference between baseline and 12 months was –0.9, 95% CI –3.0 to 1.2, p=0.37. Of the secondary measures, a significant reduction was observed for HADS anxiety score after 1 year of –0.9 (95% CI –1.8 to –0.1) points, p=0.038 and an increase in the 6MWT at 1 year, of 65 (95% CI 35 to 99) m compared with baseline p<0.001.

Conclusions

Our findings support the feasibility of long-term participation in a community singing group for adults with COPD who have completed PR and are enrolled in a weekly community exercise group and provide evidence of improved exercise capacity and a reduction in anxiety.

Trial registration number

ACTRN12615000736549; Results.



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Estimated reductions in cardiovascular and gastric cancer disease burden through salt policies in England: an IMPACTNCD microsimulation study

Objective

To estimate the impact and equity of existing and potential UK salt reduction policies on primary prevention of cardiovascular disease (CVD) and gastric cancer (GCa) in England.

Design

A microsimulation study of a close-to-reality synthetic population. In the first period, 2003–2015, we compared the impact of current policy against a counterfactual ‘no intervention’ scenario, which assumed salt consumption persisted at 2003 levels. For 2016–2030, we assumed additional legislative policies could achieve a steeper salt decline and we compared this against the counterfactual scenario that the downward trend in salt consumption observed between 2001 and 2011 would continue up to 2030.

Setting

Synthetic population with similar characteristics to the non-institutionalised population of England.

Participants

Synthetic individuals with traits informed by the Health Survey for England.

Main measure

CVD and GCa cases and deaths prevented or postponed, stratified by fifths of socioeconomic status using the Index of Multiple Deprivation.

Results

Since 2003, current salt policies have prevented or postponed ~52 000 CVD cases (IQR: 34 000–76 000) and 10 000 CVD deaths (IQR: 3000–17 000). In addition, the current policies have prevented ~5000 new cases of GCa (IQR: 2000–7000) resulting in about 2000 fewer deaths (IQR: 0–4000). This policy did not reduce socioeconomic inequalities in CVD, and likely increased inequalities in GCa. Additional legislative policies from 2016 could further prevent or postpone ~19 000 CVD cases (IQR: 8000–30 000) and 3600 deaths by 2030 (IQR: –400–8100) and may reduce inequalities. Similarly for GCa, 1200 cases (IQR: –200–3000) and 700 deaths (IQR: –900–2300) could be prevented or postponed with a neutral impact on inequalities.

Conclusions

Current salt reduction policies are powerfully effective in reducing the CVD and GCa burdens overall but fail to reduce the inequalities involved. Additional structural policies could achieve further, more equitable health benefits.



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MyAirCoach: the use of home-monitoring and mHealth systems to predict deterioration in asthma control and the occurrence of asthma exacerbations; study protocol of an observational study

Introduction

Asthma is a variable lung condition whereby patients experience periods of controlled and uncontrolled asthma symptoms. Patients who experience prolonged periods of uncontrolled asthma have a higher incidence of exacerbations and increased morbidity and mortality rates. The ability to determine and to predict levels of asthma control and the occurrence of exacerbations is crucial in asthma management. Therefore, we aimed to determine to what extent physiological, behavioural and environmental data, obtained by mobile healthcare (mHealth) and home-monitoring sensors, as well as patient characteristics, can be used to predict episodes of uncontrolled asthma and the onset of asthma exacerbations.

Methods and analysis

In an 1-year observational study, patients will be provided with mHealth and home-monitoring systems to record daily measurements for the first-month (phase I) and weekly measurements during a follow-up period of 11 months (phase II). Our study population consists of 150 patients, aged ≥18 years, with a clinician's diagnosis of asthma, currently on controller medication, with uncontrolled asthma and/or minimally one exacerbation in the past 12 months. They will be enrolled over three participating centres, including Leiden, London and Manchester. Our main outcomes are the association between physiological, behavioural and environmental data and (1) the loss of asthma control and (2) the occurrence of asthma exacerbations.

Ethics

This study was approved by the Medical Ethics Committee of the Leiden University Medical Center in the Netherlands and by the NHS ethics service in the UK.

Trial registration number

NCT02774772.



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Impairments, activity limitations and participation restrictions experienced in the first year following a critical illness: protocol for a systematic review

Introduction

Critical illness requiring intensive care unit (ICU) management is a life-altering event with ~25% of ICU survivors experiencing persistent reductions in physical functioning, impairments in mental health, cognitive dysfunction and decreased quality of life. This constellation of problems is known as ‘postintensive care syndrome’ (PICS) and may persist for months and/or years. The purpose of this systematic review is to identify the scope and magnitude of physical problems associated with PICS during the first year after discharge from ICU, using the International Classification of Functioning, Disability and Health framework to elucidate the impairments of body functions and structures, activity limitations and participation restrictions.

Methods and analysis

Medline (Ovid), Cochrane Database of Systematic Reviews (Ovid), Cochrane Central Register of Controlled Trials (Ovid), PubMed, CINAHL (EBSCO), Web of Science and EMBASE will be systematically searched for observational studies reporting the physical impairments of body functions and structures, activity limitations and participation restrictions associated with PICS. Two reviewers will assess the articles for eligibility according to prespecified selection criteria, after which an independent reviewer will perform data extraction which will be validated by a second independent reviewer. Quality appraisal will be performed by two independent reviewers. Outcomes of the included studies will be summarised in tables and in narrative format and meta-analyses will be conducted where appropriate.

Ethics and dissemination

Formal ethical approval is not required as no primary data is collected. This systematic review will identify the scope and magnitude of physical problems associated with PICS during the first year after discharge from ICU and will be disseminated through a peer-reviewed publication and at conference meetings, to inform practice and future research on the physical problems associated with PICS.

Trial registration number

CRD42015023520.



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Job strain and the incidence of coronary heart diseases: does the association differ among occupational classes? A contribution from a pooled analysis of Northern Italian cohorts

Objectives

To assess the association between job strain (JS) and the incidence of coronary heart disease (CHD) in North Italian employed men, adopting a stratified analysis by occupational class (OC).

Methods

The study was conducted on 4103 working men, CHD-free at baseline, enrolled in population-based and factory-based cohorts. Risk factor measurements and follow-up procedures were carried out adopting the WHO MONICA standardised procedures. OCs were derived from the Erikson-Goldthorpe-Portocarero classification. JS categories were defined based on overall sample medians of psychological job demand (PJD) and decision latitude (DL) derived from items of the Job Content Questionnaire, satisfying construct validity criteria. Age-adjusted and risk factors-adjusted CHD HRs were estimated from Cox models, contrasting high-strain (high PJD and low DL) versus non-high-strain categories.

Results

In a median follow-up of 14.6 years, 172 CHD events occurred, corresponding to a CHD incidence rate of 2.78/1000 person-years. In the overall sample, high-strain compared with non-high-strain workers evidenced a 39% excess CHD risk, not statistically significant. No association was found among managers and proprietors. Conversely, the HR of high strain versus non-high strain was 1.78 (95% CI 1.20 to 2.66) among non-manual and manual workers, with no substantial differences between them. The exclusion of the events occurring in the first 3 years of follow-up did not change the results. Adopting the quadrant-term JS groupings, among manual and non-manual workers, high-strain and active (high PJD and high DL) categories in comparison to the low strain one (low PJD and high DL) showed HRs of 2.92 and 2.47, respectively.

Conclusions

Our findings support the association of JS and CHD incidence among manual and non-manual workers. The non-high strain may not be the best reference category, when assessing the contribution of JS in determining CHD incidence.



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Use and outcomes of targeted therapies in early and metastatic HER2-positive breast cancer in Australia: protocol detailing observations in a whole of population cohort

Background

The management of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has changed dramatically with the introduction and widespread use of HER2-targeted therapies. However, there is relatively limited real-world information on patterns of use, effectiveness and safety in whole of population cohorts. The research programme detailed in this protocol will generate evidence on the prescribing patterns, safety monitoring and outcomes of patients with BC treated with HER2-targeted therapies in Australia.

Methods/design

Our ongoing research programme will involve a series of retrospective cohort studies that include every patient accessing Commonwealth-funded HER2-targeted therapies for the treatment of early BC and advanced BC in Australia. At the time of writing, our cohorts consist of 11 406 patients with early BC and 5631 with advanced BC who accessed trastuzumab and lapatinib between 2001 and 2014. Pertuzumab and trastuzumab emtansine were publicly funded for metastatic BC in 2015, and future data updates will include patients accessing these medicines. We will use dispensing claims for cancer and other medicines, medical service claims and demographics data for each patient accessing HER2-targeted therapies to undertake this research.

Ethics and dissemination

Ethics approval has been granted by the Population Health Service Research Ethics Committee and data access approval has been granted by the Australian Department of Human Services (DHS) External Review Evaluation Committee. Our findings will be reported in peer-reviewed publications, conference presentations and policy forums. By providing detailed information on the use and outcomes associated with HER2-targeted therapies in a national cohort treated in routine clinical care, our research programme will better inform clinicians and patients about the real-world use of these treatments and will assist third-party payers to better understand the use and economic costs of these treatments.



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Assessing potential population impact of statin treatment for primary prevention of atherosclerotic cardiovascular diseases in the USA: population-based modelling study

Objective

New cholesterol treatment guidelines from American College of Cardiology/American Heart Association recommend statin treatment for more of US population to prevent atherosclerotic cardiovascular disease (ASCVD). It is important to assess how new guidelines may affect population-level health. This study assessed the impact of statin use for primary prevention of ASCVD under the new guidelines.

Methods

We used data from 2010 US Multiple Cause Mortality, Third National Health and Nutrition Examination Survey (NHANES III) Linked Mortality File (1988–2006, n=8941) and NHANES 2005–2010 (n=3178) participants 40–75 years of age for the present study.

Results

Among 33.0 million adults meeting new guidelines for primary prevention of ASCVD, 8.8 million were taking statins; 24.2 million, including 7.7 million with diabetes, are eligible for statin treatment. If all those with diabetes used a statin, 2514 (95% CI 592 to 4142) predicted ASCVD deaths would be prevented annually with 482 (0 to 2239) predicted annual additional cases of myopathy based on randomised clinical trials (RCTs), and 11 801 (9251 to 14 916) using population-based study. Among 16.5 million without diabetes, 5425 (1276 to 8935) ASCVD deaths would be prevented annually with 16 406 (4922 to 26 250) predicted annual additional cases of diabetes and between 1030 (0 to 4791) and 24 302 (19 363 to 30 292) additional cases of myopathy based on RCTs and population-based study. Assuming 80% eligible population take statins with 80% medication adherence, among those without diabetes, the corresponding numbers were 3472 (817 to 5718) deaths, 10 500 (3150 to 16 800) diabetes, 660 (0 to 3066) myopathy (RCTs), and 15 554 (12 392 to 19 387) myopathy (population-based). The estimated total annual cost of statins use ranged from US$1.65 to US$6.5 billion if 100% of eligible population take statins.

Conclusions

This population-based modelling study focused on impact of statin use on ASCVD mortality. Under the new guidelines, if all those eligible for primary prevention of ASCVD take statins, up to 12.6% of annual ASCVD deaths might be prevented, though additional cases of diabetes and myopathy likely occur.

Disclaimer:

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.



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IJMS, Vol. 18, Pages 246: Mblk-1 Transcription Factor Family: Its Roles in Various Animals and Regulation by NOL4 Splice Variants in Mammals

Transcription factors play critical roles in regulation of neural development and functions. A transcription factor Mblk-1 was previously reported from a screen for factors possibly important for the higher brain functions of the honeybee. This review first summarizes how Mblk-1 was identified, and then provides an overview of the studies of Mblk-1 and their homologs. Mblk-1 family proteins are found broadly in animals and are shown to affect transcription activities. Studies have revealed that the mammalian homologs can interact with several cofactors and together regulate transcription. Interestingly, a recent study using the mouse homologs, Mlr1 and Mlr2, showed that one of their cofactor proteins, NOL4, have several splice variants with different effects on the transactivation activities of Mlr proteins. These findings suggest that there is an additional layer of the regulation of Mblk-1 family proteins by cofactor splice variants and provide novel insights into our current understanding of the roles of the conserved transcription factor family.

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IJMS, Vol. 18, Pages 240: GGCX-Associated Phenotypes: An Overview in Search of Genotype-Phenotype Correlations

Gamma-carboxylation, performed by gamma-glutamyl carboxylase (GGCX), is an enzymatic process essential for activating vitamin K-dependent proteins (VKDP) with important functions in various biological processes. Mutations in the encoding GGCX gene are associated with multiple phenotypes, amongst which vitamin K-dependent coagulation factor deficiency (VKCFD1) is best known. Other patients have skin, eye, heart or bone manifestations. As genotype–phenotype correlations were never described, literature was systematically reviewed in search of patients with at least one GGCX mutation with a phenotypic description, resulting in a case series of 47 patients. Though this number was too low for statistically valid correlations—a frequent problem in orphan diseases—we demonstrate the crucial role of the horizontally transferred transmembrane domain in developing cardiac and bone manifestations. Moreover, natural history suggests ageing as the principal determinant to develop skin and eye symptoms. VKCFD1 symptoms seemed more severe in patients with both mutations in the same protein domain, though this could not be linked to a more perturbed coagulation factor function. Finally, distinct GGCX functional domains might be dedicated to carboxylation of very specific VKDP. In conclusion, this systematic review suggests that there indeed may be genotype–phenotype correlations for GGCX-related phenotypes, which can guide patient counseling and management.

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IJMS, Vol. 18, Pages 245: Identifying the Long-Term Role of Inducible Nitric Oxide Synthase after Contusive Spinal Cord Injury Using a Transgenic Mouse Model

Inducible nitric oxide synthase (iNOS) is a potent mediator of oxidative stress during neuroinflammation triggered by neurotrauma or neurodegeneration. We previously demonstrated that acute iNOS inhibition attenuated iNOS levels and promoted neuroprotection and functional recovery after spinal cord injury (SCI). The present study investigated the effects of chronic iNOS ablation after SCI using inos-null mice. iNOS−/− knockout and wild-type (WT) control mice underwent a moderate thoracic (T8) contusive SCI. Locomotor function was assessed weekly, using the Basso Mouse Scale (BMS), and at the endpoint (six weeks), by footprint analysis. At the endpoint, the volume of preserved white and gray matter, as well as the number of dorsal column axons and perilesional blood vessels rostral to the injury, were quantified. At weeks two and three after SCI, iNOS−/− mice exhibited a significant locomotor improvement compared to WT controls, although a sustained improvement was not observed during later weeks. At the endpoint, iNOS−/− mice showed significantly less preserved white and gray matter, as well as fewer dorsal column axons and perilesional blood vessels, compared to WT controls. While short-term antagonism of iNOS provides histological and functional benefits, its long-term ablation after SCI may be deleterious, blocking protective or reparative processes important for angiogenesis and tissue preservation.

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Somatic mutation profiling of hobnail variant of papillary thyroid carcinoma

Hobnail variant of papillary thyroid carcinoma (HPTC) represents a recently described, aggressive and rare group of thyroid tumors with poorly understood pathogenesis. Molecular data about this group of cancers are few, and a more detailed molecular characterization of these tumors is needed. The main objective of the study is to define a comprehensive molecular typing of HPTC. Eighteen patients affected by HPTC, including eighteen primary tumors and four lymph node metastases, were screened for NRAS, KRAS, HRAS, BRAF, TP53, PIK3CA, hTERT, PTEN, CDKN2A, EGFR, AKT1, CTNNB1 and NOTCH1 gene mutations. Sequencing is conducted on the MiSEQ system, and molecular data are compared with clinical-pathologic data and follow-up. The patients include 14 women and 4 men. Ages range from 23 to 87 years. All 18 primary tumors of HPTC showed ≥30% hobnail features. BRAF and TP53 mutations are by far the most common genetic alterations in primary HPTC (72.2% and 55.6%, respectively), followed by hTERT (44.4%), PIK3CA (27.8%), CTNNB1 (16.7%), EGFR (11.1%), AKT1 (5.5%) and NOTCH1 (5.5%). The mutational pattern in primary tumors and metastasis was usually maintained. Univariate Cox regression analyses with bootstrap procedure indicated a significantly increased mortality risk in patients harboring BRAF mutation and BRAF mutation associated with TP53 and/or PIK3CA mutations. The detection of these multiple mutations appears to allow the identification of a subset of more aggressive tumors within the group and to bear information that should be useful for prognostic stratification of these patients including the planning of adjuvant therapy.



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Corrigendum



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Issue Information



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Ultra-high-performance liquid chromatography tandem mass spectrometry determination of GHB, GHB-glucuronide in plasma and cerebrospinal fluid of narcoleptic patients under sodium oxybate treatment

Type 1 narcolepsy (NT1) is a neurological disorder caused by the loss of orexin (hypocretin) neurons in the lateral hypothalamus, probably due to an autoimmune mechanism. It is characterized by excessive daytime sleepiness (EDS) with sleep attacks, cataplexy episodes, hypnagogic hallucinations, sleep paralysis, and disturbed nighttime sleep patterns [1–4]. Cataplexy, i.e. sudden loss of muscle tone, mostly triggered by strong emotions [5] is a particularly troublesome symptom of NT1.

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PARP-1 Expression Quantified by [18F]FluorThanatrace: A Biomarker of Response to PARP Inhibition Adjuvant to Radiation Therapy

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


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Cytotoxic Effects of the Therapeutic Radionuclide Rhenium-188 Combined with Taxanes in Human Prostate Carcinoma Cell Lines

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


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Downregulation of Extracellular Matrix Metalloproteinase Inducer by scFv-M6-1B9 Intrabody Suppresses Cervical Cancer Invasion Through Inhibition of Urokinase-Type Plasminogen Activator

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


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Starting periods at a young age is linked to early menopause

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Girls who begin menstruating before their 12th birthday may be more likely to hit the menopause before age 40, and find it more difficult to have children

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The folds in your brain may be linked to how neurotic you are

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Brain scans of 500 people have revealed an association between the thickness and structure of the cortex, and how neurotic or open a person is

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Parasite turns wasp into zombie then drills through its head

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It’s Russian dolls of nature’s manipulators: a wasp that fools oak trees to make it a crypt to live in is in turn made to drill a route out of the crypt by another wasp

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Starting periods at a young age is linked to early menopause

Girls who begin menstruating before their 12th birthday may be more likely to hit the menopause before age 40, and find it more difficult to have children

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The folds in your brain may be linked to how neurotic you are

Brain scans of 500 people have revealed an association between the thickness and structure of the cortex, and how neurotic or open a person is

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Parasite turns wasp into zombie then drills through its head

It’s Russian dolls of nature’s manipulators: a wasp that fools oak trees to make it a crypt to live in is in turn made to drill a route out of the crypt by another wasp

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Ultrasonographic assessment of tonsillar volume in children

Adenotonsillar hypertrophy in children is the most common anatomical abnormality associated with obstructive sleep apnoea. Perioperative complications associated with adenotonsillectomy are more common in children with severe obstructive sleep apnoea. An objective preoperative method to determine the size of tonsils is missing. This study assessed the validity of ultrasound as a tool for measuring tonsillar size in children.

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Gender-specific determinants of asthma among U.S. adults

Asthma, a chronic respiratory disease affecting over 18.7 million American adults, has marked disparities by gender, race/ethnicity and socioeconomic status. Our goal was to identify gender-specific demographi...

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Study establishes new standard of care for pancreatic cancer patients

A combination of two chemotherapy drugs – gemcitabine and capecitabine - should be the new standard of care for pancreatic cancer patients who have had surgery to remove their tumour, according to a Cancer Research UK-funded study published in The...

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Redirecting the focus of cancer immunotherapy to premalignant conditions

Much progress has been made in introducing immunological treatment approaches for cancer, with lessons learned from both the successes and failures of immunotherapy. Among the challenges of immunotherapeutic approaches for cancer are the multitudes of mechanisms by which cancers are known to subvert the immune defenses. This has led to the incorporation into the immunotherapeutic arsenal strategies by which to overcome the cancer’s immunological blockades. What has been only superficially explored is the immunological milieu of premalignant lesions and the possibility of immunological approaches for the treatment of premalignant lesions so as to prevent secondary premalignant lesions and their progression to cancer.

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Broad spectrum antibiotic enrofloxacin modulates contact sensitivity through gut microbiota in a murine model

Antibiotic-induced dysbiosis, characterized by increased levels of Bacteroidetes, Bifidobacterium spp., Clostridium cluster XIVa and XIVab, but decreased proportions of segmented filamentous bacteria, effectively inhibits contact sensitivity by inducing a variety of regulatory cells.

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Ultra-high-performance liquid chromatography tandem mass spectrometry determination of GHB, GHB-glucuronide in plasma and cerebrospinal fluid of narcoleptic patients under sodium oxybate treatment

Type 1 narcolepsy (NT1) is a neurological disorder caused by the loss of orexin (hypocretin) neurons in the lateral hypothalamus, probably due to an autoimmune mechanism. It is characterized by excessive daytime sleepiness (EDS) with sleep attacks, cataplexy episodes, hypnagogic hallucinations, sleep paralysis, and disturbed nighttime sleep patterns [1–4]. Cataplexy, i.e. sudden loss of muscle tone, mostly triggered by strong emotions [5] is a particularly troublesome symptom of NT1.

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