Πέμπτη, 4 Μαΐου 2017

E2F1interactive with BRCA1 pathway induces HCC two different small molecule metabolism or cell cycle regulation via mitochondrion or CD4+T to cytosol

Abstract

Breast cancer 1 (BRCA1) and E2F transcription factor 1 (E2F1) are related to metabolism and cell cycle regulation. However, the corresponding mechanism is not clear in HCC. High BRCA1 direct pathway was constructed with 11 molecules from E2F1 feedback-interactive network in HCC by GRNInfer based on 39 Pearson mutual positive corelation CC >0.25 molecules with E2F1. Integration of GRNInfer with GO, KEGG, BioCarta, GNF_U133A, UNIGENE_EST, Disease, GenMAPP databases by DAVID and MAS 3.0, E2F1 feedback-interactive BRCA1 indirect mitochondrion to cytosol pathway was identified as upstream LAPTM4B activation, feedback UNG, downstream BCAT1-HIST1H2AD-TK1 reflecting protein and DNA binding with enrichment of small molecule metabolism; The corresponding BRCA1 indirect membrane to cytosol pathway as upstream CCNB2-NUSAP1 activation, feedback TTK-HIST1H2BJ-CENPF, downstream MCM4-TK1 reflecting ATP and microtubule binding with enrichment of CD4+T-related cell cycle regulation in HCC. Therefore, we propose that E2F1 interactive with BRCA1 pathway induces HCC two different small molecule metabolism or cell cycle regulation via mitochondrion or CD4+T to cytosol. Knowledge analysis demonstrates our E2F1 feedback-interactive BRCA1 pathway wide disease distribution and reflects a novel common one of tumor and cancer. This article is protected by copyright. All rights reserved



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IDH1 or - 2 mutations do not predict outcome and do not cause loss of 5-hydroxymethylcytosine or altered histone modifications in central chondrosarcomas

Abstract

Background

Mutations in isocitrate dehydrogenase (IDH)1 or -2 are found in ~50% of conventional central chondrosarcomas and in up to 87% of their assumed benign precursors enchondromas. The mutant enzyme acquires the activity to convert α-ketoglutarate into the oncometabolite d-2-hydroxyglutarate (d-2-HG), which competitively inhibits α-ketoglutarate dependent enzymes such as histone- and DNA demethylases.

Methods

We therefore evaluated the effect of IDH1 or -2 mutations on histone modifications (H3K4me3, H3K9me3 and H3K27me3), chromatin remodeler ATRX expression, DNA modifications (5-hmC and 5-mC), and TET1 subcellular localization in a genotyped cohort (IDH, succinate dehydrogenase (SDH) and fumarate hydratase (FH)) of enchondromas and central chondrosarcomas (n = 101) using immunohistochemistry.

Results

IDH1 or -2 mutations were found in 60.8% of the central cartilaginous tumours, while mutations in FH and SDH were absent. The mutation status did not correlate with outcome. Chondrosarcomas are strongly positive for the histone modifications H3K4me3, H3K9me3 and H3K27me3, which was independent of the IDH1 or -2 mutation status. Two out of 36 chondrosarcomas (5.6%) show complete loss of ATRX. Levels of 5-hmC and 5-mC are highly variable in central cartilaginous tumours and are not associated with mutation status. In tumours with loss of 5-hmC, expression of TET1 was more prominent in the cytoplasm than the nucleus (p = 0.0001).

Conclusions

In summary, in central chondrosarcoma IDH1 or -2 mutations do not affect immunohistochemical levels of 5-hmC, 5mC, trimethylation of H3K4, -K9 and K27 and outcome, as compared to wildtype.



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Histone 3.3 hotspot mutations in conventional osteosarcomas: a comprehensive clinical and molecular characterization of six H3F3A mutated cases

Abstract

Background

Histone 3.3 (H3.3) hotspot mutations in bone tumors occur in the vast majority of giant cell tumors of bone (GCTBs; 96%), chondroblastomas (95%) and in a few cases of osteosarcomas. However, clinical presentation, histopathological features, and additional molecular characteristics of H3.3 mutant osteosarcomas are largely unknown.

Methods

In this multicentre, retrospective study, a total of 106 conventional high-grade osteosarcomas, across all age groups were re-examined for hotspot mutations in the H3.3 coding genes H3F3A and H3F3B. H3.3 mutant osteosarcomas were re-evaluated in a multidisciplinary manner and analyzed for genome-wide DNA-methylation patterns and DNA copy number aberrations alongside H3.3 wild-type osteosarcomas and H3F3A G34W/L mutant GCTBs.

Results

Six osteosarcomas (6/106) carried H3F3A hotspot mutations. No mutations were found in H3F3B. All patients with H3F3A mutant osteosarcoma were older than 30 years with a median age of 65 years. Copy number aberrations that are commonly encountered in high-grade osteosarcomas also occurred in H3F3A mutant osteosarcomas. Unlike a single osteosarcoma with a H3F3A K27M mutation, the DNA methylation profiles of H3F3A G34W/R mutant osteosarcomas were clearly different from H3.3 wild-type osteosarcomas, but more closely related to GCTBs. The most differentially methylated promoters between H3F3A G34W/R mutant and H3.3 wild-type osteosarcomas were in KLLN/PTEN (p < 0.00005) and HIST1H2BB (p < 0.0005).

Conclusions

H3.3 mutations in osteosarcomas may occur in H3F3A at mutational hotspots. They are overall rare, but become more frequent in osteosarcoma patients older than 30 years. Osteosarcomas carrying H3F3A G34W/R mutations are associated with epigenetic dysregulation of KLLN/PTEN and HIST1H2BB.



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Diarrhea

Diarrhea: A common condition that involves unusually frequent and liquid bowel movements. The opposite of constipation. There are many infectious and noninfectious causes of diarrhea. Persistent diarrhea is both uncomfortable and dangerous to the health because it can indicate an underlying infection and may mean that the body is not able to absorb some nutrients due to a problem in the bowels. Treatment includes drinking plenty of fluids to prevent dehydration and taking over-the-counter remedies. People with diarrhea that persists for more than a couple days, particularly small children or elderly people, should seek medical attention.



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How Marketing Changed the Way We See Avocados

Once upon a time, Americans didn't know what to do with "alligator pears." Now we can't get enough.

-- Read more on ScientificAmerican.com
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How Marketing Changed the Way We See Avocados

Once upon a time, Americans didn't know what to do with "alligator pears." Now we can't get enough.

-- Read more on ScientificAmerican.com
feed?d=yIl2AUoC8zA feed?d=qj6IDK7rITs feed?d=l6gmwiTKsz0 feed?i=SBXJTTnQ9fE:R9CrrjunJNA:gIN9vFwOq feed?d=ZC7T4KBF6Nw feed?d=I9og5sOYxJI feed?d=QXVau8BzmBE


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Effect of Water-Extractable Arabinoxylans from Wheat Aleurone and Bran on Lipid Peroxidation and Factors Influencing their Antioxidant Capacity

Publication date: Available online 4 May 2017
Source:Bioactive Carbohydrates and Dietary Fibre
Author(s): Lovemore Nkhata Malunga, Marta Izydorczyk, Trust Beta
Dietary lipid hydroperoxides (LOOH) are implicated in the rise of colon cancers. We investigated the effect of water-extractable arabinoxylans (WEAX) on lipid peroxidation under simulated gastric conditions. Water-extractable fractions containing mostly arabinoxylans were isolated from wheat aleurone and wheat bran and fractionated by stepwise precipitation with (NH4)2SO4 at 50 and 75% saturation. LOOH concentration (121.2 ± 3.8µM/g) of grilled chicken breast muscle increased by 30%; however, it remained unaltered or decreased (≤35%) depending on type and concentration of WEAX fractions. Antioxidant capacity of WEAX fractions based on DPPH, ABTS and ORAC was 28.2 – 147.9, 91.2 – 355.3, and 185.9 – 527.5µM TE/g, respectively. The content of ferulic acid residues in WEAX fractions (R = 0.99) and relative proportions of monosubstituted xylose residues (R = 0.80) influenced the antioxidant capacity. Consumption of diets rich in feruloylated WEAX may offer protection against oxidative damage in the gastrointestinal tract.



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Nkx3.2 induces oxygen concentration-independent and lysosome-dependent degradation of HIF-1α to modulate hypoxic responses in chondrocytes

Publication date: Available online 4 May 2017
Source:Cellular Signalling
Author(s): Suhjean Im, Dae-Won Kim
Hypoxia-inducible factor 1-alpha (HIF-1α) is a DNA-binding transcription factor regulating hypoxic responses. It plays a key role in vascularization and angiogenesis as well as various metabolic pathways. Interestingly, during early phase endochondral ossification when HIF expression in chondrocytes is evident, developing cartilage primordia remains avascular until hypertrophic calcification commences. In this work, we uncovered a novel pathway causing oxygen concentration-independent and proteasome-independent degradation of HIF-1α protein. In this pathway, Nkx3.2, a chondrogenic factor, in conjunction with CHIP E3 ligase and p62/SQSTM1 adaptor, induces HIF-1α degradation via a macroautophagy pathway in a hypoxic environment. Consistent with these findings, Nkx3.2 was capable of suppressing HIF-dependent reporter gene activity as well as endogenous HIF target genes in in vitro cell culture. Furthermore, we observed that cartilage-specific Nkx3.2 overexpression in mice attenuates HIF-1α protein levels as well as vascularization in cartilage growth plates. Therefore, these results suggest that Nkx3.2-mediated HIF regulation may allow cartilage-specific avascularity under hypoxic conditions during endochondral skeleton development.

Graphical abstract

image


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The BMJ Awards 2017: Outstanding Contribution to Health

Ben Goldacre, a doctor with a visible public presence as a newspaper columnist who relished taking on quacks and charlatans, says the experience has proved valuable in his new role as a defender of...
recent?d=yIl2AUoC8zA recent?d=dnMXMwOfBR0 recent?i=FfFIXUtjKjQ:YQMMzmMnqpY:V_sGLiP recent?d=qj6IDK7rITs recent?i=FfFIXUtjKjQ:YQMMzmMnqpY:gIN9vFw recent?d=l6gmwiTKsz0 recent?d=7Q72WNTAKBA recent?i=FfFIXUtjKjQ:YQMMzmMnqpY:F7zBnMy recent?i=FfFIXUtjKjQ:YQMMzmMnqpY:-BTjWOF


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Demographics and clinical features predictive of allergic versus non-allergic rhinitis in children aged 6–18 years: A single-center experience of 1535 patients

Chronic rhinitis (CR) is one of the most common causes accounting for lost-school days, absenteeism and resource utilization in pediatric patients. Distinction between common causes of CR, allergic (AR)and non-allergic rhinitis (NAR), based upon clinical features is critical, especially in primary care settings or facilities with lack of allergen sensitivity testing, as management strategies differ considerably. The current study elucidates clinical factors, particularly facial features associated with AR and NAR using a large cohort.

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Epiglottitis as the Presenting Sign of Mucous Membranous Pemphigoid: A Case Report

Mucous membranous pemphigoid (MMP) is an autoimmune disease of the mucous membranes characterized by formation of subepithelial blisters. MMP commonly involves the ocular and oral mucosa. Laryngeal MMP is very rare, estimated as occurring in 1 of 10 million persons in the general population. It mostly affects the supraglottis, but may also involve other laryngeal sites as well as extralaryngeal areas. This report describes the clinical picture, workup to diagnosis, and differential diagnosis of an isolated epiglottic process in an elderly female who presented with isolated, long-standing, nonresolving epiglottitis, later diagnosed as MMP with epiglottal and oral involvement.

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Novel androgen receptor co-regulator GRHL2 exerts both oncogenic and anti-metastatic functions in prostate cancer

Alterations to the expression and activity of androgen receptor (AR) co-regulators in prostate cancer is an important mechanism driving disease progression and therapy resistance. Using a novel proteomic technique, we identified a new AR co-regulator, the transcription factor Grainyhead-like 2 (GRHL2), and demonstrated its essential role in the oncogenic AR signaling axis. GRHL2 colocalized with AR in prostate tumors and was frequently amplified and upregulated in prostate cancer. Importantly, GRHL2 maintained AR expression in multiple prostate cancer model systems, was required for cell proliferation, enhanced AR's transcriptional activity, and co-located with AR at specific sites on chromatin to regulate genes relevant to disease progression. GRHL2 is itself an AR-regulated gene, creating a positive feedback loop between the two factors. The link between GRHL2 and AR also applied to constitutively active truncated AR variants (ARVs), as GRHL2 interacted with and regulated ARVs and vice versa. These oncogenic functions of GRHL2 were counterbalanced by its ability to suppress epithelial-mesenchymal transition and cell invasion. Mechanistic evidence suggested that AR assisted GRHL2 in maintaining the epithelial phenotype. In summary, this study has identified a new AR co-regulator with a multifaceted role in prostate cancer, functioning as an enhancer of the oncogenic AR signaling pathway but also a suppressor of metastasis-related phenotypes.

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Oncogenic RAS regulates long non-coding RNA Orilnc1 in human cancer

RAS and its downstream cascades transmit cellular signals resulting in increased transcription of genes involved in cell growth and division. Protein-coding gene targets of RAS signaling have been characterized extensively, but long non-coding RNAs (lncRNA) regulated by these processes have not. Using a custom-designed lncRNA microarray, we identified the lncRNA Orilnc1 as a genetic target of RAS that is critical for RAS oncogenicity. Orilnc1 expression was regulated by RAS-RAF-MEK-ERK signaling via the transcription factor AP1. Orilnc1 was highly expressed in BRAF-mutant cancers such as melanoma. Silencing of Orilnc1 blocked tumor cell proliferation and growth in vitro and in vivo. Additionally, Orilnc1 blockade reduced expression of Cyclin E1 and induced G1/S cell cycle arrest in tumor cells. Taken together, our results identify Orilnc1 as a novel, non-protein mediator of RAS/RAF activation which may serve as a therapeutic target in RAS/RAF-driven cancers.

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Beta-blocker drug use and survival among patients with pancreatic adenocarcinoma

Preclinical studies have suggested that β-adrenergic signaling is involved in pancreatic cancer progression. Prompted by such studies, we investigated an association between beta-blocker drug use with improved cancer-specific survival in a large, general population-based cohort of patients with pancreatic ductal adenocarcinoma (PDAC). All patients diagnosed with a first primary PDAC in Sweden between 2006 and 2009 were identified through the Swedish Cancer Register (n=2,394). We obtained information about use of beta-blockers and other medications through linkage with the national Prescribed Drug Register. Cancer-specific mortality was assessed using the Swedish Cause of Death Register. We used multivariable Cox regression adjusted for sociodemographic factors, tumor characteristics, comorbidity score and other medications to estimate hazard ratios (HR) and 95% confidence intervals (CI) for cancer-specific mortality associated with beta-blocker use during the 90 day period before cancer diagnosis. A total of 2,054 (86%) died with pancreatic cancer recorded as the underlying cause of death during a maximum of 5 years follow-up (median 5 months). Patients who used beta-blockers (n=522) had a lower cancer-specific mortality rate than non-users (adjusted HR 0·79; 95% CI 0·70-0·90, p<0·001). This observed rate reduction was more pronounced among patients with localized disease at diagnosis (n=517; adjusted HR 0·60; 95% CI 0·43-0·83, p=0·002), especially for users with higher daily doses (HR 0·54; 95% CI 0·35-0·83, p=0·005). No clear rate differences were observed by beta-blocker receptor selectivity. Our results support the concept that beta-blocker drugs may improve the survival of PDAC patients, particularly among those with localized disease.

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Allergen-specific IgG antibodies signaling via FcγRIIb promote food tolerance

IgG:FcγRIIb ligation restrains allergic pathology and provides a handle for tolerance restoration in food allergy.

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A review of metabolomics approaches and their application in identifying causal pathways of childhood asthma

As asthma is a disease that results from host x environment interactions, an approach which allows assessment of the impact of the environment on the host is needed to understand disease. Metabolomics has appealing potential as an application to study pathways to childhood asthma development. The objective of this review is to provide an overview of metabolomics methods, and their application to understanding host x environment pathways in asthma development. We reviewed recent literature on advances in metabolomics and their application to study pathways to childhood asthma development.

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Efficacy and safety of dupilumab for the treatment of adult atopic dermatitis: A meta-analysis of randomized clinical trials



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Inflammatory phenotypes in severe asthma are associated with distinct airway microbiology

Utilizing a large, well-defined severe asthma cohort, we show that sputum neutrophilia, but not eosinophilia, was a strong predictor for airway microbiota diversity. These results highlight the divergence in pathophysiology based on asthma inflammatory phenotype.

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Glycans and Glycan-specific IgE in Clinical and Molecular Allergology - Sensitization, Diagnostics and Clinical Symptoms

Glycan-specific IgE antibodies are cross-reacting with highly similar or even identical carbohydrate structures on a variety of different natural allergens, the so-called cross-reactive carbohydrate determinants (CCDs). In clinical practice, CCDs often interfere with the specificity of in vitro allergy diagnostics, thus impairing allergy therapy decisions for individual patients. Strikingly, these IgE antibodies directed against CCD often do not cause clinically relevant allergy symptoms. Opposed to that, the IgE-binding glycan allergen galactose-α-(1,3)-galactose (α-Gal) is associated with IgE-mediated delayed anaphylaxis in meat allergy.

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Forkhead Box Protein 3 (FoxP3) Demethylation is Associated with Tolerance Induction in Peanut-Induced Intestinal Allergy

FoxP3+ T regulatory cells are significantly decreased in the jejunum and mesenteric lymph nodes following sensitization and challenge. With induction of tolerance, these numbers are increased as well as demethylation of FoxP3.

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CDC42-related genes are upregulated in helper T cells from obese asthmatic children

Pediatric obesity-related asthma is more severe and less responsive to medications than asthma in normal-weight children. Obese asthmatic children have nonatopic TH1-polarized systemic inflammation that correlates with pulmonary function deficits, but the pathways underlying TH1-polarized inflammation are not well understood.

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Cross-reactivity in Fish Allergy: A Double-Blind Placebo-Controlled Food Challenge Trial

One third of fish-allergic patients tolerate at least one fish species. Specific IgE testing can identify most patients with fish allergy and reduce the need of oral challenges in the diagnostic work-up.

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The number and affinity of productive IgE pairs determine allergen activation of mast cells

IgE composition (number and concentration of IgE pairs, IgE clonality, and IgE affinity) determines number of mast cells reacting and allergen threshold for activation and may dictate the threshold allergen dose and severity of allergy symptoms in the individual allergic patient.

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Desiccating stress worsens alkali burn injury by magnifying caspase-8-induced imbalance of NLRP3 and NLRP6

We reveal novel discoveries of an innate immune pathway mediated by the imbalanced activation of NLRP3 and NLRP6 promoted by caspase-8 activation in AB and secondary dry eye and create new intervention strategies to treat inflammatory diseases.

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Electron–Hole Symmetry Breaking in Charge Transport in Nitrogen-Doped Graphene

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b00313
ancac3?d=yIl2AUoC8zA


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Analysis of PEG Oligomers in Black Gel Inks: Discrimination and Ink Dating

The gel ink pen was first on the market of Japan in the mid 1980s [1]. Due to its smooth writing, quick drying, good color fastness and low cost, it has become a popular modern writing instrument [1–4]. Black gel inks that use carbon black as colorant, have such good color fastness that they can be written on important contracts, loan receipts or other credentials. In China, ink entries written by carbon-based black gel ink are common samples in forensic practice of questioned document examination.

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Evaluation for inherited and acquired prothrombotic defects predisposing to symptomatic thromboembolism in children with acute lymphoblastic leukemia: a protocol for a prospective, observational, cohort study

Thromboembolism (TE) is a serious complication in children with acute lymphoblastic leukemia (ALL). The incidence of symptomatic thromboembolism is as high as 14% and case fatality rate of ~15%. Further, devel...

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Clinical value of R-spondins in triple-negative and metaplastic breast cancers

Clinical value of R-spondins in triple-negative and metaplastic breast cancers

British Journal of Cancer advance online publication, May 4 2017. doi:10.1038/bjc.2017.131

Authors: F Coussy, F Lallemand, S Vacher, A Schnitzler, W Chemlali, M Caly, A Nicolas, S Richon, D Meseure, R El Botty, L De-Plater, L Fuhrmann, T Dubois, S Roman-Roman, V Dangles-Marie, E Marangoni & I Bièche



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Efficacy and safety of gemcitabine plus S-1 in pancreatic cancer: a pooled analysis of individual patient data

Efficacy and safety of gemcitabine plus S-1 in pancreatic cancer: a pooled analysis of individual patient data

British Journal of Cancer advance online publication, May 4 2017. doi:10.1038/bjc.2017.128

Authors: Chikuma Hamada, Takuji Okusaka, Takaaki Ikari, Hiroyuki Isayama, Junji Furuse, Hiroshi Ishii, Yousuke Nakai, Shogo Imai & Shota Okamura



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Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer

Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer

British Journal of Cancer advance online publication, May 4 2017. doi:10.1038/bjc.2017.132

Authors: Steffen Wagner, Claus Wittekindt, Shachi Jenny Sharma, Nora Wuerdemann, Theresa Jüttner, Miriam Reuschenbach, Elena-Sophie Prigge, Magnus von Knebel Doeberitz, Stefan Gattenlöhner, Ernst Burkhardt, Jörn Pons-Kühnemann & Jens Peter Klussmann



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One-carbon metabolism in cancer

One-carbon metabolism in cancer

British Journal of Cancer advance online publication, May 4 2017. doi:10.1038/bjc.2017.118

Authors: Alice C Newman & Oliver D K Maddocks



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Treatment decisions in metastatic colorectal cancer - beyond first and second line combination therapies

Overall survival (OS) for patients with metastatic colorectal cancer (mCRC) has markedly improved within the last 2 decades and the most recent generation of randomized clinical trials have yielded median OS durations of 30 months or longer.[1–3] Reasons for this improvement are numerous and multifactorial, although three main points are considered to be the most relevant:

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Colorectal cancer subtypes: Translation to routine clinical pathology

Colorectal cancer (CRC) is the second most common cause of cancer death in Europe [1]. Although outcomes have improved over the past decades, predominantly as a result of improvements in surgical technique and adjuvant/neo-adjuvant therapies, survival remains poor, with an overall 5-year survival of approximately 50% [2]. Therefore, there remains a need to identify characteristics pertaining to both the tumour and microenvironment which may not only guide prognosis, but also provide novel targets for adjuvant therapies.

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Treatment decisions in metastatic colorectal cancer - beyond first and second line combination therapies

Overall survival (OS) for patients with metastatic colorectal cancer (mCRC) has markedly improved within the last 2 decades and the most recent generation of randomized clinical trials have yielded median OS durations of 30 months or longer.[1–3] Reasons for this improvement are numerous and multifactorial, although three main points are considered to be the most relevant:

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Colorectal cancer subtypes: Translation to routine clinical pathology

Colorectal cancer (CRC) is the second most common cause of cancer death in Europe [1]. Although outcomes have improved over the past decades, predominantly as a result of improvements in surgical technique and adjuvant/neo-adjuvant therapies, survival remains poor, with an overall 5-year survival of approximately 50% [2]. Therefore, there remains a need to identify characteristics pertaining to both the tumour and microenvironment which may not only guide prognosis, but also provide novel targets for adjuvant therapies.

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Heterogeneity of tumor and immune cell PD-L1 expression and lymphocyte counts in surgical NSCLC samples.

Expression of PD-L1 in tumor cells and infiltrating immune cells was retrospectively analyzed in a cohort of surgically-treated non-small cell lung cancer patients. There was significant discordance of PD-L1 expression between different tumor areas, especially in the immune cell compartment. Heterogeneous PD-L1 expression represents a challenge for adequate biomarker-based selection of patients for PD-1/PD-L1-directed therapies.

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Hepatic protein phosphatase 1 regulatory subunit 3B (Ppp1r3b) promotes hepatic glycogen synthesis and thereby regulates fasting energy homeostasis [Metabolism]

Maintenance of whole-body glucose homeostasis is critical to glycemic function. Genetic variants mapping to chromosome 8p23.1 in genome-wide association studies have been linked to glycemic traits in humans. The gene of known function closest to the mapped region, PPP1R3B (protein phosphatase 1 regulatory subunit 3B), encodes a protein (GL) that regulates glycogen metabolism in the liver. We therefore sought to test the hypothesis that hepatic PPP1R3B is associated with glycemic traits. We generated mice with either liver-specific deletion (Ppp1r3bΔhep) or liver-specific overexpression of Ppp1r3b. The Ppp1r3b deletion significantly reduced glycogen synthase protein abundance, and the remaining protein was predominantly phosphorylated and inactive. As a consequence, glucose incorporation into hepatic glycogen was significantly impaired, total hepatic glycogen content was substantially decreased, and mice lacking hepatic Ppp1r3b had lower fasting plasma glucose than controls. The concomitant loss of liver glycogen impaired whole-body glucose homeostasis and increased hepatic expression of glycolytic enzymes in Ppp1r3bΔhep mice relative to controls in the postprandial state. Eight hours of fasting significantly increased the expression of two critical gluconeogenic enzymes, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6PC), above the levels in control livers. Conversely, the liver-specific overexpression of Ppp1r3b enhanced hepatic glycogen storage above that of controls and, as a result, delayed the onset of fasting-induced hypoglycemia. Moreover, mice overexpressing hepatic Ppp1r3b upon long-term fasting (12-36 hrs) were protected from blood ketone-body accumulation unlike control and Ppp1r3bΔhep mice. These findings indicate a major role for Ppp1r3b in regulating hepatic glycogen stores and whole-body glucose/energy homeostasis.

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Antagonistic regulation of cell cycle and differentiation gene programs in neonatal cardiomyocytes by homologous MEF2 transcription factors [Genomics and Proteomics]

Cardiomyocytes acquire their primary specialized function (contraction) prior to exiting the cell cycle. Proliferation and differentiation must be precisely coordinated for proper cardiac morphogenesis. Here, we have investigated the complex transcriptional mechanisms employed by cardiomyocytes to coordinate antagonistic cell cycle and differentiation gene programs through the molecular dissection of the core cardiac transcription factor, MEF2. Knockdown of individual MEF2 proteins, MEF2A, C, and D, in primary neonatal cardiomyocytes resulted in radically distinct and opposite effects on cellular homeostasis and gene regulation. MEF2A and MEF2D were absolutely required for cardiomyocyte survival whereas MEF2C, despite its major role in cardiac morphogenesis and direct reprogramming, was dispensable for this process. Inhibition of MEF2A or D also resulted in the activation of cell cycle genes and downregulation of markers of terminal differentiation. In striking contrast, the regulation of cell cycle and differentiation gene programs by MEF2C were antagonistic to that of MEF2A and D. Computational analysis of regulatory regions from MEF2 isoform-dependent gene sets identified the Notch and Hedgehog signaling pathways as key determinants in coordinating MEF2 isoform-specific control of antagonistic gene programs. These results reveal that mammalian MEF2 family members have distinct transcriptional functions in cardiomyocytes, and suggest that these differences are critical for proper development and maturation of the heart. Analysis of MEF2 isoform-specific function in neonatal cardiomyocytes has yielded insight into an unexpected transcriptional regulatory mechanism by which these specialized cells utilize homologous members of a core cardiac transcription factor to coordinate cell cycle and differentiation gene programs.

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Expression, Purification, and Spectral Tuning of RhoGC, a Retinylidene/Guanylyl Cyclase Fusion Protein and Optogenetics Tool from the Aquatic Fungus Blastocladiella emersonii [Membrane Biology]

RhoGC is a rhodopsin (Rho)-guanylyl cyclase (GC) gene fusion molecule that is central to zoospore phototaxis in the aquatic fungus Blastocladiella emersonii. It has generated considerable excitement because of its demonstrated potential as a tool for optogenetic manipulation of cell-signaling pathways involving cyclic nucleotides. However, a reliable method for expressing and purifying RhoGC is currently lacking. We present here an expression and purification system for isolation of the full-length RhoGC protein expressed in HEK293 cells in detergent solution. The protein exhibits robust light-dependent guanylyl cyclase activity, while a truncated form lacking the 17-20 kDa N-terminal domain is completely inactive under identical conditions. Moreover, we designed several RhoGC mutants to increase the utility of the protein for optogenetic studies. The first class we generated has altered absorption spectra designed for selective activation by different wavelengths of light. Two mutants were created with blue-shifted (E254D, λmax = 390 nm and D380N, λmax = 506 nm) and one with red-shifted (D380E, λmax = 533 nm) absorption maxima relative to the wild-type protein (λmax = 527 nm). We also engineered a double mutant, E497K/C566D, which changes the enzyme to a specific, light-stimulated adenylyl cyclase that catalyzes the formation of cAMP from ATP. We anticipate that this expression/purification system and these RhoGC mutants will facilitate mechanistic and structural exploration of this important enzyme.

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An engineered cyclic peptide alleviates symptoms of inflammation in a murine model of inflammatory bowel disease [Protein Structure and Folding]

Inflammatory bowel diseases (IBDs) are a set of complex and debilitating diseases, for which there is no satisfactory treatment. Recent studies have shown that small peptides show promise for reducing inflammation in models of IBD. However, these small peptides are likely to be unstable and rapidly cleared from the circulation, and therefore, if not modified for better stability, represent non-viable drug leads. We hypothesized that improving the stability of these peptides by grafting them into a stable cyclic peptide scaffold may enhance their therapeutic potential. Using this approach, we have designed a novel cyclic peptide, which comprises a small bioactive peptide from the annexin A1 protein grafted into a sunflower trypsin inhibitor cyclic scaffold. We used native chemical ligation to synthesize the grafted cyclic peptide. This engineered cyclic peptide maintained the overall fold of the naturally occurring cyclic peptide, was more effective at reducing inflammation in a mouse model of acute colitis than the bioactive peptide alone, and showed enhanced stability in human serum. Our findings suggest that the use of cyclic peptides as structural backbones offers a promising approach for the treatment of IBD and potentially other chronic inflammatory conditions.

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Screening for Specific Language Impairment in Preschool Children: Evaluating a Screening Procedure Including the Token Test

Abstract

Specific language impairment (SLI) comprises impairments in receptive and/or expressive language. Aim of this study was to evaluate a screening for SLI. 61 children with SLI (SLI-children, age-range 4–6 years) and 61 matched typically developing controls were tested for receptive language ability (Token Test—TT) and for intelligence (Wechsler Preschool-and-Primary-Scale-of-Intelligence—WPPSI). Group differences were analyzed using t tests, as well as direct and stepwise discriminant analyses. The predictive value of the WPPSI with respect to TT performance was analyzed using regression analyses. SLI-children performed significantly worse on both TT and WPPSI ( \(p \le .0001\) ). The TT alone yielded an overall classification rate of 79%, the TT and the WPPSI together yielded an overall classification rate of 80%. TT performance was significantly predicted by verbal intelligence in SLI-children and nonverbal intelligence in controls whilst WPPSI subtest arithmetic was predictive in both groups. Without further research, the Token Test cannot be seen as a valid and sufficient tool for the screening of SLI in preschool children but rather as a tool for the assessment of more general intellectual capacities. SLI-children at this age already show impairments typically associated with SLI which indicates the necessity of early developmental support or training. Token Test performance is possibly an indicator for a more general developmental factor rather than an exclusive indicator for language difficulties.



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Fracture Healing and Imaging Evaluation

Abstract

Purpose of Review

This article reviews current fracture healing concepts to help radiologists understand what constitutes fracture healing, image fractures most effectively, and recognize complications.

Recent Findings

Ongoing bone biology research is leading to greater understanding of fracture healing mechanisms and potential therapies. Also recent work has attempted to scientifically validate fracture healing criteria, while technological imaging advances provide better tools for evaluating fracture healing and diagnosing fracture complications.

Summary

A greater understanding of fracture healing impacts imaging and treatment strategies. Radiography remains essential in follow-up care but can be supplemented by several imaging techniques when complications arise.



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The BMJ Awards 2017: Outstanding Contribution to Health

Ben Goldacre, a doctor with a visible public presence as a newspaper columnist who relished taking on quacks and charlatans, says the experience has proved valuable in his new role as a defender of...
recent?d=yIl2AUoC8zA recent?d=dnMXMwOfBR0 recent?i=FfFIXUtjKjQ:YQMMzmMnqpY:V_sGLiP recent?d=qj6IDK7rITs recent?i=FfFIXUtjKjQ:YQMMzmMnqpY:gIN9vFw recent?d=l6gmwiTKsz0 recent?d=7Q72WNTAKBA recent?i=FfFIXUtjKjQ:YQMMzmMnqpY:F7zBnMy recent?i=FfFIXUtjKjQ:YQMMzmMnqpY:-BTjWOF


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Sex differences in the association between area deprivation and generalised anxiety disorder: British population study

Objective

Studies have shown that area-level deprivation measured by factors, such as non-home ownership, non-car ownership and household overcrowding, can increase the risk for mental disorders over and above individual-level circumstances, such as education and social class. Whether area-level deprivation is associated with generalised anxiety disorder (GAD) independent of personal circumstances, and whether this association is different between British women and men is unknown.

Design

Large, population study.

Setting

UK population-based cohort.

Participants

30 445 people from the general population aged 40 years and older and living in England consented to participate at study baseline, and of these, 21 921 participants completed a structured health and lifestyle questionnaire used to capture GAD. Area deprivation was measured in 1991 using Census data, and GAD was assessed in 1996–2000. 10 275 women and 8219 men had complete data on all covariates.

Main outcome measure

Past-year GAD defined according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV).

Results

In this study, 2.5% (261/10 275) of women and 1.8% (145/8219) of men had GAD. Women living in the most deprived areas were over 60% more likely to develop anxiety than those living in areas that were not deprived (OR=1.63, 95% CI 1.21 to 2.21; p=0.001), but this association between deprivation and GAD was not apparent in men (OR=1.13, 95% CI 0.72 to 1.77; p=0.598).

Conclusions

The absolute numbers of people living in deprived conditions are large worldwide. This, combined with a growing mental health burden, means that the findings obtained in this study remain highly relevant. The WHO has emphasised the need to reduce social and health inequalities. Our findings provide a strong evidence base to this call, showing that the environment needs to be taken into account when developing mental health policy; gender is important when it comes to assessing the influence of the environment on our mental health.



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Reliability and validity of the SF-36 Health Survey Questionnaire in patients with brain tumors: a cross-sectional study

Deterioration of health related quality of life (HRQoL) is common in brain tumor patients. This study evaluated validity and reliability of the Medical Outcomes Study 36-Item Short Form (SF-36) in patients wit...

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Reliability analysis of the Chinese version of the Functional Assessment of Cancer Therapy – Leukemia (FACT-Leu) scale based on multivariate generalizability theory

The Functional Assessment of Cancer Therapy–Leukemia (FACT-Leu) scale, a leukemia-specific instrument for determining the health-related quality of life (HRQOL) in patients with leukemia, had been developed an...

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Current Views on the Interval Between Neoadjuvant Chemoradiation and Surgery for Rectal Cancer

Abstract

Neoadjuvant chemoradiation (CRT) has been established as standard treatment for stage II and III rectal cancer, and delayed interval between CRT and rectal resection has emerged as appropriate treatment due to the marked benefits associated with this approach. Despite favorable findings on downstaging and pathological complete response without increasing in morbidity and mortality, no significant improvement in sphincter preservation rate and rectal cancer overall survival has been observed with the current recommended 6–8-week interval. Trials are currently underway and may provide answers regarding the optimal interval between CRT and surgical resection, but until now, the best interval between CRT and surgery remains unclear.



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Targeting Multiple Myeloma Cancer Stem Cells with Natural Products – Lessons from Other Hematological Malignancies

10-1055-s-0043-109558_pmb0172-1.jpg

Planta Med
DOI: 10.1055/s-0043-109558

Multiple myeloma is characterized by the accumulation of malignant plasma cells in the bone marrow. Multiple myeloma is the second most frequently diagnosed hematological malignancy, predominantly affecting the elderly. Despite recent advances in the development of novel therapies, multiple myeloma remains an incurable malignancy where the majority of patients relapse, develop resistance, and eventually die from the disease. This has been attributed to the fact that conventional therapy currently in use targets mainly the bulk of tumor cells, but not the tumor-initiating cancer stem cells. Cancer stem cells are a highly resistant subpopulation of cells believed to be responsible for the initiation, progression, metastasis, and relapse of cancer. Enormous efforts have been invested in the characterization of cancer stem cells. These efforts led to the characterization of key cellular signaling pathways responsible for conferring stem cell characteristics including self-renewal, differentiation, migratory, survival, and intracellular detoxification capabilities. Targeting these protective mechanisms offers a valuable strategy that may help combat a major driving force behind cancers. The use of natural products offers a promising therapeutic approach for targeting cancer stem cells. In this review, recent advances achieved in the characterization of cancer stem cells derived from hematological malignancies, with a particular focus on multiple myeloma, are discussed and major natural products that target cancer stem cells are presented. As natural products remain an essential source of novel chemical structures and medicinal leads, the exploitation of this immense reservoir is used to draw lessons in targeting multiple myeloma-cancer stem cells.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text



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Denudatin A, a Dimeric Acylphloroglucinol from Hypericum denudatum Presents an Antinociceptive Effect in Mice

10-1055-s-0043-109567_pmb0082-1.jpg

Planta Med
DOI: 10.1055/s-0043-109567

A new dimeric acylphloroglucinol, denudatin A (1), was isolated from the flowering aerials parts of Hypericum denudatum, along with the known phloroglucinols selancin A (2), hyperbrasilol A (3), uliginosin B (4), and isouliginosin B (5). The structure of 1 was elucidated using 1D, 2D NMR, and MS experiments, and by comparison with previously reported data for Hypericum dimeric acylphloroglucinols. Denudatin A (1) and selancin A (2) were administered orally to mice displaying antinociceptive activity in the hot plate test. The compounds did not induce motor impairment in the rotarod apparatus.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text



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Prediction of Permeation and Cellular Transport of Silybum marianum Extract Formulated in a Nanoemulsion by Using PAMPA and Caco-2 Cell Models

10-1055-s-0043-110052_pmb0077-1.jpg

Planta Med
DOI: 10.1055/s-0043-110052

The present study explores the potential of nanoemulsion, a lipid drug delivery system, to improve solubility and oral absorption of Silybum marianum extract. The optimized formulation contained 40 mg/mL of commercial extract (4 % w/w) and it was composed of 2.5 g labrasol (20 %) as the oil phase, 1.5 g cremophor EL as the surfactant, and 1 g labrafil as the cosurfactant (mixture surfactant/cosurfactant, 20 %).The system was characterized by dynamic light scattering, transmission electron microscopy, and HPLC-DAD analyses in order to evaluate size, homogeneity, morphology, and encapsulation efficiency. Physical and chemical stabilities were assessed during 40 days at 4 °C and 3 months at 25 °C. Stability in simulated gastric fluid followed by simulated intestinal conditions was also considered. In vitro permeation studies were performed to determine the suitability of the prepared nanoemulsion for oral delivery. Different models such as the parallel artificial membrane permeability assay and Caco-2 cell lines were applied.The nanoemulsion showed a good solubilizing effect of the extract, with a pronounced action also on its permeability, in respect to a saturated aqueous solution. The Caco-2 test confirmed the parallel artificial membrane permeability assay results and they revealed the suitability of the prepared nanoemulsion for oral delivery.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text



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Diterpene Lipo-Alkaloids with Selective Activities on Cardiac K+ Channels

10-1055-s-0043-109556_pmb0144-1.jpg

Planta Med
DOI: 10.1055/s-0043-109556

Aconitum diterpene alkaloids are known for their remarkable toxicity, which is due to their effect on ion channels. Activation of voltage-gated Na+ channels is the major cause of their cardiotoxicity, however, influence on K+ channels may also play a role in the overall effect.Here we report the synthesis of a series of lipo-alkaloids, including four new compounds, based on the 14-benzoylaconine structure, which is the core of a vast number of diterpene alkaloids naturally occurring in Aconitum species. The activities of these compounds were measured in vitro on K+ ion channels using the whole-cell patch-clamp technique. Structure-activity analysis was carried out based on the data of 51 compounds (32 genuine diterpene alkaloids, 5 fatty acids, and 14 lipo-alkaloids). Depending on their substitution, these compounds exert different activities on GIRK (G protein-coupled inwardly-rectifying potassium channel) and hERG (human ether-à-go-go-related gene) channels. Fatty acids and diterpene alkaloids show lower activity on the GIRK channel than lipo-alkaloids. Lipo-alkaloids also have less pronounced hERG inhibitory activity compared to the cardiotoxic aconitine. Considering the GIRK/hERG selectivity as an indicator of perspective therapeutic applicability, lipo-alkaloids are significantly more selective than the genuine diterpene alkaloids. 14-Benzoyl-8-O-eicosa-8Z,11Z,14Z-trienoate and 14-benzoyl-8-O-eicosa-11Z,14Z,17Z-trienoate are strong and selective inhibitors of GIRK channels, thus, they are promising subjects for further studies to develop diterpene alkaloid-based antiarrhythmic pharmacons.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text



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Experimental approach to IGF-1 therapy in CCl4-induced acute liver damage in healthy controls and mice with partial IGF-1 deficiency

Cell necrosis, oxidative damage, and fibrogenesis are involved in cirrhosis development, a condition in which insulin-like growth factor 1 (IGF-1) levels are diminished. This study evaluates whether the exogen...

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Distinct gene expression profiles associated with Notch ligands Delta-like 4 and Jagged1 in plaque material from peripheral artery disease patients: a pilot study

The lack of early diagnosis, progression markers and effective pharmacological treatment has dramatic unfavourable effects on clinical outcomes in patients with peripheral artery disease (PAD). Addressing thes...

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Lost benefits and carbon uptake by protection of Indian plantations

Abstract

There is a range of problems in assessing how protection of a specific forest to Reduce Emissions from Deforestation and forest Degradation (REDD+) affect global emissions of greenhouse gases. This paper shows how knowledge and information about the biophysical characteristics of forests can be combined with theories of forest management and economic behaviour to derive the impacts on global emissions of REDD+. A modelling experiment from India, where 10% of the forest plantations in eight different regions are protected, shows that the biophysical characteristics of forests are decisive for the global impacts on emissions. In regions with slow-growing forests, agents in the non-protected forests are able to increase their output significantly to fill the demand from the protected forests. This opportunity is strictly limited in regions with fast-growing forests. Therefore, prices increase far more in regions with fast-growing forests than in slow-growing forests. Over time, the markets for Indian forestry products contribute to reduce the resulting price differences across regions. When the carbon uptake from protected forests approaches zero, the leakage of emissions to other Indian forests is between 20 and 40%. Only a small part of this is international leakage. Combining different models also helps to identify knowledge gaps, and to distinguish gaps that potentially may be filled with data and new knowledge, and gaps due to different angling of modelling biophysical processes and modelling of economic behaviour.



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Clinical value of R-spondins in triple-negative and metaplastic breast cancers



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One-carbon metabolism in cancer



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Efficacy and safety of gemcitabine plus S-1 in pancreatic cancer: a pooled analysis of individual patient data



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Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer



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[Editorial] The next chapter in malaria eradication

The narrative around combating malaria has long been equal parts optimism and pessimism. Remarkably, it was only a decade ago that Bill and Melinda Gates made the game-changing call for the eradication of malaria. Previous control efforts to reduce the burden, particularly in low-resource, malaria-endemic countries in sub-Saharan Africa, were limited by poor access to tools such as insecticide-treated nets, and faced rapidly drug-resistant strains of the highly lethal Plasmodium falciparum parasite requiring treatment with costly artemisinin-combination therapies.

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[Editorial] An ounce of prevention

The Robert Wood Johnson Foundation has released its fourth annual National Health Security Preparedness Index report for the USA, and while there is slow improvement, the results still contain warnings for the state of health security in the USA. The index uses over 200 individual measures across six domains. They range from incident and information management to environmental and occupational health, in order to take a snapshot of the state of preparedness for a health crisis; from an outbreak of expanding infectious diseases, such as Zika or a severe influenza outbreak, to climate-change-fuelled floods and droughts that might displace large numbers of people.

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[Correspondence] Mortality decrease according to socioeconomic groups

In their Article, Enrique Regidor and colleagues (Nov 26, p 2642)1 conclude that “In Spain, probably due to the decrease in exposure to risk factors, all-cause mortality decreased more during the economic crisis than before the economic crisis, especially in low socioeconomic groups”. This statement is misleading from both a methodological and conceptual perspective.

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[Correspondence] Mortality decrease according to socioeconomic groups

Enrique Regidor and colleagues' Article1 analysed the effect of the economic crisis in Spain on age-adjusted mortality for different socioeconomic groups. We wish to point out that the results are consistent with a hypothesis of no difference between people of different socioeconomic groups, despite the authors' conclusions.

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[Correspondence] Mortality decrease according to socioeconomic groups – Authors' reply

Samuel Watson and Richard Lilford point out that the economic crisis in Spain might have caused households to downsize or to sell a car. If that was the case, people in those households would have had reduced exposure to the risk of traffic accidents and might also have greatly reduced their exposure to life-threatening lifestyles, such as smoking or alcohol consumption, because of the need to use their scarce financial resources to meet basic needs. The expected effect would not only be a reduction in mortality in low socioeconomic groups, but also an increased annual percentage reduction in mortality during the crisis in these groups.

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[World Report] Health care in Turkey in the Erdogan era

In 2013, The Lancet reviewed the trajectory of Turkey's health systems reforms.

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[Obituary] Alexis Shelokov

Physician scientist specialising in infectious disease. He was born in Harbin, China, on Oct 18, 1919, and died with aplastic anaemia in Dallas, TX, USA, on Dec 16, 2016, aged 97 years.

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[Comment] The prescribing cascade revisited

A prescribing cascade begins when a drug is prescribed, an adverse drug event occurs that is misinterpreted as a new medical condition, and a subsequent drug is prescribed to treat this drug-induced adverse event (figure). We first described the idea of a prescribing cascade in The Lancet in 1995,1 and expanded on this concept in The BMJ in 1997.2 The identification and interruption of prescribing cascades is an important, actionable, and underappreciated opportunity to improve medication safety in older people.

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[Perspectives] The other face of honour

In his Odes, the poet Horace wrote “Dulce et decorum est pro patria mori”. (sweet and honourable it is to die for one's country). Yet there are many soldiers who do not die an “honourable” death, and return from war deeply scarred both psychologically and physically. That is what happens to Jess, the lead character of Ugly Lies the Bone, a play written by Lyndsey Ferrentino and directed by Indhu Rubasingham at the National Theatre in London.

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[Comment] Making sense of polycystic kidney disease

The term polycystic kidneys was first coined by Felix Lejars in 1888 to describe the clinical signs of bulky kidneys following earlier anatomical and pathological descriptions. Polycystic kidney disease (PKD) is now known to encompass not only the autosomal dominant form (ADPKD) but also includes many rare forms. Since the work of Lejars and his contemporaries, the pathogenesis of PKD has continued to provoke much debate and study.1

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[World Report] Frontline: Providing care in the midst of the Syrian crisis

Robert Mardini is the International Committee of the Red Cross' (ICRC's) Director for the Middle East.

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[Comment] Offline: Is the NHS in crisis?

The most commonly used word in the political lexicon today is “crisis”. A crisis demands our attention now. It necessitates action now. At the London School of Hygiene and Tropical Medicine last week, four speakers gathered to answer the question, “Is the NHS in crisis?” As the UK accelerates its way through an election campaign, the second most important concern among voters (after Brexit) is the National Health Service (NHS). It is just possible the NHS may emerge as a decisive issue before June 8, polling day.

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[Perspectives] Admissions and exits

He is vain, angry, self-important, and has sagging, elderly buttocks: Henry Marsh tells us this about himself in his new book Admissions: A Life In Brain Surgery—honest to the point of brutal. This is the life and times of a famous neurosurgeon, entering retirement, who at once seems to be delighted by his renown but also despises it. Marsh names people that he has bitterly fallen out with; shamefully documents how he pulled the nose of a nurse over a dispute about a nasogastric tube; describes his own treatment by a psychiatrist; spells out his guilty mistakes in operating; and describes how, if terminally ill, he would regard palliative care specialists as professionals who “derive their own sense of meaning and purpose from my suffering”.

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[World Report] Concern over India's move to cut funds for PHFI

A cancellation notice from the government to prevent the Public Health Foundation of India from receiving funding from foreign donors raises concerns. Dinesh C Sharma reports.

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[Perspectives] The Anatomy of Melancholy revisited

Dr Samuel Johnson struggled to get out of bed in the morning. This was a symptom of what he called his “black dog”—the depression of which he wrote one of the most memorable of all descriptions in a letter to Hester Thrale in 1783: “When I rise my breakfast is solitary, the black dog waits to share it, from breakfast to dinner he continues barking…After dinner what remains but to count the clock, and hope for that sleep which I can scarce expect.” But, according to his devoted biographer James Boswell, there was one book that gave Johnson the will to get up early: “Burton's Anatomy of Melancholy, he said, was the only book that ever took him out of bed two hours sooner than he wished to rise.” Johnson also gave Boswell, who himself suffered from severe bouts of depression, a valuable piece of advice from Burton: “The great direction which Burton has left to men disordered like you, is this, Be not solitary; be not idle.” He added that the advice should be modified to the effect that those of an idle disposition should not be solitary and those who are solitary should not be idle.

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[Correspondence] Who is responsible for the health care of refugees?

We share in this Correspondence our reflections from our involvement in a medical mission in Greece, and highlight the need for global collaboration to improve health care for refugees.

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Downregulation of ATP1A1 promotes cancer development in renal cell carcinoma

Abstract

Background

Aberrant expression of Na+/K+-ATPase α1 subunit (ATP1A1) is widely observed in multiple types of tumors, and its tissue-specific expression relates to cancer development. However, the functions and molecular mechanisms in renal cell carcinoma (RCC) are not fully understood.

Methods

We investigated the ATP1A1 expression changes and possible roles in RCC through a quantitative proteomic approach and an integrative biochemical assessment. We detected ATP1A1 in RCC with LC–MS/MS, and further validated its expression with immunohistochemical analyses of 80 pairs of the RCC tumor and non-tumor tissues samples. The association of ATP1A1 expression with RCC pathology was statistically analyzed. Cell proliferation, migration and apoptosis were measured by CCK-8, boyden chamber assay and flow cytometry, respectively. The production of reactive oxygen species (ROS) was labeled with a single staining using a commercial kit, and was further detected with flow cytometry.

Results

The ATP1A1 shows a significantly decreased expression in human RCC tissues than in the adjacent non-tumor tissues. The RCC patients with ATP1A1-positive expression exhibit longer overall survival time than the ATP1A1-negative patients. The exogenous overexpression of ATP1A1 inhibits RCC cell proliferation and cell migration by increasing the production of ROS. In addition, ATP1A1-mediated Raf/MEK/ERK signaling pathway is suppressed in RCC cells, indicating the possible occurrence of induced cell apoptosis.

Conclusions

Our in vitro and in vivo data of ATP1A1 inhibitory roles in RCC progression suggest that ATP1A1 is a potential novel suppressor protein for renal cancer.



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Evaluation of the Case–Crossover (CCO) Study Design for Adverse Drug Event Detection

Abstract

Introduction

The case–crossover (CCO) design was originally intended to study exposures characterized as intermittent with acute effects. The performance of the CCO design is not well characterized under alternative exposure and outcome relationships.

Objective

The purpose of this study was to evaluate the ability of the CCO to identify simulated treatment effects under different drug exposures and outcomes relationships while varying the duration of the 1:1 matched risk and control windows.

Methods

The simulated data were obtained from the Observational Medical Dataset Simulator, version 2 (OSIM2). The area under the receiver operator characteristic curve (AUC) was calculated to compare CCO performance across outcome types, simulated relative risk (RR), and duration of risk and control windows.

Results

The AUC for acute outcomes was higher for shorter risk and control windows and improved with higher simulated RR. For example, the AUC for the simulated RR of 4 was 0.95 for a 30-day window length and 0.78 for a 360-day window length. The AUC for the accumulative outcomes increased with longer risk and control windows and stronger simulated RR. For example, the AUC for the simulated RR of 4 was 0.85 for a 360-day window length and 0.23 for a 30-day window length. Risk and control window lengths did not appear to sufficiently alter the AUC for insidious onset outcomes.

Conclusions

The CCO performed best for acute-onset outcomes, but may be useful for exploring adverse outcomes with accumulative effects. Careful consideration must be given to the hypothesized drug exposure and outcome distribution because specification of risk and control window duration affects CCO performance.



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What are the prospects for citizen science in agriculture? Evidence from three continents on motivation and mobile telephone use of resource-poor farmers

by Eskender Beza, Jonathan Steinke, Jacob van Etten, Pytrik Reidsma, Carlo Fadda, Sarika Mittra, Prem Mathur, Lammert Kooistra

As the sustainability of agricultural citizen science projects depends on volunteer farmers who contribute their time, energy and skills, understanding their motivation is important to attract and retain participants in citizen science projects. The objectives of this study were to assess 1) farmers’ motivations to participate as citizen scientists and 2) farmers’ mobile telephone usage. Building on motivational factors identified from previous citizen science studies, a questionnaire based methodology was developed which allowed the analysis of motivational factors and their relation to farmers’ characteristics. The questionnaire was applied in three communities of farmers, in countries from different continents, participating as citizen scientists. We used statistical tests to compare motivational factors within and among the three countries. In addition, the relations between motivational factors and farmers characteristics were assessed. Lastly, Principal Component Analysis (PCA) was used to group farmers based on their motivations. Although there was an overlap between the types of motivations, for Indian farmers a collectivistic type of motivation (i.e., contribute to scientific research) was more important than egoistic and altruistic motivations. For Ethiopian and Honduran farmers an egoistic intrinsic type of motivation (i.e., interest in sharing information) was most important. While fun has appeared to be an important egoistic intrinsic factor to participate in other citizen science projects, the smallholder farmers involved in this research valued ‘passing free time’ the lowest. Two major groups of farmers were distinguished: one motivated by sharing information (egoistic intrinsic), helping (altruism) and contribute to scientific research (collectivistic) and one motivated by egoistic extrinsic factors (expectation, expert interaction and community interaction). Country and education level were the two most important farmers’ characteristics that explain around 20% of the variation in farmers motivations. For educated farmers, contributing to scientific research was a more important motivation to participate as citizen scientists compared to less educated farmers. We conclude that motivations to participate in citizen science are different for smallholders in agriculture compared to other sectors. Citizen science does have high potential, but easy to use mechanisms are needed. Moreover, gamification may increase the egoistic intrinsic motivation of farmers.

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Characteristics and timing of recurrence during postoperative surveillance after curative resection for lung adenocarcinoma

Abstract

Purpose

To establish the most effective methods of postoperative surveillance to detect early recurrence of lung adenocarcinoma.

Methods

The subjects of this retrospective study were 485 patients with p-stage I–III lung adenocarcinoma, who underwent postoperative surveillance. We examined the sites and detection modes of recurrence and calculated the recurrence-free probabilities. Patients with stage I disease were divided into low- and high-risk recurrence groups using a risk score calculated by assigning points proportional to risk factor regression coefficients.

Results

Of the 112 patients with recurrence, 86 had intrathoracic recurrence. Routine computed tomography (CT) revealed recurrence in 60 patients. The recurrence-free probability curves showed that 95% of recurrences were identified within the first 4 years after resection in patients with stage II/III disease. In patients with stage I disease, the predictors of recurrence included male sex, positive pleural lavage cytology, moderate-to-poor differentiation, and visceral pleural invasion. Postoperative recurrences were detected throughout the follow-up period in the high-risk group.

Conclusions

Routine chest CT plays an important role in the postoperative surveillance of lung adenocarcinoma. We recommend intensive follow-up during the early post-resection period for patients with advanced stage disease and long-term follow-up for high-risk patients with stage I disease.



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Republican-led US House votes to repeal Affordable Care Act

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The bill now needs to be debated in the Senate, but could cost millions of people their health insurance if it passes

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Acute kidney injury in the ICU: from injury to recovery: reports from the 5th Paris International Conference

The French Intensive Care Society organized its yearly Paris International Conference in intensive care on June 18–19, 2015. The main purpose of this meeting is to gather the best experts in the field in order...

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Binding time: Evidence for integration of temporal stimulus features

Abstract

Several lines of evidence suggest that during processing of events, the features of these events become connected via episodic bindings. Such bindings have been demonstrated for a large number of visual and auditory stimulus features, like color and orientation, or pitch and loudness. Importantly, most visual and auditory events typically also involve temporal features, like onset time or duration. So far, however, whether temporal stimulus features are also bound into event representations has never been tested directly. The aim of the present study was to investigate possible binding between stimulus duration and other features of auditory events. In Experiment 1, participants had to respond with two keys to a low or high pitch sinus tone. Critically, the tones were presented with two different presentation durations. Sequential analysis of RT data indicated binding of stimulus duration into the event representation: at pitch repetitions, performance was better when both pitch and duration repeated, relative to when only pitch repeated and duration switched. This finding was replicated with loudness as relevant stimulus feature in Experiment 2. In sum, the results demonstrate that temporal features are bound into auditory event representations. This finding is an important advancement for binding theory in general, and raises several new questions for future research.



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The open-object illusion: size perception is greatly influenced by object boundaries

Abstract

This study presents a new powerful visual illusion, in which simple "open" objects—ones with missing boundaries—are perceived as bigger than the same size, fully "closed" objects. In a series of experiments that employed a continuous-response adjustment procedure, it was found that the lack of vertical boundaries inflated the perceived width of an object, whereas the lack of horizontal boundaries inflated its perceived length. The effect was highly robust and it was replicated across different stimulus types and experimental parameters, with almost all observers exhibiting a strong effect. In contrast to the overestimation of the size of an object due to missing boundaries, the inclusion of inner boundaries within an object caused observers to underestimate its size, suggesting that filled space sometimes shrinks, rather than inflates, the perceived size of an object. The open-object illusion bears practical implications for graphics and design as well as important theoretical implications. Specifically, it indicates that the perception of an object's area is not veridical but rather critically depends on contour closure. It is suggested that the visual system extends the missing boundaries of open contour objects, which results in an overestimation of the object's size.



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What Type of Food Can Older Adults Masticate?: Evaluation of Mastication Performance Using Color-Changeable Chewing Gum

Abstract

This study determines if older adults can masticate regular foods via a simple test conducted using a color-changeable chewing gum. Seventy-nine consecutive inpatients of our clinic receiving rehabilitation and general medicine were assessed for eligibility. The inclusion criterion was >65 years. Thirty patients consented to participate. The main outcome variable was the food bolus texture at the swallowing threshold for five regular foods. The main explanatory variable was the a* value of the color-changeable chewing gum after 120 s of chewing (a* represents the degree of color between red and green, and a positive a* value indicates red). The mean age ± standard deviation of the participants was 81.6 ± 8.6 years, and 40% were men. Participants being able to prepare the food with suitable texture for swallowing was positively associated with the a* values in boiled rice, ginger-fried pork loin, boiled fish-paste, and rice cracker (Crude OR 1.18, 1.15, 1.17, and 1.50; P < 0.001, = 0.026, <0.001, and <0.001, respectively). The cut-off a* values had markedly high specificities (1.0) for boiled rice and boiled fish-paste and high sensitivities (0.86–0.94) for three foods, except boiled rice. We believe that mastication evaluation using the color-changeable chewing gum is not only useful but also extremely practical, even for older adults in a wide range of settings, including an individual’s home. This approach would lead to a reduction in unnecessary mechanically altered or pureed food for older adults who can eat pureed food and safely provide palatable food.



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Dysphagia in Friedreich Ataxia

Abstract

The objective of the study was to comprehensively characterise dysphagia in Friedreich ataxia (FRDA) and identify predictors of penetration/aspiration during swallowing. We also investigated the psychosocial impact of dysphagia on individuals with FRDA. Sixty participants with FRDA were screened for dysphagia using a swallowing quality of life questionnaire (Swal-QOL) and case history. Individuals reporting dysphagia underwent a standardised oromotor assessment (Frenchay Dysarthria Assessment, 2, FDA-2) and videofluoroscopic study of swallowing (VFSS). Data were correlated with disease parameters (age at symptom onset, age at assessment, disease duration, FXN intron 1 GAA repeat sizes, and Friedreich Ataxia Rating Scale (FARS) score). Predictors of airway penetration/aspiration were explored using logistic regression analysis. Ninety-eight percent (59/60) of participants reported dysphagia, of whom 35 (58.3%) underwent FDA-2 assessment, and 38 (63.3%) underwent VFSS. Laryngeal, respiratory, and tongue dysfunction was observed on the FDA-2. A Penetration–Aspiration Scale score above 3 (deemed significant airway compromise based on non-clinical groups) was observed on at least one consistency in 13/38 (34.2%) participants. All of those who aspirated (10/38, 26.3%) did so silently, with no overt signs of airway entry such as reflexive cough. Significant correlations were observed between dysphagic symptoms and disease duration and severity. No reliable predictors of penetration or aspiration were identified. Oropharyngeal dysphagia is commonly present in individuals with FRDA and worsens with disease duration and severity. Individuals with FRDA are at risk of aspiration at any stage of the disease and should be reviewed regularly. Instrumental analysis remains the only reliable method to detect aspiration in this population. Dysphagia significantly affects the quality of life of individuals with FRDA.



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Niraparib: First Global Approval

Abstract

Oral niraparib, a highly-selective, potent poly(ADP-ribose) polymerase (PARP)-1 and PARP-2 inhibitor, is approved in the USA for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. It is also under regulatory review in the EU for use in maintenance treatment in patients with platinum-sensitive, recurrent epithelial ovarian cancer who are in response to platinum-based chemotherapy. In the multinational, phase 3 NOVA trial in adult patients with platinum-sensitive, recurrent ovarian cancer, niraparib significantly prolonged median progression-free survival, irrespective of the presence or absence of a germline BRCA (gBRCA) mutation and irrespective of the presence or absence of homologous recombinant deficiency. Niraparib is also in development for use in other solid tumours, including breast and prostate cancer. This article summarizes the milestones in the development of niraparib leading to its first global approval for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer.



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Gas-Phase Intercluster Thiyl-Radical Induced C–H Bond Homolysis Selectively Forms Sugar C2-Radical Cations of Methyl D-Glucopyranoside: Isotopic Labeling Studies and Cleavage Reactions

Abstract

A suite of isotopologues of methyl D-glucopyranosides is used in conjunction with multistage mass spectrometry experiments to determine the radical site and cleavage reactions of sugar radical cations formed via a recently developed 'bio-inspired' method. In the first stage of CID (MS2), collision-induced dissociation (CID) of a protonated noncovalent complex between the sugar and S-nitrosocysteamine, [H3NCH2CH2SNO + M]+, unleashes a thiyl radical via bond homolysis to give the noncovalent radical cation, [H3NCH2CH2S + M]+. CID (MS3) of this radical cation complex results in dissociation of the noncovalent complex to generate the sugar radical cation. Replacement of all exchangeable OH and NH protons with deuterons reveals that the sugar radical cation is formed in a process involving abstraction of a hydrogen atom from a C–H bond of the sugar coupled with proton transfer to the sugar, to form [M – H + D+]. Investigation of this process using individual C-D labeled sugars reveals that the main site of H/D abstraction is the C2 position, since only the C2-deuterium labeled sugar yields a dominant [M – D + H+] product ion. The fragmentation reactions of the distonic sugar radical cation, [M – H+ H+], were studied by another stage of CID (MS4). 13C-labeling studies revealed that a series of three related fragment ions each contain the C1–C3 atoms; these arise from cross-ring cleavage reactions of the sugar.

Graphical Abstract



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