Bortezomib enhances radiosensitivity in oral cancer through inducing autophagy-mediated TRAF6 oncoprotein degradation

Abstract

Background

Oral squamous cell carcinoma (OSCC) is a malignant tumor that may occur anywhere within the oral cavity. The survival rate of OSCC patients has not improved over the past decades due to its heterogeneous etiology, genetic aberrations, and treatment outcomes. We investigated the role of tumor necrosis factor receptor-associated factor 6 (TRAF6) in OSCC cells treated with bortezomib (a proteasome inhibitor) combined with irradiation (IR) treatment.

Methods

The effects of combined treatment in OSCC cells were investigated using assays of cell viability, autophagy, apoptosis, western blotting, and immunofluorescence staining. The ubiquitination of proteins was analyzed by immunoprecipitation. Stable knockdown of TRAF6 in OSCC cells was constructed with lentivirus. The xenograft murine models were used to observe tumor growth.

Results

We found synergistic effects of bortezomib and IR on the viability of human oral cancer cells. The combination of bortezomib and IR treatment induced autophagic cell death. Furthermore, bortezomib inhibited IR-induced TRAF6 ubiquitination and inhibited TRAF6-mediated Akt activation. Bortezomib reduced TRAF6 protein expression through autophagy-mediated lysosomal degradation. TRAF6 played an oncogenic role in tumorigenesis of human oral cancer cells and oral tumor growth was suppressed by bortezomib and IR treatment. In addition, OSCC patients with expression of TRAF6 showed a trend towards poorer cancer-specific survival when compared with patients without TRAF6 expression.

Conclusions

A combination of a proteasome inhibitor, IR treatment and TRAF6 inhibition could be a novel therapeutic strategy in OSCC.

https://ift.tt/2vQjxfl

SMAD4 and NF1 mutations as potential biomarkers for poor prognosis to cetuximab-based therapy in Chinese metastatic colorectal cancer patients

Abstract

Background

Cetuximab, an anti-EGFR monoclonal antibody, is used in combination with chemotherapy in clinic to enhance the outcome in metastatic colorectal cancer (mCRC) patients with only ~ 20% response rate. To date only activating mutations in KRAS and NRAS have been identified as poor prognosis biomarkers in cetuximab-based treatment, which makes an urgent need for identification of novel prognosis biomarkers to precisely predict patients' response in order to maximize the benefit.

Methods

In this study, we analysed the mutation profiles of 33 Chinese mCRC patients using comprehensive next-generation sequencing (NGS) targeting 416 cancer-relevant genes before cetuximab treatment. Upon receiving cetuximab-based therapy, patients were evaluated for drug response, and the progression-free survival (PFS) was monitored. The association of specific genetic alterations and cetuximab efficacy was analyzed.

Results

Patients carrying SMAD4 mutations (SMAD4^mut, n = 8) or NF1 mutations (NF1^mut, n = 4) had significantly shorter PFS comparing to those carrying wildtype SMAD4 (SMAD4^wt, n = 25) (P = 0.0081) or wildtype NF1 (NF1^wt, n = 29) (P = 0.0028), respectively. None of the SMAD4^mut or NF1^mut patients showed response to cetuximab when assessed at 12-week post-treatment. Interestingly, two patients carrying both SMAD4^mut and NF1^mut showed the shortest PFS among all the patients.

Conclusions

Our results demonstrated that SMAD4 and NF1 mutations can serve as potential biomarkers for poor prognosis to cetuximab-based therapy in Chinese mCRC patients.

https://ift.tt/2r3gmMR

Cholesterol synthesis pathway genes in prostate cancer are transcriptionally downregulated when tissue confounding is minimized

Abstract

Background

The relationship between cholesterol and prostate cancer has been extensively studied for decades, where high levels of cellular cholesterol are generally associated with cancer progression and less favorable outcomes. However, the role of in vivo cellular cholesterol synthesis in this process is unclear, and data on the transcriptional activity of cholesterol synthesis pathway genes in tissue from prostate cancer patients are inconsistent.

Methods

A common problem with cancer tissue data from patient cohorts is the presence of heterogeneous tissue which confounds molecular analysis of the samples. In this study we present a general method to minimize systematic confounding from stroma tissue in any prostate cancer cohort comparing prostate cancer and normal samples. In particular we use samples assessed by histopathology to identify genes enriched and depleted in prostate stroma. These genes are then used to assess stroma content in tissue samples from other prostate cancer cohorts where no histopathology is available. Differential expression analysis is performed by comparing cancer and normal samples where the average stroma content has been balanced between the sample groups. In total we analyzed seven patient cohorts with prostate cancer consisting of 1713 prostate cancer and 230 normal tissue samples.

Results

When stroma confounding was minimized, differential gene expression analysis over all cohorts showed robust and consistent downregulation of nearly all genes in the cholesterol synthesis pathway. Additional Gene Ontology analysis also identified cholesterol synthesis as the most significantly altered metabolic pathway in prostate cancer at the transcriptional level.

Conclusion

The surprising observation that cholesterol synthesis genes are downregulated in prostate cancer is important for our understanding of how prostate cancer cells regulate cholesterol levels in vivo. Moreover, we show that tissue heterogeneity explains the lack of consistency in previous expression analysis of cholesterol synthesis genes in prostate cancer.

https://ift.tt/2vSO7VK

Investigation of the SLC22A23 gene in laryngeal squamous cell carcinoma

Abstract

Background

Laryngeal squamous cell carcinoma (LSCC) is the second most common cancer of the head and neck. In order to identify differentially expressed genes which may have a role in LSCC carcinogenesis, we performed GeneFishing Assay. One of the differentially expressed genes was the SLC22A23 (solute carrier family 22, member 23) gene.

SLC22A23 belongs to a family of organic ion transporters that are responsible for the absorption or excretion of many drugs, xenobiotics and endogenous compounds in a variety of tissues. SLC22A23 is expressed in a various tissues but no substrates or functions have been identified for it. Although the exact function is unknown, single nucleotide polymorphisms (SNPs) which are located in SLC22A23 gene were associated with inflammatory bowel disease (IBD), endometriosis-related infertility and the clearance of antipsychotic drugs. On the other hand SLC22A23 is identified as a prognostic gene to predict the recurrence of triple-negative breast cancer.

Methods

To understand the role of the SLC22A23 gene in laryngeal carcinogenesis, we investigated its mRNA expression level in laryngeal tumor tissue and adjacent non-cancerous tissue samples obtained from 83 patients by quantitative real-time PCR. To understand the association between SNPs in SLC22A23 and LSCC, selected genetic variations (rs4959235, rs6923667, rs9503518) were genotyped.

Results

We found that SLC22A23 expression was increased in 46 of 83 tumor tissues (55.4%) and was decreased in 30 of 83 (36.1%) tumor tissues compared to normal tissues. 77.2% of patients were homozygote for genotype rs9503518-AA and they most frequently had histological grade 2 and 3 tumors. We also found that rs9503518-AA genotype is associated with increased SLC22A23 expression.

Conclusions

Our results indicate that SLC22A23 may play a role in the development of laryngeal cancer.

https://ift.tt/2r2SQzx

Medical Treatment Options for Patients with Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer Suffering from Brain Metastases and/or Leptomeningeal Disease

Abstract

Brain metastases and/or leptomeningeal disease (LMD) with associated central nervous system (CNS) metastases are known complications of advanced epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). It is important, therefore, to assess the activity of EGFR tyrosine kinase inhibitors (TKIs) versus such CNS complications. This review explores the literature reporting the intracranial activity of EGFR TKIs, and finds that there is evidence for varying efficacy of the approved agents, erlotinib, gefitinib, afatinib, and osimertinib in patients with CNS metastases. Other EGFR TKIs in development, such as AZD3759, may have a future role as therapeutic options in this setting. Emerging evidence indicates that the second- and third-generation EGFR TKIs, afatinib and osimertinib, effectively penetrate the blood-brain barrier, and therefore represent viable treatment options for CNS lesions, and can reduce the risk of CNS progression. These agents should therefore be considered as first-line treatment options in patients with EGFR mutation-positive NSCLC who have brain metastases and/or LMD. While there are currently no prospective data comparing the intracranial efficacy of second- and third-generation EGFR TKIs in this setting, CNS activity and protection offered by different EGFR TKIs should be an additional consideration when making decisions about the optimal sequence of treatment with EGFR TKIs in order to maximize survival benefit in individual patients.

https://ift.tt/2r2U3qi

Effects of megavoltage computed tomographic scan methodology on setup verification and adaptive dose calculation in helical TomoTherapy

Abstract

Background

To evaluate the effect of pretreatment megavoltage computed tomographic (MVCT) scan methodology on setup verification and adaptive dose calculation in helical TomoTherapy.

Methods

Both anthropomorphic heterogeneous chest and pelvic phantoms were planned with virtual targets by TomoTherapy Physicist Station and were scanned with TomoTherapy megavoltage image-guided radiotherapy (IGRT) system consisted of six groups of options: three different acquisition pitches (APs) of 'fine', 'normal' and 'coarse' were implemented by multiplying 2 different corresponding reconstruction intervals (RIs). In order to mimic patient setup variations, each phantom was shifted 5 mm away manually in three orthogonal directions respectively. The effect of MVCT scan options was analyzed in image quality (CT number and noise), adaptive dose calculation deviations and positional correction variations.

Results

MVCT scanning time with pitch of 'fine' was approximately twice of 'normal' and 3 times more than 'coarse' setting, all which will not be affected by different RIs. MVCT with different APs delivered almost identical CT numbers and image noise inside 7 selected regions with various densities. DVH curves from adaptive dose calculation with serial MVCT images acquired by varied pitches overlapped together, where as there are no significant difference in all p values of intercept & slope of emulational spinal cord (p = 0.761 & 0.277), heart (p = 0.984 & 0.978), lungs (p = 0.992 & 0.980), soft tissue (p = 0.319 & 0.951) and bony structures (p = 0.960 & 0.929) between the most elaborated and the roughest serials of MVCT. Furthermore, gamma index analysis shown that, compared to the dose distribution calculated on MVCT of 'fine', only 0.2% or 1.1% of the points analyzed on MVCT of 'normal' or 'coarse' do not meet the defined gamma criterion. On chest phantom, all registration errors larger than 1 mm appeared at superior-inferior axis, which cannot be avoided with the smallest AP and RI. On pelvic phantom, craniocaudal errors are much smaller than chest, however, AP of 'coarse' presents larger registration errors which can be reduced from 2.90 mm to 0.22 mm by registration technique of 'full image'.

Conclusions

AP of 'coarse' with RI of 6 mm is recommended in adaptive radiotherapy (ART) planning to provide craniocaudal longer and faster MVCT scan, while registration technique of 'full image' should be used to avoid large residual error. Considering the trade-off between IGRT and ART, AP of 'normal' with RI of 2 mm was highly recommended in daily practice.

https://ift.tt/2KdUqqd

The effects of short-term fasting on quality of life and tolerance to chemotherapy in patients with breast and ovarian cancer: a randomized cross-over pilot study

Abstract

Background

This pilot trial aimed to study the feasibility and effects on quality of life (QOL) and well-being of short-term fasting (STF) during chemotherapy in patients with gynecological cancer.

Methods

In an individually-randomized cross-over trial patients with gynecological cancer, 4 to 6 planned chemotherapy cycles were included. Thirty-four patients were randomized to STF in the first half of chemotherapies followed by normocaloric diet (group A;n = 18) or vice versa (group B;n = 16). Fasting started 36 h before and ended 24 h after chemotherapy (60 h-fasting period). QOL was assessed by the FACIT-measurement system.

Results

The chemotherapy-induced reduction of QOL was less than the Minimally Important Difference (MID; FACT-G = 5) with STF but greater than the MID for non-fasted periods. The mean chemotherapy-induced deterioration of total FACIT-F was 10.4 ± 5.3 for fasted and 27.0 ± 6.3 for non-fasted cycles in group A and 14.1 ± 5.6 for non-fasted and 11.0 ± 5.6 for fasted cycles in group B. There were no serious adverse effects.

Conclusion

STF during chemotherapy is well tolerated and appears to improve QOL and fatigue during chemotherapy. Larger studies should prove the effect of STF as an adjunct to chemotherapy.

Trial registration

This trial was registered at clinicaltrials.gov: NCT01954836.

https://ift.tt/2I3kxzh

Comprehensive gene expression analysis of canine invasive urothelial bladder carcinoma by RNA-Seq

Abstract

Background

Invasive urothelial carcinoma (iUC) is a major cause of death in humans, and approximately 165,000 individuals succumb to this cancer annually worldwide. Comparative oncology using relevant animal models is necessary to improve our understanding of progression, diagnosis, and treatment of iUC. Companion canines are a preferred animal model of iUC due to spontaneous tumor development and similarity to human disease in terms of histopathology, metastatic behavior, and treatment response. However, the comprehensive molecular characterization of canine iUC is not well documented. In this study, we performed transcriptome analysis of tissue samples from canine iUC and normal bladders using an RNA sequencing (RNA-Seq) approach to identify key molecular pathways in canine iUC.

Methods

Total RNA was extracted from bladder tissues of 11 dogs with iUC and five healthy dogs, and RNA-Seq was conducted. Ingenuity Pathway Analysis (IPA) was used to assign differentially expressed genes to known upstream regulators and functional networks.

Results

Differential gene expression analysis of the RNA-Seq data revealed 2531 differentially expressed genes, comprising 1007 upregulated and 1524 downregulated genes, in canine iUC. IPA revealed that the most activated upstream regulator was PTGER2 (encoding the prostaglandin E₂ receptor EP2), which is consistent with the therapeutic efficiency of cyclooxygenase inhibitors in canine iUC. Similar to human iUC, canine iUC exhibited upregulated ERBB2 and downregulated TP53 pathways. Biological functions associated with cancer, cell proliferation, and leukocyte migration were predicted to be activated, while muscle functions were predicted to be inhibited, indicating muscle-invasive tumor property.

Conclusions

Our data confirmed similarities in gene expression patterns between canine and human iUC and identified potential therapeutic targets (PTGER2, ERBB2, CCND1, Vegf, and EGFR), suggesting the value of naturally occurring canine iUC as a relevant animal model for human iUC.

https://ift.tt/2Fn6uS6

Regulation of calretinin in malignant mesothelioma is mediated by septin 7 binding to the CALB2 promoter

Abstract

Background

The calcium-binding protein calretinin (gene name: CALB2) is currently considered as the most sensitive and specific marker for the diagnosis of malignant mesothelioma (MM). MM is a very aggressive tumor strongly linked to asbestos exposure and with no existing cure so far. The mechanisms of calretinin regulation, as well as its distinct function in MM are still poorly understood.

Methods

We searched for transcription factors binding to the CALB2 promoter and modulating calretinin expression. For this, DNA-binding assays followed by peptide shotgun-mass spectroscopy analyses were used. CALB2 promoter activity was assessed by dual-luciferase reporter assays. Furthermore, we analyzed the effects of CALB2 promoter-binding proteins by lentiviral-mediated overexpression or down-regulation of identified proteins in MM cells. The modulation of expression of such proteins by butyrate was determined by subsequent Western blot analysis. Immunohistochemical analysis of embryonic mouse lung tissue served to verify the simultaneous co-expression of calretinin and proteins interacting with the CALB2 promoter during early development. Finally, direct interactions of calretinin with target proteins were evidenced by co-immunoprecipitation experiments.

Results

Septin 7 was identified as a butyrate-dependent transcription factor binding to a CALB2 promoter region containing butyrate-responsive elements (BRE) resulting in decreased calretinin expression. Accordingly, septin 7 overexpression decreased calretinin expression levels in MM cells. The regulation was found to operate bi-directionally, i.e. calretinin overexpression also decreased septin 7 levels. During murine embryonic development calretinin and septin 7 were found to be co-expressed in embryonic mesenchyme and undifferentiated mesothelial cells. In MM cells, calretinin and septin 7 colocalized during cytokinesis in distinct regions of the cleavage furrow and in the midbody region of mitotic cells. Co-immunoprecipitation experiments revealed this co-localization to be the result of a direct interaction between calretinin and septin 7.

Conclusions

Our results demonstrate septin 7 not only serving as a "cytoskeletal" protein, but also as a transcription factor repressing calretinin expression. The negative regulation of calretinin by septin 7 and vice versa sheds new light on mechanisms possibly implicated in MM formation and identifies these proteins as transcriptional regulators and putative targets for MM therapy.

https://ift.tt/2I3ZLPY

Computerized tomography findings in calcified signet-ring gastric cancer receiving chemotherapy: a case report

Abstract

Background

Calcification in primary gastric cancer is very rare. In this report, we describe the computerized tomography (CT) changes in calcification in a patient with locally advanced signet-ring gastric cancer treated with chemotherapy.

Case presentation

A 49-year-old man presented with 5 months' history of abdominal pain, anorexia, and rapid weight loss. He had undergone Billroth-II subtotal gastrectomy for a bleeding gastric ulcer 30 years ago. Abdominal CT showed irregular thickening of the gastric wall and miliary calcifications. Histologic examination of specimen obtained by endoscopic biopsy showed poorly differentiated calcified signet-ring gastric cancer. The patient was clinically staged T4N2M0 and treated with docetaxel, cisplatin, and fluorouracil (DCF)/oxaliplatin and S-1 (XLOX)/S-1. After five cycles of chemotherapy, the general condition of the patient improved and tumor markers (CEA, CA125, CA199) decreased. However, follow-up CT scans showed continuing increase in the calcification.

Conclusions

To conclude, in this case report we have described the dynamic changes in calcification in a gastric cancer patient receiving chemotherapy. One explanation for the observed increase in calcifications could be that the ischemic necrosis resulting from chemotherapy creates an alkaline environment, which promotes deposition of calcium salts. Our theory needs to be confirmed with histological evidence from a large series of patients. Nevertheless, we hope that these findings will improve understanding of the mechanism of calcification in gastric cancer.

https://ift.tt/2FlDMkx

Putative cancer stem cells may be the key target to inhibit cancer cell repopulation between the intervals of chemoradiation in murine mesothelioma

Abstract

Background

Cancer cell repopulation during chemotherapy or radiotherapy is a major factor limiting the efficacy of treatment. Cancer stem cells (CSC) may play critical roles during this process. We aim to demonstrate the role of mesothelioma stem cells (MSC) in treatment failure and eventually to design specific target therapies against MSC to improve the efficacy of treatment in malignant mesothelioma.

Methods

Murine mesothelioma AB12 and RN5 cells were used to compare tumorigenicity in mice. The expression of CSC-associated genes was evaluated by quantitative real-time PCR in both cell lines treated with chemo-radiation. Stemness properties of MSC-enriched RN5-EOS-Puro2 cells were characterized with flow cytometry and immunostaining. A MSC-specific gene profile was screened by microarray assay and confirmed thereafter. Gene Ontology analysis of the selected genes was performed by GOMiner.

Results

Tumor growth delay of murine mesothelioma AB12 cells was achieved after each cycle of cisplatin treatment, however, tumors grew back rapidly due to cancer cell repopulation between courses of chemotherapy. Strikingly, a 10-times lower number of irradiated cells in both cell lines led to a similar tumor incidence and growth rate as with untreated cells. The expression of CSC-associated genes such as CD24, CD133, CD90 and uPAR was dramatically up-regulated, while others did not change significantly after chemoradiation. Highly enriched MSC after selection with puromycin displayed an increasing GFP-positive population and showed typical properties of stemness. Comparatively, the proportion of MSC significantly increased after RN5-EOS parental cells were treated with either chemotherapy, γ-ray radiation, or a combination of the two, while MSC showed more resistance to the above treatments. A group of identified genes are most likely MSC-specific, and major pathways related to regulation of cell growth or apoptosis are involved. Upregulation of the gene transcripts Tnfsf18, Serpinb9b, Ly6a, and Nppb were confirmed.

Conclusion

Putative MSC possess the property of stemness showing more resistance to chemoradiation, suggesting that MSC may play critical roles in cancer cell repopulation. Further identification of selected genes may be used to design novel target therapies against MSC, so as to eliminate cancer cell repopulation in mesothelioma.

https://ift.tt/2I25Nkh

Attenuation of TGFBR2 expression and tumour progression in prostate cancer involve diverse hypoxia-regulated pathways

Abstract

Background

Dysregulation of transforming growth factor β (TGF-β) signaling and hypoxic microenvironment have respectively been reported to be involved in disease progression in malignancies of prostate. Emerging evidence indicates that downregulation of TGFBR2, a pivotal regulator of TGF-β signaling, may contribute to carcinogenesis and progression of prostate cancer (PCa). However, the biological function and regulatory mechanism of TGFBR2 in PCa remain poorly understood. In this study, we propose to investigate the crosstalk of hypoxia and TGF-β signaling and provide insight into the molecular mechanism underlying the regulatory pathways in PCa.

Methods

Prostate cancer cell lines were cultured in hypoxia or normoxia to evaluate the effect of hypoxia on TGFBR2 expression. Methylation specific polymerase chain reaction (MSP) and demethylation agents was used to evaluate the methylation regulation of TGFBR2 promoter. Besides, silencing of EZH2 via specific siRNAs or chemical inhibitor was used to validate the regulatory effect of EZH2 on TGFBR2. Moreover, we conducted PCR, western blot, and luciferase assays which studied the relationship of miR-93 and TGFBR2 in PCa cell lines and specimens. We also detected the impacts of hypoxia on EZH2 and miR-93, and further examined the tumorigenic functions of miR-93 on proliferation and epithelial-mesenchymal transition via a series of experiments.

Results

TGFBR2 expression was attenuated under hypoxia. Hypoxia-induced EZH2 promoted H3K27me3 which caused TGFBR2 promoter hypermethylation and contributed to its epigenetic silencing in PCa. Besides, miR-93 was significantly upregulated in PCa tissues and cell lines, and negatively correlated with the expression of TGFBR2. Ectopic expression of miR-93 promoted cell proliferation, migration and invasion in PCa, and its expression could also be induced by hypoxia. In addition, TGFBR2 was identified as a bona fide target of miR-93.

Conclusions

Our findings elucidate diverse hypoxia-regulated pathways including EZH2-mediated hypermethylation and miR-93-induced silencing contribute to attenuation of TGFBR2 expression and promote cancer progression in prostate cancer.

https://ift.tt/2I4cbYi

Photophysical Behavior of mNeonGreen, an Evolutionarily Distant Green Fluorescent Protein

Fluorescent proteins (FPs) feature complex photophysical behavior that must be considered when studying the dynamics of fusion proteins in model systems and live cells. In this work, we characterize mNeonGreen (mNG), a recently introduced FP from the bilaterian Branchiostoma lanceolatum, in comparison to the well-known hydrozoan variants enhanced green fluorescent protein (EGFP) and Aequorea coerulescens GFP by steady-state spectroscopy and fluorescence correlation spectroscopy in solutions of different pH.

https://ift.tt/2HxSJWE

Orthodontic treatment of a patient with maxillary lateral incisors with dens invaginatus: 6-year follow-up

Dens invaginatus is an anomaly of dental development in which calcified tissues, such as enamel and dentin, are invaginated into the pulp cavity. This morphologic alteration is more frequent in maxillary permanent lateral incisors and makes them more susceptible to carious lesions and pulp alterations.

https://ift.tt/2JwgBqx

Longitudinal eruptive and posteruptive tooth movements, studied on oblique and lateral cephalograms with implants

The purpose of this study was to investigate the eruptive and posteruptive tooth displacements of untreated growing subjects longitudinally and the potential connections between posteruptive displacement of the maxillary and mandibular first molars and skeletal facial growth.

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Information for readers

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Three-dimensional evaluation of dentofacial transverse widths of adults with various vertical facial patterns

The purpose of this study was to investigate maxillomandibular transverse widths and molar inclinations of adults with hypodivergent, normodivergent, and hyperdivergent facial patterns using cone-beam computed tomography.

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Editorial Board

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Directory: AAO Officers and Organizations

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Table of Contents

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Three-dimensional mandibular regional superimposition in growing patients

The aims of this study were to identify stable mandibular structures in 3 dimensions in growing patients using a regional implant technique and to test the reproducibility of mandibular regional superimposition in 3 dimensions using the regions identified.

https://ift.tt/2KhqKZb

On being human

You always thought that you were gifted. Not because you were the best athlete in your class or the best-looking student in your dorm, or because you were named the valedictorian at high school graduation. In fact, you were none of these, and in some cases, far from it. There were plenty of instances when you wished you could come up with that game-winning play, emit the charisma of a screen star when you walked into a party, or achieve the highest score on an examination. Rather, you felt gifted because you always knew that you wanted to be an orthodontist.

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Three-dimensional computed tomography analysis of mandibular morphology in patients with facial asymmetry and mandibular retrognathism

The purpose of this study was to analyze the morphologic features of skeletal units in the mandibles of patients with facial asymmetry and mandibular retrognathism using cone-beam computed tomography.

https://ift.tt/2KgCRpz

Prevalence of gingival recession after orthodontic tooth movements

In the May 2017 issue of the AJO-DO, Morris et al1 evaluated the long-term prevalence of gingival recession after orthodontic treatment. As discussed in the article, periodontal disease2-4 and mechanical trauma2,5,6 are believed to be the primary etiologic factors in the development of gingival recession. However, orthodontic therapy may also contribute to gingival recession.7

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Influence of orthodontic mini-implant penetration of the maxillary sinus in the infrazygomatic crest region

Mini-implants are widely used for predictable tooth movements, but insertion is often restricted by anatomic structures. The aims of this study were to investigate the incidence of penetration of mini-implants into the sinus and the relationship between penetration depth and sinus tissue.

https://ift.tt/2KgCOtT

Residents' journal review

As new imaging techniques become widespread in orthodontics, understanding their applications and limitations is imperative. With cephalometric films having high importance for diagnostics in orthodontics, many orthodontists rely on these 2-dimensional images for diagnostics and superimpositions. As cone-beam computed tomography (CBCT) technology becomes increasingly popular, studies examining CBCT images should be increasing and sought after by many orthodontists who use this technology. There are many advantages to using CBCT scans for initial records of orthodontic patients, such as negating the need for additional images for impacted teeth, root resorption, atypical condylar morphology, and alveolar morphology for implant placement.

https://ift.tt/2JwgnQd

Factors affecting treatment duration of labial inversely impacted maxillary central incisors

A labial inversely impacted maxillary central incisor is a relatively rare occurrence. The crown of the tooth is directed upward, and its palatal aspect is facing labially. This typical orientation can be the result of trauma to the deciduous incisor transmitted to the palatal side of the crown of the permanent incisor. Labial inversely impacted maxillary central incisors are most commonly combined with labial-lingual root dilacerations. The aim of this study was to examine factors that affect the surgical-orthodontic treatment duration of labial inversely impacted maxillary central incisors.

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Authors' response

First and foremost, we wish to thank the authors for taking the time to consider our work and the AJO-DO for giving us an opportunity to respond to their concerns.

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Age-dependent biologic response to orthodontic forces

Orthodontic tooth movement results from increased inflammation and osteoclast activation. Since patients of all ages now routinely seek orthodontics treatment, we investigated whether age-dependent biologic responses to orthodontic force correlate with the rate of tooth movement.

https://ift.tt/2KhcSyc

Principles of ethical practice

Nearly 2500 years ago, Socrates asserted that ethical principles are the essence of humanity; living life without them would be like wandering in search of direction without the sun to guide us. In today's world, guidance options are as close as our phones. Even so, living and working with ethical guidance remains as valuable now as it was in Socrates' time.

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Using a single cone-beam computed tomography scan to obtain full occlusal details, with the mandible in centric relation and maximum intercuspation

One obstacle with the implementation of digital technology in orthodontics is the acquisition of occlusal details while maintaining the mandible in the full interdigitation position. With 1 cone-beam computed tomography (CBCT) scan of the patient and 1 digital scan of the patient's dental models in occlusion, it might be possible to obtain full occlusal details and generate 2 volumes, with the mandible in centric relation and maximum intercuspation positions. The purpose of this article was to describe the technique.

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May 2018:153(5)

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SLC22A16 upregulation is an independent unfavorable prognostic indicator in gastric cancer

Future Oncology, Ahead of Print.


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Regulation of the Cell Biology of Antigen Cross-Presentation

Annual Review of Immunology, Volume 36, Issue 1, Page 717-753, April 2018.


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Cell Biology of T Cell Receptor Expression and Regulation

Annual Review of Immunology, Volume 36, Issue 1, Page 103-125, April 2018.


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ZAP-70 in Signaling, Biology, and Disease

Annual Review of Immunology, Volume 36, Issue 1, Page 127-156, April 2018.


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IgA Function in Relation to the Intestinal Microbiota

Annual Review of Immunology, Volume 36, Issue 1, Page 359-381, April 2018.


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Apoptosis and Clearance of Apoptotic Cells

Annual Review of Immunology, Volume 36, Issue 1, Page 489-517, April 2018.


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Autophagy and Inflammation

Annual Review of Immunology, Volume 36, Issue 1, Page 73-101, April 2018.


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Antigen Presentation by Extracellular Vesicles from Professional Antigen-Presenting Cells

Annual Review of Immunology, Volume 36, Issue 1, Page 435-459, April 2018.


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Host Control of Fungal Infections: Lessons from Basic Studies and Human Cohorts

Annual Review of Immunology, Volume 36, Issue 1, Page 157-191, April 2018.


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Self-Reactive B Cells in the Germinal Center Reaction

Annual Review of Immunology, Volume 36, Issue 1, Page 339-357, April 2018.


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Immune Responses in the Liver

Annual Review of Immunology, Volume 36, Issue 1, Page 247-277, April 2018.


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The Formation and Function of Granulomas

Annual Review of Immunology, Volume 36, Issue 1, Page 639-665, April 2018.


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The Immune Response to Mycobacterium tuberculosis in HIV-1-Coinfected Persons

Annual Review of Immunology, Volume 36, Issue 1, Page 603-638, April 2018.


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Genetics of Natural Killer Cells in Human Health, Disease, and Survival

Annual Review of Immunology, Volume 36, Issue 1, Page 519-548, April 2018.


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Evolution of Alternative Adaptive Immune Systems in Vertebrates

Annual Review of Immunology, Volume 36, Issue 1, Page 19-42, April 2018.


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Connections Between Metabolism and Epigenetics in Programming Cellular Differentiation

Annual Review of Immunology, Volume 36, Issue 1, Page 221-246, April 2018.


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Rebooting Human Immunology

Annual Review of Immunology, Volume 36, Issue 1, Page 843-864, April 2018.


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Exploiting Nanobodies’ Singular Traits

Annual Review of Immunology, Volume 36, Issue 1, Page 695-715, April 2018.


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Immune Response to Dengue and Zika

Annual Review of Immunology, Volume 36, Issue 1, Page 279-308, April 2018.


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Editorial Board

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Masthead

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Table of Contents

https://ift.tt/2HtHeQm

Inhibition of the Wnt/{beta}-catenin pathway overcomes resistance to enzalutamide in castration-resistant prostate cancer

Enzalutamide is a second-generation nonsteroidal antiandrogen clinically approved for the treatment of castration-resistant prostate cancer (CRPC), yet resistance to endocrine therapy has limited its success in this setting. Although the androgen receptor (AR) has been associated with therapy failure, the mechanisms underlying this failure have not been elucidated. Bioinformatics analysis predicted that activation of the Wnt/β-catenin pathway and its interaction with AR play a major role in acquisition of enzalutamide resistance. To validate the finding, we show upregulation of β-catenin and AR in enzalutamide-resistant cells, partially due to reduction of β-TrCP mediated-ubiquitination. While activation of the Wnt/β-catenin pathway in enzalutamide-sensitive cells led to drug resistance, combination of β-catenin inhibitor ICG001 with enzalutamide inhibited expression of stem-like markers, cell proliferation, and tumor growth synergistically in various models. Analysis of clinical datasets revealed a molecule pattern shift in different stages of PCa, where we detected a significant correlation between AR and β-catenin expression. These data identify activation of the Wnt/β-catenin pathway as a major mechanism contributing to enzalutamide resistance and demonstrate the potential to stratify patients with high risk of said resistance.

https://ift.tt/2FkzKcu

Zika virus selectively kills aggressive human embryonal CNS tumor cells in vitro and in vivo

Zika virus (ZIKV) is largely known for causing brain abnormalities due to its ability to infect neural progenitor stem cells (NPC) during early development. Here we show that ZIKV is also capable of infecting and destroying stem-like cancer cells from aggressive human embryonal tumors of the central nervous system (CNS). When evaluating the oncolytic properties of Brazilian Zika virus strain (ZIKVBR) against human breast, prostate, colorectal, and embryonal CNS tumor cell lines, we verified a selective infection of CNS tumor cells followed by massive tumor cell death. ZIKVBR was more efficient in destroying embryonal CNS tumorspheres than normal stem cell neurospheres. A single intracerebroventricular injection of ZIKVBR in BALB/c nude mice bearing orthotopic human embryonal CNS tumor xenografts resulted in a significantly longer survival, decreased tumor burden, fewer metastasis, and complete remission in some animals. Tumor cells closely resembling neural stem cells at the molecular level with activated Wnt signaling were more susceptible to the oncolytic effects of ZIKVBR. Furthermore, modulation of Wnt signaling pathway significantly affected ZIKVBR-induced tumor cell death and viral shedding. Altogether, these preclinical findings indicate that ZIKVBR could be an efficient agent to treat aggressive forms of embryonal CNS tumors and provide mechanistic insights regarding its oncolytic effects.

https://ift.tt/2I4p04P

MVisAGe identifies concordant and discordant genomic alterations of driver genes in squamous tumors

Integrated analyses of multiple genomic datatypes are now common in cancer profiling studies. Such data present opportunities for numerous computational experiments, yet analytic pipelines are limited. Tools such as the cBioPortal and Regulome Explorer, while useful, are not easy to access programmatically or implement locally. Here we introduce the MVisAGe R package, which allows users to quantify gene-level associations between two genomic datatypes in order to investigate the effect of genomic alterations (e.g. DNA copy number changes on gene expression). Visualizing Pearson/Spearman correlation coefficients according to the genomic positions of the underlying genes provides a powerful yet novel tool for conducting exploratory analyses. We demonstrate its utility by analyzing three publicly available cancer datasets. Our approach highlights canonical oncogenes in chr11q13 that displayed the strongest associations between expression and copy number, including CCND1 and CTTN, genes not identified by copy number analysis in the primary reports. We demonstrate highly concordant usage of shared oncogenes on chr3q, yet strikingly diverse oncogene usage on chr11q as a function of HPV infection status. Regions of chr19 that display remarkable associations between methylation and gene expression were identified, as were previously unreported miRNA-gene expression associations that may contribute to the epithelial-to-mesenchymal transition.

https://ift.tt/2FkJrYj

Lymphatic endothelial progenitor cells: origins and roles in lymphangiogenesis

Jan Kazenwadel | Natasha L Harvey

https://ift.tt/2vSxd9S

Involvement of ion channels in allergy

Lucette Pelletier | Magali Savignac

https://ift.tt/2r45FZm

EM Nerd-The Case of the Temporal Fallacy

Inadvertent catastrophes are often hidden just beneath good intentions. Such is the case with the most recent iteration of the Surviving Sepsis Campaign's treatment bundle. Published in Intensive Care Medicine by Levy et al, this special editorial includes the Surviving Sepsis Campaign's most recent recommendations for the early and aggressive treatment of sepsis (1). Most […]

EMCrit Project by Rory Spiegel.

https://ift.tt/2r3wZap

Transoral endoscopic examination of head and neck region

Digestive Endoscopy, EarlyView.


https://ift.tt/2vSn5he

A dualistic model of primary anal canal adenocarcinoma with distinct cellular origins, etiologies, inflammatory microenvironments and mutational signatures: implications for personalised medicine

A dualistic model of primary anal canal adenocarcinoma with distinct cellular origins, etiologies, inflammatory microenvironments and mutational signatures: implications for personalised medicine

A dualistic model of primary anal canal adenocarcinoma with distinct cellular origins, etiologies, inflammatory microenvironments and mutational signatures: implications for personalised medicine, Published online: 27 April 2018; doi:10.1038/s41416-018-0049-2

A dualistic model of primary anal canal adenocarcinoma with distinct cellular origins, etiologies, inflammatory microenvironments and mutational signatures: implications for personalised medicine

https://ift.tt/2FhBFOV

Study of the Efficiency of the Hydroporation for Delivery of Plasmid DNA to the Cells on the Model of Toxic Neuropathy

We compared the efficiency of delivery of plasmid DNA (active ingredient concentration 1 mg/kg) that provides production of nerve growth factor (NGF) after intravenous administration to rats and after administration by hydroporation. The method of hydroporation ensured plasmid penetration into the liver tissue and lengthened the time of its detection in the organ. DNA concentration in 1 h after its introduction by hydroporation or intravenous route was 0.7 and 0.05 ng/mg tissue, respectively. The use of this transfection method ensured preservation of NGF DNA in the liver tissue at a level of 0.24 ng/mg of tissue 1 day after administration of the plasmid construct, while after intravenous administration, expression of the analyzed DNA was not detected in blood and liver samples. After hydroporation, the maximum of relative normalized expression of cDNA (270 rel. units) was observed after 4 h, and after 1 day, this parameter decreased to 35 rel. units. Introduction of plasmid DNA of NGF by hydroporation prevented the development of disorders of neuromuscular conduction in a rats model of toxic neuropathy induced by subacute administration of malathion in a dose of 0.5 LD₅₀.

https://ift.tt/2KdzdwB

Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy

Abstract

Several genes related to mitochondrial functions have been identified as causative genes of neuropathy or ataxia. Cytochrome c oxidase assembly factor 7 (COA7) may have a role in assembling mitochondrial respiratory chain complexes that function in oxidative phosphorylation. Here we identified four unrelated patients with recessive mutations in COA7 among a Japanese case series of 1396 patients with Charcot-Marie-Tooth disease (CMT) or other inherited peripheral neuropathies, including complex forms of CMT. We also found that all four patients had characteristic neurological features of peripheral neuropathy and ataxia with cerebellar atrophy, and some patients showed leukoencephalopathy or spinal cord atrophy on MRI scans. Validated mutations were located at highly conserved residues among different species and segregated with the disease in each family. Nerve conduction studies showed axonal sensorimotor neuropathy. Sural nerve biopsies showed chronic axonal degeneration with a marked loss of large and medium myelinated fibres. An immunohistochemical assay with an anti-COA7 antibody in the sural nerve from the control patient showed the positive expression of COA7 in the cytoplasm of Schwann cells. We also observed mildly elevated serum creatine kinase levels in all patients and the presence of a few ragged-red fibres and some cytochrome c oxidase-negative fibres in a muscle biopsy obtained from one patient, which was suggestive of subclinical mitochondrial myopathy. Mitochondrial respiratory chain enzyme assay in skin fibroblasts from the three patients showed a definitive decrease in complex I or complex IV. Immunocytochemical analysis of subcellular localization in HeLa cells indicated that mutant COA7 proteins as well as wild-type COA7 were localized in mitochondria, which suggests that mutant COA7 does not affect the mitochondrial recruitment and may affect the stability or localization of COA7 interaction partners in the mitochondria. In addition, Drosophila COA7 (dCOA7) knockdown models showed rough eye phenotype, reduced lifespan, impaired locomotive ability and shortened synaptic branches of motor neurons. Our results suggest that loss-of-function COA7 mutation is responsible for the phenotype of the presented patients, and this new entity of disease would be referred to as spinocerebellar ataxia with axonal neuropathy type 3.

https://ift.tt/2HW89DM

Drug-Related Endocarditis Cases Up From 2007 to 2015

THURSDAY, April 26, 2018 -- Over the last nine years, there was an increase in the number of endocarditis cases, which mirrored the increase in concomitant use of mixed drugs, according to a study presented at the annual meeting of the Society for...

https://ift.tt/2KiWpcM

Inadequate Functional Health Literacy Mars Post-Op Recovery

THURSDAY, April 26, 2018 -- For patients undergoing day surgery, inadequate functional health literacy (FHL) is associated with poorer postoperative recovery and lower health-related quality of life, according to a study published online April 25 in...

https://ift.tt/2JyIcHE

Improvement in Race-Based Disparities in Years of Life Lost

THURSDAY, April 26, 2018 -- From 1990 to 2014 there was a decrease in race-based disparities in years of life lost (YLL) in the United States, according to a study published online April 25 in PLOS ONE. Jeanine M. Buchanich, Ph.D., from the...

https://ift.tt/2KjlcgH

Low-Dose Hyaluronidase Can Remove Hyaluronic Acid Fillers

THURSDAY, April 26, 2018 -- Very low doses of hyaluronidase can remove hyaluronic acid filler nodules, but more rapid resolution is seen with slightly higher doses, according to a study published online April 25 in JAMA Dermatology. Murad Alam,...

https://ift.tt/2Jr3Ygf

In Regard to Mohan et al

To the Editor: We enjoyed the critical review by Mohan et al discussing technical improvements to empower proton therapy (PT) (1). They acknowledge a lack of data showing PT delivers better clinical outcomes than photon therapy (1, 2) and suggest this is because most of the experience to date is with passive scattering PT, which is dosimetrically inferior to intensity modulated PT (IMPT). They argue that if the limitations of IMPT can be addressed, the clinical benefits of PT will become apparent.

https://ift.tt/2HvSonu

In Regard to Yoon et al

To the Editor: We read with interest this study by Yoon et al (1), who suggested harnessing the ultraviolet (UV) light (Cherenkov radiation) produced during megavoltage radiation therapy to photoactivate psolaren and cause DNA damage to irradiated cells. To test this approach, they generated light by applying megavoltage radiation to a solid-water slab, over which they had placed cancer cell cultures containing various concentrations of psolaren. They then measured cell viability, immunogenicity, and reproductive integrity and found that light generated in the slab, presumably through the Cherenkov effect, is sufficiently strong to photoactivate psolaren and cause detectable biological changes.

https://ift.tt/2HsK5Zv

The Oncologist's Role in Managing Financial Toxicity

This letter was received by e-mail from a patient in late October 2017 and is shared here with permission.It has been a while but at the urging of the rest of my team I wanted to reach out to you about what happened…. While my insurance was "accepted" it was considered out-of-network care. No one informed me of this. I had already met my out of pocket max for the year, and should not have paid a single cent for the rest of 2017 for covered care. Instead, they hit me with an additional bill of $7000.

https://ift.tt/2HsK3kl

Accurate, Precision Radiation Medicine: A Meta-Strategy for Impacting Cancer Care, Global Health, and Nuclear Policy and Mitigating Radiation Injury From Necessary Medical Use, Space Exploration, and Potential Terrorism

The era of precision medicine with extraordinary potential for dramatic progress is occurring in a world of paradoxes. In this world scientific opportunities are challenged by science skeptics, and spectacular advances are made in medical technology, yet many people in the developing world are without effective health care and any access to cancer care (1). Furthermore, the necessity for multinational consortia is challenged by growing nationalism, and the threat of nuclear terrorism and state-sponsored nuclear confrontation needs to be countered by nuclear nonproliferation and global partnerships for peace.

https://ift.tt/2r208Tf

Current Opportunities and Future Vision of Precision Medicine in Radiation Oncology

At the 2016 American Society for Radiation Oncology annual meeting, Dr Thomas Lynch delivered a keynote address in which he presented the remarkable development of targeted therapy for non-small cell lung cancer with activating mutations in the epidermal growth factor receptor (EGFR) (1). He described the care of 1 patient, whose lung cancer had had an exceptional response to a first-generation EGFR inhibitor but that ultimately progressed, with tumor cells harboring a resistant EGFR mutation. The patient subsequently derived benefit from a next-generation EGFR inhibitor.

https://ift.tt/2HtjCeB

The Inca Trail to the Present: The Development of Radiation Therapy in Peru

Peru has a recorded history dating back millennia and a rich mixture of cultures. Peruvian medicine has evolved to reflect this rich history and the diversity of its peoples' beliefs. Understanding our origins and learning about our ancestors help us to understand and calculate the future of health care in Peru.

https://ift.tt/2r4R2Fn

Regional Nodal Irradiation in the Modern Era of Breast Cancer Management

Management of the axilla has undergone a tremendous evolution in recent years. Although surgery has become progressively less invasive, data supporting a larger role and extent of regional nodal irradiation (RNI) have grown. For example, the AMAROS trial (After Mapping of the Axilla Radiation or Surgery) demonstrated that axillary radiation therapy (AXL-RT) can be used as an alternative to completion axillary lymph node dissection (cALND) in node-positive patients, yielding extremely low rates of axillary recurrence and less morbidity than surgical resection (1).

https://ift.tt/2HvSYSo

In Reply to Pratx and Kapp

To the Editor: We thank Drs. Pratx and Kapp for their interest in the RECA approach (Radiotherapy Enhanced by Cherenkov photo-Activation) and for raising valuable questions (1, 2).

https://ift.tt/2r38PfT

Honor Was Never Lost: The National Farm Machinery Show and the American Society for Radiation Oncology Annual Meeting

For more than 50 years, the annual National Farm Machinery Show has been one of the top agricultural industry events. More than 300,000 people will attend the 2018 edition, with more than 850 exhibitors showcasing their wares in 1.2 million square feet of the Kentucky Exposition Center (Fig. 1). Admission is free, as is entrance to 15 educational seminars ranging in topics from "What's New with Combines?" to "In Season Crop Fertility: Options for Your Farm."

https://ift.tt/2HuS20j

Meetings

June 25-26, 2018

https://ift.tt/2r4QYp7

Issue Highlights: Precision Medicine In Radiation Oncology

Marks et al

https://ift.tt/2HsJOpr

Radiation, then On to Surgery

To formulate an individualized treatment plan, we would first carefully assess the patient's goals of care and priorities. Because she (1) is not eligible for up-front surgery or preoperative chemotherapy and because locoregional progression will further impact quality of life, we would recommend neoadjuvant radiation therapy (RT) targeting the whole breast, ipsilateral axilla, and supraclavicular fossa with or without the internal mammary chain. We favor preoperative RT using definitive doses over palliative RT or supportive care alone, because this strategy is generally well-tolerated and offers the best chance for tumor shrinkage to provide durable symptom and locoregional control, potentially enabling surgical resection and reducing the risk of distant metastasis.

https://ift.tt/2HtjAU1

Radiation, then Rethink

This is an elderly patient with comorbidities, compromised performance status, and a locally advanced (possibly inflammatory) triple-negative cancer (1). The volume of disease and associated skin involvement are such that cytoreduction with preoperative systemic therapy (PST) is the preferred initial approach. This would hopefully treat micrometastatic distant disease and permit surgical resection.

https://ift.tt/2r2t2Ti

Between a Rock and a Hard Place

For this noninflammatory primary (1), if reduced-dose chemotherapy could be given safely to reduce tumor burden and increase the duration and likelihood of control provided by radiation without surgery, then that is desirable.

https://ift.tt/2HtjAmZ

In Reply to Azria et al

To the Editor: We thank the authors of the letter for their interest in our work (1). Our approach (2) is based on radiation-induced ATM nucleo-shuttling (RIANS) (3-5). Unlike radiation-induced lymphocyte apoptosis (RILA), it provides a relevant interpretation of the linear-quadratic (LQ) model, descriptive basis of radiation response (5).

https://ift.tt/2r4QPSB

Safeguarding Physician Education From Inappropriate Influence

We can all agree that clinicians are expected to provide safe, effective, cost-effective, compassionate care based on best practice and evidence. This professionalism is the basis of medicine's contract with society. To fulfill our obligations, we in the medical community must work together to continue to ensure that accredited continuing medical education (CME) offers clinicians a protected space to learn and teach without commercial influence and to help physicians differentiate between accredited activities and the promotional activities of industry.

https://ift.tt/2HuwP71

In Regard to Pereira et al

To the Editor: We read with interest the article by Pereira et al on the radiosensitivity assay (1). We would like to express some comments on certain aspects of the article.

https://ift.tt/2r4QOhv

Evaluation of a decision aid for incidental genomic results, the Genomics ADvISER: protocol for a mixed methods randomised controlled trial

Introduction

Genome sequencing, a novel genetic diagnostic technology that analyses the billions of base pairs of DNA, promises to optimise healthcare through personalised diagnosis and treatment. However, implementation of genome sequencing faces challenges including the lack of consensus on disclosure of incidental results, gene changes unrelated to the disease under investigation, but of potential clinical significance to the patient and their provider. Current recommendations encourage clinicians to return medically actionable incidental results and stress the importance of education and informed consent. Given the shortage of genetics professionals and genomics expertise among healthcare providers, decision aids (DAs) can help fill a critical gap in the clinical delivery of genome sequencing. We aim to assess the effectiveness of an interactive DA developed for selection of incidental results.

Methods and analysis

We will compare the DA in combination with a brief Q&A session with a genetic counsellor to genetic counselling alone in a mixed-methods randomised controlled trial. Patients who received negative standard cancer genetic results for their personal and family history of cancer and are thus eligible for sequencing will be recruited from cancer genetics clinics in Toronto. Our primary outcome is decisional conflict. Secondary outcomes are knowledge, satisfaction, preparation for decision-making, anxiety and length of session with the genetic counsellor. A subset of participants will complete a qualitative interview about preferences for incidental results.

Ethics and dissemination

This study has been approved by research ethics boards of St. Michael's Hospital, Mount Sinai Hospital and Sunnybrook Health Sciences Centre. This research poses no significant risk to participants. This study evaluates the effectiveness of a novel patient-centred tool to support clinical delivery of incidental results. Results will be shared through national and international conferences, and at a stakeholder workshop to develop a consensus statement to optimise implementation of the DA in practice.

Trial registration number

NCT03244202; Pre-results.

https://ift.tt/2vP6vil

Vibration-controlled Transient Elastography to Assess Fibrosis and Steatosis in Patients With Nonalcoholic Fatty Liver Disease

Vibration controlled transient elastography is a non-invasive method of detecting liver fat and fibrosis in patients with nonalcoholic fatty liver disease.

https://ift.tt/2JxO03X

Fat deposits as manifestation of alcohol use disorder: Madelung’s Disease

https://ift.tt/2KgZtWN

Distal attachment devices in colonoscopy: should they routinely be added?

https://ift.tt/2Ju28Lw

Acetyl-CoA Carboxylase Inhibitor GS-0976 for 12 Weeks Reduces Hepatic De Novo Lipogenesis and Steatosis in Patients with Nonalcoholic Steatohepatitis

Increased de novo lipogenesis (DNL) contributes to the pathogenesis of nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase catalyzes the rate-limiting step in DNL. We evaluated the safety and efficacy of GS 0976, a small molecule inhibitor of acetyl-CoA carboxylase, in patients with NASH.

https://ift.tt/2KipiFS

Characteristics and Outcomes Reported by Patients With Primary Sclerosing Cholangitis Through an Online Registry

We found that that a patient-driven online registry (the PSC Partners Patient Registry) is effective in recruiting patients for analysis of treatment, symptoms, and disease progression, and can provide information not obtained by studies performed at specialized centers, although many results are similar.

https://ift.tt/2KgpQw0

circRNA disease: a manually curated database of experimentally supported circRNA-disease associations

circRNA disease: a manually curated database of experimentally supported circRNA-disease associations

circRNA disease: a manually curated database of experimentally supported circRNA-disease associations, Published online: 27 April 2018; doi:10.1038/s41419-018-0503-3

circRNA disease: a manually curated database of experimentally supported circRNA-disease associations

https://ift.tt/2HvIthW

DNA methylation, through DNMT1, has an essential role in the development of gastrointestinal smooth muscle cells and disease

DNA methylation, through DNMT1, has an essential role in the development of gastrointestinal smooth muscle cells and disease

DNA methylation, through DNMT1, has an essential role in the development of gastrointestinal smooth muscle cells and disease, Published online: 27 April 2018; doi:10.1038/s41419-018-0495-z

DNA methylation, through DNMT1, has an essential role in the development of gastrointestinal smooth muscle cells and disease

https://ift.tt/2r4lHCH

The therapeutic effect of miR-125b is enhanced by the prostaglandin endoperoxide synthase 2/cyclooxygenase 2 blockade and hampers ETS1 in the context of the microenvironment of bone metastasis

The therapeutic effect of miR-125b is enhanced by the prostaglandin endoperoxide synthase 2/cyclooxygenase 2 blockade and hampers ETS1 in the context of the microenvironment of bone metastasis

The therapeutic effect of miR-125b is enhanced by the prostaglandin endoperoxide synthase 2/cyclooxygenase 2 blockade and hampers ETS1 in the context of the microenvironment of bone metastasis, Published online: 27 April 2018; doi:10.1038/s41419-018-0499-8

The therapeutic effect of miR-125b is enhanced by the prostaglandin endoperoxide synthase 2/cyclooxygenase 2 blockade and hampers ETS1 in the context of the microenvironment of bone metastasis

https://ift.tt/2HrZJV4

c-MYC and reactive oxygen species play roles in tetrandrine-induced leukemia differentiation

c-MYC and reactive oxygen species play roles in tetrandrine-induced leukemia differentiation

c-MYC and reactive oxygen species play roles in tetrandrine-induced leukemia differentiation, Published online: 27 April 2018; doi:10.1038/s41419-018-0498-9

c-MYC and reactive oxygen species play roles in tetrandrine-induced leukemia differentiation

https://ift.tt/2r1NFPr

HOXA4, down-regulated in lung cancer, inhibits the growth, motility and invasion of lung cancer cells

HOXA4, down-regulated in lung cancer, inhibits the growth, motility and invasion of lung cancer cells

HOXA4, down-regulated in lung cancer, inhibits the growth, motility and invasion of lung cancer cells, Published online: 27 April 2018; doi:10.1038/s41419-018-0497-x

HOXA4, down-regulated in lung cancer, inhibits the growth, motility and invasion of lung cancer cells

https://ift.tt/2HtH5fC

YAP1 contributes to NSCLC invasion and migration by promoting Slug transcription via the transcription co-factor TEAD

YAP1 contributes to NSCLC invasion and migration by promoting Slug transcription via the transcription co-factor TEAD

YAP1 contributes to NSCLC invasion and migration by promoting Slug transcription via the transcription co-factor TEAD, Published online: 27 April 2018; doi:10.1038/s41419-018-0515-z

YAP1 contributes to NSCLC invasion and migration by promoting Slug transcription via the transcription co-factor TEAD

https://ift.tt/2r5s0pt

Reduction of Endoplasmic Reticulum Stress Improves Angiogenic Progenitor Cell function in a Mouse Model of Type 1 Diabetes

Reduction of Endoplasmic Reticulum Stress Improves Angiogenic Progenitor Cell function in a Mouse Model of Type 1 Diabetes

Reduction of Endoplasmic Reticulum Stress Improves Angiogenic Progenitor Cell function in a Mouse Model of Type 1 Diabetes, Published online: 27 April 2018; doi:10.1038/s41419-018-0501-5

Reduction of Endoplasmic Reticulum Stress Improves Angiogenic Progenitor Cell function in a Mouse Model of Type 1 Diabetes

https://ift.tt/2r5s08X

A severe hemojuvelin mutation leading to late onset of HFE2-hemochromatosis

https://ift.tt/2r3OMOs

Leveraging organismal biology to forecast the effects of climate change

Abstract

Despite the pressing need for accurate forecasts of ecological and evolutionary responses to environmental change, commonly used modelling approaches exhibit mixed performance because they omit many important aspects of how organisms respond to spatially and temporally variable environments. Integrating models based on organismal phenotypes at the physiological, performance and fitness levels can improve model performance. We summarize current limitations of environmental data and models and discuss potential remedies. The paper reviews emerging techniques for sensing environments at fine spatial and temporal scales, accounting for environmental extremes, and capturing how organisms experience the environment. Intertidal mussel data illustrate biologically important aspects of environmental variability. We then discuss key challenges in translating environmental conditions into organismal performance including accounting for the varied timescales of physiological processes, for responses to environmental fluctuations including the onset of stress and other thresholds, and for how environmental sensitivities vary across lifecycles. We call for the creation of phenotypic databases to parameterize forecasting models and advocate for improved sharing of model code and data for model testing. We conclude with challenges in organismal biology that must be solved to improve forecasts over the next decade.acclimation, biophysical models, ecological forecasting, extremes, microclimate, spatial and temporal variability

https://ift.tt/2HyXmjC

Mitochondrial adaptations to variable environments and their role in animals’ stress tolerance

Abstract

Mitochondria are the key organelles involved in energy and redox homeostasis, cellular signaling and survival. Animal mitochondria are exquisitely sensitive to environmental stress, and stress-induced changes in the mitochondrial integrity and function have major consequences for the organismal performance and fitness. Studies in the model organisms such as terrestrial mammals and insects showed that mitochondrial dysfunction is a major cause of injury during pathological conditions and environmental insults such as hypoxia, ischemia-reperfusion and exposure to toxins. However, animals from highly stressful environments (such as the intertidal zone of the ocean) can maintain mitochondrial integrity and function despite intense and rapid fluctuations in abiotic conditions of their habitats and associated changes in the intracellular milieu. Recent studies demonstrate that mitochondria of intertidal organisms (including mollusks, crustaceans and fish) are capable of maintaining activity of mitochondrial electron transport system (ETS), ATP synthesis and mitochondrial coupling in a broad range of temperature, osmolarity and ion content. Mitochondria of intertidal organisms such as mollusks are also resistant to hypoxia-reoxygenation injury and show stability or even upregulation of the mitochondrial ETS activity and ATP synthesis capacity during intermittent hypoxia. In contrast, pH optima for mitochondrial ATP synthesis and respiration are relatively narrow in intertidal mollusks and may reflect adaptation to suppress metabolic rate during pH shifts caused by extreme stress. Sensitivity to anthropogenic pollutants (such as trace metals) in intertidal mollusks appears similar to that of other organisms (including mammals) and may reflect the lack of adaptation to these evolutionarily novel stressors. The mechanisms of the exceptional mitochondrial resilience to temperature, salinity and hypoxic stress are not yet fully understood in intertidal organisms, yet recent studies demonstrate that they may involve rapid modulation of the ETS capacity (possibly due to post-translation modification of mitochondrial proteins), upregulation of antioxidant defenses in anticipation of oxidative stress and high activity of mitochondrial proteases involved in degradation of damaged mitochondrial proteins. With rapidly developing molecular tools for non-model organisms, future studies of mitochondrial adaptations should pinpoint the molecular sites associated with the passive tolerance and/or active regulation of mitochondrial activity during stress exposures in intertidal organisms, investigate the roles of mitochondria in transduction of stress signals and explore the interplay between bioenergetics and mitochondrial signaling in facilitating survival in these highly stressful environments.

https://ift.tt/2r2xrp8

A dualistic model of primary anal canal adenocarcinoma with distinct cellular origins, etiologies, inflammatory microenvironments and mutational signatures: implications for personalised medicine

https://ift.tt/2r3Pr2j

Inside EMS Podcast: Is intubation dead in EMS?

Our co-hosts discuss the ever-changing practice of airway management

https://ift.tt/2HxRq6f

Intravenous Fish Oil Lipid Emulsion Prevents Catheter-Related Thromboses in Pediatric Patients with Intestinal Failure

A central venous catheter is a risk factor for deep vein thrombosis. We compared the incidence of deep vein thrombosis in children with intestinal failure patients receiving soy oil lipid emulsion (n = 35) vs fish oil lipid emulsion (n = 35). Ten deep vein thrombosis occurred in the soy oil lipid emulsion group, and none in the fish oil lipid emulsion group (P < .001).

https://ift.tt/2r7RXoD

Risk Factors, Geographic Distribution, and Healthcare Burden of Symptomatic Congenital Cytomegalovirus Infection in the United States: Analysis of a Nationally Representative Database, 2000-2012

To assess risk factors, geographic distribution, length of stay, and total charges per case of symptomatic congenital cytomegalovirus infection (cCMV).

https://ift.tt/2r7S1ET

Evaluation of FODMAP Carbohydrates Content in Selected Foods in the United States

We analyzed the fermentable oligosaccharide, disaccharide, monosaccharide, and polyols (FODMAP) content of several foods potentially low in FODMAP which are commonly consumed by children. We determined that several processed foods (eg, gluten-free baked products) had unlabeled FODMAP content. Determining FODMAP content within foods distributed in the US may support educational and dietary interventions.

https://ift.tt/2Hslcgx

Chronic School Absenteeism of Children with Chronic Kidney Disease

We evaluated the frequency of chronic school absenteeism (≥18 missed school days per year) among children with mild-to-moderate chronic kidney disease. Chronic absenteeism was present in 17.3% of children with chronic kidney disease, compared with 2.7% of children in the US National Health and Nutrition Examination Survey.

https://ift.tt/2HtshO4

Immediate Superficial Venous Thrombophlebitis Associated with Intravenous Administration of Ciprofloxacin

An 8-year-old child had asthma and a history of bladder exstrophy repair that was complicated by vesicocutaneous fistula formation. He underwent antegrade nephrostogram and nephrostomy tube replacement and received intravenous midazolam, fentanyl, and propofol for general anesthesia. The procedures were without complication. About 1.5 hours after the procedures while the patient was stable, he was given intravenous ciprofloxacin, which he had received the day before, via a peripheral line on his right hand.

https://ift.tt/2r3z45W

Regimen of procarbazine, lomustine, and vincristine versus temozolomide for gliomas

Cancer, EarlyView.


https://ift.tt/2Kd3bAR

More frequent use of health care services among distressed compared with nondistressed survivors of lymphoma and chronic lymphocytic leukemia: Results from the population‐based PROFILES registry

Cancer, EarlyView.


https://ift.tt/2JtWJUF

The Lambda Select cII Mutation Detection System

We describe a detailed protocol for the Lambda Select cII mutation assay in cultured cells of transgenic rodents or the corresponding animals treated with a chemical/physical agent of interest. This approach has been widely used for mutagenicity testing of carcinogens in mammalian cells.

https://ift.tt/2qZWv14

Fluorescence Molecular Tomography for In Vivo Imaging of Glioblastoma Xenografts

Orthotopic intracranial injection of tumor cells has been used in cancer research to study brain tumor biology, progression, evolution, and therapeutic response. Here we present fluorescence molecular tomography of tumor xenografts, which provides real-time intravital imaging and quantification of a tumor mass in preclinical glioblastoma models.

https://ift.tt/2HtCytz

Use of Two Dimensional Semi-denaturing Detergent Agarose Gel Electrophoresis to Confirm Size Heterogeneity of Amyloid or Amyloid-like Fibers

Here we use two-dimensional semi-denaturing agarose gel electrophoresis to confirm the presence of amyloid-like fibers of heterogeneous size and exclude the possibility that the size heterogeneity is due to dissociation of the amyloid fibers during the gel running process.

https://ift.tt/2r1L0oQ

Salinity effect on the metabolic pathway and microbial function in phenanthrene degradation by a halophilic consortium

With the close relationship between saline environments and industry, polycyclic aromatic hydrocarbons (PAHs) accumulate in saline/hypersaline environments. Therefore, PAHs degradation by halotolerant/halophil...

https://ift.tt/2Hxz6hx

Combinational Treatment of Trichostatin A and Vitamin C Improves the Efficiency of Cloning Mice by Somatic Cell Nuclear Transfer

We describe a dramatically improved method for mouse cloning using trichostatin A, vitamin C, and deionized bovine serum albumin. We show a simplified, reproducible protocol that supports efficient development of cloned embryos. Hence, this method could become a standardized procedure for mouse cloning.

https://ift.tt/2r3CeGO

Congressional baseball practice gunshot victim reunites with paramedics

By EMS1 Staff ALEXANDRIA, Va. — A lobbyist who was shot at the GOP congressional baseball team practice last June reunited with the paramedics who saved him. WTOP reported that paramedic Chad Shade and now-retired paramedic Fiona Apple reunited with Tyson Foods lobbyist Matt Mika at the first practice since the incident at Eugene Simpson Field, where James Hodgkinson opened fire near the third ...

https://ift.tt/2FjdTBS

NYPD officers help save elderly tourist in cardiac arrest

The police officers were driving by when they noticed a commotion around Ron Gargalowitz, who had gone into cardiac arrest while walking with his family

https://ift.tt/2Kg4b72

Dynamic human immune and tumour cells cross-talk in PDX-humanised mice warrants checkpoint inhibitor cancer immunotherapies assessment

The concept of exploiting the host's immune system to fight cancer relies on the concept of tumour immune surveillance, the insight that the immune system should eliminate malignant cells. Immunotherapy is a form of treatment aimed at manipulating the immune system to activate, break, regulate or reinforce immune functions. Cancer immunotherapy is revolutionising cancer treatment through the discovery and development of novel approaches that enhance the body's antitumour immune functions by 'releasing the brake' on the immune system: the so-called immune checkpoints (eg, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed death 1 (PD-1)) whose physiological functions are to limit autoimmune processes but are also co-opted by tumours allowing cancer immune escape mechanisms. In initial trials, checkpoint blockade showed success in promoting anti-tumour immunity and durable responses in patients with solid tumours. Several antibodies against the PD-1/PD-ligand-1 (PD-L1) checkpoint pathway have recently been approved in diverse indications (melanoma, non-small-cell lung cancer, head and neck...

https://ift.tt/2r7zXeT

Volunteering Could Equal Better Well Being

Whether you are feeling excited to get more involved, or glad that your volunteering time has concluded with this year's convention there is mounting evidence to support that the simple act of volunteering may positively impact your well-being.  A 2016 longitudinal study found that participants who regularly partook in volunteer activities experienced greater mental well-being ratings using the General Health Questionnaire.

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Establishing Mouse Models for Zika Virus-induced Neurological Disorders Using Intracerebral Injection Strategies: Embryonic, Neonatal, and Adult

Here we describe a method for establishing a model of Zika virus-induced microcephaly in mouse. This protocol includes methods for embryonic, neonatal, and adult-stage intracerebral inoculation of the Zika virus.

https://ift.tt/2vLXaYM

Assessment of the Effects of Endocrine Disrupting Compounds on the Development of Vertebrate Neural Network Function Using Multi-electrode Arrays

Exposure to environmental toxins can acutely impact developing embryos. Endocrine disrupting chemicals such as bisphenols are known to adversely affect the nervous system. Here we describe a protocol using an in vitro vertebrate (chick embryo) neuronal network model to study the functional impact of toxin exposure on early embryos.

https://ift.tt/2HSKNyM

Multiple Anesthesia Exposures Affect Learning and Attention

THURSDAY, April 26, 2018 -- Children with multiple exposures to anesthesia before age 3 are more likely to develop adverse outcomes related to learning and attention, according to a recent study published in Anesthesiology. Danqing Hu, M.D., from...

https://ift.tt/2r3EKgr

Multiple Myeloma Risk May Be Up for WTC-Exposed Firefighters

THURSDAY, April 26, 2018 -- World Trade Center-exposed firefighters have increased prevalence of monoclonal gammopathy of undetermined significance (MGUS) and light-chain MGUS, which are precursors to multiple myeloma, as well as an increased cancer...

https://ift.tt/2r7o4Vt

Patient Mortality Lower for Older Versus Young Surgeons

THURSDAY, April 26, 2018 -- For patients undergoing non-elective surgery, patient mortality is lower for older versus younger surgeons, according to a study published online April 25 in The BMJ. Yusuke Tsugawa, M.D., M.P.H., Ph.D., from the...

https://ift.tt/2HtwwJF

Proactive Swallowing Rehab Program Helpful in Phalangeal CA

THURSDAY, April 26, 2018 -- A proactive speech and language pathology (SLP) program is beneficial for patients with head and neck squamous cell carcinoma (HNSCC), according to a study published online April 19 in JAMA Otolaryngology-Head & Neck...

https://ift.tt/2HuQJyD

Saturday Is National Prescription Drug Take Back Day

THURSDAY, April 26, 2017 -- The U.S. Drug Enforcement Administration and local agencies are holding the 15th National Prescription Drug Take Back Day across the country this Saturday, April 28. Pills or patches can be dropped off between 10 a.m. and...

https://ift.tt/2r35RYL

Pros and Cons for E-Cigarettes As Aid to Smoking Cessation

THURSDAY, April 26, 2018 -- Evidence relating to the pros and cons of electronic cigarettes (e-cigarettes) as helpful smoking cessation tools is presented and discussed in a head to head article published online April 25 in The BMJ. Paul Aveyard,...

https://ift.tt/2HsXTmY

ACOG Committee Recommends Better, Ongoing Postpartum Care

THURSDAY, April 26, 2018 -- Postpartum care should become an ongoing process rather than a single visit in order to optimize the health of women and infants, according to a Committee Opinion published in the May issue of Obstetrics &...

https://ift.tt/2r2GB55

AAN: Cerliponase Alfa Beneficial for Form of Batten's Disease

THURSDAY, April 26, 2018 -- For children with neuronal ceroid lipofuscinosis type 2 (CLN2) disease, intraventricular infusion of cerliponase alfa is associated with reduced decline in motor and language function, according to a study published...

https://ift.tt/2HsXEs4

Tenecteplase Appears Superior to Alteplase After Ischemic Stroke

THURSDAY, April 26, 2018 -- For patients with ischemic stroke, treatment with tenecteplase within 4.5 hours of symptom onset and before thrombectomy is associated with better outcomes than treatment with alteplase during the same timeframe,...

https://ift.tt/2r0mdBq

Substance Use Disorders Linked to Conversion to Schizophrenia

THURSDAY, April 26, 2018 -- Substance use disorders are associated with conversion from schizotypal disorder to schizophrenia, according to a study published online April 25 in JAMA Psychiatry. Carsten Hjorthøj, Ph.D., from Copenhagen University...

https://ift.tt/2vNSb9L

Intracranial meningioma with carcinoma tumor-to-tumor metastasis: two case reports

CNS Oncology, Ahead of Print.


https://ift.tt/2I01ohE

Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology

Abstract

Neurogranin (Ng) is a post-synaptic protein that previously has been shown to be a biomarker for synaptic function when measured in cerebrospinal fluid (CSF). The CSF concentration of Ng is increased in Alzheimer's disease dementia (ADD), and even in the pre-dementia stage. In this prospective study, we used an enzyme-linked immunosorbent assay that quantifies Ng in CSF to test the performance of Ng as a marker of synaptic function. In 915 patients, CSF Ng was evaluated across several different neurodegenerative diseases. Of these 915 patients, 116 had a neuropathologically confirmed definitive diagnosis and the relation between CSF Ng and topographical distribution of different pathologies in the brain was evaluated. CSF Ng was specifically increased in ADD compared to eight other neurodegenerative diseases, including Parkinson's disease (p < 0.0001), frontotemporal dementia (p < 0.0001), and amyotrophic lateral sclerosis (p = 0.0002). Similar results were obtained in neuropathologically confirmed cases. Using a biomarker index to evaluate whether CSF Ng contributed diagnostic information to the core AD CSF biomarkers (amyloid β (Aβ), t-tau, and p-tau), we show that Ng significantly increased the discrimination between AD and several other disorders. Higher CSF Ng levels were positively associated with greater Aβ neuritic plaque (Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuritic plaque score, p = 0.0002) and tau tangle pathology (Braak neurofibrillary tangles staging, p = 0.0007) scores. In the hippocampus and amygdala, two brain regions heavily affected in ADD with high expression of Ng, CSF Ng was associated with plaque (p = 0.0006 and p < 0.0001), but not with tangle, α-synuclein, or TAR DNA-binding protein 43 loads. These data support that CSF Ng is increased specifically in ADD, that high CSF Ng concentrations likely reflect synaptic dysfunction and that CSF Ng is associated with β-amyloid plaque pathology.

https://ift.tt/2JsYFNf

Spred1 Safeguards Hematopoietic Homeostasis against Diet-Induced Systemic Stress

Tadokoro et al. show that Spred1 negatively regulates HSC self-renewal in a manner supported by ROCK activity and that Spred1 safeguards HSC homeostasis under high-fat diet (HFD) conditions by regulating HSC self-renewal. The gut microbiota dysbiosis induced by HFD disrupts the fine-tuning of Spred1-mediated signals that govern HSC homeostasis.

https://ift.tt/2r1fnvC

Complex life cycle, broad host range and adaptation strategy of the intranuclear Paramecium symbiont Preeria caryophila comb. nov.

Summary

Holospora and related bacteria are a group of obligate Paramecium symbionts. Characteristic features are their infectivity, the presence of two distinct morphotypes, and usually a strict specialization for a single Paramecium species as host and a nuclear compartment (either somatic or generative nucleus) for reproduction. Holospora caryophila steps out of line, naturally occurring in Paramecium biaurelia and Paramecium caudatum. This study addresses the phylogenetic relationship among H. caryophila and other Holospora species based on 16S rRNA gene sequence comparison analysing the type strain and seven new macronuclear symbionts. Key aspects of Holospora physiology such as infectivity, symbiosis establishment, and host range were determined by comprehensive infection assays. Detailed morphological investigations and sequence-based phylogeny confirmed a high similarity between the type strain of H. caryophila and the novel strains. Surprisingly, they are only distantly related to other Holospora species suggesting that they belong to a new genus within the family Holosporaceae, here described as Preeria caryophila comb. nov. Adding to this phylogenetic distance, we also observed a much broader host range, comprising at least eleven Paramecium species. As these potential host species exhibit substantial differences in frequency of sexual processes, P. caryophila demonstrates which adaptations are crucial for macronuclear symbionts facing regular destruction of their habitat.

https://ift.tt/2JtR7Kk

The role of bacteria in pine wilt disease: insights from microbiome analysis

Abstract

Pine Wilt Disease (PWD) has a significant impact on Eurasia pine forests. The microbiome of the nematode (the primary cause of the disease), its insect vector, and the host tree may be relevant for the disease mechanism. The aim of this study was to characterize these microbiomes, from three PWD-affected areas in Portugal, using Denaturing Gradient Gel Electrophoresis, 16S rRNA gene pyrosequencing, and a functional inference-based approach (PICRUSt). The bacterial community structure of the nematode was significantly different from the infected trees but closely related to the insect vector, supporting the hypothesis that nematode microbiome might be in part inherited from the insect. Sampling location influenced mostly the tree microbiome (P < 0.05). Genes related both with plant growth promotion and phytopathogenicity were predicted for the tree microbiome. Xenobiotic degradation functions were predicted in the nematode and insect microbiomes. Phytotoxin biosynthesis was also predicted for the nematode microbiome, supporting the theory of a direct contribution of the microbiome to tree wilting. This is the first study that simultaneously characterized the nematode, tree and insect-vector microbiomes, from the same affected areas and overall the results support the hypothesis that PWD microbiome plays an important role in the disease development.

https://ift.tt/2KgcnEv

MetaCompare: A computational pipeline for prioritizing environmental resistome risk

Abstract

The spread of antibiotic resistance is a growing public health concern. While numerous studies have highlighted the importance of environmental sources and pathways of the spread of antibiotic resistance, a systematic means of comparing and prioritizing risks represented by various environmental compartments is lacking. Here we introduce MetaCompare, a publicly-available tool for ranking 'resistome risk,' which we define as the potential for antibiotic resistance genes (ARGs) to be associated with mobile genetic elements (MGEs) and mobilize to pathogens based on metagenomic data. A computational pipeline was developed in which each ARG is evaluated based on relative abundance, mobility, and presence within a pathogen. This is determined through assembly of shotgun sequencing data and analysis of contigs containing ARGs to determine if they contain sequence similarity to MGEs or human pathogens. Based on the assembled metagenomes, samples are projected into a 3-D hazard space and assigned resistome risk scores. To validate, we tested previously published metagenomic data derived from distinct aquatic environments. Based on unsupervised machine learning, the test samples clustered in the hazard space in a manner consistent with their origin. The derived scores produced a well-resolved ascending resistome risk ranking of: wastewater treatment plant effluent, dairy lagoon, hospital sewage.

https://ift.tt/2Jt7giV

Influence of uvrA, recJ and recN gene mutations on nucleoid reorganization in UV-treated Escherichia coli cells

Abstract

Exposure to ultraviolet (UV) radiation blocks DNA replication and arrests cellular division in Escherichia coli. Restoration of chromosome replication involves nucleoid reorganization, which involves the participation of the recombination-catalysing proteins RecA, RecO, RecR and RecN. In the present work, we evaluated the influence of recN, uvrA and recJ gene mutations on post-irradiation nucleoid reorganization. We used isogenic E. coli strains that are defective for these genes to study post-irradiation kinetics of the nucleoid shape fractions using fluorescence microscopy. The results showed that in the wild-type strain, post-irradiation nucleoid reorganization occurs, which restores the nucleoid shape fractions in the cells to those observed prior to irradiation. First, the nucleoid condenses into the central area of the irradiated cell. Second, the nucleoid disperses along the cell. Third, the cell enters the chromosome replicative phase and cytokinesis. E. coli cells with a recN mutation did not exhibit increased nucleoid condensation, but chromosome replication and cytokinesis occurred. In the uvrA and recJ strains, the condensation step was delayed compared to the wild-type strain, and chromosome replication and cytokinesis did not occur. The results are discussed with an emphasis on the functions of RecN, UvrA and RecJ in nucleoid reorganization in UV-irradiated E. coli cells.

https://ift.tt/2Hvo9cj

The use of gamification in the teaching of disease epidemics and pandemics

https://ift.tt/2I0YtFD

Dissemination of blaNDM-5 gene via an IncX3-type plasmid among non-clonal Escherichia coli in China

The emergence and spread of New Delhi metallo-β-lactamase-producing Enterobacteriaceae has been a serious challenge to manage in the clinic due to its rapid dissemination of multi-drug resistance worldwide. As on...

https://ift.tt/2r2EHBl

Does Non-Adherence Increase Treatment Costs in Schizophrenia?

Abstract

Introduction

Medication non-adherence is a serious barrier to treatment of schizophrenia. Understanding the impact of non-adherence on costs is essential to the assessment of the cost effectiveness of interventions in which adherence to treatment is a concern.

Objectives

We undertook a comprehensive review of the available literature on the impact on costs of non-adherence to antipsychotics in the treatment of schizophrenia.

Methods

We performed a search on multiple databases (MEDLINE, Embase, PsycINFO and Health Management Information Consortium) for any study reporting the impact of adherence to antipsychotics on costs in patients with schizophrenia up to February 2018. We included trials of behavioural interventions but excluded comparisons of different pharmacological therapies. Studies were included if at least one-third of the study population had schizophrenia and costs were reported.

Results

Thirty-four publications on 28 studies met the inclusion criteria. Twenty studies reported analyses of administrative databases, primarily Medicaid. Findings on healthcare costs were mixed but suggested that lower pharmacy costs in non-adherent patients may outweigh increased hospitalisation costs where drug costs are relatively high. A few studies published analysis of prospective cohort data, or trials of behavioural interventions intended to influence adherence, mainly in a European setting. Findings were again mixed but indicate that increasing adherence does not reduce overall costs.

Conclusions

Inference from analysis of administrative data is limited by the risk of selection bias. Inference from trials is limited by small sample sizes. The literature does not consistently support an assumption that non-adherence increases healthcare costs.

https://ift.tt/2HuO204

A case–control study of HIV infection and cancer in the era of antiretroviral therapy in Rwanda

International Journal of Cancer, EarlyView.


https://ift.tt/2r1b0AQ

Phase Ib/II study of safety and efficacy of low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory alimentary tract cancer

International Journal of Cancer, EarlyView.


https://ift.tt/2HsHq28

Bacteria boost antifungal drug resistance in severe childhood tooth decay

Some young children experience severe tooth decay that resist normal therapies. New research shows how plaque's protective matrix can shield fungal cells from the drugs intended to kill them.

https://ift.tt/2HVXbyd

Microwave‐Assisted Extraction of Lipids from Wet Microalgae Paste: A Quick and Efficient Method

European Journal of Lipid Science and Technology, EarlyView.


https://ift.tt/2r01rlq

Changing directions for emergency medicine in 2018: from the ‘Beast from the East’ to the ‘Best in the West’

No abstract available

https://ift.tt/2r0pTnz

‘Single-checked’ Patient Group Directions during initial nurse assessment within paediatric emergency departments of the UK and Ireland

Objective Double checking medications at initial assessment within paediatric emergency departments (EDs) has the potential to delay patient flow, and doubt has been cast on the efficacy of double checking in all but high-risk medications. We aimed to benchmark current practice for the use of Patient Group Direction (PGD) medications at initial assessment in EDs within the Paediatric Emergency Research UK and Ireland (PERUKI) network, with a focus on the use of 'single-checker' PGDs. Methods Online survey was distributed to the research representative at each PERUKI site. The survey was open for 5 weeks (from March 2015 to April 2015) and was completed by any appropriate clinician within the site. Results The response rate was 84% (36/43 EDs). From these, 22 out of 36 (61%) EDs were using single-checker PGDs. The commonest single-checked medications in use were paracetamol and ibuprofen for pain. Among PERUKI sites, 21.9% of EDs reported drug errors related to standard (double-checked) PGDs, whereas 13.6% of those with single-checked PGDs reported drug errors (Fisher's exact test with significance level of 0.05, P=0.501). The commonest errors reported were duplicated dose, incorrect weight, incorrect volume drawn up, contraindication missed. Conclusion Single-checker PGDs are currently in use in nearly two-thirds of PERUKI sites. No evidence of increased medication errors was reported with this practice; however, more detailed studies are required to support this finding and to inform best practice.

https://ift.tt/2HudfUa

Reliability and validity of emergency department triage tools in low- and middle-income countries: a systematic review

Objective Despite the universal acknowledgment that triage is necessary to prioritize emergency care, there is no review that provides an overview of triage tools evaluated and utilized in resource-poor settings, such as low- and middle-income countries (LMICs). We seek to quantify and evaluate studies evaluating triage tools in LMICs. Methods We performed a systematic review of the literature between 2000 and 2015 to identify studies that evaluated the reliability and validity of triage tools for adult emergency care in LMICs. Studies were then evaluated for the overall quality of evidence using the GRADE criteria. Results Eighteen studies were included in the review, evaluating six triage tools. Three of the 18 studies were in low-income countries and none were in rural hospitals. Two of the six tools had evaluations of reliability. Each tool positively predicted clinical outcomes, although the variety in resource environments limited ability to compare the predictive nature of any one tool. The South African Triage Scale had the highest quality of evidence. In comparison with high-income countries, the review showed fewer studies evaluating reliability and presented a higher number of studies with small sample sizes that decreased the overall quality of evidence. Conclusion The quality of evidence supporting any single triage tool's validity and reliability in LMICs is moderate at best. Research on triage tool applicability in low-resource environments must be targeted to the actual clinical environment where the tool will be utilized, and must include low-income countries and rural, primary care settings.

https://ift.tt/2HRr1DY

Prognostic value of infrared thermography in an emergency department

Objective In this study, we aimed to investigate the prognostic potential of infrared thermography in a population of medical patients admitted to the emergency department. Central-to-peripheral temperature gradients were analyzed for association with 30-day mortality. Methods This prospective observational study included 198 medical patients admitted to the Emergency Department, at Odense University Hospital. A standardized thermal picture was taken and temperatures of the inner canthus, the earlobe, the nose tip, and the tip of the third finger were reported. The inner canthus was chosen as a marker for central temperature and the three others as markers for peripheral temperatures, resulting in three gradients per patient. Thirty-day follow-up was performed and 30-day mortality was reported. Results One hundred and ninety-eight patients were included and the number of events was nine. The gradient between the inner canthus and the nose tip (ΔN) and the gradient between the inner canthus and the fingertip (ΔF) showed a significant association with 30-day mortality (ΔN: odds ratio: 1.31; 95% confidence interval: 1.05–1.64 and ΔF: odds ratio: 1.27; 95% confidence interval: 1.02–1.57). Conclusion ΔN and ΔF showed a significant association with 30-day mortality, suggesting a prognostic value. However, this was a small pilot study with few events. Larger studies are warranted for confirmation of these findings.

https://ift.tt/2JsJaEZ

Review of existing measurement tools to assess spinal motion during prehospital immobilization

The quantification of spinal movement to investigate the efficacy of prehospital immobilization devices and techniques remains difficult. Therefore, we aim to systematically review the literature on reported measurement tools applicable within this research field. A keyword literature search of relevant articles was performed using the database of PubMed including international literature published in English between January 2010 and December 2015. Only studies describing methods applicable to estimate spinal movement during prehospital immobilization were included. Six measurement tools were found that have either been used (goniometer/inclinometer, imaging modalities, electromagnetic systems, and optoelectronic systems) or have the potential to be used (inertial measurement units and a combination of strain gauge technology and accelerometers) in this research field. Novel devices can assess spinal motion during prehospital care including extrication, application of immobilization devices, and transportation from the site of the accident to the final destination, and therefore can be considered for usage.

https://ift.tt/2r2FdQE

Improved response time following a change in the transport system of newborns

No abstract available

https://ift.tt/2JwjCXx

Emergency Heart Failure Mortality Risk Grade score performance for 7-day mortality prediction in patients with heart failure attended at the emergency department: validation in a Spanish cohort

Objective The Emergency Heart Failure Mortality Risk Grade (EHMRG) scale, derived in 86 Canadian emergency departments (EDs), stratifies patients with acute-decompensated heart failure (ADHF) according to their 7-day mortality risk. We evaluated its external validity in a Spanish cohort. Patients and methods We applied the EHMRG scale to ADHF patients consecutively included in the Epidemiology of Acute Heart Failure in Emergency departments (EAHFE) registry (29 Spanish EDs) and measured its performance. Patients were distributed into quintiles according to the original and their self-defined score cutoffs. The 7-day mortality rates were compared internally among different categories and with categories of Canadian cohorts. Results The EAHFE group [n: 1553 patients; 80 (10) years; 55.6% women] had a 5.5% 7-day mortality rate and the EHMRG scale c-statistic was 0.741 (95% confidence interval: 0.688–0.793) compared with 0.807 (0.761–0.842) and 0.804 (0.763–0.840) obtained in the Canadian derivation and validation cohorts. The mortality rate of the EAHFE group mortality increased progressively as the quintile categories increased using intervals defined by either the Canadian or the Spanish EHMRG score cutoffs, although with more regular increments with the EAHFE-defined intervals; using the latter, patients at quintiles 2, 3, 4, 5a and 5b had (compared with quintile 1) odds ratios of 1.77, 3.36, 4.44, 9.39 and 16.19, respectively. Conclusion The EHMRG scale stratified risk in an ADHF cohort that included both palliative and nonpalliative patients in Spanish EDs, showing an extrapolation to a higher mortality risk cohort than the original derivation sample. Stratification improved when the score was recalibrated in the Spanish cohort.

https://ift.tt/2HObbK6

Impact of a general practitioners’ strike and of terrorist attacks on a call centre

Objective We aimed to evaluate the impact of the same-day GPs' strike and terrorist attacks on a call centre's activity. Methods We compared the number of calls received, the number of patient's medical files (PMFs) created and the number of mobile ICU (MICU) dispatched per hour on Friday, 13 November, to the repository established on the five previous Fridays. As previously published, the variation criterion was set to an activity variation above 20% for more than 2 h. Results On Friday, 13 November, 1745 calls were received compared with 1455 calls, on average, for the five previous Fridays. The number of calls received increased after the terrorist attacks (≤90%) and remained above the threshold for 3 h. The number of PMFs exceeded the threshold from 10:00 a.m. to 05:00 p.m., but was not affected by the attacks. The number of MICUs dispatched exceeded the threshold (>500%) in the first hour after the attacks. Conclusion The GPs' strike and the terrorist attacks did not impact our call centre's activity in the same manner. The strike increased the number of PMFs without increasing the number of calls received. The attacks increased the number of calls received and MICU dispatched without increasing the number of PMFs. Many markers are at the disposal of call centres to evaluate the impact of healthcare events.

https://ift.tt/2JtvutC

Value of the coronary artery disease consortium rule in patients with acute chest pain and negative troponins referred for exercise stress testing

Objective To assess the value of the pretest probability (PTP) of coronary artery disease (CAD) for predicting stress testing results and coronary events in patients with acute chest pain and negative troponins. Patients and methods A total of 3527 patients without a history of CAD referred to our chest pain unit with suspected acute coronary syndromes, nondiagnostic ECGs, and negative troponin levels underwent exercise stress testing. PTP was estimated with the CAD consortium prediction rule, and was categorized as low (85%). The endpoints were the presence of signs of inducible myocardial ischemia on stress testing and the occurrence of coronary events within 6 months. Results The probability of exercise-induced myocardial ischemia was 2.6, 12.6, 42.9, and 82.1% in patients with low, low–intermediate, intermediate–high, and high PTP, respectively (Ptrend

https://ift.tt/2HSdHyR