Critical Care Ultrasound: A Systematic Review of International Training Competencies and Programmes

Objectives: Critical care ultrasonography has become established within ICUs as a diagnostic tool and to guide management strategies and practical procedures. Following an international consensus statement in 2011, various national professional societies and organizations have sought to develop and deliver training programmes. The aim of this review was to assess the similarities and differences among these postgraduate intensive care/critical care training programmes. Data Sources: A systematic review was performed in two steps. First, we searched medical databases and national societies' websites for documents meeting predefined inclusion criteria. If not found, professionals related to critical care ultrasonography were contacted. Data Extraction: Data were extracted independently by two authors. Analyses were conducted on general training requirements as well as specific competencies defined in the documents. Data Synthesis: Eight national programmes from seven countries were identified from a total of 25 countries; all identified programmes have defined competencies for core critical care ultrasonography. Although there were common themes across these programmes, significant variations in training requirements and assessments existed, for example, number of scans required for echocardiography training ranged from 10 to 100. Furthermore, the specifics of each ultrasound module varied between programmes. Conclusions: Despite widespread and increasing use of ultrasound in ICUs, the majority of countries lacked a formal training programme and clearly defined competencies. Even among the countries where these are available, there remains variability. There is a need to better define the competencies required in core critical care ultrasonography and standardize the assessment process. The idea for the article was conceived by Drs. Wong and Galarza. Contacting the various national and professional societies was carried out by all three authors. Analysis of the various programmes was carried out by Drs. Wong and Galarza. All three authors drafted the article and have read and approved the final article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://bit.ly/29S62lw). Funding for publication cost supported by unrestricted grant Q37 for Dr. Duska from Charles University, Prague, Czech Republic. Drs. Wong and Duska are members of the Clinical Training Committee. Dr. Galarza is a member of the NEXT Committee. All authors are members of the European Society of Intensive Care Medicine. Ethical approval: This is a narrative review and no ethical approval or consent was required. Availability of data and material: Data sharing not applicable to this article as no datasets were generated or analyzed during the current status. For information regarding this article, E-mail: avkwong@mac.com Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

http://bit.ly/2RqPAgo

A Pilot Study Identifying Brain-Targeting Adaptive Immunity in Pediatric Extracorporeal Membrane Oxygenation Patients With Acquired Brain Injury

Objectives: Extracorporeal membrane oxygenation provides short-term cardiopulmonary life support, but is associated with peripheral innate inflammation, disruptions in cerebral autoregulation, and acquired brain injury. We tested the hypothesis that extracorporeal membrane oxygenation also induces CNS-directed adaptive immune responses which may exacerbate extracorporeal membrane oxygenation-associated brain injury. Design: A single center prospective observational study. Setting: Pediatric and cardiac ICUs at a single tertiary care, academic center. Patients: Twenty pediatric extracorporeal membrane oxygenation patients (0–14 yr; 13 females, 7 males) and five nonextracorporeal membrane oxygenation Pediatric Logistic Organ Dysfunction score matched patients Interventions: None. Measurements and Main Results: Venous blood samples were collected from the extracorporeal membrane oxygenation circuit at day 1 (10–23 hr), day 3, and day 7 of extracorporeal membrane oxygenation. Flow cytometry quantified circulating innate and adaptive immune cells, and CNS-directed autoreactivity was detected using an in vitro recall response assay. Disruption of cerebral autoregulation was determined using continuous bedside near-infrared spectroscopy and acquired brain injury confirmed by MRI. Extracorporeal membrane oxygenation patients with acquired brain injury (n = 9) presented with a 10-fold increase in interleukin-8 over extracorporeal membrane oxygenation patients without brain injury (p

http://bit.ly/2RmiiyZ

Six Hours of Manual Ventilation With a Bag-Valve-Mask Device Is Feasible and Clinically Consistent

Objectives: Manual ventilation of intubated patients is a common intervention. It requires skill as well as physical effort and is typically restricted to brief periods. Prolonged manual ventilation may be unavoidable in some scenarios, for example, extreme mass casualty incidents. The present study tested whether nurses are capable of appropriately manually ventilating patients for 6 hours. Design: Volunteers performed ventilation on an electronic simulator for 6 hours while their own cardiorespiratory variables and the quality of the delivered ventilation were measured and recorded. The volunteers scored their perceived level of effort on a standard Borg Scale. Setting: Research laboratory at the Emergency Department, Tel Aviv Medical Center. Subjects: Ten nursing staff members of the Tel Aviv Sourasky Medical Center, 25–43 years old. Interventions: Volunteers ventilated manually a lung simulator for 6 hours. Measurements and Main Results: The subjects' physiologic states, including blood pressure, heart rate, respiratory rate, and oxygen saturation, showed no significant changes over time. The quality of delivered ventilation was somewhat variable, but it was stable on the average: average tidal volume ranged between 524.8 and 607.0 mL (p = 0.33). There was a slight but significant increase (7.3–10.9 L/min [p = 0.048]) in minute volume throughout the test period, reaching values consistent with mild hyperventilation. The subjects scored their perceived working effort as very light to fairly light, with a nonsignificant gradual increase in the Borg score as the study progressed. Conclusions: Manual ventilation of intubated patients can be performed continuously for 6 hours without excessive physical effort on the part of the operator. The quality of delivered ventilation was clinically adequate for all of them. There was a mild but significant trend toward hyperventilation, albeit within safe clinical levels, which was due to an increasing ventilatory rate rather than an increase in tidal volume. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: dr_halperin@tlvmc.gov.il Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

http://bit.ly/2Cgiy8n

Durotaxis by Human Cancer Cells

Durotaxis is a type of directed cell migration in which cells respond to a gradient of extracellular stiffness. Using automated tracking of positional data for large sample sizes of single migrating cells, we investigated: (a) whether cancer cells can undergo durotaxis, (b) whether cell durotactic efficiency varies depending on the regional compliance of stiffness gradients, (c) whether a specific cell migration parameter such as speed or time of migration correlates with durotaxis, and (d) whether Arp2/3, previously implicated in leading edge dynamics and migration, contributes to cancer cell durotaxis.

http://bit.ly/2SLzbzD

Fold-change detection of NF-κB at target genes with different transcript outputs

The transcription factor NF-κB promotes inflammatory and stress-responsive gene transcription across a range of cell types in response to the cytokine tumor necrosis factor (TNF). Although NF-κB signaling exhibits significant variability across single cells, some target genes supporting high levels of TNF-inducible transcription exhibit fold-change detection of NF-κB, which may buffer against stochastic variation in signaling molecules. It is unknown if fold-change detection is maintained at NF-κB target genes with low levels of TNF-inducible transcription, for which stochastic promoter events may be more pronounced.

http://bit.ly/2SKFnrW

A dynamic hydrophobic core and surface salt bridges thermostabilize a designed three-helix bundle

Thermostable proteins are advantageous in industrial applications, as pharmaceuticals or biosensors, and as templates for directed evolution. As protein design methodologies improve, bioengineers are able to design proteins to perform a desired function. While many rationally designed proteins end up being thermostable, how to intentionally design de novo, thermostable proteins is less clear. UVF is a de novo designed protein based on the backbone structure of the Engrailed homeodomain (EnHD) and is highly thermostable (Tm > 99°C vs.

http://bit.ly/2AGD6Xu

Identification of Binding Sites for Efflux Pump Inhibitors of the Escherichia coli AcrAB-TolC component AcrA

The overexpression of multidrug efflux pumps is an important mechanism of clinical resistance in Gram-negative bacteria. Recently, four small molecules were discovered that inhibit efflux in Escherichia coli and interact with the AcrAB-TolC efflux pump component AcrA. However, the binding site(s) for these molecules was not determined. Here, we combine ensemble docking and molecular dynamics simulations with tryptophan fluorescence spectroscopy, site-directed mutagenesis, and antibiotic susceptibility assays to probe binding sites and effects of binding of these molecules.

http://bit.ly/2AIGNfD

Design and antimicrobial activities of LL‐37 derivatives inhibiting the formation of Streptococcus mutans biofilm

This study indicates that IG‐13‐1 and IG‐13‐2 are potent antimicrobial peptides in inhibiting the growth of Streptococcus mutans and the formation of its biofilm. The modes of action of these peptides are involved with the interaction with the bacterial membrane which led to the disruption of the integrity of cell membrane. Therefore, IG‐13‐1 and IG‐13‐2 show a potential application for the prevention and treatment of dental caries.

Abstract

Dental plaque is closely related to the occurrence of dental caries, of which the main causative bacterium is Streptococcus mutans (S. mutans). In this study, to create potent antibiofilm agents, we chose a human antimicrobial peptide LL‐37 as our starting material and modified it by cutting it shorter and varying its charge and hydrophobicity. The results of anti‐S. mutans as well as biofilm inhibitory activity tests indicated that two derivatives, IG ‐13‐1 and IG‐13‐2, were the most potent one toward both planktonic and biofilm S. mutans cells with the minimal inhibitory concentration of 5.0 μM and minimal biofilm inhibitory concentrations of 5.91 ± 0.91 μM and 7.58 ± 0.23 μM, respectively. The modes of action study showed that IG ‐13‐1 and IG‐13‐2 were functioned by disrupting the bacterial membrane, causing the leakage of inner contents, thereby leading to the death of bacterial cells eventually. In addition, IG ‐13‐1 and IG‐13‐2 were able to suppress the expression of proinflammatory cytokine of TNF‐α and reduce the level of nuclear transcription factor‐κB, which indicated the potential anti‐inflammatory activity of these peptides. Conclusively, this study indicated that IG‐13‐1 and IG‐13‐2 are potent peptides in both anti‐S. mutans and anti‐inflammatory activities, therefore, showing a potential application for the prevention and treatment of dental caries.

http://bit.ly/2RFs2E1

Cover Image, Volume 176A, Number 12, December 2018

The cover image is based on the Research Article Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features by Caleb P. Bupp et al., DOI: 10.1002/ajmg.a.40523.

http://bit.ly/2SVnuqx

Abundant GAD‐reactive B cells in GAD‐antibody‐associated neurological disorders

ABSTRACT

High levels of antibodies against glutamic acid decarboxylase (GAD) are observed in patients with different neurological disorders, but cells producing these auto‐antibodies are largely unexplored. We detect circulating GAD‐reactive B cells in peripheral blood that readily differentiate into antibody‐producing cells. These cells are highly elevated in most patients with GAD‐antibody‐associated disorders (n=15) compared to controls (n=19). They mainly produce GAD65‐antibodies of the IgG1 and IgG4 subclasses and are as abundant as B cells reactive for common recall antigens. Bone marrow cells represent an additional source of GAD‐antibodies. The identification of GAD‐antibody‐producing cells has implications for the selection of cell‐specific biologics.

This article is protected by copyright. All rights reserved.

http://bit.ly/2FtYN0f

Cerebellar degeneration correlates with motor symptoms in Huntington's disease

ABSTRACT

Objective

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by variable motor and behavioural symptoms attributed to major neuropathology of mainly the basal ganglia and cerebral cortex. The role of the cerebellum, a brain region involved in the coordination of movements, in HD neuropathology has been controversial. This study utilises post‐mortem human brain tissue to investigate whether Purkinje cell degeneration in the neocerebellum is present in HD, and how this relates to disease symptom profiles.

Methods

Unbiased stereological counting methods were used to quantify the total number of Purkinje cells in 15 HD cases and 8 neurologically normal control cases. Based on their predominant symptoms, the HD cases were categorised into two groups: "motor" or "mood".

Results

The results demonstrated a significant 43% loss of Purkinje cells in HD cases with predominantly motor symptoms, and no cell loss in cases showing a major mood phenotype. There was no significant correlation between Purkinje cell loss and striatal neuropathological grade, post‐mortem delay, CAG repeat in the IT15 gene or age at death.

Interpretation

This study shows a compelling relationship between Purkinje cell loss in the HD neocerebellum and the HD motor symptom phenotype, which, together with our previous human brain studies on the same HD cases, provide novel perspectives interrelating and correlating the variable cerebellar, basal ganglia and neocortical neuropathology with the variability of motor/mood symptom profiles in the human HD brain.

This article is protected by copyright. All rights reserved.

http://bit.ly/2Fx5IpJ

APRIL‐mediated anti‐inflammatory response of astrocytes in multiple sclerosis

Abstract

Objective

the two related TNF members APRIL and BAFF are currently targeted in autoimmune diseases as B‐cell regulators. In multiple sclerosis (MS), combined APRIL/BAFF blockade led to an unexpected exacerbated inflammation in the central nervous system (CNS) of patients. Here, we investigate the role of the APRIL/BAFF axis in the CNS.

Methods

APRIL expression was analyzed in MS lesions by immunohistochemistry. The in vivo role of APRIL was assessed in the murine MS model, experimental autoimmune encephalitis (EAE). Functional in vitro studies were performed with human and mouse astrocytes.

Results

APRIL was expressed in lesions from EAE. In its absence, the disease was worst. Lesions from MS patients also showed APRIL expression upon infiltration of macrophages. Notably, all the APRIL secreted by these macrophages specifically targeted astrocytes. The upregulation of chondroitin sulfate proteoglycan (CSPG) bearing sometimes chondroitin sulfate of type E sugar moieties, binding APRIL, in reactive astrocytes explained the latter selectivity. Astrocytes responded to APRIL by producing sufficient amount of IL‐10 to dampen antigen‐specific T‐cell proliferation and pathogenic cytokine secretion. Finally, an intraspinal delivery of recombinant APRIL before disease onset shortly reduced EAE symptoms. Repeated intravenous injections of recombinant APRIL before and even at disease onset had also an effect.

Interpretation

our data show that APRIL mediates an anti‐inflammatory response from astrocytes in MS lesions. This protective activity is not shared with BAFF.

This article is protected by copyright. All rights reserved.

http://bit.ly/2Fq6vJE

Brain and cord imaging features in neuromyelitis optica spectrum disorders

Abstract

Objectives

To validate imaging features able to discriminate neuromyelitis optica spectrum disorders from multiple sclerosis with conventional MRI.

Methods

In this cross‐sectional study, brain and spinal cord scans were evaluated from 116 neuromyelitis optica spectrum disorders patients (98 seropositive and 18 seronegative) in chronic disease phase and 65 age‐, sex‐ and disease duration‐matched multiple sclerosis patients. To identify independent predictors of neuromyelitis optica diagnosis, after assessing the prevalence of typical/atypical findings, the original cohort was 2:1 randomized in a training sample (where a multivariate logistic regression analysis was run) and a validation sample (where the performance of the selected variables was tested and validated).

Results

Typical brain lesions occurred in 50.9% of neuromyelitis optica patients (18.1% brainstem periventricular/periaqueductal; 32.7% periependymal along lateral ventricles, 3.4% large hemispheric; 6.0% diencephalic; 4.3% cortico‐spinal tract), 72.2% had spinal cord lesions (46.3% long transverse myelitis, 36.1% short transverse myelitis) 37.1% satisfied 2010 McDonald criteria and none had cortical lesions. Fulfillment of at least 2/5 of: absence of juxtacortical/cortical lesions, absence of periventricular lesions, absence of Dawson's fingers, presence of long transverse myelitis or presence of periependymal lesions along lateral ventricles, discriminated neuromyelitis optica patients in both training (sensitivity [95% confidence interval ]=0.92 [0.84‐0.97], specificity=0.91 [0.78‐0.97]) and validation samples (sensitivity=0.82 [0.66‐0.92], specificity=0.91 [0.71‐0.99]). MRI findings and criteria performance were similar irrespective of serostatus.

Interpretation

Although up to 50% of neuromyelitis optica patients have no typical lesions and a relatively high percentage of them satisfies multiple sclerosis criteria, several easily applicable imaging features can help to identify neuromyelitis optica from multiple sclerosis.

This article is protected by copyright. All rights reserved.

http://bit.ly/2FuFaW6

Amyloid‐β Immunotherapy for Alzheimer's Disease – Is It Now A Long Shot…?

Abstract

The amyloid‐β (Aβ) cascade hypothesis of Alzheimer's disease (AD) holds that brain accumulation of Aβ initiates the disease process. Accordingly, drug research has targeted Aβ production, clearance or deposition as therapeutic strategies. Unfortunately, candidate drugs have failed to show clinical benefit in established, early or prodromal disease, or those with high AD risk. Currently, monoclonal antibodies specifically directed against the most neurotoxic Aβ forms are undergoing large scale trials to confirm initially encouraging results. However, recent findings on the normal physiology of Aβ suggest that accumulation may be compensatory rather than the pathological initiator. If this is true, alternative strategies will be needed to defeat this devastating disease.

This article is protected by copyright. All rights reserved.

http://bit.ly/2Fq6qpk

SLC13A3 variants cause acute reversible leukoencephalopathy and αKG accumulation

Abstract

Objective

SLC13A3 encodes the plasma membrane Na⁺/Dicarboxylate Cotransporter 3 (NaDC3), which imports inside the cell four to six carbon dicarboxylates as well as N‐acetylaspartate (NAA). SLC13A3 is mainly expressed in kidney, in astrocytes and in the choroid plexus. We describe two unrelated patients presenting with acute, reversible (and recurrent in one) neurological deterioration during a febrile illness. Both patients exhibited a reversible leukoencephalopathy and a markedly increased and persisting over time urinary excretion of α‐ketoglutarate (αKG). In one patient, increased cerebrospinal fluid NAA and dicarboxylates (including αKG) concentrations were observed. Extensive workup was unsuccessful and a genetic cause was suspected.

Methods

Whole exome sequencing (WES) was performed. Our teams were connected through GeneMatcher.

Results

WES analysis revealed variants in SLC13A3. A homozygous missense mutation (p.Ala254Asp) was found in the first patient. The second patient was heterozygous for another missense mutation (p.Gly548Ser) and an intronic mutation affecting splicing as demonstrated by RT‐PCR performed in muscle tissue (c.1016+3A>G). Mutations and segregation were confirmed by Sanger sequencing. Functional studies performed on HEK293T cells transiently transfected with wild type and mutant SLC13A3 indicated that the missense mutations caused a marked reduction in the capacity to transport αKG, succinate and NAA.

Interpretation

SLC13A3 deficiency causes acute and reversible leukoencephalopathy with marked accumulation of αKG. Urine organic acids (especially αKG and NAA) and SLC13A3 mutations should be screened in patients presenting with unexplained reversible leukoencephalopathy for which SLC13A3 deficiency is a novel differential diagnosis.

This article is protected by copyright. All rights reserved.

http://bit.ly/2FoHy1g

Long Non-Coding RNA SPRY4-IT1 Can Predict Poor Prognosis in Digestive System Malignancies: a Meta-Analysis

Abstract

Recent studies have reported that long non-coding RNA SPRY4 intron transcript 1 (SPRY4-IT1) is abnormally expressed in malignant digestive tumors and associated with prognosis. But its clinical relevance is unclear. Here, we performed a meta-analysis aims to evaluate the prognostic value of SPRY4-IT1 in digestive system malignancies. We systematic search the PubMed, Web of Science, ScienceDirect and Wiley Online Library database to eligible studies. The pooled hazard ratios (HRs) with a 95% confidence interval (95% CI) were calculated to explored the association of lncRNA SPRY4-IT1 with prognosis. Five studies were eligible for analysis, a total of 518 patients were included. Meta-analysis indicated that overexpression of SPRY4-IT1 was associated with poor over survival (OS) (HR = 1.24, 95%CI:0.49–1.98; random-effects model). The clinicopathological parameters analysis further showed that increased expression level of SPRY4-IT1 was positively correlated with lymph node metastasis (HR = 1.45, 95% CI =0.88–2.02; fixed-effects model), TNM stage (HR = 1.24,95% CI = 0.78–1.70; fixed-effects model), and invasion depth (HR = 1.25,95% CI = 0.63–1.88; fixed-effects model). lncRNA SPRY4-IT1 may serve as a potential prognostic marker in malignant digestive tumors.

http://bit.ly/2ADWIM0

Neutrophilia and the JAK2 V617F Mutation

http://bit.ly/2SP45aD

Modulation of temporal resolution and speech long-latency auditory-evoked potentials by transcranial direct current stimulation in children and adolescents with dyslexia

Abstract

In recent years, transcranial direct current stimulation (tDCS) has been used as a safe and non-invasive method for children and adolescents with dyslexia. Our aim in this study was to investigate the effect of tDCS on variables of temporal resolution and speech long-latency auditory-evoked potentials with two electrode arrays on superior temporal gyrus (STG). A total of 17 children and adolescents with dyslexia (age 9–12 years) were included in our study. All participants underwent the gap in noise (GIN) test and long-latency auditory-evoked potentials recording at baseline without applying tDCS, sham (placebo), and after 20 min of exposure to two different tDCS polarities: anode of tDCS on left STG/cathode on the right shoulder and anode on the left STG/cathode on right STG to enhance left lateralization. Our results showed significant decreases in the threshold value and increases in the percentages of correct responses in the GIN test. We also found reduced latency and increased amplitude of the P1, N1, and P2 waves in two stimulation polarities compared with baseline and sham. Our findings indicate the potential role of tDCS on improving the characteristics of central auditory processing, especially temporal information processing in children and adolescents with dyslexia, and could introduce a new strategy to facilitate the rehabilitation of central auditory processing disorders in future.

http://bit.ly/2FloVuZ

Vaccine-induced memory CD8+ T cells provide clinical benefit in HER2 expressing breast cancer: a mouse to human translational study

Purpose: Immune-based therapy for metastatic breast cancer has had limited success, particularly in molecular subtypes with low somatic mutations rates. Strategies to augment T cell infiltration of tumors include vaccines targeting established oncogenic drivers like the genomic amplification of HER2. We constructed a vaccine based on a novel alphaviral vector encoding a portion of HER2 (VRP-HER2). Experimental Design: In preclinical studies, mice were immunized with VRP-HER2 before or after implantation of hHER2+ tumor cells and HER2-specific immune responses and anti-tumor function were evaluated. We tested VRP-HER2 in a Phase I clinical trial where subjects with advanced HER2-overexpressing malignancies in cohort 1 received VRP-HER2 every 2 weeks for a total of three doses. In cohort 2, subjects received the same schedule concurrently with a HER2-targeted therapy. Results: Vaccination in preclinical models with VRP-HER2 induced HER2-specific T cells and antibodies while inhibiting tumor growth. VRP-HER2 was well tolerated in patients and vaccination induced HER2-specific T cells and antibodies. Although a phase I study, there was one partial response and two patients with continued stable disease. Median OS was 50.2 months in cohort 1 (n=4) and 32.7 months in cohort 2 (n=18). Perforin expression by memory CD8 T cells post-vaccination significantly correlated with improved PFS. Conclusions: VRP-HER2 increased HER2-specific memory CD8 T cells and had anti-tumor effects in preclinical and clinical studies. The expansion of HER2-specific memory CD8 T cells in vaccinated patients was significantly correlated with increased PFS. Subsequent studies will seek to enhance T cell activity by combining with anti-PD-1.

http://bit.ly/2QGs9ug

WNT/{beta}-catenin pathway activation correlates with immune exclusion across human cancers

Purpose: The T cell-inflamed phenotype correlates with efficacy of immune-checkpoint blockade while non-T cell-inflamed tumors infrequently benefit. Tumor-intrinsic WNT/β-catenin signaling mediates immune exclusion in melanoma, but association with the non-T cell-inflamed tumor microenvironment in other tumor types is not well understood. Experimental Design: Using The Cancer Genome Atlas (TCGA), a T cell-inflamed gene expression signature segregated samples within tumor types. Activation of WNT/β-catenin signaling was inferred using three approaches: somatic mutations or somatic copy number alterations (SCNAs) in β-catenin signaling elements including CTNNB1, APC, APC2, AXIN1, AXIN2; pathway prediction from RNAseq gene expression; and inverse correlation of β-catenin protein levels with the T cell-inflamed gene expression signature. Results: Across TCGA, 3137/9244 (33.9%) tumors were non-T cell-inflamed while 3161/9244 (34.2%) were T cell-inflamed. Non-T cell-inflamed tumors demonstrated significantly lower expression of T cell inflammation genes relative to matched normal tissue, arguing for loss of a natural immune phenotype. Mutations of β-catenin signaling molecules in non-T cell-inflamed tumors were enriched three-fold relative to T cell-inflamed tumors. Across 31 tumors, 28 (90%) demonstrated activated β-catenin signaling in the non-T cell-inflamed subset by at least one method. This included target molecule expression from somatic mutations and/or SCNAs of β-catenin signaling elements (19 tumors, 61%), pathway analysis (14 tumors, 45%), and increased β-catenin protein levels (20 tumors, 65%). Conclusions: Activation of tumor-intrinsic WNT/β-catenin signaling is enriched in non-T cell-inflamed tumors. These data provide a strong rationale for development of pharmacologic inhibitors of this pathway with the aim of restoring immune cell infiltration and augmenting immunotherapy.

http://bit.ly/2VEWwVE

The Misclassification of Diffuse Gliomas: Rates and Outcomes

Background: The integrated histopathological and molecular diagnoses of the 2016 WHO classification of CNS tumors have revolutionized patient care by improving diagnostic accuracy and reproducibility; however, the frequency and consequences of misclassification of histologically-diagnosed diffuse gliomas are unknown. Methods: Patients with newly-diagnosed ICD-O-3 histologically-encoded diffuse gliomas from 2010-2015 were identified from the National Cancer Database-the misclassification rates and overall survival (OS) of which were assessed by WHO grade and 1p/19q status. Additionally, misclassification rates by IDH, ATRX, and p53 statuses were examined in an analogous multi-institutional cohort of registry-encoded diffuse gliomas. Results: Of 74,718 diffuse glioma patients, only 74.4% and 78.8% of molecularly-characterized WHO grade II and III oligodendrogliomas were in fact 1p/19q-codeleted. Additionally, 28.9% and 36.8% of histologically-encoded grade II and III "oligoastrocytomas", and 6.3% and 8.8% of grade II and III astrocytomas had 1p/19q-codeletion, thus molecularly representing oligodendrogliomas if also IDH-mutant. OS significantly depended on accurate WHO grading and 1p/19q status. Conclusions: Based on 1p/19q, IDH, ATRX, and p53, the misclassification rates of histologically-encoded oligodendrogliomas, astrocytomas, and glioblastomas are ~21-35%, ~6-9%, and ~9%, respectively; with significant clinical implications. Our findings suggest that when compared to historical histology-only classified data-in national registry, as well as, institutional databases-there is the potential for false-positive results in contemporary trials of molecularly-classified diffuse gliomas, which could contribute to a seemingly positive phase II trial (based on historical comparison) failing at the phase III stage. Critically, findings from diffuse glioma clinical trials and historical cohorts using prior histology-only WHO schemes must be cautiously re-interpreted.

http://bit.ly/2QGrWqY

Autophagy inhibition to augment mTOR inhibition: A phase I/II trial of everolimus and hydroxychloroquine in patients with previously treated renal cell carcinoma

Purpose Everolimus inhibits the mechanistic target of rapamycin (mTOR), activating cytoprotective autophagy. Hydroxychloroquine (HCQ) inhibits autophagy. Based on preclinical data demonstrating synergistic cytotoxicity when mTOR inhibitors are combined with an autophagy inhibitor, we launched a clinical trial of combined everolimus and HCQ, to determine its safety and activity in patients with clear cell renal carcinoma (ccRCC). Experimental Design Three centers conducted a phase I/II trial of everolimus 10 mg daily and HCQ in patients with advanced ccRCC. The objectives were to determine the maximum tolerated dose of HCQ with daily everolimus, and to estimate the rate of 6 month progression-free survival (PFS) in ccRCC patients receiving everolimus/HCQ after 1-3 prior treatment regimens. Correlative studies to identify patient subpopulations that achieved the most benefit included population pharmacokinetics, measurement of autophagosomes by electron microscopy and next generation tumor sequencing. Results No DLT was observed in the phase I trial. The recommended phase II dose of HCQ 600 mg bid with everolimus was identified. Disease control (Stable disease (SD) + partial response (PR)) occurred in 22/33 (67%) evaluable patients. Partial response was observed in 2/33 patients (6%). PFS ≥6 months was achieved in 15/33 (45%) of patients who achieved disease control. Conclusion Combined HCQ 600mg twice daily with 10 mg daily everolimus was tolerable. The primary endpoint of >40% 6 month PFS rate was met. HCQ is a tolerable autophagy inhibitor in future RCC or other trials.

http://bit.ly/2VNvlIb

PRMT5-mediated H4R3sme2 confers cell differentiation in Pediatric B-cell Precursor Acute Lymphoblastic Leukemia

Purpose: Little is known about the function of histone arginine methylation in acute lymphoblastic leukemia. The objective was to evaluate whether protein arginine methyltransferase 5 (PRMT5) plays a role in pediatric acute lymphoblastic leukemia and to determine the possible mechanism of epigenetic regulation. Experimental Design: We used bone marrow (BM) samples from pediatric acute lymphoblastic leukemia (ALL) patients, the Nalm6 cell line, mature B cell lines, and mouse xenograft models to evaluate the function of PRMT5 in ALL tumorigenesis. Results: This study showed that PRMT5 and the symmetric dimethylation of H4R3 (H4R3sme2) were upregulated in most initially diagnosed (n=15; 100%) and relapsed (n=4; 75%) BM leukemia cells from pediatric B-cell precursor ALL (BCP-ALL) patients and were decreased when the disease was in remission (n=15; 6.7%). Downregulation of H4R3sme2 by PRMT5 silencing induced BCP-ALL cell differentiation from the pre-B to immature B stage, whereas overexpressed PRMT5 with enhanced H4R3sme2 promoted human mature B cells to dedifferentiate back to the pre-B II/immature B stages in vitro. High PRMT5 expression enhanced the proportion of CD43+/B220+/sIgM- B leukocytes in recipient mice. CLC and CTSB were identified as potential target genes of PRMT5 in BCP-ALL cells and were inhibited by H4R3sme2 in gene promoters. Conclusions: We demonstrate that enhanced PRMT5 promotes BCP-ALL leukemogenesis partially by the dysregulation of B cell lineage differentiation. H4R3sme2 and PRMT5 may serve as potential sensitive biomarkers of pediatric BCP-ALL. Suppression of the activation of PRMT5 and its downstream targets may offer a promising therapeutic strategy against pediatric BCP-ALL.

http://bit.ly/2QCU5iR

Combination Paclitaxel and Palbociclib: Results of a Phase I Trial in Advanced Breast Cancer

Purpose: The CDK 4/6 inhibitor palbociclib rapidly and reversibly inhibits the cell cycle. The goal of this study was to exploit the cell cycle through intermittent, alternating dosing with palbociclib/paclitaxel to enhance efficacy. We determined the combination dose-limiting toxicity in patients with retinoblastoma (Rb) protein-expressing, advanced breast cancer (ABC). Experimental Design: This open-label phase I trial (NCT01320592) enrolled patients to sequential cohorts of palbociclib orally dosed intermittently between days 1 and 19 of a 28 day cycle alternating with weekly paclitaxel. Dose escalation proceeded in a standard 3 + 3 design. Ten additional patients received the combination at the recommended phase 2 dose (RP2D). Those who reached response plateau ≥6 cycles could continue on palbociclib alone on a 3 week on/1 week off schedule at one dose level above their combination dose. Results: Twenty seven patients enrolled. Although there was only 1 DLT (grade 3 ALT/AST at 125 mg), neutropenia requiring dose modification in cycle 1 resulted in an RP2D of 75 mg palbociclib/80mg/m2 paclitaxel. During cycle 1, the most common adverse event was neutropenia, occurring in 15 patients (55.6%); grade 1 or 2 nausea and peripheral neuropathy was also observed in 8 patients each (29.6%). Clinical benefit rate was 55% at the RP2D; benefit was observed across all receptor subtypes. Conclusions: Alternating sequential palbociclib/paclitaxel in patients with Rb+ ABC is feasible and safe, without evidence of additive toxicity. This represents a new application for CDK 4/6 inhibitors in Rb+ breast cancer, regardless of subtype; efficacy trials are warranted.

http://bit.ly/2VIqjNr

UBQLN4 Regulates DNA Repair Pathway Choice [Research Watch]

The proteasomal shuttle factor UBQLN4 represses homologous recombination–mediated DNA repair (HRR).

http://bit.ly/2QEVQvN

TINAGL1 Represses Breast Cancer Tumorigenesis and Metastasis [Research Watch]

The secreted protein TINAGL1 inhibits TNBC progression and metastasis.

http://bit.ly/2VIqjwV

KRAS-Driven Cancers Are Dependent on METTL13-Mediated eEF1A Methylation [Research Watch]

Methylation of eEF1A by METTL13 is required for KRAS-driven pancreatic and lung tumorigenesis.

http://bit.ly/2QGPhsO

Exosomes from Nischarin-Expressing Cells Reduce Breast Cancer Cell Motility and tumor growth

Exosomes are small extracellular microvesicles that are secreted by cells when intracellular multivesicular bodies (MVB) fuse with the plasma membrane. We have previously demonstrated that Nischarin inhibits focal adhesion formation, cell migration, and invasion, leading to reduced activation focal adhesion kinase. In this study, we propose that the tumor suppressor Nischarin regulates the release of exosomes. When co-cultured on exosomes from Nischarin-positive cells, breast cancer cells exhibited reduced survival, migration, adhesion, and spreading. The same co-cultures formed xenograft tumors of significantly reduced volume following injection into mice. Exosomes secreted by Nischarin-expressing tumors inhibited tumor growth. Expression of only one allele of Nischarin increased secretion of exosomes, and Rab14 activity modulated exosome secretions and cell growth. Taken together, the present study reveals a novel role for Nischarin in preventing cancer cell motility, which contributes to our understanding of exosome biology.

http://bit.ly/2CdiPZI

Modified BuCy is an alternative conditioning regimen for lymphoma patients undergoing autologous stem cell transplantation

Abstract

The aim of this study is to determine whether the modified BuCy (semustine, cytarabine, busulfan, and cyclophosphamide, mBuCy) conditioning regimen can be safely used as an alternative to the SEAM (semustine, etoposide, cytarabine, and melphalan) regimen by comparing the efficacy and toxicity of the mBuCy and SEAM regimens. We matched 34 pairs of patients with regard to disease status at the time of autologous stem cell transplantation (auto-SCT). We found no significant difference in the time of platelet engraftment between the two groups. Furthermore, neutrophil engraftment was somewhat faster in the mBuCy group than in the SEAM group (median: 9 days vs 10 days, p = 0.015). With regard to toxicity, the incidence of nausea/vomiting, hepatic impairment, renal impairment, pulmonary infection, and treatment-related mortality (TRM) was similar between the two groups. In addition, compared to patients conditioned with SEAM, patients conditioned with mBuCy were less likely to develop mucositis and diarrhea (p = 0.027; p = 0.050). The 2-year progression-free survival (PFS) rates in the mBuCy and SEAM groups were 79% and 70% (p = 0.378), respectively, and the 2-year overall survival (OS) rates were 81% and 78.0%, respectively (p = 0.789). These analyses showed that the mBuCy conditioning regimen was well tolerated and can be used as an alternative to the SEAM regimen for lymphoma.

http://bit.ly/2QErrOk

Epidemiological and clinical analyses of cervical cancer using data from the population-based Osaka cancer registry

Cervical cancer screening rate is extremely low and the governmental recommendation of HPV vaccine has been suspended for 5years in Japan. Here we utilize data from the Osaka Cancer Registry, collected between 1976 and 2012, to evaluate cervical cancer trends in Japan. Age-adjusted incidence, relative survival, and conditional survival rates were calculated using multiple imputation methods and period analyses in 25,826 cervical cancer cases. Association of survival rates and clinical factors, including patients' age, clinical stage, and treatment procedures, were also analyzed. A trend for significantly decreasing age-adjusted incidence of cervical cancer (per 100,000) began in 1976 but reversed after 2000, increasing significantly to date (APC = 3.8, 95% CI: 2.7 to 4.8; age-adjusted rate: 28.0 in 1976, 9.1 in 2000, 14.1 in 2012). The ten-year relative survival rate improved significantly after 2002, especially in cases of "localized" and "adjacent organs" disease; this was likely due to the introduction of concurrent chemotherapy and radiation (CCRT). The conditional five-year relative survival rate improved significantly yearly until the fourth survival year. In the surgery-based group, we observed no age-dependent differences in outcomes. Unexpectedly, however, prognosis for younger age groups was poorer in the radiation-based treatment group. These results indicate that although relative survival rates have recently increased, treatment for more advanced cases with distant metastasis requires further improvement. Additionally, this study is the first to suggest that age might be an important predictor of radiotherapy resistance in cervical cancer.　

http://bit.ly/2RlDVzw

Conditional Synaptic Vesicle Markers for Drosophila

The release of neurotransmitters from synaptic vesicles (SVs) at pre-synaptic release sites is the principle means by which information transfer between neurons occurs. Knowledge of the location of SVs within a neuron can thus provide valuable clues about the location of neurotransmitter release within a neuron and the downstream neurons to which a given neuron is connected, important information for understanding how neural circuits generate behavior. Here the development and characterization of four conditional tagged SV markers for Drosophila melanogaster is presented. This characterization includes evaluation of conditionality, specificity for SV localization, and sensitivity of detection in diverse neuron subtypes. These four SV markers are genome-edited variants of the synaptic vesicle-specific protein Rab3. They depend on either the B2 or FLP recombinases for conditionality, and incorporate GFP or mCherry fluorescent proteins, or FLAG or HA epitope tags, for detection.

http://bit.ly/2D3z11o

Smoking Associated With Worse Bladder Cancer Outcomes

FRIDAY, Jan. 11, 2019 -- Cigarette smoking is linked to a poor response to cisplatin-based neoadjuvant chemotherapy (NAC) among patients with muscle-invasive bladder cancer (MIBC) who undergo radical cystectomy (RC), according to a study published...

http://bit.ly/2FlDq27

Drug Overdose Death Rate Increasing Among Middle-Aged Women

FRIDAY, Jan. 11, 2019 -- From 1999 to 2017, the drug overdose death rate increased 260 percent among women aged 30 to 64 years, according to research published in the Jan. 11 issue of the U.S. Centers for Disease Control and Prevention Morbidity and...

http://bit.ly/2FrsG1f

CDC: Flu Cases Hit 7 Million in the United States

FRIDAY, Jan. 11, 2019 -- The flu season is picking up steam, with about 7 million Americans having been struck by a strain of the flu virus, health officials said Friday. Almost half of those individuals went to a doctor, while 69,000 to 84,000...

http://bit.ly/2FwKpof

Number of Colorectal CA Deaths Projected to Rise Worldwide

FRIDAY, Jan. 11, 2019 -- An overall rise in the number of colorectal cancer deaths worldwide is expected through 2035, according to a study recently published in the International Journal of Cancer. Marzieh Araghi, Ph.D., M.P.H., from the...

http://bit.ly/2FmwrWq

About Half of Young Patients Have Had Private Time With Doctors

FRIDAY, Jan. 11, 2019 -- About half of adolescent and young adult (AYA) patients report having had private time with a health care provider (HCP) and having spoken to an HCP about confidentiality, according to a study published online Jan. 9 in the...

http://bit.ly/2FwKp7J

Exam 2: Patient-Reported Outcomes and Endoscopic Appearance of Ulcerative Colitis: A Systematic Review and Meta-analysis

http://bit.ly/2FnrcGi

Issue Information

No abstract is available for this article.

http://bit.ly/2FpITnI

Holding gastroenterologists accountable for colonoscopy through MACRA episode-based cost measure

http://bit.ly/2D3mFX4

Analysis of Clinical Outcomes of Pseudomyxoma Peritonei from Appendicular Origin Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy-A Retrospective Study from INDEPSO

Abstract

To evaluate the clinical outcomes of patients of pseudomyxoma peritonei of appendiceal origin undergoing cytoreductive surgery and HIPEC. Data collected from members, an independent collaborative group of Indian surgeons specializing in the management of peritoneal surface malignancy (INDEPSO), was analyzed retrospectively. Clinicopathological and perioperative outcomes of patients treated for pseudomyxoma peritonei (PMP) of appendicular origin were evaluated. Ninety-one patients were diagnosed with pseudomyxoma peritonei of appendicular origin between March 2013 and December 2017. The median age was 53 years and 60% were females. The median PCI was 27 [range 3–39] and a CC-0/1 resection was achieved in 83.5% patients. The most common histological grade was low-grade PMP, seen in 71.4% cases. The overall rate of grades 3–4 morbidity was 33% (30/91) and the 90-day mortality rate reported was 6.5%. Pulmonary complications and systemic sepsis emerged as the most significant factors affecting morbidity, mortality, and failure to rescue. At a median follow-up of 24 months, the median OS was not reached and the median PFS was 53 months. On univariate and multivariate analysis, high-grade histology, prior chemotherapy, debulking surgery alone without HIPEC, and high PCI > 10 were predictors of poor progression-free survival. The survival and morbidity results of pseudomyxoma peritonei from appendicular origin following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are encouraging. With further awareness and understanding of the disease, and improvement in surgical expertise and learning curve, there is scope for further reduction in morbidity and better improvement in survival.

http://bit.ly/2CfJbKx

Diagnostic performance of 68 Ga-PSMA PET/CT in the detection of prostate cancer prior to initial biopsy: comparison with cancer-predicting nomograms

Abstract

Purpose

To assess the diagnostic performance of ⁶⁸Ga-PSMA PET/CT for detecting suspected prostate cancer (PCa) and to compare it with that of two cancer-predicting nomograms.

Methods

We performed a retrospective analysis of 146 consecutive patients with suspected PCa based on symptoms or elevated total prostate-specific antigen (tPSA) levels who underwent ⁶⁸Ga-PSMA PET/CT and histopathologic examinations from April 2017 to April 2018 in a large tertiary care hospital in China. The ⁶⁸Ga-PSMA PET/CT results (PCa or benignancy) were evaluated by two experienced nuclear medicine specialists. The risk of positive PCa was evaluated using ERSPC and PCPT nomograms. The diagnostic performances of ⁶⁸Ga-PSMA PET/CT and that of the two nomograms were compared via receiver operating characteristic (ROC) curve analysis, decision curve analysis, and logistic regression.

Results

A total of 58 patients with tPSA of 0.4–50 ng/ml were included in the final analysis; PCa diagnosis was confirmed in 37 patients and excluded in 21 patients. ROC analysis showed that the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ⁶⁸Ga-PSMA PET/CT were 91.67, 81.82, 89.19, and 85.71%, respectively, in per-patient analyses. ⁶⁸Ga-PSMA PET/CT exhibited a higher AUC (0.867) than those of ERSPC-RC3 (0.855) and PCPT-RC (0.770). The net benefit of ⁶⁸Ga-PSMA PET/CT was greatest for patients within threshold probabilities of 15–90%. Among the 58 patients, 11 (19%) biopsies suggested by ERSPC-RC3 were unnecessary and could have been avoided if judged by the ⁶⁸Ga-PSMA PET/CT results. Multivariate analysis revealed that the maximum standardised uptake value (SUV_max) and prostate volume were significant predictive factors for positive PCa results.

Conclusion

In suspected PCa patients with tPSA of 0.4–50 ng/ml, ⁶⁸Ga-PSMA PET/CT outperformed the nomograms in predicting cancer and reducing unnecessary biopsies. In addition, the risk of PCa was positively correlated with a higher SUV_max and lower prostate volume, which could help clinicians in making preliminary estimates of individual cancer risk, monitoring ⁶⁸Ga-PSMA PET/CT false-positive results and making biopsy decisions in daily medical practice.

http://bit.ly/2D4zYGJ

Development of a Novel EGFR-Targeting Antibody-Drug Conjugate for Pancreatic Cancer Therapy

Abstract

Background

Overexpression of epidermal growth factor receptor (EGFR) is common in pancreatic cancer and associated with the poor prognosis of this malignancy.

Objective

To develop anti-EGFR antibody–drug conjugates (ADCs) for use in a novel EGFR-targeting approach to treat pancreatic cancer.

Methods

A humanized anti-EGFR monoclonal antibody (RC68) was generated by mouse immunization and complementary-determining region grafting technology. Two RC68-based ADCs, RC68-MC-VC-PAB-MMAE and RC68-PY-VC-PAB-MMAE, were synthesized by conjugating monomethyl auristatin E (MMAE), a small-molecule cytotoxin, to RC68 through two distinct linkers (MC and PY). Internalization of the RC68-based ADCs was examined by flow cytometry. The in vitro and in vivo antitumor activities of RC68-based ADCs were evaluated in human pancreatic cancer cells and in a BXPC-3 xenograft nude mouse model, respectively.

Results

The RC68-based ADCs bound to EGFR on the surface of tumor cells and were effectively internalized, resulting in the death of EGFR-positive cancer cell lines. The RC68-based ADCs (at 5 or 10 mg/kg) were more potent than gemcitabine hydrochloride (60 mg/kg) at inhibiting the growth of BXPC-3 xenografts. Moreover, RC68-PY-VC-PAB-MMAE was found to have superior stability in human plasma compared with RC68-MC-VC-PAB-MMAE.

Conclusion

A novel EGFR-targeting ADC, RC68-PY-VC-PAB-MMAE, shows promise as an effective, selective, and safe therapeutic agent for EGFR-positive pancreatic cancer.

http://bit.ly/2SWHXuI

Establishing Cell Lines Overexpressing DR3 to Assess the Apoptotic Response to Anti-mitotic Therapeutics

Establishing a stable cell line overexpressing a gene of interest to study gene function can be done by stable transfection-picking single clones after transfecting them via retroviral infection. Here we show that HT29-DR3 cell lines generated in this way elucidate the mechanisms by which death receptor 3 (DR3) contributes to antimitotics-induced apoptosis.

http://bit.ly/2M3CXSu

Impact of Olive leaf yellowing associated virus on olive (Olea europaea L.) oil

Summary

Among the fifteen virus species detected in olive trees, Olive leaf yellowing associated virus (OLYaV) was found with high incidence and frequency in Southern Italy in particular. Effects of OLYaV on virgin olive oil yield and quality of 'Leccino' and 'Ottobratica' cultivars in Calabria region (Southern Italy) were analysed. Oil yield, free acidity, number of peroxides, spectrophotometric indexes, total content of chlorophylls and carotenoids, total phenol content, composition of the fatty acids, total tocopherols and total sterols content were determined on oil obtained from olive fruits collected in healthy/virus‐free and OYLaV‐infected trees. Almost all analysed oil parameters were not statistically different with some exceptions. Oils derived from 'Ottobratica' OLYaV‐infected plants had free acidity significantly lower than oil from healthy plants. K₂₃₂ of oil from virus‐free 'Leccino' trees was significantly lower than oil from infected trees. Even though some quality parameter differences between healthy and OLYaV‐infected oils were found, it is important to highlight that all oils can be considered in extra virgin olive oil category, within the UE maximum limit acceptance range. Results suggest a no negative interference by OYLaV in oil yield and quality, except for K₂₃₂ values, whereas surprisingly suggested a positive effect of virus infection on free acidity parameter.

Practical applications: Based on the evidence that OYLaV does not interfere negatively in oil yield and quality parameters, it seems appropriate that the European Union Council Directives (2014/96/EU, 2014/97/EU, 2014/98/EU) introduced in the last olive certification scheme only ArMV, CLRV and SLRSV. The application of compulsory EU directive, in Italy as in other countries, will improve the facilities of olive plants commercialization, guaranteeing enough their sanitary status. The findings here reported support the suggestion that the Italian Ministry of Agriculture could be less restrictive in voluntary Italian regulation (D.M. 20/11/2006).

http://bit.ly/2RKMYt4

Endoscopic Ultrasound Through‐The‐Needle Biopsy Diagnosis of a Pancreatic Lymphoepithelial Cyst

Abstract

We performed an EUS‐TTNB (endoscopic ultrasound through‐the‐needle biopsy) in a 48‐year‐old man with an asymptomatic 4 cm pancreatic neck hypodense lesion, with inhomogeneous slight contrast enhancement. On T2‐weighted magnetic resonance imaging (MRI), the lesion appeared as a complex cystic lesion with internal septa, with positive contrast enhancement. Endoscopic ultrasound (EUS) showed a septate PCL (pancreatic cystic lesion) with granular internal aspect, lobulated contours, and no visible cystic walls or mural nodules.

This article is protected by copyright. All rights reserved.

http://bit.ly/2RjYiwZ

Screening of Axonal Degeneration in Carpal Tunnel Syndrome Using Ultrasonography and Nerve Conduction Studies

Here we present a protocol using nerve conduction studies and ultrasound to screen potential axonal degeneration associated with carpal tunnel syndrome. The criteria for differentiation are established. Compared to conventional approaches, this method is noninvasive, convenient, and efficient, with an overall satisfactory accuracy, sensitivity, and specificity.

http://bit.ly/2sl5zxJ

Nerve Stem Cell Differentiation by a One-step Cold Atmospheric Plasma Treatment In Vitro

This protocol aims to provide detailed experimental steps of a cold atmospheric plasma treatment on neural stem cells and immunofluorescence detection for differentiation enhancement.

http://bit.ly/2M3vxi6

Artificial Intelligence Can Use Routine ECGs to ID Heart Disease

FRIDAY, Jan. 11, 2019 -- Artificial intelligence (AI) can identify asymptomatic left ventricular dysfunction (ALVD) using results from a routine electrocardiogram (ECG), according to a research letter published online Jan. 7 in Nature...

http://bit.ly/2TGCBE0

Statin Therapy Reduces Risk for Diabetic Retinopathy in T2DM

FRIDAY, Jan. 11, 2019 -- For Taiwanese patients with type 2 diabetes and dyslipidemia, statin therapy is associated with a reduced risk for diabetic retinopathy, according to a study published online Jan. 10 in JAMA Ophthalmology. Eugene Yu-Chuan...

http://bit.ly/2D4Fedq

Prices Still Explain High U.S. Health Care Spending

FRIDAY, Jan. 11, 2019 -- The difference in health spending between the United States and other countries is still explained by health care prices, according to a study published in the January issue of Health Affairs. Gerard F. Anderson, Ph.D., from...

http://bit.ly/2TDDcGo

Drug Repurposing May Provide More Psychiatric Tx Options

FRIDAY, Jan. 11, 2019 -- Three classes of drugs hold potential as repurposed agents to treat patients with serious mental illness, according to a study published online Jan. 9 in JAMA Psychiatry. Joseph F. Hayes, Ph.D., from University College...

http://bit.ly/2D4501u

Persistent Opioid Use High in Head, Neck Cancer Patients

FRIDAY, Jan. 11, 2019 -- Persistent opioid use at three and six months remains high among patients undergoing treatment for head and neck squamous cell cancer, according to a study recently published in Otolaryngology-Head and Neck Surgery. Jessica...

http://bit.ly/2TGQj9T

Chronic Fatigue Patients May Not Receive Proper ED Care

FRIDAY, Jan. 11, 2019 -- Many patients with chronic fatigue syndrome (CFS) do not receive proper care in the emergency department, according to a study published online Jan. 11 in Open Access Emergency Medicine. Christian R. Timbol, M.D., and James...

http://bit.ly/2D2MKp8

Sociodemographic Factors Predict Recovery After Traumatic Injury

FRIDAY, Jan. 11, 2019 -- Most traditional measures of injury severity may not be predictive of trauma recovery, but some sociodemographic characteristics are predictive of recovery, according to a study published online Dec. 13 in the Annals of...

http://bit.ly/2TKNnsZ

High Fiber Intake Tied to Lower Risk for Noncommunicable Disease

FRIDAY, Jan. 11, 2019 -- High intake of fiber is associated with a reduced risk for several noncommunicable diseases (NCDs), according to research published online Jan. 10 in the The Lancet. Andrew Reynolds, Ph.D., from the University of Otago in...

http://bit.ly/2D3kBhR

Use of Diabetes Monitoring Tests in Primary Care Suboptimal

FRIDAY, Jan. 11, 2019 -- Many primary care patients are not given tests recommended for monitoring diabetes, according to a study published in the December issue of Family Medicine and Community Health. Mingliang Dai, Ph.D., from the American Board...

http://bit.ly/2TH06gg

Adverse Birth Outcomes Up for Women With H1N1 Flu in ICU

FRIDAY, Jan. 11, 2019 -- Pregnant women with 2009 H1N1 influenza admitted to an intensive care unit (ICU) have an increased risk for adverse birth outcomes, according to a study published online Jan. 9 in Birth Defects Research. Kim Newsome, M.P.H.,...

http://bit.ly/2D4FdWU

Fetal phenotype of Rubinstein‐Taybi syndrome caused by CREBBP mutations

Rubinstein‐Taybi syndrome (RSTS; OMIM 180849) is an autosomal dominant developmental disorder characterized by facial dysmorphism, broad thumbs and halluces associated with intellectual disability. RSTS is caused by alterations in CREBBP (about 60%) and EP300 genes (8%). RSTS is often diagnosed at birth or during early childhood but generally not suspected during antenatal period. We report nine cases of well‐documented fetal RSTS. Two cases were examined after death in utero at 18 and 35 weeks of gestation and seven cases after identification of ultrasound abnormalities and termination of pregnancy. On prenatal sonography, a large gallbladder was detected in two cases, and brain malformations were noted in four cases, especially cerebellar hypoplasia. However, the diagnosis of RSTS has not been suggested during pregnancy. Fetal autopsy showed that all fetuses had large thumbs and/or suggestive facial dysmorphism. A CREBBP gene anomaly was identified in all cases. Alterations were similar to those found in typical RSTS children. This report will contribute to a better knowledge of the fetal phenotype to consider the hypothesis of RSTS during pregnancy. Genotyping allows reassuring genetic counseling.

http://bit.ly/2CfgKwh

Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies syndrome due to disruption of BPTF in a 35‐year‐old man initially diagnosed with Silver‐Russell syndrome

http://bit.ly/2RlinD3

Clinical, biomarker and genetic spectrum of Niemann‐Pick type C in Egypt: The detection of nine novel NPC1 mutations

http://bit.ly/2CeDkFs

Issue Information ‐ Editorial Board

http://bit.ly/2Rlg3Mm

Correction to: Mutational characteristics of ANK1 and SPTB genes in hereditary spherocytosis

http://bit.ly/2CdGoBM

ASO Author Reflections: Impact of SPECT/CT on Sentinel Lymph Node Biopsy in Head and Neck Melanoma

http://bit.ly/2AFECcK

Well-Differentiated Papillary Mesothelioma of the Peritoneum: A Retrospective Study from the RENAPE Observational Registry

Abstract

Background

Well-differentiated papillary mesothelioma of the peritoneum (WDPMP) is a rare entity. Questions regarding management are still being debated as no more than 50 cases have been reported in the literature.

Objective

We aimed to analyze the clinical, therapeutic, and prognostic data of patients with WDPMP from the RENAPE observational registry.

Patients and Methods

All patients diagnosed with WDPMP and prospectively included in the RENAPE national registry between 2010 and 2018 were also included in our study. Expert pathologists from the RENA-PATH group confirmed all cases. All clinical, therapeutic, postoperative, and prognostic data were extracted and analyzed.

Results

We report on 56 patients with a mean age of 52 years (range 21–74). WDPMP was incidentally diagnosed during imaging or surgery in 16% and 36% of patients, respectively, and an association with synchronous malignancy was found in 18% of patients. Nine lesions showed discrete signs of fatty invasion. The median Peritoneal Cancer Index was 11 (range 0–33). Eleven patients were treated with definitive excision, 4 were treated with cytoreductive surgery (CRS) only, 37 were treated with CRS and hyperthermic intraperitoneal chemotherapy (HIPEC), and 2 were treated with CRS plus HIPEC plus early postoperative intraperitoneal chemotherapy. CRS was considered to be complete in 90% of cases. One patient died postoperatively and 16 patients (31%) faced postoperative complications. The median disease-free survival was 144 months; Four patients relapsed, with a median period of 27 months. No prognostic factors could be identified.

Conclusions

Our analysis confirms the favorable prognosis of WDPMP. CRS and HIPEC could be a therapeutic option for diffuse, symptomatic, and/or recurrent disease.

http://bit.ly/2SRrND2

Use of Electron Paramagnetic Resonance in Biological Samples at Ambient Temperature and 77 K

Electron paramagnetic resonance (EPR) spectroscopy is an unambiguous method to measure free radicals. The use of selective spin probes allows for detection of free radicals in different cellular compartments. We present a practical, efficient method to collect biological samples that facilitate treating, storing, and transferring samples for EPR measurements.

http://bit.ly/2AEGwdu

Generation of Human Primordial Germ Cell-like Cells at the Surface of Embryoid Bodies from Primed-pluripotency Induced Pluripotent Stem Cells

Primordial germ cells (PGCs) are common precursors of both sperm and eggs. Human embryonic PGCs are specified from pluripotent epiblast cells through interactions of cytokines. Here, we describe a 13-day protocol of inducing human cells transcriptomally resembling PGCs at the surface of embryoid bodies from primed-pluripotency induced pluripotent stem cells.

http://bit.ly/2SPeCTh

Chronic retroviral infection of mice promotes tumor development, but CD137 agonist therapy restores effective tumor immune surveillance

Abstract

T cell responses are crucial for anti-tumor immunity. In chronic viral infections, anti-tumor T cell responses can be compromised due to various immunological mechanisms, including T cell exhaustion. To study mechanisms of anti-tumor immunity during a chronic viral infection, we made use of the well-established Friend virus (FV) mouse model. Chronically FV-infected mice are impaired in their ability to reject FBL-3 cells—a virus-induced tumor cell line of C57BL/6 origin. Here we aimed to explore therapeutic strategies to overcome the influence of T cell exhaustion during chronic viral infection, and reactivate effector CD8⁺ and CD4⁺ T cells to eliminate tumor cells. For T cell stimulation, agonistic antibodies against the tumor necrosis factor receptor (TNFR) superfamily members CD137 and CD134 were used, because they were reported to augment the cytotoxic program of T cells. αCD137 agonistic therapy, but not αCD134 agonistic therapy, resulted in FBL-3 tumor elimination in chronically FV-infected mice. CD137 stimulation significantly enhanced the cytotoxic activity of both CD4⁺ and CD8⁺ T cells, which were both required for efficient tumor control. Our study suggests that agonistic antibodies to CD137 can efficiently enhance anti-tumor immunity even in the setting of chronic viral infection, which might have promising therapeutic applications.

http://bit.ly/2SRknjk

Cerebral and skeletal muscle feed artery vasoconstrictor responses in a mouse model with greater large elastic artery stiffness

New Findings

What is the central question of this study?

Greater large artery stiffness is associated with dysfunctional resistance artery vasodilatory responses, impaired memory and greater Alzheimer's disease risk. However, it is unknown if stiffer large arteries affect cerebral and skeletal muscle feed artery responses to vasoconstrictors.

What is the main finding and its importance?

In a mouse model with greater large artery stiffness (Eln^+/−), we find an exacerbated vasoconstriction response to angiotensin II in cerebral arteries, but not skeletal muscle feed arteries, thus implicating altered cerebral artery angiotensin II responsiveness in the poor brain outcomes associated with greater large artery stiffness.

ABSTRACT

Greater stiffness of the large elastic arteries is associated with end‐organ damage and dysfunction. At the same time, resistance artery vasoconstrictor responsiveness influences vascular tone and organ blood flow. However, it is unknown if large elastic artery stiffness modulates the responsiveness to vasoconstrictors in resistance arteries of the cerebral or skeletal muscle circulations. We previously described the elastin haploinsufficient (Eln^+/−) mouse as a model with greater aortic stiffness, but with similar cerebral and skeletal muscle feed artery stiffness to wildtype (Eln^+/+) mice. Here, we utilized this model to examine the relation between large elastic artery stiffness and resistance artery vasoconstrictor responses. In middle cerebral arteries (MCAs), vasoconstriction to angiotensin II (Ang II) was ∼40% greater in Eln^+/‐ compared with Eln^+/+ mice (p = 0.02), and this group difference was ameliorated by losartan, indicating a role for Ang II type 1 receptors (AT1Rs). In gastrocnemius feed arteries (GFAs), Eln^+/− and Eln^+/+ mice did not differ in the response to Ang II. In addition, the vasoconstrictor responses to norepinephrine, endothelin‐1, and potassium chloride were not different between Eln^+/− and Eln^+/+ mice for either MCAs or GFAs. MCA AT1R gene expression did not differ between groups, while Ang II type 2 receptor gene expression was ∼50% lower in MCAs from Eln^+/− vs. Eln^+/+ (p = 0.01). In conclusion, greater large elastic artery stiffness is associated with an exacerbated vasoconstriction response to Ang II in cerebral arteries, but not associated with the responses to other vasoconstrictors in cerebral or skeletal muscle feed arteries.

This article is protected by copyright. All rights reserved

http://bit.ly/2D3l2J1

Chronic retroviral infection of mice promotes tumor development, but CD137 agonist therapy restores effective tumor immune surveillance

Abstract

T cell responses are crucial for anti-tumor immunity. In chronic viral infections, anti-tumor T cell responses can be compromised due to various immunological mechanisms, including T cell exhaustion. To study mechanisms of anti-tumor immunity during a chronic viral infection, we made use of the well-established Friend virus (FV) mouse model. Chronically FV-infected mice are impaired in their ability to reject FBL-3 cells—a virus-induced tumor cell line of C57BL/6 origin. Here we aimed to explore therapeutic strategies to overcome the influence of T cell exhaustion during chronic viral infection, and reactivate effector CD8⁺ and CD4⁺ T cells to eliminate tumor cells. For T cell stimulation, agonistic antibodies against the tumor necrosis factor receptor (TNFR) superfamily members CD137 and CD134 were used, because they were reported to augment the cytotoxic program of T cells. αCD137 agonistic therapy, but not αCD134 agonistic therapy, resulted in FBL-3 tumor elimination in chronically FV-infected mice. CD137 stimulation significantly enhanced the cytotoxic activity of both CD4⁺ and CD8⁺ T cells, which were both required for efficient tumor control. Our study suggests that agonistic antibodies to CD137 can efficiently enhance anti-tumor immunity even in the setting of chronic viral infection, which might have promising therapeutic applications.

http://bit.ly/2SRknjk

Timeline and location of recurrence following successful ablation in Barretts oesophagus: an international multicentre study

Objective

Surveillance interval protocols after complete remission of intestinal metaplasia (CRIM) post radiofrequency ablation (RFA) in Barrett's oesophagus (BE) are currently empiric and not based on substantial evidence. We aimed to assess the timeline, location and patterns of recurrence following CRIM to inform these guidelines.

Design

Data on patients undergoing RFA for BE were obtained from prospectively maintained databases of five (three USA and two UK) tertiary referral centres. RFA was performed until CRIM was confirmed on two consecutive endoscopies.

Results

594 patients achieved CRIM as of 1 May 2017. 151 subjects developed recurrent BE over a median (IQR) follow-up of 2.8 (1.4–4.4) years. There was 19% cumulative recurrence risk of any BE within 2 years and an additional 49% risk over the next 8.6 years. There was no evidence of a clinically meaningful change in the recurrence hazard rate of any BE, dysplastic BE or high-grade dysplasia/cancer over the duration of follow-up, with an estimated 2% (95% CI –7% to 12%) change in recurrence rate of any BE in a doubling of follow-up time. 74% of BE recurrences developed at the gastro-oesophageal junction (GOJ) (24.1% were dysplastic) and 26% in the tubular oesophagus. The yield of random biopsies from the tubular oesophagus, in the absence of visible lesions, was 1% (BE) and 0.2% (dysplasia).

Conclusions

BE recurrence risk following CRIM remained constant over time, suggesting that lengthening of follow-up intervals, at least in the first 5 years after CRIM, may not be advisable. Sampling the GOJ is critical to detecting recurrence. The requirement for random biopsies of the neosquamous epithelium in the absence of visible lesions may need to be re-evaluated.

http://bit.ly/2QJ14XC

Identification of trimethylamine N-oxide (TMAO)-producer phenotype is interesting, but is it helpful?

We read with great interest the paper by Wu et al1 reporting on the development of a carnitine challenge test to facilitate the identification of trimethylamine N-oxide (TMAO)-producer phenotype and host-diet-gut dysbiosis. Such a test assumes that, according to a partial reading of the literature, TMAO plays a key role in cardiovascular disease (CVD). Accordingly, the authors assert the implied importance of the potential for adverse CVD-inducing actions of compounds generating TMAO subsequent to the action of gut microbiota on dietary carnitine. However, a more objective reading of the literature shows that the biomedical community is still debating the potential involvement of TMAO in inducing CVD and/or other diseases.2–4 For example, there is substantial evidence that TMAO may not be associated with CVD, and even that low rather than high TMAO levels are associated with CVD and cardiometabolic risk in general. Collins...

http://bit.ly/2VL7lpa

Endoscopic scar assessment after colorectal endoscopic mucosal resection scars: when is biopsy necessary (ESCAPE trial)

Objective

It is unclear whether endoscopic assessment of scars after colorectal endoscopic mucosal resection (EMR) has to include biopsies, even if endoscopy is negative. Vice versa, endoscopic diagnosis of recurrent adenoma may not require biopsy before endoscopic reinterventions. We prospectively analysed various endoscopic modalities in the diagnosis of recurrence following EMR.

Design

We conducted a prospective study of patients undergoing colonoscopy after EMR of large (≥20 mm) colorectal neoplasia. Endoscopists predicted recurrence and confidence level with four imaging modes: high-definition white light (WL) and narrow-band imaging (NBI) with and without near focus (NF). Separately, 26 experienced endoscopists assessed offline images.

Results

Two hundred and thirty patients with 255 EMR scars were included. The prevalence of recurrent adenoma was 24%. Diagnostic values were high for all modes (negative predictive value (NPV) ≥97%, positive predictive value (PPV) ≥81%, sensitivity ≥90%, specificity ≥93% and accuracy ≥93%). In high-confidence cases, NBI with NF had NPV of 100% (95% CI 98% to 100%) and sensitivity of 100% (95% CI 93% to 100%). Use of clips at initial EMR increased diagnostic inaccuracy (adjusted OR=1.68(95% CI 1.01 to 2.75)). In offline assessment, specificity was high for all imaging modes (mean: ≥93% (range: 55%–100%)), while sensitivity was significantly higher for NBI-NF (92%(72%–93%)%)) compared with WL (69%(38%–86%); p<0.001), WL-NF (68%(55%–83%); p<0.001) and NBI (71%(59%–90%); p<0.001).

Conclusion

Our study demonstrates very high NPV and accuracy for all four imaging modalities, especially NBI with NF, for diagnosis of recurrent neoplasia after EMR. Our data strongly suggest that in cases of high confidence negative optical diagnosis based on NBI-NF, no biopsy is needed to confirm absence of recurrence during colorectal EMR follow-up. A high confidence positive optical diagnosis can lead to immediate resection of any suspicious area. In all cases of low confidence, biopsy is still required.

Trial registration number

NCT02668198.

http://bit.ly/2QGdYFx

MicroRNA-92a-1-5p increases CDX2 by targeting FOXD1 in bile acids-induced gastric intestinal metaplasia

Background and aims

Gastric intestinal metaplasia (IM) is common in the gastric epithelium of patients with chronic atrophic gastritis. CDX2 activation in IM is driven by reflux of bile acids and following chronic inflammation. But the mechanism underlying how bile acids activate CDX2 in gastric epithelium has not been fully explored.

Methods

We performed microRNA (miRNA) and messenger RNA (mRNA) profiling using microarray in cells treated with bile acids. Data integration of the miRNA/mRNA profiles with gene ontology (GO) analysis and bioinformatics was performed to detect potential miRNA-mRNA regulatory circuits. Transfection of gastric cancer cell lines with miRNA mimics and inhibitors was used to evaluate their effects on the expression of candidate targets and functions. Immunohistochemistry and in situhybridisation were used to detect the expression of selected miRNAs and their targets in IM tissue microarrays.

Results

We demonstrate a bile acids-triggered pathway involving upregulation of miR-92a-1–5p and suppression of its target FOXD1 in gastric cells. We first found that miR-92a-1–5p was increased in IM tissues and induced by bile acids. Moreover, miR-92a-1–5p was found to activate CDX2 and downstream intestinal markers by targeting FOXD1/FOXJ1 axis and modulating activation of nuclear factor kappa B (NF-B) pathway. Furthermore, these effects were found to be clinical relevant, as high miR-92a-1–5p levels were correlated with low FOXD1 levels and high CDX2 levels in IM tissues.

Conclusion

These findings suggest a miR-92a-1–5p/FOXD1/NF-B/CDX2 regulatory axis plays key roles in the generation of IM phenotype from gastric cells. Suppression of miR-92a-1–5p and restoration of FOXD1 may be a preventive approach for gastric IM in patients with bile regurgitation.

http://bit.ly/2VKDFIV

Poly I:C-based rHBVvac therapeutic vaccine eliminates HBV via generation of HBV-specific CD8+ effector memory T cells

Objective

Chronic hepatitis B (CHB) virus infection is a global health problem. Finding a cure for CHB remains a challenging task.

Design

In this study, poly I:C was employed as an adjuvant for HBV therapeutic vaccine (referred to as pHBV-vaccine) and the feasibility and efficiency of pHBV-vaccine in CHB treatment were evaluated in HBV-carrier mice.

Results

We found that pHBV-vaccine decreased HBsAg and HBV DNA efficiently and safely in HBV-carrier mice. Further investigation showed that pHBV-vaccine promoted maturation and antigen presentation ability of dendritic cells in vivo and in vitro. This vaccine successfully restored the exhaustion of antigen-specific CD8⁺ T cells and partly broke the immune tolerance established in HBV-carrier mice. pHBV-vaccine also enhanced the proliferation and polyfunctionality of HBV-specific CD11a^hi CD8α^lo cells. Importantly, we observed that T cell activation molecule KLRG1 was only expressed on HBV specific CD11a^hi CD8α^lo cells. Furthermore, pHBV-vaccine reduced the expression of Eomes and increased the serum IL-12 levels, which in turn promoted the generation of effector memory short-lived effector cells (SLECs) to exhibit a critical role in HBV clearance. SLECs induced by pHBV-vaccine might play a crucial role in protecting from HBV reinfection.

Conclusions

Findings from this study provide a new basis for the development of therapeutic pHBV-vaccine, which might be a potential candidate for clinical CHB therapy.

http://bit.ly/2QFFliX

Fused Filament Fabrication (FFF) of Metal-Ceramic Components

This study shows multi-material additive manufacturing (AM) using fused filament fabrication (FFF) of stainless steel and zirconia.

http://bit.ly/2FlUODE

Encoding of kinetic and kinematic movement parameters in the sensorimotor cortex: A Brain‐Computer Interface perspective

Abstract

For severely paralyzed people, Brain‐Computer Interfaces (BCIs) can potentially replace lost motor output and provide a brain‐based control signal for augmentative and alternative communication devices or neuroprosthetics. Many BCIs focus on neuronal signals acquired from the hand area of the sensorimotor cortex, employing changes in the patterns of neuronal firing or spectral power associated with one or more types of hand movement. Hand and finger movement can be described by two groups of movement features, namely kinematics (spatial and motion aspects) and kinetics (muscles and forces). Despite extensive primate and human research, it is not fully understood how these features are represented in the SMC and how they lead to the appropriate movement. Yet, the available information may provide insight into which features are most suitable for BCI control. To that purpose, the current paper provides an in‐depth review on the movement features encoded in the SMC. Even though there is no consensus on how exactly the SMC generates movement, we conclude that some parameters are well represented in the SMC and can be accurately used for BCI control with discrete as well as continuous feedback. However, the vast evidence also suggests that movement should be interpreted as a combination of multiple parameters rather than isolated ones, pleading for further exploration of sensorimotor control models for accurate BCI control.

This article is protected by copyright. All rights reserved.

http://bit.ly/2SOEXkh

The role of aquaporin‐4 and transient receptor potential vaniloid isoform 4 channels in the development of cytotoxic edema and associated extracellular diffusion parameter changes

Abstract

The proper function of the nervous system is dependent on the balance of ions and water between the intracellular and extracellular space (ECS). It has been suggested that the interaction of aquaporin‐4 (AQP4) and the transient receptor potential vaniloid isoform 4 (TRPV4) channels play a role in water balance and cell volumeregulation, and indirectly, of the ECS volume. Using the real time‐iontophoretic method, we studied the changes of the ECS diffusion parameters: ECS volume fraction α (α = ECS volume fraction/total tissue volume) and tortuosity λ (λ² = free/apparent diffusion coefficient) in mice with a genetic deficiency of AQP4 or TRPV4 channels, and in control animals. The cytotoxix edema models that were used included: mild and severe hypotonic stress or oxygen glucose deprivation (OGD) in situ and terminal ischemia/anoxia in vivo. This study shows that an AQP4 or TRPV4 deficit slows down the ECS volume shrinkage during severe ischemia in vivo. We further demonstrate that a TRPV4 deficit slows down the velocity and attenuates an extent of the ECS volume decrease during OGD treatment in situ. However, in any of the cytotoxic edema models in situ (OGD, mild or severe hypotonic stress), we did not detect any alterations in the cell swelling or volume regulation caused by AQP4 deficiency. Overall, our results indicate that the AQP4 and TRPV4 channels may play a crucial role in severe pathological states associated with their overexpression and enhanced cell swelling. However, detailed interplay between AQP4 and TRPV4 channels requires further studies and additional research.

This article is protected by copyright. All rights reserved.

http://bit.ly/2AEAhq4

Epigenetic regulation of myelination in health and disease

Abstract

Myelin is lipid‐rich structure that is necessary to avoid leakage of electric signals and to ensure saltatory impulse conduction along axons. Oligodendrocytes in central nervous system (CNS) and Schwann cells in peripheral nervous system (PNS) are responsible for myelin formation. Axonal demyelination after injury or diseases greatly impairs normal nervous system function. Therefore, understanding how the myelination process is programmed, coordinated, and maintained is crucial for developing therapeutic strategies for remyelination in the nervous system. Epigenetic mechanisms have been recognized as a fundamental contributor in this process. In recent years, histone modification, DNA modification, ATP‐dependent chromatin remodeling, and non‐coding RNA modulation are very active area of investigation. We will present a conceptual framework that integrates crucial epigenetic mechanisms with the regulation of oligodendrocyte and Schwann cell lineage progression during development and myelin degeneration in pathological conditions. It is anticipated that a refined understanding of the molecular basis of myelination will aid in the development of treatment strategies for debilitating disorders that involve demyelination, such as multiple sclerosis in the CNS and neuropathies in the PNS.

This article is protected by copyright. All rights reserved.

http://bit.ly/2SP7FSb

Single‐item discrimination of quality‐of‐life–altering dysphagia among 714 long‐term oropharyngeal cancer survivors: Comparison of patient‐reported outcome measures of swallowing

Background

Two patient‐reported outcomes (PROs) of swallowing and their correlation to quality of life (QOL) were compared in long‐term survivors of oropharyngeal cancer (OPC).

Methods

Scores on the single dysphagia item from the 28‐item, multisymptom MD Anderson Symptom Inventory‐Head and Neck (MDASI‐HN‐S) were compared with scores on the dysphagia‐specific composite MD Anderson Dysphagia Inventory (MDADI) and the EuroQol visual analog scale (EQ‐VAS) in 714 patients who had received definitive radiotherapy ≥12 months before the survey. An MDASI‐HN‐S score ≥6 and an MDADI composite score <60 were considered representative of moderate/severe swallowing dysfunction.

Results

Moderate/severe dysphagia was reported by 17% and 16% of respondents on the MDASI‐HN‐S and the composite MDADI, respectively. Both swallow PROs were predictive of QOL, and the MDASI‐HN‐S model was slightly more parsimonious for the discrimination of EQ‐VAS scores compared with MDADI scores (Bayesian information criteria, 6062 vs 6076, respectively). An MDASI‐HN‐S cutoff score of ≥6 correlated best with a declining EQ‐VAS score (P < .0001) and was associated with increased radiotherapy dose to several normal swallowing structures.

Conclusions

In this cohort, the single‐item MDASI‐HN‐S performed favorably for the discrimination of QOL compared with the multi‐item MDADI. A time‐efficient model for PRO measurement of swallowing is proposed in which the MDADI may be reserved for patients who score ≥6 on the MDASI‐HN‐S.

http://bit.ly/2FllfJU

Progressive resistance training to prevent arm lymphedema in the first year after breast cancer surgery: Results of a randomized controlled trial

Background

Existing research suggests that progressive resistance training (PRT) after breast cancer (BC) surgery is safe, but the preventive effect on arm lymphedema has yet to be determined.

Methods

Women aged 18 to 75 years who were undergoing BC surgery with axillary lymph node dissection were eligible for the study. Recruited on the day of surgery, participants were allocated to intervention or usual care by computer randomization. The intervention consisted of PRT 3 times per week: in the first 20 weeks as a supervised group exercise and in the last 30 weeks as a self‐administered exercise. The primary outcome was arm lymphedema, which was defined as a >3% increase in the interlimb volume difference by water displacement. Measurements were made at the baseline and at a 12‐month follow‐up by physiotherapists blinded to group allocation. Analyses of effects included t tests and regression models; missing data were addressed by multiple imputation.

Results

Among the 158 randomized women, no mean group difference was found in arm volume (0.3%; 95% confidence interval, –1.7% to 2.3%) or lymphedema incidence (adjusted odds ratio, 1.2; 95% confidence interval, 0.5‐2.8). None of the participants exited the program because of adverse events.

Conclusions

This study provides no evidence that PRT can prevent arm lymphedema in the first year after BC, but the results corroborate the importance and safety of resistance training for patients, including women at high risk for lymphedema.

http://bit.ly/2FtxCmu

Impact of tumor, treatment, and access on outcomes in bladder cancer: Can equal access overcome race‐based differences in survival?

Abstract

Background

There are race‐based differences in bladder cancer survival. To better understand this phenomenon, this study was designed to assess the statistical contributions of tumor, treatment, and access variables to race‐based differences in survival.

Methods

Data were extracted from the National Cancer Data Base on black and white adults with muscle‐invasive bladder cancer from 2004 to 2015. The impact of tumor, access, and treatment variables on differences in survival was inferred by the performance of sequential propensity score–weighted analyses in which black and white patients were balanced with respect to demographics and health status (comorbidities) tumor characteristics, treatment, and access‐related variables. The propensity score–weighted hazard of death (black vs white) was calculated after each iteration.

Results

This study identified 44,577 patients with a median follow‐up of 77 months. After demographics and health status were balanced, black race was associated with 18% worse mortality (hazard ratio, 1.18; 95% confidence interval [CI], 1.12‐1.25; P < .001). Balancing by tumor characteristics reduced this to 16%, balancing by treatment reduced this to 10%, and balancing by access‐related variables resulted in no difference. Access‐related variables explained 40% (95% CI, 22.9%‐57.0%) of the excess risk of death in blacks, whereas treatment factors explained 35% (95% CI, 22.2%‐46.9%). The contribution of tumor characteristics was not significant.

Conclusions

In the models, differences in survival for black and white patients with bladder cancer are best explained by disparities in access and treatment, not tumor characteristics. Access to care is likely a key factor in racial disparities in cancer.

http://bit.ly/2Fm91R6

The effects of a randomized trial of brief forms of stress management on RAGE‐associated S100A8/A9 in patients with breast cancer undergoing primary treatment

Background

Women with breast cancer (BCa) experience heightened distress, which is related to greater inflammation and poorer outcomes. The s100 protein family facilitates the inflammatory response by regulating myeloid cell function through the binding of Toll‐like receptor 4 and the receptor for advanced glycation end products (RAGE). The heterodimer s100A8/A9 RAGE ligand is associated with hastened tumor development and metastasis. Previously, a 10‐week stress‐management intervention using cognitive behavioral therapy (CBT) and relaxation training (RT) was associated with less leukocyte inflammatory gene expression in patients with BCa; however, its impact on s100A8/A9 was not examined. Because a 10‐week intervention may be impractical during primary treatment for BCa, the authors developed briefer forms of CBT and RT and demonstrated their efficacy in reducing distress over 12 months of primary treatment. Here, the effects of these briefer interventions were tested effects on s100A8/A9 levels over the initial 12 months of BCa treatment.

Methods

Postsurgical patients with BCa (stage 0‐IIIB) were randomized to a 5‐week, group‐based condition: CBT, RT, or health education control (HE). At baseline and at 12 months, women provided sera from which s100A8/A9 levels were determined using any enzyme‐linked immunosorbent assay.

Results

Participants (mean age ± standard deviation, 54.81 ± 9.63 years) who were assigned to either CBT (n = 41) or RT (n = 38) had significant s100A8/A9 decreases over 12 months compared with those who were assigned to HE (n = 44; F _[1,114] = 4.500; P = .036) controlling for age, stage, time since surgery, and receipt of chemotherapy or radiation. Greater increases in stress‐management skills from preintervention to postintervention predicted greater reductions in s100A8/A9 levels over 12 months (β = −0.379; t _[101] = −4.056; P < .001).

Conclusions

Brief, postsurgical, group‐based stress management reduces RAGE‐associated s100A8/A9 ligand levels during primary treatment for BCa.

http://bit.ly/2FowosB

Understanding the engagement of key decision support persons in patient decision making around breast cancer treatment

Background

Patients with breast cancer involve multiple decision support persons (DSPs) in treatment decision making, yet little is known about DSP engagement in decision making and its association with patient appraisal of the decision process.

Methods

Patients newly diagnosed with breast cancer reported to Georgia and Los Angeles Surveillance, Epidemiology, and End Results registries in 2014‐2015 were surveyed 7 months after their diagnosis. The individual most involved in each respondent's decision making (the key DSP) was surveyed. DSP engagement was measured across 3 domains: 1) informed about decisions, 2) involved in decisions, and 3) aware of patient preferences. Patient decision appraisal included subjective decision quality (SDQ) and deliberation. This study evaluated bivariate associations with chi‐square tests between domains of DSP engagement and independent DSP variables. Analysis of variance and multivariable logistic regression were used to compare domains of DSP engagement with patient decision appraisal.

Results

In all, 2502 patients (68% response rate) and 1203 eligible DSPs (70% response rate) responded. Most DSPs were husbands/partners or daughters, were white, and were college graduates. Husbands/partners were more likely to be more informed, involved, and aware (all P values < .01). English‐ and Spanish‐speaking Latinos had a higher extent of (P = .02) but lower satisfaction with involvement (P < .01). A highly informed DSP was associated with higher odds of patient‐reported SDQ (odds ratio, 1.46; 95% confidence interval, 1.03‐2.08; P = .03). A highly aware DSP was associated with higher odds of patient‐reported deliberation (odds ratio, 1.83; 95% confidence interval, 1.36‐2.47; P < .01).

Conclusions

In this population‐based study, informal DSPs were engaged with and positively contributed to patients' treatment decision making. To improve decision quality, future interventions should incorporate DSPs.

http://bit.ly/2swgh4F

Obesity and cancer treatment efficacy: Existing challenges and opportunities

http://bit.ly/2M9zRg0

Issue Information

http://bit.ly/2sjTLf2

American College of Radiology takes steps to lower CT scan radiation exposure

http://bit.ly/2M4Aebw

Duke researchers assess risks of opioid use in patients with cancer

http://bit.ly/2smiOxV

Pediatric computed tomography scans: Weighing the risks and benefits

http://bit.ly/2M4zL9g

Cancers, Vol. 11, Pages 82: Targeting the mTOR Signaling Pathway Utilizing Nanoparticles: A Critical Overview

Cancers, Vol. 11, Pages 82: Targeting the mTOR Signaling Pathway Utilizing Nanoparticles: A Critical Overview

Cancers doi: 10.3390/cancers11010082

Authors: Mariia Lunova Barbora Smolková Anna Lynnyk Mariia Uzhytchak Milan Jirsa Šárka Kubinová Alexandr Dejneka Oleg Lunov

Proteins of the mammalian target of rapamycin (mTOR) signaling axis are overexpressed or mutated in cancers. However, clinical inhibition of mTOR signaling as a therapeutic strategy in oncology shows rather limited progress. Nanoparticle-based mTOR targeted therapy proposes an attractive therapeutic option for various types of cancers. Along with the progress in the biomedical applications of nanoparticles, we start to realize the challenges and opportunities that lie ahead. Here, we critically analyze the current literature on the modulation of mTOR activity by nanoparticles, demonstrate the complexity of cellular responses to functionalized nanoparticles, and underline challenges lying in the identification of the molecular mechanisms of mTOR signaling affected by nanoparticles. We propose the idea that subcytotoxic doses of nanoparticles could be relevant for the induction of subcellular structural changes with possible involvement of mTORC1 signaling. The evaluation of the mechanisms and therapeutic effects of nanoparticle-based mTOR modulation will provide fundamental knowledge which could help in developing safe and efficient nano-therapeutics.

http://bit.ly/2slqVuL

ZNF671 DNA methylation as a molecular predictor for the early recurrence of serous ovarian cancer

Abstract

Serous ovarian cancer is the most frequent type of epithelial ovarian cancer. Despite the use of surgery and platinum‐based chemotherapy, many patients suffer from recurrence within 6 months, termed platinum‐resistance. Currently, the lack of relevant molecular biomarkers for the prediction of the early recurrence of serous ovarian cancers is linked to the poor prognosis. To identify an effective biomarker for early recurrence, we analyzed the genome‐wide DNA methylation status characteristic of early recurrence after treatment. The patients in the TCGA dataset who showed a complete response after the first therapy were categorized into two groups: early recurrence serous ovarian cancer (ERS, recurrence ≤12 months, n=51) and late recurrence serous ovarian cancer (LRS, recurrence >12 months, n=158). Among the 12 differently methylated probes identified between the two groups, we found that ZNF671 was the most significantly methylated gene in the early recurrent group. A validation cohort of 78 serous ovarian cancers showed that patients with ZNF671 DNA methylation had a worse prognosis (P<0.05). The multivariate analysis revealed that the methylation status of ZNF671 was an independent factor for predicting the recurrence of serous ovarian cancer patients both in the TCGA dataset and our cohort (P=0.049 and P=0.021, respectively). Functional analysis revealed that the depletion of ZNF671 expression conferred a more migratory and invasive phenotype to the ovarian cancer cells. Our data indicates that ZNF671 functions as a tumor suppressor in ovarian cancer and that the DNA methylation status of ZNF671 might be an effective biomarker for the recurrence of serous ovarian cancer after platinum‐based adjuvant chemotherapy.

This article is protected by copyright. All rights reserved.

http://bit.ly/2SRgScw

UNC5D, suppressed by promoter hypermethylation, inhibits cell metastasis by activating DAPK1 in prostate cancer

Summary

Prostate cancer (PCa) death primarily occurs due to metastasis of the cells, but little is known about the underlying molecular mechanisms. This study aimed to evaluate the expression of UNC5D, a newly identified tumor suppressor gene, analyze its epigenetic alterations, and elucidate its functional relevance to PCa metastasis. Meta‐analysis of publicly available microarray datasets revealed that UNC5D expression was frequently down‐regulated in PCa tissues and inversely associated with the PCa metastasis. These results were verified in clinical specimens by real‐time PCR and immunohistochemistry assays. Through methylation analysis, the down‐regulated expression of UNC5D in PCa tissues and cell lines was found to be attributable to the hypermethylation of the promoter. A negative correlation was observed between methylation and UNC5D mRNA expression in PCa samples. The ectopic expression of UNC5D in PCa cells effectively reduced their ability to migrate and invade both in vitro and in vivo, and siRNA‐mediated knockdown of UNC5D yielded consistent results. UNC5D can recruit and activate DAPK1, which remained to be essential for its metastatic suppressor function. In conclusion, these results suggested that UNC5D as a novel putative metastatic suppressor gene that is commonly down‐regulated by hypermethylation in PCa.

This article is protected by copyright. All rights reserved.

http://bit.ly/2AIFEEz

Does Complete Pathologic Response Come to Those Who Wait?

http://bit.ly/2AGXAzz

New Research From Psychological Science

Read about the latest research published in Psychological Science:

Lexical Acquisition Through Category Matching: 12-Month-Old Infants Associate Words to Visual Categories
Barbara Pomiechowska and Teodora Gliga

How do infants learn what objects and words belong to different categories before mastering language? Pomiechowska and Gliga familiarized 12-month-olds with objects from two novel categories (coffee makers and staplers) in a way that fostered category learning (i.e., blocked by category) or in a way that did not foster category learning (i.e., randomly). Then, they showed infants an exemplar of the category with a verbal label (e.g., "This is a toma."). In the test phase, infants' gaze was measured by an eye tracker while they were presented with two never-seen objects, one from each category, and were prompted to look at one of them (e.g., "Look at the toma."). Infants looked at the correct object when they had learned the category but not when they had randomly seen members of the two categories. When infants were not exposed to the category name (in this example, toma) and were presented during the test with an object from one of the old categories and an object from a new category (garlic press), infants who learned the old categories gazed more at the new-category object, indicating new-category learning. Moreover, when infants were not familiarized with the categories, they did not exhibit the ability to extend labels to new objects but were able to recognize old objects as part of the category. Taken together, these results indicate that infants are able to use preverbal category knowledge to discover word meanings. Thus, individual differences in category learning may be a source of differences in the rate of language acquisition (e.g., poor category learning in autism may explain slower vocabulary growth).

Working Memory Has Better Fidelity Than Long-Term Memory: The Fidelity Constraint Is Not a General Property of Memory After All
Natalie Biderman, Roy Luria, Andrei R. Teodorescu, Ron Hajaj, and Yonatan Goshen-Gottstein

Although it is undeniable that memory for details changes with the passage of time, there is disagreement over whether these changes are different in working memory (WM) and long-term memory (LTM). To examine declines in the level of information, or fidelity, in WM versus LTM, the authors showed participants images of everyday objects in different colors, and tested their memory for those objects either immediately after the presentation of each object (WM test) or after the presentation of all the objects (LTM test). In the tests, participants looked at an object in gray scale and indicated whether they had seen it before and in which color. Overall, participants had better color memory, showing higher fidelity, in the WM test than in the LTM test. However, color memory got worse as participants did more memory trials and when they had to study more objects, suggesting that memory fidelity decreases because of mechanisms that occur over time, such as interference, but not necessarily because of the passage of time itself. The results indicate that WM and LTM are separate memory systems that do not share the same constraints of fidelity.

http://bit.ly/2RpssPx

Composition of the cutaneous bacterial community of a cave amphibian, Proteus anguinus

Abstract

The European cave salamander Proteus anguinus is a charismatic amphibian endemic to the concealed and inaccessible subterranean waters of the Dinaric Karst. Despite its exceptional conservation importance not much is known about its ecology and interactions with the groundwater microbiome. The cutaneous microbiota of amphibians is an important driver of metabolic capabilities and immunity, and thus a key factor of their wellbeing and survival. We used high-throughput 16S rRNA gene sequencing based on seven variable regions to examine the bacteriome of the skin of five distinct evolutionary lineages of P. anguinus and in their groundwater environment. The skin bacteriomes turned out to be strongly filtered subsamples of the environmental microbial community. The resident microbiota of the analyzed individuals was dominated by five bacterial taxa. Despite an indicated functional redundancy, the cutaneous bacteriome of P. anguinus presumably provides protection against invading microbes by occupying the niche, and thus could serve as indicator of health status. Besides conservation implications for P. anguinus, our results provide a baseline for future studies on other endangered neotenic salamanders.

http://bit.ly/2FoyRmO