Treating Immune-Related Epilepsy

Abstract

Purpose of Review

This review explores different treatment modalities for immune-mediated epilepsy, including epilepsy caused by autoantibodies as well as epilepsy in the context of systemic autoimmune disease.

Recent Findings

Autoimmune epilepsy is an increasingly recognized entity. Conventional treatments for epilepsy, such as antiseizure medications and epilepsy surgery, are less successful in treating epilepsy caused by autoimmune disease. Immunomodulatory therapies such as corticosteroids, intravenous immunoglobulin, and plasma exchange are generally more successful in treating immune-mediated epilepsy than conventional epilepsy therapies.

Summary

Autoimmune epilepsy should be considered as a possible etiology for patients with frequent seizures of unknown etiology. The response to immunotherapies is often promising, particularly in patients with antibodies to neuronal cell surface antigens.

http://ift.tt/2Br23aC

The Neuropsychological Consequences of Armed Conflicts and Torture

Abstract

Purpose of Review

At any point in time, there are hundreds of armed conflicts throughout the world. Neuropsychological disorders are a major cause of morbidity during and after armed conflicts. Conditions such as closed and open head injuries, acute stress disorder, post-traumatic stress disorder, depression, anxiety, and psychosis are prevalent among survivors. Herein, we summarize information on the various forms of torture, the resultant neuropsychological pathology, and treatment strategies to help survivors.

Recent Findings

Strategies to address the needs of individuals who experienced neuropsychological trauma due to armed conflicts and torture include pharmacological and psychological interventions. The former includes antidepressant, antianxiety, and antipsychotic medications. The latter includes narrative exposure therapy and trauma-focused cognitive-behavioral therapy.

Summary

Neuropsychological disorders are major causes of morbidity among survivors of armed conflicts and torture. Treatment strategies must be affordable, applicable across cultures, and deliverable by individuals who understand the victims' psychosocial and ethnic background.

http://ift.tt/2BZPc0p

Neurological Complications of Acute and Chronic Otitis Media

Abstract

Purpose of Review

The aim of this study is to discuss the symptoms, diagnosis, and management of the neurologic complications of acute and chronic otitis media.

Recent Findings

Antibiotic therapy has greatly reduced the frequency of complications of otitis media. However, it is of vital importance to remain aware of the possible development of neurologic complications. There is a trend toward less severe presenting symptoms including otorrhea, headache, nausea, and fever, with altered mental status and focal neurologic deficits presenting later. In order to reduce morbidity, early deployment of a multidisciplinary approach with prompt imaging and laboratory studies is imperative to guide appropriate management.

Summary

Complications of acute and chronic otitis media may present with neurologic signs and symptoms. It is important to recognize the possible otitic origin of such complications to ensure proper management and to decrease overall morbidity and mortality

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Energy Analysis of a Complementary Heating System Combining Solar Energy and Coal for a Rural Residential Building in Northwest China

In order to utilize solar energy to meet the heating demands of a rural residential building during the winter in the northwestern region of China, a hybrid heating system combining solar energy and coal was built. Multiple experiments to monitor its performance were conducted during the winter in 2014 and 2015. In this paper, we analyze the efficiency of the energy utilization of the system and describe a prototype model to determine the thermal efficiency of the coal stove in use. Multiple linear regression was adopted to present the dual function of multiple factors on the daily heat-collecting capacity of the solar water heater; the heat-loss coefficient of the storage tank was detected as well. The prototype model shows that the average thermal efficiency of the stove is 38%, which means that the energy input for the building is divided between the coal and solar energy, 39.5% and 60.5% energy, respectively. Additionally, the allocation of the radiation of solar energy projecting into the collecting area of the solar water heater was obtained which showed 49% loss with optics and 23% with the dissipation of heat, with only 28% being utilized effectively.

http://ift.tt/2F2A68T

Tough Composite Hydrogels with High Loading and Local Release of Biological Drugs

Abstract

Hydrogels are under active development for controlled drug delivery, but their clinical translation is limited by low drug loading capacity, deficiencies in mechanical toughness and storage stability, and poor control over the drug release that often results in burst release and short release duration. This work reports a design of composite clay hydrogels, which simultaneously achieve a spectrum of mechanical, storage, and drug loading/releasing properties to address the critical needs from translational perspectives. The clay nanoparticles provide large surface areas to adsorb biological drugs, and assemble into microparticles that are physically trapped within and toughen hydrogel networks. The composite hydrogels demonstrate feasibility of storage, and extended release of large quantities of an insulin-like growth factor-1 mimetic protein (8 mg mL⁻¹) over four weeks. The release rate is primarily governed by ionic exchange and can be upregulated by low pH, which is typical for injured tissues. A rodent model of Achilles tendon injury is used to demonstrate that the composite hydrogels allow for highly extended and localized release of biological drugs in vivo, while demonstrating biodegradation and biocompatibility. These attributes make the composite hydrogel a promising system for drug delivery and regenerative medicine.

This work reports biocompatible composite hydrogels with high loading and extremely extended, localized release of biological drugs. The hydrogels demonstrate high mechanical toughness (sustain >80% compressive strains), large drug loading capacity (8 mg mL⁻¹), extended release duration (28 d), and highly localized drug release (the ratio of tissue- and serum-level of the drug >10 000).

http://ift.tt/2o8WtSi

Injectable, Tough Alginate Cryogels as Cancer Vaccines

Abstract

A covalently crosslinked methacrylated (MA)-alginate cryogel vaccine has been previously shown to generate a potent response against murine melanoma, but is not mechanically robust and requires a large 16G needle for delivery. Here, covalent and ionic crosslinking of cryogels are combined with the hypothesis that this will result in a tough MA-alginate cryogel with improved injectability. All tough cryogels can be injected through a smaller, 18G needle without sustaining any damage, while covalently crosslinked-only cryogels break after injection. Cytosine-phosphodiester-guanine (CpG)-delivering tough cryogels effectively activate dendritic cells (DCs). Granulocyte macrophage colony-stimulating factor releasing tough cryogels recruit four times more DCs than blank gels by day 7 in vivo. The tough cryogel vaccine induces strong antigen-specific cytotoxic T-lymphocyte and humoral responses. These vaccines prevent tumor formation in 80% of mice inoculated with HER2/neu-overexpressing DD breast cancer cells. The MA-alginate tough cryogels provide a promising minimally invasive delivery platform for cancer vaccinations.

Combining covalent and ionic crosslinking of cryogels results in a tough methacrylated-alginate cryogel with improved injectability in vitro and in vivo. The tough-cryogel-based cancer vaccine generates strong antigen-specific cellular and humoral responses in vivo, and induces potent antibreast cancer prophylactic efficacy in mice. The tough cryogels are a promising minimally invasive delivery platform for cancer vaccinations.

http://ift.tt/2nYYQrv

A Sulfur–Limonene-Based Electrode for Lithium–Sulfur Batteries: High-Performance by Self-Protection

Abstract

The lithium–sulfur battery is considered as one of the most promising energy storage systems and has received enormous attentions due to its high energy density and low cost. However, polysulfide dissolution and the resulting shuttle effects hinder its practical application unless very costly solutions are considered. Herein, a sulfur-rich polymer termed sulfur–limonene polysulfide is proposed as powerful electroactive material that uniquely combines decisive advantages and leads out of this dilemma. It is amenable to a large-scale synthesis by the abundant, inexpensive, and environmentally benign raw materials sulfur and limonene (from orange and lemon peels). Moreover, owing to self-protection and confinement of lithium sulfide and sulfur, detrimental dissolution and shuttle effects are successfully avoided. The sulfur–limonene-based electrodes (without elaborate synthesis or surface modification) exhibit excellent electrochemical performances characterized by high discharge capacities (≈1000 mA h g⁻¹ at C/2) and remarkable cycle stability (average fading rate as low as 0.008% per cycle during 300 cycles).

A sulfur–limonene-based cathode material is produced by large-scale synthesis using the abundant, inexpensive, and environmentally benign raw materials sulfur and limonene. Owing to self-protection and confinement of lithium sulfide and sulfur, detrimental dissolution and shuttle effects are successfully avoided. As a result, the sulfur–limonene-based electrodes exhibit excellent electrochemical performances and remarkable cycle stability.

http://ift.tt/2BsYpgu

High expression of DJ-1 promotes growth and invasion via the PTEN-AKT pathway and predicts a poor prognosis in colorectal cancer

Abstract

Cancer cell invasion and unlimited proliferation are key factors in patients with colorectal cancer (CRC). Increased protein deglycase DJ-1 in cancer cells is known to promote tumor growth; however, its role in CRC progression is not well defined. In this study, we investigated 100 CRC patients with disease stages I–IV to determine whether DJ-1 could serve as a prognostic biomarker in CRC. These results showed that DJ-1 expression in CRC tissues was higher than that in normal colon tissues and was associated with the (Tumor Node Metastasis) TNM stage. CRC patients with low DJ-1 expression had a longer overall survival than those with high expression, and multivariate and univariate analyses indicated that DJ-1 expression was an independent prognostic factor for overall survival in CRC. Furthermore, DJ-1 overexpression in two colon cancer cell lines, HCT116 and SW480, activated protein kinase AKT and downregulated tumor suppressor PTEN, whereas DJ-1 knockdown upregulated PTEN expression and effectively suppressed CRC cell invasion and proliferation both in vitro and in vivo, revealing a mechanism underlying DJ-1 pro-oncogenic activity in CRC. Treatment of MK2206, the specific AKT inhibitor, significantly decreased DJ-1-mediated cell proliferation and mobility in vitro. Taken together, these results suggest that DJ-1 may be a novel prognostic biomarker and potential therapeutic target in human CRC.

Our data suggest that DJ-1 may be a novel prognostic biomarker and a potential therapeutic target in human CRC.

http://ift.tt/2nX0Q3o

Protein phosphatase 2A (PP2A) inhibitor CIP2A indicates resistance to radiotherapy in rectal cancer

Abstract

Preoperative (chemo)radiotherapy, (C)RT, is an essential part of the treatment of rectal cancer patients, but tumor response to this therapy among patients is variable. Thus far, there are no clinical biomarkers that could be used to predict response to (C)RT or to stratify patients into different preoperative treatment groups according to their prognosis. Overexpression of cancerous inhibitor of protein phosphatase 2A (CIP2A) has been demonstrated in several cancers and is frequently associated with reduced survival. Recently, high CIP2A expression has also been indicated to contribute to radioresistance in head and neck squamous cell carcinoma, but few studies have examined the connection between CIP2A and radiation response regarding other malignancies. We have evaluated CIP2A protein expression levels in relation to tumor regression after preoperative (C)RT and survival of rectal adenocarcinoma patients. The effects of CIP2A knockdown by siRNA on cell survival were further investigated in colorectal cancer cells exposed to radiation. Patients with low-CIP2A-expressing tumors had more frequently moderate or excellent response to long-course (C)RT than patients with high-CIP2A-expressing tumors. They also had higher 36-month disease-specific survival (DSS) rate in categorical analysis. In the multivariate analysis, low CIP2A expression level remained as an independent predictive factor for increased DSS. Suppression of CIP2A transcription by siRNA was found to sensitize colorectal cancer cells to irradiation and decrease their survival in vitro. In conclusion, these results suggest that by contributing to radiosensitivity of cancer cells, low CIP2A protein expression level associates with a favorable response to long-course (C)RT in rectal cancer patients.

Low CIP2A protein expression level associates with a favorable response to long-course chemoradiotherapy in rectal cancer patients. Suppression of CIP2A transcription by siRNA sensitizes colorectal cancer cells to irradiation and decreases their survival in vitro.

http://ift.tt/2o3t6AA

Knowledge about cervical cancer and barriers toward cervical cancer screening among HIV-positive women attending public health centers in Addis Ababa city, Ethiopia

Abstract

Screening rate for cervical cancer among HIV-infected women and among women overall is low in Ethiopia despite the high burden of the disease and HIV infection, which increases cervical cancer risk. In this paper, we assessed knowledge about cervical cancer symptoms, prevention, early detection, and treatment and barriers to screening among HIV-positive women attending community health centers for HIV-infection management in Addis Ababa. A cross-sectional survey of 581 HIV-positive women aged 21–64 years old attending 14 randomly selected community health centers without cervical cancer screening service in Addis Ababa. We used univariate analysis to calculate summary statistics for each variable considered in the analysis, binary logistic regression analysis to measure the degree of association between dependent and independent variables, and multiple regressions for covariate adjusted associations. Statistical significance for all tests was set at P < 0.05. We used thematic analysis to describe the qualitative data. Of the 581 women enrolled in the study with mean age 34.9 ± 7.7 years, 57.8% of participants had heard of cervical cancer and 23.4% were knowledgeable about the symptoms, prevention, early detection, and treatment of the disease. In multivariate analysis, higher educational attainment and employment were significantly associated with good knowledge about cervical cancer. In addition, only 10.8% of the participants ever had screening and 17% ever received recommendation for it. However, 86.2% of them were willing to be screened if free of cost. Knowledge about cervical cancer is poor and cervical cancer screening rate and provider recommendation are low among HIV-positive women attending community health centers for management and follow-up of their disease in Addis Ababa. These findings underscore the need to scale up health education about cervical cancer prevention and early detection among HIV-positive women as well as among primary healthcare providers in the city.

Knowledge about cervical cancer is poor, and cervical cancer screening rate and recommendation are low among HIV-positive women attending community health centers for management and follow-up of their HIV infection in Addis Ababa. These findings underscore the need to scale up health education about cervical cancer prevention and early detection among HIV-positive women as well as among primary healthcare providers in the city.

http://ift.tt/2nYk8pd

Characteristic findings of high-grade cervical intraepithelial neoplasia or more on magnifying endoscopy with narrow band imaging

Abstract

Background

Colposcopy, which is a standard modality for diagnosing cervical intraepithelial neoplasia (CIN), can have limited accuracy owing to poor visibility. Flexible magnifying endoscopy with narrow band imaging (ME-NBI) has excellent diagnostic accuracy for early gastrointestinal neoplasms and is expected to be highly useful for CIN diagnosis. This study aimed to determine the characteristic findings and evaluate the diagnostic ability of ME-NBI for lesions ≥ CIN 3.

Methods

A well-designed prospective diagnostic case series conducted at multiple tertiary-care centers. A total of 24 patients who underwent cervical conization with a preoperative diagnosis of high-grade squamous cell intraepithelial lesions (HSILs) or lesions ≥ CIN 3 were enrolled. Prior to conization, still images and video of ME-NBI were captured to investigate the cervical lesions. The images were reviewed based on histological examination of the resected specimens.

Results

The NBI-ME images revealed the following abnormal findings: (1) light white epithelium (l-WE), (2) heavy white epithelium (h-WE), and (3) atypical intra-epithelial papillary capillary loop (IPCL). Pathological examination of the resected specimens confirmed cervical lesions ≥ CIN 3 in 21 patients. The ME-NBI findings were classified into four groups: l-WE, l-WE with atypical IPCL, h-WE, and h-WE with atypical IPCL, at rates of 0, 23.8, 9.5, and 66.7%, respectively. Additionally, all 3 patients with micro-invasive carcinoma showed a strong irregularity of IPCLs.

Conclusion

The lesions ≥ CIN 3 demonstrated characteristic ME-NBI findings of h-WE alone, or l-/h-WE with atypical micro-vessels. This study indicates that ME-NBI may have novel value for CIN diagnosis.

http://ift.tt/2GdVJTf

The clinical features of squamous cell lung carcinoma with sensitive EGFR mutations

Abstract

Background

The process of selecting patients on the basis of epidermal growth factor receptor (EGFR) mutations would likely result in a patient population with greater sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, EGFR mutation status is not routinely examined in patients with squamous cell lung cancer (Sq) because of the low incidence of EGFR mutations and the poor clinical response to EGFR-TKIs.

Methods

We retrospectively reviewed the clinical features of patients at our hospital with Sq who carried EGFR-TKI-sensitive EGFR mutations and assessed their responses to EGFR-TKIs.

Results

EGFR mutation status was tested in 23 of 441 patients with Sq (5.2%) admitted to our hospital during the study period. An EGFR mutation (exon 19 deletion 3, L858R 2) was identified in five of the 23 patients (21.7%), all of whom were female never-smokers. Of these five patients, four (4/9; 44.4%) were in the normal lung group, one (1/12; 8.3%) was in the emphysematous lung group, and none (0/2; 0%) in the fibrotic lung group. Two of these five patients with the EGFR mutation received gefitinib and two received afatinib. Although the two patients who were treated with gefitinib did not respond well to treatment (stable disease, 1 patient; progressive disease, 1 patient), the two patients who were treated with afatinib showed a good response (partial response, 2 patients).

Conclusion

The administration of afatinib to Sq patients after selecting patients using the EGFR mutation test based on their underlying pulmonary disease and smoking status would likely result in a population with a greater sensitivity to afatinib.

http://ift.tt/2HeEOB2

Issue Information

http://ift.tt/2Ckn83g

Inducible nitric oxide synthase inhibition by 1400W limits pain hypersensitivity in a neuropathic pain rat model

Abstract

Peripheral neuropathic pain (PNP) resulting from injury or dysfunction to a peripheral nerve, is a major health problem affecting 7–8% of the population. It is inadequately controlled by current drugs, and is characterized by pain hypersensitivity which is believed to be due to sensitization of peripheral and CNS neurons by various inflammatory mediators. Here we examined, in a rat model of PNP: a) whether reducing levels of nitric oxide (NO), with 1400 W, a highly selective inhibitor of inducible NO synthase (iNOS), would prevent/attenuate pain hypersensitivity, and b) the effects of 1400 W on plasma levels of several cytokines that are secreted post iNOS upregulation during chronic pain states. The L5-spinal nerve axotomy (SNA) model of PNP was used, and 1400 W (20 mg kg⁻¹) administered intraperitoneally at 8 hour intervals for three days starting at 18 hours post-SNA. Changes in plasma concentrations of 12 cytokines in SNA rats treated with 1400 W were examined using multiplex ELISA. SNA rats developed behavioural signs of mechanical and heat hypersensitivity. Compared with the vehicle/control, 1400 W significantly: (a) limited development of mechanical hypersensitivity at 66 hours post-SNA, as well as heat hypersensitivity at 42 hours and at several time-points tested thereafter, and (b) increased the plasma concentrations of IL-1α, IL-1β, and IL-10 in the SNA rats. The findings suggest that 1400 W may exert its analgesic effects by reducing iNOS and altering the balance between the pro-inflammatory (IL-1β and IL-1α) and anti-inflammatory (IL-10) cytokines and that therapies targeting NO or its enzymes may be effective for the treatment of PNP.

This article is protected by copyright. All rights reserved

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Computed tomography densitometric study of anti-angiogenic effect of regorafenib in colorectal cancer liver metastasis

Future Oncology, Ahead of Print.


http://ift.tt/2styvqe

Genomic Predictions and Genome-Wide Association Study of Resistance Against Piscirickettsia salmonis in Coho Salmon (Oncorhynchus kisutch) Using ddRAD Sequencing

Piscirickettsia salmonis is one of the main infectious diseases affecting coho salmon (Oncorhynchus kisutch) farming, and current treatments have been ineffective for the control of this disease. Genetic improvement for P. salmonis resistance has been proposed as a feasible alternative for the control of this infectious disease in farmed fish. Genotyping by sequencing (GBS) strategies allow genotyping of hundreds of individuals with thousands of single nucleotide polymorphisms (SNPs), which can be used to perform genome wide association studies (GWAS) and predict genetic values using genome-wide information. We used double-digest restriction-site associated DNA (ddRAD) sequencing to dissect the genetic architecture of resistance against P. salmonis in a farmed coho salmon population and to identify molecular markers associated with the trait. We also evaluated genomic selection (GS) models in order to determine the potential to accelerate the genetic improvement of this trait by means of using genome-wide molecular information. A total of 764 individuals from 33 full-sib families (17 highly resistant and 16 highly susceptible) were experimentally challenged against P. salmonis and their genotypes were assayed using ddRAD sequencing. A total of 9,389 SNPs markers were identified in the population. These markers were used to test genomic selection models and compare different GWAS methodologies for resistance measured as day of death (DD) and binary survival (BIN). Genomic selection models showed higher accuracies than the traditional pedigree-based best linear unbiased prediction (PBLUP) method, for both DD and BIN. The models showed an improvement of up to 95% and 155% respectively over PBLUP. One SNP related with B-cell development was identified as a potential functional candidate associated with resistance to P. salmonis defined as DD.

http://ift.tt/2Hd4pu9

The Balance Players of the Adaptive Immune System

Equilibrium between immune activation and suppression may be necessary to maintain immune homeostasis, because proinflammatory effector T cells (defined as antiregulatory T cells) counteract the functions of regulatory immune cells. These self-reactive T cells recognize human leukocyte antigen (HLA)–restricted epitopes derived from proteins expressed by regulatory immune cells such as IDO, PD-L1, PD-L2, or arginase. The activation of such proinflammatory effector T cells offers a novel way to directly target the tumor microenvironment, potentially giving them considerable clinical value, especially in patients with cancer. Vaccination against genetically stable cells with regular HLA expression is an attractive way to directly target immunosuppressive cells in addition to attracting proinflammatory cells into the tumor microenvironment. Importantly, vaccination toward IDO or PD-L1 to potentiate such T cells have proven safe, with minimal toxicity in the clinical phase I trials conducted thus far.Significance: Autoreactive effector T cells that specifically recognize regulatory cells might be useful to harness for cancer immunotherapy to target the immune-suppressive tumor microenvironment. Cancer Res; 1–4. ©2018 AACR.

http://ift.tt/2Bu0oBr

SPON2 Promotes M1-like Macrophage Recruitment and Inhibits Hepatocellular Carcinoma Metastasis by Distinct Integrin-Rho GTPase-Hippo Pathways

Tumor-associated macrophages (TAM) represent key regulators of the complex interplay between cancer and the immune microenvironment. Matricellular protein SPON2 is essential for recruiting lymphocytes and initiating immune responses. Recent studies have shown that SPON2 has complicated roles in cell migration and tumor progression. Here we report that, in the tumor microenvironment of hepatocellular carcinoma (HCC), SPON2 not only promotes infiltration of M1-like macrophages but also inhibits tumor metastasis. SPON2-α4β1 integrin signalling activated RhoA and Rac1, increased F-actin reorganization, and promoted M1-like macrophage recruitment. F-actin accumulation also activated the Hippo pathway by suppressing LATS1 phosphorylation, promoting YAP nuclear translocation, and initiating downstream gene expression. However, SPON2-α5β1 integrin signaling inactivated RhoA and prevented F-actin assembly, thereby inhibiting HCC cell migration; the Hippo pathway was not noticeably involved in SPON2-mediated HCC cell migration. In HCC patients, SPON2 levels correlated positively with prognosis. Overall, our findings provide evidence that SPON2 is a critical factor in mediating the immune response against tumor cell growth and migration in HCC.

http://ift.tt/2BXtmdE

A DDX31/mutant-p53/EGFR axis promotes multistep progression of muscle invasive bladder cancer

The p53 and EGFR pathways are frequently altered in bladder cancers, yet their contributions to its progression remain elusive. Here we report that DEAD box polypeptide 31 (DDX31) plays a critical role in the multistep progression of muscle invasive bladder cancer (MIBC) through its sequential interactions with mutant p53 (mutp53) and EGFR. In early MIBC cells, nuclear DDX31 bound mutp53/SP1 and enhanced mutp53 transcriptional activation, leading to migration and invasion of MIBC. Cytoplasmic DDX31 also bound EGFR and phospho-nucleolin (p-NCL) in advanced MIBC, leading to EGFR-Akt signaling activation. High expression of both cytoplasmic DDX31 and p53 proteins correlated with poor prognosis in patients with MIBC, and blocking the DDX31-NCL interaction resulted in downregulation of EGFR-Akt signaling, eliciting an in vivo anti-tumor effect against bladder cancer. These findings reveal that DDX31 cooperates with mutp53 and EGFR to promote progression of MIBC, and inhibition of DDX31-NCL formation may lead to potential treatment strategies for advanced MIBC.

http://ift.tt/2BuHcDC

The FACT inhibitor CBL0137 synergizes with cisplatin in small cell lung cancer by increasing NOTCH1 expression and targeting tumor-initiating cells

Traditional treatments of small cell lung cancer (SCLC) with cisplatin, a standard of care therapy, spare the tumor-initiating cells (TIC) that mediate drug resistance. Here we report a novel therapeutic strategy that preferentially targets TIC in SCLC in which cisplatin is combined with CBL0137, an inhibitor of the histone chaperone facilitates chromatin transcription (FACT), which is highly expressed in TIC. Combination of cisplatin and CBL0137 killed patient-derived and murine SCLC cell lines synergistically. In response to CBL0137 alone, TIC were more sensitive than non-TIC, in part because CBL0137 increased expression of the tumor suppressor NOTCH1 by abrogating the binding of negative regulator SP3 to the NOTCH1 promoter, and in part because treatment decreased the high expression of stem cell transcription factors. The combination of cisplatin and CBL0137 greatly reduced the growth of a patient-derived xenograft in mice and also the growth of a syngeneic mouse SCLC tumor. Thus, CBL0137 can be a highly effective drug against SCLC, especially in combination with cisplatin.

http://ift.tt/2BVUTMD

Questioning the Extreme Neurovirulence of Monkey B Virus (Macacine alphaherpesvirus 1)

Monkey B virus (Macacine alphaherpesvirus 1; BV) occurs naturally in macaques of the genus Macaca, which includes rhesus and long-tailed (cynomolgus) monkeys that are widely used in biomedical research. BV is closely related to the human herpes simplex viruses (HSV), and BV infections in its natural macaque host are quite similar to HSV infections in humans. Zoonotic BV is extremely rare, having been diagnosed in only a handful of North American facilities with the last documented case occurring in 1998. However, BV is notorious for its neurovirulence since zoonotic infections are serious, usually involving the central nervous system, and are frequently fatal. Little is known about factors underlying the extreme neurovirulence of BV in humans. Here we review what is actually known about the molecular biology of BV and viral factors affecting its neurovirulence. Based on what is known about related herpesviruses, areas for future research that may elucidate mechanisms underlying the neurovirulence of this intriguing virus are also reviewed.

http://ift.tt/2F0DjWr

Avoiding the Trap of Misdiagnosis: Valuable Teaching Points Derived from a Case of Longstanding Popliteal Artery Entrapment Syndrome

Popliteal artery entrapment syndrome (PAES), a condition predominantly affecting young individuals, is a rare clinical entity that can result in significant morbidity. The presence of lower limb pain and claudication in young, physically active individuals should prompt consideration for PAES. Early diagnosis and management is crucial to prevent long-term complications; however, diagnosis is fraught with challenges due to the rarity of the disease and its similar clinical presentation with more common conditions. We present a case of a young female with PAES who was misdiagnosed and underwent a tarsal tunnel release for suspected tarsal tunnel syndrome and subsequent fasciotomies for presumed chronic exertional compartment syndrome (CECS) without any relief. We outline the insidious undiagnosed course of her condition over a period of 12 years, discuss teaching points of how to recognize key differences of PAES and associated conditions, and provide recommendations for how to make the right diagnosis.

http://ift.tt/2BZmGvT

Acyclovir 400mg Tablets by Apace Packaging: Recall - Product Mix-up

Audience: Pharmacy, Patient [Posted 02/13/2018] ISSUE: Apace Packaging LLC is voluntarily recalling one lot of Acyclovir Tablet, USP, 400mg, 50ct Unit Dose, NDC# 50268-061-15, Lot Number 19900, to the retail level. These products have been recalled...

http://ift.tt/2Cjrtnm

Acyclovir 400mg Tablets by Apace Packaging: Recall - Product Mix-up

Audience: Pharmacy, Patient [Posted 02/13/2018] ISSUE: Apace Packaging LLC is voluntarily recalling one lot of Acyclovir Tablet, USP, 400mg, 50ct Unit Dose, NDC# 50268-061-15, Lot Number 19900, to the retail level. These products have been recalled...

http://ift.tt/2Cjrtnm

A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma

A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma

A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma, Published online: 13 February 2018; doi:10.1038/bjc.2017.495

A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma

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Telomere length and genetics are independent colorectal tumour risk factors in an evaluation of biomarkers in normal bowel

Telomere length and genetics are independent colorectal tumour risk factors in an evaluation of biomarkers in normal bowel

Telomere length and genetics are independent colorectal tumour risk factors in an evaluation of biomarkers in normal bowel, Published online: 13 February 2018; doi:10.1038/bjc.2017.486

Telomere length and genetics are independent colorectal tumour risk factors in an evaluation of biomarkers in normal bowel

http://ift.tt/2Gd2ODE

Randomised study shows that repeated self-sampling and HPV test has more than two-fold higher detection rate of women with CIN2+ histology than Pap smear cytology

Randomised study shows that repeated self-sampling and HPV test has more than two-fold higher detection rate of women with CIN2+ histology than Pap smear cytology

Randomised study shows that repeated self-sampling and HPV test has more than two-fold higher detection rate of women with CIN2+ histology than Pap smear cytology, Published online: 13 February 2018; doi:10.1038/bjc.2017.485

Randomised study shows that repeated self-sampling and HPV test has more than two-fold higher detection rate of women with CIN2+ histology than Pap smear cytology

http://ift.tt/2GbpiES

IKKα is required in the intestinal epithelial cells for tumour stemness

IKKα is required in the intestinal epithelial cells for tumour stemness

IKK<i>α</i> is required in the intestinal epithelial cells for tumour stemness, Published online: 13 February 2018; doi:10.1038/bjc.2017.459

IKKα is required in the intestinal epithelial cells for tumour stemness

http://ift.tt/2Ha02QN

Strategies for clinical development of monoclonal antibodies beyond first-in-human trials: tested doses and rationale for dose selection

Strategies for clinical development of monoclonal antibodies beyond first-in-human trials: tested doses and rationale for dose selection

Strategies for clinical development of monoclonal antibodies beyond first-in-human trials: tested doses and rationale for dose selection, Published online: 13 February 2018; doi:10.1038/bjc.2017.473

Strategies for clinical development of monoclonal antibodies beyond first-in-human trials: tested doses and rationale for dose selection

http://ift.tt/2G9owIE

A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424

A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424

A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424, Published online: 13 February 2018; doi:10.1038/bjc.2017.484

A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424

http://ift.tt/2GamEz8

Regulation of ITGA3 by the dual-stranded microRNA-199 family as a potential prognostic marker in bladder cancer

Regulation of ITGA3 by the dual-stranded microRNA-199 family as a potential prognostic marker in bladder cancer

Regulation of ITGA3 by the dual-stranded <i>microRNA</i>-199 family as a potential prognostic marker in bladder cancer, Published online: 13 February 2018; doi:10.1038/bjc.2017.439

Regulation of ITGA3 by the dual-stranded microRNA-199 family as a potential prognostic marker in bladder cancer

http://ift.tt/2HeAB0v

An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma

An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma

An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma, Published online: 13 February 2018; doi:10.1038/bjc.2018.3

An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma

http://ift.tt/2H9ZQkx

High Prevalence of Liver Fibrosis Among European Adults with Unknown Liver Disease. A Population-Based Study

Liver fibrosis is the main determinant of long-term outcome in chronic liver diseases. Little is known about prevalence of liver fibrosis in general population. Aim of the study was to investigate the prevalence of liver fibrosis in general adult population with unknown liver disease.

http://ift.tt/2sueNdL

Characteristics of Heat Illness during Hajj: A Cross-Sectional Study

Introduction. Data regarding the characteristics and outcomes of heat illness are lacking in the literature. The present study aimed to identify the clinical characteristics, morbidity, management, and mortality associated with heat illness among Hajj participants. Methods. A cross-sectional study was conducted during the Hajj in 2016 on patients who presented to emergency departments and were diagnosed with heat exhaustion or heatstroke. Data were collected using a structured collection sheet developed based on the literature. Results. A total of 267 patients were recruited. Of these, 80 (29%) and 187 (67.75%) were diagnosed with heatstroke and heat exhaustion, with 6.3% and 0.0% mortality, respectively. The mean age of the patients was years. Diabetes mellitus was the most common comorbidity among both heatstroke and heat exhaustion patients. The majority of patients had hyperthermia and electrolyte imbalance. Most of the heat illness cases were treated per heat illness guidelines. Conclusions. Although authorities are working on research and forming interdisciplinary teams to prevent health problems during the Hajj, the mortality rate from heatstroke is high and the majority of the patients had hyperthermia, varied signs and symptoms, elevated creatinine levels, and electrolyte imbalances.

http://ift.tt/2o5oOsp

Feasibility of EUS-guided Nd:YAG laser ablation of unresectable pancreatic adenocarcinoma

Endoscopic ultrasound (EUS) has become an interventional technique in which a needle may be used as a vehicle to deliver therapeutic agents. Laser ablation (LA) has been used to treat many primary and secondary neoplasms. This study aimed to assess the feasibility of EUS-guided LA for unresectable (UR) pancreatic cancer.

http://ift.tt/2F21i7E

Clinical outcomes and factors related with colonic perforations in patients receiving self-expandable metal stent insertion for malignant colorectal obstruction

Although colonic perforation is a dreadful adverse event associated with stent placement, data on this topic are sparse. We aimed to investigate the clinical outcomes of colonic perforation and factors related with its occurrence in patients who receiving self-expanding metal stents (SEMSs) for malignant colorectal obstruction.

http://ift.tt/2o5Kgxl

PGRN promotes lymphangiogenesis through VEGF-C and is an independent risk factor in human esophageal cancers

Lymph node metastasis is one of the most important predictor of the prognosis for esophageal cancer (EC) patients. Yet, the mechanism underlying the lymph node metastasis is largely unknown. Progranulin (PGRN) is shown to be highly expressed in various types of cancers and could promote the angiogenesis and epithelial mesenchymal transition (EMT) of cancer cells in previous studies. However, the expression status of PGRN and its effects on the lymphangiogenesis in EC is largely unclear. In this study, we show for the first time that PGRN is expressed in EC tissue samples and cell lines and could promote the expression of VEGF-C in vitro, a well-known lymphangiogenesis inducer, through the putative signaling transducers p-ERK and p-AKT.

http://ift.tt/2C1ntMK

Lymphocytic Colitis: Pathologic predictors of response to therapy

While the presence of intraepithelial lymphocytosis with surface epithelial damage is a unifying feature of lymphocytic colitis, there are non-classical features that create morphologic heterogeneity between cases. Limited data are available on the significance of these secondary histologic features. Cases of lymphocytic colitis diagnosed between 2002 and 2013 were identified using the Research Patient Data Registry of a tertiary referral center. Diagnostic biopsy slides were reviewed and evaluated for histologic features of lymphocytic colitis.

http://ift.tt/2sqNa5x

Prognostic value of [18F]-fluoromethylcholine PET/CT Before Stereotactic Body Radiotherapy For Oligometastatic Prostate Cancer

Treating oligometastases detected by [18F]-fluoromethylcholine positron-emission tomography/computed tomography (PET/CT) with stereotactic body radiotherapy (SBRT) may postpone initiation of androgen-deprivation therapy, and possibly prolong progression-free survival (PFS). However, better prognostic factors are needed to improve patient selection. We investigated the predictive value of [18F]-fluoromethylcholine-PET/CT-derived parameters on PFS in oligometastatic prostate cancer patients treated with SBRT.

http://ift.tt/2nXlh0a

Implications of Pathological Complete Response (pCR) Beyond Mediastinal Nodal Clearance with High-dose Neoadjuvant Chemoradiotherapy (CRT) in Locally Advanced, Non-Small Cell Lung Cancer (LA-NSCLC)

Mediastinal response guides decision for surgery in LA-NSCLC patients treated with neoadjuvant therapy, where mediastinal nodal clearance (MNC) is strongly associated with improved survival. The added benefit of a pathologic complete response (pCR), with no viable tumor in both the mediastinum and primary site is not known, which is the objective of this large, single-institutional analysis using a high-dose neoadjuvant chemoradiation (CRT) approach.

http://ift.tt/2nXsVri

Risk of late urinary complications following image-guided adaptive brachytherapy for locally advanced cervical cancer: refining bladder dose/volume parameters

To study correlations between dose/volume parameters of the whole bladder and bladder trigone and late urinary toxicity in locally advanced cervical cancer (LACC) patients treated with pulsed dose rate brachytherapy (PDR-BT).

http://ift.tt/2o35Sus

Automated treatment planning system for uveal melanomas treated with proton therapy: a proof of concept analysis

By pre-calculation of an entire set of planning solutions for protons, penalizing them and providing a graphical navigator tool (Automated Treatment Planning, ATP), we aim to improve the efficiency of the planning procedure for uveal melanoma (UM) and make it independent of treatment planner experience.

http://ift.tt/2nYHifb

A prospective cohort study on gated stereotactic liver radiotherapy based on continuous internal electromagnetic motion monitoring

Intra-fraction motion may compromise the treatment accuracy in liver stereotactic body radiotherapy (SBRT). Respiratory gating can improve treatment delivery, but gating based on external surrogates is inaccurate. This study presents the use of Calypso-based internal electromagnetic motion monitoring for gated liver SBRT.

http://ift.tt/2o4MddB

Effects of synchrotron X-ray micro-beam irradiation on normal mouse ear pinnae

Synchrotron micro-beam radiation-therapy (MRT) can deliver very high doses of ortho-voltage X-rays to tumors apparently without inducing severe damage to surrounding normal tissues. The aim of the present study was to analyze the effects of micro-beam irradiation (MBI) on the normal tissues of the mouse ear.

http://ift.tt/2o3VMtq

Bio-coloration of bacterial cellulose assisted by immobilized laccase

In this work a process for the bio-coloration of bacterial cellulose (BC) membranes was developed. Laccase from Myceliophthora thermophila was immobilized onto BC membranes and retained up to 88% of residual acti...

http://ift.tt/2EoZ5lV

Effect of long-term fertilization strategies on bacterial community composition in a 35-year field experiment of Chinese Mollisols

Bacteria play vital roles in soil biological fertility; however, it remains poorly understood about their response to long-term fertilization in Chinese Mollisols, especially when organic manure is substituted...

http://ift.tt/2F2TCCq

Update: Can Newer Rapid Influenza Tests Rule Out Disease?

Of the 162 studies included for full-text review, 38 were excluded for not reporting influenza A and B results separately, leaving 124 articles for quantitative analysis. Overall, the new rapid influenza tests, digital immunoassays, and rapid nucleic acid amplification tests demonstrated strikingly higher sensitivities for influenza A and B compared with the more traditional rapid influenza diagnostic tests. The pooled sensitivities varied widely between test types (ranging from 53% to 95%), whereas the pooled specificities were consistently greater than 98.3%.

http://ift.tt/2Bso1tU

Does Lidocaine Gel Decrease Procedural Pain for Pediatric Urethral Catheterization?

Of 211 potentially relevant studies identified, authors included 5 North American studies for analysis, with 369 patients. Four of these studies were randomized double-blind placebo-controlled trials, and the remaining study was a randomized single-blind placebo-controlled trial. Four studies evaluated patients younger than 4 years in the emergency department (ED) who were undergoing transurethral bladder catheterization for urine collection, comparing lidocaine 2% gel and nonanesthetic gel, and one study evaluated patients aged 4 to 11 years in an outpatient setting, comparing lidocaine 2% gel and chlorhexidine gel for cystogram.

http://ift.tt/2BXb50d

Association between Oxidative Stress, Genetic Factors, and Clinical Severity in Children with Sickle Cell Anemia

To investigate the associations between several sickle cell disease genetic modifiers (beta-globin haplotypes, alpha-thalassemia, and glucose-6-phosphate dehydrogenase deficiency) and the level of oxidative stress and to evaluate the association between oxidative stress and the rates of vaso-occlusive events.

http://ift.tt/2EGxjEM

IL-10+ NK and TGF-β+ NK cells play negative regulatory roles in HIV infection

Natural killer (NK) cells play cytotoxic roles by targeting tumor cells or virus infected cells, they also play regulatory roles by secreting cytokines and chemokines. Transforming growth factor (TGF)-β and in...

http://ift.tt/2EmdOhb

Prospective study on human fecal carriage of Enterobacteriaceae possessing mcr-1 and mcr-2 genes in a regional hospital in Hong Kong

Human fecal carriage of Enterobacteriaceae possessing mobilized colistin resistance genes (mcr-1 and mcr-2) remains obscure in Hong Kong. As part of routine surveillance on emerging antibiotic resistance, we cond...

http://ift.tt/2F0TWBB

Simple descriptive missing data indicators in longitudinal studies with attrition, intermittent missing data and a high number of follow-ups

Missing data in longitudinal studies may constitute a source of bias. We suggest three simple missing data indicators for the initial phase of getting an overview of the missingness pattern in a dataset with a...

http://ift.tt/2HcwDFn

Histopathologic characteristics of biopsies from dogs undergoing surgery with concurrent gross splenic and hepatic masses: 125 cases (2012–2016)

To investigate the histopathologic characteristics of concurrent splenic and liver masses in dogs undergoing splenectomy and liver mass biopsy/resection. Medical records of 125 client-owned dogs found to have ...

http://ift.tt/2HezFca

Potassium permanganate cleansing is an effective sanitary method for the reduction of bacterial bioload on raw Coriandrum sativum

Raw vegetables including flowers, leaves, stems, and roots are important carriers of food borne pathogens. We evaluated the bacteriological contamination of unwashed coriander leaves, and effectiveness of clea...

http://ift.tt/2GcFDsZ

Variability of phenolic and alkaloid content in different plant parts of Carissa edulis Vahl and Zanthoxylum chalybeum Engl.

The objective of the study was to investigate the relative abundance and effect of post-harvest treatment on total phenolics (TP) and total alkaloids in the leaves and bark of Carissa edulis and Zanthoxylum chaly...

http://ift.tt/2Hf56n0

Randomised study shows that repeated self-sampling and HPV test has more than two-fold higher detection rate of women with CIN2+ histology than Pap smear cytology

http://ift.tt/2nY1H3N

IKKα is required in the intestinal epithelial cells for tumour stemness

http://ift.tt/2o3sY4f

Strategies for clinical development of monoclonal antibodies beyond first-in-human trials: tested doses and rationale for dose selection

http://ift.tt/2o2jEyr

A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424

http://ift.tt/2o6oxp5

Regulation of ITGA3 by the dual-stranded microRNA-199 family as a potential prognostic marker in bladder cancer

http://ift.tt/2nY6fHE

A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma

http://ift.tt/2o52QWt

An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma

http://ift.tt/2nZygyg

Does industry-sponsored education foster overdiagnosis and overtreatment of depression, osteoporosis and over{-}active bladder syndrome? An Australian cohort study

Objectives

To investigate patterns of industry-sponsored educational events that focus on specific health conditions for which there are concerns about overdiagnosis and overtreatment.

Design and setting

This retrospective cohort study examines publicly reported industry-sponsored events in Australia from October 2011 to September 2015 for three conditions potentially subject to overdiagnosis and overtreatment: depression, osteoporosis and overactive bladder. We used a database of transparency reports to identify events with a focus on depression, osteoporosis and overactive bladder and compared these with other sponsored events. We hypothesised that companies marketing treatments for each condition would sponsor related events and that target audiences would mainly work in primary care, reflecting a broad patient population.

Main outcome measures

Event and attendee characteristics, sponsoring companies, related marketed treatments, cost-effectiveness ratings and dispensing rates.

Results

Over the study period, we identified 1567 events focusing on depression, 1375 on osteoporosis and 190 on overactive bladder (total n=3132, with 96 660 attendees). These events were attended by primary care doctors more often than sponsored events without a focus on these three conditions: relative risk (RR)=3.06 (95% CI 2.81 to 3.32) for depression, RR=1.48 (95% CI 1.41 to 1.55) for osteoporosis and RR=2.59 (95% CI 2.09 to 3.21) for overactive bladder. Servier, which markets agomelatine and AstraZeneca (quetiapine) sponsored 51.2% and 23.0% of depression events, respectively. Amgen and GlaxoSmithKline, which co-market denosumab, sponsored 49.5% of osteoporosis events and Astellas and Commonwealth Serum Laboratories (CSL) (mirabegron and solifenacin) sponsored 80.5% of overactive bladder events.

Conclusions

This 4-year overview of industry-sponsored events on three overdiagnosed and overtreated conditions found that primary care clinicians were often targeted, dinner was often provided and that a few companies sponsored most events. In most cases, sponsors' products are not cost-effective choices for the specified condition. This pattern highlights the need for professional education to be free of commercial sponsorship.

http://ift.tt/2o4tcYV

Multiparametric Imaging Improves Confidence in the Diagnosis of Multinodular and Vacuolating Neuronal Tumor of the Cerebrum [LETTERS]

http://ift.tt/2nXZ4zc

Leukoaraiosis Attenuates Diagnostic Accuracy of Large-Vessel Occlusion Scales [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Prehospital stroke scales may help identify patients likely to have large-vessel occlusion to facilitate rapid triage to thrombectomy-capable stroke centers. Scale misclassification may result in inaccurate decisions and possible harm. Pre-existing leukoaraiosis has been shown to attenuate the association between deficit type and stroke severity. We sought to determine whether leukoaraiosis affects the predictive ability of 5 commonly used large-vessel occlusion scales.

MATERIALS AND METHODS:

We retrospectively analyzed 274 consecutive patients with stroke with available brain MR imaging and vessel imaging. We used the following large-vessel occlusion scales: the 3-Item Stroke Scale; Field Assessment Stroke Triage for Emergency Destination; Rapid Arterial Occlusion Evaluation; Vision, Aphasia, Neglect score; and Cincinnati Prehospital Stroke Severity Scale. For diagnostic scale accuracy, we assessed sensitivity, specificity, positive predictive value, negative predictive value, and . Multivariable logistic regression was used to determine the predictive ability of the scales after adjustment for leukoaraiosis and potential confounders.

RESULTS:

In unadjusted analyses, all scales predicted the presence of large-vessel occlusion (n = 46, P < .01 each), though diagnostic accuracy was attenuated among patients with moderate-to-severe leukoaraiosis. After adjustment, the Field Assessment Stroke Triage for Emergency Destination (OR = 3.2; 95% CI, 1.1–9.5; P = .033) and Rapid Arterial Occlusion Evaluation (OR = 3.7; 95% CI, 1.3–10.8; P = .015), but not the 3-Item Stroke Scale (OR = 5.4; 95% CI, 0.86–33.9; P = .073), Vision, Aphasia, Neglect score (OR = 2.5; 95% CI, 0.8–7.2), and Cincinnati Prehospital Stroke Severity Scale (OR = 2.8; 95% CI, 1.0–8.0), predicted large-vessel occlusion.

CONCLUSIONS:

The diagnostic accuracy of the tested large-vessel occlusion scales was attenuated in the presence of moderate-to-severe leukoaraiosis. This information that may aid the design of future studies that require large-vessel occlusion scale screening of patients who are likely to have concomitant leukoaraiosis.

http://ift.tt/2nX3pm8

Feasibility of Brain Atrophy Measurement in Clinical Routine without Prior Standardization of the MRI Protocol: Results from MS-MRIUS, a Longitudinal Observational, Multicenter Real-World Outcome Study in Patients with Relapsing-Remitting MS [ADULT BRAIN]

BACKGROUND AND PURPOSE:

Feasibility of brain atrophy measurement in patients with MS in clinical routine, without prior standardization of the MRI protocol, is unknown. Our aim was to investigate the feasibility of brain atrophy measurement in patients with MS in clinical routine.

MATERIALS AND METHODS:

Multiple Sclerosis and Clinical Outcome and MR Imaging in the United States (MS-MRIUS) is a multicenter (33 sites), retrospective study that included patients with relapsing-remitting MS who began treatment with fingolimod. Brain MR imaging examinations previously acquired at the baseline and follow-up periods on 1.5T or 3T scanners with no prior standardization were used, to resemble a real-world situation. Brain atrophy outcomes included the percentage brain volume change measured by structural image evaluation with normalization of atrophy on 2D-T1-weighted imaging and 3D-T1WI and the percentage lateral ventricle volume change, measured by VIENA on 2D-T1WI and 3D-T1WI and NeuroSTREAM on T2-fluid-attenuated inversion recovery examinations.

RESULTS:

A total of 590 patients, followed for 16 months, were included. There were 585 (99.2%) T2-FLAIR, 425 (72%) 2D-T1WI, and 166 (28.2%) 3D-T1WI longitudinal pairs of examinations available. Excluding MR imaging examinations with scanner changes, the analyses were available on 388 (65.8%) patients on T2-FLAIR for the percentage lateral ventricle volume change, 259 and 257 (43.9% and 43.6%, respectively) on 2D-T1WI for the percentage brain volume change and the percentage lateral ventricle volume change, and 110 (18.6%) on 3D-T1WI for the percentage brain volume change and percentage lateral ventricle volume change. The median annualized percentage brain volume change was –0.31% on 2D-T1WI and –0.38% on 3D-T1WI. The median annualized percentage lateral ventricle volume change was 0.95% on 2D-T1WI, 1.47% on 3D-T1WI, and 0.90% on T2-FLAIR.

CONCLUSIONS:

Brain atrophy was more readily assessed by estimating the percentage lateral ventricle volume change on T2-FLAIR compared with the percentage brain volume change or percentage lateral ventricle volume change using 2D- or 3D-T1WI in this observational retrospective study. Although measurement of the percentage brain volume change on 3D-T1WI remains the criterion standard and should be encouraged in future prospective studies, T2-FLAIR–derived percentage lateral ventricle volume change may be a more feasible surrogate when historical or other practical constraints limit the availability of percentage brain volume change on 3D-T1WI.

http://ift.tt/2nZpfVW

The Anesthesiologist, Rather Than the Anesthesia, May Influence the Outcomes following Stroke Thrombectomy [LETTERS]

http://ift.tt/2nXRILR

Intranasal Esthesioneuroblastoma: CT Patterns Aid in Preventing Routine Nasal Polypectomy [HEAD & NECK]

BACKGROUND AND PURPOSE:

Esthesioneuroblastoma is a neuroectodermal tumor that commonly arises in the nasal cavity olfactory recess and, when isolated to the intranasal cavity, can be indistinguishable from benign processes. Because lesional aggressiveness requires a more invasive operation for resection than polypectomy, patients with isolated intranasal lesions were studied to define distinguishing CT characteristics.

MATERIALS AND METHODS:

Patients with intranasal esthesioneuroblastoma and controls without esthesioneuroblastoma with olfactory recess involvement were identified by using a report search tool. Studies demonstrating skull base invasion and/or intracranial extension were excluded. The imaging spectrum of these lesions was reviewed on both CT and MR imaging, and CT findings were compared with those of controls without esthesioneuroblastoma. Two blinded readers assessed subjects with esthesioneuroblastomas and controls without esthesioneuroblastoma and, using only CT criteria, rated their level of suspicion for esthesioneuroblastoma in each case.

RESULTS:

Eight histologically proved cases of intranasal esthesioneuroblastoma were reviewed. All cases had CT demonstrating 3 main findings: 1) an intranasal polypoid lesion with its epicenter in a unilateral olfactory recess, 2) causing asymmetric olfactory recess widening, and 3) extending to the cribriform plate. Twelve patients with non-esthesioneuroblastoma diseases involving the olfactory recess were used as controls. Using these 3 esthesioneuroblastoma CT criteria, 2 blinded readers evaluating patients with esthesioneuroblastoma and controls had good diagnostic accuracy (area under the curve = 0.85 for reader one, 0.81 for reader 2) for predicting esthesioneuroblastoma.

CONCLUSIONS:

Esthesioneuroblastoma can present as a well-marginated intranasal lesion that unilaterally widens the olfactory recess. CT patterns can help predict esthesioneuroblastoma, potentially preventing multiple operations by instigating the correct initial operative management.

http://ift.tt/2nXnsRb

Economic Considerations in MR Imaging of Patients with Cardiac Devices [LETTERS]

http://ift.tt/2o5ahgu

Clinical and Radiologic Characteristics of Deep Lumbosacral Dural Arteriovenous Fistulas [SPINE]

BACKGROUND AND PURPOSE:

Spinal dural arteriovenous fistulas located in the deep lumbosacral region are rare and the most difficult to diagnose among spinal dural arteriovenous fistulas located elsewhere in the spinal dura. Specific clinical and radiologic features of these fistulas are still inadequately reported and are the subject of this study.

MATERIALS AND METHODS:

We retrospectively evaluated all data of patients with spinal dural arteriovenous fistulas treated and/or diagnosed in our institution between 1990 and 2017. Twenty patients with deep lumbosacral spinal dural arteriovenous fistulas were included in this study.

RESULTS:

The most common neurologic findings at the time of admission were paraparesis (85%), sphincter dysfunction (70%), and sensory disturbances (20%). Medullary T2 hyperintensity and contrast enhancement were present in most cases. The filum vein and/or lumbar veins were dilated in 19/20 (95%) patients. Time-resolved contrast-enhanced dynamic MRA indicated a spinal dural arteriovenous fistula at or below the L5 vertebral level in 7/8 (88%) patients who received time-resolved contrast-enhanced dynamic MRA before DSA. A bilateral arterial supply of the fistula was detected via DSA in 5 (25%) patients.

CONCLUSIONS:

Clinical symptoms caused by deep lumbosacral spinal dural arteriovenous fistulas are comparable with those of spinal dural arteriovenous fistulas at other locations. Medullary congestion in association with an enlargement of the filum vein or other lumbar radicular veins is a characteristic finding in these patients. Spinal time-resolved contrast-enhanced dynamic MRA facilitates the detection of the drainage vein and helps to localize deep lumbosacral-located fistulas with a high sensitivity before DSA. Definite detection of these fistulas remains challenging and requires sufficient visualization of the fistula-supplying arteries and draining veins by conventional spinal angiography.

http://ift.tt/2nXCLJE

Reply: [LETTERS]

http://ift.tt/2nXROmR

Combining Quantitative Susceptibility Mapping with Automatic Zero Reference (QSM0) and Myelin Water Fraction Imaging to Quantify Iron-Related Myelin Damage in Chronic Active MS Lesions [ADULT BRAIN]

BACKGROUND AND PURPOSE:

A hyperintense rim on susceptibility in chronic MS lesions is consistent with iron deposition, and the purpose of this study was to quantify iron-related myelin damage within these lesions as compared with those without rim.

MATERIALS AND METHODS:

Forty-six patients had 2 longitudinal quantitative susceptibility mapping with automatic zero reference scans with a mean interval of 28.9 ± 11.4 months. Myelin water fraction mapping by using fast acquisition with spiral trajectory and T2 prep was obtained at the second time point to measure myelin damage. Mixed-effects models were used to assess lesion quantitative susceptibility mapping and myelin water fraction values.

RESULTS:

Quantitative susceptibility mapping scans were on average 6.8 parts per billion higher in 116 rim-positive lesions compared with 441 rim-negative lesions (P < .001). All rim-positive lesions retained a hyperintense rim over time, with increasing quantitative susceptibility mapping values of both the rim and core regions (P < .001). Quantitative susceptibility mapping scans and myelin water fraction in rim-positive lesions decreased from rim to core, which is consistent with rim iron deposition. Whole lesion myelin water fractions for rim-positive and rim-negative lesions were 0.055 ± 0.07 and 0.066 ± 0.04, respectively. In the mixed-effects model, rim-positive lesions had on average 0.01 lower myelin water fraction compared with rim-negative lesions (P < .001). The volume of the rim at the initial quantitative susceptibility mapping scan was negatively associated with follow-up myelin water fraction (P < .01).

CONCLUSIONS:

Quantitative susceptibility mapping rim-positive lesions maintained a hyperintense rim, increased in susceptibility, and had more myelin damage compared with rim-negative lesions. Our results are consistent with the identification of chronic active MS lesions and may provide a target for therapeutic interventions to reduce myelin damage.

http://ift.tt/2nXRfJL

[other]

http://ift.tt/2o2crxa

Feasibility of Permanent Stenting with Solitaire FR as a Rescue Treatment for the Reperfusion of Acute Intracranial Artery Occlusion [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

The Solitaire FR can be used not only as a tool for mechanical thrombectomy but also as a detachable permanent stent. Our aim was to assess the feasibility and safety of permanent stent placement with the Solitaire FR compared with other self-expanding stents for intracranial artery recanalization for acute ischemic stroke.

MATERIALS AND METHODS:

From January 2011 through January 2016, we retrospectively selected 2979 patients with acute ischemic stroke. Among them, 27 patients who underwent permanent stent placement (13 patients with the Solitaire FR [Solitaire group] and 14 patients with other self-expanding stents [other stent group]) were enrolled. The postprocedural modified TICI grade and angiographic and clinical outcomes were assessed. The safety and efficacy of permanent stent placement of the Solitaire FR for acute large-artery occlusion were evaluated.

RESULTS:

Stent placement was successful in all cases. Modified TICI 2b–3 reperfusion was noted in 84.6% of the Solitaire group and in 78.6% of the other stent group. Procedural time was significantly shorter in the Solitaire group than in the other stent group (P = .022). Shorter procedural time was correlated with favorable outcome ( = 0.46, P = .035). No significant differences were found in the modified TICI grade, NIHSS score, mRS, and hemorrhagic transformation rate between the 2 groups. The acute in-stent thrombosis rate at discharge was significantly lower when a glycoprotein IIb/IIIa inhibitor was injected during the procedure (P = .013).

CONCLUSIONS:

Permanent stent placement with the Solitaire FR compared with other self-expanding stents appears to be feasible and safe as a rescue tool for refractory intra-arterial therapy.

http://ift.tt/2nXRd4B

Radiomics in Brain Tumor: Image Assessment, Quantitative Feature Descriptors, and Machine-Learning Approaches [ADULT BRAIN]

SUMMARY:

Radiomics describes a broad set of computational methods that extract quantitative features from radiographic images. The resulting features can be used to inform imaging diagnosis, prognosis, and therapy response in oncology. However, major challenges remain for methodologic developments to optimize feature extraction and provide rapid information flow in clinical settings. Equally important, to be clinically useful, predictive radiomic properties must be clearly linked to meaningful biologic characteristics and qualitative imaging properties familiar to radiologists. Here we use a cross-disciplinary approach to highlight studies in radiomics. We review brain tumor radiologic studies (eg, imaging interpretation) through computational models (eg, computer vision and machine learning) that provide novel clinical insights. We outline current quantitative image feature extraction and prediction strategies with different levels of available clinical classes for supporting clinical decision-making. We further discuss machine-learning challenges and data opportunities to advance radiomic studies.

http://ift.tt/2nXlu3n

Semiautomated Middle Ear Volume Measurement as a Predictor of Postsurgical Outcomes for Congenital Aural Atresia [HEAD & NECK]

BACKGROUND AND PURPOSE:

Middle ear space is one of the most important components of the Jahrsdoerfer grading system (J-score), which is used to determine surgical candidacy for congenital aural atresia. The purpose of this study was to introduce a semiautomated method for measuring middle ear volume and determine whether middle ear volume, either alone or in combination with the J-score, can be used to predict early postoperative audiometric outcomes.

MATERIALS AND METHODS:

A retrospective analysis was conducted of 18 patients who underwent an operation for unilateral congenital aural atresia at our institution. Using the Livewire Segmentation tool in the Carestream Vue PACS, we segmented middle ear volumes using a semiautomated method for all atretic and contralateral normal ears on preoperative high-resolution CT imaging. Postsurgical audiometric outcome data were then analyzed in the context of these middle ear volumes.

RESULTS:

Atretic middle ear volumes were significantly smaller than those in contralateral normal ears (P < .001). Patients with atretic middle ear volumes of >305 mm³ had significantly better postoperative pure tone average and speech reception thresholds than those with atretic ears below this threshold volume (P = .01 and P = .006, respectively). Atretic middle ear volume incorporated into the J-score offered the best association with normal postoperative hearing (speech reception threshold ≤ 30 dB; OR = 37.8, P = .01).

CONCLUSIONS:

Middle ear volume, calculated in a semiautomated fashion, is predictive of postsurgical audiometric outcomes, both independently and in combination with the conventional J-score.

http://ift.tt/2nXXWeW

John Nash and the Organization of Stroke Care [research-article]

SUMMARY:

The concept of Nash equilibrium, developed by John Forbes Nash Jr, states that an equilibrium in noncooperative games is reached when each player takes the best action for himself or herself, taking into account the actions of the other players. We apply this concept to the provision of endovascular thrombectomy in the treatment of acute ischemic stroke and suggest that collaboration among hospitals in a health care jurisdiction could result in practices such as shared call pools for neurointervention teams, leading to better patient care through streamlined systems.

http://ift.tt/2o3jxlb

Temporal Lobe Malformations in Achondroplasia: Expanding the Brain Imaging Phenotype Associated with FGFR3-Related Skeletal Dysplasias [PEDIATRICS]

SUMMARY:

Thanatophoric dysplasia, achondroplasia, and hypochondroplasia belong to the fibroblast growth factor receptor 3 (FGFR3) group of genetic skeletal disorders. Temporal lobe abnormalities have been documented in thanatophoric dysplasia and hypochondroplasia, and in 1 case of achondroplasia. We retrospectively identified 13 children with achondroplasia who underwent MR imaging of the brain between 2002 and 2015. All children demonstrated a deep transverse temporal sulcus on MR imaging. Further common neuroimaging findings were incomplete hippocampal rotation (12 children), oversulcation of the mesial temporal lobe (11 children), loss of gray-white matter differentiation of the mesial temporal lobe (5 children), and a triangular shape of the temporal horn (6 children). These appearances are very similar to those described in hypochondroplasia, strengthening the association of temporal lobe malformations in FGFR3-associated skeletal dysplasias.

http://ift.tt/2nXR69b

MR Perfusion to Determine the Status of Collaterals in Patients with Acute Ischemic Stroke: A Look Beyond Time Maps [ADULT BRAIN]

BACKGROUND AND PURPOSE:

Patients with acute stroke with robust collateral flow have better clinical outcomes and may benefit from endovascular treatment throughout an extended time window. Using a multiparametric approach, we aimed to identify MR perfusion parameters that can represent the extent of collaterals, approximating DSA.

MATERIALS AND METHODS:

Patients with anterior circulation proximal arterial occlusion who had baseline MR perfusion and DSA were evaluated. The volume of arterial tissue delay (ATD) at thresholds of 2–6 seconds (ATD^{2–6 seconds}) and >6 seconds (ATD^{>6 seconds}) in addition to corresponding values of normalized CBV and CBF was calculated using VOI analysis. The association of MR perfusion parameters and the status of collaterals on DSA were assessed by multivariate analyses. Receiver operating characteristic analysis was performed.

RESULTS:

Of 108 patients reviewed, 39 met our inclusion criteria. On DSA, 22/39 (56%) patients had good collaterals. Patients with good collaterals had significantly smaller baseline and final infarct volumes, smaller volumes of severe hypoperfusion (ATD^{>6 seconds}), larger volumes of moderate hypoperfusion (ATD^{2–6 seconds}), and higher relative CBF and relative CBV values than patients with insufficient collaterals. Combining the 2 parameters into a Perfusion Collateral Index (volume of ATD^{2–6 seconds}x relative CBV^{2–6 seconds}) yielded the highest accuracy for predicting collateral status: At a threshold of 61.7, this index identified 15/17 (88%) patients with insufficient collaterals and 22/22 (100%) patients with good collaterals, for an overall accuracy of 94.1%.

CONCLUSIONS:

The Perfusion Collateral Index can predict the baseline collateral status with 94% diagnostic accuracy compared with DSA.

http://ift.tt/2nZq7Kc

Carotid Artery Wall Imaging: Perspective and Guidelines from the ASNR Vessel Wall Imaging Study Group and Expert Consensus Recommendations of the American Society of Neuroradiology [EXTRACRANIAL VASCULAR]

SUMMARY:

Identification of carotid artery atherosclerosis is conventionally based on measurements of luminal stenosis and surface irregularities using in vivo imaging techniques including sonography, CT and MR angiography, and digital subtraction angiography. However, histopathologic studies demonstrate considerable differences between plaques with identical degrees of stenosis and indicate that certain plaque features are associated with increased risk for ischemic events. The ability to look beyond the lumen using highly developed vessel wall imaging methods to identify plaque vulnerable to disruption has prompted an active debate as to whether a paradigm shift is needed to move away from relying on measurements of luminal stenosis for gauging the risk of ischemic injury. Further evaluation in randomized clinical trials will help to better define the exact role of plaque imaging in clinical decision-making. However, current carotid vessel wall imaging techniques can be informative. The goal of this article is to present the perspective of the ASNR Vessel Wall Imaging Study Group as it relates to the current status of arterial wall imaging in carotid artery disease.

http://ift.tt/2C15Cpc

On the Reproducibility of Inversion Recovery Intravoxel Incoherent Motion Imaging in Cerebrovascular Disease [ADULT BRAIN]

BACKGROUND AND PURPOSE:

Intravoxel incoherent motion imaging can measure both microvascular and parenchymal abnormalities simultaneously. The contamination of CSF signal can be suppressed using inversion recovery preparation. The clinical feasibility of inversion recovery–intravoxel incoherent motion imaging was investigated in patients with cerebrovascular disease by studying its reproducibility.

MATERIALS AND METHODS:

Sixteen patients with cerebrovascular disease (66 ± 8 years of age) underwent inversion recovery–intravoxel incoherent motion imaging twice. The reproducibility of the perfusion volume fraction and parenchymal diffusivity was calculated with the coefficient of variation, intraclass correlation coefficient, and the repeatability coefficient. ROIs included the normal-appearing white matter, cortex, deep gray matter, white matter hyperintensities, and vascular lesions.

RESULTS:

Values for the perfusion volume fraction ranged from 2.42 to 3.97 x10^–2 and for parenchymal diffusivity from 7.20 to 9.11 x 10^–4 mm²/s, with higher values found in the white matter hyperintensities and vascular lesions. Coefficients of variation were <3.70% in normal-appearing tissue and <9.15% for lesions. Intraclass correlation coefficients were good to excellent, showing values ranging from 0.82 to 0.99 in all ROIs, except the deep gray matter and cortex, with intraclass correlation coefficients of 0.66 and 0.54, respectively. The repeatability coefficients ranged from 0.15 to 0.96 x 10^–2 and 0.10 to 0.37 x 10^–4 mm²/s for perfusion volume fraction and parenchymal diffusivity, respectively.

CONCLUSIONS:

Good reproducibility of inversion recovery–intravoxel incoherent motion imaging was observed with low coefficients of variation and high intraclass correlation coefficients in normal-appearing tissue and lesion areas in cerebrovascular disease. Good reproducibility of inversion recovery–intravoxel incoherent motion imaging in cerebrovascular disease is feasible in monitoring disease progression or treatment responses in the clinic.

http://ift.tt/2o70CFY

A first in human study of the new oral selective estrogen receptor degrader AZD9496 for HR+/HER2- advanced breast cancer

Purpose: AZD9496 is an oral non-steroidal, small-molecule inhibitor of estrogen receptor alpha (ERα), and a potent and selective antagonist and degrader of ERα. This first in human Phase 1 study determined the safety and tolerability of ascending doses of oral AZD9496 in women with estrogen receptor (ER)+/HER2- advanced breast cancer, characterized its pharmacokinetic (PK) profile, and made preliminary assessment of antitumor activity. Experimental Design: Forty-five patients received AZD9496 (20 mg once daily to 600 mg twice daily) in a dose-escalation, dose- expansion 'rolling 6' design. Safety, tolerability, and PK activity in each cohort was reviewed before escalating to the next dose. PK was determined by mass spectrometry. Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Objective tumor response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Results: Most common causally related AEs were diarrhea (35.6%), fatigue (31.1%), and nausea (22.2%), and seven patients had grade ≥3 AEs. Three patients experienced a dose-limiting toxicity (DLT): one each at 150 mg BID (abnormal hepatic function), 400 mg BID (diarrhea and elevated liver function tests) and 600 mg BID (diarrhea), and all were reversible. The maximum tolerated dose was not reached. Partial response was confirmed in one patient, who also had decreased tumor marker Ca15.3. Four patients had stable disease at 12 months' follow up. Conclusions: AZD9496 is well tolerated with an acceptable safety profile, showing evidence of prolonged disease stabilization in heavily pre-treated patients with ER+/HER2- advanced breast cancer.

http://ift.tt/2svfxPO

Shedding light on IDH1 mutation in gliomas

IDH mutation is of central importance in the diagnosis and treatment of gliomas. Fourier-transform infrared spectroscopy, in combination with a supervised machine-learning approach, can be used to detect metabolic alterations induced by IDH1 mutations in a fraction of the time of conventional techniques.

http://ift.tt/2BUYZEM

Effect of mitochondrial uncouplers niclosamide ethanolamine (NEN) and oxyclozanide on hepatic metastasis of colon cancer

Effect of mitochondrial uncouplers niclosamide ethanolamine (NEN) and oxyclozanide on hepatic metastasis of colon cancer

Effect of mitochondrial uncouplers niclosamide ethanolamine (NEN) and oxyclozanide on hepatic metastasis of colon cancer, Published online: 13 February 2018; doi:10.1038/s41419-017-0092-6

Effect of mitochondrial uncouplers niclosamide ethanolamine (NEN) and oxyclozanide on hepatic metastasis of colon cancer

http://ift.tt/2srIUml

KRAS induces lung tumorigenesis through microRNAs modulation

KRAS induces lung tumorigenesis through microRNAs modulation

KRAS induces lung tumorigenesis through microRNAs modulation, Published online: 13 February 2018; doi:10.1038/s41419-017-0243-9

KRAS induces lung tumorigenesis through microRNAs modulation

http://ift.tt/2sqiEsv

Human umbilical cord mesenchymal stem cell-derived extracellular vesicles promote lung adenocarcinoma growth by transferring miR-410

Human umbilical cord mesenchymal stem cell-derived extracellular vesicles promote lung adenocarcinoma growth by transferring miR-410

Human umbilical cord mesenchymal stem cell-derived extracellular vesicles promote lung adenocarcinoma growth by transferring miR-410, Published online: 13 February 2018; doi:10.1038/s41419-018-0323-5

Human umbilical cord mesenchymal stem cell-derived extracellular vesicles promote lung adenocarcinoma growth by transferring miR-410

http://ift.tt/2BVHbtp

Baicalin induces cellular senescence in human colon cancer cells via upregulation of DEPP and the activation of Ras/Raf/MEK/ERK signaling

Baicalin induces cellular senescence in human colon cancer cells via upregulation of DEPP and the activation of Ras/Raf/MEK/ERK signaling

Baicalin induces cellular senescence in human colon cancer cells via upregulation of DEPP and the activation of Ras/Raf/MEK/ERK signaling, Published online: 13 February 2018; doi:10.1038/s41419-017-0223-0

Baicalin induces cellular senescence in human colon cancer cells via upregulation of DEPP and the activation of Ras/Raf/MEK/ERK signaling

http://ift.tt/2BYkkNO

Inhibition of KRAS-dependent lung cancer cell growth by deltarasin: blockage of autophagy increases its cytotoxicity

Inhibition of KRAS-dependent lung cancer cell growth by deltarasin: blockage of autophagy increases its cytotoxicity

Inhibition of KRAS-dependent lung cancer cell growth by deltarasin: blockage of autophagy increases its cytotoxicity, Published online: 13 February 2018; doi:10.1038/s41419-017-0065-9

Inhibition of KRAS-dependent lung cancer cell growth by deltarasin: blockage of autophagy increases its cytotoxicity

http://ift.tt/2soS7eW

Floral homeotic proteins modulate the genetic program for leaf development to suppress trichome formation in flowers [RESEARCH ARTICLE]

Diarmuid S. OMaoileidigh, Darragh Stewart, Beibei Zheng, George Coupland, and Frank Wellmer

As originally proposed by Goethe in 1790, floral organs are derived from leaf-like structures. The conversion of leaves into different types of floral organ is mediated by floral homeotic proteins, which, as described by the ABCE model of flower development, act in a combinatorial manner. However, how these transcription factors bring about this transformation process is not well understood. We have previously shown that floral homeotic proteins are involved in suppressing the formation of branched trichomes, a hallmark of leaf development, on reproductive floral organs of Arabidopsis. Here, we present evidence that the activities of the C function gene AGAMOUS (AG) and the related SHATTERPROOF1/2 genes are superimposed onto the regulatory network that controls the distribution of trichome formation in an age-dependent manner. We show that AG regulates cytokinin responses and genetically interacts with the organ polarity gene KANADI1 to suppress trichome initiation on gynoecia. Thus, our results show that parts of the genetic program for leaf development remain active during flower formation but have been partially rewired through the activities of the floral homeotic proteins.

http://ift.tt/2F1UmHN

To endocycle or endomitose? An unusual cell cycle switch [RESEARCH HIGHLIGHT]

http://ift.tt/2EmFySU

To endocycle or endomitose? An unusual cell cycle switch [RESEARCH HIGHLIGHT]

http://ift.tt/2EmFySU

Floral homeotic proteins modulate the genetic program for leaf development to suppress trichome formation in flowers [RESEARCH ARTICLE]

Diarmuid S. OMaoileidigh, Darragh Stewart, Beibei Zheng, George Coupland, and Frank Wellmer

As originally proposed by Goethe in 1790, floral organs are derived from leaf-like structures. The conversion of leaves into different types of floral organ is mediated by floral homeotic proteins, which, as described by the ABCE model of flower development, act in a combinatorial manner. However, how these transcription factors bring about this transformation process is not well understood. We have previously shown that floral homeotic proteins are involved in suppressing the formation of branched trichomes, a hallmark of leaf development, on reproductive floral organs of Arabidopsis. Here, we present evidence that the activities of the C function gene AGAMOUS (AG) and the related SHATTERPROOF1/2 genes are superimposed onto the regulatory network that controls the distribution of trichome formation in an age-dependent manner. We show that AG regulates cytokinin responses and genetically interacts with the organ polarity gene KANADI1 to suppress trichome initiation on gynoecia. Thus, our results show that parts of the genetic program for leaf development remain active during flower formation but have been partially rewired through the activities of the floral homeotic proteins.

http://ift.tt/2F1UmHN

Variant cell cycles regulated by Notch signaling control cell size and ensure a functional blood-brain barrier [RESEARCH ARTICLE]

Jessica R. Von Stetina, Laura E. Frawley, Yingdee Unhavaithaya, and Terry L. Orr-Weaver

Regulation of cell size is crucial in development. In plants and animals two cell cycle variants are employed to generate large cells by increased ploidy: the endocycle and endomitosis. The rationale behind the choice of which of these cycles is implemented is unknown. We show that in the Drosophila nervous system the subperineurial glia (SPG) are unique in using both the endocycle and endomitosis to grow. In the brain, the majority of SPG initially endocycle, then switch to endomitosis during larval development. The Notch signaling pathway and the String Cdc25 phosphatase are crucial for the endocycle versus endomitosis choice, providing the means experimentally to change cells from one to the other. This revealed fundamental insights into the control of cell size and the properties of endomitotic cells. Endomitotic cells attain a higher ploidy and larger size than endocycling cells, and endomitotic SPG are necessary for the blood-brain barrier. Decreased Notch signaling promotes endomitosis even in the ventral nerve cord SPG that normally are mononucleate, but not in the endocycling salivary gland cells, revealing tissue-specific cell cycle responses.

http://ift.tt/2EnJKlw

Molecular characteristics and successful management of a respiratory syncytial virus outbreak among pediatric patients with hemato-oncological disease

Respiratory syncytial virus (RSV) is responsible for upper and lower respiratory tract infection in adults and children. Especially immunocompromised patients are at high risk for a severe course of infection,...

http://ift.tt/2HdPUXh

Racial Differences in Sepsis Mortality at U.S. Academic Medical Center–Affiliated Hospitals

Objectives: To determine the racial disparities in severe sepsis hospitalizations and outcomes in U.S. academic medical center–affiliated hospitals. Design: Retrospective analysis of sepsis hospitalizations. Settings: U.S. academic medical center–affiliated hospitals participating in Vizient Consortium from 2012 to 2014. Patients: Sepsis hospitalizations using International Classification of Diseases, Ninth revision, discharge diagnoses codes defined by the Angus method. Interventions: None. Measurements and Main Results: We compared rates of sepsis hospitalization, ICU admission, organ dysfunction, and hospital mortality between blacks and whites. We repeated the analyses stratified by community-acquired, healthcare-associated, and hospital-acquired sepsis subtypes. Of 10,244,780 hospitalizations in our cohort, 1,114,386 (10.9%) had sepsis. Sepsis subtypes included community-acquired sepsis (61.8%), healthcare-associated sepsis (23.8%), and hospital-acquired sepsis (14.4%). Although the proportion of discharges with sepsis was lower for blacks than whites (106.72 vs 109.43 per 1,000 hospitalizations; p

http://ift.tt/2soOFRw

The Randomized Educational Acute Respiratory Distress Syndrome Diagnosis Study: A Trial to Improve the Radiographic Diagnosis of Acute Respiratory Distress Syndrome

Objectives: Radiographic criteria for acute respiratory distress syndrome have been criticized for poor reliability. Our objective was to test an educational intervention to improve the radiographic identification of acute respiratory distress syndrome by participants in the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure study. Design: Randomized controlled trial. Settings: Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure study centers. Subjects: Study coordinators in the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure study. Interventions: Participants were randomized to either an online training module followed by a test module (intervention) or test module followed by training module (control). Measurements and Main Results: The primary outcome was the number of radiographs correctly identified as meeting criteria for acute respiratory distress syndrome on an online test module (out of 11). Prespecified secondary analyses included a comparison of agreement between the groups and subgroup analyses by profession, age, years of experience, and stated familiarity with diagnostic criteria for acute respiratory distress syndrome. Four-hundred sixty-three study participants consented to participate. There was no effect of the intervention on correct answers by participants (proportion correct 58% [intervention] vs 56% [control]; p = 0.15), or in any subgroup analyses. Overall agreement between raters was 0.296 for the intervention and 0.272 for the control (p

http://ift.tt/2EGMhe4

Measurements of Waves in a Wind-wave Tank Under Steady and Time-varying Wind Forcing

This manuscript describes a fully computer-controlled procedure that allows obtaining reliable statistical parameters from experiments of water waves excited by steady and unsteady wind forcing in a small-scale facility.

http://ift.tt/2soUL4A

Outcome measures in coeliac disease trials: the Tampere recommendations

Objective

A gluten-free diet is the only treatment option of coeliac disease, but recently an increasing number of trials have begun to explore alternative treatment strategies. We aimed to review the literature on coeliac disease therapeutic trials and issue recommendations for outcome measures.

Design

Based on a literature review of 10 062 references, we (17 researchers and 2 patient representatives from 10 countries) reviewed the use and suitability of both clinical and non-clinical outcome measures. We then made expert-based recommendations for use of these outcomes in coeliac disease trials and identified areas where research is needed.

Results

We comment on the use of histology, serology, clinical outcome assessment (including patient-reported outcomes), quality of life and immunological tools including gluten immunogenic peptides for trials in coeliac disease.

Conclusion

Careful evaluation and reporting of outcome measures will increase transparency and comparability of coeliac disease therapeutic trials, and will benefit patients, healthcare and the pharmaceutical industry.

http://ift.tt/2EAD6vD

Immune activation underlies a sustained clinical response to Yttrium-90 radioembolisation in hepatocellular carcinoma

Objectives

Yttrium-90 (Y90)-radioembolisation (RE) significantly regresses locally advanced hepatocellular carcinoma and delays disease progression. The current study is designed to deeply interrogate the immunological impact of Y90-RE, which elicits a sustained therapeutic response.

Design

Time-of-flight mass cytometry and next-generation sequencing (NGS) were used to analyse the immune landscapes of tumour-infiltrating leucocytes (TILs), tumour tissues and peripheral blood mononuclear cells (PBMCs) at different time points before and after Y90-RE.

Results

TILs isolated after Y90-RE exhibited signs of local immune activation: higher expression of granzyme B (GB) and infiltration of CD8⁺ T cells, CD56⁺ NK cells and CD8⁺ CD56⁺ NKT cells. NGS confirmed the upregulation of genes involved in innate and adaptive immune activation in Y90-RE-treated tumours. Chemotactic pathways involving CCL5 and CXCL16 correlated with the recruitment of activated GB⁺CD8⁺ T cells to the Y90-RE-treated tumours. When comparing PBMCs before and after Y90-RE, we observed an increase in tumour necrosis factor-α on both the CD8⁺ and CD4⁺ T cells as well as an increase in percentage of antigen-presenting cells after Y90-RE, implying a systemic immune activation. Interestingly, a high percentage of PD-1⁺/Tim-3⁺CD8⁺ T cells coexpressing the homing receptors CCR5 and CXCR6 denoted Y90-RE responders. A prediction model was also built to identify sustained responders to Y90-RE based on the immune profiles from pretreatment PBMCs.

Conclusion

High-dimensional analysis of tumour and systemic immune landscapes identified local and systemic immune activation that corresponded to the sustained response to Y90-RE. Potential biomarkers associated with a positive clinical response were identified and a prediction model was built to identify sustained responders prior to treatment.

http://ift.tt/2Bs3NAo

A systematic review of the effects of acupuncture on xerostomia and hyposalivation

Saliva is fundamental to our oral health and our well-being. Many factors can impair saliva secretion, such as adverse effects of prescribed medication, auto-immune diseases (for example Sjögren's syndrome) an...

http://ift.tt/2CisCvx

Effect of tendon vibration during wide-pulse neuromuscular electrical stimulation (NMES) on muscle force production in people with spinal cord injury (SCI)

Neuromuscular electrical stimulation (NMES) is commonly used in skeletal muscles in people with spinal cord injury (SCI) with the aim of increasing muscle recruitment and thus muscle force production. NMES has...

http://ift.tt/2HeuJnY

New Cancer Treatment Approach Targets Circadian Clock

Two compounds that target components of the circadian clock killed several types of cancer cells in the lab and slowed the growth of brain tumors in mice without harming healthy cells, a new study showed.

http://ift.tt/2GaPks1

Transcranial direct current stimulation generates a transient increase of small-world in brain connectivity: an EEG graph theoretical analysis

Abstract

Transcranial direct current stimulation (tDCS) is a non-invasive technique able to modulate cortical excitability in a polarity-dependent way. At present, only few studies investigated the effects of tDCS on the modulation of functional connectivity between remote cortical areas. The aim of this study was to investigate—through graph theory analysis—how bipolar tDCS modulate cortical networks high-density EEG recordings were acquired before and after bipolar cathodal, anodal and sham tDCS involving the primary motor and pre-motor cortices of the dominant hemispherein 14 healthy subjects. Results showed that, after bipolar anodal tDCS stimulation, brain networks presented a less evident "small world" organization with a global tendency to be more random in its functional connections with respect to prestimulus condition in both hemispheres. Results suggest that tDCS globally modulates the cortical connectivity of the brain, modifying the underlying functional organization of the stimulated networks, which might be related to changes in synaptic efficiency of the motor network and related brain areas. This study demonstrated that graph analysis approach to EEG recordings is able to intercept changes in cortical functions mediated by bipolar anodal tDCS mainly involving the dominant M1 and related motor areas. Concluding, tDCS could be an useful technique to help understanding brain rhythms and their topographic functional organization and specificity.

http://ift.tt/2EAgFGX

The frequency of Klebsiella pneumonia encoding genes for CTX-M, TEM-1 and SHV-1 extended-spectrum beta lactamases enzymes isolated from urinary tract infection

The extended- spectrum β-lactamase producing bacteria are widely spread worldwide. The productions of these enzymes cause bacterial resistance to a wide range of antibiotics. The aim of this study was to inves...

http://ift.tt/2nWC2Zj

Does Akkermansia muciniphila play a role in type 1 diabetes?

A field currently attracting increasing interest concerns the possible role that the intestinal microbiota might play in human health and disease. The fact that novel sequencing approaches applied to the microbiota genome are available has definitely favoured the rapid development of this field. The recent re-emergence in this area began with studies on obesity and metabolic diseases. Various associations between microbiota composition and metabolic diseases such as obesity and type 2 diabetes have been reported, in both rodents and humans, emphasising the key role of dietary habits in the composition of the bacterial population.1–3 However, experiments aimed at changing microbiota composition and transferring/exchanging the intestinal microbiota to alter the metabolism of the host have proved somewhat controversial and failed to unequivocally establish a causal role for the gut microbiota in metabolic diseases.4 Whatever the case, it is noteworthy that a specific bacterium, Akkermansia...

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Comprehensive characterisation of compartment-specific long non-coding RNAs associated with pancreatic ductal adenocarcinoma

Objective

Pancreatic ductal adenocarcinoma (PDA) is a highly metastatic disease with limited therapeutic options. Genome and transcriptome analyses have identified signalling pathways and cancer driver genes with implications in patient stratification and targeted therapy. However, these analyses were performed in bulk samples and focused on coding genes, which represent a small fraction of the genome.

Design

We developed a computational framework to reconstruct the non-coding transcriptome from cross-sectional RNA-Seq, integrating somatic copy number alterations (SCNA), common germline variants associated to PDA risk and clinical outcome. We validated the results in an independent cohort of paired epithelial and stromal RNA-Seq derived from laser capture microdissected human pancreatic tumours, allowing us to annotate the compartment specificity of their expression. We employed systems and experimental biology approaches to interrogate the function of epithelial long non-coding RNAs (lncRNAs) associated with genetic traits and clinical outcome in PDA.

Results

We generated a catalogue of PDA-associated lncRNAs. We showed that lncRNAs define molecular subtypes with biological and clinical significance. We identified lncRNAs in genomic regions with SCNA and single nucleotide polymorphisms associated with lifetime risk of PDA and associated with clinical outcome using genomic and clinical data in PDA. Systems biology and experimental functional analysis of two epithelial lncRNAs (LINC00673 and FAM83H-AS1) suggest they regulate the transcriptional profile of pancreatic tumour samples and PDA cell lines.

Conclusions

Our findings indicate that lncRNAs are associated with genetic marks of pancreatic cancer risk, contribute to the transcriptional regulation of neoplastic cells and provide an important resource to design functional studies of lncRNAs in PDA.

http://ift.tt/2EoETnZ

A novel small molecular STAT3 inhibitor, 5Br-6b, induces apoptosis and inhibits migration in colorectal cancer cells

Signal transducers and activators of transcription 3 (STAT3) represent a transcription factor that is constitutively activated in various cancers. Numerous studies have shown that STAT3 plays crucial roles in cell proliferation and survival, angiogenesis, tumor-promoting inflammation, and suppression of antitumor host immune response in the tumor microenvironment. In this study, we investigated a novel inhibitor, called -6b, to target STAT3 in colorectal cancer cells. The influence of 5Br-6b on the proliferation of colorectal cell lines SW480 and HCT116 was evaluated using an 3-(4, 5-dimethylthiazolyl)-2 and 5-diphenyltetrazolium bromide assay. We detected cell apoptosis after the treatment of 5Br-6b by flow cytometry. In addition, 5Br-6b caused the cleavage of caspase-3 and decreased the expression of Bcl-2. Cancer cell invasion and migration were measured by transwell and wound-healing assay. The potential mechanism was evaluated by western blotting and immunofluorescence. The results show that 5Br-6b inhibits the activation of STAT3, and decreases the expression of its target genes that regulate cell proliferation, migration, and apoptosis. Thus, 5Br-6b is a promising therapeutic drug candidate for colorectal cancer by inhibiting persistent STAT3 signaling. Correspondence to Maode Lai, PhD, Department of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu Province, People's Republic of China Tel/fax: +86 25 86185555; e-mail: lmd@cpu.edu.cn Received October 9, 2017 Accepted January 19, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2nVFOSK

Treatment of pancreatic cancer with intravenous vitamin C: a case report

Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis and is often discovered at an advanced stage with few therapeutic options. Current conventional regimens for PDA are associated with significant morbidity, decreased quality of life, and a considerable financial burden. As a result, some patients turn to integrative medicine therapies as an alternate option after a diagnosis of PDA. Intravenous pharmacologic ascorbic acid (PAA) is one such treatment. The use of PAA has been passionately debated for many years, but more recent rigorous scientific research has shown that there are significant blood concentration differences when ascorbic acid is given parenterally when compared to oral dosing. This pharmacologic difference appears to be critical for its role in oncology. Here, we report the use of PAA in a patient with poorly differentiated stage IV PDA as an exclusive chemotherapeutic regimen. The patient survived nearly 4 years after diagnosis, with PAA as his sole treatment, and he achieved objective regression of his disease. He died from sepsis and organ failure from a bowel perforation event. This case illustrates the possibility of PAA to effectively control tumor progression and serve as an adjunct to standard of care PDA chemotherapy regimens. Our patient's experience with PAA should be taken into consideration, along with previous research in cell, animal, and clinical experiments to design future treatment trials. Written work prepared by employees of the Federal Government as part of their official duties is, under the US. Copyright Act, a 'work of the United States Government' for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government. Correspondence to Jeanne A. Drisko, MD, University of Kansas Health System, 3901 Rainbow Blvd, Mail Stop 1017, Kansas City, KS 66160, USA Tel: +1 913 588 6208; fax: +1 913 588 0012; e-mail: jdrisko@kumc.edu Received November 2, 2017 Accepted January 17, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2o4G80O