Cancers, Vol. 10, Pages 69: Nano-Pulse Stimulation Ablates Orthotopic Rat Hepatocellular Carcinoma and Induces Innate and Adaptive Memory Immune Mechanisms that Prevent Recurrence

Cancers, Vol. 10, Pages 69: Nano-Pulse Stimulation Ablates Orthotopic Rat Hepatocellular Carcinoma and Induces Innate and Adaptive Memory Immune Mechanisms that Prevent Recurrence

Cancers doi: 10.3390/cancers10030069

Authors: Brittany Lassiter Siqi Guo Stephen Beebe

Nano-pulse stimulation (NPS), previously called nsPEFs, induced a vaccine-like effect after ablation of orthotopic N1-S1 hepatocellular carcinoma (HCC), protecting rats from subsequent challenges with N1-S1 cells. To determine immunity, immune cell phenotypes were analyzed in naïve, treated and protected rats. NPS provides a positive, post-ablation immuno-therapeutic outcome by alleviating immunosuppressive T regulatory cells (Treg) in the tumor microenvironment (TME), allowing dendritic cell influx and inducing dynamic changes in natural killer cells (NKs), NKT-cells and T-lymphocytes in blood, spleen and liver. NPS induced specific increases in NKs and NKT-cells expressing CD8 and activation receptors CD314-NKG2D and CD161 (NK1.1) in the TME after treatment, as well as some variable changes in CD4+ and CD8+ effector (Tem) and central memory (Tem) lymphocytes in blood and spleen. After orthotopic challenge, CD8+ T-cells were cytotoxic, inducing apoptosis in N1-S1 cells; additionally, in contrast to post-treatment immune responses, CD4+ and CD8+ memory precursor effector cells (MPECs) and short-lived effector cells (SLECs) were present, while still including CD8+ CD161 NK cells, but not involving CD8+ CD314-NKG2D+ NKs. This immunity was N1-S1-specific and was sustained for at least 8 months. NPS vaccinates rats in vivo against HCC by activating innate and adaptive immune memory mechanisms that prevent HCC recurrence.

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Coccidioidal Meningitis: A Review on Diagnosis, Treatment, and Management of Complications

Abstract

Purpose of review

This article summarizes the diagnosis and treatment of coccidioidal meningitis (CM) and its complications. An overview of current and prospective pharmacologic treatment options and monitoring parameters is provided. A consensus has not been reached regarding universally accepted therapeutic serum levels for azoles because of insufficient evidence. We describe the preferred therapeutic drug level ranges that our institution uses to monitor azole therapy.

Recent findings

Ho et al. described the preparation and administration of intrathecally delivered amphotericin B deoxycholate. Thompson et al. described possible benefits of controversial adjuvant corticosteroid therapy for secondary prevention of vasculitic infarction secondary to CM.

Summary

CM was universally fatal until the advent of intrathecal amphotericin B deoxycholate therapy, the introduction of which changed the natural history of the disease in much the same way as penicillin changed the natural history of bacterial meningitis. Although there was still significant morbidity, survival rates drastically increased to approximately 70%. The introduction of azole therapy has decreased the side effects and burden of treatment but without a significant change in CM-related mortality and morbidity compared with the use of intrathecal amphotericin B deoxycholate therapy.

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Learning alternative movement coordination patterns using reinforcement feedback

Abstract

One of the characteristic features of the human motor system is redundancy—i.e., the ability to achieve a given task outcome using multiple coordination patterns. However, once participants settle on using a specific coordination pattern, the process of learning to use a new alternative coordination pattern to perform the same task is still poorly understood. Here, using two experiments, we examined this process of how participants shift from one coordination pattern to another using different reinforcement schedules. Participants performed a virtual reaching task, where they moved a cursor to different targets positioned on the screen. Our goal was to make participants use a coordination pattern with greater trunk motion, and to this end, we provided reinforcement by making the cursor disappear if the trunk motion during the reach did not cross a specified threshold value. In Experiment 1, we compared two reinforcement schedules in two groups of participants—an abrupt group, where the threshold was introduced immediately at the beginning of practice; and a gradual group, where the threshold was introduced gradually with practice. Results showed that both abrupt and gradual groups were effective in shifting their coordination patterns to involve greater trunk motion, but the abrupt group showed greater retention when the reinforcement was removed. In Experiment 2, we examined the basis of this advantage in the abrupt group using two additional control groups. Results showed that the advantage of the abrupt group was because of a greater number of practice trials with the desired coordination pattern. Overall, these results show that reinforcement can be successfully used to shift coordination patterns, which has potential in the rehabilitation of movement disorders.

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Intracranial pressure in patients with papilloedema

Objectives

Papilloedema is a clinical manifestation of chronically raised intracranial pressure (ICP), often seen in idiopathic intracranial hypertension (IIH). However, the extent of intracranial hypertension required to produce papilloedema is not known. We compare ICP values in IIH patients who developed papilloedema and those who did not. We aim to identify a pathological ICP threshold predictive of the development of papilloedema in IIH patients.

Materials and Methods

Single-centre cohort of IIH patients (2006-2016) who underwent 24-hour ICP monitoring (ICPM) and ophthalmology assessments, prior to intervention. Papilloedema was graded according to the Frisén scale. An unpaired t-test compared 24-hour ICPM between papilloedema and no-papilloedema groups. Fisher's exact test was used to determine predictive value of ICP.

Results

Thirty-six patients with IIH (35 F: 1M), mean age 32.5 ± 9.49 years (mean ± SD) were included. Patients with papilloedema had a mean median 24-hour ICP of 10.4 ± 5.32 mm Hg (n = 25), significantly higher than the group without papilloedema 6.31 ± 3.30 mm Hg (n = 11) (P < .05). The papilloedema group were exposed to higher pressures (10 mm Hg) for 30 minutes or more. Using 24-hour median ICP of 10 mm Hg as a minimum cut-off predictive value gives a specificity = 91%, sensitivity = 48%, PPV = 92% and NPV = 44% of detecting papilloedema.

Conclusions

A 24-hour ICP of 10 mmHg or more is a good predictor for papilloedema and reflects a pathological threshold. The range varied widely suggesting papilloedema can occur at even lower pressures. These results are consistent with emerging evidence suggest that pathologically "high" 24 hours ICP is lower than previously quoted.

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NKG2D and its ligands in cancer

Payal Dhar | Jennifer D Wu

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Metabolites, genome organization, and cellular differentiation gene programs

Danielle A Chisolm | Amy S Weinmann

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Editorial Board

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Table of Contents

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Rodent-borne and rodent-related diseases in Iran

Abstract

Rodents cause large financial losses all over the world; in addition, these animals can also act as a reservoir and intermediate host or vector of diseases. Rodents have an important role in the distribution of diseases in an area. Sometimes, the distribution of a particular disease in an area depends on the distribution of rodents in that area. This study focuses on the distribution of rodent-related diseases in Iran. Rodent-borne and rodent-related diseases and diseases with suspected relationship with rodents have been reviewed in this study. Iran, due to the circumstances in which different species of rodents are able to live, has a high prevalence of certain diseases associated with rodents in urban and rural areas. Awareness about the distribution of rodent-related diseases can be a great help to rodent's control and prevention against the spread of the diseases.

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Differential Expression Profiling of Microspores During the Early Stages of Isolated Microspore Culture Using the Responsive Barley Cultivar Gobernadora

In barley, it is possible to induce embryogenesis in the haploid and uninucleate microspore to obtain a diploid plant that is perfectly homozygous. To change developmental fates in this fashion, microspores need to engage in cellular de-differentiation, interrupting the pollen formation, and restore totipotency prior to engaging in embryogenesis. In this work, we used the barley cultivar Gobernadora to characterize the transcriptome of microspores prior to (day 0) and immediately after (days 2 and 5) the application of a stress pretreatment. A deep RNA-seq analysis revealed that microspores at these three time points exhibit a transcriptome of ~14k genes, ~90% of which were shared. An expression analysis identified a total of 3,382 differentially expressed genes (DEGs); of these, 2,155 and 2,281 DEGs were respectively identified when contrasting expression at days 0 and 2 and at days 2 and 5. These define 8 expression profiles in which DEGs share a common up- or down-regulation at these time points. Up-regulation of numerous glutathione S-transferase and heat shock protein genes as well as down-regulation of ribosomal subunit protein genes was observed between days 0 and 2. The transition from microspores to developing embryos (days 2 vs 5) was marked by the induction of transcription factor genes known to play important roles in early embryogenesis, numerous genes involved in hormone biosynthesis and plant hormonal signal transduction in addition to genes involved in secondary metabolism. This work sheds light on transcriptional changes accompanying an important developmental shift and provides candidate biomarkers for embryogenesis in barley.

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Fast Ordered Sampling of DNA Sequence Variants

Explosive growth in the amount of genomic data is matched by increasing power of consumer grade computers. Even applications that require powerful servers can be quickly tested on desktop or laptop machines if we can generate representative samples from large data sets. I describe a fast and memory efficient implementation of an on-line sampling method developed for tape drives 30 years ago. Focusing on genotype files, I test the performance of this technique on modern solid-state and spinning hard drives, and show that it performs well compared to a simple sampling scheme. I illustrate its utility by developing a method to quickly estimate genome-wide patterns of linkage disequilibrium (LD) decay with distance. I provide open-source software that samples loci from several variant format files, a separate program that performs LD decay estimates, and a C++ library that lets developers incorporate these methods into their own projects.

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Tight Regulation of Srs2 Helicase Activity Is Crucial for Proper Functioning of DNA Repair Mechanisms

Proper DNA damage repair is one of the most vital and fundamental functions of every cell. Several different repair mechanisms exist to deal with various types of DNA damage, in various stages of the cell cycle and under different conditions. Homologous recombination is one of the most important repair mechanisms in all organisms. Srs2, a regulator of homologous recombination, is a DNA helicase involved in DNA repair, cell cycle progression and genome integrity. Srs2 can remove Rad51 from ssDNA, and is thought to inhibit unscheduled recombination. However, Srs2 has to be precisely regulated, as failure to do so is toxic and can lead to cell death. We noticed that a very slight elevation of the levels of Srs2 (by addition of a single extra copy of the SRS2 gene) leads to hyper-sensitivity of yeast cells to methyl methanesulfonate (MMS, a DNA damaging agent). This effect is seen in haploid, but not in diploid, cells. We analyzed the mechanism that controls haploid/diploid sensitivity and arrived to the conclusion that the sensitivity requires the activity of RAD59 and RDH54, whose expression in diploid cells is repressed. We carried out a mutational analysis of Srs2 to determine the regions of the protein required for the sensitization to genotoxins. Interestingly, Srs2 needs the HR machinery and its helicase activity for its toxicity, but does not need to dismantle Rad51. Our work underscores the tight regulation that is required on the levels of Srs2 activity, and the fact that Srs2 helicase activity plays a more central role in DNA repair than the ability of Srs2 to dismantle Rad51 filaments.

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Mutation in the Squalene epoxidase gene of Trichophyton interdigitale and Trichophyton rubrum associated with allylamine resistance [PublishAheadOfPrint]

Dermatophytosis, the commonest superficial fungal infection, has gained recent attention due to its change of epidemiology and treatment failures. Despite availability of several effective antifungal agents against dermatophytes, the incidence of chronic infection, re-infection and treatment failures are on the rise. Trichophyton rubrum and Trichophyton interdigitale are the two frequent clinical isolates in India. Consecutive patients (n=195) with suspected dermatophytosis during second half of 2014 were included in this study. Patients were categorized into relapse and new cases according to standard definitions. Antifungal susceptibility testing of the isolated Trichophyton species (n=127) was carried out against 12 antifungal agents —fluconazole, voriconazole, itraconazole, ketoconazole, sertaconazole, clotrimazole, terbinafine, naftifine, amorolfine, ciclopirox olamine, griseofulvin and luliconazole. Squalene epoxidase gene was evaluated for mutation (if any) in 15 - T. interdigitale and five - T. rubrum isolates exhibiting high minimum inhibitory concentration to terbinafine. T1189C mutation was observed in four T. interdigitale and two T. rubrum isolates. This transition leads to the substitution of amino acid phenylalanine to leucine in 397^th position of the squalene epoxidase enzyme. In homology modelling the mutant residue was smaller than wild type and positioned in the dominant site of squalene epoxidase during drug interaction, which may lead to failure to block ergosterol biosynthesis pathway by the antifungal drug.

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Bacterial adaptation to antibiotics through regulatory RNAs [PublishAheadOfPrint]

The extensive use of antibiotics has resulted in a situation where multidrug-resistant pathogens have become a severe menace to human health worldwide. A deeper understanding of the principles used by pathogens to adapt, respond and resist against antibiotics will pave the road to drugs with novel mechanisms. For bacteria, antibiotics are clinically-relevant stresses that induce protective responses. The recent implication of regulatory RNAs (sRNAs) into antibiotic response and resistance in many bacterial pathogens suggests that they should be considered as innovative drug targets. This review discusses sRNA-mediated mechanisms exploited by bacterial pathogens to fight against antibiotics. A critical discussion of the newest findings in the field is provided, with emphasis on the implication of sRNAs in major mechanisms leading to antibiotic resistance: drug uptake, active drug efflux, drug target modifications, biofilms, cell wall and LPS biosynthesis. Of interest is the lack of knowledge about sRNAs implicated in Gram-positive resistance, compared to Gram-negative bacteria.

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Clinical and genetic risk factors for biofilm-forming Staphylococcus aureus [PublishAheadOfPrint]

Background. Molecular and clinical factors associated with biofilm-forming methicillin-resistant Staphylococcus aureus (MRSA) are incompletely understood.

Methods. Biofilm production was quantified in 182 MRSA isolates from clinical culture sites (2004-2013). Microbiologic toxins, pigmentation, and genotypes were evaluated, and patient demographics were collected. Logistic regression was used to quantify the effect of strong biofilm production (versus weak) on clinical outcomes and independent predictors of strong biofilm.

Results. Of isolates evaluated, 25.8% (47/182) produced strong biofilm, and 40.7% (74/182) produced weak biofilm. Strong biofilm-producing isolates were more likely to be from MLST clonal complex 8 (34.0% vs. 14.9%; P=0.01), but less likely to be from MLST CC5 (48.9% vs. 73.0%, P=0.007). Predictors for strong biofilm were spa type t008 (aOR 4.54 95%CI 1.21-17.1), and receiving chemotherapy or immunosuppressants in the previous 90 days (aOR 33.6; 95%CI 1.68-673). Conversely, patients with high serum creatinine (aOR 0.33; 95%CI 0.15-0.72) or who previously received vancomycin (aOR 0.03; 95%CI 0.002-0.39) were less likely to harbor strong biofilm-producing MRSA. Beta-toxin producing isolates (aOR 0.31; 95%CI 0.11-0.89) and isolates with spa type t895 (aOR 0.02 95%CI <0.001-0.47) were less likely to produce strong biofilm. Patient outcomes also varied between the two groups. Specifically, patients with strong biofilm-forming MRSA were significantly more likely to be readmitted within 90 days (aOR 5.43; 95%CI 1.69-17.4), but tended to have decreased 90 day mortality (aOR 0.36; 95%CI 0.12-1.06).

Conclusions: Patients that harbored t008 and received immunosuppressants were more likely to have a strong biofilm-producing MRSA. Clinically, patients with strong biofilm-forming MRSA were less likely to die at 90 days, but five times more likely to be re-admitted.

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In Vitro Antifungal Activity of Novel Triazole Efinaconazole and Five Comparators Against Dermatophyte Isolates [PublishAheadOfPrint]

The objective was to assess the in vitro activity of the novel triazole antifungal drug, efinaconazole, and five comparators (luliconazole, lanoconazole, terbinafine, itraconazole and fluconazole) against a large collection of Trichophyton interdigitale and Trichophyton rubrum clinical isolates. The geometric mean MICs were the lowest for luliconazole (0.0005 μg/mL), followed by lanoconazole (0.002 μg/mL), efinaconazole (0.007 μg/mL), terbinafine (0.011 μg/mL), itraconazole (0.095 μg/mL) and fluconazole (12.77 μg/mL). It appears that efinaconazole, lanoconazole and luliconazole are promising candidates for the treatment of dermatophytosis due to T. interdigitale and T. rubrum.

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Elimination of doripenem during dialysis and pharmacokinetic evaluation of post-hemodialytic dosing in intermittent renal replacement therapy [PublishAheadOfPrint]

Objectives: Doripenem is a broad-spectrum parenteral carbapenem with enhanced activity against Pseudomonas aeruginosa and Enterobacteriaceae. Current dosing regimens recommend the administration of 0.25-0.5 g once daily in patients undergoing intermittent renal replacement therapy. As patients are usually dialyzed thrice weekly, we aimed to investigate a 1-g post-hemodialysis regimen, thus reducing treatment costs and enhancing patient compliance. A second objective of this trial was to describe the pharmacokinetics of intradialytic doripenem.

Patients: Ten oliguric or anuric patients in need of intermittent renal replacement therapy were included in this trial. All patients suffered from a septic episode.

Results: The mean hemofilter clearance was 123.46 ± 42.03 ml/min, and the total body clearance in between hemodialysis sessions was 16.79 ± 6.02 ml/min. The average pre-hemodialysis trough concentration was 2.4 ± 1.3 mg/l, while the EUCAST resistance breakpoint for Enterobacteriaceae is set at 2 mg/l. The interpatient variability was considerably higher than the intrapatient variability. Apart from one patient who suffered an allergic reaction, doripenem was tolerated well by all patients.

Conclusion: Our data indicate, that post-hemodialysis administration of 1 g doripenem result in sufficient plasma levels in anuric, but not oliguric patients during the entire dosing interval.

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In vitro activity of lefamulin against sexually transmitted bacterial pathogens [PublishAheadOfPrint]

The pleuromutilin antibiotic lefamulin demonstrated in vitro activity against the most relevant bacterial pathogens causing sexually transmitted infections (STI) including Chlamydia trachomatis (MIC_50/90 of 0.02/0.04 mg/L, n=15), susceptible and multidrug-resistant Mycoplasma genitalium (MIC range 0.002-0.063 mg/L, n=6) and susceptible and resistant Neisseria gonorrhoeae (MIC_50/90, 0.12/0.5 mg/L, n=25). The results suggest that lefamulin could be a promising first-line antibiotic for the treatment of STI, particularly in populations with high resistance rates to standard of care antibiotics.

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Selection and Characterization of Rupintrivir-Resistant Norwalk Virus Replicon Cells in vitro [PublishAheadOfPrint]

Human norovirus (HuNoV) is a major cause of nonbacterial gastroenteritis worldwide yet, despite their impact on society, vaccines and antivirals are currently lacking. A HuNoV replicon system has been widely applied to the evaluation of antiviral compounds and has thus accelerated the process of drug discovery against HuNoV infection. Rupintrivir, an irreversible inhibitor of the human rhinovirus 3C protease, has been reported to inhibit the replication of the Norwalk virus replicon via the inhibition of the norovirus protease. Here we report, for the first time, the generation of rupintrivir-resistant human Norwalk virus replicon in vitro. Sequence analysis revealed that these replicon cells contained amino acid substitutions of alanine 105 to valine (A105V) and isoleucine 109 to valine (I109V) in the viral protease NS6. The application of a cell-based fluorescence resonance energy transfer (FRET) assay for protease activity demonstrated that these substitutions were involved in the enhanced resistance to rupintrivir. Furthermore, we validated the effect of these mutations using the reverse genetics in murine norovirus (MNV), demonstrating that a recombinant MNV with a single I109V substitution in the protease also showed reduced susceptibility to rupintrivir. In summary, using a combination of different approaches, we have demonstrated that, under the correct conditions, mutations in the norovirus protease can rapidly occur that lead to the generation of resistant mutants.

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Heavy Metal Susceptibility on Escherichia coli from Urine Samples from Sweden, Germany and Spain [PublishAheadOfPrint]

Antimicrobial resistance is a major health care problem, with the intensive use of heavy metals and biocides recently being identified as potential contributing factors to the aggravation of this situation. This study investigated heavy metal susceptibility and genetic resistance determinants in Escherichia coli isolated from clinical urine samples from Sweden, Germany and Spain. A total of 186 isolates were tested for minimal inhibition concentration to sodium arsenite, silver nitrate and copper (II) sulphate. In addition, 88 of these isolates were whole genome sequenced for the characterization of their genetic resistance determinants and epidemiology. For sodium arsenite, the isolates could be categorized into a resistant and a non-resistant group, based on MIC values: isolates of the resistant group exhibited the chromosomal ars operon and belonged to non-B2 phylogenetic groups; in contrast, within the B2 phylogroup, no ars operon was found and the isolates were susceptible to sodium arsenite. Two isolates also harbored the silver/copper resistance determinant pco/sil and belonged to sequence types ST10 (phylogroup A) and ST295 (phylogroup C). The ST295 isolate had a silver nitrate MIC ≥ 512 mg/L and additionally produced extended spectrum beta-lactamases. To our knowledge, this is the first study that describes the distribution of the arsenic resistance operon ars within phylogroups of E. coli isolated from patients with urinary tract infections. The arsenic operon ars was only present in all non-B2 clades, which have previously been associated with the environment and commensalism in both humans and animals, while B2-clades lacked the ars operon.

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Discovery of a Novel Metallo-ss-Lactamase Inhibitor, which can Potentiate Meropenem Activity against Carbapenem-Resistant Enterobacteriaceae [PublishAheadOfPrint]

Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) are increasingly prevalent and have become a major worldwide threat to human health. Carbapenem resistance is driven primarily by the acquisition of β-lactamase enzymes which are able to degrade carbapenem antibiotics (hence termed carbapenemases) and can result in high levels of resistance and treatment failure. Clinically relevant carbapenemases include both serine-β-lactamases (SBLs, e.g. KPC-2 and OXA-48) and metallo-β-lactamases (MBLs), such as NDM-1. MBL-producing strains are endemic within the community in many Asian countries, have successfully spread worldwide, and account for many significant CRE outbreaks. Recently approved combinations of β-lactam antibiotics with β-lactamase inhibitors are only active against SBL-producing pathogens. Therefore, new drugs that specifically target MBLs and which restore carbapenem efficacy against MBL-producing CRE pathogens are urgently needed. Here, we report the discovery of a novel MBL inhibitor, ANT431, that can potentiate the activity of MEM against a broad range of MBL-producing CRE, and restore its efficacy against an Escherichia coli NDM-1 strain in a murine thigh infection model. This is a strong starting point for a chemistry lead optimization program that could deliver a first-in-class MBL inhibitor/carbapenem combination. This would complement the existing weaponry against CREs and address an important and growing unmet medical need.

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Inactivation of the Pseudomonas-Derived Cephalosporinase-3 (PDC-3) by Relebactam [PublishAheadOfPrint]

Pseudomonas aeruginosa is a prevalent and life-threatening Gram-negative pathogen acquired predominantly by immunosuppressed patients during hospitalization. Relebactam, a diazabicyclooctane β-lactamase inhibitor, potently inactivates the Pseudomonas-Derived Cephalosporinase (PDC-3) with a k₂/K of 41,400 M^-1s^-1 and a k_off of 0.00095 s^-1. Relebactam restored susceptibility to imipenem in 62% of multidrug-resistant (MDR) P. aeruginosa clinical isolates, while only 21% of isolates were susceptible to imipenem-cilastatin alone. Relebactam promises to increase the efficacy of imipenem-cilastatin against P. aeruginosa.

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Micafungin breakthrough fungemia in patients with hematological disorders [PublishAheadOfPrint]

Limited data are available on micafungin breakthrough fungemia (MBF), fungemia that develops on administration of micafungin, in patients with hematological disorders. We reviewed medical and microbiological records of patients with hematological disorders who developed MBF between January 2008 and June 2015. A total of 39 patients with MBF were identified and Candida (30 strains) and non-Candida (9 strains) fungal species were recognized as causative strains. Among 35 stored strains, C. parapsilosis (14 strains), Trichosporon asahii (7 strains), C. glabrata (5 strains), and other fungal species (9 strains) were identified by sequencing. Neutropenia was identified as an independent predictor of non-Candida fungemia (P = 0.023). T. asahii was the most common causative strain (7/19) during neutropenia. The 14-day crude mortality rate of patients treated with early micafungin change (EMC) to other antifungal agents was lower than that of the patients not treated with EMC (14% vs. 43%, P = 0.044). Most of the stored causative Candida strains were susceptible (80%) or showed wild-type susceptibility (72%) to micafungin. The minimum inhibitory concentrations (MICs) of voriconazole for T. asahii were low (range, 0.015 to 0.12 μg/mL), whereas MICs of amphotericin B for T. asahii were high (range, 2 to 4 μg/mL). MBF caused by non-Candida fungus should be considered, especially in patients with neutropenia. EMC could improve early mortality. Based on epidemiology and drug susceptibility profiling, empiric voriconazole-containing therapy might be suitable for treating MBF during neutropenia to cover for T. asahii.

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TLR7 agonists display potent antiviral effects against norovirus infection via innate stimulation [PublishAheadOfPrint]

Norovirus infections are a significant health and economic burden globally, accounting for hundreds of millions of cases of acute gastroenteritis every year. In the absence of an approved norovirus vaccine, there is an urgent need to develop antivirals to treat chronic infections, and provide prophylactic therapy to limit viral spread during epidemics and pandemics. Toll-like receptor (TLR) agonists have been explored widely for their antiviral potential and several are progressing through clinical trials for the treatment of human immunodeficiency virus (HIV), hepatitis B virus (HBV) and as adjuvants for norovirus virus-like particle (VLP) vaccines. However, developing norovirus therapies are largely direct-acting antivirals (DAAs) with fewer compounds that target the host. Our aim was to assess the antiviral potential of TLR7 agonist immunomodulators on norovirus infection using the murine norovirus (MNV) and human Norwalk replicon models. TLR7 agonists R-848, Gardiquimod, GS-9620, R-837 and Loxoribine were screened using a plaque reduction assay and each displayed inhibition of MNV replication (EC₅₀ values: 23.5 nM, 134.4 nM, 0.59 μM, 1.5 μM and 79.4 μM, respectively). RNA-sequencing of TLR7 stimulated cells revealed a predominant upregulation of innate immune response genes and ISGs that are known to drive an antiviral state. Furthermore, the combination of R-848 and the nucleoside analogue (NA) 2' C-methylcytidine elicited a synergistic antiviral effect against MNV demonstrating that combinational therapy of host-modulators and DAA's could be used to reduce drug cytotoxicity. In summary, we have identified that TLR7 agonists display potent inhibition of norovirus replication and are a therapeutic option to combat norovirus infections.

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Posaconazole-Induced Pseudohyperaldosteronism [PublishAheadOfPrint]

A woman in her late 60s with disseminated histoplasmosis was treated with posaconazole since first-line therapies were not tolerated. She subsequently presented with decompensated heart failure, hypertension, and hypokalemia. Labs revealed low renin and aldosterone levels. A potential mechanism is inhibition of the enzyme 11 beta-hydroxysteroid dehydrogenase 2, with resultant apparent mineralocorticoid excess.

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Association of Vancomycin MIC and Molecular Characteristics With Clinical Outcomes in Methicillin-Susceptible Staphylococcus aureus Acute Hematogenous Osteoarticular Infections in Children [PublishAheadOfPrint]

Background: Methicillin-resistant Staphylococcus aureus (MRSA), particularly those belonging to the USA300 pulsotype, have been well described to cause severe osteoarticular infections (OAI). Vancomycin MIC ≥ 1.5 μg/ml has been demonstrated to contribute to disease severity in adults with MRSA and even MSSA bacteremia. Little data exists describing the outcomes of MSSA OAI in terms of molecular characteristics and vancomycin MIC.

Methods: All patients/isolates were chosen from a surveillance study at Texas Children's Hospital (TCH). S. aureus OAI isolates were identified from 2011-2016 and subjected to vancomycin E-tests, PFGE and PCR for PVL and agr group.

Results: 252 cases of S. aureus OAI were identified; 183 were MSSA (72.6%). During the study period, a decrease in the proportion of cases secondary to MRSA was observed, declining from 37.8% to 15.9% (p=0.02). 26.2% and 23.5% of MSSA isolates were USA300 and PVL-positive, respectively. An increase in the proportion of MSSA isolates with a vancomycin MIC ≥ 1.5 μg/ml occurred in the study period (p=0.004). In MSSA, elevated vancomycin MIC was associated with multiple surgical procedures and and venous thromboses even when adjusting for empiric β-lactam use. An increase in vancomycin MIC was noted among isolates belonging to agr group 4 during the study period.

Conclusion: Methicillin-resistance is declining among S. aureus OAI isolates at TCH. Simultaneously, vancomycin E-test MICs are increasing among MSSA isolates. Vancomycin MIC ≥ 2 μg/ml are associated with adverse clinical outcomes in MSSA irrespective of antibiotic choice suggesting that this may be a surrogate for organism virulence.

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Potent Activity of Luliconazole, Lanoconazole and Eight Comparators against Molecularly Characterized Fusarium species [PublishAheadOfPrint]

A collection of clinical (n=47) and environmental (n=79) Fusarium isolates were tested against 10 antifungal drugs, including two novel imidazoles. Luliconazole and lanoconazole demonstrated very low GM MIC values of 0.005 μg/ml and 0.013 μg/ml, respectively, in comparison with 0.51 μg/ml for micafungin, 0.85 μg/ml for efinaconazole, 1.12 μg/ml for natamycin, 1.18 μg/ml for anidulafungin, 1.31 μg/ml for voriconazole, 1.35 μg/ml for caspofungin, 1.9 μg/ml for amphotericin B and 4.08 μg/ml for itraconazole. Results show that these drugs are potential candidates for (topical) treatment of skin and nail infections due to Fusarium species.

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The combination of tedizolid and daptomycin against methicillin-resistant Staphylococcus aureus in an in vitro model of simulated endocardial vegetations [PublishAheadOfPrint]

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen responsible for healthcare-associated infections, and treatment options are limited. Tedizolid (TZD), is a novel, oxazolidinone antibiotic with activity against MRSA. Previously, daptomycin (DAP), has demonstrated synergy with other antibiotics against MRSA. We sought to determine the efficacy of the combination of TZD + DAP against MRSA in an in vitro model of simulated endocardial vegetations (SEVs).

Methods: TZD simulations of 200 mg once daily and DAP simulations of 6-mg/kg and 10-mg/kg once daily were tested alone and in the combinations of TZD + DAP 6-mg/kg or DAP 10-mg/kg against two clinical strains of MRSA, 494 and 67. These regimens were tested in SEV models over 8 days to determine antibacterial activity of the regimens and whether synergy or antagonism might be present between the agents.

Results: Against both 494 and 67 and at both DAP dose regimens, the combination of TZD and DAP was antagonistic at 192 hours. In all cases, DAP alone was statistically superior to DAP + TZD. When the combination was stopped after 96 hours, transitioning to DAP 6-mg/kg or DAP 10-mg/kg alone resulted in better antibacterial activity than either of the TZD + DAP combinations, further demonstrating antagonistic effects.

Conclusions: Against MRSA, we have demonstrated that TZD and DAP have antagonistic activity that hinders overall antimicrobial efficacy. The exact nature of this antagonistic relationship is as of yet undetermined, but its presence warrants further study into the potentially harmful grouping of these two antibiotics in clinical use.

http://ift.tt/2FD0mGk

10. Phenotypic variability in motor neuron disease: Site of onset and patterns of disease spread

The clinical heterogeneity across motor neuron disease (MND) is well known, and largely attributed to differences in the relative mix of upper (UMN) and lower motor neuron (LMN) dysfunction, site of onset, and rate of disease progression. These differences hold prognostic significance and clues to patterns of disease spread. Objective understanding of motor dysfunction across these clinical phenotypes is thus pivotal for unravelling disease pathogenesis and mechanisms underpinning disease spread.

http://ift.tt/2tFmApL

11. Studying human neurophysiology using the mouse tail!

Non-invasive threshold-tracking techniques have been used in vivo to probe the biophysical basis of many neuromuscular conditions in human subjects. However, there are ethical and practical limitations to the study of human subjects, and mouse models provide an alternative and complementary path. Transgenic mouse models and the use of mice during drug development make them attractive targets for axonal excitability studies.

http://ift.tt/2FyloKB

13. Threshold-tracking TMS without an MEP

Transcranial magnetic stimulation (TMS) is a useful tool for quantifying cortical hyperexcitability in ALS. Short-interval intracortical inhibition (SICI) measures the suppression of descending corticomotoneuronal volleys by GABA-ergic inhibitory interneurons. Threshold-tracking TMS (tt-TMS) studies were developed to overcome the marked variability of motor evoked potentials (MEPs); tt-TMS "tracks" the stimulus intensity required to just evoke a small target MEP. Despite the success of studies using the tt-TMS technique, fasciculations can complicate recordings.

http://ift.tt/2tFmwq1

4. Median/ulnar nerve ultrasound cross-sectional area ratio in ALS

It has been shown that hand muscle wasting in amyotrophic lateral sclerosis (ALS) preferentially affects the thenar muscles, with relative sparing of the hypothenar muscles. This so-called "split-hand" is clinical sign that can be used to differentiate ALS from mimic disorders, and is thought to be caused by a difference in nerve excitability between median and ulnar nerve. The split-hand phenomenon has been largely discussed in regard to neurophysiological finding, but no studies performed comparing median and ulnar nerve size using ultrasound.

http://ift.tt/2GlozlM

01-High frequency oscillations – A revolution in electroencephalography?

From its very birth in 1924, the clinical electroencephalography (EEG) underwent a relatively smooth evolution, in which the most important milestones have been digitalization and introduction of advanced methods for mathematical analyses of EEG signals. In the clinical practice however, we still evaluate the same curves as Hans Berger did almost one century ago, and their visual analysis remains a gold standard for all the time of EEG method's utilization. Nevertheless, in the last decade we faced a convincing proofs of existence and practical contribution of the piece of information hidden in the EEG curve, about which we had no idea till the of the 20th century.

http://ift.tt/2tFmq1D

25-Influence of vestibular neurectomy on posture of the head and shoulder

The aim of this study was quantitative evaluation of vestibular head tilt in 3 D. Patients after vestibular neurectomy served as model of acute unilateral vestibular failure.

http://ift.tt/2FwiAh1

9. Upper motor neuron dysfunction and neuropsychological profile in PLS: Another entrant on the ALS-FTD spectrum

Primary lateral sclerosis (PLS), a rare upper motor neuron disorder, remains a debated entity as an upper motor neuron extreme form of amyotrophic lateral sclerosis (ALS) or a distinct disease. It is now well established that ALS and frontotemporal dementia (FTD) lie on two ends of the frontal neurodegenerative spectrum. While early descriptions of PLS excluded cognitive dysfunction, there is accumulating evidence of varying degrees of frontal lobe deficits accompanying structural and functional changes in the brain in PLS.

http://ift.tt/2GmozlD

04-Local synchrony in EEG as a marker of epileptogenic zone

Approximately a 1/3 of epileptic patients suffer from pharmacoresistant epilepsy. The surgery is often the only possible treatment, which brings a need for finding epileptogenic zone. The task is intricate in non-lesional patients in whom magnetic resonance imaging is uninformative. Our goal is to find a set of non-invasive imaging methods that would find the epileptogenic zone. We show first results with Local Synchrony (LS) method, that evaluates functional connectivity between cortical areas in short distances.

http://ift.tt/2tFmdvn

23-Prenatal stress, mood, and gray matter volume in young adulthood

This study aimed to determine whether prenatal stress, measured by the number of stressful life events during the first 20 weeks of pregnancy, might relate to mood dysregulation and altered brain structure in young adulthood. Participants included 93 mother – offspring pairs from a community-based birth cohort from the Czech Republic (European Longitudinal Study of Pregnancy and Childhood; ELSPAC-CZ). MRI analyses focused on overall cortical gray matter (GM) volume and GM volume of cortical regions previously associated with major depression.

http://ift.tt/2Fy9sbu

05-qEEG predictors of response to antidepressive treatment with ketamine

Time-course of ketamine effect was assessed in depressive patients by QEEG to elucidate changes associated with treatment and to assess potential predictors of response.

http://ift.tt/2tGcXHp

P02-Brain-mapping on animal models

Electroencephalography (EEG) is a method that reflects the electrical activity of the brain. Changes in electrical activity can be reflected also in 2D or 3D maps Measurements of brain electrical activity in animals are essential for the validation of the pharmaco-effect on the brain. The translational approach using similar methods for quantitative EEG needs to be analysed in animal models.We measured nine brains of Wistar rats using dental X-ray. We compared these values with the model from atlas (3d Brain Atlas Reconstructor).

http://ift.tt/2Fy9mRa

06-Diagnostic substantiation and current possibilities of VEPS examination

The aim of this introductory lecture is to point out that despite the intensive use of modern imagine techniques (MRI, OCT, etc.), the diagnostic applications of visual evoked potentials (VEPs) need not be obsolete, if not preferable in many cases. This objective, fully non-invasive, low-cost electrophysiological method can detect functional problems of the optic pathway and various brain cortical areas even before a development of the first displayable morphological changes.For the increased sensitivity of VEPs, it is necessary to use a larger spectrum of visual stimuli (activating quite selectively different subsystems of the visual pathway and visual cortex) compared to standards recommended by ISCEV or IFCN.

http://ift.tt/2tJDiEB

P06-Cortical somatosensory processing after botulinum toxin therapy in post-stroke spasticity

In movement disorders, neurophysiology and functional MRI demonstrated abnormalities of sensorimotor processing, responding to peripheral botulinum toxin A (BoNT) treatment. We used Modified Ashworth scale (MAS) to assess spasticity and median nerve somatosensory evoked potentials (SEP) to study changes in sensorimotor cortical areas after BoNT therapy of post-stroke arm spasticity.Seventeen patients (10 men, 7 women, average age 60.2 years) with post-stroke arm spasticity were treated with BoNT into the affected muscles.

http://ift.tt/2GkApg3

07-Connectivity of the anterior insula differentiates participants with first-episode schizophrenia spectrum disorders from controls: A machine-learning study

Early diagnosis of schizophrenia might reduce the negative impact of the untreated disease. Progressive functional/structural changes were repeatedly detected using classical between-group statistics. However, these findings have been due to their low sensitivity and specificity not clinically useful. Machine learning methods are able to learn from the data and make predictions on the individual level, which might have a diagnostic potential. We performed a classification of patients with the first episode of schizophrenia (FES) and healthy controls (HC) from the resting state functional connectivity (rsFC) and fractional anisotropy (FA) using machine learning on 1:1 age and sex matched samples of 63/63 patients/HC (rsFC) and 77/77 (DTI).

http://ift.tt/2tGsmrh

Contents

http://ift.tt/2FwaW5Z

Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab: a pooled analysis of five prospective trials

Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab: a pooled analysis of five prospective trials

Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab: a pooled analysis of five prospective trials, Published online: 13 March 2018; doi:10.1038/s41416-018-0015-z

Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab: a pooled analysis of five prospective trials

http://ift.tt/2FObZO2

Influence of obesity-related risk factors in the aetiology of glioma

Influence of obesity-related risk factors in the aetiology of glioma

Influence of obesity-related risk factors in the aetiology of glioma, Published online: 13 March 2018; doi:10.1038/s41416-018-0009-x

Influence of obesity-related risk factors in the aetiology of glioma

http://ift.tt/2FKju8W

Pre-B acute lymphoblastic leukaemia recurrent fusion, EP300-ZNF384, is associated with a distinct gene expression

Pre-B acute lymphoblastic leukaemia recurrent fusion, EP300-ZNF384, is associated with a distinct gene expression

Pre-B acute lymphoblastic leukaemia recurrent fusion, <i>EP300-ZNF384</i>, is associated with a distinct gene expression, Published online: 13 March 2018; doi:10.1038/s41416-018-0022-0

Pre-B acute lymphoblastic leukaemia recurrent fusion, EP300-ZNF384, is associated with a distinct gene expression

http://ift.tt/2HtfHdk

From checkpoint to checkpoint: DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation

From checkpoint to checkpoint: DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation

From checkpoint to checkpoint: DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation, Published online: 13 March 2018; doi:10.1038/s41416-018-0017-x

From checkpoint to checkpoint: DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation

http://ift.tt/2FIGOE1

A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours

A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours

A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours, Published online: 13 March 2018; doi:10.1038/s41416-018-0006-0

A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours

http://ift.tt/2FCAxGo

New Insights into Genomics of Pediatric Cancers [News in Brief]

Mutation type, number differ from those driving adult cancers, studies find.

http://ift.tt/2FMTKJ2

B7-H3 negatively modulates CTL-mediated cancer immunity

Purpose: Anti-programmed-death-1 (PD-1) immunotherapy improves survival in non-small cell lung cancer (NSCLC), but some cases are refractory to treatment, thereby requiring alternative strategies. B7-H3, an immune-checkpoint molecule, is expressed in various malignancies. To our knowledge, this study is the first to evaluate B7-H3 expression in NSCLCs treated with anti-PD-1 therapy and the therapeutic potential of a combination of anti-PD-1 therapy and B7-H3 targeting. Experimental Design: B7-H3 expression was evaluated immunohistochemically in patients with NSCLC (n = 82), and its relationship with responsiveness to anti-PD-1 therapy and CD8⁺ tumor infiltrating lymphocytes (TILs) was analyzed. The antitumor efficacy of dual anti-B7-H3 and anti-programmed death ligand-1 (PD-L1) antibody therapy was evaluated using a syngeneic murine cancer model. T-cell numbers and functions were analyzed by flow cytometry. Results: B7-H3 expression was evident in 74% of NSCLCs and was correlated critically with nonresponsiveness to anti-PD-1 immunotherapy. A small number of CD8⁺ TILs was observed as a subpopulation with PD-L1 tumor proportion score less than 50%, whereas CD8⁺ TILs were still abundant in tumors not expressing B7-H3. Anti-B7-H3 blockade showed antitumor efficacy accompanied with an increased number of CD8⁺ TILs and recovery of effector function. CD8⁺ T-cell depletion negated antitumor efficacy induced by B7-H3 blockade, indicating that improved antitumor immunity is mediated by CD8⁺ T-cells. Compared to a single blocking antibody, dual blockade of B7-H3 and PD-L1 enhanced the anti-tumor reaction. Conclusions:B7-H3 expressed on tumor cells potentially circumvents CD8⁺-T-cell-mediated immune surveillance. Anti-B7-H3 immunotherapy combined with anti-PD-1/PD-L1 antibody therapy is a promising approach for B7-H3-expressing NSCLCs.

http://ift.tt/2tGoCpJ

High p95HER2/HER2 Ratio Associated With Poor Outcome in Trastuzumab-Treated HER2-Positive Metastatic Breast Cancer NCCTG N0337 and NCCTG 98-32-52 (Alliance)

Background: p95HER2 is a truncated form of human epidermal growth factor receptor 2 (HER2) that confers resistance to trastuzumab in vitro, but clinical results have been conflicting to date. Given that p95HER2 levels correlate with total HER2 expression levels, which confer better outcomes, we sought to evaluate the p95HER2/HER2 ratio in the North Central Cancer Treatment Group N0337 and N98-32-52 trials. Methods: The HERmark assay and VeraTag technology (Monogram Biosciences) were used to measure total HER2 and p95HER2 expression levels in 91 patient samples. Results: In the multivariate model, increasing total HER2 level was significantly associated with longer overall survival (OS) (hazard ratio [HR]=0.33; P=.002) and decreasing p95HER2 level was significantly associated with longer OS (HR=4.2; P=.01). Total HER2 expression level was significantly associated with longer progression-free survival (PFS) (HR=0.57; P=.04) whereas p95HER2 level was not (HR= 1.7; P= .25). However, there was a positive association between p95HER2 and total HER2 expression levels (R2= 0.48; P<.001). Consistent with our hypothesis, the ratio of p95HER2/HER2 was significantly associated with worsening PFS (HR= 1.7; P= .04) and OS (HR=2.8; P=.002). Patients with the highest tertile of p95HER2/HER2 values had significantly less favorable PFS (HR=1.8; P=.06) and OS (HR=2.3; P=.02). Conclusions: A high p95HER2/HER2 ratio identified patients with metastatic breast cancer with poor outcomes on trastuzumab-based therapies.

http://ift.tt/2Gmki1p

Lipidomic profiling links the Fanconi anemia pathway to glycosphingolipid metabolism in head and neck cancer cells

Purpose:Mutations in Fanconi anemia (FA) genes are common in sporadic squamous cell carcinoma of the head and neck (HNSCC) and we have previously demonstrated that FA pathway depletion in HNSCC cell lines stimulates invasion. The goal of our studies was to use a systems approach in order to define FA pathway-dependent lipid metabolism, and to extract lipid-based signatures and effectors of invasion in FA-deficient cells. Experimental Design: We subjected FA-isogenic HNSCC keratinocyte cell lines to untargeted and targeted lipidomics analyses to discover novel biomarkers and candidate therapeutic targets in FA-deficient cells. Cellular invasion assays were carried out in the presence and absence of N-butyldeoxynojirimycin (NB-DNJ), a biosynthetic inhibitor of the newly identified class of gangliosides, to investigate the requirement of ganglioside upregulation in FA-deficient HNSCC cells. Results: The most notable element of the lipid profiling results was a consistent elevation of glycosphingolipids, and particularly the accumulation of gangliosides. Conversely, repression of this same class of lipids was observed upon genetic correction of FA patient derived HNSCC cells. Functional studies demonstrate that ganglioside upregulation is required for HNSCC cell invasion driven by FA pathway loss. The motility of non-transformed keratinocytes in response to FA loss displayed a similar dependence, thus supporting early and late roles for the FA pathway in controlling keratinocyte invasion through lipid regulation.   Conclusions: Elevation of glycosphingolipids including the ganglioside GM3 in response to FA loss stimulates invasive characteristics of immortalized and transformed keratinocytes. An inhibitor of glycosphingolipid biosynthesis NB-DNJ attenuates invasive characteristics of FA-deficient HNSCC cells.

http://ift.tt/2tGowhR

Association of p27 and cyclin D1 expression and benefit from adjuvant trastuzumab treatment in HER2-positive early breast cancer: a TransHERA study

Purpose: To assess the prognostic and predictive value of selected biomarkers involved in cell cycle regulation or proliferation in HER2-positive early breast cancer patients. Methods: Protein expression of TOP2A, Ki67, cyclin D1 and p27 was immunohistochemically determined in tissue microarrays of surgical specimens from 862 patients randomized to trastuzumab (1 or 2 year; N=561) and observation (N=301) arms of the HERA trial. The primary analysis endpoint was disease-free survival (DFS). Biomarkers were examined as continuous or categorical variables (pre-defined cutoffs). Interaction terms between biomarkers and treatment were assessed in multivariate Cox models adjusted for variables of clinical interest. Results: A significant interaction was detected between p27 and treatment (adjusted p=0.0049). Trastuzumab effect was significant in the p27 low subgroup (≤70% p27-positive tumor cells; N=318). HR _{CombTrast vs. Obs} 0.44, 95% CI: 0.29-0.65 (p<0.001). No trastuzumab effect was observed in the p27 high subgroup N=435; HR _{Comb Trast vs. Obs} 0.97, 95% CI: 0.66-1.44, p=0.89), indicating that these patients derived little or no benefit from trastuzumab treatment. A prognostic effect of p27 on DFS was observed, with p27 high patients experiencing half the hazard of a DFS event compared to low ones (HR _{p27 High vs. Low} 0.49, 95% CI: 0.32-0.75). TOP2A, Ki67 and cyclin D1, as categorical variables were not predictive, whereas cyclin D1 as continuous variable was predictive of trastuzumab benefit. Conclusions: In TransHERA, HER2-positive early breast cancer patients with low p27 expression in their tumors benefited from trastuzumab treatment, whereas patients with high p27 expression did not.

http://ift.tt/2FvYzqK

Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance.

Purpose: To identify molecular factors that determine duration of response to EGFR tyrosine kinase inhibitors and to identify novel mechanisms of drug resistance, we molecularly profiled EGFR mutant tumors prior to treatment and after progression on EGFR TKI using targeted next-generation sequencing.      Experimental Design: Targeted next-generation sequencing was performed on 374 consecutive patients with metastatic EGFR mutant lung cancer. Clinical data were collected and correlated with somatic mutation data. Erlotinib resistance due to acquired MTOR mutation was functionally evaluated by in vivo and in vitro studies. Results: In 200 EGFR-mutant pre-treatment samples, the most frequent concurrent alterations were mutations in TP53, PIK3CA, CTNNB1 and RB1 and focal amplifications in EGFR, TTF1, MDM2, CDK4, and FOXA1.  Shorter time to progression on EGFR TKI was associated with amplification of ERBB2 (HR=2.4, p=0.015) or MET (HR 3.7, p=0.019), or mutation in TP53 (HR 1.7, p=0.006). In the 136 post-treatment samples, we identified known mechanisms of acquired resistance: EGFR T790M (51%), MET (7%) and ERBB2 amplifications (5%). In the 38 paired samples, novel acquired alterations representing putative resistance mechanisms included BRAF fusion, FGFR3 fusion, YES1 amplification, KEAP1 loss, and an MTOR E2914K mutation. Functional studies confirmed the contribution of the latter to reduced sensitivity to EGFR TKI in vitro and in vivo. Conclusions: EGFR-mutant lung cancers harbor a spectrum of concurrent alterations that have prognostic and predictive significance. By utilizing paired samples, we identified several novel acquired alterations that may be relevant in mediating resistance, including an activating mutation in MTOR further validated functionally.

http://ift.tt/2tHL9lW

Activation of the receptor tyrosine kinase AXL regulates the immune microenvironment in glioblastoma

Glioblastoma (GBM) is a lethal disease with no effective therapies available. We previously observed upregulation of the TAM (Tyro-3, Axl, and Mer) receptor tyrosine kinase family member AXL in mesenchymal GBM and showed that knockdown of AXL induced apoptosis of mesenchymal, but not proneural, glioma sphere cultures (GSC). In this study, we report that BGB324, a novel small molecule inhibitor of AXL, prolongs the survival of immunocompromised mice bearing GSC-derived mesenchymal GBM-like tumors. We show that protein S (PROS1), a known ligand of other TAM receptors, was secreted by tumor-associated macrophages/microglia and subsequently physically associated with and activated AXL in mesenchymal GSC. PROS1-driven phosphorylation of AXL (pAXL) induced NF-κB activation in mesenchymal GSC, which was inhibited by BGB324 treatment. We also found that treatment of GSC-derived mouse GBM tumors with Nivolumab, a blocking antibody against the immune checkpoint protein PD-1, increased intratumoral macrophages/microglia and activation of AXL. Combinatorial therapy with Nivolumab plus BGB324 effectively prolonged the survival of mice bearing GBM tumors. Clinically, expression of AXL or PROS1 was associated with poor prognosis for GBM patients. Our results suggest that the PROS1-AXL pathway regulates intrinsic mesenchymal signaling as well as the extrinsic immune microenvironment, contributing to the growth of aggressive GBM tumors.

http://ift.tt/2FIZTWF

RIPK1 binds MCU to mediate induction of mitochondrial Ca2+ uptake and promote colorectal oncogenesis

The receptor-interacting protein kinase 1 (RIPK1) is an essential signaling molecule in pathways for cell survival, apoptosis, and necroptosis. We report here that RIPK1 is upregulated in human colorectal cancer (CRC) and promotes cell proliferation when overexpressed in a colon cancer cell line. RIPK1 interacts with mitochondrial Ca2+ uniporter (MCU) to promote proliferation by increasing mitochondrial Ca2+ uptake and energy metabolism. The ubiquitination site of RIPK1 (RIPK1-K377) was critical for this interaction with MCU and function in promoting cell proliferation. These findings identify the RIPK1-MCU pathway as a promising target to treat CRC.

http://ift.tt/2FCURHV

Acetylation within the N- and C-terminal domains of Src regulate distinct roles of STAT3-mediated tumorigenesis

Post-translational modifications of mammalian c-Src N-terminal and C-terminal domains regulate distinct functions: myristoylation of G2 controls its cell membrane association and phosphorylation of Y419/Y527 controls its activation or inactivation, respectively. We provide evidence that Src-cell membrane association-dissociation and catalytic activation-inactivation are both regulated by acetylation. In EGF-treated cells, CREB binding protein (CBP) acetylated an N-terminal lysine cluster (K5, K7, and K9) of c-Src to promote dissociation from the cell membrane. CBP also acetylated the C-terminal K401, K423, and K427 of c-Src to activate intrinsic kinase activity for STAT3 recruitment and activation. N-terminal domain phosphorylation (Y14, Y45, and Y68) of STAT3 by c-Src activated transcriptionally active dimers of STAT3. Moreover, acetyl-Src translocated into nuclei where it formed the Src-STAT3 enhanceosome for gene regulation and cancer cell proliferation. Thus, c-Src acetylation in the N-terminal and C-terminal domains play distinct roles in Src activity and regulation.

http://ift.tt/2FLFZtR

Utility of preoperative 3-D simulation of laparoscopic lateral pelvic lymph node dissection for advanced rectal cancer: Surgical outcomes of 10 initial cases

Abstract

Introduction

Laparoscopic lateral pelvic lymph node dissection (LPLD) is technically challenging because of the complicated anatomy of the pelvic wall. To overcome this difficulty, we introduced preoperative 3-D simulation. The aim of the study is to investigate the usefulness of preoperative 3-D simulation for the safe conduct of laparoscopic LPLD for rectal cancer.

Methods

After undergoing colonoscopy, patients were brought to the radiology suite where multi-detector row CT was performed. Three-dimensional images were constructed at a workstation and showed branches of the iliac artery and vein, ureter, urinary bladder, and enlarged lymph nodes. All members of the surgical team participated in preoperative simulation using the 3-D images.

Results

A total of 10 patients with advanced lower rectal cancer and enlarged lateral pelvic lymph nodes underwent laparoscopic unilateral LPLD after total mesorectal excision, tumor-specific mesorectal excision, or total proctocolectomy. Four of the 10 patients (40%) had variations in pelvic vascular anatomy. The median operative time for unilateral LPLD was 91 min (range, 66–142 min) and gradually declined, suggesting a good learning curve. The median number of lateral pelvic lymph nodes harvested was nine (range, 3–16). The median estimated blood loss was 13 mL (range, 10–160 mL). No conversion to open surgery or intraoperative complications occurred. No patient had major postoperative complications.

Conclusion

Preoperative 3-D simulation may be useful for the safe conduct of laparoscopic LPLD, especially for surgeons with limited prior experience.

http://ift.tt/2IonxWQ

Preserved somatosensory discrimination predicts consciousness recovery in unresponsive wakefulness syndrome

Unresponsive Wakefulness Syndrome (UWS) is a disorder of consciousness (DOC) characterized by spontaneous eye opening in the absence of consistent behavioral responses to external stimuli. When reproducible verbal or motor signs of awareness are detected, the clinical condition is defined as Minimally Conscious State (MCS). In clinical practice, different bedside assessment tools are used to detect purposeful behavior and discriminate between DOCs. Among them, the Coma Recovery Scale-Revised (CRS-R, Kalmar and Giacino, 2005) is considered the most sensitive tool.

http://ift.tt/2Fwl12R

Targeting MDSCs and PD-L1 confers the therapeutic advantage of ablative hypofractionated radiotherapy over conventional fractionated radiotherapy

This study compared the immune alterations in response to ablative hypofractionated radiotherapy (AHFRT) and conventional fractionated radiotherapy (CFRT) under the same BED, and showed that AHFRT suppressed recruitment of MDSCs into tumors, releasing the inhibition on CD8+ T cells, and boosting not only local but also systemic anti-cancer immunity. Adding anti-PD-L1 immunotherapy further boosted the potency of AHFRT. This study extended the mechanisms underlying the efficacy of AHFRT and proposed strategy to combine radiotherapy with immunotherapy.

http://ift.tt/2DlD1XS

Incomplete systematic meta-analysis of pharmacological therapies for opioid induced constipation

Re: Drugs for treating opioid-induced constipation: A mixed treatment comparison network meta-analysis of randomized controlled clinical trials. J Pain Symptom Manage 2018 Feb;55:468-479.e1. doi: 10.1016/j.jpainsymman.2017.08.022.Epub 2017 Sep 15. One question came in mind was the completeness of systematic review reported by Sridharan et al.1) While our publication on naldemedine 2) (reference 40) was included in the analysis, at least two other key papers on naldemedine published before the cutoff date were missed (Webster et al3), Pain Med.

http://ift.tt/2tGftNV

Distinct Patterns of Conjoint Symptom Distress and Functional Impairment in the Last Year of Life Predict Terminally Ill Cancer Patients’ Survival

Our study addressed important knowledge gaps about trajectories of distinct conjoint symptom-functional states, i.e., patterns for different levels of combined symptom distress and functional impairment, over cancer patients' last year and their ability to predict survival.

http://ift.tt/2Fy9Xm9

Necrolytic acral erythema leading to diagnosis of chronic hepatitis C

http://ift.tt/2p7EqME

Study of the standard direct costs of various techniques of advanced endoscopy. Comparison with surgical alternatives

The complexity of endoscopy has carried out an increase in cost that has a direct effect on the healthcare systems. However, few studies have analyzed the cost of advanced endoscopic procedures (AEP).

http://ift.tt/2IoUbaY

Number of Advanced Adenomas on Index Colonoscopy: Important risk factor for Metachronous Advanced Colorectal Neoplasia

Although the patients with multiple advanced adenomas (AA) in index colonoscopy may have an increased risk for subsequent advanced colorectal neoplasia (CRN), the current guidelines do not consider this factor. We aimed to compare the risk of metachronous advanced CRN according to the number of AAs.

http://ift.tt/2p7EpIA

A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours

http://ift.tt/2ImpRNV

Pre-B acute lymphoblastic leukaemia recurrent fusion, EP300-ZNF384, is associated with a distinct gene expression

http://ift.tt/2p7CDHq

From checkpoint to checkpoint: DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation

http://ift.tt/2Ik6gho

Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab: a pooled analysis of five prospective trials

http://ift.tt/2pdlMDg

Influence of obesity-related risk factors in the aetiology of glioma

http://ift.tt/2IoFLYm

miR-129-5p targets Wnt5a to block PKC/ERK/NF-κB and JNK pathways in glioblastoma

miR-129-5p targets Wnt5a to block PKC/ERK/NF-κB and JNK pathways in glioblastoma

miR-129-5p targets Wnt5a to block PKC/ERK/NF-κB and JNK pathways in glioblastoma, Published online: 12 March 2018; doi:10.1038/s41419-018-0343-1

miR-129-5p targets Wnt5a to block PKC/ERK/NF-κB and JNK pathways in glioblastoma

http://ift.tt/2p4zEjY

miR-27a inhibits cervical adenocarcinoma progression by downregulating the TGF-βRI signaling pathway

miR-27a inhibits cervical adenocarcinoma progression by downregulating the TGF-βRI signaling pathway

miR-27a inhibits cervical adenocarcinoma progression by downregulating the TGF-βRI signaling pathway, Published online: 12 March 2018; doi:10.1038/s41419-018-0431-2

miR-27a inhibits cervical adenocarcinoma progression by downregulating the TGF-βRI signaling pathway

http://ift.tt/2DmEjC9

Paraoxonase 2 overexpression inhibits tumor development in a mouse model of ovarian cancer

Paraoxonase 2 overexpression inhibits tumor development in a mouse model of ovarian cancer

Paraoxonase 2 overexpression inhibits tumor development in a mouse model of ovarian cancer, Published online: 12 March 2018; doi:10.1038/s41419-018-0395-2

Paraoxonase 2 overexpression inhibits tumor development in a mouse model of ovarian cancer

http://ift.tt/2p2lLmk

LASP1 promotes nasopharyngeal carcinoma progression through negatively regulation of the tumor suppressor PTEN

LASP1 promotes nasopharyngeal carcinoma progression through negatively regulation of the tumor suppressor PTEN

LASP1 promotes nasopharyngeal carcinoma progression through negatively regulation of the tumor suppressor PTEN, Published online: 12 March 2018; doi:10.1038/s41419-018-0443-y

LASP1 promotes nasopharyngeal carcinoma progression through negatively regulation of the tumor suppressor PTEN

http://ift.tt/2HsXD2U

Psychological Treatment

Psychological approaches to pain management have been demonstrated to be effective for individuals newly diagnosed with cancer, in remission, and/or with progressive or terminal disease. Modalities that have been demonstrated to be most effective are cognitive behavioral approaches that include relaxation skills and/or hypnotherapy.

http://ift.tt/2FwcnBr

Fatal Firearm Incidents Before and After Australia's 1996 National Firearms Agreement Banning Semiautomatic Rifles

http://ift.tt/2p5alxU

Bronchial Thermoplasty for Severe Asthmatic Cough

http://ift.tt/2FxM9yw

Engaging Survivors of Human Trafficking: Complex Health Care Needs and Scarce Resources

Human trafficking, also known as modern-day slavery, is an egregious human rights violation associated with wide-ranging medical and mental health consequences. Because of the extensive health problems related to trafficking, health care providers play a critical role in identifying survivors and engaging them in ongoing care. Although guidelines for recognizing affected patients and a framework for developing response protocols in health care settings have been described, survivors' ongoing engagement in health care services is very challenging. High rates of disengagement, lost contact, premature termination, and attrition are common outcomes. For interventions to be effective in this marginalized population, challenges in engaging survivors in long-term therapeutic primary and mental health care must be better understood and overcome. This article uses the socioecological model of public health to identify barriers to engagement; offers evidence- and practice-based recommendations for overcoming these barriers; and proposes an interdisciplinary call to action for developing more flexible, adaptable models of care.

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Effect of a Digital Health Intervention on Receipt of Colorectal Cancer Screening in Vulnerable Patients A Randomized Controlled Trial

Background:

Screening for colorectal cancer (CRC) reduces mortality, yet more than one third of age-eligible Americans are unscreened.

Objective:

To examine the effect of a digital health intervention, Mobile Patient Technology for Health–CRC (mPATH-CRC), on rates of CRC screening.

Design:

Randomized clinical trial. (ClinicalTrials.gov: NCT02088333)

Setting:

6 community-based primary care practices.

Participants:

450 patients (223 in the mPATH-CRC group and 227 in usual care) scheduled for a primary care visit and due for routine CRC screening.

Intervention:

An iPad application that displays a CRC screening decision aid, lets patients order their own screening tests, and sends automated follow-up electronic messages to support patients.

Measurements:

The primary outcome was chart-verified completion of CRC screening within 24 weeks. Secondary outcomes were ability to state a screening preference, intention to receive screening, screening discussions, and orders for screening tests. All outcome assessors were blinded to randomization.

Results:

Baseline characteristics were similar between groups; 37% of participants had limited health literacy, and 53% had annual incomes less than $20 000. Screening was completed by 30% of mPATH-CRC participants and 15% of those receiving usual care (logistic regression OR, 2.5 [95% CI, 1.6 to 4.0]). Compared with usual care, more mPATH-CRC participants could state a screening preference, planned to be screened within 6 months, discussed screening with their provider, and had a screening test ordered. Half of mPATH-CRC participants (53%; 118 of 223) "self-ordered" a test via the program.

Limitation:

Participants were English speakers in a single health care system.

Conclusion:

A digital health intervention that allows patients to self-order tests can increase CRC screening. Future research should identify methods for implementing similar interventions in clinical care.

Primary Funding Source:

National Cancer Institute.

http://ift.tt/2FwJXYe

A Health App to Promote Colorectal Cancer Screening

http://ift.tt/2DmEbCk

Does Using an iPad Make an Intervention Innovative?

Miller and colleagues report the results of a randomized trial of an iPad-based decision aid and patient self-ordering intervention that achieved a 30% colorectal cancer screening rate, compared with 15% among control patients. The editorialists speculate on what aspect of the intervention might account for the effect observed and how an even more effective intervention could be designed.

http://ift.tt/2Fwa1CH

Colonoscopy and Colorectal Cancer Mortality in the Veterans Affairs Health Care System A Case–Control Study

Background:

Colonoscopy is widely used in the Veterans Affairs (VA) health care system for colorectal cancer (CRC) prevention, but its effect on CRC mortality is unknown.

Objective:

To determine whether colonoscopy is associated with decreased CRC mortality in veterans and whether its effect differs by anatomical location of CRC.

Design:

Case–control study.

Setting:

VA–Medicare administrative data.

Participants:

Case patients were veterans aged 52 years or older who were diagnosed with CRC between 2002 and 2008 and died of the disease by the end of 2010. Case patients were matched to 4 control patients without prior CRC on the basis of age, sex, and facility. Conditional logistic regression was performed to calculate odds ratios (ORs) for exposure to colonoscopy, with adjustment for race, Charlson Comorbidity Index score, selected chronic conditions, nonsteroidal anti-inflammatory drug use, and family history of CRC.

Measurements:

Exposure to colonoscopy was determined from 1997 to 6 months before CRC diagnosis in case patients and to a corresponding date in control patients. Subgroup analysis was performed for patients who had undergone screening colonoscopy.

Results:

A total of 4964 case patients and 19 856 control patients were identified. Case patients were significantly less likely to have undergone any colonoscopy (OR, 0.39 [95% CI, 0.35 to 0.43]). Colonoscopy was associated with reduced mortality for left-sided cancer (OR, 0.28 [CI, 0.24 to 0.32]) and right-sided cancer (OR, 0.54 [CI, 0.47 to 0.63]). The results were similar for patients who had undergone screening colonoscopy (overall OR, 0.30 [CI, 0.24 to 0.38]). Sensitivity analyses that varied the interval between CRC diagnosis and colonoscopy exposure did not affect the primary findings.

Limitation:

Unmeasured confounding.

Conclusion:

In this study using national VA–Medicare data, colonoscopy was associated with significant reductions in CRC mortality among veterans and was associated with greater benefit for left-sided cancer than right-sided cancer.

Primary Funding Source:

U.S. Department of Veterans Affairs.

http://ift.tt/2DpUTRC

Human Trafficking: A Health and Human Rights Agenda

In their current article in Annals, Judge and colleagues make a valuable contribution by analyzing the nature, scope, and challenges associated with caring for victims of human trafficking. The editorialists discuss the article and the need for empirical evidence to define how to best care for this vulnerable population.

http://ift.tt/2FvVRSf

California Casualty helping first responders with their home security

California Casualty wants to help first responders protect important items and hard-to replace collectibles with the "Better Safe Than Sorry" Work Hard/Play Hard Sweepstakes for 2018. Enter now at www.contest4heroes.com. The deadline to enter is November 12, 2018, with winners announced in December. Three winners will each receive $2,250 to purchase the Liberty Colonial Safe of their choice ...

http://ift.tt/2p5lz5x

Monitoring Cell-to-cell Transmission of Prion-like Protein Aggregates in Drosophila Melanogaster

Accumulating evidence supports the idea that pathogenic protein aggregates associated with neurodegenerative diseases spread between cells with prion-like properties. Here, we describe a method that enables visualization of cell-to-cell spreading of prion-like aggregates in the model organism, Drosophila melanogaster.

http://ift.tt/2DjHQ3P

Neurovascular Embolization Coils: Healthcare Provider Letter - Potential for Increased Image Artifact When Using Magnetic Resonance Angiography For Follow-Up

Audience: Cardiology, Surgery [Posted 03/12/2018] ISSUE: The FDA is providing information about the potential for increased image artifact associated with Magnetic Resonance Angiography (MRA) imaging for patient follow-up of certain post...

http://ift.tt/2DlnXtr

Mechanical Ventilation Boot Camp Curriculum

This curriculum outlines how to execute a simulation-based boot camp to teach providers how to manage mechanically ventilated patients.

http://ift.tt/2p4HiKR

Neurovascular Embolization Coils: Healthcare Provider Letter - Potential for Increased Image Artifact When Using Magnetic Resonance Angiography For Follow-Up

Audience: Cardiology, Surgery [Posted 03/12/2018] ISSUE: The FDA is providing information about the potential for increased image artifact associated with Magnetic Resonance Angiography (MRA) imaging for patient follow-up of certain post...

http://ift.tt/2DlnXtr

Overexpression of SLC7A11: a novel oncogene and an indicator of unfavorable prognosis for liver carcinoma

Future Oncology, Ahead of Print.


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Does sarcopenia affect outcome in patients with non-small-cell lung cancer harboring EGFR mutations?

Future Oncology, Ahead of Print.


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IFN-α in advanced well-differentiated neuroendocrine tumors: the neglected drug?

Future Oncology, Ahead of Print.


http://ift.tt/2DmqumU

Comparison of primary breast cancer and paired metastases: biomarkers discordance influence on outcome and therapy

Future Oncology, Ahead of Print.


http://ift.tt/2Glj7Q1

Different inhibitors for the same target in metastatic luminal breast cancer: is there any difference?

Future Oncology, Ahead of Print.


http://ift.tt/2FzTPMQ

Utilization of radiotherapy and stereotactic body radiation therapy for renal cell cancer in the USA

Future Oncology, Ahead of Print.


http://ift.tt/2Fv7OHD

Triple negative breast cancer: are we scoring a home run?

Future Oncology, Ahead of Print.


http://ift.tt/2FzeAbn

Drug May Help Prevent Resistance to Toxin-Based Leukemia Therapy

A new study has identified a possible strategy for improving the efficacy of a toxin-based cancer treatment, moxetumomab pasudotox, in some patients with acute lymphoblastic leukemia (ALL).

http://ift.tt/2FtC3yN

CRISPR/Cas9-mediated Targeted Integration In Vivo Using a Homology-mediated End Joining-based Strategy

The clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9) system provides a promising tool for genetic engineering, and opens up the possibility of targeted integration of transgenes. We describe a homology-mediated end joining (HMEJ)-based strategy for efficient DNA targeted integration in vivo and targeted gene therapies using CRISPR/Cas9.

http://ift.tt/2tK7e38

Improvement of a Closed Chest Porcine Myocardial Infarction Model by Standardization of Tissue and Blood Sampling Procedures

Here we demonstrate a protocol to standardize sampling procedures of an established porcine model of acute myocardial infarction in order to increase its translational value in the understanding of the pathophysiology of myocardial ischemia/reperfusion injury and to test novel drug candidates.

http://ift.tt/2FvkHl4

Nanofibered Gelatin-Based Nonwoven Elasticity Promotes Epithelial Histogenesis

Abstract

Regarding tissue regeneration, mechanics of biomaterials gains progressive importance. Therefore, this study reports on in situ crosslinked electrospun gelatin nonwoven mats (NWMs) whose distinct modulus of elasticity (ME) promotes epithelial tissue formation in a graded manner. NWMs, comprising fiber diameters in various distributions, yield an ME of about 2.1, 3.2, and 10.9 kPa. A two-step approach of preclinical in vitro validation identifies the elasticity of 3.2 kPa as superior to the other, regarding the histogenetic epithelial outcome. Hence, this 3.2 kPa candidate NWM is colonized with oral mucosal epithelial keratinocytes in the absence or presence of mesenchymal fibroblasts and/or endothelial cells. Evaluation of epithelial histogenesis at days 1 to 10 occurs by colorimetric and fluorescence-based immunohistochemistry (IHCH) of specific biomarkers. These include cytokeratins (CK) 14, CK1, and involucrin that indicate different stages of epithelial differentiation, as well as the basement membrane constituent collagen type IV and Ki-67 as a proliferation marker. Intriguingly, histogenesis and IHCH reveal the best resemblance of the native epithelium by the NWM alone, irrespective of other cell counterparts. These findings prove the gelatin NWM a convenient cell matrix, and evidence that NWM mechanics is important to promote epithelial histogenesis in view of prospective clinical applications.

Biomechanical properties influence cell and tissue behavior and consequently biomaterial success in the context of tissue regeneration. Modulus of elasticity of 3.2 kPa of in situ crosslinked gelatin nonwoven mats supports epithelial tissue formation, regarding stratification and differentiation, with no need of in vivo mesenchymal cell counterparts. This novel finding supports the efficient design of biomaterials for adjusted tissue engineering.

http://ift.tt/2FLXN8k

Collaboration, campaigns and champions for appropriate imaging: feedback from the Zagreb workshop

Abstract

Leading radiologists and representatives from national radiation protection regulatory authorities and health ministries from 19 countries of the European region worked together with five experts at the workshop on justification and appropriate use of imaging in Zagreb, Croatia, from 26 to 28 October 2017 jointly organised by the IAEA and the European Society of Radiology. The workshop served as a forum to exchange information on challenges and solutions for improving justification and the appropriate use of diagnostic imaging. Common barriers to improving the use of imaging referral guidelines were discussed and the need for increased collaboration identified. Examples of good practices were presented, including use of Clinical Decision Support (CDS) systems to facilitate rapid and good justification decisions. The workshop identified some of the needs of European countries for achieving more appropriate imaging proposing wider use of collaboration, campaigns and champions.

Main messages

• Drivers for appropriate imaging in Europe are similar to those elsewhere globally.

• Implementing imaging referral guidelines is the main barrier to more appropriate imaging.

• Clinical Decision Support systems (CDS) facilitates good referral practice and justification decisions.

• Collaboration, campaigns and champions may improve awareness, appropriateness and audit.

http://ift.tt/2Iluhol

Firefighters rescue teen trapped 350 feet inside cave

Firefighters secured the girl with a harness after she became stuck while on a school field trip

http://ift.tt/2Io6swi

Recent Progress in the Study of Molecularly Doped Metals

Abstract

A unique materials' methodology enables the doping of metals with functional molecules, polymers, enzymes, and nanoparticles. The resulting materials have either the combined properties of the metal and the dopants, or new, sometimes synergetic properties that are not found in the separate components, emerge. Metals that have been doped so far include gold, silver, copper, iron, gallium, palladium, platinum, and several alloys. Numerous applications have been demonstrated including catalysis, biocatalysis, bioactivity, electrochemistry (including new type of batteries), corrosion resistance, induction of chirality, tailoring unconventional properties to metals, and more. Doping of metals and adsorption on them are completely different processes, doping being a 3D event, while adsorption is a 2D process. Thus, practically all special properties and functionalities that have been demonstrated are apparent only in the doped case. Here, progress made in this field in the past four years is reviewed, including methodologies for obtaining metallic doped thin films, enhancing corrosion resistance, biomedical applications, and the use of doped metals for complex catalytic network of reactions.

A materials methodology is described, which enables molecular doping of metals. It is shown that the resulting modified metals have properties that are either a combination of the metal characteristics and the functionality of the dopant, or that display altered or synergistic properties of the components. Thin doped metallic films, new catalysts, and new biomaterials are described.

http://ift.tt/2Hr1jC9

Moving Upwards: A Simple and Flexible In Vitro Three-dimensional Invasion Assay Protocol

This protocol describes an inverted vertical invasion assay that could be used to quantify the migration and invasion capabilities of cells in a three-dimensional setting while preserving the cell microenvironment. This assay is suitable for rare and/or sensitive cells.

http://ift.tt/2GkYP90

Practical Considerations in Studying Metastatic Lung Colonization in Osteosarcoma Using the Pulmonary Metastasis Assay

The goal of this article is to provide a detailed description of the protocol for the pulmonary metastasis assay (PuMA). This model permits researchers to study metastatic osteosarcoma (OS) cell growth in lung tissue using a widefield fluorescence or confocal laser-scanning microscope.

http://ift.tt/2tFtuex

Factors affecting outcomes following pelvic exenteration for locally recurrent rectal cancer

Background

Pelvic exenteration for locally recurrent rectal cancer (LRRC) is associated with variable outcomes, with the majority of data from single-centre series. This study analysed data from an international collaboration to determine robust parameters that could inform clinical decision-making.

Methods

Anonymized data on patients who had pelvic exenteration for LRRC between 2004 and 2014 were accrued from 27 specialist centres. The primary endpoint was survival. The impact of resection margin, bone resection, node status and use of neoadjuvant therapy (before exenteration) was assessed.

Results

Of 1184 patients, 614 (51·9 per cent) had neoadjuvant therapy. A clear resection margin (R0 resection) was achieved in 55·4 per cent of operations. Twenty-one patients (1·8 per cent) died within 30 days and 380 (32·1 per cent) experienced a major complication. Median overall survival was 36 months following R0 resection, 27 months after R1 resection and 16 months following R2 resection (P < 0·001). Patients who received neoadjuvant therapy had more postoperative complications (unadjusted odds ratio (OR) 1·53), readmissions (unadjusted OR 2·33) and radiological reinterventions (unadjusted OR 2·12). Three-year survival rates were 48·1 per cent, 33·9 per cent and 15 per cent respectively. Bone resection (when required) was associated with a longer median survival (36 versus 29 months; P < 0·001). Node-positive patients had a shorter median overall survival than those with node-negative disease (22 versus 29 months respectively). Multivariable analysis identified margin status and bone resection as significant determinants of long-term survival.

Conclusion

Negative margins and bone resection (where needed) were identified as the most important factors influencing overall survival. Neoadjuvant therapy before pelvic exenteration did not affect survival, but was associated with higher rates of readmission, complications and radiological reintervention.

http://ift.tt/2FvRJlb

Estimation of transversely isotropic material properties from magnetic resonance elastography using the optimised virtual fields method

Summary

Magnetic resonance elastography (MRE) has been used to estimate isotropic myocardial stiffness. However, anisotropic stiffness estimates may give insight into structural changes that occur in the myocardium as a result of pathologies such as diastolic heart failure. The virtual fields method (VFM) has been proposed for estimating material stiffness from image data. This study applied the optimised VFM to identify transversely isotropic material properties from both simulated harmonic displacements in a left ventricular (LV) model with a fibre field measured from histology as well as isotropic phantom MRE data. Two material model formulations were implemented, estimating either three or five material properties. The three-parameter formulation writes the transversely isotropic constitutive relation in a way that dissociates the bulk modulus from other parameters. Accurate identification of transversely isotropic material properties in the LV model was shown to be dependent on the loading condition applied, amount of Gaussian noise in the signal and frequency of excitation. Parameter sensitivity values showed that shear moduli are less sensitive to noise than the other parameters. This preliminary investigation showed the feasibility and limitations of using the VFM to identify transversely isotropic material properties from MRE images of a phantom as well as simulated harmonic displacements in an LV geometry. This article is protected by copyright. All rights reserved.

http://ift.tt/2HsmKCQ

What are we measuring? Refocusing on some fundamentals in the age of desktop bibliometrics

BibliometricsResearch evaluationConstruct validity

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Cutaneous Leiomyosarcoma: On the Importance of Histologic Location

B. Llombart
Actas Dermosifiliogr 2018;109:98

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Clinical Research at the Heart of the Spanish Academy of Dermatology and Venereology

M.A. Descalzo
Actas Dermosifiliogr 2018;109:99

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The Future of Treatment for Capillary Malformations

R. del Río
Actas Dermosifiliogr 2018;109:99

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Allergic Reactions to Tattoo Inks: A New Diagnostic Challenge

D. Muñoz Borrás
Actas Dermosifiliogr 2018;109:100

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Psoriasis-Arthritis Units: Three Years On

A. López-Ferrer, A. Láiz-Alonso
Actas Dermosifiliogr 2018;109:101-3

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Genetic Diagnosis of Epidermolysis Bullosa: Recommendations From an Expert Spanish Research Group

C. Sánchez-Jimeno, M.J. Escámez, C. Ayuso, M.J. Trujillo-Tiebas, M. del Río
Actas Dermosifiliogr 2018;109:104-22

Abstract - Full text - PDF

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Melanoma Arising in a Melanocytic Nevus

A. Martín-Gorgojo, E. Nagore
Actas Dermosifiliogr 2018;109:123-32

Abstract - Full text - PDF

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Empowerment in Dermatology

J.J. Domínguez-Cruz, J.J. Pereyra-Rodríguez, R. Ruiz-Villaverde
Actas Dermosifiliogr 2018;109:133-9

Abstract - Full text - PDF

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Clinical and Histopathologic Findings of Cutaneous Leiomyosarcoma: Correlation With Prognosis in 12 Patients

E. Rodríguez-Lomba, I. Molina-López, V. Parra-Blanco, R. Suárez-Fernández, A. Pulido-Pérez
Actas Dermosifiliogr 2018;109:140-7

Abstract - Full text - PDF

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Clinical Research at Territorial Section Meetings of the Spanish Academy of Dermatology and Venereology (AEDV)

Á. Iglesias-Puzas, A. Batalla, Á. Flórez
Actas Dermosifiliogr 2018;109:148-54

Abstract - Full text - PDF

http://ift.tt/2FBQSLs

Capillary Malformations Treated With Sequential Pulsed Dye and Nd:YAG Laser Therapy: A Retrospective Study

J. Alcántara-González, P. Boixeda, M.T. Truchuelo-Díez, N. Jiménez-Gómez, B. Pérez-García, L. Pérez-Carmona, P. Jaén Olasolo
Actas Dermosifiliogr 2018;109:155-61

Abstract - Full text - PDF

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Diagnostic Tools to Use When We Suspect an Allergic Reaction to a Tattoo: A Proposal Based on Cases at Our Hospital

I. González-Villanueva, J.F. Silvestre Salvador
Actas Dermosifiliogr 2018;109:162-72

Abstract - Full text - PDF

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Confluent and Reticulated Papillomatosis With Linear Pseudo-striae: A Description of 20 Cases

C.A. Morales-Cardona, C. Tejada-Figueroa, D.M. Méndez-Velasco
Actas Dermosifiliogr 2018;109:e7-e11

Abstract - Full text - PDF

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Erythematous Lesion on the Nose

D. González Fernández, S. Requena López, F. Valdés Pineda
Actas Dermosifiliogr 2018;109:173-4

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Vasculitis With Lesions on the Scalp as the Only Cutaneous Manifestation

F.C. Benavente Villegas, J.M. Sánchez Motilla, N. Rausell Fontestad
Actas Dermosifiliogr 2018;109:175-6

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Rituximab: Revolutionizing the Treatment of Pemphigus

D. Morgado-Carrasco, P. Giavedoni, X. Fustà-Novell, P. Iranzo
Actas Dermosifiliogr 2018;109:177-8

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Viscerocutaneous Loxoscelism

R. Cullen, P. Hasbún, M.P. Piquer
Actas Dermosifiliogr 2018;109:179

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Síndrome de CLAPO

M.Á. Flores-Terry, P. Zamberk-Majlis, M.P. Cortina-de la Calle, M. García-Arpa
Actas Dermosifiliogr 2018;109:180

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Malignant Blue Nevus: A Challenge for Dermatologists and Dermatopathologists

T. Toledo-Pastrana, I. Rodríguez Pérez, P. Eguino Gorrochategui
Actas Dermosifiliogr 2018;109:181-3

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Cutaneous Solitary Fibrous Tumor: A Spindle Cell Neoplasm With Distinctive Immunohistochemical Features

J. Santos-Juanes, B. García-García, Y. Hidalgo, B. Vivanco
Actas Dermosifiliogr 2018;109:183-5

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Draining Setons as Definitive Management of Fistula-in-Ano

BACKGROUND: The ideal management for fistula-in-ano would resolve the disease while preserving anal continence. OBJECTIVE: The purpose of this study was to determine the efficacy of draining seton alone in achieving resolution or significant amelioration of symptoms for patients with fistula-in-ano. DESIGN: This was a retrospective case series involving chart review and telephone interviews. A single colorectal surgeon performed surgeries between June 1, 2005, and June 30, 2014. SETTINGS: The study was conducted by a single surgeon in a large urban city. PATIENTS: Patient ≥18 years of age presenting with fistula-in-ano of cryptoglandular origin were included. MAIN OUTCOME MEASURES: Resolution of symptoms or significant symptom improvement requiring no additional surgical management and rate of recurrence were measured. RESULTS: A total of 76 patients (53 men) met the inclusion criteria. Mean age was 45 years (range, 19–73 y). The average time to seton removal was 36.6 weeks (range, 6.0–188.0 wk). Mean follow-up was 63 months (range, 7–121 mo). Fifty-seven patients (75%) were reached for telephone interview. Fifty-six patients (73.7%) had complete symptom resolution, and 14 (18.4%) had significant amelioration of symptoms with no additional surgical management required. Six (7.9%) had persistent severe symptoms. Five (7.1%) had a recurrence after seton removal. Rates of symptom resolution and recurrence were similar between patients whose setons were removed before or after 26 weeks (median time of seton removal) from the time of placement. Twenty-one patients (27.6%) required 1 or more additional operative procedures before planned seton removal to unroof a collection and/or replace the seton, and this represented the most significant risk factor for failure of resolution or improvement or recurrence (relative risk = 7.0). LIMITATIONS: This study was retrospective and represents a single surgeon experience. CONCLUSIONS: Placement of draining seton alone is a viable treatment option for definitive symptomatic management of fistula-in-ano. Because draining setons are sphincter and function preserving, their use should be considered as primary management for fistula-in-ano. See Video Abstract at http://ift.tt/2Dm8EAs.

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Colorectal Cancer Screening and Diagnosis: A Patient-Centered Approach to Understanding Avoidance

No abstract available

http://ift.tt/2p4orQ9

The Authors Reply

No abstract available

http://ift.tt/2Dn3Yu5

What Every Colorectal Surgeon Should Know About: CMS Survey of Global Period Surgical Services

No abstract available

http://ift.tt/2p5fhTw

A Novel Closure Technique for Complex Abdominal Wounds

INTRODUCTION: Abdominal wound closure is a challenge in patients undergoing colorectal surgery with a complex history of multiple abdominopelvic operations. Loss of domain of the abdominal fascia because of prior laparotomies precludes the use of simple, everyday abdominal wound closure techniques. Furthermore, ongoing intra-abdominal sepsis, with or without a concurrent entero- or colocutaneous fistula, increases the risk of postoperative morbidity and mortality in this patient population. We propose an abdominal wound closure technique for patients with multiple previous complex operations and subsequent ongoing abdominopelvic sepsis. TECHNIQUE: Following completion of the intra-abdominal component of the operation, the abdominal wall fascial edges are identified and mobilized to allow for a smooth skin closure. The skin is brought together with a small amount of subcutaneous tissue in the abdominal wound line and sutured with a 1.0 Prolene stitch by using the vertical mattress technique. For both wound edges, a dental roll is inserted between the entry and exit points of the suture, with the suture material placed above and over the dental roll, and thus the dental roll is incorporated within the stitch when it is tied down. These stitches and dental rolls are placed along the length of the wound. No mesh is utilized, and the technique achieves skin closure with development of a subsequent ventral hernia. RESULTS: Good postoperative short-term and long-term overall outcomes were achieved in 14 patients who underwent complex abdominal wound closure. Two patients required further late operative intervention because of the incarceration of the known ventral hernia (at 34 and 120 months postoperatively). CONCLUSIONS: Complex abdominal wound closure in this setting is safe and feasible to achieve a healthy abdominal wall closure and enable healing by primary intention after colorectal surgery.

http://ift.tt/2DkXzQg

Consensus Statement of Definitions for Anorectal Physiology Testing and Pelvic Floor Terminology (Revised)

No abstract available

http://ift.tt/2p3OHKK

Announcements

No abstract available

http://ift.tt/2DkeToD

Perioperative Management of Biologic and Immunosuppressive Medications in Patients With Crohn’s Disease

No abstract available

http://ift.tt/2p4uu7u