Αρχειοθήκη ιστολογίου

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Πέμπτη 4 Ιανουαρίου 2018

Control of vertical posture while standing on a sliding board and pushing an object

Abstract

Voluntary pushing or translation perturbation of the support surface each induces a body perturbation that affects postural control. The objective of the study was to investigate anticipatory (APA) and compensatory (CPA) postural adjustments when pushing an object (that induces self-initiated perturbation) and standing on a sliding board (that induces translational perturbation). Thirteen healthy young participants were instructed to push a handle with both hands while standing on a sliding board that was either free to move in the anterior–posterior direction or stationary. Electromyographic activity (EMG) of trunk and lower extremity muscles, center of pressure (COP) displacements, and the forces exerted by the hand were recorded and analyzed during the APA and CPA phases. When the sliding board was free to move during pushing (translation perturbation), onsets of activity of ventral leg muscles and COP displacement were delayed as compared to pushing when standing on a stationary board. Moreover, magnitudes of shank muscle activity and the COP displacement were decreased. When pushing heavier weight, magnitudes of muscle activity, COP displacement, and pushing force increased. The magnitude of activity of the shank muscles during the APA and CPA phases in conditions with translational perturbation varied with the magnitude of the pushing weight. The outcome of the study suggests that the central nervous system prioritizes the pushing task while attenuates the source of additional perturbation induced by translation perturbation. These results could be used in the development of balance re-training paradigms involving pushing weight while standing on a sliding surface.



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Significance of poor performance status after resection of colorectal liver metastases

Abstract

Background

Performance status (PS) is known as one of the strongest prognostic factors for survival in metastatic colorectal cancer patients. The aim of the present study was to analyze factors associated with poor PS assessed after resection for colorectal liver metastases and the impact on survival.

Methods

All patients undergoing curative resection for colorectal liver metastases between 2010 and 2015 in a single center were reviewed retrospectively.

Results

A total of 284 patients were included, out of whom 74 patients (26%) presented with a postoperative PS WHO > 2 precluding administration of adjuvant chemotherapy. These patients had a shorter recurrence-free survival (P = 0.002) and shorter overall survival (P < 0.001). Multivariable analysis showed that patients with PS > 2 after surgery had higher preoperative ASA score, had a higher frequency of major complications after surgery, and had more frequently synchronous liver and lung metastases. PS was found to be the strongest independent factor predicting survival (hazard ratio 0.45). When patients with postoperative PS > 2 developed recurrent disease (54 of 74), 43 (80%) received tumor specific treatment.

Conclusions

Patients with postoperative PS > 2 who did not receive adjuvant chemotherapy had decreased recurrence-free and overall survival after liver resection for colorectal liver metastases. After recurrence, a large majority of these patients had had improvement in PS allowing for administration of tumor specific treatment.



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Pharmacokinetics of dacarbazine (DTIC) in pregnancy

Abstract

Purpose

The purpose of this report is to describe, for the first time, the pharmacokinetics of dacarbazine (DTIC) and its metabolites [5-[3-methyl-triazen-1-yl]-imidazole-4-carboxamide (MTIC), 5-[3-hydroxymethyl-3-methyl-triazen-1-yl]-imidazole-4-carboxamide (HMMTIC) and 5-aminoimidazole-4-carboxamide (AIC)] during pregnancy (n = 2) and postpartum (n = 1).

Methods

Non-compartmental DTIC, MTIC, HMMTIC, and AIC pharmacokinetics (PK) were estimated in one case at 29 week gestation and 18 day postpartum and a second case at 32 week gestation, in women receiving DTIC in combination with doxorubicin, bleomycin, and vinblastine for treatment of Hodgkin's lymphoma. Drug concentrations were measured by HPLC.

Results

In the subject who completed both pregnancy and postpartum study days, DTIC area under the concentration–time curve (AUC) was 27% higher and metabolite AUCs were lower by 27% for HMMTIC, 38% for MTIC, and 83% of AIC during pregnancy compared to postpartum. At 7 and 9 year follow-up, both subjects were in remission of their Hodgkin's lymphoma.

Conclusions

Based on these two case reports, pregnancy appears to decrease the metabolism of the pro-drug dacarbazine, likely through inhibition of CYP1A2 activity. Lower concentrations of active metabolites and decreased efficacy may result, although both these subjects experienced long-term remission of their Hodgkin's lymphoma.



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Cardiolipin activates antigen-presenting cells via TLR2-PI3K-PKN1-AKT/p38-NF-kB signaling to prime antigen-specific naïve T cells in mice

Abstract

Mitochondrial defects and anti-mitochondrial cardiolipin (CL) antibodies are frequently detected in autoimmune disease patients. CL from dysregulated mitochondria activates various pattern recognition receptors, such as NLRP3. However, the mechanism by which mitochondrial CL activates antigen-presenting cells (APCs) as a damage-associated molecular pattern to prime antigen-specific naïve T cells, which is crucial for T-cell-dependent anti-cardiolipin IgG antibody production in autoimmune diseases is unelucidated. Here we show, that CL increases the expression of costimulatory molecules in CD11c+ APCs both in vitro and in vivo. CL activates CD11c+ APCs via TLR2-PI3K-PKN1-AKT/p38MAPK-NF-κB signaling. CD11c+ APCs that have been activated by CL are sufficient to prime H-Y peptide-specific naïve CD4+ T cells and OVA-specific naïve CD8+ T cells. TLR2 is necessary for anti-CL IgG antibody responses in vivo. Intraperitoneal injection of CL does not activate CD11c+ APCs in CD14 KO mice to the same extent as in wild-type mice. CL binds to CD14 (Kd = 7 × 10−7 M). CD14, but not MD2, plays a role in NF-kB activation by CL, suggesting that CD14+ macrophages contribute to recognizing CL. In summary, CL activates signaling pathways in CD11c+ APCs through a mechanism similar to gram (+) bacteria and plays a crucial role in priming antigen-specific naïve T cells.

This article is protected by copyright. All rights reserved



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Cancers, Vol. 10, Pages 12: New Interactors of the Truncated EBNA-LP Protein Identified by Mass Spectrometry in P3HR1 Burkitt’s Lymphoma Cells

Cancers, Vol. 10, Pages 12: New Interactors of the Truncated EBNA-LP Protein Identified by Mass Spectrometry in P3HR1 Burkitt's Lymphoma Cells

Cancers doi: 10.3390/cancers10010012

Authors: Sonia Chelouah Emilie Cochet Sophie Couvé Sandy Balkaran Aude Robert Evelyne May Vasily Ogryzko Joëlle Wiels

The Epstein-Barr virus nuclear antigen leader protein (EBNA-LP) acts as a co-activator of EBNA-2, a transcriptional activator essential for Epstein-Barr virus (EBV)-induced B-cell transformation. Burkitt's lymphoma (BL) cells harboring a mutant EBV strain that lacks both the EBNA-2 gene and 3′ exons of EBNA-LP express Y1Y2-truncated isoforms of EBNA-LP (tEBNA-LP) and better resist apoptosis than if infected with the wild-type virus. In such BL cells, tEBNA-LP interacts with the protein phosphatase 2A (PP2A) catalytic subunit (PP2A C), and this interaction likely plays a role in resistance to apoptosis. Here, 28 cellular and four viral proteins have been identified by mass spectrometry as further possible interactors of tEBNA-LP. Three interactions were confirmed by immunoprecipitation and Western blotting, namely with the A structural subunit of PP2A (PP2A A), the structure-specific recognition protein 1 (SSRP1, a component of the facilitate chromatin transcription (FACT) complex), and a new form of the transcription factor EC (TFEC). Thus, tEBNA-LP appears to be involved not only in cell resistance to apoptosis through its interaction with two PP2A subunits, but also in other processes where its ability to co-activate transcriptional regulators could be important.



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Issue Information



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Issue Information



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Inhibition of neddylation facilitates cell migration through enhanced phosphorylation of caveolin-1 in PC3 and U373MG cells

Abstract

Background

Protein neddylation is a post-translational modification by a covalent conjugation with the neural precursor cell expressed, developmentally downregulated 8 (NEDD8). Although this process has been reported to participate in diverse cellular signaling, little is known about its role in cancer cell migration. Given a recent proteomics report showing that NEDD8 is downregulated in prostate cancer tissues versus normal prostate tissues, we tested the possibility that neddylation plays a role in cancer evolution, and then tried to identify target proteins of the neddylation.

Methods

The neddylation process was inhibited by transfecting cancer cells with NEDD8-targeting siRNAs or by treating the cells with a NAE1 inhibitor MLN4924. Cell migration was evaluated by an in vitro wound-healing assay and a Transwell migration assay. His/NEDD8-conjugated proteins were pulled down with nickel-affinity beads under a denaturing condition, and identified by Western blotting. All data were processed using the Microsoft Excel program and analyzed statistically by two-sided, unpaired Student's t-test.

Results

Caveolin-1, which plays a critical role in cell migration, was identified to be conjugated with NEDD8. When the neddylation was inhibited, the phosphorylation of caveolin-1 at Tyr14 was augmented in PC3 and U373MG cells, thereby leading to increased cell migration. Such consequences by neddylation inhibition were abolished in the presence of a Src family kinase inhibitor PP2.

Conclusions

NEDD8 seems to inhibit the Src-mediated phosphorylation of caveolin-1 by modifying the structure of caveolin-1 protein, which blocks the migration of cancer cells. Although the neddylation process is currently regarded as an emerging target for cancer therapy, our results suggest the possibility that the inhibition of neddylation could facilitate cancer invasion or metastasis at least in some types of cancers.



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Evolutionary aspects of non-metastatic breast cancer after primary treatment in a sub-Saharan African setting: a 16-year retrospective review at the Douala general hospital, Cameroon

Abstract

Background

Breast cancer has a high case fatality rate in sub-Saharan Africa, and this is chiefly because of late detection and inadequate treatment resources. Progressive renovations in diagnostic and management modalities of non-metastatic breast cancer (NMBC) have been noted in the region but there is paucity of data describing the clinical progress of patients with NMBC. This study sought to determine the rates of local relapse, distant metastasis and sequelae and the time span from initial treatment to the occurrence of these adverse events among patients with NMBC.

Methods

This was a retrospective review of medical records of patients with histologically confirmed NMBC at the department of radiation therapy and oncology of the Douala General Hospital in Cameroon from the January 1997 to December 2012 period. Clinicopathological and treatment characteristics as well as occurrences of adverse events were studied.

Results

A total of 260 cases were reviewed of which 224/260 (86.2%) had invasive ductal carcinoma. Surgery was performed on 258/260 cases (99.2%) with 187/258 (72.5%) being modified radical mastectomies. Various treatment combinations were used in up to 228/260 patients (87.5%) while surgery alone was the treatment in the remaining 32 cases (12.5%). Metastasis occurred in 142/260 cases (54.6%) of which 68/142 (26.2%) were local relapses and 74/142 (28.5%) were distant metastases. Among the cases of distant metastasis, 9.2% were bone, 8.5% lungs, 6.9% nodal, and 5.4% brain. Metastasis to multiple organs was noted in 4.7% of these cases. The median periods of occurrence of local relapse and distant metastases were 13 and 12 months respectively. Sequelae occurred in 26/260 cases (10%) and were noted after an average of 30 months. The main sequelae were lymphoedema (6.5%) and lung fibrosis (1.5%). At the end of the period under review, 118/260 patients (45.4%) were alive and disease-free with a median follow up time of 24 months.

Conclusions

Adverse events were frequent among patients who received primary treatment for NMBC. Available cancer therapeutic modalities ought to be supplemented with efficient strategies of follow-up and monitoring so as to optimize the care provided to these patients and improve on their survival.



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Evaluation of bone stimulation by different designs of microthreaded implants in enhancing osseointegration: An in vivo animal study supported by a numerical analysis

Abstract

Background

An optimal shape of the thread design of the implants is required for equal distribution of stresses to the surrounding bone matrix and for stimulation and promotion of bone remodeling.

Purpose

The study was construed with the aim of histomorphometric evaluation of bone stimulation generated by different microthread designed implants in enhancing osseointegration, and to assess the pattern of stress dissipation through a two-dimensional finite element analysis.

Material and Methods

Computer Aided Designing of two type of microthreads, one V-shaped and the other Power-shaped microthreaded dental implants with only microthreads all along body of the implant from the neck to the apex was made and 30 implant prototypes were milled. Two-dimensional finite elemental analysis (FEA) was carried out to assess the pattern of stress distribution in the bone around these implant designs and for In vivo study 24 implant prototypes were placed in rabbits tibia and femur, out of which 12 were with V-shaped microthreads and the other 12 were with Power-shaped microthreads. Histomorphometric analysis was carried out of the sections obtained from the enbloc specimen retrieved from the sacrificed rabbits.

Results

FEA showed less stress around the V-shaped microthreaded implant model when compared to Power-shaped microthreaded implant model. Hitomorphometry showed statistical significance difference in new bone volume (BV) and Total BV for V-shaped microthreaded prototype implant.

Conclusions

V-shaped microthreaded dental implant design can be preferred over Power-shaped microthreaded dental implant for proper stress distribution and for promoting osseointegration.



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Prognostic value of the Glasgow Prognostic Score for patients with metastatic renal cell carcinoma treated by cytoreductive nephrectomy

Abstract

Background

The aim of the present study was to evaluate the prognostic significance of the Glasgow Prognostic Score (GPS) in metastatic renal cell carcinoma (mRCC) patients treated by cytoreductive nephrectomy (CN), and the accuracy of the GPS as a prognostic factor.

Methods

We retrospectively analyzed the data of patients who underwent CN for mRCC between March 1984 and August 2015. In accordance with the GPS criteria, the patients were classified into three groups: GPS 0: C-reactive protein (CRP) ≤ 1.0 mg/dl and albumin ≥ 3.5 g/dl; GPS 1: CRP > 1.0 mg/dl or albumin < 3.5 g/dl; and GPS 2: CRP > 1.0 mg/dl and albumin < 3.5 g/dl.

Results

We enrolled 170 patients (72% male; median age 63.5 years). Fifty-six (33%), 67 (39%), and 47 (28%) patients had a GPS of 0, 1, and 2, respectively. The median overall survivals after CN were 52.4, 19.1, and 8.9 months for patients with a GPS of 0, 1, and 2, respectively (P < 0.0001). In addition to the GPS, Eastern Cooperative Oncology Group performance status (ECOG-PS), Memorial Sloan-Kettering Cancer Center (MSKCC) risk classification, histology, sarcomatoid change, clinical T stage, primary tumor size, number of metastatic organs, non-regional lymph node metastasis, and liver metastasis were included in the Cox hazards regression model. Multivariate analysis of these factors revealed that the GPS was an independent prognostic factor of overall survival (P < 0.0001). Harrell's concordance index in the multivariate prognostic model based on ECOG-PS, MSKCC risk criteria, histology, sarcomatoid change, clinical T stage, primary tumor size, number of metastatic organs, non-regional lymph node metastasis, and liver metastasis was 0.609, which increased to 0.652 after the inclusion of the GPS.

Conclusions

GPS represents an independent prognostic factor for patients who undergo CN for mRCC.



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Methanogens: biochemical background and biotechnological applications

Since fossil sources for fuel and platform chemicals will become limited in the near future, it is important to develop new concepts for energy supply and production of basic reagents for chemical industry. On...

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Multiple Origin but Single Domestication Led to Oryza sativa

The domestication scenario that led to Asian rice (Oryza sativa) is a contentious topic. Here, we have reanalyzed a previously published large-scale wild and domesticated rice dataset, which were also analyzed by two studies but resulted in two contrasting domestication models. We suggest the analysis of false positive selective sweep regions and phylogenetic analysis of concatenated genomic regions may have been the sources that contributed to the different results. In the end, our result indicates Asian rice originated from multiple wild progenitor subpopulations; however, de novo domestication appears to have occurred only once and the domestication alleles were transferred between rice subpopulation through introgression.



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An RNA-based digital circulating tumor cell signature is predictive of drug response and early dissemination in prostate cancer [Research Articles]

Blood-based biomarkers are critical in metastatic prostate cancer, where characteristic bone metastases are not readily sampled, and they may enable risk stratification in localized disease. We established a sensitive and high-throughput strategy for analyzing prostate circulating tumor cells (CTCs) using microfluidic cell enrichment followed by digital quantitation of prostate-derived transcripts. In a prospective study of 27 metastatic castration-resistant prostate cancer patients treated with first-line abiraterone, pretreatment elevation of the digital CTCM Score identifies a high risk population with poor overall survival (HR 6.0, P=0.01) and short radiographic progression-free survival (HR 3.2, P=0.046). Expression of HOXB13 in CTCs identifies 6/6 patients with ≤12 months survival, with a subset also expressing the AR-V7 splice variant. In a second cohort of 34 men with localized prostate cancer, an elevated preoperative CTCL Score predicts microscopic dissemination to seminal vesicles and/or lymph nodes (P<0.001). Thus, digital quantitation of CTC-specific transcripts enables noninvasive monitoring that may guide treatment selection in both metastatic and localized prostate cancer.



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Establishing A Preclinical Multidisciplinary Board for Brain Tumors

Purpose: Curing all children with brain tumors will require an understanding of how each subtype responds to conventional treatments and how best to combine existing and novel therapies.  It is extremely challenging to acquire this knowledge in the clinic alone, especially among patients with rare tumors.  Therefore, we developed a preclinical brain tumor platform to test combinations of conventional and novel therapies in a manner that closely recapitulates clinic trials.  Experimental Design: A multidisciplinary team was established to design and conduct neurosurgical, fractionated radiotherapy and chemotherapy studies, alone or in combination, in accurate mouse models of supratentorial ependymoma (SEP) subtypes and choroid plexus carcinoma (CPC).  Extensive drug repurposing screens, pharmacokinetic, pharmacodynamic and efficacy studies were used to triage active compounds for combination preclinical trials with 'standard-of-care' surgery and radiotherapy. Results: Mouse models displayed distinct patterns of response to surgery, irradiation and chemotherapy that varied with tumor subtype.  Repurposing screens identified three hour infusions of gemcitabine as a relatively non-toxic and efficacious treatment of SEP and CPC.  Combination neurosurgery, fractionated irradiation and gemcitabine proved significantly more effective than surgery and irradiation alone, curing one half of all animals with aggressive forms of SEP. Conclusions: We report a comprehensive preclinical trial platform to assess the therapeutic activity of conventional and novel treatments among rare brain tumor subtypes. It also enables the development of complex, combination treatment regimens that should deliver optimal trial designs for clinical testing.  Post-irradiation gemcitabine infusion should be tested as new treatments of SEP and CPC.



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Activation of 4-1BB on liver myeloid cells triggers hepatitis via an interleukin-27 dependent pathway

Purpose: Agonist antibodies targeting the T cell co-stimulatory receptor 4-1BB (CD137) are among the most effective immunotherapeutic agents across pre-clinical cancer models. In the clinic, however, development of these agents has been hampered by dose-limiting liver toxicity. Lack of knowledge of the mechanisms underlying this toxicity has limited the potential to separate 4-1BB agonist driven tumor immunity from hepatotoxicity. Experimental Design: The capacity of 4-1BB agonist antibodies to induce liver toxicity was investigated in immunocompetent mice, with or without co-administration of checkpoint blockade, via 1) measurement of serum transaminase levels, 2) imaging of liver immune infiltrates, and 3) qualitative and quantitative assessment of liver myeloid and T cells via flow cytometry. Knockout mice were used to clarify the contribution of specific cell subsets, cytokines and chemokines. Results: We find that activation of 4-1BB on liver myeloid cells is essential to initiate hepatitis. Once activated, these cells produce interleukin-27 that is required for liver toxicity. CD8 T cells infiltrate the liver in response to this myeloid activation and mediate tissue damage, triggering transaminase elevation. FoxP3+ regulatory T cells limit liver damage, and their removal dramatically exacerbates 4-1BB agonist-induced hepatitis. Co-administration of CTLA-4 blockade ameliorates transaminase elevation, whereas PD-1 blockade exacerbates it. Loss of the chemokine receptor CCR2 blocks 4-1BB agonist hepatitis without diminishing tumor-specific immunity against B16 melanoma. Conclusions: 4-1BB agonist antibodies trigger hepatitis via activation and expansion of interleukin-27-producing liver Kupffer cells and monocytes. Co-administration of CTLA-4 and/or CCR2 blockade may minimize hepatitis, but yield equal or greater antitumor immunity.



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Identification of a novel, EBV-based antibody risk stratification signature for early detection of nasopharyngeal carcinoma in Taiwan

Background.Epstein-Barr virus (EBV) is necessary for the development of nasopharyngeal carcinoma (NPC). By adulthood, ~90% of individuals test EBV-positive, but only a fraction develop cancer. Factors that identify which individuals are most likely to develop disease, including differential antibody response to the virus, could facilitate detection at early stages when treatment is most effective. Methods. We measured anti-EBV IgG and IgA antibody responses in 607 Taiwanese individuals. Antibodies were measured using a custom protein microarray targeting 199 sequences from 86 EBV proteins. Variation in response patterns between NPC cases and controls was used to develop an antibody-based risk score for predicting NPC. The overall accuracy (area under the curve[AUC]) of this risk score, and its performance relative to currently-used biomarkers, was evaluated in two independent Taiwanese cohorts. Findings. Levels of 60 IgA and 73 IgG anti-EBV antibodies differed between Stage I/IIa NPC cases and controls (P<0·0002). Risk prediction analyses identified antibody targets that best discriminated NPC status-BXLF1,LF2,BZLF1,BRLF1,EAd, BGLF2,BPLF1,BFRF1, and BORF1. When combined with currently-used VCA/EBNA1 IgA biomarkers, the resulting risk score predicted NPC with 93% accuracy (95%CI 87-98%) in the general Taiwanese population, a significant improvement beyond current biomarkers alone (82%;95%CI 75-90%,P<0·01). This EBV-based risk score also improved NPC prediction in genetically high-risk families (89%;95%CI 82-96%) compared to current biomarkers (78%;95%CI 66-90%,P<0·03). Interpretation. We identified NPC-related differences in 133 anti-EBV antibodies and developed a risk score using this microarray dataset that targeted immune responses against EBV proteins from all stages of the viral life cycle, significantly improving the ability to predict NPC.



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p53-reactive T cells are associated with clinical benefit in patients with platinum-resistant epithelial ovarian cancer after treatment with a p53 vaccine and gemcitabine chemotherapy

Purpose: To conduct a Phase I trial of a Modified Vaccinia Ankara vaccine delivering wild type human p53 (p53MVA) in combination with gemcitabine chemotherapy in patients with platinum-resistant ovarian cancer. Experimental Design: Patients received gemcitabine on days 1 and 8 and p53MVA vaccine on day 15, during the first 3 cycles of chemotherapy. Toxicity was classified using the NCI Common Toxicity Criteria and clinical response assessed by CT scan. Peripheral blood samples were collected for immunophenotyping and monitoring of anti-p53 immune responses. Results: 11 patients were evaluated for p53MVA/gemcitabine toxicity, clinical outcome and immunological response. Toxicity: There were no DLTs but 3/11 patients came off study early due to gemcitabine-attributed adverse events (AEs). Minimal AEs were attributed to p53MVA vaccination. Immunological and Clinical Response: Enhanced in vitro recognition of p53 peptides was detectable after immunization in both the CD4+ and CD8+ T cell compartments in 5/11 and 6/11 patients respectively. Changes in peripheral T regulatory cells (Tregs) and myeloid derived suppressor cells (MDSC) did not correlate significantly with vaccine response or progression free survival (PFS). Patients with the greatest expansion of p53-reactive T cells had significantly longer PFS than patients with lower p53-reactivity post therapy. Tumor shrinkage or disease stabilization occurred in 4 patients. Conclusions: p53MVA was well tolerated, but gemcitabine without steroid pre-treatment was intolerable in some patients. However, elevated p53-reactive CD4+ and CD8+T cell responses post therapy correlated with longer PFS. Therefore, if responses to p53MVA could be enhanced with alternative agents, superior clinical responses may be achievable.



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Efficacy, safety and pharmacokinetics of axitinib in nasopharyngeal carcinoma: a preclinical and phase 2 correlative study

Purpose:We hypothesized that axitinib is active with improved safety profile in nasopharyngeal carcinoma (NPC). Experimental Design: We evaluated axitinib in preclinical models of NPC, and studied its efficacy in a phase 2 clinical trial in recurrent or metastatic NPC patients who progressed after at least one line of prior platinum-based chemotherapy. We excluded patients with local recurrence or vascular invasion. Axitinib was started at 5 mg twice-daily in continuous 4-weeks cycles. Primary endpoint was clinical benefit rate (CBR), defined as percent of patients achieving complete response (CR), partial response (PR) or stable disease (SD) by RECIST criteria for more than 3 months. Results:We recruited 40 patients, who received a median of 3 lines of prior chemotherapy. Axitinib was administered for a mean of 5.6 cycles, with 16 patients (40%) received ≥6 cycles. Of 37 patients evaluable for response, CBR was 78.4% (95% CI: 65.6-91.2%) at 3 months and 43.2% (30.4-56.1%) at 6 months. Grade 3/4 toxicities were uncommon, including hypertension (8%), diarrhea (5%), weight loss (5%) and pain (5%). All hemorrhagic events were grade 1 (15%) or grade 2 (3%). Elevated diastolic blood pressure during first 3 months of axitinib treatment was significantly associated with improved overall survival (HR=0.29, 95% C.I 0.13-0.64, P=0.0012). Patient reported fatigue symptom was associated with hypothyroidism (p=0.039). Axitinib PK parameters (C max and AUC(0-t)) were significantly correlated with tumor response, toxicity and serum thyroid-stimulating hormone (TSH) changes. Conclusions: Axitinib achieved durable disease control with a favorable safety profile in heavily pretreated NPC patients.



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Pharmacological inhibition of NOS activates ASK1/JNK pathway augmenting docetaxel-mediated apoptosis in triple negative breast cancer

Purpose: Chemoresistance in triple negative breast cancer (TNBC) is associated with the activation of a survival mechanism orchestrated by the endoplasmic reticulum (EnR) stress response and by inducible nitric oxide synthase (iNOS). Our aim was to determine the effects of pharmacological NOS-inhibition on TNBC. Experimental Design: TNBC cell lines, SUM-159PT, MDA-MB-436, and MDA-MB-468, were treated with docetaxel and NOS-inibitor (L-NMMA) for 24, 48 and 72 hours. Apoptosis was assessed by flow cytometry using Annexin-V and propidium iodide. Western Blot was used to assess ER-stress and apoptosis; rtPCR, to evaluate s-XBP1. TNBC patient derived xenografts (PDXs) were treated either with vehicle, docetaxel, or combination therapy (NOS-inhibition + docetaxel). Mouse weight and tumor volumes were recorded twice weekly. Docetaxel concentration was determined using mass spectrometry. To quantify proliferation and apoptosis PDX tumor samples were stained using Ki67 and TUNEL assay. Results: In-vitro, L-NMMA ameliorated the iNOS upregulation associated with docetaxel. Apoptosis increased when TNBC cells were treated with combination therapy. In TNBC PDXs, combination therapy significantly reduced tumor volume growth and increased survival proportions. In the BCM-5998 PDX model, intratumoral docetaxel concentration was higher in mice receiving combination therapy. Coupling docetaxel with NOS-inhibition increased EnR-stress response via co-activation of ATF4 and CHOP, which triggered pASK1/JNK proapoptotic pathway, promoting cleavage of caspases 3 and 9. Conclusion: iNOS is a critical target for docetaxel resistance in TNBC. Pharmacological inhibition of NOS enhanced chemotherapy response in TNBC PDX models. Combination therapy may improve prognosis and prevent relapse in TNBC patients who have failed conventional chemotherapy.



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Laparoscopic appendectomy during the third trimester: Case presentation and literature review

Abstract

Acute appendicitis is the most common general surgical problem encountered during pregnancy. Laparoscopic appendectomy (LA) is widely accepted as a minimally invasive procedure for acute appendicitis. However, LA during the third trimester is associated with problems, including technical difficulty, risk of preterm delivery, and fetal loss. We successfully managed three cases of LA during the third trimester between 2011 and 2016. None of the cases required conversion to an open procedure, and none of the patients had postoperative complications and/or fetal loss. We reviewed the literature using the PubMED database from 2007 to 2016 to acquire further evidence and identified 6 reports and 17 cases. The conversion rate was 11.8% (2 cases), the complication rate was 6.67% (1 case), and the preterm delivery rate was 20% (3 cases); no fetal loss was observed. Our study and literature review highlights the role of LA as a potentially feasible treatment approach for appendicitis during the third trimester.



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False-Positive Heat-Damaged RBC Scan for Splenosis: Case of Retroperitoneal Extramedullary Hematopoiesis

imageExtramedullary hematopoiesis (EMH) is a well-known compensatory response to severe anemia, most commonly due to a chronic hemolytic anemia such as thalassemia or sickle cell disease. We present a case of a 72-year-old man with autoimmune hemolytic anemia refractory to steroids and splenectomy. An incidental retroperitoneal mass on CT was suggestive of ectopic splenic tissue. However, an alternative diagnosis of EMH was considered, given an atypical appearance on heat-damaged 99mTc-RBC scan, and was confirmed with biopsy. The case report illustrates the imaging characteristics of EMH, widely known to have increased activity on 99mTc-sulfur colloid scans.

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Reply to ‘Comment on ‘A meta-analysis of CXCL12 expression for cancer prognosis”

Reply to 'Comment on 'A meta-analysis of CXCL12 expression for cancer prognosis"

Reply to 'Comment on 'A meta-analysis of CXCL12 expression for cancer prognosis", Published online: 04 January 2018; doi:10.1038/bjc.2017.445

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Deletion of the von Hippel-Lindau gene in hemangioblasts causes hemangioblastoma-like lesions in murine retina

von Hippel-Lindau (VHL) disease is an autosomal dominant tumor predisposition syndrome characterized by the development of highly vascularized tumors and cysts. Loss of heterozygosity (LOH) of the VHL gene results in aberrant upregulation of hypoxia-inducible factors (HIF) and has been associated with tumor formation. Hemangioblastomas of the central nervous system and retina represent the most prevalent VHL-associated tumors, but no VHL animal model has reproduced retinal capillary hemangioblastomas (RCH), the hallmark lesion of ocular VHL. Here we report our work in developing a murine model of VHL-associated RCH by conditionally inactivating Vhl in a hemangioblast population using a Scl-Cre-ERT2 transgenic mouse line. In transgenic mice carrying the conditional allele and the Scl-Cre-ERT2 allele, 64% exhibited various retinal vascular anomalies following tamoxifen induction. Affected Vhl mutant mice demonstrated retinal vascular lesions associated with prominent vasculature, anomalous capillary networks, hemorrhage, exudates, and localized fibrosis. Histological analyses showed RCH-like lesions characterized by tortuous, dilated vasculature surrounded by "tumorlet" cell cluster and isolated foamy stromal cells, which are typically associated with RCH. Fluorescein angiography suggested increased vascular permeability of the irregular retinal vasculature and hemangioblastoma-like lesions. Vhl deletion was detected in "tumorlet" cells via microdissection. Our findings provide a phenotypic recapitulation of VHL-associated RCH in a murine model that may be useful to study RCH pathogenesis and therapeutics aimed at treating ocular VHL.

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Cardiac Fibroma: An Uncommon Cause of a Fixed Defect on Myocardial Perfusion Imaging

imageA 66-year-old woman was referred for evaluation of coronary artery disease. Myocardial perfusion imaging (MPI) was performed, and showed a medium-sized, severe fixed perfusion defect in the inferior and inferolateral wall from apex to midcavity. On review of prior imaging, it was noted that the patient had an incidental finding of an intramural cardiac mass on chest CT performed 8 years prior. Subsequent cardiac MRI showed findings consistent with a cardiac fibroma in the left ventricle, at the location of the perfusion defect on MPI. Our case demonstrates an uncommon cause of a fixed perfusion defect on MPI.

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A Novel Technique to Measure the Intensity of Abnormality on GI Bleeding Scans: Development, Initial Implementation, and Correlation With Conventional Angiography

imagePurpose Develop a technique to quantify intensity of lower gastrointestinal bleeding (LGIB) on 99mTc-labeled red blood cell (RBC) scintigraphy, correlate with angiography, and determine the tool's predictive value. Materials and Methods An IRB-approved, single institution database query of GI bleeding scans performed between January 2013 and December 2015. Reports from all studies and imaging from all positive studies were reviewed. A technique was developed for scan analysis, allowing for calculation of percent increase of activity in the region of interest (ROI, area of bleeding) and ROI in the aorta and liver (controls). Database query determined which patients underwent angiography, and which had positive angiograms. Median ROI percent increase in patients with positive scintigraphy and positive angiography was compared to those with positive scintigraphy and negative angiography. Results Of 194 bleeding scans performed during the study period, 71 were positive for active LGIB, 37 had angiography, and 9 had active contrast extravasation. The new tool was used to analyze the 37 cases with positive nuclear scans sent for angiography. Median percent increase in ROI activity was 50% in those with positive scan and positive angiogram and 26.8% in those with positive scan but negative angiogram. Using ROI percent change quartiles, we observed a statistically significant association between percent increase in ROI activity from baseline and the probability of having a positive angiogram (Cochran-Armitage trend test, P = 0.01), such that there are no positive angiogram cases when ROI change was

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123I-FP-CIT SPECT Accurately Distinguishes Parkinsonian From Cerebellar Variant of Multiple System Atrophy

imagePurpose Dopamine transporter SPECT imaging is a valuable tool to estimate the integrity of presynaptic dopaminergic pathways in degenerative parkinsonisms. Evidence about SPECT differential pattern between parkinsonian and cerebellar forms of multiple system atrophy (MSA-P and MSA-C) is lacking. We aimed at assessing whether MSA-P and MSA-C variants have a distinct semiquantitative 123I-FP-CIT SPECT pattern. Methods We studied a unicentric 13-year (2003–2016) retrospective cohort of subjects with possible or probable MSA and scanned with the same acquisition and reconstruction SPECT protocol. Age-dependent semiquantitative reference limits for striatal volumes of interest, asymmetry indices, and caudate/putamen ratio were previously established with a percentile approach on a cohort of subjects with nondegenerative conditions and normal visual scan. Results Thirty-four subjects with clinical MSA (28 MSA-P and 6 MSA-C) were identified (mean age, 68.2 ± 10.1 years; male/female ratio 1.00; disease duration, 2.5 ± 2.2 years; Movement Disorders Society Unified Parkinson's Disease Rating Scale III score, 33.8 ± 12.4). The MSA-P subjects exhibited lower uptake values for all volumes of interest, for example, striatal uptake on the more affected side (1.10 ± 0.51) compared with MSA-C (2.30 ± 0.41, P = 0.0005), as well as significantly higher asymmetry indices % (24.7 ± 24.8 vs 6.3 ± 4.5, P = 0.028) and caudate/putamen ratio (2.26 ± 1.23 vs 1.13 ± 0.17, P = 0.00148). Conclusions The MSA-P and MSA-C subjects exhibited significantly distinct semiquantitative SPECT pattern with severe uptake impairment and high asymmetry for MSA-P and borderline uptake values for MSA-C. Clinical distinction of these 2 phenotypical entities is necessary in order to evaluate SPECT potential to discriminate between degenerative parkinsonisms.

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18F-FDG PET/CT in Diagnostic and Prognostic Evaluation of Patients With Suspected Recurrence of Chondrosarcoma

imagePurpose The aim of the study was to analyze the diagnostic and prognostic utility of 18F-FDG PET/CT to predict the disease-specific survival (DSS) with FDG uptake and tumor grade in recurrent chondrosarcoma. Methods Retrospective analysis of FDG PET/CT findings in 31 previously treated patients (46 studies) with mean follow-up period of 40.7 ± 23.9 months (range, 3–77 months) from the date of first PET/CT study was done. Kaplan-Meier DSS analysis was made with respect to tumor grade, FDG uptake at the recurrent primary sites, and a combination of grade and FDG uptake as parameters. Results Recurrence (local and distant) was shown in 28 (60.8%) of 46 FDG PET/CT studies with sensitivity and specificity of 88.9% and 78.9%, respectively. The median SUVmax at the recurrent primary sites differed significantly (P = 0.008) among 3 tumor grade groups, with higher median SUVmax in higher grades. There was significant difference in median SUVmax among different grade groups except between grade II and grade III. Recurrent primary site SUVmax cutoff at 6.15 derived from the receiver operating characteristic curve yielded significant difference (P

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SUV as a Possible Predictor of Disease Extent and Therapy Duration in Complex Tuberculosis

imageObjective 18F-FDG PET/CT provides information on disease extension and activity in neoplastic and inflammatory conditions. So far, little is known about whether SUVmax of a reference lesion can allow a prognosis to be given regarding patient-specific outcome parameters in complex cases of tuberculosis (TB). Methods We retrospectively identified 37 patients (21 men, 16 women; mean age, 50.4 years) who underwent 18F-FDG PET/CT for the evaluation of active TB before treatment initiation. The aims were to examine whether the reference lesion SUVmax differed between patients with standard (≤9 months) and long-term (>9 months) therapy and to define an SUVmax cutoff distinguishing those groups. In addition, we analyzed the prognostic value of SUVmax with regard to estimation of initial disease extent and lesion distribution pattern. Results Median therapy duration was 10 months (interquartile range, 3.25 months), and median SUVmax was 8 (interquartile range, 8.54). SUVmax was significantly (P = 0.036) higher in patients treated longer than 9 months (10.1 vs 5.5). When applying a receiver operating characteristic curve analysis, an SUVmax cutoff value of 10 differentiated the standard and the long-term therapy group with a sensitivity of 50% and a specificity of 78.6% (P = 0.087). Higher SUVmax corresponded with a larger number of affected organ systems (P = 0.012 for ≤/>1). Patients with extrathoracic involvement showed significantly higher SUVmax than did patients with limited intrathoracic disease (P = 0.024) and received significantly longer antimycobacterial therapy (P = 0.011). Conclusions Reference lesion SUVmax from pretherapy 18F-FDG PET/CT may have prognostic properties in complicated cases of TB, especially regarding therapy duration and disease extent.

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Artifactual Hepatic Metastasis on FDG PET/CT Secondary to Cryoablation for Adrenal Metastasis

imageA 65-year-old woman with metastatic lung cancer was referred for CT-guided cryoablation of a right adrenal metastasis. For cryoablation, probes were placed into the adrenal region. FDG PET/CT 3 months later showed new activity in hepatic segment 6 initially suspected to be metastasis. Proximity of the hepatic lesion to the adrenal metastasis was a strange coincidence and prompted review of imaging from the cryoablation. CT showed the probe entered the liver, and postablation image demonstrated injury to the liver adjacent to the adrenal metastasis. Careful review of treatment history and imaging from ablation procedures are important to avoid this pitfall.

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Quality and Safety in Health Care, Part XXXII: Additional Outcome Predictors for Transcatheter Aortic Valve Replacement

Mortality 12 months after a transcatheter aortic valve replacement (TAVR) is partly due to a number of reasons in addition to the usual preprocedural medical patient risk factors. In patients who need a permanent pacemaker placed after the procedure, the mortality risk goes up. The death rate following a TAVR varies considerably at different institutions, and the past death rate of TAVR patients at an institution is predictive of the mortality rate of new patients having this procedure. In addition, the quality of life of the individual before the procedure is predictive of the 12-month mortality outcome after the TAVR is done.

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Subacute Cerebellar Infarction With Uptake on 68Ga–Prostate-Specific Membrane Antigen PET/CT

imageWe report a case of subacute cerebellar infarction mimicking metastasis on prostate-specific membrane antigen (PSMA) PET/CT. A 77-year-old man with prostate cancer treated with androgen deprivation therapy and radiotherapy with rising prostate-specific antigen was referred for 68Ga-PSMA PET/CT. Apart from PSMA-expressing tumor of the left prostate, PSMA PET/CT demonstrated radiotracer uptake in the right cerebellar hemisphere, corresponding to a site of subacute infarction demonstrated on an MRI of the brain performed 35 days previously. As cerebellar infarcts are considerably less common than cerebral infarcts, they may not be anticipated as a potential cause for false-positive radiotracer uptake on PSMA PET.

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Imaging of Acquired Demyelinating Syndrome With 18F-FDG PET/CT

imageAcquired demyelinating syndromes include acute disseminated encephalomyelitis, transverse myelitis and may progress to multiple sclerosis (MS). Acute disseminated encephalomyelitis is characterized by impairment of level of consciousness and multifocal neurological deficits and transverse myelitis by back pain, weakness and sphincter dysfunction. Only a few cases of acquired demyelinating syndrome have been imaged with 18F-FDG PET/CT. We present two such cases.

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Ventriculopleural Shunt Dysfunction Due to a Loculated Pleural Collection Demonstrated on SPECT/CT Imaging

imageA 35-year-old woman presented with increasing drowsiness on a background of childhood meningitis and hydrocephalus managed with a ventriculopleural shunt. Her cerebral CT and chest radiograph were unchanged from previous imaging and did not identify significant pathology. Because of clinical suspicion of cerebrospinal fluid shunt dysfunction, she was referred for a cerebrospinal fluid shunt study, which demonstrated tracer accumulation within a loculated pleural collection in the left costophrenic recess.

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Salivary Gland Activity Obscures Mandibular Metastasis of Prostate Carcinoma on 68Ga–Prostate-Specific Membrane Antigen PET

imageWe report a case of a 65-year-old man with prostate cancer; his treatment history included radical prostatectomy followed by radiation therapy and subsequent androgen deprivation therapy for more than 5 years. He currently presented with a history of rising prostate-specific antigen and complained of jaw aches. 68Ga–prostate-specific membrane antigen PET/CT study performed for suspected biochemical recurrence demonstrated vertebral lesions and lesion in his jaw. Subsequent biopsy of jaw lesion demonstrated prostate cancer metastases.

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Dilated Internal Thoracic Vertebral Venous Plexus Simulating Bone Metastases on FDG PET/CT

imageA 42-year-old woman with a newly diagnosed malignant thymoma underwent FDG PET/CT, which demonstrated an increased uptake in anterior mediastinal tumor and several pleural masses in the right hemithorax, compatible with "drop metastases." In addition, contrast-enhanced CT images showed hyperdense abnormality in T2 vertebral body, congruent with intensely increased FDG uptake, raising suspicion of skeletal metastasis. This is a rare but important potential pitfall either in CT and FDG PET/CT—a "false-positive" bony lesion not attributed to skeletal metastasis but to dilated internal thoracic vertebral venous plexus associated with collateral circulation due to superior vena cava syndrome.

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Intense 68Ga-PSMA Uptake in Diverticulum of the Sigmoid Colon

imageWe present a case of a diverticulum of the sigmoid colon with intense prostate-specific membrane antigen (PSMA) activity on 68Ga-PSMA PET/CT. CT scan and colonoscopy showed no signs of inflammation or malignancy. This case presents an addition to the collection of benign pitfalls when reporting PSMA PET/CT; however, a 68Ga-PSMA up-taking focus in the colon should always cause further examination, as malignant etiology must be ruled out.

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Cone beam CT of the musculoskeletal system: clinical applications

Abstract

Objectives

The aim of this pictorial review is to illustrate the use of CBCT in a broad spectrum of musculoskeletal disorders and to compare its diagnostic merit with other imaging modalities, such as conventional radiography (CR), Multidetector Computed Tomography (MDCT) and Magnetic Resonance Imaging.

Background

Cone Beam Computed Tomography (CBCT) has been widely used for dental imaging for over two decades.

Discussion

Current CBCT equipment allows use for imaging of various musculoskeletal applications. Because of its low cost and relatively low irradiation, CBCT may have an emergent role in making a more precise diagnosis, assessment of local extent and follow-up of fractures and dislocations of small bones and joints. Due to its exquisite high spatial resolution, CBCT in combination with arthrography may be the preferred technique for detection and local staging of cartilage lesions in small joints. Evaluation of degenerative joint disorders may be facilitated by CBCT compared to CR, particularly in those anatomical areas in which there is much superposition of adjacent bony structures. The use of CBCT in evaluation of osteomyelitis is restricted to detection of sequestrum formation in chronic osteomyelitis. Miscellaneous applications include assessment of (symptomatic) variants, detection and characterization of tumour and tumour-like conditions of bone.

Teaching Points

• Review the spectrum of MSK disorders in which CBCT may be complementary to other imaging techniques.

• Compare the advantages and drawbacks of CBCT compared to other imaging techniques.

• Define the present and future role of CBCT in musculoskeletal imaging.



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Lanthanum-Induced Mucosal Alterations in the Stomach (Lanthanum Gastropathy): a Comparative Study Using an Animal Model

Abstract

Lanthanum (La) carbonate (LC) is one of the most potent phosphate binders that prevents the elevation of serum phosphate levels in patients with end-stage renal diseases undergoing dialysis. LC binds strongly to dietary phosphate and forms insoluble complexes that pass through the gastrointestinal tract. La deposition in patients treated with LC is a recently documented finding particularly observed in gastric mucosa. We herein describe the detailed gastric mucosal lesions in 45 LC-treated patients and address the potential underlying pathologic mechanism using oral LC administration in rats. Microscopically, La deposition, as shown by subepithelial collections of plump eosinophilic histiocytes or small foreign body granulomas containing coarse granular or amorphous inclusion bodies, was found in the gastric mucosa of 44 (97.8%) of the 45 dialysis patients in the study cohort, which was most frequently associated with foveolar hyperplasia (37.8%). Using oral administration of rats with 1000 mg/day LC for 2 or more weeks, La deposition was consistently detectable in the gastric mucosa but not in other organs examined. In addition, various histologic alterations such as glandular atrophy, stromal fibrosis, proliferation of mucous neck cells, intestinal metaplasia, squamous cell papilloma, erosion, and ulcer were demonstrated in the rat model. Thus, orally administered LC can induce mucosal injury, designated here as La gastropathy, which may alter the local environment and result in La deposition in the gastric mucosa, thereby potentially inducing abnormal cell proliferation or neoplastic lesions.



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Fixed dosing of intravenous tocilizumab in rheumatoid arthritis. Results from a population pharmacokinetic analysis.

Abstract

Aim

Intravenous tocilizumab is currently dosed on body weight although a weak correlation between body weight and clearance has been described. The aim of the study was to assess the current dosing strategy and provide a scientific rational for dosing using a modeling and simulation approach.

Methods

Serum concentrations and covariates were obtained from intravenous tocilizumab treated subjects at a dose of 4, 6 or 8 mg every 28 days. A population pharmacokinetic analysis was performed using nonlinear mixed effects modeling. The final model was used to simulate tocilizumab exposure to assess a dosing strategy based on body-weight or fixed dosing, using as target a cumulative area under the curve at 24 weeks of treatment above 100 · 103 μg·h/mL.

Results

A one-compartment disposition model with parallel linear and nonlinear elimination best described the concentration–time data. The typical population mean values for clearance, apparent volume of distribution, maximum elimination rate and Michaelis-Menten constant were 0.0104 L/h, 4.83 L, 0.239 mg/h and 4.22 μg/mL, respectively. Interindividual variability was included for clearance (17.0%) and volume of distribution (30.8%). Significant covariates for clearance were patient body weight and C-reactive protein serum levels. An estimated exponent for body weight of 0.360 confirms the weak relationship with tocilizumab clearance. Simulations demonstrate that patients with lower weights are at risk of underdosing if the weight-based dosing approach is used. However, fixed-dosing provides a more consistent drug exposure regardless of weight category.

Conclusions

Our study provides evidence to support fixed dosing of intravenous tocilizumab in rheumatoid arthritis patients since it reduces variability in tocilizumab exposure among weight categories compared to the current weight-based dosing approach.



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Implementing Routine Palliative Care Consultation Prior to LVAD Implantation: A Single Center Experience

Left-ventricular assist devices (LVADs) are increasingly used to improve quality of life for end-stage heart failure patients. The Joint Commission now requires pre-implantation palliative care assessment, however many palliative care teams have little experience providing this service.

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Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition



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Comment on ‘A meta-analysis of CXCL12 expression for cancer prognosis’



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Reply to ‘Comment on ‘A meta-analysis of CXCL12 expression for cancer prognosis”



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Inside EMS Podcast: How to make 2018 the year you achieve your EMS goals

Download this podcast on iTunes, SoundCloud or via RSS feed In this Inside EMS Podcast episode, co-hosts Chris Cebollero and Kelly Grayson kick off the new year with a discussion on vision, goal setting and developing a plan to make 2018 a great year for achieving the best outcome for your personal and professional success. Learn more about the EMS1 Academy and schedule a free demo.

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Neurophysiologic characterization of periodic paralysis episode in a patient with Andersen-Tawil syndrome

Primary period paralysis (PP) are rare disorders of skeletal muscle characterized by episodic attacks of muscle weakness. These episodes can be triggered by exercise and result from abnormal muscle membrane excitability. The diagnosis is based on clinical features, positive family history, serum potassium level during episodes and response to treatment. However the diagnosis is not always straightforward since some of these features may be absent (Venance et al., 2006). Post-exercise electrophysiological testing can be useful in guiding the diagnosis, as changes in compound motor action potential (CMAP) after exercise correlate with exercise induced weakness and ion channel mutation (Fournier et al., 2004).

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The critical warning sign of real-time brainstem auditory evoked potentials during microvascular decompression for hemifacial spasm

Hemifacial spasm (HFS) presents as involuntary, intermittent spasm and is caused by facial nerve compression, secondary to arterial or venous compression at the root exit zone (REZ) (Barker et al., 1995; McLaughlin et al., 1999). Microvascular decompression (MVD) surgery, which involves relieving neurovascular compression, is a widely popular treatment for HFS (Jannetta, 1975; Barker et al., 1995). Since the vestibulocochlear nerve is directly adjacent to the facial nerve, the vestibulocochlear nerve can be damaged during MVD surgery, which could lead to hearing loss (HL) (Barker et al., 1995; Park et al., 2009).

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Predicting postoperative language outcome using presurgical fMRI, MEG, TMS, and high gamma ECoG

About 1% of people in the United States suffer from epilepsy, and one-fifth of epilepsy cases are pharmacologically intractable (Begley et al., 2000). Resection of the seizure onset zone is an effective treatment for intractable epilepsy but it carries the risk of postoperative impairment of essential brain functions, especially language. Presurgical language mapping is usually performed to minimize this risk. Cortical stimulation mapping (CSM) serves as the clinical gold standard for presurgical language mapping (Ojemann et al., 1989), though it has several limitations (Lesser et al., 1984; Blume et al., 2004; Brunner et al., 2009; Borchers et al., 2012; Wray et al., 2012; Desmurget et al., 2013; Papanicolaou et al., 2014).

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Predictors of clinical outcome of colonic stents in patients with malignant large-bowel obstruction due to extracolonic malignancy

Colonic stent placement in patients with large-bowel obstruction (LBO) secondary to extra colonic malignancy (ECM) has been evaluated in small series with heterogeneous results. Our aim is to better characterize the technical and clinical success of colonic stent placement and to identify factors that affect this success in ECM patients.

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Assessment of Peri-Polyp Biopsies of Flat Mucosa in Patients with Inflammatory Bowel Disease

When colon polyps are removed in the setting of inflammatory bowel disease (IBD) involving the large intestine, biopsies of the flat mucosa surrounding such polyps have been recommended, but there are no data to support this practice.

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Dedifferentiated liposarcoma composed predominantly of rhabdoid/epithelioid cells: a frequently misdiagnosed highly aggressive variant

Dedifferentiated liposarcoma is one of the most common sarcoma types in adults with a predilection for the retroperitoneum. We have recently encountered 6 cases of DDL composed predominantly of rounded, rhabdoid or epithelioid cells mimicking rhabdoid melanoma, epithelioid rhabdomyosarcoma or undifferentiated carcinoma. Patients were 5 males and one female aged 64 to 81 years (median, 68). Tumors originated in the retroperitoneum (n=5; 3 in the psoas muscle) and deep soft tissue of the thigh (n=1).

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Histologic and immunohistochemical differences between hereditary and sporadic diffuse gastric carcinoma

We aimed to identify histopathologic features unique in hereditary diffuse gastric cancer (HDGC) by comparing with its sporadic counterpart (SDGC). 11 patients with confirmed CDH1 mutation who were found to have HDGC in a prophylactic total gastrectomy were collected. Median age of HDGC patients was 39 years (range 24-57). All HDGC cases had intramucosal signet ring cell carcinoma. Twenty-three invasive tumor foci from 7 patients with HDGC were available for ancillary studies, and we evaluated each focus separately.

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Effective use of Twitter and Facebook in pathology practice

Social networking has become a part of daily life for most people. In the era of globalization, it has become indispensable for effective communication between friends and peers across the world. Today, social media use is not only restricted to our personal lives; it is becoming increasingly incorporated into our professional lives, as well. Social media platforms are rapidly becoming a necessary tool for medical professionals. Apt use of social media platforms can revolutionize scientific communication and collaboration.

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Prognostic Role of Tumoral PDL1 Expression and Peritumoral FoxP3+ Lymphocytes in Vulvar Melanomas

Prognostic role of PDL1 expression, CD8+ and FoxP3+ lymphocytes in vulvar melanomas has not been studied. We correlated PDL1 expression, and CD8+ and FoxP3+ immune infiltrates with clinicopathologic variables and patient outcomes in a series of 75 vulvar melanomas. Tumoral PDL1 expression (>5%) was seen in 23% of cases. By Fisher's Exact test, PDL1 expression and peritumoral FoxP3+ lymphocytes significantly correlated with less disease-specific death. By linear regression analysis, correlations between tumoral PDL1 expression with the density of tumoral CD8+ and peritumoral CD8+ lymphocytes; tumoral FoxP3+ with tumoral CD8+ lymphocytes; and peritumoral FoxP3+ with peritumoral CD8+ lymphocytes were observed.

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MVP Immunohistochemistry is a Useful Adjunct in Distinguishing Leiomyosarcoma from Leiomyoma and Leiomyoma with Bizarre Nuclei

Morphologically, distinguishing between leiomyoma (LM) and leiomyosarcoma (LMS) is not always straightforward, especially with benign variants such as bizarre leiomyoma (BLM). To identify potential markers of malignancy in uterine smooth muscle tumors, proteomic studies were performed followed by assessment of protein expression by immunohistochemistry. Archival formalin-fixed paraffin-embedded (FFPE) tissues from tumors (n=23) diagnosed as LM, BLM and LMS (using published criteria) were selected for the study.

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Tumor budding as a novel predictor of occult metastasis in cT2N0 tongue squamous cell carcinoma

Occult neck metastasis is an important prognostic factor in patients with tongue squamous cell carcinoma (TSCC) who are deemed clinically negative for neck metastasis. The purpose of this study was to identify predictive factors for occult neck metastasis arising from TSCC and to determine patient prognosis. Ninety-seven patients with cT2N0 TSCC who underwent surgical resection of their primary lesion as initial therapy were enrolled in this retrospective study. Cutoff values for depth of invasion (≥3.3 mm) and the tumor budding score (≥4) were determined using receiver operator characteristic analyses.

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Classic Hodgkin lymphoma with osseous involvement mimicking Langerhans cell histiocytosis in a child

Hodgkin lymphoma (HL) commonly presents the superficial lymphadenopathy. In addition, HL cells can arise in various organs including the liver and spleen as an extranodal lymphoma. HL in bone is unusual at the initial diagnosis, although some cases show late stage localization of lymphoma cells to bone. We report the rare case of a young patient with cranial bone classic HL, presumably originating from the skull without any involvement of lymph nodes. As the main clinical manifestation was only tumor mass in the skull without osteoscopic pain, the tentative diagnosis of Langerhans cell histiocytosis was histologically confirmed by an excisional biopsy.

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Genomic heterogeneity in primary colorectal carcinomas and their metastases: born bad or brought up a villain?

Progression of solid cancers, colorectal carcinomas among them, from their primaries to metastatic lesions traditionally is thought to proceed by a step-wise acquisition of and selection for genomic aberrations. To test if patterns of genomic aberrations would be consistent with this model, we studied ten colorectal carcinoma primary-metastasis pairs, nine with one liver metastasis each, and one with two metastases. Next generation targeted sequencing (50 gene panel) with samples obtained from different regions of the primaries and their metastases demonstrated 1–11 gene mutations per lesion.

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Short diffusion time DWI with oscillating gradient preparation as an early MRI biomarker for radiation therapy response monitoring in glioblastoma: A pre-clinical feasibility study

This study investigates DWI at very short diffusion times (Δeff) as a novel tool for radiotherapy monitoring and response detection in a glioblastoma mouse model. Using oscillating gradient diffusion MRI (OGSE) to overcome Δeff limits in conventional DWI we show that ADC mapping at short Δeff can detect radiation changes significantly earlier and more robustly than standard clinical DWI. We believe that short Δeff DWI is highly promising for radiotherapy monitoring on a cellular level.

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Improving Quality and Consistency in NRG Oncology RTOG 0631 for Spine Radiosurgery via Knowledge-Based Planning

Consistency and standardization of radiotherapy plan quality in multi-institutional clinical trials are always challenging, and non-protocol compliant radiotherapy plans have been shown to impact patient outcomes. This study aimed to use knowledge-based planning (KBP) as a method of producing high quality, consistent, protocol-compliant treatment plans, in a complex setting of spine SBRT on NRG Oncology RTOG 0631.

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Wise as an…Wait…Young as an Owl!!

The fact that outer hair cells in birds are regenerated naturally after the damage has been known for decades. Most of this knowledge has been accumulated through experiments where a bird's hair cells are deliberately and carefully damaged using a toxic agent such as noise. Scientists then observe the regeneration of hair cells in the areas of damage and an approximate return of function. The restoration of function is documented through electrophysiological measures such as the ABR as well as behavioral measures.



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Duodenal perforation caused by early migration of a biliary plastic stent: Closure with over-the-scope clip



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Yield of higher-grade neoplasia in Barrett’s esophagus with low-grade dysplasia is double in the first year following diagnosis



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“Wandering Liver” Associated to Bowel Obstruction



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Features of Adult Autoimmune Enteropathy Compared With Refractory Celiac Disease

Little is known about the features of immune-mediated non-celiac villous atrophies, such as autoimmune enteropathy (AIE). We investigated the demographic, clinical, and histologic features of adults with AIE compared to adults with refractory celiac disease type 1. We also report outcomes of treatment with open-label budesonide.

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Herbal and Dietary Supplement-induced Liver Injuries in the Spanish DILI Registry

There have been increasing reports of liver injury associated with use of herbal and dietary supplements, likely due to easy access to these products and beliefs among consumers that they are safer or more effective than conventional medications. We aimed to evaluate clinical features and outcomes of patients with herbal and dietary supplement-induced liver injuries included in the Spanish DILI Registry.

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Insightec Announces $150 Million Investment

InsightecLogo 101011 200Israeli company Insightec shared news that Koch Disruptive Technologies, a subsidiary of Koch Industries, will lead a $150 million round of investment in the company. Insightec plans to use the funds to drive commercialization of their essential tremor treatment and accelerate innovation in product development.

Read the press release > 

 

 

 

 



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MR imaging features of benign retroperitoneal paragangliomas and schwannomas

To determine whether MRI feature analysis can differentiate benign retroperitoneal extra-adrenal paragangliomas and schwannomas.

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Genoprotective, antioxidant, antifungal and anti-inflammatory evaluation of hydroalcoholic extract of wild-growing Juniperus communis L. (Cupressaceae) native to Romanian southern sub-Carpathian hills

Juniperus communis L. represents a multi-purpose crop used in the pharmaceutical, food, and cosmetic industry. Several studies present the possible medicinal properties of different Juniperus taxa native to speci...

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Visualizing Leukocyte Rolling and Adhesion in Angiotensin II-Infused Mice: Techniques and Pitfalls

This manuscript describes the use of transgenic reporter mice and different administration routes of fluorescent dyes in angiotensin II-induced hypertension using intravital video microscopy of blood vessels to evaluate the activation of immune cells and their ability to roll and adhere to the endothelium.

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“Will I Look Dumb?” When Virtual Assistants Deter Help-Seeking

Virtual assistants have become increasingly sophisticated—and more humanlike—since the days when Clippy asked if you needed help with your document. These assistants are intended to make programs and apps easier to use, but research published in Psychological Science suggests that humanlike virtual assistants may actually deter some people from seeking help on tasks that are supposed to measure achievement. Psychological Science is a journal of the Association for Psychological Science.

"We demonstrate that anthropomorphic features may not prove beneficial in online learning settings, especially among individuals who believe their abilities are fixed and who thus worry about presenting themselves as incompetent to others," says psychological scientist and study author Daeun Park of Chungbuk National University. "Our results reveal that participants who saw intelligence as fixed were less likely to seek help, even at the cost of lower performance."

Previous research has shown that people are inclined to see computerized systems as social beings with only a couple social cues. This social dynamic can make the systems seem less intimidating and more user-friendly, but Park and coauthors Sara Kim and Ke Zhang wondered whether that would be true in a context where performance matters, such as with online learning platforms.

"Online learning is an increasingly popular tool across most levels of education and most computer-based learning environments offer various forms of help, such as a tutoring system that provides context-specific help," says Park. "Often, these help systems adopt humanlike features; however, the effects of these kinds of help systems have never been tested."

In one online study, the researchers had 187 participants complete a task that supposedly measured intelligence. In the task, participants saw a group of three words (e.g., room, blood, salts) and were supposed to come up with a fourth word that related to all three (e.g., bath). On the more difficult problems, they automatically received a hint from an onscreen computer icon – some participants saw a computer "helper" with humanlike features including a face and speech bubble, whereas others saw a helper that looked like a regular computer.

Participants reported greater embarrassment and concerns about self-image when seeking help from the anthropomorphized computer versus the regular computer, but only if they believed that intelligence is a fixed, not malleable trait.

The findings indicated that a couple of anthropomorphic cues are sufficient to elicit concern about seeking help, at least for some individuals. Park and colleagues decided to test this directly in a second experiment with 171 university students.

In the experiment, the researchers manipulated how the participants thought about intelligence by having them read made-up science articles that highlighted either the stability or the malleability of intelligence. The participants completed the same kind of word problems as in the first study – this time, they freely chose whether to receive a hint from the computer "helper."

The results showed that students who were led to think about intelligence as fixed were less likely to use the hints when the helper had humanlike features than when it didn't. More importantly, they also answered more questions incorrectly. Those who were led to think about intelligence as a malleable trait showed no differences.

These findings could have implications for our performance using online learning platforms, the researchers conclude:

"Educators and program designers should pay special attention to unintended meanings that arise from humanlike features embedded online learning features," says Park. "Furthermore, when purchasing educational software, we recommend parents review not only the contents but also the way the content is delivered."

This research was supported by a research grant (General Research Fund: HKU17500715) awarded to the first author by the Hong Kong Special Administrative Region Research Grants Council.

All data and materials have been made publicly available via the Open Science Framework. The complete Open Practices Disclosure for this article can be found online. This article has received the badges for Open Data and Open Materials.



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Utilization of Stop-flow Micro-tubing Reactors for the Development of Organic Transformations

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A protocol for organic reaction screening using stop-flow micro-tubing (SFMT) reactors employing gaseous reactants and/or visible-light mediated reactions is presented.

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The first report of a 5-year period cancer registry in Greece (2009–2013): a pathology-based cancer registry

Abstract

Cancer registries are essential in health care, since they allow more accurate planning of necessary health services and evaluation of programs for cancer prevention and control. The Hellenic Society of Pathology (HSP) having recognized the lack of such information in Greece has undertaken the task of a 5-year pathology-based cancer registry in Greece (2009–2013). In this study, > 95% of all pathology laboratories in the national health system hospitals and 100% of pathology laboratories in private hospitals, as well as > 80% of private pathology laboratories have contributed their data. The most common cancer types overall were as follows: breast cancer (18.26%), colorectal cancer (15.49%), prostate cancer (13.49%), and lung cancer (10.24% of all registered cancers). In men, the most common neoplasms were as follows: prostate cancer, colorectal cancer, lung cancer, and gastric cancer. In women, the most common neoplasms were as follows: breast cancer, colorectal cancer, thyroid cancer, and lung cancer. The data on cancer burden in Greece, presented herein, fill the void of cancer information in Greece that affects health care not only nationally but Europe-wise.



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Musculoskeletal Ultrasound Liberating PRM: A Reinforcement for “Runners”, a Reminder for “Walkers” and the Last Call for “Couch Potatoes”

No abstract available

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Inability to Perform the Repeated Chair Stand Task Predicts Fall-related Injury in Older Primary Care Patients

AbstractObjectiveTo examine whether the chair stand component of the Short Physical Performance Battery (SPPB) predicts fall-related injury among older adult primary care patients.Design2-year longitudinal cohort study of 430 Boston-area primary care patients aged ≥65 years screened to be at risk for mobility decline. The three components of the SPPB (balance time, gait speed, and chair stand time) were measured at baseline. Participants reported incidence of fall-related injuries quarterly for two years. Complementary log-log discrete time hazard models were constructed to examine the hazard of fall-related injury across SPPB scores, adjusting for age, gender, race, Digit Symbol Substitution Test score, and fall history.ResultsParticipants were 68% female and 83% white, with a mean age of 76.6 (SD=7.0). A total of 137 (32%) reported a fall-related injury during the follow-up period. Overall, inability to perform the chair stand task was a significant predictor of fall-related injury (HR [hazard ratio]=2.11, 95% CI=1.23-3.62, p=0.01). Total SPPB score, gait component score, and balance component score were not predictive of fall-related injury.ConclusionInability to perform the repeated chair stand task was associated with increased hazard of an injurious fall over 2 years among a cohort of older adult primary care patients. Objective To examine whether the chair stand component of the Short Physical Performance Battery (SPPB) predicts fall-related injury among older adult primary care patients. Design 2-year longitudinal cohort study of 430 Boston-area primary care patients aged ≥65 years screened to be at risk for mobility decline. The three components of the SPPB (balance time, gait speed, and chair stand time) were measured at baseline. Participants reported incidence of fall-related injuries quarterly for two years. Complementary log-log discrete time hazard models were constructed to examine the hazard of fall-related injury across SPPB scores, adjusting for age, gender, race, Digit Symbol Substitution Test score, and fall history. Results Participants were 68% female and 83% white, with a mean age of 76.6 (SD=7.0). A total of 137 (32%) reported a fall-related injury during the follow-up period. Overall, inability to perform the chair stand task was a significant predictor of fall-related injury (HR [hazard ratio]=2.11, 95% CI=1.23-3.62, p=0.01). Total SPPB score, gait component score, and balance component score were not predictive of fall-related injury. Conclusion Inability to perform the repeated chair stand task was associated with increased hazard of an injurious fall over 2 years among a cohort of older adult primary care patients. Corresponding Author: Cristina Shea, Spaulding Hospital Cambridge, 1575 Cambridge St., Cambridge, MA 02138, Phone: 617-952-6956, Fax: 617-952-6965, sheacristina@gmail.com. Author Disclosures: There are no competing interests or financial benefits to the authors to disclose. This work was supported by the National Institute on Aging (R01 AG032052-03), Eunice Kennedy Shriver National Institute of Child Health and Human Development (1K24HD070966-01), and the National Center for Research Resources in a grant to the Harvard Clinical and Translational Science Center (1 UL1 RR025758-01). The main results of this study have been presented as a poster presentation at the 2017 American Congress of Rehabilitation Medicine conference. This study has not been previously submitted to any journal. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Sonographically Detected Transligamentous Median Nerve Branch

No abstract available

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The Adverse Effects of Se Toxicity on Inflammatory and Immune Responses in Chicken Spleens

Abstract

Selenium (Se) is an essential trace element, but excessive intake of Se could induce Se poisoning, and result in various health problems. NF-κB regulated many molecules of the immune response and the inflammatory response, and Th1/Th2 balance played a key in the regulation of immune response. The aim of this study is to investigate the role of NF-κB pathway and Th1/Th2 imbalance in the adverse influence of Se poisoning on chicken spleens. In the current study, 90 chickens were randomly divided into two groups (n = 45 per group). The chickens were maintained either on a basal diet (the control group) containing 0.2 mg/kg Se or a high supplemented diet (the Se group) containing 15 mg/kg Se for 45 days. Then, we observed the pathohistology of spleen cells and detected NO content, iNOS activity, and the expression of NF-κB, iNOS, COX-2, PTGE, IL-6, TNF-α, Foxp3, IL-4, and IFN-γ in chicken spleens. In chicken spleens of the Se group, the result showed typical characteristics of inflammation: the content of NO and the activity of iNOS were increased, and the expression of NF-κB, iNOS, COX-2, PTGE, IL-6, TNF-α, and IL-4 was enhanced and that of Foxp3 and IFN-γ was decreased. Our study showed that Se toxicity could promote inflammation via NF-κB pathway, impairing the immune function, and changing Th1/Th2 balance in the chicken spleens.



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Sample Preparation and Imaging of Exosomes by Transmission Electron Microscopy

This protocol describes the various techniques necessary for transmission electron microscopy including negative staining, ultrathin sectioning for detailed structure, and immuno-gold labelling to determine the positions of specific proteins in exosomes.

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Studying the Hypothalamic Insulin Signal to Peripheral Glucose Intolerance with a Continuous Drug Infusion System into the Mouse Brain

This protocol studies the role of chemokine (C-C motif) ligand 5 (CCL5) in the hypothalamus by delivering an antagonist, MetCCL5, into the mouse brain using a micro-osmotic pump brain infusion system. This transient inhibition of CCL5 activity interrupted hypothalamic insulin signaling, leading to glucose intolerance and peripheral systemic insulin sensitivity.

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Dedicated Afternoon Rounds for ICU Patients’ Families and Family Satisfaction With Care

Objective: It was hypothesized that adding dedicated afternoon rounds for patients' families to supplement standard family support would improve overall family satisfaction with care in a neuroscience ICU. Design: Pre- and postimplementation (pre-I and post-I) design. Setting: Single academic neuroscience ICU. Patients: Patients in the neuroscience ICU admitted for longer than 72 hours or made comfort measures only at any point during neuroscience ICU admission. Intervention: The on-service attending intensivist and a neuroscience ICU nursing leader made bedside visits to families to address concerns during regularly scheduled, advertised times two afternoons each week. Measurements and Main Results: One family member per patient during the pre-I and post-I periods was recruited to complete the Family Satisfaction in the ICU 24 instrument. Post-I respondents indicated whether they had participated in the afternoon rounds. For primary outcome, the mean pre-I and post-I composite Family Satisfaction in the ICU 24 scores (on a 100-point scale) were compared. A total of 146 pre-I (March 2013 to October 2014; capture rate, 51.6%) and 141 post-I surveys (October 2014 to December 2015; 47.2%) were collected. There was no difference in mean Family Satisfaction in the ICU 24 score between groups (pre-I, 89.2 ± 11.2; post-I, 87.4 ± 14.2; p = 0.6). In a secondary analysis, there was also no difference in mean Family Satisfaction in the ICU 24 score between the pre-I respondents and the 39.0% of post-I respondents who participated in family rounds. The mean Family Satisfaction in the ICU 24 score of the post-I respondents who reported no participation trended lower than the mean pre-I score, with fewer respondents in this group reporting complete satisfaction with emotional support (75% vs. 54%; p = 0.002), coordination of care (82% vs. 68%; p = 0.03), and frequency of communication by physicians (60% vs. 43%; p = 0.03). Conclusions: Dedicated afternoon rounds for families twice a week may not necessarily improve an ICU's overall family satisfaction. Increased dissatisfaction among families who do not or cannot participate is possible. Work was performed at Yale New-Haven Hospital, New Haven, CT. All listed authors contributed to the conception, design, execution, and writing of this article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/29S62lw). Supported by the Department of Neurology Research Fund at the Yale School of Medicine. The sources of funding had no role in study design, data collection, analyses, interpretations, and decision to submit the article for publication. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: david.hwang@yale.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Contemporary Risk Factors and Outcomes of Transfusion-Associated Circulatory Overload

Objectives: Transfusion-associated circulatory overload is characterized by hydrostatic pulmonary edema following blood transfusion. Restrictive transfusion practice may affect the occurrence and severity of transfusion-associated circulatory overload in critically ill patients. We sought to examine contemporary risk factors and outcomes for transfusion-associated circulatory overload. Design: Case-control study. Setting: Four tertiary care hospitals. Patients: We prospectively enrolled 200 patients with transfusion-associated circulatory overload identified by active surveillance and 405 controls matched by transfusion intensity. Interventions: None. Measurements and Main Results: Among 20,845 transfused patients who received 128,263 blood components from May 2015 until July 2016, transfusion-associated circulatory overload incidence was one case per 100 transfused patients. In addition to cardiovascular comorbidities, multivariable analysis identified the following independent predictors of transfusion-associated circulatory overload: acute kidney injury, emergency surgery, pretransfusion diuretic use, and plasma transfusion—the latter especially in females. Compared with matched controls, transfusion-associated circulatory overload cases were more likely to require mechanical ventilation (71% vs 49%; p

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Early Postoperative Neutrophil Gelatinase Associated Lipocalin Predicts the Development of Chronic Kidney Disease Following Liver Transplantation

AbstractBackgroundUrinary NGAL (uNGAL)-associated acute kidney injury (AKI) is common following liver transplant (LT), but whether early AKI predicts chronic kidney disease (CKD) and mortality remains uncertain.MethodsAdults with LT from 2008-2010 in a previously published prospective cohort evaluating serial uNGAL pre- and post-LT were retrospectively assessed to evaluate uNGAL as a predictor of long-term outcomes post-LT. The primary outcomes were post-LT CKD, defined as MDRD estimated glomerular filtration rate (GFR)

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Microbial contamination during kidney ex vivo normothermic perfusion

No abstract available

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Long-term Nonhuman Primate Renal Allograft Survival Without Ongoing Immunosuppression in Recipients of Delayed Donor Bone Marrow Transplantation

ABSTRACTBackgroundWe have previously reported successful induction of renal allograft tolerance in nonhuman primates (NHP) following an initial posttransplant period of conventional immunosuppression (delayed tolerance) using a nonmyeloablative conditioning regimen consisting of anti-CD154 and anti-CD8 mAbs plus equine ATG (Atgam) and donor bone marrow transplantation (DBMT). Since these reagents are not currently clinically available, the protocol was revised to be applicable to human recipients of deceased donor allografts.MethodFour cynomolgus monkeys received MHC-mismatched kidney allografts with conventional immunosuppression for 4 months. The recipients were then treated with a nonmyeloablative conditioning regimen consisting of thymoglobulin, belatacept, and DBMT. The results were compared with recipients treated with conditioning regimen consisting of Atgam and anti-CD154 mAb, with and without anti-CD8 mAb.ResultsIn 4 consecutive NHP recipients treated with the modified conditioning regimen, homeostatic recovery of CD8+ TEM was delayed until after day 20 and multilineage chimerism was successfully induced. Three of the 4 recipients achieved long-term allograft survival (>728, >540, >449 days) without ongoing maintenance immunosuppression. Posttransplant MLR showed loss of anti-donor CD8+ T cell and CD4+ IFNγ responses with expansion of CD4+FOXP3+ regulatory T cells. However, the late development of DSA in NHP recipients confirms the need for additional anti-B cell depletion with agents, such as rituximab, as has been shown in our clinical trials.ConclusionThis study provides proof of principle that induction of mixed chimerism and long-term renal allograft survival without immunosuppression after delayed donor bone marrow transplantation is possible with clinically available reagents. Background We have previously reported successful induction of renal allograft tolerance in nonhuman primates (NHP) following an initial posttransplant period of conventional immunosuppression (delayed tolerance) using a nonmyeloablative conditioning regimen consisting of anti-CD154 and anti-CD8 mAbs plus equine ATG (Atgam) and donor bone marrow transplantation (DBMT). Since these reagents are not currently clinically available, the protocol was revised to be applicable to human recipients of deceased donor allografts. Method Four cynomolgus monkeys received MHC-mismatched kidney allografts with conventional immunosuppression for 4 months. The recipients were then treated with a nonmyeloablative conditioning regimen consisting of thymoglobulin, belatacept, and DBMT. The results were compared with recipients treated with conditioning regimen consisting of Atgam and anti-CD154 mAb, with and without anti-CD8 mAb. Results In 4 consecutive NHP recipients treated with the modified conditioning regimen, homeostatic recovery of CD8+ TEM was delayed until after day 20 and multilineage chimerism was successfully induced. Three of the 4 recipients achieved long-term allograft survival (>728, >540, >449 days) without ongoing maintenance immunosuppression. Posttransplant MLR showed loss of anti-donor CD8+ T cell and CD4+ IFNγ responses with expansion of CD4+FOXP3+ regulatory T cells. However, the late development of DSA in NHP recipients confirms the need for additional anti-B cell depletion with agents, such as rituximab, as has been shown in our clinical trials. Conclusion This study provides proof of principle that induction of mixed chimerism and long-term renal allograft survival without immunosuppression after delayed donor bone marrow transplantation is possible with clinically available reagents. Correspondence author: Tatsuo Kawai, M.D., PhD., White 521, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, E-mail: TKAWAI@mgh.harvard.edu Authorship: K.H. designed and performed the experiments, analyzed the data, and wrote the manuscript. T.O. contributed to the design of experiments and interpretation of results. A.B. performed pre- and posttransplant care of the animals. S.B. designed and performed the experiments and analyzed data. M.M. performed the experiments. I.R., R.N.S., and R.B.C. performed pathological studies. A.B.C designed the study and edited the manuscript. T.K. conceived and directed the study, performed experiments, and wrote the manuscript. Disclosure: The authors have no conflicts of interest to disclose. Funding: The present work was supported in part by Grant 5U19AI102405, part of the NIH NHP Transplantation Tolerance Cooperative Study Group and sponsored by the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Canadian Foundation for Innovation. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Fifteen-Year Trends in Pediatric Liver Transplants: Split, Whole Deceased, and Living Donor Grafts

To evaluate changes in patient and graft survival for pediatric liver transplant recipients since 2002, and to determine if these outcomes vary by graft type (whole liver transplant, split liver transplant [SLT], and living donor liver transplant [LDLT]).

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Completing the Dissection in Melanoma: Increasing Decision Precision



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Dissemination of Minimally Invasive Liver Resection for Primary Malignancy: Reevaluating Effectiveness

Abstract

Background

Experiences at specialized hepatobiliary centers have demonstrated efficacy of minimally invasive liver resection, but concerns exist regarding whether these procedures would remain effective once disseminated to a broad range of clinical practices. We sought to present the first comparison of MILR and open liver resection (OLR) for primary liver malignancy from a nationally representative cancer registry.

Methods

Cases of liver and intrahepatic bile duct cancer were identified from the National Cancer Data Base Participant Use File. Mixed effects logistic regression and stratified Cox proportional hazards regression were used for analysis. A propensity score matched cohort was used as an alternative form of analysis to evaluate the robustness of results.

Results

A total of 3236 cases were analyzed from 2010 to 2011 with 2581 OLR (80%) and 655 MILR (20%). Of the variation in patient selection for MILR 28.5% was related to treatment at a specific treatment center; however, the proportion of MILR was similar among low-, medium-, and high-volume centers. Overall 90-day mortality was lower at high-volume centers (odds ratio [OR] 0.58; 95% confidence interval [CI] 0.40–0.85) compared with low-volume centers. MILR was similar to OLR in both 90-day mortality and overall survival (OR 0.9; 95% CI 0.62–1.10) and hazard ratio [HR] 0.88 (95% CI 0.72–1.07), regardless of treatment center volume.

Conclusions

MILR for primary liver malignancy is used across a variety of practice settings, with similar outcomes to OLR. While volume is associated with short-term outcomes of liver resection as a whole, this relationship is not explained by adoption of MILR at low-volume centers.



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Microscopic Venous Invasion in Pancreatic Cancer

Abstract

Background

Microscopic venous invasion (MVI) and the subsequent peripheral blood circulation of cancer cells are considered to be the primary route for systemic dissemination of pancreatic cancer.

Methods

Patients who underwent pancreatectomy for invasive ductal carcinoma of the pancreas between January 2007 and December 2015 were retrospectively reviewed. The prognostic significance of MVI was analyzed.

Results

A total of 352 patients underwent pancreatectomy for invasive ductal carcinoma of the pancreas. A pathologic examination showed MVI in 228 (64.5%) of the patients. The median survival time (MST) was 21 months for the patients with MVI and 58 months for those without MVI (p < 0.001). A multivariate analysis showed the following to be significant prognostic factors: non-administration of adjuvant chemotherapy [hazard ratio (HR) 2.37; p < 0.001], lymph node metastasis (HR 2.95; p = 0.001), CA19-9 value of 300 U/ml or higher (HR 1.70; p = 0.018), and MVI (HR 1.84; p = 0.011). The overall survival was clearly stratified into three groups; favorable (MST not reached in stage 1 or 2A without MVI; p = 0.867), moderate (30 months in stage 2A with MVI and 30 months in stage 2B without MVI; p = 0.528), and poor (19 months in stage 2B with MVI and 17 months in stage 4; p = 0.322). The differences between these three groups all were significant.

Conclusions

Approximately two-thirds of patients with radiologically resectable pancreatic cancer had MVI and were considered to have potentially systemic disease. This study identified MVI as one of the significant factors for a poor prognosis and a valuable complement of tumor-node-metastasis staging.



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Ihor R. Lemischka (1953–2017)

"Ihor loved science and life, and to him they were two sides of the same coin. As a graduate student, he cloned genes and was fascinated by pseudo-genes. As a mature scientist, he plumbed the depths of hematopoietic stem cells and development, producing papers with massive data and insights. He left us much too soon." —Phillip Sharp, Ph.D., Nobel Laureate, MIT

http://ift.tt/2CpeCRF

Mentoring the Next Generation: Brigid Hogan

Mentor-mentee relationships are essential for professional development, but developing these interpersonal skills is not often highlighted as a priority in scientific endeavors. In a yearlong series, Cell Stem Cell interviews prominent scientists who have prioritized mentorship over the years. Here, we chat with Dr. Brigid Hogan about her views.

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Think About the Environment: Cellular Reprogramming by the Extracellular Matrix

In this issue of Cell Stem Cell, Yui et al. (2018) show how tissue regeneration is driven by changes in the microenvironment. During intestinal regeneration, the epithelium is reprogrammed into a fetal state by an altered extracellular matrix (ECM), which is dependent on YAP/TAZ activation.

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Endogenous Reprogramming of Alpha Cells into Beta Cells, Induced by Viral Gene Therapy, Reverses Autoimmune Diabetes

Reprograming of endogenous mouse alpha cells into functional beta cells, which significantly delays diabetes onset in autoimmune diabetic mice, and the successful reprograming of human alpha cells into beta cells with the same strategy represent a promising way for treating type 1 diabetes.

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Self-Renewal and Lineage Transitions

2007 was a year of renewed possibilities in stem cell research. iPSCs had just been discovered, genome-wide sequencing technologies were coming online, and the ISSCR was expanding its international influence and membership. It was also the year that Cell Stem Cell published its first papers. Over a decade later, we again find ourselves eagerly anticipating the next stage in the development of the field with application of stem cell-based therapies moving closer to clinical reality, and the study of embryos and pluripotent stem cells yielding unprecedented insights into human development and disease.

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iPSC-Derived Organs In Vivo: Challenges and Promise

Transplanting iPSCs into the embryos of another species can generate functional organs for basic research and translational applications. We discuss forward-looking approaches and address key remaining challenges of generating iPSC-derived human organs in vivo.

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Alpha to Beta Cell Reprogramming: Stepping toward a New Treatment for Diabetes

Beta cell replacement strategies hold promise for permanently treating type 1 diabetes. In Cell Stem Cell, Xiao et al. restore pancreatic beta cell mass and normalize blood glucose in diabetic mice by reprogramming pancreatic alpha to beta cells using Pdx1- and Mafa-expressing adeno-associated virus infused into the pancreatic duct.

http://ift.tt/2CqxpMm

The Skin(ny) on Regenerating the Largest Organ to Save a Patient’s Life

Stem cells hold enormous potential to regenerate an entire organ for organ replacement therapy. Recently, in Nature, Hirsch et al. (2017) restored the expression of laminin-332 in epidermal stem cells isolated from an individual with junctional epidermolysis bullosa and grafted the entire skin back to save the patient's life.

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Capturing Totipotent Stem Cells

Baker and Pera review the biological and molecular characterization of cultured cells with developmental potential similar to totipotent blastomeres, and assess recent progress toward the capture and stabilization of the totipotent state in vitro.

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A Coated Sponge: Toward Neonatal Brain Repair

In this issue of Cell Stem Cell, Jinnou et al. (2018) identify a limited time window wherein neonatal brain injuries may be treated through neuroblast migration toward the injury site on radial glial fibers. Implanting a sponge coated with an adhesive factor in the injured neonatal brain supports the migration of neuroblasts and improves functional recovery.

http://ift.tt/2CScqmt

Chewing through Roots: How Leukemia Invades and Disrupts the Bone Marrow Microenvironment

The bone marrow (BM) niche is a complex microenvironment that supports healthy hematopoietic stem cells (HSCs) throughout life. In this issue of Cell Stem Cell, Duarte et al. (2018) reveal the spatio-temporal progress of leukemic cells as they invade and occupy the niche, ultimately outcompeting native HSCs.

http://ift.tt/2CqqjHG

Turning up the Heat with Therapeutic Epigenome Editing

CRISPR-Cas9 has been touted for therapeutic genome editing, but limitations include inefficient correction of disease-causing mutations and off-target mutagenesis. In the latest issue of Cell, Liao et al. show that a modified version of CRISPR-Cas9 can target and activate key therapeutic genes in vivo without altering DNA sequence identity.

http://ift.tt/2CSM97M

Assessment of piRNA biogenesis and function in testicular germ cell tumors and their precursor germ cell neoplasia in situ

Abstract

Background

Aberrant overexpression of PIWI/piRNA pathway proteins is shown for many types of tumors. Interestingly, these proteins are downregulated in testicular germ cell tumors (TGCTs) compared to normal testis tissues. Here, we used germline and TGCT markers to assess the piRNA biogenesis and function in TGCTs and their precursor germ cell neoplasia in situ (GCNIS).

Methods

We used small RNA deep sequencing, qRT-PCR, and mining public RNAseq/small RNA-seq datasets to examine PIWI/piRNA gene expression and piRNA biogenesis at four stages of TGCT development: (i) germ cells in healthy testis tissues, (ii) germ cells in testis tissues adjacent to TGCTs, (iii) GCNIS cells and (iv) TGCT cells. To this end, we studied three types of samples: (a) healthy testis, (b) testis tissues adjacent to two types of TGCTs (seminomas and nonseminomas) and containing both germ cells and GCNIS cells, as well as (c) matching TGCT samples.

Results

Based on our analyses of small RNA-seq data as well as the presence/absence of expression correlation between PIWI/piRNA pathway genes and germline or TGCT markers, we can suggest that piRNA biogenesis is intact in germ cells present in healthy adult testes, and adjacent to TGCTs. Conversely, GCNIS and TGCT cells were found to lack PIWI/piRNA pathway gene expression and germline-like piRNA biogenesis. However, using an in vitro cell line model, we revealed a possible role for a short PIWIL2/HILI isoform expressed in TGCTs in posttranscriptional regulation of the youngest members of LINE and SINE classes of transposable elements. Importantly, this regulation is also implemented without involvement of germline-like biogenesis of piRNAs.

Conclusions

Though further studies are warranted, these findings suggest that the conventional germline-like PIWI/piRNA pathway is lost in transition from germ cells to GCNIS cells.



http://ift.tt/2CFoF8i

Optimising the chick chorioallantoic membrane xenograft model of neuroblastoma for drug delivery

Abstract

Background

Neuroblastoma is a paediatric cancer that despite multimodal therapy still has a poor outcome for many patients with high risk tumours. Retinoic acid (RA) promotes differentiation of some neuroblastoma tumours and cell lines, and is successfully used clinically, supporting the view that differentiation therapy is a promising strategy for treatment of neuroblastoma. To improve treatment of a wider range of tumour types, development and testing of novel differentiation agents is essential. New pre-clinical models are therefore required to test therapies in a rapid cost effective way in order to identify the most useful agents.

Methods

As a proof of principle, differentiation upon ATRA treatment of two MYCN-amplified neuroblastoma cell lines, IMR32 and BE2C, was measured both in cell cultures and in tumours formed on the chick chorioallantoic membrane (CAM). Differentiation was assessed by 1) change in cell morphology, 2) reduction in cell proliferation using Ki67 staining and 3) changes in differentiation markers (STMN4 and ROBO2) and stem cell marker (KLF4). Results were compared to MLN8237, a classical Aurora Kinase A inhibitor. For the in vivo experiments, cells were implanted on the CAM at embryonic day 7 (E7), ATRA treatment was between E11 and E13 and tumours were analysed at E14.

Results

Treatment of IMR32 and BE2C cells in vitro with 10 μM ATRA resulted in a change in cell morphology, a 65% decrease in cell proliferation, upregulation of STMN4 and ROBO2 and downregulation of KLF4. ATRA proved more effective than MLN8237 in these assays. In vivo, 100 μM ATRA repetitive treatment at E11, E12 and E13 promoted a change in expression of differentiation markers and reduced proliferation by 43% (p < 0.05). 40 μM ATRA treatment at E11 and E13 reduced proliferation by 37% (p < 0.05) and also changed cell morphology within the tumour.

Conclusion

Differentiation of neuroblastoma tumours formed on the chick CAM can be analysed by changes in cell morphology, proliferation and gene expression. The well-described effects of ATRA on neuroblastoma differentiation were recapitulated within 3 days in the chick embryo model, which therefore offers a rapid, cost effective model compliant with the 3Rs to select promising drugs for further preclinical analysis.



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