It is difficult to predict if and when massively parallel sequencing of forensic STR loci will replace capillary electrophoresis as the new standard technology in forensic genetics. The main benefits of sequencing are increased multiplexing scales and SNP detection. There is not yet a consensus on how sequenced profiles should be reported. We present the Forensic Loci Allele Database (FLAD) service, made freely available on http://ift.tt/2oYHRnc. It offers permanent identifiers for sequenced forensic alleles (STR or SNP) and their microvariants for use in forensic allele nomenclature. Analogous to Genbank, its aim is to provide permanent identifiers for forensically relevant allele sequences. Researchers that are developing forensic sequencing kits or are performing population studies, can register on http://ift.tt/2oYHRnc and add loci and allele sequences with a short and simple application interface (API). (C) 2015 Elsevier Ireland Ltd. All rights reserved.
http://ift.tt/2o1A7TX
Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Τρίτη 4 Απριλίου 2017
Forensic Loci Allele Database (FLAD): Automatically generated, permanent identifiers for sequenced forensic alleles
Evaluation of an Epigenetic Profile for the Detection of Bladder Cancer in Patients with Hematuria
Purpose: Many patients enter the care cycle with gross or microscopic hematuria and undergo cystoscopy to rule out bladder cancer. Sensitivity of this invasive examination is limited, leaving many patients at risk for undetected cancer. To improve current clinical practice more sensitive and noninvasive screening methods should be applied. Materials and Methods: A total of 154 urine samples were collected from patients with hematuria, including 80 without and 74 with bladder cancer. DNA from cells in the urine was epigenetically profiled using 2 independent assays. Methylation specific polymerase chain reaction was performed on TWIST1. SNaPshot (TM) methylation analysis was done for different loci of OTX1 and ONECUT2. Additionally all samples were analyzed for mutation status of TERT (telomerase reverse transcriptase), PIK3CA, FGFR3 (fibroblast growth factor receptor 3), HRAS, KRAS and NRAS. Results: The combination of TWIST1, ONECUT2 (2 loci) and OTX1 resulted in the best overall performing panel. Logistic regression analysis on these methylation markers, mutation status of FGFR3, TERT and HRAS, and patient age resulted in an accurate model with 97% sensitivity, 83% specificity and an AUC of 0.93 (95% CI 0.88-0.98). Internal validation led to an optimism corrected AUC of 0.92. With an estimated bladder cancer prevalence of 5% to 10% in a hematuria cohort the assay resulted in a 99.6% to 99.9% negative predictive value. Conclusions: Epigenetic profiling using TWIST1, ONECUT2 and OTX1 results in a high sensitivity and specificity. Accurate risk prediction might result in less extensive and invasive examination of patients at low risk, thereby reducing unnecessary patient burden and health care costs.
http://ift.tt/2nItS4N
Discovery of new methylation markers to improve screening for cervical intraepithelial neoplasia grade 2/3
Background: Assessment of DNA promoter methylation markers in cervical scrapings for the detection of cervical intraepithelial neoplasia (CIN) and cervical cancer is feasible, but finding methylation markers with both high sensitivity as well as high specificity remains a challenge. In this study, we aimed to identify new methylation markers for the detection of high-grade CIN (CIN2/3 or worse, CIN2+) by using innovative genome-wide methylation analysis (MethylCap-seq). We focused on diagnostic performance of methylation markers with high sensitivity and high specificity considering any methylation level as positive. Results: MethylCap-seq of normal cervices and CIN2/3 revealed 176 differentially methylated regions (DMRs) comprising 164 genes. After verification and validation of the 15 best discriminating genes with methylation-specific PCR (MSP), 9 genes showed significant differential methylation in an independent cohort of normal cervices versus CIN2/3 lesions (p < 0.05). For further diagnostic evaluation, these 9 markers were tested with quantitative MSP (QMSP) in cervical scrapings from 2 cohorts: (1) cervical carcinoma versus healthy controls and (2) patients referred from population-based screening with an abnormal Pap smear in whom also HPV status was determined. Methylation levels of 8/9 genes were significantly higher in carcinoma compared to normal scrapings. For all 8 genes, methylation levels increased with the severity of the underlying histological lesion in scrapings from patients referred with an abnormal Pap smear. In addition, the diagnostic performance was investigated, using these 8 new genes and 4 genes (previously identified by our group: C13ORF18, JAM3, EPB41L3, and TERT). In a triage setting (after a positive Pap smear), sensitivity for CIN2+ of the best combination of genes (C13ORF18/JAM3/ANKRD18CP) (74 %) was comparable to hrHPV testing (79 %), while specificity was significantly higher (76 % versus 42 %, p <= 0.05). In addition, in hrHPV-positive scrapings, sensitivity and specificity for CIN2+ of this best-performing combination was comparable to the population referred with abnormal Pap smear. Conclusions: We identified new CIN2/3-specific methylation markers using genome-wide DNA methylation analysis. The diagnostic performance of our new methylation panel shows higher specificity, which should result in prevention of unnecessary colposcopies for women referred with abnormal cytology. In addition, these newly found markers might be applied as a triage test in hrHPV-positive women from population-based screening. The next step before implementation in primary screening programs will be validation in population-based cohorts.
http://ift.tt/2oYOkhJ
Validation of a DNA Methylation-Mutation Urine Assay to Select Patients with Hematuria for Cystoscopy
Purpose: Only 3% to 28% of patients referred to the urology clinic for hematuria are diagnosed with bladder cancer. Cystoscopy leads to high diagnostic costs and a high patient burden. Therefore, to improve the selection of patients for cystoscopy and reduce costs and over testing we aimed to validate a recently developed diagnostic urine assay. Materials and Methods: Included in study were 200 patients from a total of 3 European countries who underwent cystoscopy for hematuria, including 97 with bladder cancer and 103 with nonmalignant findings. Voided urine samples were collected prior to cystoscopy. DNA was extracted and analyzed for mutations in FGFR3, TERT and HRAS, and methylation of OTX1, ONECUT2 and TWIST1. Logistic regression was used to analyze the association between predictor variables and bladder cancer. Results: Combining the methylation and mutation markers with age led to an AUC of 0.96 (95% CI 0.92e0.99) with 93% sensitivity and 86% specificity, and an optimism corrected AUC of 0.95. The AUC was higher for T1 or greater tumors compared to Ta tumors (0.99 vs 0.93). The AUC was also higher for high grade tumors compared to low grade tumors (1.00 vs 0.93). Overall negative predictive value was 99% based on the 5% to 10% prevalence of bladder cancer in patients with hematuria. This would lead to a 77% reduction in diagnostic cystoscopy. Conclusions: Analyzing hematuria patients for the risk of bladder cancer using novel molecular markers may lead to a reduction in diagnostic cystoscopy. Combining methylation analysis (OTX1, ONECUT2 and TWIST1) with mutation analysis (FGFR3, TERT and HRAS) and patient age resulted in a validated accurate prediction model.
http://ift.tt/2oByWvs
Identification and Validation of WISP1 as an Epigenetic Regulator of Metastasis in Oral Squamous Cell Carcinoma
Lymph node (LN) metastasis is the most important prognostic factor in oral squamous cell carcinoma (OSCC) patients. However, in approximately one third of OSCC patients nodal metastases remain undetected, and thus are not adequately treated. Therefore, clinical assessment of LN metastasis needs to be improved. The purpose of this study was to identify DNA methylation biomarkers to predict LN metastases in OSCC. Genome wide methylation assessment was performed on six OSCC with (N+) and six without LN metastases (N0). Differentially methylated sequences were selected based on the likelihood of differential methylation and validated using an independent OSCC cohort as well as OSCC from The Cancer Genome Atlas (TCGA). Expression of WISP1 using immunohistochemistry was analyzed on a large OSCC cohort (n = 5204). MethylCap-Seq analysis revealed 268 differentially methylated markers. WISP1 was the highest ranking annotated gene that showed hypomethylation in the N+ group. Bisulfite pyrosequencing confirmed significant hypomethylation within the WISP1 promoter region in N+ OSCC (P = 0.03) and showed an association between WISP1 hypomethylation and high WISP1 expression (P = 0.01). Both these results were confirmed using 148 OSCC retrieved from the TCGA database. In a large OSCC cohort, high WISP1 expression was associated with LN metastasis (P = 0.05), disease-specific survival (P = 0.022), and regional disease-free survival (P = 0.027). These data suggest that WISP1 expression is regulated by methylation and WISP1 hypomethylation contributes to LN metastasis in OSCC. WISP1 is a potential biomarker to predict the presence of LN metastases. (c) 2015 Wiley Periodicals, Inc.
http://ift.tt/2o1koEi
RAB25 expression is epigenetically downregulated in oral and oropharyngeal squamous cell carcinoma with lymph node metastasis
Oral and oropharyngeal squamous cell carcinoma (OOSCC) have a low survival rate, mainly due to metastasis to the regional lymph nodes. For optimal treatment of these metastases, a neck dissection is required; however, inaccurate detection methods results in under- and over-treatment. New DNA prognostic methylation biomarkers might improve lymph node metastases detection. To identify epigenetically regulated genes associated with lymph node metastases, genome-wide methylation analysis was performed on 6 OOSCC with (pN+) and 6 OOSCC without (pN0) lymph node metastases and combined with a gene expression signature predictive for pN+ status in OOSCC. Selected genes were validated using an independent OOSCC cohort by immunohistochemistry and pyrosequencing, and on data retrieved from The Cancer Genome Atlas. A two-step statistical selection of differentially methylated sequences revealed 14 genes with increased methylation status and mRNA downregulation in pN+ OOSCC. RAB25, a known tumor suppressor gene, was the highest-ranking gene in the discovery set. In the validation sets, both RAB25 mRNA (P = 0.015) and protein levels (P = 0.012) were lower in pN+ OOSCC. RAB25 mRNA levels were negatively correlated with RAB25 methylation levels (P < 0.001) but RAB25 protein expression was not. Our data revealed that promoter methylation is a mechanism resulting in downregulation of RAB25 expression in pN+ OOSCC and decreased expression is associated with lymph node metastasis. Detection of RAB25 methylation might contribute to lymph node metastasis diagnosis and serve as a potential new therapeutic target in OOSCC.
http://ift.tt/2oYUQVT
Molecular and epigenetic features of melanomas and tumor immune microenvironment linked to durable remission to ipilimumab-based immunotherapy in metastatic patients
Background: Ipilimumab (Ipi) improves the survival of advanced melanoma patients with an incremental long-term benefit in 10-15 % of patients. A tumor signature that correlates with this survival benefit could help optimizing individualized treatment strategies. Methods: Freshly frozen melanoma metastases were collected from patients treated with either Ipi alone (n: 7) or Ipi combined with a dendritic cell vaccine (TriMixDC-MEL) (n: 11). Samples were profiled by immunohistochemistry (IHC), whole transcriptome (RNA-seq) and methyl-DNA sequencing (MBD-seq). Results: Patients were divided in two groups according to clinical evolution: durable benefit (DB; 5 patients) and no clinical benefit (NB; 13 patients). 20 metastases were profiled by IHC and 12 were profiled by RNA-and MBD-seq. 325 genes were identified as differentially expressed between DB and NB. Many of these genes reflected a humoral and cellular immune response. MBD-seq revealed differences between DB and NB patients in the methylation of genes linked to nervous system development and neuron differentiation. DB tumors were more infiltrated by CD8(+) and PD-L1(+) cells than NB tumors. B cells (CD20(+)) and macrophages (CD163(+)) co-localized with T cells. Focal loss of HLA class I and TAP-1 expression was observed in several NB samples. Conclusion: Combined analyses of melanoma metastases with IHC, gene expression and methylation profiling can potentially identify durable responders to Ipi-based immunotherapy.
http://ift.tt/2n9PvPh
Ability of an epigenetic assay to identify anterior prostate tumors based on a negative 12-core biopsy.
https://biblio.ugent.be/publication/8516972
BMP-SMAD Signaling Regulates Lineage Priming, but Is Dispensable for Self-Renewal in Mouse Embryonic Stem Cells
Naive mouse embryonic stem cells (mESCs) are in a metastable state and fluctuate between inner cell mass-and epiblast-like phenotypes. Here, we show transient activation of the BMP-SMAD signaling pathway in mESCs containing a BMP-SMAD responsive reporter transgene. Activation of the BMP-SMAD reporter transgene in naive mESCs correlated with lower levels of genomic DNA methylation, high expression of 5-methylcytosine hydroxylases Tet1/2 and low levels of DNA methyltransferases Dnmt3a/b. Moreover, naive mESCs, in which the BMP-SMAD reporter transgene was activated, showed higher resistance to differentiation. Using double Smad1; Smad5 knockout mESCs, we showed that BMP-SMAD signaling is dispensable for self-renewal in both naive and ground state. These mutant mESCs were still pluripotent, but they exhibited higher levels of DNA methylation than their wild-type counterparts and had a higher propensity to differentiate. We showed that BMP-SMAD signaling modulates lineage priming in mESCs, by transiently regulating the enzymatic machinery responsible for DNA methylation.
http://ift.tt/2o1roAS
DNA methylation profiling of primary neuroblastoma tumors using methyl-CpG-binding domain sequencing
Comprehensive genome-wide DNA methylation studies in neuroblastoma (NB), a childhood tumor that originates from precursor cells of the sympathetic nervous system, are scarce. Recently, we profiled the DNA methylome of 102 well-annotated primary NB tumors by methyl-CpG-binding domain (MBD) sequencing, in order to identify prognostic biomarker candidates. In this data descriptor, we give details on how this data set was generated and which bioinformatics analyses were applied during data processing. Through a series of technical validations, we illustrate that the data are of high quality and that the sequenced fragments represent methylated genomic regions. Furthermore, genes previously described to be methylated in NB are confirmed. As such, these MBD sequencing data are a valuable resource to further study the association of NB risk factors with the NB methylome, and offer the opportunity to integrate methylome data with other -omic data sets on the same tumor samples such as gene copy number and gene expression, also publically available.
http://ift.tt/2o1rokm
Dynamic epigenetic changes to VHL occur with sunitinib in metastatic clear cell renal cancer
Background: Genetic intratumoral heterogeneity (ITH) hinders biomarker development in metastatic clear cell renal cancer (mccRCC). Epigenetic relative to genetic ITH or the presence of consistent epigenetic changes following targeted therapy in mccRCC have not been evaluated. The aim of this study was to determine methylome/genetic ITH and to evaluate specific epigenetic and genetic changes associated with sunitinib therapy. Patients and methods: Multi-region DNA sampling performed on sequential frozen pairs of primary tumor tissue from 14 metastatic ccRCC patients, in the Upfront Sunitinib (SU011248) Therapy Followed by Surgery in Patients with Metastatic Renal Cancer: a Pilot Phase II Study (SuMR; ClinicalTrials.gov identifier: NCT01024205), at presentation (biopsy) and after 3-cycles of 50mg sunitinib (nephrectomy). Untreated biopsy and nephrectomy samples before and after renal artery ligation were controls. Ion Proton sequencing of 48 key ccRCC genes, and MethylCap-seq DNA methylation analysis was performed, data was analysed using the statistical computing environment R. Results: Unsupervised hierarchical clustering revealed complete methylome clustering of biopsy and three nephrectomy samples for each patient (14/14 patients). For mutational status, untreated biopsy and all treated nephrectomy samples clustered together in 8/13 (61.5%) patients. The only methylation target significantly altered following sunitinib therapy was VHL promoter region 7896829 which was hypermethylated with treatment (FDR=0.077, P<0.001) and consistent for all patients (pre-treatment 50% patients had VHL mutations, 14% patients VHL hypermethylation). Renal artery ligation did not affect this result. No significant differences in driver or private mutation count was found with sunitinib treatment. Conclusions: Demonstration of relative methylome homogeneity and consistent VHL hypermethylation, after sunitinib, may overcome the hurdle of ITH present at other molecular levels for biomarker research.
http://ift.tt/2oYGDYW
A genome-wide search for eigenetically regulated genes in zebra finch using MethylCap-seq and RNA-seq
expression changes. Here, we aimed at establishing a genome-wide DNA methylation map of the zebra finch genome, a model organism in neuroscience, as well as identifying putatively epigenetically regulated genes. RNA-and MethylCap-seq experiments were performed on two zebra finch cell lines in presence or absence of 5-aza-2'-deoxycytidine induced demethylation. First, the MethylCap-seq methodology was validated in zebra finch by comparison with RRBS-generated data. To assess the influence of (variable) methylation on gene expression, RNA-seq experiments were performed as well. Comparison of RNA-seq and MethylCap-seq results showed that at least 357 of the 3,457 AZA-upregulated genes are putatively regulated by methylation in the promoter region, for which a pathway analysis showed remarkable enrichment for neurological networks. A subset of genes was validated using Exon Arrays, quantitative RT-PCR and CpG pyrosequencing on bisulfite-treated samples. To our knowledge, this study provides the first genome-wide DNA methylation map of the zebra finch genome as well as a comprehensive set of genes of which transcription is under putative methylation control.
http://ift.tt/2o1sKM1
Risk score predicts high-grade prostate cancer in DNA-methylation positive, histopathologically negative biopsies
BACKGROUNDProstate cancer (PCa) diagnosis is challenging because efforts for effective, timely treatment of men with significant cancer typically result in over-diagnosis and repeat biopsies. The presence or absence of epigenetic aberrations, more specifically DNA-methylation of GSTP1, RASSF1, and APC in histopathologically negative prostate core biopsies has resulted in an increased negative predictive value (NPV) of approximate to 90% and thus could lead to a reduction of unnecessary repeat biopsies. Here, it is investigated whether, in methylation-positive men, DNA-methylation intensities could help to identify those men harboring high-grade (Gleason score7) PCa, resulting in an improved positive predictive value. METHODSTwo cohorts, consisting of men with histopathologically negative index biopsies, followed by a positive or negative repeat biopsy, were combined. EpiScore, a methylation intensity algorithm was developed in methylation-positive men, using area under the curve of the receiver operating characteristic as metric for performance. Next, a risk score was developed combining EpiScore with traditional clinical risk factors to further improve the identification of high-grade (Gleason Score 7) cancer. RESULTSCompared to other risk factors, detection of DNA-methylation in histopathologically negative biopsies was the most significant and important predictor of high-grade cancer, resulting in a NPV of 96%. In methylation-positive men, EpiScore was significantly higher for those with high-grade cancer detected upon repeat biopsy, compared to those with either no or low-grade cancer. The risk score resulted in further improvement of patient risk stratification and was a significantly better predictor compared to currently used metrics as PSA and the prostate cancer prevention trial (PCPT) risk calculator (RC). A decision curve analysis indicated strong clinical utility for the risk score as decision-making tool for repeat biopsy. CONCLUSIONSLow DNA-methylation levels in PCa-negative biopsies led to a NPV of 96% for high-grade cancer. The risk score, comprising DNA-methylation intensity and traditional clinical risk factors, improved the identification of men with high-grade cancer, with a maximum avoidance of unnecessary repeat biopsies. This risk score resulted in better patient risk stratification and significantly outperformed current risk prediction models such as PCPTRC and PSA. The risk score could help to identify patients with histopathologically negative biopsies harboring high-grade PCa. Prostate 76:1078-1087, 2016. (c) 2016 The Authors. The Prostate Published by Wiley Periodicals, Inc.
http://ift.tt/2o1ywNF
Multiple cutaneous reticulohistiocytosis with T-cell large granular lymphocyte clonopathy
Abstract
A 63-year-old Caucasian man presented with a 4-month history of disseminated asymptomatic reddish-brown papulonodular lesions. A skin biopsy showed dermal infiltration with CD68+ histiocytes, predominantly with eosinophilic cytoplasm, some with a ground-glass cytoplasm, and a small number of giant cells. The diagnosis of multiple cutaneous reticulohistiocytosis was made. Bone marrow immunophenotyping due to peripheral blood lymphocytosis revealed the presence of a monoclonal population of CD3+, CD8+ CD57+ large granular lymphocytes. The present case suggests the coexistence of multiple cutaneous reticulohistiocytosis with an underlying disorder.
http://ift.tt/2oAjcZW
Unusual clinical umbilical hernia: pitfall
Description
A 75-year-old alcoholic male patient with severe malnutrition was admitted to the hospital with the diagnosis of pneumonia. The finding of a symptomatic umbilical hernia on patient examination mandated a surgical consultation with the question of an operative hernia repair.
Clinically, the abdomen was distended with spider angiomas. Palpation of the umbilical hernia was painless. The hernia content was not reducible. A suspicious murmur (Cruveilhier-Baumgarten murmur) was identified on auscultation of the umbilicus (figure 1). The abdominal CT scan showed signs of portal hypertension. A large recanalised paraumbilical vein coursing from the left side of the portal vein through the falciform ligament and draining into a large umbilical varicose vein was visible. An enlarged right inferior epigastric vein originating from the umbilical varicose vein drained into the right femoral vein. The hernial sac contained only the umbilical varicose (figure 2A,B,C). On further investigation,...
http://ift.tt/2oAmYT9
Biologics,Biologic Response Modifiers,Biopharmaceutical.
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
http://ift.tt/2o8ab9i
Biologics,Biologic Response Modifiers,Biopharmaceutical.
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
Predictors of hearing recovery in patients with severe sudden sensorineural hearing loss
Sudden sensorineural hearing loss (SSHL) is a disease, which severely affects the patient's social and relational life. The underlying pathomechanisms have not been finally clarified yet and outcome is not pre...
http://ift.tt/2oB68TF
The T4/T3 quotient as a risk factor for differentiated thyroid cancer: a case control study
The incidence of thyroid nodules is increasing among patients in North America. Few of these nodules harbour malignancy, thus further research is required to identify predictive markers of malignant thyroid di...
http://ift.tt/2nI7J6v
Systemic therapy in the curative treatment of head and neck squamous cell cancer: a systematic review
To review the available evidence and make recommendations regarding use of systemically administered drugs in combination or in sequence with radiation (RT) and/or surgery for cure and/or organ preservation in...
http://ift.tt/2nI90dV
Recovery of Abnormal ABR in Neonates and Infants at Risk of Hearing Loss
The purpose of this retrospective study is to present the clinical experience of a single institution on the recovery of ABR thresholds in a large population of neonates and infants at risk of hearing loss. Potential prognostic factors associated with this phenomenon were also investigated. Out of 2248 high risk infants, 384 had abnormal ABR at initial hearing evaluation and 168 of them had absent ABR or a threshold ≥80 dBnHL. From this subgroup, a significant percentage showed complete or partial recovery on reexamination (32.7% and 9.3%, resp.), performed 4–6 months later. The presence of normal otoacoustic emissions was associated with the ABR restoration on reexamination. Moreover, the very young age at the initial hearing screening seems to be related to higher probabilities of false positive ABR. The potential recovery of hearing in HR infants raises concerns about the very early cochlear implantation in HR infants less than one year. Such a treatment modality should be decided cautiously and only after obtaining valid and stable objective and subjective hearing thresholds. This holds especially true for infants showing an auditory neuropathy profile, as they presented a much greater probability of ABR recovery.
http://ift.tt/2oxq5L4
Idiopathic atrophoderma of Pasini and Pierini: A case study of collagen and elastin texture by multiphoton microscopy
The diagnosis of idiopathic atrophoderma of Pasini and Pierini (IAPP) relies on typical clinical features, particularly distinctive pigmented ovular/round depressed plaques. Histologic examination often reveals no obvious changes, but patterns of collagen distribution, using multiphoton imaging and second harmonic generation can help track hidden details of tissue organization contributing to atrophy.
http://ift.tt/2oAUgkK
Topical Drug Therapies for Chronic Rhinosinusitis
Chronic rhinosinusitis is recognized as an inflammatory syndrome involving the nose and paranasal sinuses of multifactorial etiology. Research has demonstrated a complex interplay between host factors, microbiota, environmental exposures, and epigenetics resulting in chronic mucosal inflammation. The mainstay of medical therapy addresses this inflammation. In previously operated sinuses this includes topical saline and corticosteroids, reserving antibiotics for culture-directed acute exacerbations. Topical antiinflammatory therapies allow increased local concentration of drugs while minimizing side effects. Topical therapies have advanced the surgical field by improving and maintaining postoperative outcomes. The topical therapies include saline, corticosteroids, antibiotics, and antifungals.
http://ift.tt/2nC0PyO
Evolution in Visualization for Sinus and Skull Base Surgery
Rhinoscopy became a formal field of study in the mid-nineteenth century as improvements in nasal specula were made and the potent vasoconstrictive effects of cocaine on the intranasal tissues were discovered. Since then, a multitude of advances in visualization and illumination have been made. The advent of the Storz-Hopkins endoscope in the mid-twentieth century represents a culmination of efforts spanning nearly 2 centuries, and illumination has evolved concomitantly. The future of endoscopic sinus surgery may integrate developing technologies, such as 3-dimensional endoscopy, augmented reality navigation systems, and robotic endoscope holders.
http://ift.tt/2o7wAUx
Features of sinonasal hemangioma: A retrospective study of 31 cases
Although hemangiomas are common lesions of the head and neck, sinonasal hemangiomas are rare. The purpose of this study was to analyze the clinical features (sex, age, symptoms, and size and anatomical location of the lesion) and the histological findings of sinonasal hemangioma cases, to assess preoperative transarterial embolization, and to evaluate the outcome (recurrence or no recurrence) of endoscopic sinus surgery.
http://ift.tt/2oAEoP3
A case of extensive pharyngeal vascular malformation successfully treated with Kampo medicine
To present the efficacy of Japanese-traditional medicine (Kampo) for a case with vascular malformation.
http://ift.tt/2nHCAjO
IL-5-stimulated eosinophils adherent to periostin undergo stereotypic morphological changes and ADAM8-dependent migration
Summary
Background
IL-5 causes suspended eosinophils to polarize with filamentous (F)-actin and granules at one pole and the nucleus in a specialized uropod, the "nucleopod", which is capped with P-selectin glycoprotein ligand-1 (PSGL-1). IL-5 enhances eosinophil adhesion and migration on periostin, an extracellular matrix protein upregulated in asthma by type 2 immunity mediators.
Objective
Determine how the polarized morphology evolves to foster migration of IL-5-stimulated eosinophils on a surface coated with periostin.
Methods
Blood eosinophils adhering to adsorbed periostin were imaged at different time points by fluorescent microscopy, and migration of eosinophils on periostin was assayed.
Results
After 10 min in the presence of IL-5, adherent eosinophils were polarized with PSGL-1 at the nucleopod tip and F-actin distributed diffusely at the opposite end. After 30-60 min, the nucleopod had dissipated such that PSGL-1 was localized in a crescent or ring away from the cell periphery, and F-actin was found in podosome-like structures. The periostin layer, detected with monoclonal antibody Stiny-1, shown here to recognize the FAS1 4 module, was cleared in wide areas around adherent eosinophils. Clearance was attenuated by metalloproteinase inhibitors or antibodies to disintegrin metalloproteinase 8 (ADAM8), a major eosinophil metalloproteinase, previously implicated in asthma pathogenesis. ADAM8 was not found in podosome-like structures, which are associated with proteolytic activity in other cell types. Instead, immunoblotting demonstrated proteoforms of ADAM8 that lack the cytoplasmic tail in the supernatant. Anti-ADAM8 inhibited migration of IL-5-stimulated eosinophils on periostin.
Conclusions and Clinical Relevance
Migrating IL-5-activated eosinophils on periostin exhibit loss of nucleopodal features and appearance of prominent podosomes along with clearance of the Stiny-1 periostin epitope. Migration and epitope clearance are both attenuated by inhibitors of ADAM8. We propose, therefore, that eosinophils remodel and migrate on periostin-rich extracellular matrix in the asthmatic airway in an ADAM8-dependent manner, making ADAM8 a possible therapeutic target.
This article is protected by copyright. All rights reserved.
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A randomized controlled phase II clinical trial comparing ONO-4053, a novel DP1 antagonist, with a leukotriene receptor antagonist pranlukast in patients with seasonal allergic rhinitis
Abstract
Background
Prostaglandin D2 (PGD2) is primarily produced by mast cells and is contributing to the nasal symptoms including nasal obstruction and rhinorrhea.
Objective
This study aimed to evaluate the efficacy and safety of a novel PGD2 receptor 1 (DP1) antagonist, ONO-4053, in patients with seasonal allergic rhinitis (SAR).
Methods
This study was a multicenter, randomized, double-blind, parallel-group study of patients with SAR. Following a one-week period of placebo run-in, patients who met the study criteria were randomized to either the ONO-4053, leukotriene receptor antagonist pranlukast, or placebo group for a two-week treatment period. 200 patients were planned to be randomly assigned to receive ONO-4053, pranlukast, or placebo in a 2:2:1 ratio. Nasal and eye symptoms were evaluated.
Results
Both ONO-4053 and pranlukast had higher efficacy than placebo on all nasal and eye symptoms. ONO-4053 outperformed pranlukast in a total of three nasal symptom scores (T3NSS) as well as in individual scores for sneezing, rhinorrhea, and nasal itching. For T3NSS, the Bayesian posterior probabilities that pranlukast was better than placebo and ONO-4053 was better than pranlukast were 70.0% and 81.6%, respectively, suggesting that ONO-4053 has a higher efficacy compared with pranlukast. There was no safety-related issue in this study.
Conclusions
We demonstrated that the efficacy of ONO-4053 was greater than that of pranlukast with a similar safety profile. This study indicates the potential of ONO-4053 for use as a treatment for SAR (JapicCTI-142706).
This article is protected by copyright. All rights reserved.
http://ift.tt/2o0NZxm
RNase 7 downregulates TH2 cytokine production by activated human T-cells
Abstract
Background
The antimicrobial peptide (AMP) RNase 7 is constitutively expressed in the epidermis of healthy human skin and has been found to be upregulated in chronic inflammatory skin diseases such as atopic dermatitis and psoriasis. Activated T-cells in lesional skin of patients with atopic dermatitis (AD) and psoriasis (PSO) might be directly exposed to RNase 7. In addition to their antimicrobial activity immunoregulatory functions have been published for several AMPs. In this study we investigated immunoregulatory effects of the antimicrobial peptide RNase 7 on activated T-cells.
Methods
Isolated human CD3+ T-cells were stimulated with RNase 7 and screened for possible effects by mRNA microarray analysis. The results of the mRNA microarray were confirmed in isolated CD4+T-cells and in polarised TH2 cells using skin derived native RNase 7 and a recombinant ribonuclease-inactive RNase 7 mutant. Activation of GATA3 was analysed by electrophoretic mobility shift assay.
Results
Treatment of activated human CD4+ T-cells and TH2 cells with RNase 7 selectively reduced the expression of TH2 cytokines (IL-13, IL-4 and IL-5). Experiments with a ribonuclease-inactive recombinant RNase 7 mutant showed that RNase 7 ribonuclease activity is dispensable for the observed regulatory effect. We further demonstrate that CD4+T-cells from AD patients revealed a significantly less pronounced downregulation of IL-13 in response to RNase 7 compared to healthy control. Finally, we show that GATA3 activation was diminished upon cultivation of T-cells with RNase7.
Conclusion
Our data indicate that RNase 7 has immunomodulatory functions on TH2-cells and decreases the production of TH2 cytokines in the skin
This article is protected by copyright. All rights reserved.
http://ift.tt/2nCfLNl
Magnetic resonance imaging predicts chronic dizziness after benign paroxysmal positional vertigo
We aimed to evaluate the clinical implications of magnetic resonance imaging (MRI) findings in patients with benign paroxysmal positional vertigo (BPPV).
http://ift.tt/2oG4woQ
Quantitative imaging analysis of transcanal endoscopic Infracochlear approach to the internal auditory canal
A transcanal endoscopic infracochlear surgical approach to the internal auditory canal in a human temporal bone model has been described. The proportion of patients with favorable anatomy for this novel surgical technique is unknown. Herein, we perform a quantitative analysis of the infracochlear corridor to the IAC based on computed tomography.
http://ift.tt/2oAA3LJ
Prognostic factors in head and neck mucosal malignant melanoma
Source:Auris Nasus Larynx
Author(s): Şenol Çomoğlu, Beldan Polat, Mehmet Çelik, Bayram Şahin, Necati Enver, Meryem Nesil Keleş, Şule Öztürk Sarı
ObjectivePrimary mucosal malignant melanoma of the head and neck (HN-PMMM) is an aggressive and uncommon neoplasm. Herein, we present a series of 33 patients and the results of treatment, and aimed to determine prognostic factors in HN-PMMM.MethodsPatients who were diagnosed as having HN-PMMM in our reference hospital, between 2005 and 2014 were evaluated. Thirty-three of these patients who had follow-up data were included. Surgical margin status was extracted from the original pathology reports. Archived materials were retrieved for the histopathologic findings: ulceration, necrosis, lymphovascular invasion, perineural invasion, pigmentation, and presence of an in situ component. Mitotic activity was evaluated using phosphohistone H3 (PHH3) immunohistochemical staining.ResultsWe found an association of PHH3 mitotic activity with overall survival in a univariate analysis and to our knowledge, this is the first report among the available case series of HN-PMMM to evaluate mitotic activity using immunohistochemical staining. We also investigated the relationship between multicentricity and locoregional recurrence, which the authors believe is also a first.ConclusionPHH3 mitotic activity can be used a prognostic factor for head and neck mucosal malignant melanoma.
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Differenzialtherapie des fortgeschrittenen metastasierten kleinzelligen Lungenkarzinoms
Zusammenfassung
Hintergrund
Das aggressive biologische Verhalten des kleinzelligen Lungenkarzinoms (SCLC) im Sinne einer kurzen Tumorverdopplungszeit und frühen Metastasierungstendenz begründet, dass 70 % der Betroffenen bereits bei Erstdiagnose an einem fortgeschrittenen metastasierten Krankheitsstadium leiden. Die genetische Komplexität und Instabilität des SCLC sowie die frühe Selektion therapieresistenter Zelllinien bedingt eine ausgeprägte Neigung zu Rezidiven, liefert jedoch Ansatzpunkte für zielgerichtete Therapien. Insgesamt ist die Chemotherapie ein wesentliches Standbein der multimodalen und interdisziplinären Behandlung.
Material und Methoden
Die Arbeit basiert auf einer selektiven Literaturrecherche der Datenbanken PubMed und Cochrane zum Thema metastasiertes kleinzelliges Lungenkarzinom.
Ergebnisse und Schlussfolgerung
Das SCLC ist mit hohen Ansprechraten besonders chemotherapiesensibel. Die Standardtherapie in der Erstlinie stellt auch nach 25 Jahren noch die Platindoublette in Kombination mit Etoposid dar und erreicht ein Tumoransprechen von 60–70 % mit einer Komplettremissionsrate von über 30 %. Das Tumorrezidiv ist jedoch obligat. In der zweiten Therapielinie führt Topotecan zu einer Verlängerung des Überlebens und einer Verbesserung der Lebensqualität und kann äquieffektiv oral oder parenteral appliziert werden. Amrubicin und andere anthrazyklinhaltige Polychemotherapien stellen eine wirksame Therapiealternative in der Zweitlinie dar. In der Drittlinie gibt es keine validierten Strategien; häufig wird jedoch auf Kombinationen aus der Erstlinie oder Monotherapien zurückgegriffen. Die moderne zielgerichtete Tumortherapie hat bisher zu keiner etablierten Strategie geführt. Die frühzeitige Integration der supportiven und palliativmedizinischen Versorgung ist wesentlicher Bestandteil einer hohen Versorgungsqualität. Trotz differenzieller Ansätze und dem Einsatz zielgerichteter Therapien konnte in den letzten 30 Jahren kein nennenswerter Fortschritt in der Therapie der metastasierten Erkrankung erreicht werden.
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Epidemiologie des kleinzelligen Lungenkarzinoms in Deutschland
Zusammenfassung
Etwa jeder 5. bis 6. bösartige Tumor der Lunge, für den in den Krebsregistern spezifische histologische Angaben vorliegen, wird derzeit als kleinzelliges Lungenkarzinom (SCLC) diagnostiziert. In 2013 wurden bundesweit 7440 Neuerkrankungen erfasst, davon etwa 40 % bei Frauen. Der Anteil der SCLC ist zuletzt rückläufig, während derjenige der Adenokarzinome der Lunge − auch international − zunimmt. Die ungünstigere Verteilung der Tumorstadien gegenüber dem nichtkleinzelligen Lungenkarzinom (NSCLC) erklärt sich v. a. durch eine frühere Lymphknoten- und Fernmetastasierung; nur 5 % der SCLC werden in frühen Stadien (UICC I/II) diagnostiziert. Dies bedingt z. T. auch die mit einem relativen Fünfjahresüberleben von zuletzt 8,9 % (Frauen) bzw. 6,5 % (Männer) deutlich schlechtere Prognose im Vergleich zum NSCLC. Allerdings weisen auch bei vergleichbarem Tumorstadium Patienten mit SCLC etwas niedrigere Überlebensraten auf als solche mit NSCLC. Selbst über 3 Jahrzehnte zeigen sich anhand US-amerikanischer Daten nur geringe Verbesserungen in den Überlebensraten. Das SCLC gehört damit weiterhin zu den Malignomen mit der ungünstigsten Prognose.
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Psychoonkologische Versorgung von Patienten mit akuter Leukämie
Zusammenfassung
Die psychoonkologische Versorgung von Tumorpatienten ist in der onkologischen Medizin zunehmend etabliert, nicht zuletzt durch die Implementierung der S3-Leitlinie. Darüber hinaus gibt es bei der psychoonkologischen Versorgung von Patienten mit akuten Leukämien einige spezifische Besonderheiten zu berücksichtigen. In diesem Artikel werden Aspekte aufgezeigt, die Ärzte und Psychoonkologen bei der Unterstützung der Patienten beachten sollten.
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Efficacy and safety of setipiprant in seasonal allergic rhinitis: results from Phase 2 and Phase 3 randomized, double-blind, placebo- and active-referenced studies
Antagonism of chemoattractant receptor-homologous molecule on T-helper type-2 cells (CRTH2), a G-protein coupled receptor for prostaglandin D2, could be beneficial for treating allergic disorders. We present f...
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Sputum cell counts to manage prednisone-dependent asthma: effects on FEV1 and eosinophilic exacerbations
Prednisone dependence in asthma is usually described based on clinical and spirometric characteristics. It is generally believed that these patients have frequent exacerbations and lose lung function rapidly b...
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Nasal nitric oxide in allergic rhinitis in children and its relationship to severity and treatment
Nasal nitrous oxide (nNO) is increased in allergic rhinitis (AR), but not in asthma, and is a non-invasive marker for inflammation in the nasal passages.
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Consumer preferences for food allergen labeling
Food allergen labeling is an important tool to reduce risk of exposure and prevent anaphylaxis for individuals with food allergies. Health Canada released a Canadian food allergen labeling regulation (2008) an...
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Xylitol nasal irrigation in the treatment of chronic rhinosinusitis
Source:American Journal of Otolaryngology
Author(s): Lin Lin, Xinyue Tang, Jinjin Wei, Fei Dai, Guangbin Sun
ObjectiveTo evaluate the efficacy of xylitol nasal irrigation (XNI) treatment on chronic rhinosinusitis (CRS) and to investigate the effect of XNI on nasal nitric oxide (NO) and inducible nitric oxide synthase (iNOS) mRNA in maxillary sinus.Materials and methodsPatients with CRS were enrolled and symptoms were assessed by Visual Analog Scale (VAS) and Sino-Nasal Outcome Test 22 (SNOT-22). Nasal NO and iNOS mRNA in the right maxillary sinus were also examined. Then, they were treated with XNI (XNI group) or saline nasal irrigation (SNI, SNI group) for 30days, after which their symptoms were reassessed using VAS and SNOT-22, and nasal NO and iNOS mRNA in the right maxillary sinus were also reexamined.ResultsTwenty-five out of 30 patients completed this study. The scores of VAS and SNOT-22 were all reduced significantly after XNI treatment, but not after SNI. The concentrations of nasal NO and iNOS mRNA in the right maxillary sinus were increased significantly in XNI group. However, significant changes were not found after SNI treatment. Furthermore, there were statistical differences in the assessments of VAS and SNOT-22 and the contents of nasal NO and iNOS mRNA in the right maxillary sinus between two groups.ConclusionsXNI results in greater improvement of symptoms of CRS and greater enhancement of nasal NO and iNOS mRNA in maxillary sinus as compared to SNI.
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Quantitative imaging analysis of transcanal endoscopic Infracochlear approach to the internal auditory canal
Source:American Journal of Otolaryngology
Author(s): Judith Kempfle, Benjamin Fiorillo, Vivek V. Kanumuri, Samuel Barber, Albert Edge, Marybeth Cunnane, Aaron K. Remenschneider, Daniel J. Lee, Elliott D. Kozin
PurposeA transcanal endoscopic infracochlear surgical approach to the internal auditory canal in a human temporal bone model has been described. The proportion of patients with favorable anatomy for this novel surgical technique is unknown. Herein, we perform a quantitative analysis of the infracochlear corridor to the IAC based on computed tomography.Materials and methodsComputed tomography scans of adult temporal bones were measured to determine the accessibility of the IAC when using a transcanal, cochlear-sparing surgical corridor.ResultsThis approach to the IAC was feasible in 92% (35 of 38) specimens based on a minimum distance of 3mm between the basilar turn of the cochlear and the great vessels (jugular bulb and carotid artery).ConclusionsInfracochlear access to the IAC is feasible in the majority of adult temporal bones and has implications for future hearing preservation drug delivery approaches to the IAC.
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Magnetic resonance imaging predicts chronic dizziness after benign paroxysmal positional vertigo
Source:American Journal of Otolaryngology
Author(s): Wang Woon Cha, Kudamo Song, In Kyu Yu, Myoung Su Choi, Dong Sik Chang, Chin-Saeng Cho, Ho Yun Lee
ObjectivesWe aimed to evaluate the clinical implications of magnetic resonance imaging (MRI) findings in patients with benign paroxysmal positional vertigo (BPPV).MethodsA total of 120 patients diagnosed with BPPV completed MRI at the emergency room between December 2012 and June 2015 and met our criteria for inclusion in this study. Epidemiologic characteristics, the results of audio-vestibular testing, and MRI findings were retrospectively analyzed.ResultsThe most common findings were white matter hyperintensities (70.0%), sinusitis (34.2%), and brain atrophy (25.0%). There were no significant differences in MRI findings or epidemiologic characteristics according to BPPV subtype (p>0.05). A multiple regression analysis revealed that BPPV recurrence (odds ratio, 6.88; 95% confidence interval, 1.67–34.48; p=0.009) and brain atrophy (odds ratio, 4.39; 95% confidence interval, 1.11–21.28; p=0.036) were positively associated with dizziness lasting longer than 3months.ConclusionBrain atrophy was independently associated with long-lasting dizziness after BPPV. Although the mechanism is unclear, brain atrophy may have relevance to otoneurotologic disease-related changes in brain structure.
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The vagal nerve stimulation outcome, and laryngeal effect: Otolaryngologists roles and perspective
Source:American Journal of Otolaryngology
Author(s): Ahmad I. Al Omari, Firas Q. Alzoubi, Mohammad M. Alsalem, Samah K. Aburahma, Diala T. Mardini, Paul F. Castellanos
IntroductionEpilepsy is one of the most common neurologic disorders. Vagus nerve stimulation (VNS), first investigated in 1938 and subsequently studied as a potential therapy for epilepsy. The FDA approved the use of VNS in 1997 as an adjunctive non-pharmacologic symptomatic treatment option for refractory epilepsy for adults and adolescents over 12years.VNS can cause laryngeal and voice side effects that can be managed by otolaryngologists safely and effectively.ObjectivesThis study is to review the outcomes of vagal nerve stimulator (VNS) implantation in terms of the surgical procedures, complications, seizure frequency, and the clinical effect on larynx and vocal folds motion.MethodsSeries of thirty consecutive patients who had VNS implantation between 2007 and 2014 were recruited. Seizure-frequency outcome, surgical complications and device adverse effects of VNS were retrospectively reviewed. Additional evaluation included use of the Voice Handicap Index and Maximum Phonation Time (MPT) were conducted before and after the implantation.Videolaryngoscopy was used to evaluate the vocal fold mobility before and after the VNS implantation.ResultsSeizure frequency reduction over a minimum of 2years of follow up demonstrated: 100% in seizure frequency reduction in 1 patient, drastic reduction in seizure frequency (70–90%) in 9 patients, a good reduction in terms of seizure frequency (50%) in 8 patients, a 30% reduction in 5 patients, no response in 6 patients, and 1 patient had increased frequency.The most commonly reported adverse effects after VNS activation were coughing and voice changes with pitch breaks, as well as mild intermittent shortness of breath in 33% of patients. For those patients secondary supraglottic muscle tension and hyper function with reduced left vocal fold mobility were noticed on videolaryngoscopy, though none had aspiration problems.Surgical complications included a wound dehiscence in one patient (3%) which was surgically managed, minor intra-operative bleeding 3%; a superficial wound infection in one patient (3%) which was treated conservatively, none of the complications necessitated VNS removal.ConclusionsVNS appears to be an effective non-pharmacologic adjuvant therapy in patients with medically refractory seizures. With the favorable adverse-effect profile previously described, VNS is generally well tolerated and of a great benefit to such patients.Laryngeal side effects, of which hoarseness being of the greatest repetition, are the most common after the VNS implantation. VNS can affect the voice and reduced vocal cord motion on the implantation side with secondary supraglottic muscle tension.Otolaryngologists are not only capable of performing VNS implantation, but can also manage surgical complications, assess laryngeal side effects and treat them as needed.
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Parallel antibody germline gene and haplotype analyses support the validity of immunoglobulin germline gene inference and discovery
Publication date: July 2017
Source:Molecular Immunology, Volume 87
Author(s): Ufuk Kirik, Lennart Greiff, Fredrik Levander, Mats Ohlin
Analysis of antibody repertoire development and specific antibody responses important for e.g. autoimmune conditions, allergy, and protection against disease is supported by high throughput sequencing and associated bioinformatics pipelines that describe the diversity of the encoded antibody variable domains. Proper assignment of sequences to germline genes are important for many such processes, for instance in the analysis of somatic hypermutation. Germline gene inference from antibody-encoding transcriptomes, by using tools such as TIgGER or IgDiscover, has a potential to enhance the quality of such analyses. These tools may also be used to identify germline genes not previously known. In this study, we exploited such software for germline gene inference and define aspects of analysis settings and pre-existing knowledge of germline genes that affect the outcome of gene inference. Furthermore, we demonstrate the capacity of IGHJ and IGHD haplotype inference, whenever subjects are heterozygous with respect to such genes, to lend support to IGHV gene inference in general, and to the identification of novel alleles presently not recognized by germline gene reference directories. We propose that such haplotype analysis shall, whenever possible, be used in future best practice to support the outcome of germline gene inference. IGHJ-directed haplotype inference was also used to identify haplotypes not expressing some IGHV germline genes. In particular, we identified a haplotype that did not express several major germline genes such as IGHV1-8, IGHV3-9, IGHV3-15, IGHV1-18, IGHV3-21, and IGHV3-23. We envisage that haplotype analysis will provide an efficient approach to identify subjects for further studies of the link between the available immunoglobulin repertoire and outcomes of immune responses.
Graphical abstract
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Editorial Board/ Publication Information
Source:Molecular Immunology, Volume 85
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Effective nasal mask ventilation of a difficult airway in a patient with advanced salivary gland cancer
We report a case of successful nasal mask ventilation in a patient with a difficult airway and advanced salivary cancer.
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Use of the Laryngeal Mask Airway (LMA) Protector™ for shoulder surgeries in beach-chair position
The use of supraglottic airway devices in the management of airway for patients in beach-chair positions for shoulder surgeries is often appropriate and increasingly favoured over tracheal intubation due to the potential complications associated with the latter [1,2]. We report our initial experience and satisfactory performance of the Laryngeal Mask Airway (LMA) Protector™ in three patients scheduled for elective shoulder surgeries performed in beach-chair positions. Recently introduced in 2016, the LMA Protector™ is a single-use second-generation supraglottic airway device complete with a pharyngeal chamber and dual gastric access ports.
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The T4/T3 quotient as a risk factor for differentiated thyroid cancer: a case control study
Abstract
Background
The incidence of thyroid nodules is increasing among patients in North America. Few of these nodules harbour malignancy, thus further research is required to identify predictive markers of malignant thyroid disease. This study set out to understand the relationship between the levels of fT4 and fT3 and differentiated thyroid cancer.
Methods
A case-control study was conducted with 142 cases and 86 controls from the McGill University Teaching Hospitals. All patients underwent thyroid surgery. Cases were defined as patients with malignant nodules confirmed on final pathology and controls were defined as patients with benign nodules. The serological levels of TSH, fT4 and fT3 were measured preoperatively. Odds ratios were determined for each parameter and logistic regressions were calculated between markers and probability of malignancy. Additionally, fT4 values were divided by fT3 values (fT4/fT3 quotient) for each patient and an odds ratio was calculated.
Results
Amongst cases, the mean TSH was 2.25 ± 0.360U/mL, fT4 was 14.8 ± 0.689pmol/L, and fT3 was 4.65 ± 0.463pmol/L. Amongst controls, the mean TSH was 2.36 ± 1.68U/mL, fT4 was 14.3 ± 1.71pmol/L, and fT3 was 5.27 ± 0.957pmol/L. Patients in the control group were more likely to have low TSH, while patients in the case group would have high fT4 and patients in the control group were more likely to have a low fT4. The OR for patients with TSH >4.4U/mL was 2.13 (0.97, 4.65), and for patients with TSH <0.4U/mL was 0.46 (0.22, 0.95). The OR for patients with fT4 > 16pmol/L was 2.10 (1.09, 4.06), and for patients with fT4 < 10pmol/L was 0.45 (0.20, 0.98). The OR for patients with fT3 > 5.5pmol/L was 0.39 (0.14, 1.28). The OR for patients with fT3 < 3pmol/L was 1.83 (0.25, 13.69). The average fT4/fT3 was 3.39 ± 0.206 for cases and 2.93 ± 0.467 for controls. The fT4/fT3 quotient was considered high if it was >3.3 (OR =6.00 (2.94, 12.25)).
Conclusion
In this study, a direct relationship between high levels of fT4 and malignancy was uncovered. Furthermore, low levels of TSH and fT4 increased the likelihood that a nodule was benign. In this study a fT4/fT3 ratio >3.3 increased the risk of malignancy by 3.6 times (p-value =0.0013).
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A large giant cell tumor of the larynx: case report and review of the literature
Abstract
Background
Giant cell tumors (GCTs) are typically found in the metaphyseal-epiphyseal area of long bones but can also occur in the head and neck region. GCT of the larynx is a rare entity with only 42 reported cases in the international literature. Furthermore, to the best of our knowledge this is the largest laryngeal GCT reported in the literature to date. GCT of the larynx can present with dysphonia, dyspnea, and/or dysphagia and should be considered in the differential diagnosis of a neck mass.
Case presentation
This case report describes a giant cell tumor of the left thyroid cartilage in a 30-year-old man who initially presented with dysphonia and dysphagia. Computed tomography (CT) revealed a 5 × 5.7 cm mass centered on the left thyroid cartilage, which was further diagnosed by histopathology as giant cell tumour by open biopsy. The patient was counselled on treatment options and it was decided to proceed with a surgical approach. The patient consented to and successfully underwent a total laryngectomy (TL). Currently the patient has no evidence of disease at 13 months follow-up, has an optimal prosthetic voice, and is able to tolerate all textures of foods.
Conclusion
GCTs of the larynx have a good prognosis and can be treated successfully through complete resection of the tumor, negating the need for adjunctive therapy such as radiation, chemo or denosumab therapy.
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The first Canadian experience with the Afirma® gene expression classifier test
Abstract
Background
Thyroid nodules are common and often benign, although prove to be malignant upon surgical pathology in 5–15% of cases. When assessed with ultrasound-guided fine-needle aspiration (USFNA), 15–30% of the nodules yield an indeterminate result. The Afirma® gene expression classifier (AGEC) was developed to improve management of indeterminate thyroid nodules (ITNs) by classifying them as "benign" or "suspicious." Objectives were (1) to assess the performance of the AGEC in two Canadian academic medical centres (2), to search for inter-institutional variation and (3) to compare AGEC performance in Canadian versus American institutions.
Methods
We undertook a retrospective cohort study of patients with indeterminate cytopathology (Bethesda Class III or IV) as per USFNA who underwent AGEC testing. We reviewed patient demographics, cytopathological results, AGEC data and, if the patient underwent surgery, results from their final pathology.
Results
In total, we included 172 patients with Bethesda Class III or IV thyroid nodules underwent AGEC testing, 109 in Montreal, Quebec and 63 in St. John's, Newfoundland, in this study. Among the nodules sent for testing, 55% (60/109) in Montreal and 46% (29/63) in St. John's returned as "benign." None of these patients underwent surgery. On the other hand, 45% (49/109) nodules in Montreal and 54% (34/63) in St. John's were found to be "suspicious," for a total of 83 specimens. Seventy seven of these patients underwent surgery. Both in Montreal and St. John's, the final pathology yielded malignant thyroid disease in approximately 50% of the specimens categorized as "suspicious." Since 2013, no patient diagnosed with a benign nodule as per AGEC testing was found to harbor a malignant thyroid nodule on follow-up.
Conclusions
Molecular analysis is increasingly used in the management of indeterminate thyroid nodules. This study highlights the experience of two Canadian centres with AGEC testing. We found inter-institutional variability in the rate of nodules returning as "benign," however we found similar rates of confirmed malignancy in nodules returning as "suspicious." According the literature, results for AGEC testing in two Canadian institutions align with results reported in American centres.
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Predictors of hearing recovery in patients with severe sudden sensorineural hearing loss
Abstract
Background
Sudden sensorineural hearing loss (SSHL) is a disease, which severely affects the patient's social and relational life. The underlying pathomechanisms have not been finally clarified yet and outcome is not predictable.
Methods
We conducted a retrospective study in order to identify parameters that influence hearing recovery. The data base contains results of basic otoneurological tests and clinical parameters of 198 patients with idiopathic SSHL of at least 60 dB in at least four frequencies, diagnosed and treated at the University Hospital of Münster, Germany, between 1999 and 2015. Hearing recovery was measured by pure tone audiometry.
Results
Multivariate linear and logistic regression analyses indicate that the chance as well as the magnitude of hearing recovery is higher for patients with normal caloric testing than for patients with pathological caloric testing. However, for the subgroup of patients who attained a hearing recovery, the caloric testing result was not found to influence the magnitude. Instead, the magnitude was noticeably lower for patients within this subgroup who had a previous hearing loss. Furthermore, we found indications that the magnitude is higher for men than for women and that receiving a high-dose steroid therapy is associated with a higher chance and magnitude of a hearing recovery.
Conclusions
We conclude that SSHL associated with disorders of the vestibular system or previous hearing loss represent special sub-entities of SSHL that may be caused by unique pathophysiological mechanisms and are associated with worse outcome. Furthermore, our data support the importance of elevated dosage of steroids in SSHL therapy.
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Systemic therapy in the curative treatment of head and neck squamous cell cancer: a systematic review
Abstract
Objective
To review the available evidence and make recommendations regarding use of systemically administered drugs in combination or in sequence with radiation (RT) and/or surgery for cure and/or organ preservation in patients with locally advanced nonmetastatic (Stage III to IVB) squamous cell carcinoma of the head and neck (LASCCHN).
Method
Recognizing the Meta-analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) group reports have de facto guided practice since 2000, we searched for systematic reviews in the MEDLINE, EMBASE and Cochrane Database of Systematic Reviews published from January 2000 to February 2015 in reference to 4 research questions. A search was also conducted for randomized trials (RCTs) up to February 2015 not included in the meta-analyses.
Result
The MACH-NC reports, 5 additional meta-analyses, and 30 RCTs not included by MACH-NC were identified. For chemotherapy, MACH-NC findings showing improved overall survival with concomitant chemoRT did not require modification. High-dose cisplatin was most commonly studied. We confirmed this benefit with cisplatin monotherapy in patients treated with with postoperative concurrent chemoRT. Other than cetuximab, no targeted agents and radiosensitizers studied in RCTs were shown effective. TPF induction chemotherapy was superior to PF for tumor response and larynx preservation but not survival. Larynx preservation was reported with both CRT and induction chemotherapy approaches.
Conclusion
ChemoRT with cisplatin at least 40 mg/m2 per week given as radical or postoperative adjuvant remains a standard treatment approach for LASCCHN that improves overall survival but increases toxicity. 5-FU plus platinum is supported by less data but may be a reasonable alternative for patients unsuitable for cisplatin. Of note, stratification of outcomes by HPV-status was not available but outcomes for oropharynx cancer appeared similar to other subsites in chemoRT RCTs. No RCTs have yet demonstrated superiority or non-inferiority of cetuximab-RT to CRT. In view of this, cetuximab-RT is suggested only for patients not candidates for CRT. Taxane-based triplet induction chemotherapy is superior to doublets for rapid tumour downsizing and for larynx preservation, but does not improve overall survival and should be used with primary G-CSF prophylaxis. Further investigation of induction approaches for larynx preservation may be warranted.
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Assessment of Depression, Anxiety, Quality of Life, and Coping in Long-Standing Multiple Endocrine Neoplasia Type 2 Patients
Thyroid , Vol. 0, No. 0.
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Study of SHR-1210 Versus Investigator's Choice Standard Therapy for Participants With Advanced Esophageal Cancer
Interventions: Biological: SHR-1210; Drug: Docetaxel; Drug: Irinotecan
Sponsor: Jiangsu HengRui Medicine Co., Ltd.
Not yet recruiting - verified February 2017
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Cyclophosphamide and Sirolimus for the Treatment of Metastatic, RAI-refractory, Differentiated Thyroid Cancer
Interventions: Drug: Cyclophosphamide; Drug: Sirolimus
Sponsor: University of Michigan Cancer Center
Not yet recruiting - verified March 2017
http://ift.tt/2nGRgQ0
Tip Sheet: Immunotherapy Trials, Prostate Cancer Biology among Research Findings to Be Presented By Johns Hopkins Scientists
See below for brief descriptions of research scheduled for presentation by Johns Hopkins Kimmel Cancer Center and Bloomberg~Kimmel Institute for Cancer Immunotherapy scientists at the 2017 Annual Meeting of the American Association for Cancer Research, April 1 – 5 in Washington, D.C.
http://ift.tt/2nGP8rn
Tongue surgeries for pediatric obstructive sleep apnea: a systematic review and meta-analysis
Abstract
Objectives
To evaluate the international literature for studies reporting outcomes for obstructive sleep apnea (OSA) in children undergoing isolated tongue surgeries.
Methods
Two authors searched from inception through November 14, 2016 in four databases including PubMed/MEDLINE.
Results
351 studies were screened. Eleven studies (116 children) met criteria. Most children were syndromic and had craniofacial disorders, co-morbidities, or other serious medical issues. Surgeries included base-of-tongue (BOT) reduction (n = 114), tongue suspension (n = 1), and hypoglossal nerve stimulation (n = 1). The pre- and post-BOT reduction surgeries decreased apnea–hypopnea index (AHI) from a mean (M) and standard deviation (SD) of 16.9 ± 12.2/h to 8.7 ± 10.6/h (48.5% reduction) in 114 patients. Random effects modeling (109 patients) demonstrated a standardized mean difference for AHI of −0.78 (large magnitude of effect) [95% CI −1.06, −0.51], p value <0.00001. For BOT surgery in 53 non-syndromic children, the AHI decreased 59.2% from 14.0 ± 11.4 to 5.7 ± 6.7/h, while in 55 syndromic children, the AHI decreased 40.0% from 20.5 ± 19.1 to 12.3 ± 18.2/h. BOT reduction improved lowest oxygen saturation from M ± SD of 84.7 ± 7.4–87.9 ± 6.5% in 113 patients. Hypoglossal nerve stimulation and tongue-base suspension are limited to case reports.
Conclusions
Most children undergoing tongue surgeries in the literature were syndromic and had craniofacial disorders, co-morbidities, or other serious medical issues. Children with a body mass index <25 kg/m2 and non-syndromic children have had the most improvement in AHI. The specific type of surgery must be tailored to the patient. Patients with co-morbidities should undergo treatment in centers that are equipped to provide appropriate perioperative care.
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Reply to Baveye and Darnault: Useful models are simple and extendable [Biological Sciences]
Model building is the art of selecting those aspects of a process that are relevant to the question being asked. John H. Holland (1) Baveye and Darnault (2) contend that our model (3) is too simple and that we should have considered more intricate biofilm distributions and other microbes than...
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Hot spot of N2 fixation in the western tropical South Pacific pleads for a spatial decoupling between N2 fixation and denitrification [Biological Sciences]
Nitrogen (N) is the building block of life. Quantifying the sources and sinks of N to the ocean is essential for predicting its productivity and potential carbon sequestration. In his paper, Gruber (1) seeks for "elusive marine nitrogen fixation" following results from Knapp et al. (2), who measured unexpectedly low...
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Microbial competition and evolution in natural porous environments: Not that simple [Biological Sciences]
In their recent article, Coyte et al. (1) use an innovative combination of microfluidic experiments, mechanistic models, and game theory to study the impact of physical microenvironments on the activity of bacteria in porous media. The authors find that hydrodynamics can profoundly affect how bacteria compete and evolve in these...
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Correction for Lee et al., MicroRNA-10a is crucial for endothelial response to different flow patterns via interaction of retinoid acid receptors and histone deacetylases [Correction]
PHYSIOLOGY Correction for "MicroRNA-10a is crucial for endothelial response to different flow patterns via interaction of retinoid acid receptors and histone deacetylases," by Ding-Yu Lee, Ting-Er Lin, Chih-I Lee, Jing Zhou, Yi-Hsuan Huang, Pei-Ling Lee, Yu-Tsung Shih, Shu Chien, and Jeng-Jiann Chiu, which appeared in issue 8, February 21, 2017,...
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Correction to Supporting Information for Rascon et al., Geometry-induced capillary emptying [SI Correction]
APPLIED PHYSICAL SCIENCES Correction to Supporting Information for "Geometry-induced capillary emptying," by Carlos Rascón, Andrew O. Parry, and Dirk G. A. L. Aarts, which appeared in issue 45, November 8, 2016, of Proc Natl Acad Sci USA (113:12633–12636; first published October 24, 2016; 10.1073/pnas.1606217113). The authors note that on page...
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Correction for Tang et al., High-throughput screening of rare metabolically active tumor cells in pleural effusion and peripheral blood of lung cancer patients [Correction]
APPLIED BIOLOGICAL SCIENCES, ENGINEERING Correction for "High-throughput screening of rare metabolically active tumor cells in pleural effusion and peripheral blood of lung cancer patients," by Yin Tang, Zhuo Wang, Ziming Li, Jungwoo Kim, Yuliang Deng, Yan Li, James R. Heath, Wei Wei, Shun Lu, and Qihui Shi, which appeared in...
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Species richness alone does not predict cultural ecosystem service value [Sustainability Science]
Many biodiversity-ecosystem services studies omit cultural ecosystem services (CES) or use species richness as a proxy and assume that more species confer greater CES value. We studied wildflower viewing, a key biodiversity-based CES in amenity-based landscapes, in Southern Appalachian Mountain forests and asked (i) How do aesthetic preferences for wildflower...
http://ift.tt/2nZbRBR
In vivo optophysiology reveals that G-protein activation triggers osmotic swelling and increased light scattering of rod photoreceptors [Neuroscience]
The light responses of rod and cone photoreceptors have been studied electrophysiologically for decades, largely with ex vivo approaches that disrupt the photoreceptors' subretinal microenvironment. Here we report the use of optical coherence tomography (OCT) to measure light-driven signals of rod photoreceptors in vivo. Visible light stimulation over a 200-fold...
http://ift.tt/2oWvGqV
Numerosity representation is encoded in human subcortex [Psychological and Cognitive Sciences]
Certain numerical abilities appear to be relatively ubiquitous in the animal kingdom, including the ability to recognize and differentiate relative quantities. This skill is present in human adults and children, as well as in nonhuman primates and, perhaps surprisingly, is also demonstrated by lower species such as mosquitofish and spiders,...
http://ift.tt/2nZih3S
Ena/VASP proteins regulate activated T-cell trafficking by promoting diapedesis during transendothelial migration [Immunology and Inflammation]
Vasodilator-stimulated phosphoprotein (VASP) and Ena-VASP–like (EVL) are cytoskeletal effector proteins implicated in regulating cell morphology, adhesion, and migration in various cell types. However, the role of these proteins in T-cell motility, adhesion, and in vivo trafficking remains poorly understood. This study identifies a specific role for EVL and VASP in...
http://ift.tt/2oWpijh
Recurrent rewiring and emergence of RNA regulatory networks [Biochemistry]
Alterations in regulatory networks contribute to evolutionary change. Transcriptional networks are reconfigured by changes in the binding specificity of transcription factors and their cognate sites. The evolution of RNA–protein regulatory networks is far less understood. The PUF (Pumilio and FBF) family of RNA regulatory proteins controls the translation, stability, and...
http://ift.tt/2oWxn7W
Sensing relative signal in the Tgf-{beta}/Smad pathway [Systems Biology]
How signaling pathways function reliably despite cellular variation remains a question in many systems. In the transforming growth factor-β (Tgf-β) pathway, exposure to ligand stimulates nuclear localization of Smad proteins, which then regulate target gene expression. Examining Smad3 dynamics in live reporter cells, we found evidence for fold-change detection. Although...
http://ift.tt/2oWvGap
Inositol phosphates and phosphoinositides activate insulin-degrading enzyme, while phosphoinositides also mediate binding to endosomes [Biochemistry]
Insulin-degrading enzyme (IDE) hydrolyzes bioactive peptides, including insulin, amylin, and the amyloid β peptides. Polyanions activate IDE toward some substrates, yet an endogenous polyanion activator has not yet been identified. Here we report that inositol phosphates (InsPs) and phosphatdidylinositol phosphates (PtdInsPs) serve as activators of IDE. InsPs and PtdInsPs interact...
http://ift.tt/2nZdteT
Discovery of scmR as a global regulator of secondary metabolism and virulence in Burkholderia thailandensis E264 [Microbiology]
Bacteria produce a diverse array of secondary metabolites that have been invaluable in the clinic and in research. These metabolites are synthesized by dedicated biosynthetic gene clusters (BGCs), which assemble architecturally complex molecules from simple building blocks. The majority of BGCs in a given bacterium are not expressed under normal...
http://ift.tt/2oWi8f4
EGF and NRG induce phosphorylation of HER3/ERBB3 by EGFR using distinct oligomeric mechanisms [Biochemistry]
Heteromeric interactions between the catalytically impaired human epidermal growth factor receptor (HER3/ERBB3) and its catalytically active homologs EGFR and HER2 are essential for their signaling. Different ligands can activate these receptor pairs but lead to divergent signaling outcomes through mechanisms that remain largely unknown. We used stochastic optical reconstruction microscopy...
http://ift.tt/2oWgPwy
BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon [Neuroscience]
The ability of lysosomes to move within the cytoplasm is important for many cellular functions. This ability is particularly critical in neurons, which comprise vast, highly differentiated domains such as the axon and dendrites. The mechanisms that control lysosome movement in these domains, however, remain poorly understood. Here we show...
http://ift.tt/2oWrdVf
Ion and inhibitor binding of the double-ring ion selectivity filter of the mitochondrial calcium uniporter [Biochemistry]
The calcium (Ca2+) uniporter of mitochondria is a holocomplex consisting of the Ca2+-conducting channel, known as mitochondrial calcium uniporter (MCU), and several accessory and regulatory components. A previous electrophysiology study found that the uniporter has high Ca2+ selectivity and conductance and this depends critically on the conserved amino acid sequence...
http://ift.tt/2nZ9RcK
Activin-A co-opts IRF4 and AhR signaling to induce human regulatory T cells that restrain asthmatic responses [Immunology and Inflammation]
Type 1 regulatory T (Tr1) cells play a pivotal role in restraining human T-cell responses toward environmental allergens and protecting against allergic diseases. Still, the precise molecular cues that underlie their transcriptional and functional specification remain elusive. Here, we show that the cytokine activin-A instructs the generation of CD4+ T...
http://ift.tt/2nZoxIZ
Three-dimensional culture system identifies a new mode of cetuximab resistance and disease-relevant genes in colorectal cancer [Cell Biology]
We previously reported that single cells from a human colorectal cancer (CRC) cell line (HCA-7) formed either hollow single-layered polarized cysts or solid spiky masses when plated in 3D in type-I collagen. To begin in-depth analyses into whether clonal cysts and spiky masses possessed divergent properties, individual colonies of each...
http://ift.tt/2oWg9ay
Common nonmutational NOTCH1 activation in chronic lymphocytic leukemia [Medical Sciences]
Activating mutations of NOTCH1 (a well-known oncogene in T-cell acute lymphoblastic leukemia) are present in ∼4–13% of chronic lymphocytic leukemia (CLL) cases, where they are associated with disease progression and chemorefractoriness. However, the specific role of NOTCH1 in leukemogenesis remains to be established. Here, we report that the active intracellular...
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Feasibility, reliability, and validity of the Japanese version of the 12-item World Health Organization Disability Assessment Schedule-2 in preoperative patients
Abstract
Purpose
The avoidance of postoperative functional disability is one of the most important concerns of patients facing surgery, but methods to evaluate disability have not been definitively established. The aim of our study was to evaluate the feasibility, reliability, and validity of the Japanese version of the 12-item World Health Organization Disability Assessment Schedule-2 (WHODAS 2.0-J) in preoperative patients.
Methods
Individuals aged ≥55 years who were scheduled to undergo surgery in a tertiary-care hospital in Japan between April 2016 and September 2016 were eligible for enrolment in the study. All patients were assessed preoperatively using the WHODAS 2.0-J, the 8-Item Short Form (SF-8) questionnaire, and the Tokyo Metropolitan Institute of Gerontology Index (TMIG Index). The feasibility, reliability, and validity of WHODAS2.0-J were evaluated using response rate, Cronbach's alpha (a measure of reliability), and the correlation between the WHODAS 2.0-J and the SF-8 questionnaire and TMIG Index, respectively.
Results
A total of 934 patients were enrolled in the study during the study period, of whom 930 completed the WHODAS 2.0-J (response rate 99.5%) preoperatively. Reliability and validity were assessed in the 898 patients who completed all three assessment tools (WHODAS 2.0-J, SF-8 questionnaire, and TMIG Index) and for whom all demographic data were available. Cronbach's alpha was 0.92. The total score of the WHODAS 2.0-J showed a mild or moderate correlation with the SF-8 questionnaire and TMIG Index (r = −0.63 to −0.34).
Conclusion
The WHODAS 2.0-J is a feasible, reliable, and valid instrument for evaluating preoperative functional disability in surgical patients.
http://ift.tt/2nUcDyc
Patients with Lung Cancers Responsive to Immunotherapy Drug Beat Standard Odds of Survival
More than seven years after the start of one of the first clinical trials of the immunotherapy drug nivolumab, researchers at the Johns Hopkins Kimmel Cancer Center report that the five-year survival estimate for a limited subset of people with advanced nonsmall cell lung cancer taking the drug is 16 percent, compared with a historical survival rate for that group of 1 to 4 percent.
http://ift.tt/2n7ZZi1
AhR mediates an anti-inflammatory feed-back mechanism in human Langerhans cells involving FcεRI and IDO
Abstract
Background
Aryl hydrocarbon receptor (AhR), an important regulator of immune responses, is activated by UVB irradiation in the skin. Langerhans cells (LC) in the epidermis of atopic dermatitis (AD) patients carry the high affinity receptor for IgE, FcεRI, and are crucially involved in the pathogenesis of AD by inducing inflammatory responses and regulating tolerogenic processes.
Objectives
We investigated AhR and AhR repressor (AhRR) expression and functional consequences of AhR activation in human ex vivo skin cells and in in vitro generated LC.
Methods
Epidermal cells from healthy skin were analyzed for their expression of AhR and AhRR. LC generated from CD34+ hematopoietic stem cells (CD34LC) were treated with the UV photoproduct and AhR ligand 6-formylindolo[3,2-b]carbazole (FICZ). Cell surface receptors, transcription factors and the tolerogenic tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) were analyzed using flow cytometry and quantitative PCR.
Results
Epidermal LC and CD34LC express AhR and AhRR. AhR was also found in keratinocytes, which lack AhRR. AhR activation of LC by FICZ caused down-regulation of FcεRI in CD34LC without affecting their maturation. AhR-mediated regulation of FcεRI did not involve any known transcription factors related to this receptor. Furthermore, we could show up-regulation of IDO mediated by AhR engagement.
Conclusions
Our study shows that AhR activation by FICZ reduces FcεRI and up-regulates IDO expression in LC. This AhR-mediated anti-inflammatory feedback mechanism may dampen the allergen-induced inflammation in AD.
This article is protected by copyright. All rights reserved.
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Repairing Inconsistent Answer Set Programs Using Rules of Thumb: a Gene Regulatory Networks Case Study
Answer set programming is a form of declarative programming that can be used to elegantly model various systems. When the available knowledge about these systems is imperfect, however, the resulting programs can be inconsistent. In such cases, it is of interest to find plausible repairs, i.e.~plausible modifications to the original program that ensure the existence of at least one answer set. Although several approaches to this end have already been proposed, most of them merely find a repair which is in some sense minimal. In many applications, however, expert knowledge is available which could allow us to identify better repairs. In particular, we consider the scenario where this expert knowledge is formulated as rules of thumb, but no training data is available to learn how these rules of thumb interact. The main question we address in this paper is whether we can then still aggregate the rules of thumb in a useful way. In addition to standard aggregation techniques, we present a novel statistical approach that assigns weights to these rules of thumb, by sampling, in a particular way, from a pool of possible repairs. In particular, we evaluate how frequently each given rule of thumb is violated in the sample of repairs, and use the Z-score of this distribution to set the weight of that rule. We analyze the potential of using expert knowledge in this way, by focusing on a specific case study: Gene Regulatory Networks. We describe the rules of thumb that express available expert knowledge from the biological literature and explain how they can be encoded while repairing inconsistencies. Finally, we experimentally compare the proposed repair strategies using rules of thumb against the baseline strategy of identifying minimal repairs.
http://ift.tt/2n7Oy9O
Bone marrow myeloid cells in regulation of multiple myeloma progression
Abstract
Survival, growth, and response to chemotherapy of cancer cells depends strongly on the interaction of cancer cells with the tumor microenvironment. In multiple myeloma, a cancer of plasma cells that localizes preferentially in the bone marrow, the microenvironment is highly enriched with myeloid cells. The majority of myeloid cells are represented by mature and immature neutrophils. The contribution of the different myeloid cell populations to tumor progression and chemoresistance in multiple myeloma is discussed.
http://ift.tt/2nS0Ct3
THE ETV5 ONCOGENE IS A TARGET OF ACTIVATED ALK SIGNALING IN NEUROBLASTOMA
Neuroblastoma (NB) is an aggressive childhood cancer arising from sympatho-adrenergic neuronal progenitors. Current survival rates are still disappointingly low and novel therapeutic venues are needed to improve them. Mutant ALK is currently the most prominent druggable target being present in 10% of NB patients. Unfortunately, in most instances targeted therapies with single compounds lead to resistance and relapse. Therefore, deeper insights into the ALK downstream pathway is critical to understand resistance mechanisms and to identify additional targets for combination therapy. As part of a broader study aimed at dissecting downstream ALK signaling, we observed robust regulation of the oncogene ETV5 in multiple NB cell lines through the ALK-activated RAS/MAPK-axis. Further functional analysis revealed that ALK-mutated NB cell lines depend on ETV5 for proliferation, invasion and colony formation. The effect of ETV5 on proliferation was further supported by mouse xenografts for a NB cell line with stable ETV5 knock-down. Next, transcriptome profiling of both ETV5 knock-down cell lines and xenografts revealed an ETV5 signature which (1) identified patients with poor overall survival, (2) was enriched for an Ewing sarcoma gene signature, suggesting a possible common perturbed gene regulatory pathway and (3) contained CXCR4, an important mediator of invasion and metastasis, and TRIM67, a negative regulator of the RAS-pathway, as possible ETV5 targets. Taken together, we identified ETV5 as an important ALK-MAPK target gene impacting on the ALK driven oncogenic phenotype with CXCR4 and TRIM67 as putative ETV5 effectors which may explain aggressive behaviour and therapy resistance of NB cells.
http://ift.tt/2nTJlzC
Cognitive Style and Business Process Model Understanding
Several factors influence the level of business process model understanding. In this paper, we investigate two personal factors that potentially relate to this level: a reader's cognitive style and theoretical knowledge on business process (BP) modeling. An experiment with 183 graduate students was conducted to explore their differences in cognitive styles using Cognitive Style Index (CSI) and how these relate to their scores in process model understandability. We used two real-life BPMN collaboration diagrams as our process models in our experiment. The results indicate a significant difference between intuitive and analytic students with respect to the level of BP model understandability. The relation between students' theoretical BP modeling and notation competency, and their level of model understanding is also found significant.
http://ift.tt/2nAAnpm
Distracted Driving Awareness Events to Educate People about the Dangers of Losing Attention behind the Wheel
As part of the Maryland Trauma System distracted driving awareness statewide initiative, Johns Hopkins Health System Trauma Centers will host events to educate people about the dangers of distracted driving. The events are free and open to the public.
http://ift.tt/2nAlHqk
lncRNA discovery in the HIV replication cycle adds new layer in HIV-host interplay
Studying the effects of HIV infection on the host transcriptome has typically focused on protein-coding genes. However, recent advances in the field of RNA sequencing revealed that long non-coding RNAs (lncRNAs) add an extensive additional layer to the cell's molecular network and are crucial for normal cellular function. lncRNAs exert the ability to control a wide range of (post-)transcriptional processes and offer unique possibilities for pathogens like HIV to hijack the cellular machinery and reshape gene expression in their favor. Therefore, lncRNA discovery can result in new insights into the HIV-host interplay. We performed transcriptome profiling throughout a characterized primary HIV infection in vitro to investigate lncRNA expression at the different HIV replication cycle processes (reverse transcription, integration and particle production). Subsequently, guilt-by-association, transcription factor and co-expression analysis were performed to infer biological roles for the lncRNAs identified in the HIV-host interplay. Throughout the HIV replication cycle we identified 387 lncRNAs that were differentially expressed with the majority observed at the viral integration phase. Many of these lncRNAs (173) were suggested to play a role in mechanisms at the heart of HIV-host interplay that rely on proteasomal and ubiquitination pathways (113), apoptosis inhibition (12), BRCA1/2 DNA damage responses and ATR cell cycle regulation (12). Through transcription factor binding analysis, we found that lncRNAs display a distinct transcriptional regulation profile (ao. TAF1/3/7, CHD1 and AT3) as compared to protein coding mRNAs (ao. KLF4, SUZ12 and SOX2), suggesting that mRNAs and lncRNAs are independently modulated during HIV replication. In addition, we identified five differentially expressed lncRNA-mRNA pairs with mRNA involvement in HIV pathogenesis with possible cis regulatory lncRNAs that control nearby mRNA expression and function (ao. lnc-HES5-1 and TNFRSF14). Altogether, the present study demonstrates that lncRNAs add a new dimension to the HIV-host interplay and exhibit an independent transcriptionally regulated response. These identified lncRNAs are involved in viral and antiviral response pathways and should be further investigated as they may represent possible biomarkers or targets for controlling HIV replication.
http://ift.tt/2oVnJCm
Waiting time variation in Early Intervention Psychosis services: longitudinal evidence from the SEPEA naturalistic cohort study
Kirkbride, JB; Hameed, Y; Wright, L; Russell, K; Knight, C; Perez, J; Jones, PB; (2017) Waiting time variation in Early Intervention Psychosis services: longitudinal evidence from the SEPEA naturalistic cohort study. Social Psychiatry and Psychiatric Epidemiology 10.1007/s00127-017-1343-7 . (In press). Green open access
http://ift.tt/2oVp6kj
High mortality among tuberculosis patients on treatment in Nigeria: A retrospective cohort study
Adamu, AL; Gadanya, MA; Abubakar, IS; Jibo, AM; Bello, MM; Gajida, AU; Babashani, MM; Adamu, AL; Gadanya, MA; Abubakar, IS; Jibo, AM; Bello, MM; Gajida, AU; Babashani, MM; Abubakar, I; - view fewer (2017) High mortality among tuberculosis patients on treatment in Nigeria: A retrospective cohort study. BMC Infectious Diseases , 17 , Article 170. 10.1186/s12879-017-2249-4 . Green open access
http://ift.tt/2nYajrM
Evaluation of stiffness feedback for hard nodule identification on a phantom silicone model
Li, M; Konstantinova, J; Xu, G; He, B; Aminzadeh, V; Xie, J; Wurdemann, H; Li, M; Konstantinova, J; Xu, G; He, B; Aminzadeh, V; Xie, J; Wurdemann, H; Althoefer, K; - view fewer (2017) Evaluation of stiffness feedback for hard nodule identification on a phantom silicone model. PLOS ONE , 12 (3) , Article e0172703. 10.1371/journal.pone.0172703 . Green open access
http://ift.tt/2oVp6AP
A Review of Dynamic Datasets for Facial Expression Research
Krumhuber, EG; Skora, L; Küster, D; Fou, L; (2016) A Review of Dynamic Datasets for Facial Expression Research. Emotion Review 10.1177/1754073916670022 . (In press).
http://ift.tt/2nYnmZW
Image quality transfer and applications in diffusion MRI
Alexander, DC; Zikic, D; Ghosh, A; Tanno, R; Wottschel, V; Zhang, J; Kaden, E; Alexander, DC; Zikic, D; Ghosh, A; Tanno, R; Wottschel, V; Zhang, J; Kaden, E; Dyrby, TB; Sotiropoulos, SN; Zhang, H; Criminisi, A; - view fewer (2017) Image quality transfer and applications in diffusion MRI. NeuroImage , 152 pp. 283-298. 10.1016/j.neuroimage.2017.02.089 . Green open access
http://ift.tt/2oVhMoY
Principios de Desarrollo Profesional Docente construidos por y para Profesores de Ciencia: una propuesta sustentable que emerge desde la indagación de las propias prácticas Principies of Teacher Professional Development built by and for Science Teachers: a sustainable proposal that emerges from the inquiry of self-practices
González-Weil, C; Gómez Waring, M; Ahumada Albayay, G; Bravo González, P; Salinas Tapia, E; Avilés Cisternas, D; Pérez, JL; González-Weil, C; Gómez Waring, M; Ahumada Albayay, G; Bravo González, P; Salinas Tapia, E; Avilés Cisternas, D; Pérez, JL; Santana Valenzuela, J; - view fewer (2014) Principios de Desarrollo Profesional Docente construidos por y para Profesores de Ciencia: una propuesta sustentable que emerge desde la indagación de las propias prácticas Principies of Teacher Professional Development built by and for Science Teachers: a sustainable proposal that emerges from the inquiry of self-practices. Estudios pedagógicos (Valdivia) , 40 (Especial) pp. 105-126. 10.4067/S0718-07052014000200007 . Green open access
http://ift.tt/2nYuF3R
Cost effective but unaffordable: an emerging challenge for health systems
Charlton, V; Littlejohns, P; Kieslich, K; Mitchell, P; Rumbold, B; Weale, A; Wilson, J; Charlton, V; Littlejohns, P; Kieslich, K; Mitchell, P; Rumbold, B; Weale, A; Wilson, J; Rid, A; - view fewer (2017) Cost effective but unaffordable: an emerging challenge for health systems. BMJ , 356 , Article j1402. 10.1136/bmj.j1402 . Green open access
http://ift.tt/2oVnRBZ
Public participation in decision-making on the coverage of new antivirals for hepatitis C
Kieslich, K; Ahn, J; Badano, G; Chalkidou, K; Cubillos, L; Hauegen, RC; Henshall, C; Kieslich, K; Ahn, J; Badano, G; Chalkidou, K; Cubillos, L; Hauegen, RC; Henshall, C; Krubiner, CB; Littlejohns, P; Lu, L; Pearson, SD; Rid, A; Whitty, JA; Wilson, J; - view fewer (2016) Public participation in decision-making on the coverage of new antivirals for hepatitis C. Journal of Health Organization and Management , 30 (5) pp. 769-785. 10.1108/JHOM-03-2016-0035 .
http://ift.tt/2nYpyAS
Perceived Stigma of Sudden Bereavement as a Risk Factor for Suicidal Thoughts and Suicide Attempt: Analysis of British Cross-Sectional Survey Data on 3387 Young Bereaved Adults
Pitman, A; Rantell, K; Marston, L; King, M; Osborn, D; (2017) Perceived Stigma of Sudden Bereavement as a Risk Factor for Suicidal Thoughts and Suicide Attempt: Analysis of British Cross-Sectional Survey Data on 3387 Young Bereaved Adults. International Journal of Environmental Research and Public Health , 14 (3) , Article 286. 10.3390/ijerph14030286 . Green open access
http://ift.tt/2oVfqXj
Apparatus for histological validation of in vivo and ex vivo magnetic resonance imaging of the human prostate
Bourne, RM; Bailey, CEM; Johnston, EW; Pye, H; Heavey, S; Whitaker, H; Siow, B; Bourne, RM; Bailey, CEM; Johnston, EW; Pye, H; Heavey, S; Whitaker, H; Siow, B; Freeman, A; Shaw, GL; Sridhar, A; Mertzanidou, T; Hawkes, DJ; Alexander, DC; Punwani, S; Panagiotaki, E; - view fewer (2017) Apparatus for histological validation of in vivo and ex vivo magnetic resonance imaging of the human prostate. Frontiers in Oncology , 7 , Article 47. 10.3389/fonc.2017.00047 . Green open access
http://ift.tt/2nYdyzo
Contrasting complement control, temporal adjunct control and controlled verbal gerund subjects in ASD: The role of contextual cues in reference assignment
Janke, V; Perovic, A; (2017) Contrasting complement control, temporal adjunct control and controlled verbal gerund subjects in ASD: The role of contextual cues in reference assignment. Frontiers in Psychology , 8 , Article 448. 10.3389/fpsyg.2017.00448 . Green open access
http://ift.tt/2oVokUH
Measures and metrics for automatic emotion classification via FACET
Dente, P; Kuester, D; Skora, L; Krumhuber, E; (2017) Measures and metrics for automatic emotion classification via FACET. In: Bryson, J and De Vos, M and Padget, J, (eds.) (Proceedings) AISB Annual Convention 2017. (pp. pp. 160-163). : Bath, UK. (In press).
http://ift.tt/2nYrNUL
Severe Murine Typhus Presenting with Acalculous Cholecystitis: A Case Report and Literature Review
A 54-year-old otherwise healthy male, who was being evaluated for prolonged fever, developed clinical and ultrasonographic signs compatible with acute acalculous cholecystitis. Diagnosis of murine typhus was confirmed by serology and the patient was treated with doxycycline. He improved rapidly and all clinical and laboratory abnormalities returned to normal. The present case dictates that knowledge of the local epidemiology and keeping a high index of clinical suspicion can help recognize uncommon manifestations of murine typhus, in order to treat appropriately and avoid unnecessary investigations and interventions.
http://ift.tt/2oUXtb6
A chemoselective and continuous synthesis of m-sulfamoylbenzamide analogues
For the synthesis of m-sulfamoylbenzamide analogues, small molecules which are known for their bioactivity, a chemoselective procedure has been developed starting from m-(chlorosulfonyl) benzoyl chloride. Although a chemoselective process in batch was already reported, a continuous-flow process reveals an increased selectivity at higher temperatures and without catalysts. In total, 15 analogues were synthesized, using similar conditions, with yields ranging between 65 and 99%. This is the first automated and chemoselective synthesis of m- sulfamoylbenzamide analogues.
http://ift.tt/2oxt7j5