Identification of NTRK fusions in pediatric mesenchymal tumors

Abstract

Background

NTRK fusions are known oncogenic drivers and have recently been effectively targeted by investigational agents in adults. We sought to assess the frequency of NTRK fusions in a large series of pediatric and adolescent patients with advanced cancers.

Procedure

Genomic profiles from 2,031 advanced cancers from patients less than 21 years old who were assayed with comprehensive genomic profiling were reviewed to identify NTRK fusions.

Results

Total of nine cases (0.44%) harbored NTRK fusions, including novel partners. Four of these cases were in children less than 2 years old for which infantile fibrosarcoma was considered as a diagnosis, and two harbored the canonical ETV6-NTRK3. The remaining cases carried other diagnoses, at least one that carried the diagnosis of inflammatory myofibroblastic tumor.

Conclusions

NTRK fusions occur in a subset of young patients with mesenchymal or sarcoma-like tumors at a low frequency, and are eminently druggable targets via either investigational agents or approved drugs.

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A man-made disease: Fetal neonatal alloimmune thrombocytopenia due to incompatibility between oocyte donor and gestational mother

Abstract

The incompatibility causing fetal and neonatal alloimmune thrombocytopenia (FNAIT) results from a fetus inheriting a paternal human platelet antigen (HPA), which is different from the maternal HPA. We present a unique case of FNAIT in a pregnancy involving an oocyte recipient mother with Turner syndrome. This is the first report of FNAIT in which the suggested mechanism involves antibodies produced by a gestational mother against the incompatible HPA of the oocyte donor.

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Type III pleuropulmonary blastoma in a dicer1 germline mutation carrier: The management of residual lung cystic lesions

Abstract

Pleuropulmonary blastoma (PPB) is a rare malignancy of childhood. It often represents a manifestation of a hereditary tumor predisposition syndrome (DICER1 syndrome). Because of its malignant potential, surgical resection of cystic lung lesions is recommended in germline DICER1 mutation carriers. We present a case of a 3-year-old male child with type III PPB successfully managed with ifosfamide, vincristine, actinomycin-D, and doxorubicin (IVADo) chemotherapy and surgery. A heterozygous germline pR688X mutation of DICER1 gene was demonstrated. Six years after primary diagnosis, several small lung cysts remained stable without further therapy. The management of residual asymptomatic lung cysts represents a clinical challenge in these patients.

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The McGill Interactive Pediatric OncoGenetic Guidelines: An approach to identifying pediatric oncology patients most likely to benefit from a genetic evaluation

Abstract

Identifying cancer predisposition syndromes in children with tumors is crucial, yet few clinical guidelines exist to identify children at high risk of having germline mutations. The McGill Interactive Pediatric OncoGenetic Guidelines project aims to create a validated pediatric guideline in the form of a smartphone/tablet application using algorithms to process clinical data and help determine whether to refer a child for genetic assessment. This paper discusses the initial stages of the project, focusing on its overall structure, the methodology underpinning the algorithms, and the upcoming algorithm validation process.

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Staging Evaluation and Response Criteria Harmonization (SEARCH) for Childhood, Adolescent and Young Adult Hodgkin Lymphoma (CAYAHL): Methodology statement

Abstract

International harmonization of staging evaluation and response criteria is needed for childhood, adolescence, and young adulthood Hodgkin lymphoma. Two Hodgkin lymphoma protocols from cooperative trials in Europe and North America were compared for areas in need of harmonization, and an evidence-based approach is currently underway to harmonize staging and response evaluations with a goal to enhance comparisons, expedite identification of effective therapies, and aid in the approval process for new agents by regulatory agencies.

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Long-term follow-up of meningeal spread of otherwise stage 4S neuroblastoma without treatment

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Reliability of intraoperative frozen section for the diagnosis of renal tumors suspicious for malignancy in children and adolescents

Abstract

Background

The ability of intraoperative frozen section (IFS) to reliably diagnose renal tumors in children and adolescents is largely unknown. The objective of our study is to evaluate the ability of IFS to establish a histologic diagnosis for renal tumors in this population.

Methods

We reviewed our experience with patients who underwent IFS at the time of surgery for a renal tumor suspicious for malignancy from 2005 to 2015. The IFS was compared to the final pathology (FP). Data on concordance and reliability were analyzed.

Results

One hundred thirty patients underwent surgical interventions for a renal tumor suspicious for malignancy, and 32 (25%) patients underwent IFS. Median turnaround time for IFS was 20 min (range 13–44). The histologic IFS diagnosis correlated with FP in 26 (81.2%) cases was discrepant in three (9.4%) cases, and IFS was deferred to FP in three (9.4%) cases (kappa 0.71, 95% confidence interval [CI]: 0.52–0.899, P < 0.001). The IFS correctly distinguished between Wilms tumor and non-Wilms tumor in 30 (94%) cases (kappa 0.874, 95% CI: 0.705–1, P < 0.001). A total of 17 of 19 (89.5%) Wilms tumors were correctly diagnosed by IFS, yielding a sensitivity of 0.89 (95% CI: 0.67–0.99) and a specificity of 1 (95% CI: 0.75–1).

Conclusion

IFS is a reliable tool to establish a histologic diagnosis and to differentiate between Wilms and non-Wilms tumors in children and adolescents with renal tumors. The use of IFS should be encouraged in cases in which obtaining a diagnosis will provide guidance for important “real-time” medical decision making, specifically additional adjunctive surgical procedures.

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Primary intracranial choriocarcinoma in a very youngest child

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Alpha-thalassaemia promotes frequent vaso-occlusive crises in children with sickle cell anaemia through haemorheological changes

Abstract

Background

Sickle cell anaemia (SCA) is a severe hereditary haemoglobinopathy characterised by haemorheological abnormalities, which play a role in the occurrence of several acute and chronic clinical complications. While β^S-haplotypes and alpha-thalassaemia modulate SCA clinical severity, their effects on blood rheology have been incompletely described. The aim of this study was to test the effects of these genetic modifiers on the haemorheological properties and clinical complication of children with SCA.

Procedure

Steady-state haemorheological profile, biological parameters, β^S-haplotypes, alpha-globin status, vaso-occlusive crisis (VOC) and acute chest syndrome frequencies were analysed in 128 children (aged 5 to 18 years) with SCA.

Results

Patients with alpha-thalassaemia showed increased red blood cell (RBC) deformability and aggregation compared to those without. Median VOC rate was higher in patients with homozygous alpha-thalassaemia compared to those with a normal alpha genotype. Conversely, the haemorheological profile and clinical complications were not influenced by the β^S-haplotypes in our study.

Conclusion

Our results demonstrate that alpha-thalassaemia is associated with higher risk for VOC events in children with SCA, which may be due in part to its effects on RBC deformability and aggregation.

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Outcome of patients with intracranial relapse enrolled on national Wilms Tumor Study Group clinical trials

Abstract

Background

The occurrence of brain metastases (at diagnosis or at relapse) in patients with Wilms tumor is very rare.

Methods

We retrospectively reviewed the clinical characteristics of patients with Wilms tumor and relapse to the brain enrolled on the National Wilms Tumor Studies (NWTSs) 1–5.

Results

Intracranial relapse was documented in 47 patients (0.5%). Of the 45 patients with adequate data, 26 (58%) patients were male. Thirty-eight (84%) patients had favorable histology Wilms tumor. In 30 patients (67%), the appearance of intracranial disease was preceded by relapse at another site. Ten patients did not have any disease-directed therapy. Surgical resection was attempted in 15 patients; gross total resection was achieved in 11 patients. Twenty-nine patients received brain irradiation; the median dose was 3,000 cGy (range 1,080–4,000 cGy). Twenty-seven patients received chemotherapy. The 5-year overall survival from the time of intracranial relapse was 28.7% (95% confidence interval: 14.4–43.1%). Nine patients (all favorable histology Wilms tumor) were alive with a median follow-up from brain relapse of 140 months (range 35–381 months). All nine survivors received radiation therapy, eight received chemotherapy, and four underwent surgery (two gross total resection, two partial resection). The overall survival after brain metastases of the NWTS-5 patients was significantly higher than the overall survival of the NWTS 1–4 patients (P value = 0.029, log–rank test).

Conclusions

Patients with Wilms tumor recurrence involving the brain may have durable survival, particularly those treated in recent years. Multimodality therapy including radiation and chemotherapy should be considered for these patients.

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FISH identifies a KAT6A/CREBBP fusion caused by a cryptic insertional t(8;16) in a case of spontaneously remitting congenital acute myeloid leukemia with a normal karyotype

Abstract

Cytogenetics can inform risk stratification in pediatric acute myeloid leukemia (AML). We describe the first case of a newborn with leukemia cutis found to have AML harboring a cryptic insertional t(8;16)(p11.2;p13.3) with associated KAT6A/CREBBP fusion identified exclusively by fluorescence in situ hybridization (FISH). Expectant management resulted in spontaneous leukemia resolution. The identification of t(8;16)(p11.2;p13.3) may serve as a biomarker for spontaneous remission in congenital AML. FISH for this translocation is warranted in congenital AML with a normal karyotype, and patients with KAT6A/CREBBP fusion should be conservatively managed. While 50% of spontaneously remitting congenital AML with t(8;16)(p11.2;p13.3) may recur, high salvage rates are attained with standard therapy.

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Plaque-hyaluronidase-responsive high-density-lipoprotein-mimetic nanoparticles for multistage intimal-macrophage-targeted drug delivery and enhanced anti-atherosclerotic therapy

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Inhibitory effects of {gamma}- and {delta}-tocopherols on estrogen-stimulated breast cancer in vitro and in vivo

Estrogens have been implicated as complete carcinogens for breast and other tissues through mechanisms involving increased cell proliferation, oxidative stress and DNA damage. Because of their potent antioxidant activity and other effects, tocopherols have been shown to exert anti-tumor activities in various cancers. However, limited information is available on the effect of different forms of tocopherols in estrogen-mediated breast cancer. To address this, we examined the effects of α-, - and -tocopherols as well as a natural -tocopherol rich mixture of tocopherols, -TmT, on estrogen-stimulated MCF-7 cells in vitro and in vivo. For the in vivo studies, MCF-7 cells were injected into the mammary fat pad of immunodeficient mice previously implanted with estrogen pellets. Mice were then administered diets containing 0.2% α-, -, -tocopherol or -TmT for 5 weeks. Treatment with α-, -, -tocopherols and -TmT reduced tumor volumes by 29% (p<0.05), 45% (p<0.05), 41% (p<0.05) and 58% (p<0.01), as well as tumor weights by 20%, 37% (p<0.05), 39% (p<0.05) and 52% (p<0.05), respectively. - and -Tocopherols and -TmT inhibited the expression of cell proliferation-related genes such as cyclin D1 and c-Myc, and estrogen-related genes such as TFF/pS2, cathepsin D and progesterone receptor in estrogen-stimulated MCF-7 cells in vitro. Further, - and -tocopherols decreased the levels of estrogen-induced oxidative stress and nitrosative stress markers, 8-hydroxy-2'-deoxyguanosine and nitrotyrosine, as well as the DNA damage marker, -H2AX. Our results suggest that - and -tocopherols and the -tocopherol rich mixture are effective natural agents for the prevention and treatment of estrogen-mediated breast cancer.

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Activation of TRPA1 Channel by Antibacterial Agent Triclosan Induces VEGF Secretion in Human Prostate Cancer Stromal Cells

Accruing evidence indicates that exposure to environmental compounds may adversely impact human health and promote carcinogenesis. Triclosan (TCS), an antimicrobial agent widely used as a preservative in personal care products, has been shown to act as an endocrine disruptor in hormone-dependent tissues. Here we demonstrate a new molecular mechanism by which TCS stimulates the secretion by human prostate cancer stromal cells of Vascular Endothelial Growth Factor (VEGF), a factor known to promote tumour growth. This mechanism involves an increase in intracellular calcium levels due to the direct activation of a membrane ion channel. Using calcium imaging and electrophysiology techniques, we show for the first time that environmentally relevant concentrations of TCS activate a cation channel of the TRP family, TRPA1 (Transient Receptor Potential Ankirin 1), in primary cultured human prostate cancer stromal cells. The TCS-induced TRPA1 activation increased basal calcium in stromal cells and stimulated the secretion of VEGF and epithelial cells proliferation. Interestingly, immunofluorescence labeling performed on formalin-fixed paraffin-embedded prostate tissues showed an exclusive expression of the TRPA1 channel in prostate cancer stromal cells. Our data demonstrate an impact of the environmental factor TCS on the tumor microenvironment interactions, by activating a tumor stroma-specific TRPA1 ion channel.

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The human microbiome and cancer

Recent scientific advances have significantly contributed to our understanding of the complex connection between the microbiome and cancer. Our bodies are continuously exposed to microbial cells, both resident and transient, as well as their by-products including toxic metabolites. Circulation of toxic metabolites may contribute to cancer onset or progression at locations distant from where a particular microbe resides. Moreover, microbes may migrate to other locations in the human body and become associated with tumor development. Several case-control metagenomics studies suggest that dysbiosis in the commensal microbiota is also associated with inflammatory disorders and various cancer types throughout the body. Although the microbiome influences carcinogenesis through mechanisms independent of inflammation and immune system, the most recognizable is the link between the microbiome and cancer is via the immune system, as the resident microbiota plays an essential role in activating, training, and modulating the host immune response. Immunological dysregulation is likely to provide mechanistic explanations as to how our microbiome influences cancer development and cancer therapies. In this review, we discuss recent developments in understanding the human gut microbiome's relationship with cancer, and the feasibility of developing novel cancer diagnostics based on microbiome profiles.

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Synthetic lethality: emerging targets and opportunities in melanoma

Summary

Great progress has been made in the treatment of melanoma through use of targeted therapies and immunotherapy. One approach that has not been fully explored is synthetic lethality, which exploits somatically acquired changes, usually driver mutations, to specifically kill tumour cells. We outline the various approaches that may be applied to identify synthetic lethal interactions and define how these interactions may drive drug discovery efforts.

This article is protected by copyright. All rights reserved.

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Genomic analysis and clinical management of adolescent cutaneous melanoma

Summary

Melanoma in young children is rare, however its incidence in adolescents and young adults is rising. We describe the clinical course of a 15-year-old female diagnosed with AJCC stage IB non-ulcerated primary melanoma, who died from metastatic disease four years after diagnosis despite three lines of modern systemic therapy. We also present the complete genomic profile of her tumour and compare this to a further series of 13 adolescent melanomas, and 275 adult cutaneous melanomas. A somatic BRAF^V600E mutation and a high mutational load equivalent to that found in adult melanoma, and composed primarily of C>T mutations was observed. A germline genomic analysis alongside a series of 23 children and adolescents with melanoma revealed no mutations in known germline melanoma-predisposition genes. Adolescent melanomas appear to have genomes that are as complex as those arising in adulthood, and their clinical course can, as with adults, be unpredictable.

This article is protected by copyright. All rights reserved.

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New JLS-Factor Model versus the Standard JLS Model: A Case Study on Chinese Stock Bubbles

In this paper, we extend the Johansen-Ledoit-Sornette (JLS) model by introducing fundamental economic factors in China (including the interest rate and deposit reserve rate) and the historical volatilities of targeted and US equity indices into the original model, which is a flexible tool to detect bubbles and predict regime changes in financial markets. We then derive a general method to incorporate these selected factors in addition to the log-periodic power law signature of herding and compare the prediction accuracy of the critical time between the original and the new JLS models (termed the JLS-factor model) by applying these two models to fit two well-known Chinese stock indices in three bubble periods. The results show that the JLS-factor model with Chinese characteristics successfully depicts the evolutions of bubbles and “antibubbles” and constructs efficient end-of-bubble signals for all bubbles in Chinese stock markets. In addition, the results of standard statistical tests demonstrate the excellent explanatory power of these additive factors and confirm that the new JLS model provides useful improvements over the standard JLS model.

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Signal Factors Secreted by 2D and Spheroid Mesenchymal Stem Cells and by Cocultures of Mesenchymal Stem Cells Derived Microvesicles and Retinal Photoreceptor Neurons

We aim to identify levels of signal factors secreted by MSCs cultured in 2D monolayers (2D-MSCs), spheroids (spheroids MSCs), and cocultures of microvesicles (MVs) derived from 2D-MSCs or spheroid MSCs and retinal photoreceptor neurons. We seeded 2D-MSCs, spheroid MSCs, and cells derived from spheroids MSCs at equal numbers. MVs isolated from all 3 culture conditions were incubated with 661W cells. Levels of 51 signal factors in conditioned medium from those cultured conditions were quantified with bead-based assay. We found that IL-8, IL-6, and GROα were the top three most abundant signal factors. Moreover, compared to 2D-MSCs, levels of 11 cytokines and IL-2Rα were significantly increased in conditioned medium from spheroid MSCs. Finally, to test if enhanced expression of these factors reflects altered immunomodulating activities, we assessed the effect of 2D-MSC-MVs and 3D-MSC-MVs on CD14+ cell chemoattraction. Compared to 2D-MSC-MVs, 3D-MSC-MVs significantly decreased the chemotactic index of CD14+ cells. Our results suggest that spheroid culture conditions improve the ability of MSCs to selectively secrete signal factors. Moreover, 3D-MSC-MVs also possessed an enhanced capability to promote signal factors secretion compared to 2D-MSC-MVs and may possess enhanced immunomodulating activities and might be a better regenerative therapy for retinal degenerative diseases.

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Pharmacokinetic Properties of Adenosine Amine Congener in Cochlear Perilymph after Systemic Administration

Noise-induced hearing loss (NIHL) is a global health problem affecting over 5% of the population worldwide. We have shown previously that acute noise-induced cochlear injury can be ameliorated by administration of drugs acting on adenosine receptors in the inner ear, and a selective A1 adenosine receptor agonist adenosine amine congener (ADAC) has emerged as a potentially effective treatment for cochlear injury and resulting hearing loss. This study investigated pharmacokinetic properties of ADAC in rat perilymph after systemic (intravenous) administration using a newly developed liquid chromatography-tandem mass spectrometry detection method. The method was developed and validated in accordance with the USA FDA guidelines including accuracy, precision, specificity, and linearity. Perilymph was sampled from the apical turn of the cochlea to prevent contamination with the cerebrospinal fluid. ADAC was detected in cochlear perilymph within two minutes following intravenous administration and remained in perilymph above its minimal effective concentration for at least two hours. The pharmacokinetic pattern of ADAC was significantly altered by exposure to noise, suggesting transient changes in permeability of the blood-labyrinth barrier and/or cochlear blood flow. This study supports ADAC development as a potential clinical otological treatment for acute sensorineural hearing loss caused by exposure to traumatic noise.

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Ventricular Tachycardia Originating from Moderator Band: New Perspective on Catheter Ablation

A 59-year-old woman was referred to the institution with burdens of idiopathic ventricular tachycardia (IVT). Electroanatomic mapping revealed a complex fractionated, high frequency potential with long duration preceding the QRS onset of the IVT. The real end point of ablation was the disappearance of the conduction block of Purkinje potential during the sinus rhythm besides the disappearance of the inducible tachycardia. Location of distal catheter was at the moderator band (MB) by transthoracic echocardiography (TTE). Only irrigated radiofrequency current was delivered at both insertions of the MB which can completely eliminate the IVT.

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Survival after Abdominoperineal and Sphincter-Preserving Resection in Nonmetastatic Rectal Cancer: A Population-Based Time-Trend and Propensity Score-Matched SEER Analysis

Background. Abdominoperineal resection (APR) has been associated with impaired survival in nonmetastatic rectal cancer patients. It is unclear whether this adverse outcome is due to the surgical procedure itself or is a consequence of tumor-related characteristics. Study Design. Patients were identified from the Surveillance, Epidemiology, and End Results database. The impact of APR compared to coloanal anastomosis (CAA) on survival was assessed by Cox regression and propensity-score matching. Results. In 36,488 patients with rectal cancer resection, the APR rate declined from 31.8% in 1998 to 19.2% in 2011, with a significant trend change in 2004 at 21.6% (). To minimize a potential time-trend bias, survival analysis was limited to patients diagnosed after 2004. APR was associated with an increased risk of cancer-specific mortality after unadjusted analysis (HR = 1.61, 95% CI: 1.28–2.03, ) and multivariable adjustment (HR = 1.39, 95% CI: 1.10–1.76, ). After optimal adjustment of highly biased patient characteristics by propensity-score matching, APR was not identified as a risk factor for cancer-specific mortality (HR = 0.85, 95% CI: 0.56–1.29, ). Conclusions. The current propensity score-adjusted analysis provides evidence that worse oncological outcomes in patients undergoing APR compared to CAA are caused by different patient characteristics and not by the surgical procedure itself.

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The Function of FGFR1 Signalling in the Spinal Cord: Therapeutic Approaches Using FGFR1 Ligands after Spinal Cord Injury

Extensive research is ongoing that concentrates on finding therapies to enhance CNS regeneration after spinal cord injury (SCI) and to cure paralysis. This review sheds light on the role of the FGFR pathway in the injured spinal cord and discusses various therapies that use FGFR activating ligands to promote regeneration after SCI. We discuss studies that use peripheral nerve grafts or Schwann cell grafts in combination with FGF1 or FGF2 supplementation. Most of these studies show evidence that these therapies successfully enhance axon regeneration into the graft. Further they provide evidence for partial recovery of sensory function shown by electrophysiology and motor activity evidenced by behavioural data. We also present one study that indicates that combination with additional, synergistic factors might further drive the system towards functional regeneration. In essence, this review summarises the potential of nerve and cell grafts combined with FGF1/2 supplementation to improve outcome even after severe spinal cord injury.

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Angioimmunoblastic T-Cell Lymphoma: A Questionable Association with Follicular Dendritic Cell Sarcoma

An elderly woman presented with generalized lymphadenopathy, several systemic symptoms, and splenomegaly. An inguinal lymph node excision revealed a compound picture. One aspect of the lymph node morphology, including cells with follicular T-helper cell phenotype, was most consistent with angioimmunoblastic T-cell lymphoma. The other component, revealing spindle cells forming whorls with immunostaining for CD21, CD23, and fascin, might be an integral part of this T-cell lymphoma. However, due to the often massive involvement of the nodal tissue by these follicular dendritic cells, these areas were questionably suggestive of involvement by follicular dendritic cell sarcoma. We raise herein the issue of the borderline area between advanced follicular dendritic cell expansion in angioimmunoblastic T-cell lymphoma and a massive follicular dendritic cell proliferation consistent with follicular dendritic cells sarcoma, in the absence of a genomic analysis.

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Two-Dimensional AOA Estimation Based on a Constant Modulus Algorithm

We propose a two-dimensional (2D) angle of arrival (AOA) estimator using the algebraic constant modulus algorithm (ACMA). This algorithm was originally introduced to estimate the one-dimensional (1D) AOA. An extension to estimate and automatically pair the elevation and azimuth angles for different sources is derived and proved in this paper. The ACMA method factorises a matrix into two different matrices; one is of constant modulus and contains the azimuth AOA information; however the second was previously ignored. In this paper we will prove that this second matrix contains the elevation AOA information. Thus, 2D AOA estimation is proved possible using the ACMA method. Simulation results are presented to illustrate the proposed method’s performances under different conditions.

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A Nonmonotone Projection Method for Constrained System of Nonlinear Equations

This paper deals with the nonmonotone projection algorithm for constrained nonlinear equations. For some starting points, the previous projection algorithms for the problem may encounter slow convergence which is related to the monotone behavior of the iterative sequence as well as the iterative direction. To circumvent this situation, we adopt the nonmonotone technique introduced by Dang to develop a nonmonotone projection algorithm. After constructing the nonmonotone projection algorithm, we show its convergence under some suitable condition. Preliminary numerical experiment is reported at the end of this paper, from which we can see that the algorithm we propose converges more quickly than that of the usual projection algorithm for some starting points.

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Bond-Slip Models for FPR-Concrete Interfaces Subjected to Moisture Conditions

Environmental related durability issues have been of great concerns in the structures strengthened with the fiber reinforced polymers (FRPs). In marine environment, moisture is one of the dominant factors that adversely affect the material properties and the bond interfaces. Several short-term and long-term laboratory experimental investigations have been conducted to study such behaviors but, still, there are insufficient constitutive bond models which could incorporate moisture exposure conditions. This paper proposed a very simple approach in determining the nonlinear bond-slip models for the FRP-concrete interface considering the effect of moisture conditions. The proposed models are based on the strain results of the experimental investigation conducted by the authors using 6 different commercial FRP systems exposed to the moisture conditions for the maximum period of 18 months. The exposure effect in the moisture conditions seems to have great dependency on the FRP system. Based on the contrasting differences in the results under moisture conditions, separate bond-slip models have been proposed for the wet-layup FRP and prefabricated FRP systems. As for the verification of the proposed model under moisture conditions, predicted pull-out load was compared with the experimental pull-out load. The results showed good agreement for all the FRP systems under investigation.

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Synthesis and Growth Stimulant Properties of 2-Acetyl-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one Derivatives

A convenient, accessible, and high yield method for preparing of 6-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (1) by treatment of acetoacetic acid ethyl ester with thiourea in sodium methylate was developed. The alkylation of the latter with 3-chloro-pentane-2,4-dione and further regioselective cyclization of intermediate compound (2) in high yield afforded 2-acetyl-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one (3). The halogenation and some transformations of synthesized thiazolo[3,2-a]pyrimidine (3) due to its ketone group were carried out to obtain the corresponding carboxamide, carbothioamide, sulfonohydrazide, and oxime and its alkylated derivatives (5). At preliminary biological studies the synthesized compounds have shown growth stimulant properties. The activity of four of them was higher than 70%, compared with heteroauxin.

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Maize Fungal Growth Control with Scopoletin of Cassava Roots Produced in Benin

The chemical contamination of food is among the main public health issues in developing countries. With a view to find new natural bioactive products against fungi responsible for chemical contamination of staple food such as maize, the antifungal activity tests of scopoletin extracted from different components of the cassava root produced in Benin were carried out. The dosage of scopoletin from parts of the root (first skin, second skin, whole root, and flesh) was done by High Performance Liquid Chromatography. The scopoletin extract was used to assess the activity of 12 strains (11 strains of maize and a reference strain). The presence of scopoletin was revealed in all components of the cassava root. Scopoletin extracted from the first skin cassava root was the most active both as inhibition of sporulation (52.29 to 87.91%) and the mycelial growth (36.51–80.41%). Scopoletin extract from the cassava root skins showed significant inhibitory activity on the tested strains with fungicide concentration (MFC) between 0.0125 mg/mL and 0.1 mg/mL. The antifungal scopoletin extracted from the cassava root skins may be well beneficial for the fungal control of the storage of maize.

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Development of a Wearable Device for Motion Capturing Based on Magnetic and Inertial Measurement Units

This paper presents a novel wearable device for gesture capturing based on inertial and magnetic measurement units that are made up of micromachined gyroscopes, accelerometers, and magnetometers. The low-cost inertial and magnetic measurement unit is compact and small enough to wear and there are altogether thirty-six units integrated in the device. The device is composed of two symmetric parts, and either the right part or the left one contains eighteen units covering all the segments of the arm, palm, and fingers. The offline calibration and online calibration are proposed to improve the accuracy of sensors. Multiple quaternion-based extended Kalman filters are designed to estimate the absolute orientations, and kinematic models of the arm-hand are considered to determine the relative orientations. Furthermore, position algorithm is deduced to compute the positions of corresponding joint. Finally, several experiments are implemented to verify the effectiveness of the proposed wearable device.

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Microstructure and Magnetic Properties of NdFeB Films through Nd Surface Diffusion Process

Ta/Nd/NdFeB/Nd/Ta films were deposited by magnetron sputtering on Si (100) substrates and subsequently annealed for 30 min at 923 K in vacuum. It was found that the microstructure and magnetic properties of Ta/Nd/NdFeB/Nd/Ta films strongly depend on the NdFeB layer thickness. With NdFeB layer thickness increasing, both the grain size and the strain firstly reduce and then increase. When NdFeB layer thickness is 750 nm, the strain reaches the minimum value. Meanwhile, both the in-plane and perpendicular coercivities firstly drastically increase and then slowly decrease with NdFeB layer thickness increasing. The highest in-plane and perpendicular coercivities can be obtained at NdFeB layer thickness of 750 nm, which are 21.2 kOe and 19.5 kOe, respectively. In addition, the high remanence ratio (remanent magnetization/saturation magnetization) of 0.87 can also be achieved in Ta/Nd/NdFeB (750 nm)/Nd/Ta film.

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Bifurcation Analysis for an SEIRS-V Model with Delays on the Transmission of Worms in a Wireless Sensor Network

Hopf bifurcation for an SEIRS-V model with delays on the transmission of worms in a wireless sensor network is investigated. We focus on existence of the Hopf bifurcation by regarding the diverse delay as a bifurcation parameter. The results show that propagation of worms in the wireless sensor network can be controlled when the delay is suitably small under some certain conditions. Then, we study properties of the Hopf bifurcation by using the normal form theory and center manifold theorem. Finally, we give a numerical example to support the theoretical results.

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Neuromuscular Coordination Deficit Persists 12 Months after ACL Reconstruction But Can Be Modulated by 6 Weeks of Kettlebell Training: A Case Study in Women’s Elite Soccer

The aim of the present single-case study was to investigate the effect of 6 weeks’ kettlebell training on the neuromuscular risk profile for ACL injury in a high-risk athlete returning to sport after ACL reconstruction. A female elite soccer player (age 21 years) with no previous history of ACL injury went through neuromuscular screening as measured by EMG preactivity of vastus lateralis and semitendinosus during a standardized sidecutting maneuver. Subsequently, the player experienced a noncontact ACL injury. The player was screened again following postreconstruction rehabilitation, then underwent 6-week kettlebell training, and was subsequently screened again at 6-week follow-up. Prior to and after postreconstruction rehabilitation the player demonstrated a neuromuscular profile during sidecutting known to increase the risk for noncontact ACL injury, that is, reduced EMG preactivity for semitendinosus and elevated EMG preactivity for vastus lateralis. Subsequently, the 6-week kettlebell training increased semitendinosus muscle preactivity during sidecutting by 38 percentage points to a level equivalent to a neuromuscular low-risk profile. An ACL rehabilitated female athlete with a high-risk neuromuscular profile changed to low-risk in response to 6 weeks of kettlebell training. Thus, short-term kettlebell exercise with documented high levels of medial hamstring activation was found to transfer into high medial hamstring preactivation during a sidecutting maneuver.

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Shannon’s Energy Based Algorithm in ECG Signal Processing

Physikalisch-Technische Bundesanstalt (PTB) database is electrocardiograms (ECGs) set from healthy volunteers and patients with different heart diseases. PTB is provided for research and teaching purposes by National Metrology Institute of Germany. The analysis method of complex QRS in ECG signals for diagnosis of heart disease is extremely important. In this article, a method on Shannon energy (SE) in order to detect QRS complex in 12 leads of ECG signal is provided. At first, this algorithm computes the Shannon energy (SE) and then makes an envelope of Shannon energy (SE) by using the defined threshold. Then, the signal peaks are determined. The efficiency of the algorithm is tested on 70 cases. Of all 12 standard leads, ECG signals include 840 leads of the PTB Diagnostic ECG Database (PTBDB). The algorithm shows that the Shannon energy (SE) sensitivity is equal to 99.924%, the detection error rate (DER) is equal to 0.155%, Positive Predictivity (+P) is equal to 99.922%, and Classification Accuracy (Acc) is equal to 99.846%.

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Controllability Problem of Fractional Neutral Systems: A Survey

The following article presents recent results of controllability problem of dynamical systems in infinite-dimensional space. Generally speaking, we describe selected controllability problems of fractional order systems, including approximate controllability of fractional impulsive partial neutral integrodifferential inclusions with infinite delay in Hilbert spaces, controllability of nonlinear neutral fractional impulsive differential inclusions in Banach space, controllability for a class of fractional neutral integrodifferential equations with unbounded delay, controllability of neutral fractional functional equations with impulses and infinite delay, and controllability for a class of fractional order neutral evolution control systems.

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Improved KLT Algorithm for High-Precision Wavelength Tracking of Optical Fiber Bragg Grating Sensors

Fiber Bragg Gratings (FBGs) are among the most popular optical fiber sensors. FBGs are well suited for direct detection of temperature and strain and can be functionalized for pressure, humidity, and refractive index sensing. Commercial setups for FBG interrogation are based on white-light sources and spectrometer detectors, which are capable of decoding the spectrum of an FBG array. Low-cost spectrometers record the spectrum on a coarse wavelength grid (typically 78–156 pm), whereas wavelength shifts of 1 pm or lower are required by most of the applications. Several algorithms have been presented for detection of small wavelength shift, even with coarse wavelength sampling; most notably, the Karhunen-Loeve Transform (KLT) was demonstrated. In this paper, an improved algorithm based on KLT is proposed, which is capable of further expanding the performances. Simulations show that, reproducing a commercial spectrometer with 156 pm grid, the algorithm estimates wavelength shift with accuracy well below 1 pm. In typical signal-to-noise ratio (SNR) conditions, the root mean square error is 22–220 fm, while the accuracy is 0.22 pm, despite the coarse sampling. Results have been also validated through experimental characterization. The proposed method allows achieving exceptional accuracy in wavelength tracking, beating the picometer level resolution proposed in most commercial and research software, and, due to fast operation (>5 kHz), is compatible also with structural health monitoring and acoustics.

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Diffusion Kurtosis Imaging Detects Microstructural Changes in the Brain after Acute Alcohol Intoxication in Rats

The aim of this study was to test the technical feasibility of diffusion kurtosis imaging (DKI) in the brain after acute alcohol intoxication. Diffusion tensor imaging (DTI) and DKI during 7.0 T MRI were performed in the frontal lobe and thalamus before and 30 min, 2 h, and 6 h after ethyl alcohol administration. Compared with controls, mean kurtosis values of the frontal lobe and thalamus first decreased by 44% and 38% within 30 min ( all) and then increased by 14% and 46% at 2 h (frontal lobe, ; thalamus, ) and by 29% and 68% at 6 h (frontal lobe, ; thalamus, ) after acute intake. Mean diffusivity decreased significantly in both the frontal lobe and the thalamus at various stages. However, fractional anisotropy decreased only in the frontal lobe, with no detectable change in the thalamus. This demonstrates that DKI possesses sufficient sensitivity for tracking pathophysiological changes at various stages associated with acute alcohol intoxication and may provide additional information that may be missed by conventional DTI parameters.

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Cancer-associated fibroblasts promote M2 polarization of macrophages in pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by remarkable desmoplasia with infiltration of distinct cellular components. Cancer-associated fibroblasts (CAFs) has been shown to be among the most prominent cells and played a significant role in shaping the tumor microenvironment by interacting with other type of cells. Here, we aimed to investigate the effect of CAFs in modulating phenotype of tumor-associated macrophages (TAM). Under treatment of CAFs conditioned medium (CM) or direct co-culture with CAFs, monocytes exhibited enhanced expression of CD206 and CD163 compared with control group (P < 0.01). The induction of M2 polarization was mediated by increased reactive oxygen species (ROS) production in monocytes as ROS elimination abolished the effect of CAFs (P < 0.05). The supernatant analysis showed that pancreatic CAFs produced increased macrophage colony-stimulating factor (M-CSF). Upon treatment of M-CSF neutralizing antibody, the ROS generation and M2 polarization of CAFs CM-stimulated monocytes were significantly inhibited (P < 0.05). In addition, the CAFs-induced M2 macrophages significantly enhanced pancreatic tumor cell growth, migration, and invasion. Collectively, our data revealed that pancreatic CAFs were able to induce a tumor-promoting TAM phenotype partly through secreted M-CSF and enhanced ROS production in monocytes, indicating possible treatment strategies by targeting stromal cell interaction within PDAC microenvironment.

Pancreatic cancer-associated fibroblasts (CAFs) promote M2 polarization of macrophages by increasing ROS production. M-CSF secreted by CAF contribute to the enhanced ROS production and M2 polarization. CAF-induced M2 macrophages promote growth and migration of pancreatic tumor cells.

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Anti-folate receptor-{alpha} IgE but not IgG recruits macrophages to attack tumors via TNF-{alpha}/MCP-1 signaling

IgE antibodies are key mediators of anti-parasitic immune responses, but their potential for cancer treatment via antibody-directed cell-mediated cytotoxicity (ADCC) has been little studied. Recently, tumor antigen-specific IgEs were reported to restrict cancer cell growth by engaging high-affinity Fc receptors on monocytes and macrophages, however, the underlying therapeutic mechanisms were undefined and in vivo proof-of-concept was limited. Here, an immunocompetent rat model was designed to recapitulate the human IgE-Fcε receptor system for cancer studies. We also generated rat IgE and IgG monoclonal antibodies specific for the folate receptor (FRα), which is expressed widely on human ovarian tumors, along with a syngeneic rat tumor model expressing human FRα. Compared with IgG, anti-FRα IgE reduced lung metastases. This effect was associated with increased intra-tumoral infiltration by TNFα+ and CD80+ macrophages plus elevated TNFα and the macrophage chemoattractant MCP-1 in lung bronchoalveolar lavage fluid. Increased levels of TNFα and MCP-1 correlated with IgE-mediated tumor cytotoxicity by human monocytes and and with longer patient survival in clinical specimens of ovarian cancer. Monocytes responded to IgE but not IgG exposure by upregulating TNFα, which in turn induced MCP-1 production by monocytes and tumor cells to promote a monocyte chemotactic response. Conversely, blocking TNFα receptor signaling abrogated induction of MCP-1, implicating it in the antitumor effects of IgE. Overall, these findings show how anti-tumor IgE reprograms monocytes and macrophages in the tumor microenvironment, encouraging the clinical use of IgE antibody technology to attack cancer beyond the present exclusive reliance on IgG.

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ASTHMA - comparing the impact of vitamin D versus UVR on clinical and immune parameters

Photochem. Photobiol. Sci., 2017, Advance Article
DOI: 10.1039/C6PP00407E, Perspective

Kylie A. Morgan, Elizabeth H. Mann, Antony R. Young, Catherine M. Hawrylowicz
Asthma is estimated to affect more than 300 million individuals worldwide. Vitamin D is increasingly believed to beneficially influence asthma incidence and control, likely due to effects on innate and adaptive immunity. The primary mechanism for increasing vitamin D in the body is via UVB radiation of skin, however whether UVB has comparable effects to vitamin D on relevant immune mechanisms and asthma is unclear.
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Self-assembly, optical, thermal and electrochemical properties of bis-N-benzyl perylene diimide dye

Photochem. Photobiol. Sci., 2017, Advance Article
DOI: 10.1039/C6PP00348F, Paper

Devrim Ozdal, Nur P. Aydinlik, Jagadeesh B. Bodapati, Huriye Icil
Flexible methylene containing N,N[prime or minute]-bis-(benzyl)-3,4,9,10-perylenebis(dicarboximide) (1) was synthesized.
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Mints, gum, sprays and rinses: which should you choose to fresh your breath? - Knowridge Science Report

Knowridge Science Report

Mints, gum, sprays and rinses: which should you choose to fresh your breath? Knowridge Science Report “Other things that influence the breath are draining or infected sinuses, acid reflux, or GERD — gastroesophageal reflux disease — any kinds of systemic diseases, along with medication for these conditions, are going to influence the breath,” Cotter ...

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Super-resolution visualization of caveolae deformation in response to osmotic stress [Signal Transduction]

Caveolae are protein dense plasma membrane domains structurally composed of caveolin -1 or -3 along with other proteins. Our previous studies have shown that caveolae enhance calcium signals generated through the Gαq/phospholipase Cβ signaling pathway, and that subjecting cells to hypo-osmotic stress reverses this enhancement. In this study, we have used super-resolution fluorescence microscopy supplemented by fluorescence correlation studies to determine the structural factors that underlie this behavior. We find similar and significant populations of Gαq and one of its receptors, bradykinin type 2 receptor (β2R), as well as Gαi and its coupled 2-adrenergic receptor (βAR), localize to caveolae domains. While mild osmotic stress deforms caveolae altering interactions between caveolae and these proteins, it does not affect the general structure and the localization of caveolae components remain largely unchanged. Additionally, in contrast to calcium signals mediated through Gαq-B2R, osmotic stress does not affect cAMP signals mediated through Gαi and βAR. Structurally, we find that mild osmotic stress corresponding roughly to a pressure of 3.82 N/m2 increases the domain diameter by ~30% and increases the fluorescence intensity in the center of the domain mouth suggesting a flattening of the invagination. Approximate calculations show that caveolae in muscle tissue have the strength to handle the stress of muscle movement.

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MiR-21-mediated Radioresistance Is via Promoting Repair of DNA Double Strand Breaks [Gene Regulation]

MiR-21 as an oncogene that over-expresses in most human tumors involves radioresistance; however, the mechanism remains unclear. Here, we demonstrate that miR-21-mediated radioresistance is through promoting repair of DNA double strand breaks, which includes to facilitate both non-homologous end-joining (NHEJ) and homologous recombination repair (HRR). The miR-21-promoted NHEJ is through targeting GSK3B (a novel target of miR-21) that affects the CRY2/PP5 pathway and in turn increases DNA-PKcs activity. The miR-21-promoted HRR is through targeting both GSK3B and CDC25A (a known target of miR-21), which neutralizes the effects of targeting GSK3B-induced CDC25A increase since GSK3B promotes degradation of both CDC25A and Cyclin D1, but CDC25A and Cyclin D1 have an opposite effect on HRR. A negative correlation of expression levels between miR-21 and GSK3 exists in a subset of human tumors. Our results not only elucidate miR-21-mediated radioresistance, but also provide potential new targets for improving radiotherapy.

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O-GlcNAc expression levels epigenetically regulate colon cancer tumorigenesis by affecting the cancer stem cell compartment via modulating expression of transcriptional factor MYBL1 [Glycobiology and Extracellular Matrices]

To study the regulation of colorectal adenocarcinoma progression by O-GlcNAc, we have focused on the O-GlcNAc-mediated epigenetic regulation of human colon cancer stem cells (CCSC). Xenograft tumors from colon tumor cells with OGT knockdown grew significantly slower than those formed from control cells, indicating a reduced proliferation of tumor cells due to inhibition of OGT expression. Significant reduction of CCSC population was observed in the tumor cells after OGT knockdown, while tumor cells treated with O-GlcNAcase inhibitor showed an increased CCSC population, indicating that O-GlcNAc levels regulated the CCSC compartment. When grown in suspension, tumor cells with OGT knockdown showed a reduced ability to form tumorspheres, indicating a reduced self-renewal of CCSC due to reduced levels of O-GlcNAc. ChIP-seq experiments using an anti-O-GlcNAc antibody revealed significant chromatin enrichment of O-GlcNAc modified proteins at the promoter of the transcription factor MYBL1, which was also characterized by the presence of H3K27me3. RNA-seq analysis showed an increased expression of MYBL1 in tumor cells with OGT knockdown. Forced overexpression of MYBL1 led to a reduced population of CCSC and tumor growth in vivo, similar to the effects of OGT silencing. Moreover, two CpG islands near the TSS site of MYBL1 were identified, and O-GlcNAc levels regulated their methylation status. These results strongly argue that O-GlcNAc epigenetically regulates MYBL1, functioning similarly to H3K27me3. The aberrant CCSC compartment observed after modulating O-GlcNAc levels, therefore, is likely to result, at least in part, from the epigenetic regulation of MYBL1 expression by O-GlcNAc, thereby significantly affecting tumor progression.

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A phosphoproteomic screen identifies a guanine-nucleotide exchange factor for Rab3A as a MAP kinase phosphatase-5-regulated MAP kinase target in IL-6 secretion and myogenesis [Cell Biology]

The mitogen-activated protein kinases (MAPKs) have been shown to regulate skeletal muscle function. Previously, we showed that MAPK phosphatase-5 (MKP-5) negatively regulates myogenesis and regeneration of skeletal muscle through inhibition of p38 MAPK and c-Jun N-terminal kinase (JNK). However, the identity and contribution of MKP-5-dependent MAPK targets in the regulation of skeletal muscle function and regenerative myogenesis has not been established. In order to identify MKP-5-dependent MAPK substrates in skeletal muscle, we performed a global differential phospho-MAPK substrate screen in regenerating skeletal muscles of wild type and MKP-5-deficient mice. We discovered a novel MKP-5-regulated MAPK substrate, called guanine nucleotide exchange factor for Rab3A (GRAB) that was hyperphosphorylated on a phospho-MAPK motif, in skeletal muscle of MKP-5-deficient mice. GRAB was found to be phosphorylated by JNK on serine 169. Myoblasts overexpressing a phosphorylation-defective mutant of GRAB (GRAB-S169A) inhibited the ability of C2C12 myoblasts to differentiate. We found that GRAB phosphorylation at Ser169 was required for the secretion of the pro-myogenic cytokine interleukin 6 (IL-6). Consistent with this observation, MKP-5-deficient mice exhibited increased circulating IL-6 expression as compared with wild type mice. Collectively, these data demonstrate a novel mechanism whereby MKP-5-mediated regulation of JNK negatively regulates phosphorylation of GRAB which subsequently controls secretion of IL-6. These data support the notion that MKP-5 serves as a regulator of MAPK-dependent signaling of critical skeletal muscle signaling pathways.

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Sequences within the C-terminus of the metabotropic glutamate receptor, mGluR5, are responsible for inner nuclear membrane localization [Cell Biology]

Traditionally G-protein coupled receptors (GPCR) are thought to be located on the cell surface where they transmit extracellular signals to the cytoplasm. However recent studies indicate that some GPCRs are also localized to various subcellular compartments such as the nucleus where they appear required for various biological functions. For example, the metabotropic glutamate receptor 5, mGluR5, is concentrated at the inner nuclear membrane (INM) where it mediates Ca2+ changes in the nucleoplasm by coupling with Gq/11. Here we identified a region within the C-terminal domain (amino acids 852-876) which is necessary and sufficient for INM localization of the receptor. Because these sequences do not correspond to known NLS motifs they represent a new motif for INM trafficking. mGluR5 is also trafficked to the PM where it undergoes re-cycling/degradation in a separate receptor pool, one that does not interact with the nuclear mGluR5 pool. Finally, our data suggest that once at the INM, mGluR5 is stably retained via interactions with molecular structures such as chromatin and nuclear Lamins. Thus mGluR5 is perfectly positioned to regulate nucleoplasmic Ca2+ in situ.

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Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by {gamma}-Secretase and Amyloid-{beta} Peptide Production [Enzymology]

Recent evidence suggests involvement of biometal homeostasis in the pathological mechanisms in Alzheimer's disease (AD). For example, increased intracellular copper or zinc has been linked to a reduction in secreted levels of the AD-causing amyloid-β peptide (Aβ). However, little is known about whether these biometals modulate the generation of Aβ. In the present study, we demonstrate in both cell-free and cell-based assays that zinc and copper regulate Aβ production by distinct molecular mechanisms affecting the processing by γ-secretase of its Aβ precursor protein substrate APP-C99. We found that Zn2+ induces APP-C99 dimerization, which prevents its cleavage by γ-secretase and Aβ production, with an IC50 value of 15 μM. Importantly, at this concentration, Zn2+ also drastically raised the production of the aggregation-prone Aβ43 found in the senile plaques of AD brains and elevated the Aβ43:Aβ40 ratio, a promising biomarker for neurotoxicity and AD. We further demonstrate that the APP-C99 histidine residues H6, H13 and H14 control the Zn2+-dependent APP-C99 dimerization and inhibition of Aβ production, while the increased Aβ43:Aβ40 ratio is substrate-dimerization independent and involves the known Zn2+-binding lysine K28 residue that orientates the APP-C99 transmembrane domain within the lipid bilayer. Unlike zinc, copper inhibited Aβ production by directly targeting the subunits presenilin and nicastrin in the γ-secretase complex. Altogether, our data demonstrate that zinc and copper differentially modulate Aβ production. They further suggest that dimerization of APP-C99, or the specific targeting of individual residues regulating the production of the long, toxic Aβ species, may offer two therapeutic strategies for preventing AD.

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Functional transformation of C-reactive protein by hydrogen peroxide [Immunology]

C-reactive protein (CRP) is present at sites of inflammation including amyloid plaques, atherosclerotic lesions and arthritic joints. CRP, in its native pentameric structural conformation, binds to cells and molecules which have exposed phosphocholine (PCh) groups. CRP, in its non-native pentameric structural conformation, binds to a variety of deposited, denatured and aggregated proteins, in addition to binding to PCh-containing substances. In this study, we investigated the effects of hydrogen peroxide (H2O2), a prototypical reactive oxygen species and which is also present at sites of inflammation, on the ligand recognition function of CRP. Controlled H2O2-treatment of native CRP did not monomerize CRP and did not affect the PCh-binding activity of CRP. In solid-phase ELISA-based ligand binding assays, purified pentameric H2O2-treated CRP bound to a number of immobilized proteins including oxidized LDL, IgG, amyloid beta peptide 1-42, C4b-binding protein and factor H, in a CRP-concentration and ligand-concentration dependent manner. Using oxidized LDL as a representative protein-ligand for H2O2-treated CRP, we found that the binding occurred in a Ca2+-independent manner and did not involve the PCh-binding site of CRP. We conclude that H2O2 is a biological modifier of the structure and ligand recognition function of CRP. Overall, the data suggest that the ligand recognition function of CRP is dependent on the presence of an inflammatory microenvironment. We hypothesize that one of the functions of CRP at sites of inflammation is to sense the inflammatory microenvironment, change its own structure in response but remain pentameric, and then bind to pathogenic proteins deposited at those sites.

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Occupancy of the Zinc Binding-site by Transition Metals decreases the Substrate Affinity of the Human Dopamine Transporter by an Allosteric Mechanism. [Neurobiology]

The human dopamine transporter (DAT) has a tetrahedral Zn2+-binding site. Zn2+-binding sites are also recognized by other first row transition metals. Excessive accumulation of manganese or of copper can lead to Parkinsonism due to dopamine deficiency. Accordingly, we examined the effect of Mn2+, Co2+, Ni2+ and Cu2+on transport-associated currents through DAT and DAT-H193K, a mutant with a disrupted Zn2+-binding site. All transition metals - but Mn2+ - modulated the transport cycle of wild type DAT with affinities in the low µM range. In this concentration range they were devoid of any action on DAT-H193K. The active transition metals reduced the affinity of DAT for dopamine. The affinity shift was most pronounced for Cu2+, followed by Ni2+ and Zn2+ (= Co2+). The extent of the affinity shift and the reciprocal effect of substrate on metal affinity accounted for the different modes of action: Ni2+ and Cu2+ uniformly stimulated and inhibited, respectively, the substrate-induced steady-state currents through DAT. In contrast, Zn2+ elicited biphasic effects on transport, i.e. stimulation at 1 µM and inhibition at 10 µM. A kinetic model, which posited (i) preferential binding of transition metal ions to the outward facing apo-state of DAT and (ii) a reciprocal interaction of dopamine and transition metals, recapitulated all experimental findings. Allosteric activation of DAT via the Zn2+ binding site may be of interest to restore transport in loss-of-function mutants.

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Unique contributions of an arginine side chain to ligand recognition in a glutamate-gated chloride channel [Molecular Biophysics]

Glutamate recognition by neurotransmitter receptors often relies on arginine (Arg) residues in the binding site, leading to the assumption that charge-charge interactions underlie ligand recognition. However, assessing the precise chemical contribution of Arg side chains to protein function and pharmacology has proven to be exceedingly difficult in such large and complex proteins. Using the in vivo nonsense suppression approach, we report the first successful incorporation of the isosteric, titratable Arg analog, canavanine, into a neurotransmitter receptor in a living cell, utilizing a glutamate-gated chloride channel from the nematode Haemonchus contortus. Our data unveil a surprisingly small contribution of charge at a conserved arginine side chain previously suggested to form a salt bridge with the ligand, glutamate. Instead, our data show that Arg contributes crucially to ligand sensitivity via a hydrogen bond network, where Arg interacts both with agonist and with a conserved Thr side chain within the receptor. Together, the data provide a new explanation for the reliance of neurotransmitter receptors on Arg side chains and highlight the exceptional capacity of unnatural amino acid incorporation for increasing our understanding of ligand recognition.

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DENEDDYLASE1 counters automodification of neddylating enzymes to maintain NEDD8 homeostasis in Arabidopsis [Signal Transduction]

In eukaryotes, the conjugation of the ubiquitin-like protein NEDD8 onto protein targets is an important post-translational modification. The best understood neddylation targets are the cullins, scaffold subunits of E3 ubiquitin ligases, where neddylation as well as deneddylation, facilitated by the protease activity of the CSN (COP9 signalosome), are required to control ubiquitin ligase assembly, function and ultimately substrate degradation. Little is known about the role of other deneddylating enzymes besides CSN and the role of neddylation and deneddylation of their substrates. We previously characterized Arabidopsis thaliana mutants with defects in the conserved NEDD8-specific protease DEN1 (DENEDDYLASE1). These mutants display only subtle growth phenotypes despite the strong accumulation of a broad range of neddylated proteins. Specifically, we identified AXR1 (AUXIN RESISTANT1), a subunit of the heterodimeric NAE (E1 NEDD8 ACTIVATING ENZYME), as highly neddylated in den1 mutants. Here, we examine the mechanism and conequences of AXR1 neddylation in more detail. We find that AXR1 as well as other neddylation enzymes are autoneddylated at multiple lysines. NAE autoneddylation can be linked to reduced NCE (E2 NEDD8 CONJUGATING ENZYME) NEDD8 thioester levels, either by critically reducing the pool of free NEDD8 or by reducing NAE activity. In planta, increasing NEDD8 gene dosage is sufficient to suppress den1 mutant phenotypes. We therefore suggest that DEN1 serves to recover diverted NEDD8 moieties from autoneddylated NAE subunits, and possibly also other neddylated proteins, in order to maintain NEDD8 pathway activitiy towards other NEDD8-dependent processes such as cullin E3 ligase regulation.

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Differential Contribution of Transmembrane Domains IV, V, VI, and VII to Human Angiotensin II Type 1 Receptor Homomer Formation [Signal Transduction]

G protein-coupled receptors (GPCRs) play an important role in drug therapy, and represent one of the largest families of drug targets. The angiotensin II type 1 receptor (AT1R) is notable as it has a central role in the treatment of cardiovascular disease. Blockade of AT1R signaling has been shown to alleviate hypertension and improve outcomes in patients with heart failure. Despite this, it has become apparent that our initial understanding of AT1R signaling is over-simplified. There is considerable evidence to suggest that AT1R signaling is highly modified in the presence of receptor-receptor interactions, but there is very little structural data available to explain this phenomenon even with the recent elucidation of the AT1R crystal structure. The current study investigates the involvement of transmembrane domains in AT1R homomer assembly with the goal of identifying hydrophobic interfaces that contribute to receptor-receptor affinity. A recently published crystal structure of the AT1R was used to guide site-directed mutagenesis of outward-facing hydrophobic residues within the transmembrane region of the AT1R. Bioluminescence resonance energy transfer was employed to analyze how receptor mutation affects the assembly of AT1R homomers with a specific focus on hydrophobic residues. Mutations within transmembrane domains IV, V, VI, and VII had no effect on angiotensin-mediated β-arrestin1 recruitment; however, they exhibited differential effects on the assembly of AT1R into oligomeric complexes. Our results demonstrate the importance of hydrophobic amino acids at the AT1R transmembrane interface, and provide the first glimpse of the requirements for AT1R complex assembly.

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Measurement of immunofunctional leptin to detect and monitor patients with functional leptin deficiency

Context and aims

Functional leptin deficiency is characterized by high levels of circulating immunoreactive leptin (irLep), but a reduced bioactivity of the hormone due to defective receptor binding. As a result of the fact that affected patients can be successfully treated with metreleptin, it was aimed to develop and validate a diagnostic tool to detect functional leptin deficiency.

Methods

An immunoassay capable of recognizing the functionally relevant receptor-binding complex with leptin was developed (bioLep). The analytical quality of bioLep was validated and compared to a conventional assay for immune-reactive leptin (irLep). Its clinical relevance was evaluated in a cohort of lean and obese children and adults as well as in children diagnosed with functional leptin deficiency and their parents.

Results

In the clinical cohort, a bioLep/irLep ratio of 1.07 (range: 0.80–1.41) was observed. Serum of patients with non-functional leptin due to homozygous amino acid exchanges (D100Y or N103K) revealed high irLep but non-detectable bioLep levels. Upon treatment of these patients with metreleptin, irLep levels decreased, whereas levels of bioLep increased continuously. In patient relatives with heterozygous amino acid exchanges, a bioLep/irLep ratio of 0.52 (range: 0.48–0.55) being distinct from normal was observed.

Conclusions

The new bioLep assay is able to diagnose impaired leptin bioactivity in severely obese patients with a homozygous gene defect and in heterozygous carriers of such mutations. The assay serves as a diagnostic tool to monitor leptin bioactivity during treatment of these patients.

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Isolated GNRH deficiency: genotypic and phenotypic characteristics of the genetically heterogeneous Greek population

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Epigenetic Basis of Cancer Health Disparities: Looking Beyond Genetic Differences

Publication date: Available online 17 January 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Aamir Ahmad, Shafquat Azim, Haseeb Zubair, Mohammad Aslam Khan, Seema Singh, James E. Carter, Rodney Rocconi, Ajay P. Singh
Despite efforts at various levels, racial health disparities still exist in cancer patients. These inequalities in incidence and/or clinical outcome can only be explained by a multitude of factors, with genetic basis being one of them. Several investigations have provided convincing evidence to support epigenetic regulation of cancer-associated genes, which results in the differential transcriptome and proteome, and may be linked to a pre-disposition of individuals of certain race/ethnicity to early or more aggressive cancers. Recent technological advancements and the ability to quickly analyze whole genome have aided in these efforts, and owing to their relatively easy detection, methylation events are much well-characterized, than the acetylation events, across human populations. The early trend of investigating a pre-determined set of genes for differential epigenetic regulation is paving way for more unbiased screening. This review summarizes our current understanding of the epigenetic events that have been tied to the racial differences in cancer incidence and mortality. A better understanding of the epigenetics of racial diversity holds promise for the design and execution of novel strategies targeting the human epigenome for reducing the disparity gaps.



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Announcing additional leadership in plant biology [Editorial]

Editorial

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Integrated physiological, proteomic and metabolomic analysis of UV stress responses and adaptation mechanisms in Pinus radiata [Research]

Globally expected changes in environmental conditions, especially the increase of UV irradiation, necessitate extending our knowledge of the mechanisms mediating tree species adaptation to this stress. This is crucial for designing new strategies to maintain future forest productivity. Studies focused on environmentally realistic dosages of UV irradiation in forest species are scarce. Pinus sp. are commercially relevant trees and not much is known about their adaptation to UV. In this work, UV treatment and recovery of Pinus radiata plants with dosages mimicking future scenarios, based on current models of UV radiation, were performed in a time-dependent manner. The combined metabolome and proteome analysis were complemented with measurements of physiological parameters and gene expression. Sparse PLS analysis revealed complex molecular interaction networks of molecular and physiological data. Early responses prevented photoxicity by reducing photosystem activity and the electron transfer chain together with the accumulation of photoprotectors and photorespiration. Apart from the reduction in photosynthesis as consequence of the direct UV damage on the photosystems, the primary metabolism was rearranged to deal with the oxidative stress while minimizing ROS production. New protein kinases and proteases related to signalling, coordination, and regulation of UV stress responses were revealed. All these processes demonstrate a complex molecular interaction network extending the current knowledge on UV-stress adaptation in pine.

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Role of cardiotrophin-1 in the regulation of metabolic circadian rhythms and adipose core clock genes in mice and characterization of 24-h circulating CT-1 profiles in normal-weight and overweight/obese subjects [Research]

Cardiotrophin (CT)-1 is a regulator of glucose and lipid homeostasis. In the present study, we analyzed whether CT-1 also acts to peripherally regulate metabolic rhythms and adipose tissue core clock genes in mice. Moreover, the circadian pattern of plasma CT-1 levels was evaluated in normal-weight and overweight subjects. The circadian rhythmicity of oxygen consumption rate (Vo₂) was disrupted in aged-obese CT-1-deficient (CT-1^–/–) mice (12 mo). Although circadian rhythms of Vo₂ were conserved in young-lean CT-1^–/– mice (2 mo), CT-1 deficiency caused a phase shift of the acrophase. Most of the clock genes studied (Clock, Bmal1, and Per2) displayed a circadian rhythm in adipose tissue of both wild-type (WT) and CT-1^–/– mice. However, the pattern was altered in CT-1^–/– mice toward a lower percentage of the rhythm or lower amplitude, especially for Bmal1 and Clock. Moreover, CT-1 mRNA levels in adipose tissue showed significant circadian fluctuations in young WT mice. In humans, CT-1 plasma profile exhibited a 24-h circadian rhythm in normal-weight but not in overweight subjects. The 24-h pattern of CT-1 was characterized by a pronounced increase during the night (from 02:00 to 08:00). These observations suggest a potential role for CT-1 in the regulation of metabolic circadian rhythms.—López-Yoldi, M., Stanhope, K. L., Garaulet, M., Chen, X. G., Marcos-Gómez, B., Carrasco-Benso, M. P., Santa Maria, E. M., Escoté, X., Lee, V., Nunez, M. V., Medici, V., Martínez-Ansó, E., Sáinz, N., Huerta, A. E., Laiglesia, L. M., Prieto, J. Martínez, J. A., Bustos, M., Havel, P. J., Moreno-Aliaga, M. J. Role of cardiotrophin-1 (CT-1) in the regulation of metabolic circadian rhythms and adipose core clock genes in mice and characterization of 24-h circulating CT-1 profiles in normal-weight and overweight/obese subjects.

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Glutamate oxaloacetate transaminase enables anaplerotic refilling of TCA cycle intermediates in stroke-affected brain [Research]

Ischemic stroke results in excessive release of glutamate, which contributes to neuronal cell death. Here, we test the hypothesis that otherwise neurotoxic glutamate can be productively metabolized by glutamate oxaloacetate transaminase (GOT) to maintain cellular energetics and protect the brain from ischemic stroke injury. The GOT-dependent metabolism of glutamate was studied in primary neural cells and in stroke-affected C57-BL6 mice using magnetic resonance spectroscopy and GC-MS. Extracellular Glu sustained cell viability under hypoglycemic conditions and increased GOT-mediated metabolism in vitro. Correction of stroke-induced hypoxia using supplemental oxygen in vivo lowered Glu levels as measured by ¹H magnetic resonance spectroscopy. GOT knockdown abrogated this effect and caused ATP loss in the stroke-affected brain. GOT overexpression increased anaplerotic refilling of tricarboxylic acid cycle intermediates in mouse brain during ischemic stroke. Furthermore, GOT overexpression not only reduced ischemic stroke lesion volume but also attenuated neurodegeneration and improved post-stroke sensorimotor function. Taken together, our results show that GOT enables metabolism of otherwise neurotoxic extracellular Glu through a truncated tricarboxylic acid cycle under hypoglycemic conditions.—Rink, C., Gnyawali, S., Stewart, R., Teplitsky, S., Harris, H., Roy, S., Sen, C. K., Khanna, S. Glutamate oxaloacetate transaminase enables anaplerotic refilling of TCA cycle intermediates in stroke-affected brain.

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PR-957, a selective inhibitor of immunoproteasome subunit low-MW polypeptide 7, attenuates experimental autoimmune neuritis by suppressing Th17 cell differentiation and regulating cytokine production [Research]

Experimental autoimmune neuritis (EAN) is a CD4⁺ T cell–mediated autoimmune inflammatory demyelinating disease of the peripheral nervous system. It has been replicated in an animal model of human inflammatory demyelinating polyradiculoneuropathy, Guillain-Barré syndrome. In this study, we evaluated the therapeutic efficacy of a selective inhibitor of the immunoproteasome subunit, low-MW polypeptide 7 (PR-957) in rats with EAN. Our results showed that PR-957 significantly delayed onset day, reduced severity and shortened duration of EAN, and alleviated demyelination and inflammatory infiltration in sciatic nerves. In addition to significantly regulating expression of the cytokine profile, PR-957 treatment down-regulated the proportion of proinflammatory T helper (T_h)17 cells in sciatic nerves and spleens of rats with EAN. Data presented show the role of PR-957 in the signal transducer and activator of transcription 3 (STAT3) pathway. PR-957 not only decreased expression of IL-6 and IL-23 but also led to down-regulation of STAT3 phosphorylation in CD4⁺ T cells. Regulation of the STAT3 pathway led to a reduction in retinoid-related orphan nuclear receptor t and IL-17 production. Furthermore, reduction of STAT3 phosphorylation may have directly suppressed T_h17 cell differentiation. Therefore, our study demonstrates that PR-957 could potently alleviate inflammation in rats with EAN and that it may be a likely candidate for treating Guillain-Barré syndrome.—Liu, H., Wan, C., Ding, Y., Han, R., He, Y., Xiao, J., Hao, J. PR-957, a selective inhibitor of immunoproteasome subunit low-MW polypeptide 7, attenuates experimental autoimmune neuritis by suppressing T_h17 cell differentiation and regulating cytokine production.

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Role of the constant region domain in the structural diversity of human antibody light chains [Research]

Issues regarding the structural diversity (heterogeneity) of an antibody molecule have been the subject of discussion along with the development of antibody drugs. Research on heterogeneity has been extensive in recent years, but no clear solution has been reached. Heterogeneity is also observed in catalytic antibody light chains (CLs). In this study, we investigated how the constant region domain of CLs concerns structural diversity because it is a simple and good example for elucidating heterogeneity. By means of cation-exchange chromatography, SDS-PAGE, and 2-dimensional electrophoresis for the CL, multimolecular forms consisting of different electrical charges and molecular sizes coexisted in the solution, resulting in the similar heterogeneity of the full length of CLs. The addition of copper ion could cause the multimolecular forms to change to monomolecular forms. Copper ion contributed greatly to the enrichment of the dimer form of CL and the homogenization of the differently charged CLs. Two molecules of the CL protein bind one copper ion. The binding affinity of the ion was 48.0 μM^–1. Several divalent metal ions were examined, but only zinc showed a similar effect.—Hifumi, E., Taguchi, H., Kato, R., Uda, T. Role of the constant region domain in the structural diversity of human antibody light chains.

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Roles of 5-lipoxygenase and cyclooxygenase-2 in the biosynthesis of hemiketals E2 and D2 by activated human leukocytes [Research]

The 2 hemiketal (HK) eicosanoids HKD₂ and HKE₂ are the major products of the biosynthetic crossover of the 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2) pathways. HKs result from the rearrangement of a di-endoperoxide intermediate formed in the COX-2-dependent oxygenation of 5S-hydroxyeicosatetraenoic acid (5S-HETE). We analyzed HK biosynthesis in human leukocytes stimulated ex vivo and defined the biosynthetic roles of 5-LOX and COX-2, using inhibitors and incubations with exogenous substrates. Activation of leukocytes with LPS followed by treatment with the calcium ionophore A23187 resulted in the formation of PGE₂, 5-HETE, and LTB₄ as the principal metabolites of COX-2 and 5-LOX, respectively. The formation of HKD₂ and HKE₂ was highest after 15 min LPS treatment, and at that time, levels were similar to PGE₂, but less than 5-HETE and LTB₄. The time course of HK formation paralleled that of 5-HETE and LTB₄, implying the availability of the 5S-HETE substrate as a limiting factor in biosynthesis rather than expression levels of COX-2. Specific inhibitors of COX-2 and 5-LOX decreased formation of HKD₂ and HKE₂. Platelets did not form HKs from exogenous 5S-HETE, implying that COX-1 is not involved. HKs are early products during an inflammatory event and require cells that express 5-LOX and COX-2 for their biosynthesis.—Giménez-Bastida, J. A., Shibata, T., Uchida, K., Schneider, C. Roles of 5-lipoxygenase and cyclooxygenase-2 in the biosynthesis of hemiketals E₂ and D₂ by activated human leukocytes.

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Hypoxia-Induced Fibroblast Growth Factor 11 Stimulates Osteoclast-Mediated Resorption of Bone

Abstract

Over-activation of osteoclasts is directly responsible for pathological bone loss in conditions such as rheumatoid arthritis and cancer metastasis to bone. Hypoxia is a common feature of these conditions, associated with poor prognosis, which also stimulates osteoclast-mediated bone resorption via induction of the hypoxia-inducible transcription factor HIF-1α. Here, we investigate the effects of fibroblast growth factor 11 (FGF11) on osteoclast function. FGF11 is an intracellular FGF that was induced both by hypoxia (2% O₂, p < 0.01) and by inhibition of the HIF-regulating prolyl hydroxylase enzymes (CoCl₂, p < 0.001) in osteoclasts. Isoform-specific siRNA demonstrated that the induction of Fgf11 mRNA expression by hypoxia is HIF-1α-dependent (p < 0.01). Hypoxic stimulation of bone resorption was inhibited in osteoclasts treated with siRNA targeting FGF11 (p < 0.05). This was at least partially due to reduced secretion of an unidentified pro-resorptive factor downstream of FGF11. FGF11 expression within hypoxic, resorbing osteoclasts co-localised with microtubule-associated alpha-tubulin. FGF11 was also abundantly expressed in osteoclasts within the rheumatoid synovium and in giant cell tumour of bone. This study suggests FGF11 as a novel factor driving pathological bone resorption in osteolytic disease and as a potential target for the development of new anti-resorptive therapeutic agents.

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Research Report on Doxorubicin Market Analysis, Application Analysis, Competitive Strategies and Forecast, 2016 To ... - Medgadget (blog)

Research Report on Doxorubicin Market Analysis, Application Analysis, Competitive Strategies and Forecast, 2016 To ... Medgadget (blog) ... kidney cancer, ovarion cancer, small cell lung cancer, thyroid cancer and transitional cell bladder cancer. Drug used for treating thyroid cancer dominated the market in the recent past on account of growing incidences of thyroid cancer especially ...

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Attitudes towards fever amongst UK paediatric intensive care staff

Abstract

The role played by fever in the outcome of critical illness in children is unclear. This survey of medical and nursing staff in 35 paediatric intensive care units and transport teams in the United Kingdom and Ireland established attitudes towards the management of children with fever. Four hundred sixty-two medical and nursing staff responded to a web-based survey request. Respondents answered eight questions regarding thresholds for temperature control in usual clinical practice, indications for paracetamol use, and readiness to participate in a clinical trial of permissive temperature control. The median reported threshold for treating fever in clinical practice was 38 °C (IQR 38–38.5 °C). Paracetamol was reported to be used as an analgesic and antipyretic but also for non-specific comfort indications. There was a widespread support for a clinical trial of a permissive versus a conservative approach to fever in paediatric intensive care units. Within a trial, 58% of the respondents considered a temperature of 39 °C acceptable without treatment.

Conclusions: Staff on paediatric intensive care units in the United Kingdom and Ireland tends to treat temperatures within the febrile range. There was a willingness to conduct a randomized controlled trial of treatment of fever.

What is known:

• The effect of fever on the outcome in paediatric critical illness is unknown.

• Paediatricians have traditionally been reluctant to allow fever in sick children.

What is new:

• Paediatric intensive care staff report a tendency towards treating fever, with a median reported treatment threshold of 38 °C.

• There is widespread support amongst PICU staff in the UK for a randomized controlled trial of temperature in critically ill children.

• Within a trial setting, PICU staff attitudes to fever are more permissive than in clinical practice.

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Chronic symptoms in a representative sample of community-dwelling older people: a cross-sectional study in Switzerland

Objectives

The burden of multiple diagnoses is well documented in older people, but less is known about chronic symptoms, many of which are even not brought to medical attention. This study aimed to determine the prevalence of chronic symptoms, their relationships with disability in basic activities of daily living (BADL) and quality of life (QoL), and their public health impact.

Design

A large cross-sectional population-based study.

Setting

Community in 2 regions of French-speaking Switzerland.

Participants

Community-dwelling older adults aged 68 years and older in 2011 (N=5300).

Outcomes

Disability in BADL defined as difficulty or help needed with any of dressing, bathing, eating, getting in/out of bed or an arm chair, and using the toilet. Overall QoL dichotomised as favourable (ie, excellent or very good) or unfavourable (ie, good, fair or poor). Disturbance by any of the following 14 chronic symptoms for at least 6 months: joint pain, back pain, chest pain, dyspnoea, persistent cough, swollen legs, memory gaps, difficulty concentrating, difficulty making decisions, dizziness/vertigo, skin problems, stomach/intestine problems, urinary incontinence and impaired sexual life.

Results

Only 17.1% of participants did not report being disturbed by any of these chronic symptoms. Weighted prevalence ranged from 3.1% (chest pain) to 47.7% (joint pain). Most chronic symptoms were significantly associated with disability in BADL or unfavourable QoL, with substantial gender differences. The number of chronic symptoms was significantly associated with disability in BADL and unfavourable QoL, with gradients suggesting dose–response relationships. Joint pain and back pain had the highest population attributable fractions.

Conclusions

Chronic symptoms are highly prevalent in older people, and are associated with disability in BADL and unfavourable QoL, particularly when multiple chronic symptoms co-occur. Owing to their high public health impact, musculoskeletal chronic symptoms represent good targets for preventive interventions.

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Understanding the importance of therapeutic relationships in the development of self-management behaviours during cancer rehabilitation: a qualitative research protocol

Introduction

Cancer is a growing health, social and economic problem. 1 in 3 people in the UK will develop cancer in their lifetime. With survival rates rising to over 50%, the long-term needs of cancer survivors are of growing importance. Cancer rehabilitation is tailored to address the physical or psychosocial decline in ability to engage in daily activities. Its use is supported by high-quality international, multicentre research. Incorporating strategies for self-management behaviour development into rehabilitation can prepare individuals for cancer survivorship. However, healthcare professionals will need to adjust their therapeutic interactions accordingly. Research is yet to clarify the impact of the therapeutic relationship on rehabilitation outcomes in cancer. This study aims to explore the impact of therapeutic relationships on self-management behaviours after cancer.

Methods and analysis

This qualitative study aims to understand cancer rehabilitation participants’ beliefs regarding the importance of therapeutic relationships in developing self-management behaviours. A sample representative of a local cancer rehabilitation cohort will be asked to complete a semistructured interview to identify their perspectives on the importance of therapeutic relationships in cancer rehabilitation. Data obtained from the interviews will be analysed, coded and entered into a Delphi questionnaire for circulation to a local cancer rehabilitation population to determine if the views expressed by the interviewees are supported by group consensus.

Ethics and dissemination

This study was approved by Wales Research Ethics Committee 6 (15/WA/0331) in April 2016. Findings will be disseminated through the first author's doctoral thesis; peer-reviewed journals; local, national and international conference presentations; and public events involving research participants and the general public.

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Factors predicting antibiotic prescription and referral to hospital for children with respiratory symptoms: secondary analysis of a randomised controlled study at out-of-hours services in primary care

Objectives

Acute respiratory infections and fever among children are highly prevalent in primary care. It is challenging to distinguish between viral and bacterial infections. Norway has a relatively low prescription rate of antibiotics, but it is still regarded as too high as the antimicrobial resistance is increasing. The aim of the study was to identify predictors for prescribing antibiotics or referral to hospital among children.

Design

Secondary analysis of a randomised controlled study.

Setting

4 out-of-hours services and 1 paediatric emergency clinic in Norwegian primary care.

Participants

401 children aged 0–6 years with respiratory symptoms and/or fever visiting the out-of-hours services.

Outcomes

2 main outcome variables were registered: antibiotic prescription and referral to hospital.

Results

The total prescription rate of antibiotics was 23%, phenoxymethylpenicillin was used in 67% of the cases. Findings on ear examination (OR 4.62; 95% CI 2.35 to 9.10), parents' assessment that the child has a bacterial infection (OR 2.45; 95% CI 1.17 to 5.13) and a C reactive protein (CRP) value >20 mg/L (OR 3.57; 95% CI 1.43 to 8.83) were significantly associated with prescription of antibiotics. Vomiting in the past 24 hours was negatively associated with prescription (OR 0.26; 95% CI 0.13 to 0.53). The main predictors significantly associated with referral to hospital were respiratory rate (OR 1.07; 95% CI 1.03 to 1.12), oxygen saturation <95% (OR 3.39; 95% CI 1.02 to 11.23), signs on auscultation (OR 5.57; 95% CI 1.96 to 15.84) and the parents' assessment before the consultation that the child needs hospitalisation (OR 414; 95% CI 26 to 6624).

Conclusions

CRP values >20 mg/L, findings on ear examination, use of paracetamol and no vomiting in the past 24 hours were significantly associated with antibiotic prescription. Affected respiration was a predictor for referral to hospital. The parents' assessment was also significantly associated with the outcomes.

Trial registration number

NCT02496559; Results.

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Natural language processing to extract symptoms of severe mental illness from clinical text: the Clinical Record Interactive Search Comprehensive Data Extraction (CRIS-CODE) project

Objectives

We sought to use natural language processing to develop a suite of language models to capture key symptoms of severe mental illness (SMI) from clinical text, to facilitate the secondary use of mental healthcare data in research.

Design

Development and validation of information extraction applications for ascertaining symptoms of SMI in routine mental health records using the Clinical Record Interactive Search (CRIS) data resource; description of their distribution in a corpus of discharge summaries.

Setting

Electronic records from a large mental healthcare provider serving a geographic catchment of 1.2 million residents in four boroughs of south London, UK.

Participants

The distribution of derived symptoms was described in 23 128 discharge summaries from 7962 patients who had received an SMI diagnosis, and 13 496 discharge summaries from 7575 patients who had received a non-SMI diagnosis.

Outcome measures

Fifty SMI symptoms were identified by a team of psychiatrists for extraction based on salience and linguistic consistency in records, broadly categorised under positive, negative, disorganisation, manic and catatonic subgroups. Text models for each symptom were generated using the TextHunter tool and the CRIS database.

Results

We extracted data for 46 symptoms with a median F1 score of 0.88. Four symptom models performed poorly and were excluded. From the corpus of discharge summaries, it was possible to extract symptomatology in 87% of patients with SMI and 60% of patients with non-SMI diagnosis.

Conclusions

This work demonstrates the possibility of automatically extracting a broad range of SMI symptoms from English text discharge summaries for patients with an SMI diagnosis. Descriptive data also indicated that most symptoms cut across diagnoses, rather than being restricted to particular groups.

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Clinical management of unruptured intracranial aneurysm in Germany: a nationwide observational study over a 5-year period (2005-2009)

Objectives

Our aim was to provide nationwide age-standardised rates (ASR) on the usage of endovascular coiling and neurosurgical clipping for unruptured intracranial aneurysm (UIA) treatment in Germany.

Setting

Nationwide observational study using the Diagnosis-Related-Groups (DRG) statistics for the years 2005–2009 (overall 83 million hospitalisations).

Participants

From 2005 to 2009, overall 39 155 hospitalisations with a diagnosis of UIA occurred in Germany.

Primary outcome measures

Age-specific and age-standardised hospitalisation rates for UIA with the midyear population of Germany in 2007 as the standard.

Results

Of the 10 221 hospitalisations with UIA during the observation period, 6098 (59.7%) and 4123 (40.3%) included coiling and clipping, respectively. Overall hospitalisation rates for UIA increased by 39.5% (95% CI 24.7% to 56.0%) and 50.4% (95% CI 39.6% to 62.1%) among men and women, respectively. In 2005, the ASR per 100 000 person years for coiling was 0.7 (95% CI 0.62 to 0.78) for men and 1.7 (95% CI 1.58 to 1.82) for women. In 2009, the ASR was 1.0 (95% CI 0.90 to 1.10) and 2.4 (95% CI 2.24 to 2.56), respectively. Similarly, the ASR for clipping in 2005 amounted to 0.6 (95% CI 0.52 to 0.68) for men and 1.1 (95% CI 1.00 to 1.20) for women. These rates increased in 2009 to 0.8 (95% CI 0.72 to 0.88) and 1.7 (95% CI 1.58 to 1.82), respectively. We observed a marked geographical variation of ASR for coiling and less pronounced for clipping. For the federal state of Saarland, the ASR for coiling was 5.64 (95% CI 4.76 to 6.52) compared with 0.68 (95% CI 0.48 to 0.88; per 100 000 person years) in Saxony-Anhalt, whereas, ASR for clipping were highest in Rhineland-Palatinate (2.48, 95% CI 2.17 to 4.75) and lowest in Saxony-Anhalt (0.52, 95% CI 0.34 to 0.70).

Conclusions

To the best of our knowledge, we presented the first representative, nationwide analysis of the clinical management of UIA in Germany. The ASR increased markedly and showed substantial geographical variation among federal states for all treatment modalities during the observation period.

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