Publication date: May 2017
Source:Biomedicine & Pharmacotherapy, Volume 89
Author(s): Ângela Sena-Lopes, Raquel Nascimento das Neves, Francisco Silvestre Brilhante Bezerra, Mara Thais de Oliveira Silva, Patrick C. Nobre, Gelson Perin, Diego Alves, Lucielli Savegnago, Karine Rech Begnini, Fabiana Kommling Seixas, Tiago Collares, Sibele Borsuk
The increased prevalence of metronidazole-resistant infections has resulted in a search for alternative drugs for the treatment of trichomoniasis. In the present study, we report the preparation and in vitro activity of three 1,3-dioxolanes that contain tellurium (PTeDOX 01, PTeDOX 02, and PTeDOX 03) against Trichomonas vaginalis. Six concentrations of these compounds were analyzed for in vitro activity against ATCC 30236 isolate of T. vaginalis. PTeDOX 01 reported a cytotoxic effect against 100% of T. vaginalis trophozoites at a final concentration of 90μM with an IC50 of 60μM. The kinetic growth curve of trophozoites indicated that PTeDOX 01 reduced the growth by 22% at a concentration of 90μM after an exposure of 12h, and induced complete parasite death at 24h. It induced cytotoxicity of 44% at 90μM concentration but and had no effect in lower concentrations in a culture of CHO-K1 cells. These results confirmed that PTeDOX 01 is an important drug for the treatment of T. vaginalis, and should be evaluated in other infectious agents as well.
http://ift.tt/2lSlgLc
Παρασκευή 24 Φεβρουαρίου 2017
Antiparasitic activity of 1,3-dioxolanes containing tellurium in Trichomonas vaginalis
An alternative POLDIP3 transcript promotes hepatocellular carcinoma progression
Publication date: May 2017
Source:Biomedicine & Pharmacotherapy, Volume 89
Author(s): Xiao-Ning Liu, Ji-Hang Yuan, Tian-Tian Wang, Wei Pan, Shu-Han Sun
Alternative splicing plays critical roles in many pathophysiological processes and splicing dysregulation is a hallmark of cancer. The different isoforms may have significantly different effects on cancers. POLDIP3 is a target of ribosomal protein S6 kinase 1, and regulates DNA replication and mRNA translation. In this study, we measured the expression of an alternative POLDIP3 transcript (POLDIP3-β), which lacks exon 3 and 29 amine acids, in clinical hepatocellular carcinoma (HCC) tissues. The roles of POLDIP3-β on HCC cell proliferation, apoptosis, and migration were assessed by Glo cell viability assays, Ethynyl deoxyuridine incorporation assays, colony formation assays, TUNEL assays, Annexin V-propidium iodide staining and flow cytometry, transwell assays, wound healing assays, and in vivo xenograft growth. Our results showed that POLDIP3-β was significantly upregulated in HCC tissues compared with paired adjacent noncancerous hepatic tissues. In vitro and in vivo functional experiments results demonstrated that overexpression of POLDIP3-β drastically increased HCC cell proliferation, inhibited HCC cell apoptosis, enhanced HCC cell migration, and promoted xenograft growth. While the effects of normal POLDIP3, which contains exon 3, were much weaker. In conclusion, our study demonstrated that an alternative transcript of POLDIP3 is upregulated and functions as a critical oncogene in HCC. Selectively targeting this isoform of POLDIP3 would be a promising therapeutic strategy for HCC.
http://ift.tt/2l7UNVw
Apigenin attenuates hippocampal oxidative events, inflammation and pathological alterations in rats fed high fat, fructose diet
Publication date: May 2017
Source:Biomedicine & Pharmacotherapy, Volume 89
Author(s): Jagan Kalivarathan, Sathiya Priya Chandrasekaran, Kalpana Kalaivanan, Vidhya Ramachandran, Anuradha Carani Venkatraman
High calorie diet promotes oxidative stress and chronic low grade inflammation that predispose to brain dysfunction and neurodegeneration. Hippocampus region of the brain has been shown to be particularly sensitive to high calorie diet. We hypothesize that apigenin (API), a flavonoid could attenuate hippocampal derangements induced by high fat-high fructose diet (HFFD). In this study, we investigated the effects of API on oxidative stress and inflammation in the hippocampus, and compared with those of sitagliptin (STG), a standard drug with neuroprotective properties. The markers of oxidative stress and inflammation were examined using biochemical assays, western blotting and immunohistochemistry techniques. HFFD-fed rats showed severe pathological alterations and API treatment rescued the hippocampus from the derangements. API significantly improved the antioxidant machinery, reduced ROS levels and prevented the activation of the stress kinases, inhibitor of kappa B kinase beta (IKKβ) and c-Jun NH2 terminal kinase (JNK), and the nuclear translocation and activation of nuclear factor kappa B (NF-κB). The plasma levels of inflammatory cytokines were also reduced. Our findings suggest that hippocampal derangements triggered by HFFD feeding were effectively curtailed by API. Suppression of oxidative stress, NF-κB activation and JNK phosphorylation in the hippocampus are the mechanisms by which API offers neuroprotection in this model.
http://ift.tt/2mly5L8
Immodin and its immune system supportive role in paclitaxel therapy of 4T1 mouse breast cancer
Publication date: May 2017
Source:Biomedicine & Pharmacotherapy, Volume 89
Author(s): Vlasta Demečková, Peter Solár, Gabriela Hrčková, Dagmar Mudroňová, Bianka Bojková, Monika Kassayová, Soňa Gancarčiková
It is evident that standard chemotherapy agents may have an impact on both tumor and host immune system. Paclitaxel (PTX), a very potent anticancer drug from a taxane family, has achieved prominence in clinical oncology for its efficacy against a wide range of tumors including breast cancer. However, significant toxicity, such as myelosuppression, limit the effectiveness of Paclitaxel-based treatment regimens. Immodin (IM) is low molecular dialysate fraction of homogenate made from human leukocytes. It contains a mixture of substances from which so far have been described e.g. Imreg 1 and Imreg 2 formed by the dipeptide tyrosine-glycine and the tripeptide tyrosine-glycine-glycine, respectively. The aim of this study was to explore immunopharmacological activities of IM, using the strongly immunogenic 4T1 mouse breast cancer model, and evaluate its effect on the reactivity and the efficiency of PTX cancer therapy. The results highlight a potentially beneficial role for IM in alleviating PTX-induced toxicity, especially on the nonspecific immunity, during breast cancer therapy. Co-treatment exhibited an antitumor effect including reduced tumor growth, prolonged survival of tumor bearing mice, increased number of monocytes and lymphocytes in peripheral blood. In spleens, IM+PTX therapy elevated proportion of whole lymphocytes in the account of myelo-monocytic cells characteristic with low expression of CD11c+ and bearing Fc receptor (CD16/32) as well as T-lymphocytes, NK cells and dendritic cells. Accumulation of tumor-associated granulocytes in stroma of PTX-treated group and intensive 4T1-necrosis/apoptosis in tumors after co-treatment were also recorded. These findings suggest the possibility of using IM alongside PTX treatment for maintaining the immune system functions and increasing patient survival.
http://ift.tt/2lBYQwV
Synthesis, characterization and radiolabeling of polymeric nano-micelles as a platform for tumor delivering
Publication date: May 2017
Source:Biomedicine & Pharmacotherapy, Volume 89
Author(s): Caroline Mari Ramos Oda, Renata Salgado Fernandes, Sávia Caldeira de Araújo Lopes, Mônica Cristina de Oliveira, Valbert Nascimento Cardoso, Daniel Moreira Santos, Adriano Monteiro de Castro Pimenta, Angelo Malachias, Rogério Paniago, Danyelle M. Townsend, Patrick M. Colletti, Domenico Rubello, Ricardo José Alves, André Luís Branco de Barros, Elaine Amaral Leite
The use of nanoparticles for diagnostic approaches leads to higher accumulation in the targeting tissue promoting a better signal-to-noise ratio and consequently, early tumor detection through scintigraphic techniques. Such approaches have inherent advantages, including the possibility of association with a variety of gamma-emitting radionuclides available, among them, Tecnethium–99m (99mTc). 99mTc is readily conjugated with nanoparticles using chelating agents, such as diethylenetriaminepentaacetic acid (DTPA). Leveraging this approach, we synthesized polymeric micelles (PM) consisting of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-mPEG2000) functionalized with DTPA for radiolabeling with 99mTc. Micelles made up of DSPE-mPEG2000 and DSPE-PEG2000-DTPA had a mean diameter of ∼10nm, as measured by DLS and SAXS techniques, and a zeta potential of −2.7±1.1mV. Radiolabeled micelles exhibited high radiochemical yields and stability. In vivo assays indicated long blood circulation time (456.3min). High uptake in liver, spleen and kidneys was observed in the biodistribution and imaging studies on healthy and tumor-bearing mice. In addition, a high tumor-to-muscle ratio was detected, which increased over time, showing accumulation of the PM in the tumor region. These findings indicate that this system is a promising platform for simultaneous delivery of therapeutic agents and diagnostic probes.
http://ift.tt/2mlBz0u
RGD modified and PEGylated lipid nanoparticles loaded with puerarin: Formulation, characterization and protective effects on acute myocardial ischemia model
Publication date: May 2017
Source:Biomedicine & Pharmacotherapy, Volume 89
Author(s): Zhaoqiang Dong, Jing Guo, Xiaowei Xing, Xuguang Zhang, Yimeng Du, Qinghua Lu
ContextPuerarin has been widely used as a therapeutic agent for the treatment of cardiovascular diseases. However, its rapid elimination half-life in plasma and poor water solubility limits its clinical efficacy.ObjectiveRGD modified and PEGylated solid lipid nanoparticles loaded with puerarin (RGD/PEG-PUE-SLN) were developed to improve bioavailability of PUE, to prolong retention time in vivo and to enhance its protective effect on acute myocardial ischemia model.MethodsIn the present study, RGD-PEG-DSPE was synthesized. RGD/PEG-PUE-SLN were prepared by the solvent evaporation method with some modifications. The physicochemical properties of NPs were characterized, the pharmacokinetics, biodistribution, pharmacodynamic behavior of RGD/PEG-PUE-SLN were evaluated in acute MI rats.ResultsThe mean diameter, zeta potential, entrapment efficiency and drug loading capacity for RGD/PEG-PUE-SLN were observed as 110.5nm, −26.2mV, 85.7% and 16.5% respectively. PUE from RGD/PEG-PUE-SLN exhibited sustained drug release with a burst release during the initial 12h and a followed sustained release. Pharmacokinetics results indicated that AUC increased from 52.93 (μg/mLh) for free PUE to 176.5 (μg/mLh) for RGD/PEG-PUE-SLN. Similarly, T1/2 increased from 0.73h for free PUE to 2.62h for RGD/PEG-PUE-SLN. RGD/PEG-PUE-SLN exhibited higher drug concentration in the heart and plasma compared with other PUE formulations. It can be clearly seen that the infarct size of RGD/PEG-PUE-SLN is the lowest among all the formulation.ConclusionWe conclude that RGD modified and PEGylated SLN are promising candidate delivery vehicles for cardioprotective drugs in treatment of myocardial infarction.
http://ift.tt/2lBZ7zE
Exploring the Margin Recipe for Online Adaptive Radiation Therapy for Intermediate-Risk Prostate Cancer: An Intra-fractional Seminal Vesicles Motion Analysis
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Yang Sheng, Taoran Li, W. Robert Lee, Fang-Fang Yin, Q. Jackie Wu
PurposeTo provide a benchmark for seminal vesicle (SV) margin selection to account for intra-fractional motion, and to investigate the effectiveness of two motion surrogates in predicting intra-fractional SV coverage.Methods and Materials15 prostate patients were studied. Each patient has five pairs (one patient has four pairs) of pre-treatment and post-treatment cone-beam CTs (CBCTs). Each pair of CBCTs was registered based on prostate fiducial markers. All pre-treatment SVs were expanded with 1, 2, 3, 4, 5 and 8 mm isotropic margins to form a series of PTVs, and their intra-fractional coverage to the post-treatment SV determined the "ground truth" for exact coverage. Two motion surrogates, the center-of-mass (COM) and the border of contour, were evaluated using Pearson product-moment correlation coefficient and exponential fitting for predicting SV underdosage. Action threshold of each surrogate was calculated. The margin for each surrogate was calculated using a traditional margin recipe.Results95% post-treatment SV coverage was achieved in 9%, 53%, 73%, 86%, 95% and 97% fractions with 1, 2, 3, 4, 5 and 8 mm margin, respectively. 5 mm margins provided 95% intra-fractional SV coverage in over 90% fractions. The correlation between the COM and border was weak, moderate and strong in the LR, AP and SI directions, respectively. Exponential fitting gave the underdosage threshold of 4.5 and 7.0 mm for the COM and border. Van Herk's margin recipe recommended 0, 0.5 and 0.8 mm margins in the LR, AP and SI directions based on the COM, and 1.2, 3.9 and 2.5 mm based on the border.Conclusions5 mm isotropic margins for the SV is the minimum required to mitigate the intra-fractional motion. Both the COM and border are acceptable predictors for SV underdosage with 4.5 and 7.0 mm action threshold. Traditional margin based on the COM or border underestimates the margin.
Teaser
We investigated the minimal margin for seminal vesicles based on volumetric coverage to mitigate intra-fractional motion during prostate radiation therapy. The volume coverage based margin provided ground truth for analyzing the effectiveness of two alternative motion surrogates, the center-of-mass and the border of contour. The exponential fitting was performed to test the ability of predicting underdosage of SV for two surrogates and the Van Herk's margin calculated from both surrogates was provided for reference.http://ift.tt/2liaAlt
Multiple pharmacological targets, cytotoxicity, and phytochemical profile of Aphloia theiformis (Vahl.) Benn.
Publication date: May 2017
Source:Biomedicine & Pharmacotherapy, Volume 89
Author(s): Marie Carene Nancy Picot, Onur Bender, Arzu Atalay, Gokhan Zengin, Loïc Loffredo, Francis Hadji-Minaglou, Mohamad Fawzi Mahomoodally
Aphloia theiformis (Vahl.) Benn. (AT) is traditionally used in Sub-Saharan African countries including Mauritius as a biomedicine for the management of several diseases. However, there is a dearth of experimental studies to validate these claims. We endeavoured to evaluate the inhibitory effects of crude aqueous extract as traditionally used together with the crude methanol extracts of AT leaves on urease, angiotensin (I) converting enzyme (ACE), acetylcholinesterase (AChE), cholesterol esterase (CEase), glycogen phosphorylase a (GPa), and glycation in vitro. The crude extract showing potent activity against the studied enzymes was further partitioned using different solvents of increasing polarity. The enzyme inhibitory and antiglycation activities of each fraction was assessed. Kinetic of inhibition of the active crude extract/fractions on the aforementioned enzymes was consequently determined using Lineweaver-Burk plots. An ultra-high performance liquid chromatography (UHPLC-UV/MS) system was used to establish the phytochemical profile of AT. The real time cell analysis system (iCELLigence™) was used to monitor any cellular cytotoxicity of AT. Crude methanolextract (CME) was a potent inhibitor of the studied enzymes, with IC50 ranging from 696.22 to 19.73μg/mL. CME (82.5%) significantly (p<0.05) inhibited glycation and was comparable to aminoguanidine (81.5%). Ethyl acetate and n-butanol fractions of CME showed non-competitive, competitive, and uncompetitive mode of inhibition against ACE, CEase, and AChE respectively. Mangiferin, a xanthone glucoside was present in CME, ethyl acetate, and n-butanol fractions. Active extract/fractions were found to be non-cytotoxic (IC50>20μg/mL) according to the U.S National Cancer Institute plant screening program. This study has established baseline data that tend to justify the traditional use of AT and open new avenues for future biomedicine development.
Graphical abstract
http://ift.tt/2lBYRRv
Protective effects of total flavonoids in Caragana against hypoxia/reoxygenation-induced injury in human brain microvascular endothelial cells
Publication date: May 2017
Source:Biomedicine & Pharmacotherapy, Volume 89
Author(s): Qian-Song He, Li Zhang, Zi-Yuan Fan, Guo Feng, Fu-Jiang Wang, Zheng-Qi Liu, Ting Tang, Shi-Xiang Kuang
This study aimed to explore the protective effect of total flavonoids in Caragana against hypoxia/reoxygenation (H/R)-induced injury in human brain microvascular endothelial cells (BMECs). Human BMECs were selected and assigned into control, H/R, H/R+NMP, H/R+Low dose, H/R+Moderate dose, H/R+High dose groups. MTT and Transwell assays were used to detect cell viability and migration, respectively. Cell adhesion rate and tube formation were also detected. Real-time polymerase chain reaction (RT-PCR) and Western blotting were performed to test HIF-1α, VEGF and Notch1 mRNA and protein expressions. Compared with the H/R group, the cell viability rates in the H/R+NMP, H/R+Moderate dose and H/R+High dose groups were increased. The cell adhesion rates in the H/R+NMP, H/R+Moderate dose and H/R+High dose groups were significantly different from those in the H/R group. As compared to the H/R group, the cell migration abilities in the H/R+NMP, H/R+Moderate dose and H/R+High dose groups were enhanced. Compared with the H/R group, the number and length of tubes of BMECs in the H/R+NMP, H/R+High dose and H/R+Moderate dose groups were increased. HIF-1α, VEGF and Notch1 mRNA and protein expressions were higher in the H/R+Low dose, H/R+Moderate dose and H/R+High dose groups than in the H/R group. These findings revealed that total flavonoids in Caragana can protect BMECs from H/R-induced injury in a dose-dependent manner and it also may promote angiogenesis in BMECs by activating HIF- 1α-VEGF-Notch 1 signaling pathway.
http://ift.tt/2mltkS5
Hepatoprotective activity of Butea monosperma bark against thioacetamide-induced liver injury in rats
Publication date: May 2017
Source:Biomedicine & Pharmacotherapy, Volume 89
Author(s): Varinder Kaur, Manish Kumar, Paramjeet Kaur, Sandeep Kaur, Amrit Pal Singh, Satwinderjeet Kaur
For thousands of years, the plant-based natural products have been a source of curative agents for various ailments. Butea monosperma (Fabaceae) has an important place in Indian traditional system of medicine for curing number of disorders. The present study deals with evaluation of hepatoprotective properties of ethyl acetate fraction (Beac) from B. monosperma bark in rat model. In preliminary antioxidant studies, Beac demonstrated pronounced superoxide scavenging (IC50 88.85μg/ml) and anti-lipid peroxidation (IC50 131.66μg/ml) potential. In animal studies, Beac showed protective effect against thioacetamide-induced pathophysiology in liver of male Wistar rats. The levels of different parameters related to hepatic functions were altered by thioacetamide treatment (300mg/g bw) in rats. The pre-treatment of rats with Beac (50, 100 and 200mg/kg bw) was able to normalize the biochemical markers viz. serum bilirubin, SGOT, SGPT, albumin and ALP along with liver antioxidative molecules viz. SOD, CAT, GSH and GR. Results of histopathological and colorimetric studies revealed that Beac treatment also restored the markers of fibrosis i.e. collagen and hydroxyproline towards normal level. Beac considerably inhibited thioacetamide-induced expression of p-PI3K, p-Akt and p-mTOR in hepatocytes as revealed from immunohistochemical studies. This finding is the first evidence of inhibitory action of B. monosperma bark on these pro-carcinogenic proteins. HRMS analysis revealed the presence of quercetin, buteaspermin B and ononin in Beac fraction of Butea monosperma. From the results, it can be concluded that B. monosperma bark is a rich source of phytochemicals with in vitro and in vivo protective activities which deserves further mechanistic studies for its use as a hepatoprotective agent in the prevention of hepatic inflammation and its related malignancies.
Graphical abstract
http://ift.tt/2lBWJJi
Pharmacodynamic study of eprosartan mesylate-loaded transfersomes Carbopol® gel under Dermaroller® on rats with methyl prednisolone acetate-induced hypertension
Publication date: May 2017
Source:Biomedicine & Pharmacotherapy, Volume 89
Author(s): Abdul Ahad, Abdulmohsen A. Al-Saleh, Abdullah M. Al-Mohizea, Fahad I. Al-Jenoobi, Mohammad Raish, Alaa Eldeen B. Yassin, Mohd Aftab Alam
The objective of present study was to prepare eprosartan mesylate (EM)-loaded transfersomes Carbopol® gel and characterized for various parameters, including in vitro skin permeation, in vivo antihypertensive study, skin irritation, and histological study. Furthermore, effect of transfersomes gel on angiotensin II type-1 receptor (AT1R) mRNA and protein expressions on smooth vascular muscles of aorta was determined by real-time polymerase chain reaction (RT-PCR) and western blot analysis. The physical evaluation parameters were detected to be in correspondence with reference marketed gel formulation. The transdermal flux, permeability coefficient, and Tlag of EM from transfersomes gel were found to be 26.76 ± 1.66μg/cm2/h, 8.93 ± 0.55 ×10−3 cm/h, and 2.17 ± 0.29h, respectively, across rat skin pretreated with microneedle (Dermaroller®). Pharmacodynamic study showed prolonged and better management of hypertension after the application of transfersomes gel in experimentally induced hypertensive Wistar rats as compared with oral control formulation. The in vivo angiotensin II type-1 blocking efficacy of prepared transfersomes gel and control formulation was also supported with RT-PCR and western blot analysis of AT1R mRNA and protein expressions on smooth vascular muscles of aorta. Skin irritation and skin histological assessment showed that the prepared transfersomes Carbopol® gel was safe to be used for transdermal route. It is concluded that the incorporation of transfersomes into gel formulation offered enhanced skin contact, ease of application, and found to be a suitable drug reservoir for the transdermal delivery of EM for the management of hypertension in Wistar rats.
Graphical abstract
http://ift.tt/2lC4IGf
Curcumin and treatment of melanoma: The potential role of microRNAs
Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): Diana Lelli, Claudio Pedone, Amirhosssein Sahebkar
Melanoma is the most aggressive type of skin cancer and is characterized by poor prognosis in its advanced stages because treatments are poorly effective and burdened with severe adverse effects. MicroRNAs (miRNAs) are small non-coding RNAs that are implicated in several cellular processes; they are categorized as oncogenic and tumor suppressor miRNAs. Several miRNAs are implicated in the pathogenesis and progression of melanoma, such as the tumor suppressor miR-let7b that targets cyclin D and regulates cell cycle. Curcumin is a natural compound derived from Curcuma longa L. (turmeric) with anti-cancer properties, documented also in melanoma, and is well tolerated in humans. Pharmacological activity of curcumin is mediated by modulation of several pathways, such as JAK-2/STAT3, thus inhibiting melanoma cell migration and invasion and enhancing apoptosis of these cells. The low oral bioavailability of curcumin has led to the development of curcumin analogues, such as EF24, with greater anti-tumor efficacy and metabolic stability. Potential anti-cancer activity of curcumin and its analogues is also mediated by modulation of miRNAs such as miR21, that is implicated in cell cycle regulation and apoptosis through down-regulation of PTEN and PDCD4 proteins. Curcumin has a potential role in the treatment of melanoma, though further studies are necessary to explore its clinical efficacy.
http://ift.tt/2lBSjC9
Histologic Appearance Following Pre-operative Radiation Therapy for Soft Tissue Sarcoma: Assessment of the EORTC-STBSG Response Score
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Inga-Marie Schaefer, Jason L. Hornick, Constance M. Barysauskas, Chandrajit P. Raut, Sagar A. Patel, Trevor J. Royce, Christopher D.M. Fletcher, Elizabeth H. Baldini
PurposeHistologic appearance defined as percent necrosis following neoadjuvant therapy predicts outcome in osteosarcoma, but has not been systematically studied in soft tissue sarcoma (STS). The EORTC-STBSG has proposed a response score following neo-adjuvant radiation therapy (RT) or chemotherapy for STS based on five tiers of percent residual viable cells (1). We sought to critically assess the prognostic value of the EORTC-STBSG response score and define histologic appearance following pre-operative RT for STS.Methods and MaterialsFor a cohort of 100 patients with STS of the extremity/trunk treated at our institution with pre-operative RT followed by resection, two expert sarcoma pathologists evaluated the resected specimens for percent residual viable cells, necrosis, hyalinization/fibrosis, and infarction. The EORTC response score and other predictors of recurrence free survival (RFS), and overall survival (OS) were assessed by Kaplan Meier and proportional hazard models.ResultsMedian tumor size was 7.5 cm; 92% were intermediate or high grade. Most common histologies were unclassified sarcoma (34%) and myxofibrosarcoma (25%). Median follow-up was 60 months. Five-year LR rate was 5%, 5-year RFS was 68%, and 5-year OS 75%. Distribution of cases according to EORTC response score tiers was: no residual viable tumor for 9 cases (9% pathologic complete response); < 1% viable tumor for 0, > 1% - < 10% for 9, >10% - <50% for 44, and >50% for 38. There was no association between EORTC-STBSG response score and RFS or OS. Conversely, hyalinization/fibrosis was a significant independent favorable predictor for RFS, (HR 0.49, P = 0.007) and OS (HR 0.36, P = 0.02).ConclusionHistologic evaluation after pre-operative RT for STS showed a 9% pathologic complete response rate. The EORTC-STBSG response score and percent viable cells were not prognostic. Hyalinization/fibrosis was associated with favorable outcome, and if validated, may become a valid endpoint for neoadjuvant trials.
Teaser
Histologic treatment response predicts outcome in osteosarcoma, but has not been systematically studied in soft tissue sarcoma. EORTC-STBSG proposed a neoadjuvant response score based on five tiers of percent residual viable cells. We assessed histologic appearance after pre-operative radiation for 100 soft tissue sarcomas of extremity/trunk and found the EORTC response score was not prognostic. Whereas, extent of hyalinization/fibrosis was associated with favorable outcome, and if validated, may become a valid endpoint for neoadjuvant trials.http://ift.tt/2ligVxg
Triggering the abscopal effect; is the quality of the radiation important?
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Frederik J. Vernimmen, Jill T. Nicholson
http://ift.tt/2lBVdXE
Prospective study of cetuximab, carboplatin and radiotherapy for patients with locally advanced head and neck squamous cell cancer (HNSCC) unfit for cisplatin
Publication date: Available online 24 February 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): June Corry, Mathias Bressel, Tsien Fua, Alan Herschtal, Benjamin Solomon, Sandro V. Porceddu, Chris Wratten, Danny Rischin
PurposeTo report on the outcomes of a novel treatment regimen for patients with LAHNSCC, fit for curative treatment but not fit for cisplatin.Material and MethodsSingle arm phase I/II study of previously untreated patients with biopsy proved SCC of the oropharynx, larynx or hypopharynx. The primary endpoint was feasibility of the regimen – defined as the proportion of patients successfully completing treatment. Secondary endpoints were loco-regional control (LRC), failure free survival (FFS), overall survival (OS), and treatment toxicities.ResultsSixty patients. Mean age 66 years (range 42-87 years), 28% of patients were >70 years. The median follow-up was 4 years. Compliance with treatment was very high: feasibility was 55/60 (91.7%, 90% CI [83.3% - 96.7%]) which satisfied the pre-defined criteria. The 4 year LRC was 82% (95% CI [71 – 94]), FFS was 72% (95% CI [60 – 85]) and the OS was 77% (95% CI [66-90]). The cumulative incidences of first failure of any type at 4 years were5.2% local, 1.8% local and distant, 8.5% regional, 1.7% regional and distant, 3.5% distant, and 7.7% death (any cause). The 4 year FFS in the 70 years or less and more than 70 years patients were 71% (95% CI [58-88]) and 73% (95% CI [54-100]), respectively (logrank p=0.801). Their 4-year OS was 79% (95% CI [66-93]) and 73% (95% CI [53-100]), respectively (logrank p=0.708). Significant late treatment toxicities were very few.ConclusionThis treatment regimen was feasible and safe in this patient cohort unfit for cisplatin, 28% of whom were older than 70 years. Carboplatin and cetuximab based chemoradiation regimens warrant further investigation in patients with a contraindication to cisplatin.
Teaser
This is a prospective Phase I/II study reporting on the outcomes of a novel treatment regimen for patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC), fit for curative treatment but not fit for cisplatin. The treatment regimen was delivered in 92% patients, 4 year DFS and OS was 72% and 77%, respectively, there were minimal severe late treatment toxicities. This regimen is feasible and warrants further evaluation.http://ift.tt/2kUQzFs
The feasibility of semi-automatically generated red bone marrow segmentations based on MR-only for patients with gynecologic cancer
Source:Radiotherapy and Oncology
Author(s): Anna Andreychenko, Petra S. Kroon, Matteo Maspero, Ina Jürgenliemk-Schulz, Astrid A.C. De Leeuw, Marnix G.E.H. Lam, Jan J.W. Lagendijk, Cornelis A.T. van den Berg
PurposeFor patients with cervical cancer the delivery of chemotherapy with radiotherapy improves survival compared with radiotherapy alone. However, high rates of acute hematologic toxicity occur when combining both therapies due to the damage of the red bone marrow (RBM). This study aimed to reduce the radiation damage to the RBM. A tool has been developed for semi-automatic delineation of the red bone marrow based on MR-only. This delineation can be included into the treatment planning process to reduce the volume of RBM irradiated in patients receiving pelvic radiation therapy.Methods13 patients with cervical cancer were enrolled. All the patients underwent MR, CT and FDG-PET imaging. A tool for RBM determination from water and fat MR images was developed. Our MR-based RBM tool was optimized and validated with the FDG-PET scans of the patients.ResultsOur tool identified RBM regions in the pelvic area. The mean total volume of these regions was 34% of the pelvic bone marrow. The corresponding SUV values based on the FDG-PET scans were above the reported threshold of active/red bone marrow.ConclusionThis study shows that delineations of the RBM for the radiotherapy with RBM sparing can be generated semi-automatically using MR scans only.
http://ift.tt/2lNvsEj
Correlation of pretreatment 18 F-FDG PET tumor textural features with gene expression in pharyngeal cancer and implications for radiotherapy-based treatment outcomes
Abstract
Purpose
This study investigated the correlation of the matrix heterogeneity of tumors on 18F-fluorodeoxyglucose positron emission tomography–computed tomography (PET–CT) with gene-expression profiling in patients with pharyngeal cancer and determined the prognostic factors for radiotherapy-based treatment outcomes.
Methods
We retrospectively reviewed the records of 57 patients with stage III–IV oropharyngeal or hypopharyngeal cancer who had completed definitive therapy. Four groups of the textural features as well as 31 indices were studied in addition to maximum standard uptake value, metastatic tumor volume, and total lesion glycolysis. Immunohistochemical data from pretreatment biopsy specimens (Glut1, CAIX, VEGF, HIF-1α, EGFR, Ki-67, Bcl-2, CLAUDIN-4, YAP-1, c-Met, and p16) were analyzed. The relationships between the indices and genomic expression were studied, and the robustness of various textural features relative to cause-specific survival and primary relapse-free survival was analyzed.
Results
The overexpression of VEGF was positively associated with the increased values of the matrix heterogeneity obtained using gray-level nonuniformity for zone (GLNUz) and run-length nonuniformity (RLNU). Advanced T stage (p = 0.01, hazard ratio [HR] = 3.38), a VEGF immunoreactive score of >2 (p = 0.03, HR = 2.79), and a higher GLNUz value (p = 0.04, HR = 2.51) were prognostic factors for low cause-specific survival, whereas advanced T stage, a HIF-1α staining percentage of ≥80%, and a higher GLNUz value were prognostic factors for low primary-relapse free survival.
Conclusions
The overexpression of VEGF was associated with the increased matrix index of GLNUz and RLNU. For patients with pharyngeal cancer requiring radiotherapy, the treatment outcome can be stratified according to the textural features, T stage, and biomarkers.
http://ift.tt/2lBRHMV
Effects of biochar on enhanced nutrient use efficiency of green bean, Vigna radiata L.
Abstract
Biochar is the carbonized material produced from biomass and is used in several environmental applications. The biochar characteristics depend on the carbonization conditions and feedstock. The suitability of a given biochar for soil improvement depends on the biochar characteristics, soil properties, and target plants. Biochar has been applied at 1–20% (w/w) in the soil, but currently there is a lack of information on what type and concentration of biochar are most suitable for a specific plant and soil quality. Too much biochar will reduce plant growth because of the high alkalinity of biochar, which will cause long-term soil alkalinity. In contrast, too little biochar might be insufficient to enhance plant productivity. In this study, a suitable concentration of cassava stem (an abundant agricultural waste in Thailand) biochar produced at 350 °C was evaluated for green bean (Vigna radiata L.) growth from germination to seed production in pots over 8 weeks. The soil fertility was increased with increasing biochar concentration. At 5% (w/w) biochar, the soil fertility and plant growth were significantly enhanced, while 10% (w/w) biochar significantly enhanced bean growth and bean pod production. The increased biochar concentration in the soil significantly increased the soil total nitrogen and extractable potassium (K) levels but did not affect the amount of available phosphorous. Biochar at 10% (w/w) significantly induced the accumulation of K in the stems, leaves, nut shells, and roots but not in nut seeds. Moreover, biochar not only increased the K concentration in soil but also increased the plant nutrient use efficiency of K, which is important for plant growth.
Graphical abstract
http://ift.tt/2liovrB
Commanding CNS Invasion: GM-CSF
Publication date: 21 February 2017
Source:Immunity, Volume 46, Issue 2
Author(s): Junjie Zhao, Lillian Sun, Xiaoxia Li
Granulocyte-macrophage colony-stimulating factor (GM-CSF or Csf-2) is a pro-inflammatory mediator implicated in the pathogenesis of various autoimmune diseases. In this issue of Immunity, Spath et al. (2017) show that the dysregulated production of GM-CSF rather than IL-17 induces spontaneous immunopathology in a mouse model of CNS inflammation.
Teaser
Granulocyte-macrophage colony-stimulating factor (GM-CSF or Csf-2) is a pro-inflammatory mediator implicated in the pathogenesis of various autoimmune diseases. In this issue of Immunity, Spath et al. (2017) show that the dysregulated production of GM-CSF rather than IL-17 induces spontaneous immunopathology in a mouse model of CNS inflammation.http://ift.tt/2lBJLLO
Compliments of Factor H: What’s in it for AMD?
Publication date: 21 February 2017
Source:Immunity, Volume 46, Issue 2
Author(s): Mary J. Mattapallil, Rachel R. Caspi
Genetic variations in complement factor H (CFH) confer greater risk for age-related macular degeneration (AMD). In this issue of Immunity, Calippe et al. (2017) uncover a non-canonical role for CFH in the inhibition of mononuclear phagocyte elimination from sub-retinal lesions, providing insight into the pathophysiology of AMD associated with CFH variants.
Teaser
Genetic variations in complement factor H (CFH) confer greater risk for age-related macular degeneration (AMD). In this issue of Immunity, Calippe et al. (2017) uncover a non-canonical role for CFH in the inhibition of mononuclear phagocyte elimination from sub-retinal lesions, providing insight into the pathophysiology of AMD associated with CFH variants.http://ift.tt/2lDQ4gf
Killer ILCs in the Fat
Publication date: 21 February 2017
Source:Immunity, Volume 46, Issue 2
Author(s): Emilie Narni-Mancinelli, Eric Vivier
Innate lymphoid cells (ILCs) residing in adipose tissue participate in the pathogenesis of obesity, but their contribution toward adipose tissue homeostasis in the lean state is unclear. Boulenouar et al. (2017) now report that heterogenous type 1 ILCs in adipose tissues regulate macrophage homeostasis through cytotoxicity.
Teaser
Innate lymphoid cells (ILCs) residing in adipose tissue participate in the pathogenesis of obesity, but their contribution toward adipose tissue homeostasis in the lean state is unclear. Boulenouar et al. (2017) now report that heterogenous type 1 ILCs in adipose tissues regulate macrophage homeostasis through cytotoxicity.http://ift.tt/2lBLjoS
RSV Takes Control of Neonatal Breg Cells: Two Hands on the Wheel
Publication date: 21 February 2017
Source:Immunity, Volume 46, Issue 2
Author(s): Peter J.M. Openshaw
The viral attachment protein of RSV has many surprising features, especially its mimicry of fractalkine (CX3CL1). Zhivaki et al. (2017) now show that, in addition to using this homology to attach to ciliated cells, it activates human neonatal regulatory B cells, thereby inhibiting immunological responses.
Teaser
The viral attachment protein of RSV has many surprising features, especially its mimicry of fractalkine (CX3CL1). Zhivaki et al. (2017) now show that, in addition to using this homology to attach to ciliated cells, it activates human neonatal regulatory B cells, thereby inhibiting immunological responses.http://ift.tt/2lE1DDV
The Dark Age(ing) of the Inflammasome
Publication date: 21 February 2017
Source:Immunity, Volume 46, Issue 2
Author(s): Konrad Aden, Philip Rosenstiel
Mechanisms that contribute to healthy aging remain obscure. In a recent issue of Nature Medicine, Furman et al. (2017) describe that dietary caffeine inhibits the NLRC4 inflammasome, which is associated with disease-free aging.
Teaser
Mechanisms that contribute to healthy aging remain obscure. In a recent issue of Nature Medicine, Furman et al. (2017) describe that dietary caffeine inhibits the NLRC4 inflammasome, which is associated with disease-free aging.http://ift.tt/2lBKUTr
Antigen-Primed CD8+ T Cells Call DCs for Back Up
Publication date: 21 February 2017
Source:Immunity, Volume 46, Issue 2
Author(s): Marianne Burbage, Sebastian Amigorena
Encounters between naive T lymphocytes and dendritic cells (DCs) bearing adequate co-stimulatory signals are rare. In this issue of Immunity, Brewitz et al. (2017) show that chemokines secreted by CD8+ T cells recruit myeloid and plasmacytoid DCs that in turn boost CD8+ T cell activation.
Teaser
Encounters between naive T lymphocytes and dendritic cells (DCs) bearing adequate co-stimulatory signals are rare. In this issue of Immunity, Brewitz et al. (2017) show that chemokines secreted by CD8+ T cells recruit myeloid and plasmacytoid DCs that in turn boost CD8+ T cell activation.http://ift.tt/2lE1Dnp
Prospects for a Zika Virus Vaccine
Publication date: 21 February 2017
Source:Immunity, Volume 46, Issue 2
Author(s): Dan H. Barouch, Stephen J. Thomas, Nelson L. Michael
A recent unprecedented outbreak of Zika virus (ZIKV) in the Americas has been associated with microcephaly and other congenital malformations in infants as well as Guillain-Barre syndrome in adults. The development of a safe and effective ZIKV vaccine is therefore an urgent global health priority. Promising data from preclinical vaccine studies in mice and monkeys suggest that an effective vaccine will likely be possible, but important scientific challenges remain. Here we review the current state of ZIKV vaccine development. We discuss different vaccination strategies and we highlight challenges facing clinical evaluation of ZIKV vaccine candidates.
Teaser
The development of a safe and effective Zika virus (ZIKV) vaccine is an urgent global health priority. Barouch et al. review the current state of ZIKV vaccine development and highlight challenges facing clinical evaluation of ZIKV vaccine candidates.http://ift.tt/2lBMGns
Immunopathogenesis of Rheumatoid Arthritis
Publication date: 21 February 2017
Source:Immunity, Volume 46, Issue 2
Author(s): Gary S. Firestein, Iain B. McInnes
Rheumatoid arthritis (RA) is the most common inflammatory arthropathy. The majority of evidence, derived from genetics, tissue analyses, models, and clinical studies, points to an immune-mediated etiology associated with stromal tissue dysregulation that together propogate chronic inflammation and articular destruction. A pre-RA phase lasting months to years may be characterized by the presence of circulating autoantibodies, increasing concentration and range of inflammatory cytokines and chemokines, and altered metabolism. Clinical disease onset comprises synovitis and systemic comorbidities affecting the vasculature, metabolism, and bone. Targeted immune therapeutics and aggressive treatment strategies have substantially improved clinical outcomes and informed pathogenetic understanding, but no cure as yet exists. Herein we review recent data that support intriguing models of disease pathogenesis. They allude to the possibility of restoration of immunologic homeostasis and thus a state of tolerance associated with drug-free remission. This target represents a bold vision for the future of RA therapeutics.
Teaser
Elucidation of the immune pathogenesis of rheumatoid arthritis has prompted significant therapeutic progress. Firestein and McInnes review recent advances in understanding of immune dysregulation and stromal pathology in RA that promote development and perpetuation of disease and offer exciting new therapeutic potential.http://ift.tt/2lE1Ert
Loss of PTEN Is Associated with Resistance to Anti-PD-1 Checkpoint Blockade Therapy in Metastatic Uterine Leiomyosarcoma
Publication date: 21 February 2017
Source:Immunity, Volume 46, Issue 2
Author(s): Suzanne George, Diana Miao, George D. Demetri, Dennis Adeegbe, Scott J. Rodig, Sachet Shukla, Mikel Lipschitz, Ali Amin-Mansour, Chandrajit P. Raut, Scott L. Carter, Peter Hammerman, Gordon J. Freeman, Catherine J. Wu, Patrick A. Ott, Kwok-Kin Wong, Eliezer M. Van Allen
Response to immune checkpoint blockade in mesenchymal tumors is poorly characterized, but immunogenomic dissection of these cancers could inform immunotherapy mediators. We identified a treatment-naive patient who has metastatic uterine leiomyosarcoma and has experienced complete tumor remission for >2 years on anti-PD-1 (pembrolizumab) monotherapy. We analyzed the primary tumor, the sole treatment-resistant metastasis, and germline tissue to explore mechanisms of immunotherapy sensitivity and resistance. Both tumors stained diffusely for PD-L2 and showed sparse PD-L1 staining. PD-1+ cell infiltration significantly decreased in the resistant tumor (p = 0.039). Genomically, the treatment-resistant tumor uniquely harbored biallelic PTEN loss and had reduced expression of two neoantigens that demonstrated strong immunoreactivity with patient T cells in vitro, suggesting long-lasting immunological memory. In this near-complete response to PD-1 blockade in a mesenchymal tumor, we identified PTEN mutations and reduced expression of genes encoding neoantigens as potential mediators of resistance to immune checkpoint therapy.
Graphical abstract
Teaser
George et al. report an exceptional responder to anti-PD-1 monotherapy in uterine leiomyosarcoma and propose mediators of treatment sensitivity and resistance. Neoantigen-directed immunoreactivity was associated with sensitivity to anti-PD-1 monotherapy, whereas resistance was associated with reduction in neoantigen expression consistent with immune evasion, and biallelic PTEN loss was associated with induction of an immunosuppressive microenvironment.http://ift.tt/2lBHksk
Autocrine Loop Involving IL-6 Family Member LIF, LIF Receptor, and STAT4 Drives Sustained Fibroblast Production of Inflammatory Mediators
Publication date: 21 February 2017
Source:Immunity, Volume 46, Issue 2
Author(s): Hung N. Nguyen, Erika H. Noss, Fumitaka Mizoguchi, Christine Huppertz, Kevin S. Wei, Gerald F.M. Watts, Michael B. Brenner
Fibroblasts are major contributors to and regulators of inflammation and dominant producers of interleukin-6 (IL-6) in inflammatory diseases like rheumatoid arthritis. Yet, compared to leukocytes, the regulation of inflammatory pathways in fibroblasts is largely unknown. Here, we report that analyses of genes coordinately upregulated with IL-6 pointed to STAT4 and leukemia inhibitory factor (LIF) as potentially linked. Gene silencing revealed that STAT4 was required for IL-6 transcription. STAT4 was recruited to the IL-6 promoter after fibroblast activation, and LIF receptor (LIFR) and STAT4 formed a molecular complex that, together with JAK1 and TYK2 kinases, controlled STAT4 activation. Importantly, a positive feedback loop involving autocrine LIF, LIFR, and STAT4 drove sustained IL-6 transcription. Besides IL-6, this autorine loop also drove the production of other key inflammatory factors including IL-8, granulocyte-colony stimulating factor (G-CSF), IL-33, IL-11, IL-1α, and IL-1β. These findings define the transcriptional regulation of fibroblast-mediated inflammation as distinct from leukocytes.
Graphical abstract
Teaser
Growing evidence implicates fibroblasts as inflammatory cells in sites of peripheral inflammation. Nguyen and colleagues demonstrate that regulation of IL-6 along with a set of other inflammatory cytokines and chemokines is regulated by a positive feedback loop involving LIF, LIF receptor, and STAT4 that selectively operates in fibroblasts.http://ift.tt/2lBMipd
Dysregulation of the Cytokine GM-CSF Induces Spontaneous Phagocyte Invasion and Immunopathology in the Central Nervous System
Publication date: 21 February 2017
Source:Immunity, Volume 46, Issue 2
Author(s): Sabine Spath, Juliana Komuczki, Mario Hermann, Pawel Pelczar, Florian Mair, Bettina Schreiner, Burkhard Becher
Chronic inflammatory diseases are influenced by dysregulation of cytokines. Among them, granulocyte macrophage colony stimulating factor (GM-CSF) is crucial for the pathogenic function of T cells in preclinical models of autoimmunity. To study the impact of dysregulated GM-CSF expression in vivo, we generated a transgenic mouse line allowing the induction of GM-CSF expression in mature, peripheral helper T (Th) cells. Antigen-independent GM-CSF release led to the invasion of inflammatory myeloid cells into the central nervous system (CNS), which was accompanied by the spontaneous development of severe neurological deficits. CNS-invading phagocytes produced reactive oxygen species and exhibited a distinct genetic signature compared to myeloid cells invading other organs. We propose that the CNS is particularly vulnerable to the attack of monocyte-derived phagocytes and that the effector functions of GM-CSF-expanded myeloid cells are in turn guided by the tissue microenvironment.
Graphical abstract
Teaser
GM-CSF is a pro-inflammatory cytokine that mediates tissue-targeted autoimmune diseases. Spath and colleagues show that excess production of GM-CSF was sufficient to induce spontaneous brain inflammation and neurological disease. GM-CSF-expanded, brain-infiltrating phagocytes produced reactive oxygen species and their genetic signature differed significantly from myeloid cells invading other organs.http://ift.tt/2lBKQmF
Complement Factor H Inhibits CD47-Mediated Resolution of Inflammation
Publication date: 21 February 2017
Source:Immunity, Volume 46, Issue 2
Author(s): Bertrand Calippe, Sebastien Augustin, Fanny Beguier, Hugo Charles-Messance, Lucie Poupel, Jean-Baptiste Conart, Shulong J. Hu, Sophie Lavalette, Alexandre Fauvet, Julie Rayes, Olivier Levy, William Raoul, Catherine Fitting, Thomas Denèfle, Matthew C. Pickering, Claire Harris, Sylvie Jorieux, Patrick M. Sullivan, José-Alain Sahel, Philippe Karoyan, Przemyslaw Sapieha, Xavier Guillonneau, Emmanuel L. Gautier, Florian Sennlaub
Variants of the CFH gene, encoding complement factor H (CFH), show strong association with age-related macular degeneration (AMD), a major cause of blindness. Here, we used murine models of AMD to examine the contribution of CFH to disease etiology. Cfh deletion protected the mice from the pathogenic subretinal accumulation of mononuclear phagocytes (MP) that characterize AMD and showed accelerated resolution of inflammation. MP persistence arose secondary to binding of CFH to CD11b, which obstructed the homeostatic elimination of MPs from the subretinal space mediated by thrombospsondin-1 (TSP-1) activation of CD47. The AMD-associated CFH(H402) variant markedly increased this inhibitory effect on microglial cells, supporting a causal link to disease etiology. This mechanism is not restricted to the eye, as similar results were observed in a model of acute sterile peritonitis. Pharmacological activation of CD47 accelerated resolution of both subretinal and peritoneal inflammation, with implications for the treatment of chronic inflammatory disease.
Graphical abstract
Teaser
Variants in complement factor H (CFH) show strong association to age-related macular degeneration. Calippe et al. find that CFH binding to mononuclear phagocytes (MP) curbs the CD47-mediated elimination of MPs that maintains homeostasis in the subretinal space. The AMD-associated CFH variant CFH(H402) increases subretinal MP accumulation, providing insight into disease etiology.http://ift.tt/2lBEljQ
Adipose Type One Innate Lymphoid Cells Regulate Macrophage Homeostasis through Targeted Cytotoxicity
Publication date: 21 February 2017
Source:Immunity, Volume 46, Issue 2
Author(s): Selma Boulenouar, Xavier Michelet, Danielle Duquette, David Alvarez, Andrew E. Hogan, Christina Dold, Donal O'Connor, Suzanne Stutte, Ali Tavakkoli, Desmond Winters, Mark A. Exley, Donal O'Shea, Michael B. Brenner, Ulrich von Andrian, Lydia Lynch
Adipose tissue has a dynamic immune system that adapts to changes in diet and maintains homeostatic tissue remodeling. Adipose type 1 innate lymphoid cells (AT1-ILCs) promote pro-inflammatory macrophages in obesity, but little is known about their functions at steady state. Here we found that human and murine adipose tissue harbor heterogeneous populations of AT1-ILCs. Experiments using parabiotic mice fed a high-fat diet (HFD) showed differential trafficking of AT1-ILCs, particularly in response to short- and long-term HFD and diet restriction. At steady state, AT1-ILCs displayed cytotoxic activity toward adipose tissue macrophages (ATMs). Depletion of AT1-ILCs and perforin deficiency resulted in alterations in the ratio of inflammatory to anti-inflammatory ATMs, and adoptive transfer of AT1-ILCs exacerbated metabolic disorder. Diet-induced obesity impaired AT1-ILC killing ability. Our findings reveal a role for AT1-ILCs in regulating ATM homeostasis through cytotoxicity and suggest that this function is relevant in both homeostasis and metabolic disease.
Graphical abstract
Teaser
Boulenouar et al. define different subsets of type 1 innate lymphoid cells (AT1-ILCs) in human and murine adipose tissues and show that at steady state, AT1-ILCs kill adipose tissue macrophages (ATMs). In obesity, cytotoxicity is impaired. Interference with AT1-ILC cytotoxicity impacted ATM homeostasis and systemic metabolism, pointing to its importance in homeostasis and disease.http://ift.tt/2lBMB38
Respiratory Syncytial Virus Infects Regulatory B Cells in Human Neonates via Chemokine Receptor CX3CR1 and Promotes Lung Disease Severity
Publication date: 21 February 2017
Source:Immunity, Volume 46, Issue 2
Author(s): Dania Zhivaki, Sébastien Lemoine, Annick Lim, Ahsen Morva, Pierre-Olivier Vidalain, Liliane Schandene, Nicoletta Casartelli, Marie-Anne Rameix-Welti, Pierre-Louis Hervé, Edith Dériaud, Benoit Beitz, Maryline Ripaux-Lefevre, Jordi Miatello, Brigitte Lemercier, Valerie Lorin, Delphyne Descamps, Jenna Fix, Jean-François Eléouët, Sabine Riffault, Olivier Schwartz, Fabrice Porcheray, Françoise Mascart, Hugo Mouquet, Xiaoming Zhang, Pierre Tissières, Richard Lo-Man
Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in infants and is characterized by pulmonary infiltration of B cells in fatal cases. We analyzed the B cell compartment in human newborns and identified a population of neonatal regulatory B lymphocytes (nBreg cells) that produced interleukin 10 (IL-10) in response to RSV infection. The polyreactive B cell receptor of nBreg cells interacted with RSV protein F and induced upregulation of chemokine receptor CX3CR1. CX3CR1 interacted with RSV glycoprotein G, leading to nBreg cell infection and IL-10 production that dampened T helper 1 (Th1) cytokine production. In the respiratory tract of neonates with severe RSV-induced acute bronchiolitis, RSV-infected nBreg cell frequencies correlated with increased viral load and decreased blood memory Th1 cell frequencies. Thus, the frequency of nBreg cells is predictive of the severity of acute bronchiolitis disease and nBreg cell activity may constitute an early-life host response that favors microbial pathogenesis.
Graphical abstract
Teaser
RSV infection leads to respiratory distress in very young children whereas it is asymptomic later in life. Zhivaki et al. found a neonatal-specific regulatory B cell that is recruited in the respiratory tract, gets infected by the virus, and correlates with high viral load and disease severity.http://ift.tt/2lBHhwE
Mass Spectrometry Profiling of HLA-Associated Peptidomes in Mono-allelic Cells Enables More Accurate Epitope Prediction
Publication date: 21 February 2017
Source:Immunity, Volume 46, Issue 2
Author(s): Jennifer G. Abelin, Derin B. Keskin, Siranush Sarkizova, Christina R. Hartigan, Wandi Zhang, John Sidney, Jonathan Stevens, William Lane, Guang Lan Zhang, Thomas M. Eisenhaure, Karl R. Clauser, Nir Hacohen, Michael S. Rooney, Steven A. Carr, Catherine J. Wu
Identification of human leukocyte antigen (HLA)-bound peptides by liquid chromatography-tandem mass spectrometry (LC-MS/MS) is poised to provide a deep understanding of rules underlying antigen presentation. However, a key obstacle is the ambiguity that arises from the co-expression of multiple HLA alleles. Here, we have implemented a scalable mono-allelic strategy for profiling the HLA peptidome. By using cell lines expressing a single HLA allele, optimizing immunopurifications, and developing an application-specific spectral search algorithm, we identified thousands of peptides bound to 16 different HLA class I alleles. These data enabled the discovery of subdominant binding motifs and an integrative analysis quantifying the contribution of factors critical to epitope presentation, such as protein cleavage and gene expression. We trained neural-network prediction algorithms with our large dataset (>24,000 peptides) and outperformed algorithms trained on datasets of peptides with measured affinities. We thus demonstrate a strategy for systematically learning the rules of endogenous antigen presentation.
Graphical abstract
Teaser
HLA class I binding prediction has traditionally been based on biochemical binding experiments. Abelin and colleagues present an LC-MS/MS-based workflow and analytical framework that greatly accelerates gains in prediction performance. Key advances include the discovery of sequence motifs and improved quantification of the roles of gene expression and proteasomal processing.http://ift.tt/2lBG1tv
Fingertip forces and completion time for index finger and thumb touchscreen gestures
Publication date: Available online 24 February 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Deanna S. Asakawa, George H. Crocker, Adam Schmaltz, Devin L. Jindrich
Users actuate touchscreen computers by applying forces with their fingers to the touchscreen, although the amount and direction of the force is unknown. Our aim was to characterize the magnitude, direction and impulse of the force applied during single finger (tapping and sliding in four directions) and two finger gestures (stretch and pinch). Thirteen subjects performed repeated trials of each gesture. Mean(±SD) resultant force was 0.50(0.09) N for tap, 0.79(0.32) N to 1.18(0.47) N for sliding gestures, 1.47(0.63) N for pinch and 2.05(1.13) N for stretch. Mean resultant force was significantly less (p<0.04) for tap than for all gestures except slide right. The direction of force application was more vertical for the two-finger gestures as compared to the single- finger gestures. Tap was the fastest gesture to complete at 133(83) ms, followed by slide right at 421(181) ms. On average, participants took the longest to complete the stretch gesture at 920(398) ms. Overall, there are differences in forces, force direction, and completion times among touchscreen gestures that could be used to estimate musculoskeletal exposure and help forge guidelines to reduce risk of musculoskeletal injury.
http://ift.tt/2mlJlHt
Corrigendum to “Towards reducing the impacts of unwanted movements on identification of motion intentions” [J. Electromyogr. Kinesiol. 28 (2016) 90–98]
Publication date: Available online 24 February 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Xiangxin Li, Shixiong Chen, Haoshi Zhang, Oluwarotimi Williams Samuel, Hui Wang, Peng Fang, Xiufeng Zhang, Guanglin Li
http://ift.tt/2lBGH25
Standardised surface electromyography allows effective submental muscles assessment
Publication date: Available online 24 February 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Federica Musto, Riccardo Rosati, Chiarella Sforza, Marilisa Toma, Claudia Dellavia
The aims of this pilot study were to evaluate: i) the reproducibility and variability of an electromyographical protocol developed for the assessment of submental muscles (SM) ii) to apply the new protocol to maximal teeth clenching, a simple and largely studied static task in order to quantify the relative contribution of submental muscles. In 20 healthy subjects, aged 19-35 years, surface electromyography of SM, masseter (MM) and anterior temporalis (TA) muscles was performed during maximal voluntary clenching (MVC) with and without cotton rolls and the pushing of the tongue against the palate. Clenching on cotton rolls and pushing the tongue against the palate were used to standardise respectively MM and TA, and SM muscular potentials. The exercises were repeated in two appointments (T1-T2); submental muscles standardisation was also repeated twice (A-B) in each session to assess repeatability. Symmetry and activity were calculated for each couple of muscles. A two-way analysis of variance was computed for SM: no Factor 1 (T1 vs T2) or Factor 2 (A vs B) or F1 X F2 significant effects were found. SM recruitment was 31% of the maximal activity, with symmetry values larger than 80%. In conclusion, standardised electromyography allows a reliable assessment of Submental muscles activity.
http://ift.tt/2lBLSPt
Uptake of screening for type 2 diabetes risk in general dental practice; an exploratory study
British Dental Journal 222, 293 (2017). doi:10.1038/sj.bdj.2017.174
Authors: K. Bould, S. E. Scott, S. Dunne & K. Asimakopoulou
http://ift.tt/2li3CNc
Dental implants: Potential relationship with cancer
British Dental Journal 222, 224 (2017). doi:10.1038/sj.bdj.2017.144
Author: M. R. Norton
http://ift.tt/2lie6fx
Healthcare research: VR and AR
British Dental Journal 222, 224 (2017). doi:10.1038/sj.bdj.2017.145
Author: M. Dorri
http://ift.tt/2lhJY4c
Patient safety: Cardiac devices
British Dental Journal 222, 225 (2017). doi:10.1038/sj.bdj.2017.146
Authors: D. Raindi & J. S. Chandan
http://ift.tt/2liauKL
Anticoagulants: Lack of research
British Dental Journal 222, 225 (2017). doi:10.1038/sj.bdj.2017.147
Author: F. McDonnell
http://ift.tt/2li8Rg3
Advertising: Longstanding dislike
British Dental Journal 222, 225 (2017). doi:10.1038/sj.bdj.2017.148
Author: R. Bettles
http://ift.tt/2li4Sjz
Antimicrobial resistance: Setting the record straight
British Dental Journal 222, 225 (2017). doi:10.1038/sj.bdj.2017.149
Author: M. Armstrong
http://ift.tt/2li7yh3
Electronic cigarettes: Necrotic ulcer
British Dental Journal 222, 226 (2017). doi:10.1038/sj.bdj.2017.150
Authors: A. Cant, B. Collard & D. Cunliffe
http://ift.tt/2lhJZoM
The experience of dentists who gained enhanced skills in endodontics within a novel pilot training programme
British Dental Journal 222, 269 (2017). doi:10.1038/sj.bdj.2017.172
Authors: S. Eliyas, P. Briggs & J. E. Gallagher
http://ift.tt/2lhT6pr
Drug interactions: Time to put our pens down
British Dental Journal 222, 226 (2017). doi:10.1038/sj.bdj.2017.151
Author: V. Wilson
http://ift.tt/2li2Vn9
DCPs and research in general dental practice
British Dental Journal 222, 307 (2017). doi:10.1038/sj.bdj.2017.176
Author: B. Dawett
http://ift.tt/2lhThRE
Hypericum perforatum (St John's wort) beyond depression: A therapeutic perspective for pain conditions
Publication date: 22 March 2017
Source:Journal of Ethnopharmacology, Volume 200
Author(s): Nicoletta Galeotti
Ethnopharmacological relevanceHypericum perforatum L. (Hypericaceae), popularly called St. John's wort (SJW), has a rich historical background being one of the oldest used and most extensively investigated medicinal herbs. Many bioactivities and applications of SJW are listed in popular and in scientific literature, including antibacterial, antiviral, anti-inflammatory. In the last three decades many studies focused on the antidepressant activity of SJW extracts. However, several studies in recent years also described the antinociceptive and analgesic properties of SJW that validate the traditional uses of the plant in pain conditions.Aim of the reviewThis review provides up-to-date information on the traditional uses, pre-clinical and clinical evidence on the pain relieving activity of SJW and its active ingredients, and focuses on the possible exploitation of this plant for the management of pain.Materials and methodsHistorical ethnobotanical publications from 1597 were reviewed for finding local and traditional uses. The relevant data on the preclinical and clinical effects of SJW were searched using various databases such as PubMed, Science Direct, Scopus, and Google Scholar. Plant taxonomy was validated by the database Plantlist.org.ResultsPreclinical animal studies demonstrated the ability of low doses of SJW dry extracts (0.3% hypericins; 3–5% hyperforins) to induce antinociception, to relieve from acute and chronic hyperalgesic states and to augment opioid analgesia. Clinical studies (homeopathic remedies, dry extracts) highlighted dental pain conditions as a promising SJW application. In vivo and in vitro studies showed that the main components responsible for the pain relieving activity are hyperforin and hypericin. SJW analgesia appears at low doses (5–100mg/kg), minimizing the risk of herbal-drug interactions produced by hyperforin, a potent inducer of CYP enzymes.ConclusionPreclinical studies indicate a potential use of SJW in medical pain management. However, clinical research in this field is still scarce and the few studies available on chronic pain produced negative results. Prospective randomized controlled clinical trials performed at low doses are needed to validate its potential efficacy in humans.
Graphical abstract
http://ift.tt/2lBqhXy
Rhizoma Smilacis Glabrae inhibits pathogen-induced upper genital tract inflammation in rats through suppression of NF-κB pathway
Publication date: Available online 24 February 2017
Source:Journal of Ethnopharmacology
Author(s): Wei Zou, Hougang Zhou, Jian Hu, Li Zhang, Qiue Tang, Xiaoke Wen, Zuoqi Xiao, Wei Wang
Ethnopharmacological relevanceRhizoma Smilacis Glabrae (RSG) is traditionally used to treat gynecological disease, which is simply recorded in Chinese Pharmacopoeia. However, whether it has effect on upper genital tract inflammation (UGTI) is unclear.Aim of the studyTo evaluate the pharmacological effect of RSG on UGTI in rats and analyze its phytochemistry characteristics.Materials and methodsThe substances in RSG extract was qualified by LC-Q-TOF-MS method, and 11 substances were further quantified. The RSG extract, at dose of 241, 482 (clinical dose) and 964mg/kg/day, was orally administered to UGTI rats whose upper genital tracts were multi-infected with pathogens. Infiltrations of neutrophil and lymphocyte and productions of IL-1β, IL-6, CXCL-1, MCP-1, RANTES, PGE2, COX-2, NF-κB p65 and IκB-α in upper genital tract were examined to evaluate the effects of RSG and its potential mechanism.ResultsA total of 77 substances were detected in RSG extract, with 50 substances putatively identified, most of which were flavonoids, phenolic acids and phenylpropanoids. The quantification analysis showed flavonoid had a relative high amount. In pharmacological study, RSG extract suppressed infiltrations of inflammatory cells, reduced over-productions of factors involved in inflammation and pelvic pain. A potential mechanism of these effects was blocking NF-κB signal pathway.ConclusionsThe RSG extract exhibited anti-inflammatory effect on UGTI, with a potential mechanism of blocking the activation of NF-κB signal pathway. The effect may be involved in the presence of substances, such as flavonoids and phenolic acids.
Graphical abstract
http://ift.tt/2lBA0Nz
Protective effect of a polysaccharide from Anoectochilus roxburghii against carbon tetrachloride-induced acute liver injury in mice
Publication date: 22 March 2017
Source:Journal of Ethnopharmacology, Volume 200
Author(s): Biyu Zeng, Minghua Su, Qingxi Chen, Qiang Chang, Wei Wang, Huihua Li
Ethnopharmacological relevanceAnoectochilus roxburghii (Wall.) Lindl. is traditionally used for the treatment of various types of chronic and acute hepatitis in China. Considering that Anoectochilus roxburghii polysaccharide (ARPT) is the main constituent of Anoectochilus roxburghii, the present study was designed to investigate the hepatoprotective effect of ARPT and its possible mechanism in carbon tetrachloride (CCl4)-induced mice.Material and methodsThe hepatoprotective activity of ARPT (150, 300 and 500mg/kg) were investigated on CCl4-induced acute liver damage in mice. The activities of alanine transaminase (ALT), aspartate transaminase (AST) were determined in serum. The hepatic levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) were measured in liver homogenates. The levels of cytochrome P450 sub family 2E1 (CYP2E1), tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2), KC (Murine IL-8 ortholog), transforming growth factor-beta1 (TGF-β1), Bcl-2 and Bax were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The expressions of CYP2E1, nuclear factor-kappa B (NF-κB) p65 and caspase-3 were evaluated by western blot assays. The hepatic levels of TNF-α, IL-6, MIP-2 and TGF-β1 were measured by enzyme-linked immunosorbent assay (ELISA). Furthermore, histopathological observation and terminal-deoxynucleoitidyl transferase mediated nick end labeling assay (TUNEL) were carried out on the separated livers of mice.ResultsARPT significantly decreased serum ALT and AST activities, hepatic MDA level, and markedly enhanced antioxidant enzyme (SOD, CAT and GSH-Px) activities and GSH level in hepatic tissue, in a dose-dependent manner, when compared to the model group. Histopathological observation revealed the hepatoprotective effect of ARPT against the damage. Furthermore, ARPT remarkably inhibited CYP2E1 mRNA expression, decreased NF-κB p65 expression and therefore to prevent the secretion of pro-inflammatory cytokines (TNF-α and IL-6) and chemokines (MCP-1, MIP-2 and KC), suppressed TGF-β1 expression and hepatocytes apoptosis. Moreover, ARPT could prevent DNA fragmentation based on TUNEL assay results.ConclusionThese findings suggested that ARPT possessed hepatoprotective effect against CCl4-induced hepatotoxicity in mice and the action might in part be through reducing oxidative stress, inflammation and apoptosis.
Graphical abstract
http://ift.tt/2lBnHRa
The natural product bergenin ameliorates lipopolysaccharide-induced acute lung injury by inhibiting NF-kappaB activition
Publication date: 22 March 2017
Source:Journal of Ethnopharmacology, Volume 200
Author(s): Shengqian Yang, Ziru Yu, Lin Wang, Tianyi Yuan, Xue Wang, Xue Zhang, Jinhua Wang, Yang Lv, Guanhua Du
Ethnopharmacological relevanceBergenin, an active constituent of the plants of the genus Bergenia, was reported to have anti-inflammatory effects in the treatment of chronic bronchitis and chronic gastritis clinically. However, its therapeutic effect on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and its potential mechanisms of actions were still unknown.Aim of this studyTo evaluate the effect of bergenin on murine model of acute lung injury induced by LPS and also to explore its potential mechanisms.Materials and methodsHalf an hour and 12h after an intranasal inhalation of LPS, male BALB/c mice were treated with bergenin (50,100 and 200mg/kg) or dexamethasone (DEX, 5mg/kg) by gavage. Twenty-four hours after LPS exposure, the lung wet/dry ratio, histological changes, myeloperoxidase (MPO) in lung tissues, inflammatory cells (in BALF) and cytokines (in BALF and serum) were detected. Meanwhile, the protein expression of MyD88 and the phosphorylation of NF-κB p65 in lung tissue were analyzed using immunoblot analysis. Moreover, the nuclear translocation and the phosphorylation of NF-κB p65 in Raw264.7 cells were also analyzed. The viability of Raw264.7 cells was determined by MTT assay.ResultsResults showed that bergenin significantly decreased pulmonary edema, improved histological changes and reduced MPO activity in lung tissues. Moreover, bergenin obviously decreased inflammatory cells, IL-1β and IL-6 production in BALF, as well as IL-1β, TNF-α and IL-6 production in serum of LPS-induced ALI mice. Furthermore, bergenin markedly inhibited LPS-induced NF-κB p65 phosphorylation, as well as the expression of MyD88 but not the expression of NF-κB p65 in lung tissues. Additionally, bergenin also significantly inhibited the nuclear translocation and the phosphorylation of NF-κB p65 stimulated by LPS in Raw264.7 cells.ConclusionsThese findings suggested that bergenin had a therapeutic effect on LPS-induced ALI by inhibiting NF-κB activition.
Graphical abstract
http://ift.tt/2lBrf65
Dilodendron bipinnatum Radlk. inhibits pro-inflammatory mediators through the induction of MKP-1 and the down-regulation of MAPKp38/JNK/NF-κB pathways and COX-2 in LPS-activated RAW 264.7 cells
Publication date: Available online 24 February 2017
Source:Journal of Ethnopharmacology
Author(s): Ruberlei Godinho de Oliveira, Geovane Roberto de Campos Castilho, André Luiz da Cunha, Fábio Miyajima, Domingos Tabajara de Oliveira Martins
Ethnopharmacological relevanceThe stem bark of Dilodendron bipinnatum Radlk. (Sapindaceae), a tree native to Pantanal of Mato Grosso, Brazil, popularly known as "mulher-pobre" (poor woman), has been historically used by the locals, after decoction and maceration, for the treatment of inflammatory conditions. We have recently shown that these preparations indeed possess anti-inflammatory properties, which are mediated by the inhibition of cell migration and the modulation of Th1 and Th2 cytokines. The NO pathway was not affected.Aim of the present studyThe aim of the present study was to further investigate the mechanisms responsible for the anti-inflammatory properties of the hydroethanolic extract of the stem bark of Dilodendron bipinnatum (HEDb).Materials and methodsHEDb was obtained by maceration of the stem bark of D. bipinnatum as previously described. The corresponding effects on a macrophage-like cell line, RAW 264.7, were investigated. The apoptosis of RAW 264.7 upon treatment with LPS, HEDb and N-acetyl-L-cysteine (NAC) was assessed by flow cytometry, using an Annexin V-PE kit. The production of inflammatory cytokines (TNF-α, IL-1β and IL-10) and PGE2 were evaluated by ELISA, after cell challenge with LPS. The intracellular redox state and changes in mitochondrial membrane potential were also assessed by flow cytometry, using DCFH-DA and JC-1 as probes. The protein expression levels of MAPK p-p38, p-ERK, p-JNK, MKP-1 and COX-2 were analysed by western blotting. Nuclear translocation of NF-қB was assessed by immunofluorescence microscopy. The quantified results are presented as a nuclear:cytoplasmic ratio.ResultsLPS, HEDb and NAC did not appear to decrease the number of viable cells in comparison to control treatment. HEDb attenuated the production of pro-inflammatory cytokines (IL-1β and TNF-α) and PGE2 induced by LPS but did not affect IL-10. The production of ROS was also inhibited by HEDb (1, 5 or 20µg/mL), even at the lowest concentration; at 20µg/mL, HEDb was more effective than NAC, which was used as a positive control (74.1% and 66.2% inhibition of LPS's effect, respectively). LPS induced an increase in ΔΨm (19.2%, p <0.001), while HEDb inhibited the change in ΔΨm (7.7% at 20µg/mL, p<0.001). The results of western blotting showed that HEDb inhibited the expression of MAPK p-p38, p-JNK and COX-2, while the expression of MKP-1 was increased. p-ERK was not affected. LPS promoted the nuclear translocation of NF-қB p65 (67%, p<0.01) in RAW 264.7 cells, in comparison to baseline (33%). Pre-treatment with HEDb inhibited this translocation of NF-κB p65 (58% at 20µg/mL, p<0.001). Conclusion: HEDb has a potent anti-inflammatory activity and acts on multiple targets and biological pathways of potential therapeutic relevance.
Graphical abstract
http://ift.tt/2lBAYcJ
IFC-EDITORIAL BOARD
Publication date: March 2017
Source:Research in Developmental Disabilities, Volume 62
http://ift.tt/2lBd7cX
The Pathogenesis of OSA in People Living With HIV
Intervention:
Sponsors: University of California, San Diego; Center For AIDS Research Creative and Novel Ideas in HIV Research (CFAR CNIHR)
Recruiting - verified February 2017
http://ift.tt/2l7JgW5
The Impact of Vitamin D Deficiency on Hypocalcaemia Following Total Thyroidectomy
Intervention: Other: vitamin D levels and Calcium levels examination
Sponsor: Hillel Yaffe Medical Center
Not yet recruiting - verified February 2017
http://ift.tt/2lNqiIx
Platinum-Cetuximab Combined With Docetaxel or With 5FU in Patients With Recurrent/Metastatic HNSCC
Interventions: Drug: Cisplatin; Drug: 5-Fluorouracile; Drug: Docetaxel; Drug: Cetuximab; Drug: granulocyte colony-stimulating factor (G-CSF)
Sponsors: Groupe Oncologie Radiotherapie Tete et Cou; Grupo Español de Tratamiento de Tumores de Cabeza y Cuello; AIO-Studien-gGmbH
Recruiting - verified February 2017
http://ift.tt/2l7qIW6
Lymphohaematopoietic malignancies in Scottish military veterans: Retrospective cohort study of 57,000 veterans and 173,000 non-veterans
Source:Cancer Epidemiology, Volume 47
Author(s): Beverly P. Bergman, Daniel F. Mackay, Jill P. Pell
BackgroundLymphohaematopoietic malignancies are common in the general population. There have been concerns that military service may be associated with increased risk as a result of occupational exposures. To date, few studies have demonstrated an increased risk, although a disability pension is payable to veterans who were present at nuclear tests and who develop leukaemia (other than chronic lymphocytic leukaemia). The aim of the study was to utilise data from the Scottish Veterans Health Study to examine the risk of lymphohaematopoietic malignancy following military service in a large national cohort of veterans.MethodsRetrospective cohort study of 57,000 veterans and 173,000 non-veterans born between 1945 and 1985 matched for age, sex and area of residence, adjusted for areal deprivation and followed up for up to 30 years, using Cox proportional hazard models to compare the risk of lymphohaematopoietic malignancy overall, by diagnosis and by sex and birth cohort.ResultsWe found no statistically significant difference in risk between veterans and non-veterans either for all leukaemias (Cox proportional hazard ratio 1.03, 95% confidence intervals 0.84–1.27, p=0.773), Hodgkin lymphoma (hazard ratio 1.19, 95% confidence intervals 0.87–1.61, p=0.272) or for non-Hodgkin lymphoma (hazard ratio 0.86, 95% confidence intervals 0.71–1.04, p=0.110).ConclusionOur findings provide reassurance that service in the UK Armed Forces is not associated with increased risk of lymphohaematopoietic malignancy.
http://ift.tt/2l7Mk4N
Interim Process and Methods Guide for the Clinical Guideline Updates Using Standing Committees Pilot Programme 2013 [Internet].
This guide outlines the main elements of the interim process and methods for the NICE clinical guideline updates using standing committees pilot programme, including details of the Clinical Guidelines Updates committee, which were agreed by the NICE Board in September 2013. It complements the standard methods and processes for developing and updating clinical guidelines described in the NICE guidelines manual 2012 and the interim clinical guideline surveillance process and methods guide 2013. This process for clinical guideline updates using standing committees will be used to inform the NICE guidance development project and will then be subject to formal consultation.
http://ift.tt/2kUrDhv
Quality Adjusted Life Years (QALYs) and the Severity of Illness [Internet].
The Citizens Council provides NICE with a public perspective on overarching moral and ethical issues that NICE should take into account when producing guidance. Made up of members of the public, broadly representative of the adult UK population, the Council operates through a "citizens' jury" style meeting, to explore and respond to a question set by NICE.
http://ift.tt/2lDhy5l
The Attitude of the Public to the Use of Patient Information Obtained from Medical Records by the National Confidential Enquiries [Internet].
The Citizens Council provides NICE with a public perspective on overarching moral and ethical issues that NICE should take into account when producing guidance. Made up of members of the public, broadly representative of the adult UK population, the Council operates through a "citizens' jury" style meeting, to explore and respond to a question set by NICE.
http://ift.tt/2kUnkm6
Health Innovation and Value [Internet].
The Citizens Council provides NICE with a public perspective on overarching moral and ethical issues that NICE should take into account when producing guidance. Made up of members of the public, broadly representative of the adult UK population, the Council operates through a "citizens' jury" style meeting, to explore and respond to a question set by NICE.
http://ift.tt/2lDu7xI
What Aspects of Benefit, Cost and Need Should NICE Take into Account When Developing Social Care Guidance? [Internet].
The Citizens Council provides NICE with a public perspective on overarching moral and ethical issues that NICE should take into account when producing guidance. Made up of members of the public, broadly representative of the adult UK population, the Council operates through a "citizens' jury" style meeting, to explore and respond to a question set by NICE.
http://ift.tt/2kUwT4x
Critical time Intervention for Severely mentally ill Prisoners (CrISP): a randomised controlled trial.
'Critical time intervention' increased severely mentally ill released prisoners' contact with community mental health teams 6 weeks after discharge by about 25%
http://ift.tt/2lDxkgD
Ultra Orphan Drugs [Internet].
The Citizens Council provides NICE with a public perspective on overarching moral and ethical issues that NICE should take into account when producing guidance. Made up of members of the public, broadly representative of the adult UK population, the Council operates through a "citizens' jury" style meeting, to explore and respond to a question set by NICE.
http://ift.tt/2kUypn2
Report of the First Meeting of the NICE Citizens Council: Determining "Clinical Need" [Internet].
The Citizens Council provides NICE with a public perspective on overarching moral and ethical issues that NICE should take into account when producing guidance. Made up of members of the public, broadly representative of the adult UK population, the Council operates through a "citizens' jury" style meeting, to explore and respond to a question set by NICE.
http://ift.tt/2lDwZuA
Interim Clinical Guideline Surveillance Process and Methods Guide 2013 [Internet].
These interim process and methods aim to address concerns about the previous process (for example, the resource intensity of focused literature searching) while retaining best practice (for example, involving technical and methodological analysts and subject content experts from guideline development groups [GDGs]). In this interim surveillance process, there is a change in the frequency and type of surveillance evidence reviews from full reviews every 3 years to alternate rapid and full reviews every 2 years.
http://ift.tt/2kUvivI
Smoking and Harm Reduction [Internet].
The Citizens Council provides NICE with a public perspective on overarching moral and ethical issues that NICE should take into account when producing guidance. Made up of members of the public, broadly representative of the adult UK population, the Council operates through a "citizens' jury" style meeting, to explore and respond to a question set by NICE.
http://ift.tt/2lDkIpK
Effective patient–clinician interaction to improve treatment outcomes for patients with psychosis: a mixed-methods design.
The technology-supported DIALOG+ intervention structured patient–clinician communication in community care, improving patients' quality of life over 1 year and saving costs.
http://ift.tt/2kUnXvX
"Only in Research" [Internet].
The Citizens Council provides NICE with a public perspective on overarching moral and ethical issues that NICE should take into account when producing guidance. Made up of members of the public, broadly representative of the adult UK population, the Council operates through a "citizens' jury" style meeting, to explore and respond to a question set by NICE.
http://ift.tt/2lDwW1S
Mandatory Public Health Measures [Internet].
The Citizens Council provides NICE with a public perspective on overarching moral and ethical issues that NICE should take into account when producing guidance. Made up of members of the public, broadly representative of the adult UK population, the Council operates through a "citizens' jury" style meeting, to explore and respond to a question set by NICE.
http://ift.tt/2kUtZNa
Interventional Procedures Programme: Methods Guide [Internet].
The National Institute for Health and Clinical Excellence (NICE) produces guidance on the use of new and existing medicines, treatments and procedures within the NHS, including the efficacy and safety of interventional procedures. This guide describes the principles and methods used to assess interventional procedures. The methods are designed to ensure that robust guidance for the NHS is developed in an open, transparent and timely way that allows appropriate input from consultees and other stakeholders. This guide is intended to be complementary to the 'Interventional Procedures Programme manual' ('IP Programme manual').
http://ift.tt/2lDmRlq
Interim Methods Guide for Developing Service Guidance 2014 [Internet].
Clinical guidelines developed by NICE are published with the expectation that they will be regularly reviewed and updated as necessary. Any decision to update a guideline must balance the need to reflect changes in the evidence against the need for stability, because frequent changes to guideline recommendations would make implementation difficult. There are inherent risks that a new and less exhaustive surveillance methodology (for the 2-year, 6-year and 10-year reviews; see section 4) might have a lower sensitivity to determine which guidelines need updating, although these risks will be balanced against a new surveillance process that will allow decisions to be revisited more frequently.
http://ift.tt/2kUqxC2
Interventional Procedures Programme: Process Guide [Internet].
The process and methods described here do not affect reviews of published guidelines that arise as a result of exceptional circumstances (safety concerns, withdrawal of drugs or interventions, significant changes to legislation, etc.) of the NICE guidelines manual 2012. These will continue to be assessed on a case-by-case basis without the need for a formal guideline surveillance review.
http://ift.tt/2lDuCb3
Rule of Rescue [Internet].
The Citizens Council provides NICE with a public perspective on overarching moral and ethical issues that NICE should take into account when producing guidance. Made up of members of the public, broadly representative of the adult UK population, the Council operates through a "citizens' jury" style meeting, to explore and respond to a question set by NICE.
http://ift.tt/2kUCR5w
Interim Methods Guide for Developing Good Practice Guidance [Internet].
This interim methods guide is based on the general principles and methods included in other methods guides for developing NICE guidance. It can be used in conjunction with the Good practice guidance: integrated process statement. This interim methods guide will be considered during the wider NICE methods manual review.
http://ift.tt/2lDuAQt
What Are the Societal Values That Need to Be Considered When Making Decisions about Trade-Offs between Equity and Efficiency? [Internet].
The Citizens Council provides NICE with a public perspective on overarching moral and ethical issues that NICE should take into account when producing guidance. Made up of members of the public, broadly representative of the adult UK population, the Council operates through a "citizens' jury" style meeting, to explore and respond to a question set by NICE.
http://ift.tt/2kUxzHf
Patient Safety [Internet].
The Citizens Council provides NICE with a public perspective on overarching moral and ethical issues that NICE should take into account when producing guidance. Made up of members of the public, broadly representative of the adult UK population, the Council operates through a "citizens' jury" style meeting, to explore and respond to a question set by NICE.
http://ift.tt/2lDlnYi
Automatic detection of periods of slow wave sleep based on intracranial depth electrode recordings
Source:Journal of Neuroscience Methods
Author(s): Chrystal M. Reed, Kurtis Birch, Jan Kaminski, Shannon Sullivan, Jeffrey M. Chung, Adam Mamelak, Ueli Rutishauser
BackgroundAn automated process for sleep staging based on intracranial EEG data alone is needed to facilitate research into the neural processes occurring during slow wave sleep (SWS). Current manual methods for sleep scoring require a full polysomnography (PSG) set-up, including electrooculography (EOG), electromyography (EMG), and scalp electroencephalography (EEG). This set-up can be technically difficult to place in the presence of intracranial EEG electrodes. There is thus a need for a method for sleep staging based on intracranial recordings alone.New MethodHere we show a reliable automated method for the detection of periods of SWS solely based on intracranial EEG recordings. The method is utilizes the ratio of spectral power in delta, theta, and spindle frequencies relative to alpha and beta frequencies to classify 30-second segments as SWS or not.ResultsWe evaluated this new method by comparing its performance against visually scored patients (n=9), in which we also recorded EOG and EMG simultaneously. Our method had a mean positive predictive value of 64% across all nights. Also, an ROC analysis of the performance of our algorithm compared to manually labeled nights revealed a mean average area under the curve of 0.91 across all nights.Comparison with existing methodOur method had an average kappa score of 0.72 when compared to visual sleep scoring by an independent blinded sleep scorer.ConclusionThis shows that this simple method is capable of differentiating between SWS and non-SWS epochs reliably based solely on intracranial EEG recordings.
http://ift.tt/2lAEkMX
Automated selective disruption of slow wave sleep
Source:Journal of Neuroscience Methods
Author(s): Sharon J. Ooms, John M. Zempel, David M. Holtzman, Yo-El S. Ju
BackgroundSlow wave sleep (SWS) plays an important role in neurophysiologic restoration. Experimentally testing the effect of SWS disruption previously required highly time-intensive and subjective methods. Our goal was to develop an automated and objective protocol to reduce SWS without affecting sleep architecture.New MethodWe developed a custom Matlab™ protocol to calculate electroencephalogram spectral power every 10seconds live during a polysomnogram, exclude artifact, and, if measurements met criteria for SWS, deliver increasingly louder tones through earphones. Middle-aged healthy volunteers (n=10) each underwent 2 polysomnograms, one with the SWS disruption protocol and one with sham condition.ResultsThe SWS disruption protocol reduced SWS compared to sham condition, as measured by spectral power in the delta (0.5–4Hz) band, particularly in the 0.5–2Hz range (mean 20% decrease). A compensatory increase in the proportion of total spectral power in the theta (4–8Hz) and alpha (8–12Hz) bands was seen, but otherwise normal sleep features were preserved. N3 sleep decreased from 20±34 to 3±6minutes, otherwise there were no significant changes in total sleep time, sleep efficiency, or other macrostructural sleep characteristics.Comparison with existing methodThis novel SWS disruption protocol produces specific reductions in delta band power similar to existing methods, but has the advantage of being automated, such that SWS disruption can be performed easily in a highly standardized and operator-independent manner.ConclusionThis automated SWS disruption protocol effectively reduces SWS without impacting overall sleep architecture.
http://ift.tt/2lhxVnq
Detection of BRAF mutation in the cytocentrifugation supernatant fluid from fine-needle aspiration of thyroid lesions may enhance the diagnostic yield
CytoJournal 2017 14(1):4-4
Objective: BRAF mutations using cellular DNA from fine-needle aspiration (FNA) specimens are commonly used to support the diagnosis of papillary thyroid carcinoma (PTC). The goal of this study was to preliminarily evaluate the diagnostic utility of detecting BRAF mutations in the routinely discarded FNA specimen supernatant fluid. Materials and Methods: Seventy-eight FNAs of thyroid lesions were evaluated for BRAF mutations using both cellular and supernatant DNA. BRAF mutation data were correlated with cytology and surgical pathology. Results: Of the 78 samples evaluated, 68 (87%) had amplifiable DNA in the supernatant with 2 (3%) positive for BRAF mutations. These two samples showed no mutations in the cellular counterpart. Among the 11 samples showing morphologic findings (FNA/surgical pathology) suspicious/diagnostic of PTC, 6 (55%) samples (one supernatant and five cellulars) were positive for BRAF mutations. This suggests that testing supernatant DNA in FNA specimens may increase the diagnostic yield by 1/11 (9%) in this setting. Conclusions: The vast majority of routinely discarded FNA supernatants contain amplifiable DNA. In addition, profiling the mutations of BRAF and other genes using supernatant DNA may provide valuable diagnostic information to assist the diagnosis of PTC in patients with clinical/morphologic findings suspicious for malignancies and cellular DNA showing no mutations.
http://ift.tt/2lNf2vx
Thyroid fine-needle aspiration of an immunocompromised patient: Cytomorphological clues
CytoJournal 2017 14(1):3-3
http://ift.tt/2lhwrJC
KRAS detection on archival cytological smears by the novel fully automated polymerase chain reaction-based Idylla mutation test
CytoJournal 2017 14(1):5-5
Background: Molecular techniques are relevant to modern cytopathology, but their implementation is difficult without molecular expertise and infrastructure. The assessment of KRAS mutational status on cytological preparations may be useful either to refine uncertain diagnoses on pancreatic aspirates or to yield predictive information to plan targeted treatment of metastatic colorectal cancer (mCRC). The novel test Idylla™ enables fully automated KRAS genotyping in approximately 2 h, even in less experienced hands. Materials and Methods: This study aims to validate this methodology to detect KRAS mutations on archival cytological preparations of pancreatic cancer (n = 9) and mCRC (n = 9) by comparing the Idylla™ performance to that of standard real-time polymerase chain reaction. Results: The same 11 mutations (n = 4: p.G12D; n = 2: p.G12V; n = 2: p.A59E/G/T; n = 1: p.G12R; n = 1: p.G13D; n = 1: p.Q61H) were detected by both techniques. Conclusion: Even in less experienced laboratories, a cytopathologist may easily integrate morphological diagnostic report with accurate KRAS mutation detection, which is relevant for diagnostic and treatment decisions.
http://ift.tt/2lNfGcs
Appetitive and aversive motivation in dysphoria: A time-domain and time-frequency study of response inhibition
Source:Biological Psychology
Author(s): Simone Messerotti Benvenuti, Giulia Buodo, Daniela Palomba
The study of emotional response inhibition could provide novel insight into dysphoria-related deficits in appetitive and aversive motivational systems. Therefore, dysphoric (N=21) and nondysphoric (N=21) participants completed an emotional Go/Nogo paradigm, including the presentation of pleasant, neutral and unpleasant pictures. Behavioral measures [reaction times (RTs), accuracy to Go and Nogo stimuli] and neural correlates (Go/Nogo-N2 and Go/Nogo-P3) of response inhibition were compared between the two groups. Time-frequency analysis was also used as a novel approach to disentangle the multiple processes underlying time-domain ERP data. A reduced Go/Nogo effect for P3 and oscillatory delta activity was found in response to pleasant and neutral, but not unpleasant, stimuli in dysphoric relative to nondysphoric individuals. These findings showed that dysphoric individuals need a reduced and/or less effortful response inhibition to pleasant stimuli, suggesting that dysphoria is characterized by under-engagement of appetitive rather than over-engagement of aversive motivational system.
http://ift.tt/2l7IVCJ
Dynamic changes in prefrontal cortex involvement during verbal episodic memory formation
Source:Biological Psychology
Author(s): Giulia Galli, Matteo Feurra, Enea Francesco Pavone, Miroslav Sirota, Simone Rossi
During encoding, the neural activity immediately before or during an event can predict whether that event will be later remembered. The contribution of brain activity immediately after an event to memory formation is however less known. Here, we used repetitive Transcranial Magnetic Stimulation (rTMS) to investigate the temporal dynamics of episodic memory encoding with a focus on post-stimulus time intervals. At encoding, rTMS was applied during the online processing of the word, at its offset, or 100, 200, 300 or 400ms thereafter. rTMS was delivered to the left ventrolateral (VLPFC) or dorsolateral prefrontal cortex (DLPFC). VLPFC rTMS during the first few hundreds of milliseconds after word offset disrupted subsequent recognition accuracy. We did not observe effects of DLPFC rTMS at any time point. These results suggest that verbal encoding-related VLPFC engagement starts at a relatively late processing stage, and may reflect brain processes related to the offset of the stimulus.
http://ift.tt/2lAiTeR
Channel of viral DNA packaging motor for real time kinetic analysis of peptide oxidation states
Source:Biomaterials, Volume 126
Author(s): Shaoying Wang, Zhi Zhou, Zhengyi Zhao, Hui Zhang, Farzin Haque, Peixuan Guo
Nanopore technology has become a powerful tool in single molecule sensing, and protein nanopores appear to be more advantageous than synthetic counterparts with regards to channel amenability, structure homogeneity, and production reproducibility. However, the diameter of most of the well-studied protein nanopores is too small to allow the passage of protein or peptides that are typically in multiple nanometers scale. The portal channel from bacteriophage SPP1 has a large channel size that allows the translocation of peptides with higher ordered structures. Utilizing single channel conductance assay and optical single molecule imaging, we observed translocation of peptides and quantitatively analyzed the dynamics of peptide oligomeric states in real-time at single molecule level. The oxidative and the reduced states of peptides were clearly differentiated based on their characteristic electronic signatures. A similar Gibbs free energy (ΔG0) was obtained when different concentrations of substrates were applied, suggesting that the use of SPP1 nanopore for real-time quantification of peptide oligomeric states is feasible. With the intrinsic nature of size and conjugation amenability, the SPP1 nanopore has the potential for development into a tool for the quantification of peptide and protein structures in real time.
http://ift.tt/2lAb5d8
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Publication date: September 2017 Source: Free Radical Biology and Medicine, Volume 110 Author(s): Lucía Fernández-del-Río, Anish Nag, Elen...
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Abstract Noise pollution is a major factor of environmental complaints in many cities, which has significant impacts on human health. As a...
