Upfront surgery versus definitive chemoradiotherapy in patients with human Papillomavirus-associated oropharyngeal squamous cell cancer

Publication date: April 2018
Source:Oral Oncology, Volume 79
Author(s): Jacqueline R. Kelly, Henry S. Park, Yi An, Wendell G. Yarbrough, Joseph N. Contessa, Roy Decker, Saral Mehra, Benjamin L. Judson, Barbara Burtness, Zain Husain
ObjectivesCurrently, human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV-A OPC) is managed with either primary surgery or definitive chemoradiotherapy (CRT), despite the lack of supporting randomized prospective data. We therefore assessed the outcomes of each treatment strategy using the National Cancer Database (NCDB).MethodsThe NCDB was used to identify patients diagnosed with cT1 N2a-2b or cT2 N1-2b HPV-A OPC from 2010 to 2013 who underwent treatment with primary surgery or CRT. Demographic and clinicopathologic predictors of treatment were analyzed by the chi-square test and logistic regression. Overall survival (OS) was evaluated using multivariable Cox proportional hazard regression, Kaplan-Meier, log-rank test, and propensity score-matched analysis.ResultsWe identified 3063 patients; 1576 (51.5%) received CRT and 1487 (48.5%) underwent primary surgery. Median follow up was 32 months. 972 (65.4%) surgical patients received adjuvant CRT. On multivariable Cox regression, 3-year OS was comparable between surgery and CRT (hazard ratio [HR] 1.08, 95% confidence interval [CI] 0.83–1.41, P = 0.58). Inferior OS was significantly associated with increasing clinical T and N stage, older age, and non-private insurance. Propensity score-matching yielded a 2526 patient cohort and redemonstrated similar OS (HR, 1.09; 95% CI 0.81–1.47; P = 0.55). Comparable outcomes persisted in a subset analysis of patients with margin-negative resection, with 3-year OS 90.8% in CRT patients vs. 93.6% in surgery patients (log-rank P = 0.27).ConclusionsUpfront surgery and CRT yielded comparable 3-year OS outcomes in this cohort. In this national sample, 65.4% of surgical patients received trimodal therapy with adjuvant CRT, highlighting the need for improved patient selection for primary surgery.



http://ift.tt/2oUsluK

Chemoradiotherapy using retrograde superselective intra-arterial infusion for tongue cancer: Analysis of therapeutic results in 118 cases

Publication date: April 2018
Source:Oral Oncology, Volume 79
Author(s): Kenji Mitsudo, Yuichiro Hayashi, Shuhei Minamiyama, Nobuhide Ohashi, Masaki Iida, Toshinori Iwai, Senri Oguri, Toshiyuki Koizumi, Mitomu Kioi, Makoto Hirota, Izumi Koike, Masaharu Hata, Iwai Tohnai
ObjectivesTo evaluate the therapeutic results and rate of organ preservation in patients with squamous cell carcinoma of the tongue treated with retrograde superselective intra-arterial chemoradiotherapy.Materials and methodsBetween June 2006 and June 2015, 118 patients with tongue cancer were treated with intra-arterial chemoradiotherapy. Treatment consisted of radiotherapy (total 50–70 Gy) and daily concurrent intra-arterial chemotherapy (docetaxel, total 50–70 mg/m²; cisplatin, total 125–175 mg/m²) for 5–7 weeks. Locoregional control and overall survival rates were calculated by the Kaplan-Meier method. Cox's proportional hazards model was used for both univariate and multivariate analyses.ResultsThe median follow-up for all patients was 38.5 months (range, 3–129 months). After intra-arterial chemoradiotherapy, primary site complete response was achieved in 113 (95.8%) of 118 cases. Three-year locoregional control and overall survival rates were 80.3% and 81.5%, respectively. Grade 3 or 4 toxicities included neutropenia in 16.1% and mucositis in 87.3%. Grade 3 toxicities included anemia in 12.7%, thrombocytopenia in 3.4%, nausea/vomiting in 3.4%, dermatitis in 45.7%, dysphagia in 74.6%, and fever in 2.5% of patients. Late toxicity consisting of grade 3 osteoradionecrosis of the jaw occurred in 4.2% of patients. On univariate analysis, T stage and overall stage were significantly associated with locoregional control, and N stage and overall stage were significantly associated with overall survival. On multivariate analysis, the only significant predictor of overall survival was overall stage classification.ConclusionRetrograde superselective intra-arterial chemoradiotherapy for tongue cancer provided good overall survival and locoregional control.



http://ift.tt/2HjtEdv

Immunohistochemical Biomarkers of Gastrointestinal, Pancreatic, Pulmonary, and Thymic Neuroendocrine Neoplasms

Abstract

Neuroendocrine neoplasms (NENs) are a heterogeneous group of epithelial neoplastic proliferations that irrespective of their primary site share features of neural and endocrine differentiation including the presence of secretory granules, synaptic-like vesicles, and the ability to produce amine and/or peptide hormones. NENs encompass a wide spectrum of neoplasms ranging from well-differentiated indolent tumors to highly aggressive poorly differentiated neuroendocrine carcinomas. Most cases arise in the digestive system and in thoracic organs, i.e., the lung and thymus. A correct diagnostic approach is crucial for the management of patients with both digestive and thoracic NENs, because their high clinical and biological heterogeneity is related to their prognosis and response to therapy. In this context, immunohistochemistry represents an indispensable diagnostic tool that pathologists need to use for the correct diagnosis and classification of such neoplasms. In addition, immunohistochemistry is also useful in identifying prognostic and theranostic markers. In the present article, the authors will review the role of immunohistochemistry in the routine workup of digestive and thoracic NENs.

http://ift.tt/2Ian2zr

An internally validated prognostic model for success in revision stapes surgery for otosclerosis

Objectives/Hypothesis

To develop a prediction model that can accurately predict the chance of success following revision stapes surgery in patients with recurrent or persistent otosclerosis at 2- to 6-months follow-up and to validate this model internally.

Study Design

A retrospective cohort study of prospectively gathered data in a tertiary referral center.

Methods

The associations of 11 prognostic factors with treatment success were tested in 705 cases using multivariable logistic regression analysis with backward selection. Success was defined as a mean air-bone gap closure to 10 dB or less. The most relevant predictors were used to derive a clinical prediction rule to determine the probability of success. Internal validation by means of bootstrapping was performed. Model performance indices, including the Hosmer-Lemeshow test, the area under the receiver operating characteristics curve (AUC), and the explained variance were calculated.

Results

Success was achieved in 57.7% of cases at 2- to 6-months follow-up. Certain previous surgical techniques, primary causes of failure leading up to revision stapes surgery, and positions of the prosthesis placed during revision surgery were associated with higher success percentages. The clinical prediction rule performed moderately well in the original dataset (Hosmer-Lemeshow P = .78; AUC = 0.73; explained variance = 22%), which slightly decreased following internal validation by means of bootstrapping (AUC = 0.69; explained variance = 13%).

Conclusions

Our study established the importance of previous surgical technique, primary cause of failure, and type of the prosthesis placed during the revision surgery in predicting the probability of success following stapes surgery at 2- to 6-months follow-up.

Level of Evidence

2b. Laryngoscope, 2018

http://ift.tt/2G8znU5

Editorial Board

Publication date: July 2018
Source:Journal of Environmental Radioactivity, Volume 187





http://ift.tt/2DbcTio

Deposition of artificial radionuclides in sediments of Loch Etive, Scotland

Publication date: July 2018
Source:Journal of Environmental Radioactivity, Volume 187
Author(s): Hamza Al-Qasmi, Gareth T.W. Law, L. Keith Fifield, John A. Howe, Tim Brand, Gregory L. Cowie, Kathleen A. Law, Francis R. Livens
The nuclear fuel reprocessing plants on the Sellafield site (UK) have released low-level effluents into the Irish Sea under authorisation since 1952. This has led to the labelling of nearby offshore sediments with a range of artificial radionuclides. In turn, these sediments act as a long-term secondary source of both soluble and particle-associated radionuclides to coastal areas. These radionuclides are of interest both in assessing possible environmental impacts and as tracers for marine processes. Here we present results from a study of the geochemistry of natural (^{234, 238}U) and artificial (¹³⁷Cs, ²⁴¹Am, ²³⁸Pu, ^239+240Pu, and ²³⁶U) radionuclides and their accumulation in sediments from Loch Etive, Scotland. The data are interpreted in the context of the historical radioactive discharges to the Irish Sea and biogeochemical processes in marine sediments. Loch Etive is divided into two basins; a lower, seaward basin where the sedimentation rate (∼0.6 cm/yr) is about twice that of the more isolated upper basin (∼0.3 cm/yr). These accumulation rates are consistent with the broad distribution of ¹³⁷Cs in the sediment profiles which can be related to the maximum Sellafield discharges of ¹³⁷Cs in the mid-1970s and suggest that ¹³⁷Cs was mainly transported in solution to Loch Etive during that period. Enrichments of Mn, Fe, and Mo in sediment and porewater from both Loch Etive basins result from contemporary biogeochemical redox processes. Enrichments of ²³⁸U and ²³⁴U in the lower basin may be a result of the cycling of natural U. By contrast, the Sellafield-derived artificial isotope ²³⁶U does not seem to be affected by the redox-driven reactions in the lower basin. The ²³⁸Pu/^239,240Pu ratios suggest contributions from both historical Sellafield discharges and global fallout Pu. The uniform sediment distributions of Pu and Am, which do not reflect Sellafield historical discharges, suggest the existence of a homogenous secondary source. This could be the offshore 'mud patch' in the vicinity of Sellafield from which the supply of radionuclides reflects time-integrated Sellafield discharges. This source could also account for the continuing supply of Cs to Loch Etive, even after substantial reductions in discharge from the Sellafield site.



http://ift.tt/2FmHcbQ

Radiocesium migration in the litter layer of different forest types in Fukushima, Japan

Publication date: July 2018
Source:Journal of Environmental Radioactivity, Volume 187
Author(s): Momo Kurihara, Yuichi Onda, Hiroaki Kato, Nicolas Loffredo, Tetsuo Yasutaka, Frederic Coppin
Cesium-137 (¹³⁷Cs) migration in the litter layer consists of various processes, such as input via throughfall, output via litter decomposition, and input from deeper layers via soil organism activity. We conducted litter bag experiments over 2 years (December 2014–November 2016) to quantify the inputs and outputs of ¹³⁷Cs in the litter layer in a Japanese cedar plantation (Cryptomeria japonica) and a mixed broadleaf forest dominated by Quercus serrata located 40 km northwest of the Fukushima Dai-ichi Nuclear Power Plant. The experiments included four conditions, combining contaminated and non-contaminated litter and deeper layer material, and the inputs and outputs were estimated from the combination of ¹³⁷Cs increases and decreases in the litter layer under each condition. The ¹³⁷Cs dynamics differed between the two forests. In the C. japonica forest, some ¹³⁷Cs input via throughfall remained in the litter layer, and downward ¹³⁷Cs flux passed through the litter layer was 0.42 (/year).Upward flux of ¹³⁷Cs from the deeper layer was very restricted, < 0.017 (/year). In the broadleaf forest, migration of ¹³⁷Cs in throughfall into deeper layers was restricted, downward ¹³⁷Cs flux was less than 0.003 (/year).Upward input of ¹³⁷Cs from the deeper layer was prominent, 0.037 (/year). ¹³⁷Cs output via litter decomposition was observed in both forests. The flux in the C. japonica forest was slower than that in the broadleaf forest, 0.12 and 0.15 (/year), respectively.



http://ift.tt/2txtf5k

Updated database on natural radioactivity in building materials in Europe

Publication date: July 2018
Source:Journal of Environmental Radioactivity, Volume 187
Author(s): R. Trevisi, F. Leonardi, S. Risica, C. Nuccetelli
The paper presents the latest collection of activity concentration data of natural radionuclides (²²⁶Ra, ²³²Th and ⁴ K) in building materials. This database contains about 24200 samples of both bulk materials and their constituents (bricks, concrete, cement, aggregates) and superficial materials used in most European Union Member States and some European countries. This collection also includes radiological information about some NORM residues and by-products (by-product gypsum, metallurgical slags, fly and bottom ashes and red mud) which can be of radiological concern if recycled in building materials as secondary raw materials. Moreover, radon emanation and radon exhalation rate data are reported for bricks and concrete.



http://ift.tt/2FnGICh

Mixtures of tritiated water, zinc and dissolved organic carbon: Assessing interactive bioaccumulation and genotoxic effects in marine mussels, Mytilus galloprovincialis

Publication date: July 2018
Source:Journal of Environmental Radioactivity, Volume 187
Author(s): Holly B.C. Pearson, Lorna J. Dallas, Sean D.W. Comber, Charlotte B. Braungardt, Paul J. Worsfold, Awadhesh N. Jha
Release of tritium (³H) in the marine environment is of concern with respect to its potential bioaccumulation and detrimental impact on the biota. Previous studies have investigated the uptake and toxicity of this radionuclide in marine mussels, and the interaction of ³H with dissolved organic ligands and elevated temperature. However, despite the well-established view that toxicity is partly governed by chemical speciation, and that toxic effects of mixture of contaminants are not always additive, there have been no studies linking the prevailing chemistry of exposure waters with observed biological effects and tissue specific accumulation of ³H in combination with other constituents commonly found in natural waters. This study exposed the marine mussel Mytilus galloprovincialis for 14 days to mixtures of ³H (as tritiated water, HTO) and zinc (Zn) at 5 Mbq L⁻¹, and 383, 1913 and 3825 nM Zn, respectively, to investigate (a) ³H and Zn partitioning in soft tissues of mussels, and (b) DNA damage in haemocytes, determined using the single cell gel electrophoresis or the comet assay. Additionally, the extent of association of ³H with dissolved organic carbon (DOC, added as humic acid) over the exposure period was investigated in order to aid the interpretation of biological uptake and effects. Results concluded a clear antagonistic effect of Zn on ³H-induced DNA damage at all Zn concentrations used, likely explained by the importance of Zn in DNA repair enzymes. The interaction of DOC with ³H was variable, with strong ³H-DOC associations observed in the first 3 d of the experiment. The secretion of ³H-binding ligands by the mussels is suggested as a possible mechanism for early biological control of ³H toxicity. The results suggest risk assessments for radionuclides in the environment require consideration of potential mixture effects.



http://ift.tt/2DcHKuI

AMS assessment of U-contamination of structural materials of the Garigliano NPP under decommissioning

Publication date: July 2018
Source:Journal of Environmental Radioactivity, Volume 187
Author(s): F. Terrasi, R. Buompane, A. D'Onofrio, A. Esposito, L. Gialanella, F. Marzaioli, A. Petraglia, G. Porzio, C. Sabbarese, F. Scolamacchia, C. Sirignano
The assessment of the radiological impact of decommissioning activities at a Nuclear Power Plant requires a detailed mapping of the distribution of radionuclides both in the environment surrounding the NPP and in its structural material. The detection of long-lived actinide isotopes and possibly the identification of their origin is particularly interesting and valuable if ultrasensitive measurement of the relative abundance of U isotopes is performed via Accelerator Mass Spectrometry (AMS). In this paper we present an investigation carried out on the structural materials of the Garigliano NPP aiming to determine the abundance of ^235,236,238U in the various compartments of the plant buildings under decommissioning. Since the expected values both for isotopic ratios and total U concentrations range over different orders of magnitude, we have developed a novel methodology for the measurement of ^234,235U/²³⁸U isotopic ratios in low U concentration samples. This allowed a systematic investigation of the distribution of all U isotopes in concrete and metal matrices of the NPP. The behavior of ^235,236U/²³⁸U isotopic ratios in the different compartments of the NPP is discussed. The correlation of these ratios with ⁶⁰Co and ¹³⁷Cs specific activities is also studied to show a different behavior for concrete and metal samples. These data represent a very valuable information to direct the decommissioning procedures under course.



http://ift.tt/2FmoUYc

Complex Association Patterns for Inflammatory Mediators in Induced Sputum from Subjects with Asthma

Abstract

Background

The release of various inflammatory mediators into the bronchial lumen is thought to reflect both the type and degree of airway inflammation, eosinophilic Th2, and Th9, or neutrophilic Th1, and Th17, in patients with asthma.

Aims

We investigated whether cytokines and chemokines differed in sputum from subjects with more severe compared with milder asthma, and if unbiased factor analysis of cytokine and chemokine groupings indicates specific inflammatory pathways.

Methods

Cell-free supernatants from induced sputum were obtained from subjects with a broad range of asthma severity (n=158) and assessed using Milliplex^® Cytokines/Chemokine kits I, II, and III, measuring 75 individual proteins. Each cytokine, chemokine, or growth factor concentration was examined for differences between asthma severity groups, for association with leukocyte counts, and by factor analysis.

Results

Severe asthma subjects had 9 increased and 4 decreased proteins compared to mild asthma subjects and fewer differences compared to moderate asthma. Twenty-six mediators were significantly associated with an increasing single leukocyte type: 16 with neutrophils (3 interleukins [IL], 3 CC-chemokines, 4 CXC-chemokines, 4 growth factors, TNF-α, and CX3CL1/Fractalkine); 5 with lymphocytes (IL-7, IL-16, IL-23, IFN-α2 and CCL4/MIP1β); IL-15 and CCL15/MIP1δ with macrophages; IL-5 with eosinophils; and IL-4 and TNFSF10/TRAIL with airway epithelial cells. Factor analysis grouped 43 cytokines, chemokines and growth factors which had no missing data onto the first 10 factors, containing mixes of Th1, Th2, Th9 and Th17 inflammatory and anti-inflammatory proteins.

Conclusions

Sputum cytokines, chemokines and growth factors were increased in severe asthma, primarily with increased neutrophils. Factor analysis identified complex inflammatory protein interactions, suggesting airway inflammation in asthma is characterized by overlapping immune pathways. Thus, focus on a single specific inflammatory mediator or pathway may limit understanding the complexity of inflammation underlying airway changes in asthma and selection of appropriate therapy.

This article is protected by copyright. All rights reserved.

http://ift.tt/2oVyzdZ

Systemic nocardiosis in a lepromatous leprosy patient with type 2 reaction

http://ift.tt/2FvuovP

The histologic detection of Helicobacter pylori in seropositive subjects is affected by pathology and secretory ability of the stomach

Abstract

Background

Helicobacter pylori is unevenly distributed in hypochlorhydric environments. The study aim was to elucidate the risk factors for a negative Giemsa staining finding in seropositive subjects by measuring the secretory ability of the stomach.

Methods

Subjects aged over 18 years were included consecutively after endoscopic biopsy at gastric lesions with color or structural changes. Blood was sampled for the serum pepsinogen (PG) assay and H. pylori serology test. After excluding the subjects with past H. pylori eradication, the risk factors for a negative Giemsa staining finding in seropositive subjects were analyzed.

Results

Among 872 included subjects, a discrepancy between the serum anti-H. pylori IgG and Giemsa staining findings was found in 158 (18.1%) subjects, including 145 Giemsa-negative, seropositive subjects. Gastric adenocarcinoma/adenoma (OR = 11.090, 95% CI = 3.490-35.236) and low serum PG II level (OR = 0.931, 95% CI = 0.899-0.963) were the independent risk factors for a negative Giemsa staining finding in seropositive subjects. The cutoff value of serum PG II level was 7.45 ng/mL (area under curve [AUC] = 0.904, 95% CI = 0.881-0.927). Follow-up studies of Giemsa staining at different sites of the stomach revealed that 75% of the Giemsa-negative seropositive subjects with adenocarcinoma are positive, whereas none of those with low serum PG II level of <7.45 ng/mL revealed positive findings.

Conclusions

The risk of a negative Giemsa staining finding in seropositive subjects is increased in gastric adenocarcinoma/adenoma specimens and in subjects with a diminished gastric secretory ability with low serum PG II level of <7.45 ng/mL. A false-negative Giemsa staining finding is common in subjects with adenocarcinoma, and therefore, additional biopsies at different sites should be performed in these subjects.

http://ift.tt/2HjHr40

Beneficial effect of Burdock complex on asymptomatic Helicobacter pylori-infected subjects: A randomized, double-blind placebo-controlled clinical trial

Abstract

Background

Burdock complex (BC) constitutes of burdock (Arctium lappa), angelica (Angelica sinensis), gromwell (Lithospermum erythrorhizon), and sesame (Sesamum indicum) oil, which are commonly used in traditional Chinese medicine (TCM) for treating various disorders. This study intended to examine the anti-H. pylori activity of BC on AGS cell model as well as in asymptomatic H. pylori-infected subjects.

Materials and Methods

AGS cell incubated with H. pylori and treated with BC to evaluate the minimum inhibition concentration (MIC), cell viability (MTT) anti-adhesion activity, and inflammatory markers. In case of clinical trial, H. pylori-positive subjects (urea breath test [UBT] >10%, n = 36) were enrolled and requested to intake BC (n = 19) or placebo (n = 17) for 8 weeks. Antioxidant capacity, total phenol, UBT, inflammatory markers were analyzed at the initial, 4th, 8th, and 10th weeks. Moreover, the endoscopic examination was carried out on baseline and 10th week.

Results

In vitro studies showed that BC treatment significantly inhibited (P < .05) the inflammatory markers and adhesion of H. pylori to AGS cell. However, H. pylori-infected subject ingested with BC for 8 weeks significantly decreased (P < .05) the UBT value, inflammatory markers with improved antioxidant activity, and phenolic levels as compared to placebo. Also, consumption of BC considerably healed the ulcer wound.

Conclusion

Overall, the BC could attenuate H. pylori infection by inhibiting H. pylori adhesion and subsequent inflammatory response on the gastric epithelial cell (AGS) as well as clinically ameliorated UBT, antioxidant capacity, and alleviated inflammation to display its anti-H. pylori activity.

http://ift.tt/2FAwKwG

The histologic detection of Helicobacter pylori in seropositive subjects is affected by pathology and secretory ability of the stomach

Abstract

Background

Helicobacter pylori is unevenly distributed in hypochlorhydric environments. The study aim was to elucidate the risk factors for a negative Giemsa staining finding in seropositive subjects by measuring the secretory ability of the stomach.

Methods

Subjects aged over 18 years were included consecutively after endoscopic biopsy at gastric lesions with color or structural changes. Blood was sampled for the serum pepsinogen (PG) assay and H. pylori serology test. After excluding the subjects with past H. pylori eradication, the risk factors for a negative Giemsa staining finding in seropositive subjects were analyzed.

Results

Among 872 included subjects, a discrepancy between the serum anti-H. pylori IgG and Giemsa staining findings was found in 158 (18.1%) subjects, including 145 Giemsa-negative, seropositive subjects. Gastric adenocarcinoma/adenoma (OR = 11.090, 95% CI = 3.490-35.236) and low serum PG II level (OR = 0.931, 95% CI = 0.899-0.963) were the independent risk factors for a negative Giemsa staining finding in seropositive subjects. The cutoff value of serum PG II level was 7.45 ng/mL (area under curve [AUC] = 0.904, 95% CI = 0.881-0.927). Follow-up studies of Giemsa staining at different sites of the stomach revealed that 75% of the Giemsa-negative seropositive subjects with adenocarcinoma are positive, whereas none of those with low serum PG II level of <7.45 ng/mL revealed positive findings.

Conclusions

The risk of a negative Giemsa staining finding in seropositive subjects is increased in gastric adenocarcinoma/adenoma specimens and in subjects with a diminished gastric secretory ability with low serum PG II level of <7.45 ng/mL. A false-negative Giemsa staining finding is common in subjects with adenocarcinoma, and therefore, additional biopsies at different sites should be performed in these subjects.

http://ift.tt/2HjHr40

Beneficial effect of Burdock complex on asymptomatic Helicobacter pylori-infected subjects: A randomized, double-blind placebo-controlled clinical trial

Abstract

Background

Burdock complex (BC) constitutes of burdock (Arctium lappa), angelica (Angelica sinensis), gromwell (Lithospermum erythrorhizon), and sesame (Sesamum indicum) oil, which are commonly used in traditional Chinese medicine (TCM) for treating various disorders. This study intended to examine the anti-H. pylori activity of BC on AGS cell model as well as in asymptomatic H. pylori-infected subjects.

Materials and Methods

AGS cell incubated with H. pylori and treated with BC to evaluate the minimum inhibition concentration (MIC), cell viability (MTT) anti-adhesion activity, and inflammatory markers. In case of clinical trial, H. pylori-positive subjects (urea breath test [UBT] >10%, n = 36) were enrolled and requested to intake BC (n = 19) or placebo (n = 17) for 8 weeks. Antioxidant capacity, total phenol, UBT, inflammatory markers were analyzed at the initial, 4th, 8th, and 10th weeks. Moreover, the endoscopic examination was carried out on baseline and 10th week.

Results

In vitro studies showed that BC treatment significantly inhibited (P < .05) the inflammatory markers and adhesion of H. pylori to AGS cell. However, H. pylori-infected subject ingested with BC for 8 weeks significantly decreased (P < .05) the UBT value, inflammatory markers with improved antioxidant activity, and phenolic levels as compared to placebo. Also, consumption of BC considerably healed the ulcer wound.

Conclusion

Overall, the BC could attenuate H. pylori infection by inhibiting H. pylori adhesion and subsequent inflammatory response on the gastric epithelial cell (AGS) as well as clinically ameliorated UBT, antioxidant capacity, and alleviated inflammation to display its anti-H. pylori activity.

http://ift.tt/2FAwKwG

Editorial Board

Publication date: April 2018
Source:Biomedicine & Pharmacotherapy, Volume 100





http://ift.tt/2Fn7mv1

Cross-talk connections underlying dorsal and ventral stream integration during hand actions

Publication date: Available online 9 March 2018
Source:Cortex
Author(s): Sanja Budisavljevic, Flavio Dell'Acqua, Umberto Castiello
According to the dual-stream theory, the processing of visual information is divided into a ventral pathway mediating object recognition, and a dorsal pathway supporting visuomotor control. Increasing evidence suggests that these streams are not independent, but where this dorsal-ventral stream integration occurs, in the context of hand actions, remains unknown. We explored the candidate white matter pathways linking dorsal and ventral visual streams in 30 right-handed participants performing hand movements of varying complexity (reaching, grasping and lifting), using advanced diffusion imaging tractography based on the spherical deconvolution and kinematical analysis. We provided for the first time a direct evidence of cross-communication between dorsal and ventral visual streams in humans, through vertical occipital fasciculus and temporo-parietal fibers of the arcuate fasciculus during on-line control of skilled object-oriented hand actions. We showed that individual differences in the microstructure of these cross-talk connections were associated with the variability of arm deceleration, the grip opening phase and the grasp accuracy. This study suggests that hand kinematics, in skilled hand actions where high degree of online control is required, is related to the anatomy of the dorsal-ventral networks, bringing important insights to the dual-stream theory and the sensorimotor organization of hand actions.



http://ift.tt/2Fqkhw4

Influence of Acoustic Reflection on the Inertial Cavitation Dose in a Franz Diffusion Cell

Publication date: Available online 8 March 2018
Source:Ultrasound in Medicine & Biology
Author(s): Jeremy Robertson, Sid Becker
The exposure of the skin to low-frequency (20–100 kHz) ultrasound is a well-established method for increasing its permeability to drugs. The mechanism underlying this permeability increase has been found to be inertial cavitation within the coupling fluid. This study investigated the influence of acoustic reflections on the inertial cavitation dose during low-frequency (20 kHz) exposure in an in vitro skin sonoporation setup. This investigation was conducted using a passive cavitation detector that monitored the broadband noise emission within a modified Franz diffusion cell. Two versions of this diffusion cell were employed. One version had acoustic conditions that were similar to those of a standard Franz diffusion cell surrounded by air, whereas the second was designed to greatly reduce the acoustic reflection by submerging the diffusion cell in a water bath. The temperature of the coupling fluid in both setups was controlled using a novel thermoelectric cooling system. At an ultrasound intensity of 13.6 W/cm², the median inertial cavitation dose when the acoustic reflections were suppressed, was found to be only about 15% lower than when reflections were not suppressed.



http://ift.tt/2G5Y1Vr

Ultrasound-Guided Percutaneous Needle Biopsy for Peripheral Pulmonary Lesions: Diagnostic Accuracy and Influencing Factors

Publication date: Available online 8 March 2018
Source:Ultrasound in Medicine & Biology
Author(s): Yu-Qing Guo, Xin-Hong Liao, Zhi-Xian Li, Yuan-Yuan Chen, Si-Da Wang, Ji-Han Wang, Xian-Shan Liao, Yuan Luo
A retrospective study was carried out to evaluate the diagnostic accuracy and the factors influencing the diagnostic accuracy of 648 procedures of ultrasound-guided percutaneous needle biopsy (PNB) for peripheral pulmonary lesions (PPLs). We reviewed the histopathology results, the clinical records and the procedure reports of these 648 biopsies and the final diagnoses of 637 PPLs to determine the diagnostic accuracy of ultrasound-guided PNB. Factors that influenced the diagnostic accuracy were assessed by analysis of the biopsy procedures, which were classified as diagnostic cases (true-positive and true-negative) and non-diagnostic cases (false-positive, false-negative and indeterminate). Statistical analyses of factors that related to patient demographic characteristics, lesion characteristics and biopsy details were performed to determine possible effects on diagnostic accuracy. Biopsies were successfully performed in all cases, and 11 patients underwent second biopsies for the same lesions. Among the 637 PPLs, there were 326 (51.2%) malignant lesions, 272 (42.7%) benign lesions and 39 (6.1%) indeterminate lesions. Of the 272 benign lesions, 114 (41.9%) were found to be tuberculous. The overall diagnostic accuracy was 81.8%, and the rates of hemoptysis, symptomatic pneumothorax and chest-tube insertion were 8.0%, 1.7% and 0.9%, respectively. Lesions sizes were divided into 3 groups according to the measurement by ultrasound. For lesions that measured ≤20 mm, 21–49 mm and ≥50 mm, the diagnostic accuracy was 72.0%, 86.8% and 79.7%, while sensitivity and specificity were 54.3%–79.2%, 88.3%–90.7% and 79.4%–89.5% and 77.3%–100%, 96.8%–100% and 58.6%–100%, respectively. Diagnostic accuracy was significantly affected by lesion size when lesion size was measured by ultrasound (p = 0.006) and computed tomography (CT) (p = 0.001). In the 3 lesion groups of ≤20 mm, 21–49 mm or ≥50 mm, diagnostic accuracy among each group was significantly different (p < 0.001). When lesion size was measured by ultrasound (p < 0.001) and CT (p < 0.001) and the 3 groups were analyzed (p < 0.001), there was a statistically significant relationship between lesion size and the presence of necrosis. The rates of the presence of necrosis in lesions that measured ≤20 mm, 21–49 mm and ≥50 mm were 3.9%, 11.7% and 28.8%, respectively. No significance was found for age (p = 0.119), gender (p = 0.25), lesion location (p = 0.55), the presence of necrosis (p = 0.226), patient position (p = 0.25), needle size (p = 0.26), puncture angle (p = 0.34) and needle passes (p = 0.21). Ultrasound-guided PNB is an effective and safe diagnostic method for PPLs; the diagnostic accuracy is significantly affected by lesion size and decreases in smaller (≤20 mm) and larger (≥50 mm) lesions.



http://ift.tt/2FrBwcA

Counterfeit esthetic devices and patient safety in dermatology

Summary

This study addresses the dilemma concerned with meeting patients who may have encountered counterfeit esthetic devices in the marketplace. Over the past several years, we have witnessed a rise in counterfeit injectables and medical devices in our field. Often times, the procedures are marketed to patients at significantly reduced prices compared to competitors. Patients may be unaware that counterfeit devices exist and may unknowingly have procedures completed using untested and uncertified devices. It is important for clinicians to recognize when their patients may be encountering counterfeit devices, know what to do in this situation, and offer the best recommendations.

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Association between bilateral segmental vitiligo and lichen striatus: an expression of mosaicism?

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Counterfeit esthetic devices and patient safety in dermatology

Summary

This study addresses the dilemma concerned with meeting patients who may have encountered counterfeit esthetic devices in the marketplace. Over the past several years, we have witnessed a rise in counterfeit injectables and medical devices in our field. Often times, the procedures are marketed to patients at significantly reduced prices compared to competitors. Patients may be unaware that counterfeit devices exist and may unknowingly have procedures completed using untested and uncertified devices. It is important for clinicians to recognize when their patients may be encountering counterfeit devices, know what to do in this situation, and offer the best recommendations.

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Association between single nucleotide polymorphisms in estrogen receptor 1/2 genes and symptomatic severity of autism spectrum disorder

Publication date: Available online 8 March 2018
Source:Research in Developmental Disabilities
Author(s): Hirokazu Doi, Takashi X. Fujisawa, Ryoichiro Iwanaga, Junko Matsuzaki, Chisato Kawasaki, Mamoru Tochigi, Tsukasa Sasaki, Nobumasa Kato, Kazuyuki Shinohara
BackgroundPrevious studies on etiology of autism spectrum disorders (ASD) have shown strong contribution of hereditary factors. On the basis the heterogeneity in ASD symptoms, it is highly possible that each independent domain of ASD symptom is linked to a different set of genetic risk factors. However, few empirical investigations have been carried out to examine this hypothesis.AimsThe aim of the present study was to investigate the association between single-nucleotide polymorphisms (SNPs) in estrogen receptor genes, which several previous studies have identified as potential risk factors of ASD, and the severity of each independent aspect of ASD symptom within an Asian clinical sample.Method and proceduresWe investigated the association between severities of four ASD symptoms (Social Communication, Social Interaction, Stereotypies and Sensory Abnormalities, and Emotional Regulation) measured by childhood autism rating scale and SNPs in genes of estrogen receptor 1 and 2, ESR1 rs11155819 and ESR2 rs1152582, in 96 Japanese individuals with ASD.Outcomes and resultsThe analysis revealed that severities in the impairment of social interaction and emotional regulation were linked to SNPs in ESR1 rs11155819 and ESR2 rs1152582, respectively. The effect of genotype was not observed for the other aspects of ASD symptoms.Conclusions and implicationsThese findings support our contention that the severity of each ASD symptom domain is determined by a distinct set of genetic risk factors.



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45th Annual Meeting of the Arbeitsgemeinschaft Dermatologische Forschung (ADF) Zurich, Switzerland, March 7-10, 2018

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Clinical Snippets

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Beyond the physico-chemical barrier: Glycerol and xylitol markedly yet differentially alter gene expression profiles and modify signalling pathways in human epidermal keratinocytes

Abstract

Polyols (e.g. glycerol, xylitol) are implicated as moisturizers of the skin and other epithelial tissues. However, we lack information about their exact cellular mechanisms and their effects on the gene expression profiles. Therefore, in this study, we aimed at investigating the effects of glycerol and xylitol on human epidermal keratinocytes. The polyols (identical osmolarities; xylitol: 0.0045%-0.45%; glycerol: 0.0027%-0.27%) did not alter cellular viability or intracellular calcium concentration. However, they exerted differential effects on the expression of certain genes and signalling pathways. Indeed, both polyols up-regulated the expression of filaggrin, loricrin, involucrin and occludin; yet, xylitol exerted somewhat more profound effects. Moreover, while both polyols stimulated the MAPK pathway, only xylitol induced the activation-dependent translocation of protein kinase Cδ, a key promoter of epidermal differentiation. Finally, in various keratinocyte inflammation models, both polyols (albeit with different efficacies) exerted anti-inflammatory effects. Taken together, these data strongly suggest that glycerol and xylitol differentially modulate expressions of multiple genes and activities of signalling pathways in epidermal keratinocytes. Thus, our findings invite clinical trials to explore the applicability and the impact of a combined glycerol-xylitol therapy in the management of various skin conditions.

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A novel IKBKG mutation in a patient with incontinentia pigmenti and features of hepatic ciliopathy

Abstract

We describe a new mutation in exon 4 of IKBKG, encoding nuclear factor-kappa B in a patient with incontinentia pigmenti. The patient had a severe cholestatic liver disease with features of a ciliopathy and underwent liver transplantation. We cannot establish a link between incontinentia pigmenti, a very rare disease, and hepatic ciliopathy, but we suggest that hepatic evaluation should be considered in patients with incontinentia pigmenti.

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A case of CD8+ and CD56+ cytotoxic variant of poikilodermatous mycosis fungoides: Dermoscopic features of reticular pigmentation and vascular structures

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A case of CD8+ and CD56+ cytotoxic variant of poikilodermatous mycosis fungoides: Dermoscopic features of reticular pigmentation and vascular structures

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A novel IKBKG mutation in a patient with incontinentia pigmenti and features of hepatic ciliopathy

Abstract

We describe a new mutation in exon 4 of IKBKG, encoding nuclear factor-kappa B in a patient with incontinentia pigmenti. The patient had a severe cholestatic liver disease with features of a ciliopathy and underwent liver transplantation. We cannot establish a link between incontinentia pigmenti, a very rare disease, and hepatic ciliopathy, but we suggest that hepatic evaluation should be considered in patients with incontinentia pigmenti.

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Valoración de la reacción emocional provocada por la prueba vestibular calórica mediante monitorización de variables fisiológicas

Publication date: Available online 8 March 2018
Source:Acta Otorrinolaringológica Española
Author(s): Rafael Barona-de-Guzmán, Claudio Krstulovic-Roa, Elena Donderis-Malea, Luz Barona-Lleó
Introducción y objetivosLa valoración emocional que provoca el vértigo se realiza mediante la historia clínica y diversos cuestionarios subjetivos. El objetivo del presente trabajo es valorar la respuesta emocional de forma objetiva, en sujetos normales, durante la crisis de vértigo inducida.Material y métodoSe realizó la prueba vestibular calórica con agua fría en 30 sujetos sanos. Durante los 60s previos a la estimulación y los 60s posteriores a la misma se monitorizaron las siguientes variables fisiológicas: Conductabilidad cutánea, Volumen de pulso periférico, Temperatura corporal, Contracción muscular, Frecuencia cardiaca y Frecuencia respiratoria. Se valoró la velocidad angular máxima de la fase lenta del nistagmo provocado en cada estimulación.ResultadosDurante las crisis de vértigo, la conductabilidad cutánea presentó un aumento estadísticamente significativo con relación al periodo previo a las mismas, mientras que el volumen de pulso periférico presentó una disminución estadísticamente significativa. No hubo relación entre la velocidad angular de la fase lenta del nistagmo provocado y los cambios de la conductabilidad y el volumen de pulso periférico. La disminución provocada en el volumen de pulso periférico fue significativamente mayor en la segunda crisis de vértigo.ConclusionesLa conductabilidad cutánea y el volumen de pulso periférico cambiaron de forma significativa durante las crisis de vértigo. No Hubo relación entre la intensidad de la crisis vertiginosa provocada y los cambios producidos en estas variables. El estrés generado por la estimulación calórica es mayor en la segunda crisis, cuando el sujeto tiene experiencia del vértigo que provoca la estimulación.Introduction and objectivesThe emotional evaluation of the causes of vertigo is made using the clinical records and several subjective questionnaires. The aim of the present study is to evaluate the emotional response objectively, in normal subjects, during an induced vertigo crisis.Material and methodA caloric vestibular test with cold water was performed on 30 healthy subjects. The following physiological parameters were monitored during the 60seconds prior to and the 60seconds after the stimulation: Skin Conductivity, Peripheral Pulse Volume, Body Temperature, Muscle Contraction, Heart Rate, and Respiratory Rate. The maximum angular speed of the nystagmus slow phase at each stimulation was assessed.ResultsSkin conductance presented a statistically significant increase during the vertigo crisis in relation to the prior period while the peripheral pulse volume presented a statistically significant decrease. There was no relationship between the slow phase of the provoked nystagmus angular speed and skin conductance and peripheral pulse volume changes. The decrease in peripheral pulse volume was significantly higher in the second vertigo crisis.ConclusionsSkin conductance and peripheral pulse volume changed significantly during a vertigo crisis. There was no relation between the provoked vertiginous crisis intensity and the changes produced in those variables. The stress generated by the caloric stimulation is higher in the second crisis, when the subject has experience of the vertigo caused by the stimulation.



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Glucocorticoids induce apoptosis and matrix metalloproteinase-13 expression in chondrocytes through the NOX4/ROS/p38 MAPK pathway

Publication date: Available online 8 March 2018
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Ying Huang, Gui-quan Cai, Jian-Ping Peng, Chao Shen
Based on the results from our previous study, dexamethasone (Dex) increases reactive oxygen species (ROS) levels and subsequently induces cell death and matrix catabolism in chondrocytes. Nevertheless, the mechanism underlying this phenomenon remains unclear. Nicotinamide adenine dinucleotide (phosphate) (NADPH) oxidase 4 (NOX4) is one of the major enzymes responsible for intracellular ROS production during the inflammatory process. The objective of the current study was to investigate the role of NOX4 in Dex-induced ROS over-production. Healthy chondrocytes were harvested from the cartilage debris from 6 female patients. NOX4 and p38 mitogen-activated protein kinase (MAPK) expression levels in these cells were evaluated in the presence of Dex. Changes in the number of apoptotic and viable Dex-treated chondrocytes were recorded after the cells were treated with NOX and p38 MAPK inhibitors. Changes in matrix metalloproteinase 13 (MMP-13) expression levels in Dex-treated chondrocytes were also investigated. The Dex treatment increased NOX4 expression via the glucocorticoid receptor (GR). Treatment of cells with apocynin, a NOX inhibitor, decreased intracellular ROS levels and inhibited p38 MAPK activation. Treatment of cells with a ROS scavenger also reduced p38 MAPK expression. Treatment of cells with a NOX inhibitor, ROS scavenger and p38 MAPK inhibitor rescued chondrocytes from Dex-induced apoptosis. Moreover, treatment of cells with these agents blocked MMP-13 expression in Dex-treated chondrocytes. NOX4 silencing also suppressed p38 MAPK and MMP-13 expression. Dex triggered apoptosis and MMP-13 expression through the NOX4/ROS/p38 MAPK signaling pathway. NOX4 may be a therapeutic target in the management of Dex-induced complications.



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LINE1 contributes to autoimmunity through both RIG-I- and MDA5-mediated RNA sensing pathways

Publication date: Available online 7 March 2018
Source:Journal of Autoimmunity
Author(s): Ke Zhao, Juan Du, Yanfeng Peng, Peng Li, Shaohua Wang, Yu Wang, Jingwei Hou, Jian Kang, Wenwen Zheng, Shucheng Hua, Xiao-Fang Yu
Improper host immune activation leads to the development of the autoimmune disease Aicardi-Goutières syndrome (AGS), which is attributed to defined genetic mutations in such proteins as TREX1 and ADAR1. The mechanism of immune activation in AGS patients has not been thoroughly elucidated to date. In this study, we report that endogenous LINE1 components trigger IFNβ production in multiple human cell types, including those defective for cGAS/STING-mediated DNA sensing. In these cells, LINE1 DNA synthesis and retrotransposition were not required for LINE1-triggered immune activation, but RNA sensing pathways were essential. LINE1-triggered immune activation could be suppressed by diverse LINE1 inhibitors, including AGS-associated proteins targeting LINE1 RNA or proteins. However, AGS-associated ADAR1 or TREX1 mutants were defective in suppressing LINE1 retrotransposition or LINE1-triggered immune activation. Therefore, we have revealed a new function for LINE1 as an endogenous trigger of innate immune activation, which is important for understanding the molecular basis of IFN-based autoimmune diseases and may offer new intervention strategies.



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The effect of neoadjuvant androgen deprivation therapy on tumour hypoxia in high-grade prostate cancer: a 18F-MISO PET/MRI imaging study.

Publication date: Available online 8 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Ismini C. Mainta, Thomas Zilli, Jean-Christophe Tille, Thomas De Perrot, Jean-Paul Vallée, Franz Buchegger, Valentina Garibotto, Raymond Miralbell
PurposeTumour hypoxia is associated with radio-resistance and poor prognosis after radiotherapy (RT) for prostate cancer (PCa). In this prospective pilot study we assessed the ability of 18F-misonidazole (18F-MISO) PET/MRI to detect hypoxia in high-grade PCa patients candidates for curative RT and we evaluated 18F-MISO PET/MRI modulation after 3 months of neoadjuvant androgen-deprivation therapy (nADT).MethodsEleven PCa patients with Gleason score (GS) ≥8 underwent 18F-Choline (18F-FCH) PET/CT at diagnosis and two 18F-MISO hybrid PET/MRI before and after 3 months of nADT, respectively. Immunohistochemistry (IHC) for tissue hypoxia and proliferation-related biomarkers (Glut1, CA-IX, VEGF-A, Ki67, HIF-1-alpha, EGFR) was performed in lesions bearing the highest GS. We used non-parametric tests to assess: 1. the presence of 18F-MISO positive regions (Tumour-to-Background ratios - TBR ≥ 1.4) at baseline; 2. The correlation between imaging parameters (PET tracers uptake, Prostate Imaging Reporting and Data System (PIRADS) scores, dynamic contrast enhancement perfusion markers) at baseline; 3. The difference in IHC staining between 18F-MISO positive and 18F-MISO negative lesions; 4. The changes in 18F-MISO PET/MRI imaging after nADT.Results18F-MISO uptake was significant in 7 patients, 5 of them being coincidental with the highest GS region. A significant correlation was found at baseline between GS and 18F-MISO TBR, between 18F-MISO TBR and MRI perfusion markers, between GS and 18F-FCH SUVmax, between GS and PIRADS and between 18F-FCH SUVmax and PIRADS. No difference was found between 18F-MISO positive and negative biopsies with respect to tissue biomarkers. 18F-MISO TBR diminished significantly after nADT only in high-grade lesions and in regions with a significant uptake at baseline.Conclusions18F-MISO PET imaging showed variable uptake in PCa, associated with a higher GS, lowering significantly after 3 months of nADT in high grade lesions. These results suggest the existence of a hypoxic microenvironment in PCa and a re-oxygenation effect of nADT.

Teaser

Tumour hypoxia is associated to treatment resistance. In this prospective study of 11 patients, we evaluated the occurrence of hypoxia in high-grade prostate cancer by multiparametric integrated18F-MISO PET/MRI before and after 3 months of androgen deprivation. Our results show the presence of hypoxic conditions in prostate carcinoma, correlated with tumour grade and responding to androgen ablation, thus supporting the re-oxygenation role of a neoadjuvant androgen deprivation therapy phase in combination with curative radiotherapy.


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Hypopituitarism after Single-Fraction Pituitary Adenoma Radiosurgery: Dosimetric Analysis based on Patients treated Using Contemporary Techniques

Publication date: Available online 8 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Christopher S. Graffeo, Michael J. Link, Paul D. Brown, William F. Young, Bruce E. Pollock
PurposeHypopituitarism is the most frequent complication after pituitary adenoma radiosurgery (SRS). The dosimetric factors associated with pituitary insufficiency remain unclear despite more than 30 years of clinical usage.Methods and MaterialsRetrospective review of 97 patients having single-fraction SRS from 2007 until 2014. Eligible patients had no history of prior radiation, normal age- and gender-specific pituitary function before SRS, and at least 24 months of endocrine follow-up. Forty patients (41%) had hormone secreting tumors; 57 patients had non-secreting tumors (59%). The median prescription isodose volume was 2.8 cm³ (IQR, 1.3-4.7); the median tumor margin dose was 20 Gy (IQR, 15-25).ResultsThe median follow-up after SRS was 48 months (IQR, 34-68). Twenty-seven patients (28%) developed pituitary insufficiency at a median of 22 months (IQR, 12-36) after SRS. The rate of new endocrine deficits was 17% at 2-years (95% CI 10%-25%) and 31% at 5-years (95% CI 20%-42%). Male sex (HR=2.38, 95% CI 1.05-5.26, P=0.04), smaller pituitary gland volume (HR=0.99, 95% CI 0.99-0.99, P=0.01), and higher mean pituitary gland dose (HR=1.31, 95% CI 1.16-1.47, P<0.001) were associated with post-SRS hypopituitarism in multivariable analysis. The rate of hypopituitarism for patients with a mean gland dose <11.0 Gy at 2-years was 2% (95% CI 0%-4%) and 5-years was 5% (95% CI 0%-11%) whereas rate of hypopituitarism for patients with a mean gland dose ≥11.0 Gy at 2-years was 31% (95% CI 17%-43%) and at 5-years was 51% (95% CI 34%-65%).ConclusionsHypopituitarism after pituitary adenoma SRS increases in a time- and dose-dependent manner. Reducing the radiation exposure to the identifiable gland to a mean dose <11.0 Gy whenever feasible may lower the incidence of new hormonal deficits after pituitary adenoma SRS.



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MMRV vaccine safety

Publication date: Available online 8 March 2018
Source:Vaccine
Author(s): Patrick Cashman, Sarah Moberley, David Durrheim




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Rotavirus genotypes circulating in Ontario, Canada, before and after implementation of the rotavirus immunization program

Publication date: Available online 8 March 2018
Source:Vaccine
Author(s): Sandra Isabel, Rachel R. Higgins, Adriana Peci, Marc R. Isabel, Shelley L. Deeks, Jonathan B. Gubbay
Background and objectivesOntario introduced a universal publicly-funded group A rotavirus (RVA) immunization program in August 2011, using monovalent vaccine. RVA immunization programs have decreased the incidence of RVA acute gastroenteritis in many countries but it is unclear if it will contribute to the emergence of certain genotypes. We monitored RVA trends and genotypes in Ontario before and after implementation of the publicly-funded immunization program.MethodsRVA detection was conducted at Public Health Ontario Laboratories from January 2009 to December 2011 (pre-program period) and January 2012 to October 2015 (publicly-funded RVA immunization program period) and number of RVA-positive specimens and percent positivity were analysed. A convenience sample of RVA-positive stool specimens, from September 2010 to December 2011 (pre-program period) and January 2012 to June 2013 (program period), were genotyped using heminested PCR. A literature review on the burden of illness from emergent genotype was performed.ResultsStool specimens showed a significant decrease in RVA percent positivity from the 36 month pre-program period (14.4%; 1537/10700) to the 46 month program period (6.1%; 548/9019). An increase in the proportion of RVA G10 among genotyped specimens, associated with five different P genotypes, from the pre-program (6.3%; 13/205) to the program (31.5%; 40/127) period was observed. Our literature review identified approximately 200 G10-positive human stool specimens from 16 different countries.ConclusionsThis study documented a decrease in the number of RVA-positive specimens and percent positivity after implementation of the immunization program. An unexpected increase in the proportion of RVA G10 was detected following program introduction. Ongoing RVA surveillance is important in evaluating both the long-term impact of immunization and emergence of RVA genotypes.



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Vaccination of sheep with Quil-A® adjuvant expands the antibody repertoire to the Fasciola MF6p/FhHDM-1 antigen and administered together impair the growth and antigen release of flukes

Publication date: Available online 8 March 2018
Source:Vaccine
Author(s): Ricardo A. Orbegozo-Medina, Victoria Martínez-Sernández, Marta González-Warleta, José Antonio Castro-Hermida, Mercedes Mezo, Florencio M. Ubeira
Fasciolosis continues to be a major cause of economic losses in the livestock industry and a growing threat to humans. The limited spectrum of effective anthelmintics and the appearance of resistances urge the need for developing an effective vaccine. Most studies have been focused on the use of TH1-polarizing adjuvants and the use of recombinant Fasciola critical molecules and, despite the efforts, no reproducible protections have been achieved. The F. hepatica MF6p/FhHDM-1 protein is a heme-binding protein also reported to have immunomodulatory properties, constituting a promising target for vaccination and/or as target for the development of new flukicides. Thus, in this study, we investigated the effects of the TH1-polarizing adjuvant Quil A® on sheep immune response to MF6p/FhHDM-1, and the vaccine potential of both native and synthetic forms of this protein against ovine fasciolosis. Subcutaneous injection of Quil A® alone, i.e., without co-injecting any antigen, expands the antibody repertoire to MF6p/FhHDM-1 triggered by a subsequent primoinfection with metacercariae. This effect was not observed with aluminum hydroxide, the most frequently adjuvant used in commercial vaccines. On the other hand, vaccination with synthetic MF6p/FhHDM-1 in Quil A® prompted a 2–4-week delay in the antibody response induced in sheep by a challenge experimental infection. Moreover, fluke populations stablished showed stunted growth and low antigen release probably due to reduced metabolic activity. These observations suggest that primary circulating antibodies induced by the immunization had harmful effects on fluke development. Such effects could not be demonstrated to be associated to TH1 immune response linked events (production of IgG2 isotype antibodies and IFN-γ).



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Long-term impact of 10-valent pneumococcal conjugate vaccination on invasive pneumococcal disease among children in Finland

Publication date: Available online 8 March 2018
Source:Vaccine
Author(s): Hanna Rinta-Kokko, Arto A. Palmu, Kari Auranen, J. Pekka Nuorti, Maija Toropainen, Lotta Siira, Mikko J. Virtanen, Hanna Nohynek, Jukka Jokinen
BackgroundThe ten-valent pneumococcal conjugate vaccine (PCV10) was introduced into the Finnish National Vaccination Programme (NVP) in September 2010. The impact of PCV10 vaccination against invasive pneumococcal disease (IPD) in vaccine-eligible children has been high. We evaluated the long-term impact of PCV10 vaccination against IPD in vaccine-eligible and older, unvaccinated children six years after PCV10 introduction with a special focus on cross-protection against PCV10-related serotypes (serotypes in the same serogroups as the PCV10 types).MethodsWe used data on IPD from the national, population-based surveillance. A target cohort of vaccine-eligible children (born June 2010 or later) was followed from 3 months of age until the end of 2016. For the indirect effect, another cohort of older PCV10-ineligible children was followed from 2012 through 2016. IPD rates were compared with those of season- and age-matched reference cohorts before NVP introduction.ResultsAmong vaccine-eligible children, the incidence of all IPD decreased by 79% (95% CI 74–83%). There was a statistically significant reduction in the incidence of 6A IPD, but for 19A, the reduction was non-significant and the incidence of 19A increased towards the end of the study period in the older vaccine-eligible children. The increase in non-PCV10 related serotypes was non-significant.In the unvaccinated older children, the incidence of all IPD decreased by 33% (95% CI 8–52%) compared to the reference cohort, and there was no impact on serotype 6A or 19A IPD.ConclusionOverall, the impact of PCV10 vaccination on IPD was high in vaccine-eligible children, with a major reduction in vaccine-type disease, and without notable replacement by other serotype groups. Our data suggest that PCV10 results in long-lasting direct cross-protection against 6A IPD. For 19A, no net reduction was observed six years after NVP introduction in the vaccine-eligible cohort. The indirect impact on IPD in unvaccinated children sustained.



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Immunohistochemical investigation of predictors of response or aggressiveness of bowen disease after photodynamic therapy

Publication date: June 2018
Source:Photodiagnosis and Photodynamic Therapy, Volume 22
Author(s): M. Fernández-Guarino, M.L. González Morales, Israel Bernal, A.I. Sánchez Adrada, Sandra Pierri Ugia, J. Barrio Garde
BackgroundPhotodynamic therapy (PDT) is a good option for the treatment of Bowen's disease (BD). However, BD occasionally can progress into a squamous cell carcinoma (SCC) after PDT.ObjectiveFind predictors of aggressiveness of BD after PDTMethodsTwo biopsies of patients with BD treated with PDT with progression to SCC within three months were selected for immunohistochemical (IHC) studies. Conventional PDT was applied. IHC analysis was performed together with hematoxylin-eosin in the biopsies prior to and after treatment with PDT.ResultsAmong the IHC markers studied, none showed different expressions between pre-treatment and post-treatment biopsies except for HSP70ConclusionsThe expression of Hsp70 in BD may predict future aggressive behaviour in BD when treated with PDT. Nevertheless, due to the small number of biopsies studied, further investigations are required to draw conclusions.



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Blue light versus red light for photodynamic therapy of basal cell carcinoma in patients with Gorlin syndrome: A bilaterally controlled comparison study

Publication date: June 2018
Source:Photodiagnosis and Photodynamic Therapy, Volume 22
Author(s): Edward V. Maytin, Urvashi Kaw, Muneeb Ilyas, Judith A. Mack, Bo Hu
BackgroundPhotodynamic therapy (PDT) is a non-scarring alternative for treating basal cell carcinoma (BCC) in patients with Basal Cell Nevus Syndrome (BCNS), also known as Gorlin syndrome. In Europe, red light (635 nm) is the predominant source for PDT, whereas in the United States blue light (400 nm) is more widely available. The objective of this study was to conduct a head-to-head comparison of blue light and red light PDT in the same BCNS patients.MethodsIn a pilot study of three patients with 141 BCC lesions, 5-aminolevulinate (20% solution) was applied to all tumors. After 4 h, half of the tumors were illuminated with blue light and the remainder with red light. To ensure safety while treating this many tumors simultaneously, light doses were escalated gradually. Six treatments were administered in three biweekly sessions over 4 months, with a final evaluation at 6 months. Tumor status was documented with high-resolution photographs. Persistent lesions were biopsied at 6 months.ResultsClearance rates after blue light (98%) were slightly better than after red light (93%), with blue light shown to be statistically non-inferior to red light. Eight suspicious lesions were biopsied, 5 after red light (5/5 were BCC) and 3 after blue light (1 was BCC). Blue light PDT was reportedly less painful.ConclusionBlue light and red light PDT appear to be equally safe and perhaps equally effective for treating BCC tumors in BCNS patients. Further studies to evaluate long-term clearance after blue light PDT are needed.



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Investigation of novel pyrazole carboxamides as new apoptosis inducers on neuronal cells in Helicoverpa zea Yuanhang Ren, Na Yang,

Publication date: Available online 8 March 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Ying Yue, Hong Jin, Ke Tao, Taiping Hou
Novel pyrazole carboxamides with a diarylamine-modified scaffold were modified based on the bixafen (Bayer) fungicide, which has excellent activity against Rhizoctonia solani, Rhizoctonia cerealis and Sclerotinia sclerotiorum. To discover the potential insecticidal activity of these novel pyrazole carboxamides, the present study explored their possible cytoactivity on the insect neuronal cells (RP-HzVNC-AW1) in Helicoverpa zea. The preliminary bioassays showed that some of the target compounds exhibited good cytoactivity against AW1 cells. Among them, compounds a5 and b4-b7 showed good activity in vitro with IC50 values of 11.28, 10.46, 9.04, 11.72 and 12.19 μM, respectively. Notably, the IC50 value of compound b5 was better than 11.81 μM for fipronil. We subsequently attempted to illustrate the mechanism of b5. Intracellular biochemical assays showed that b5 induced AW1 cell apoptosis with a decrease in themitochondrial membrane potential, as well as a significantly increased intracellular calcium ion concentration and caspase-3 activity. A significant decrease in Bcl-2 levels and a marked augmentation of cytochrome-c and Bax were also detected. These results indicate that a mitochondrially dependent intrinsic pathway contributes to compound b5-induced apoptosis in AW1 cells. This study suggests that b5 may act as a potential insecticide that can be used for further optimization.

Graphical abstract

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Intensity modulated radiotherapy in locally advanced thyroid cancer: Outcomes of a sequential phase I dose-escalation study

Publication date: Available online 7 March 2018
Source:Radiotherapy and Oncology
Author(s): K.P. Rooney, A.B. Miah, S.A. Bhide, M.T. Guerrero-Urbano, M.T. Sharabiani, K.L. Newbold, L. Grove, K.J. Harrington, C.M. Nutting
Background and purposeTo determine the safety and tolerability of dose-escalation using modestly accelerated IMRT in high-risk locally advanced thyroid cancer requiring post-operative radiotherapy, and to report preliminary data on efficacy.Materials and methodsA sequential Phase I dose-escalation design was used. Dose level one (DL1) received 58.8 Gy/28F to the post-operative bed and 50 Gy/28F to elective nodes. DL2 received 66.6 Gy/30F to the thyroid bed, 60 Gy/30F to post-operative nodal levels and 54 Gy/30F to elective nodal levels. Acute (NCICTCv.2.0) and late toxicities (RTOG and modified LENTSOM) were recorded. The primary endpoint was the number of patients with ≥Grade 3 (G3) toxicity at 12 months post-treatment.ResultsFifteen patients were recruited to DL1 and twenty-nine to DL2. At 12 months ≥G3 toxicities were 8.3% in both DL1 and DL2. At 60 months, ≥G3 toxicity was reported in 3 (33%) patients in DL1 and 1 (7%) in DL2. One patient in DL2 died at 24 months from radiation-induced toxicity. Time to relapse and overall survival rates were higher in DL2, but this was not statistically significant.Dose-escalation using this accelerated regimen can be safely performed with a toxicity profile similar to reported series using conventional doses.



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Fast and robust adaptation of organs-at-risk delineations from planning scans to match daily anatomy in pre-treatment scans for online-adaptive radiotherapy of abdominal tumors

Publication date: Available online 8 March 2018
Source:Radiotherapy and Oncology
Author(s): Vikas Gupta, Yibing Wang, Alejandra Méndez Romero, Andriy Myronenko, Petr Jordan, Calvin Maurer, Ben Heijmen, Mischa Hoogeman
PurposeTo validate a novel deformable image registration (DIR) method for online adaptation of planning organ-at-risk (OAR) delineations to match daily anatomy during hypo-fractionated RT of abdominal tumors.Materials and methodsFor 20 liver cancer patients, planning OAR delineations were adapted to daily anatomy using the DIR on corresponding repeat CTs. The DIR's accuracy was evaluated for the entire cohort by comparing adapted and expert-drawn OAR delineations using geometric (Dice Similarity Coefficient (DSC), Modified Hausdorff Distance (MHD) and Mean Surface Error (MSE)) and dosimetric (Dmax and Dmean) measures.ResultsFor all OARs, DIR achieved average DSC, MHD and MSE of 86%, 2.1 mm, and 1.7 mm, respectively, within 20 s for each repeat CT. Compared to the baseline (translations), the average improvements ranged from 2% (in heart) to 24% (in spinal cord) in DSC, and 25% (in heart) to 44% (in right kidney) in MHD and MSE. Furthermore, differences in dose statistics (Dmax, Dmean and D2%) using delineations from an expert and the proposed DIR were found to be statistically insignificant (p > 0.01).ConclusionThe validated DIR showed potential for online-adaptive radiotherapy of abdominal tumors as it achieved considerably high geometric and dosimetric correspondences with the expert-drawn OAR delineations, albeit in a fraction of time required by experts.



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Contents

Publication date: February 2018
Source:Radiotherapy and Oncology, Volume 126, Issue 2





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Editorial Board

Publication date: February 2018
Source:Radiotherapy and Oncology, Volume 126, Issue 2





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Improving the quality of radiation oncology: 10years’ experience of QUATRO audits in the IAEA Europe Region

Publication date: February 2018
Source:Radiotherapy and Oncology, Volume 126, Issue 2
Author(s): Joanna Izewska, Mary Coffey, Pierre Scalliet, Eduardo Zubizarreta, Tania Santos, Ioannis Vouldis, Peter Dunscombe
Background and purposeThe IAEA has developed a methodology for comprehensive quality audits of radiotherapy practices called Quality Assurance Team for Radiation Oncology (QUATRO). This study explores the factors that impacted quality of care among QUATRO audited centres in the IAEA Europe Region.Materials and methodsThe 31 QUATRO reports collected over 10years include extensive data describing the quality of radiotherapy at the audited centres. A coding key was developed to aggregate and review these data in terms of recommendations for improvement and positive findings (commendations).ResultsOverall 759 recommendations and 600 commendations were given. Eight centres recognized as centres of competence differed from other centres mostly because they operated complete quality management systems and were adequately staffed. Other centres had excessive staff workloads and many gaps in the process of care. Insufficient equipment levels were prevalent. Patient centredness, communication, dosimetry, quality control and radiation protection were frequently commended by QUATRO.ConclusionsThis analysis points to barriers to quality care such as insufficient staffing, education/training, equipment and lack of quality management. It highlights the correlation between the human resources availability and quality of care. It has also identified common action items for enhancing quality of radiotherapy programmes in the Region.



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THE GHRELIN PARADOX IN THE CONTROL OF EQUINE CHONDROCYTE FUNCTION: THE GOOD AND THE BAD

Publication date: Available online 8 March 2018
Source:Peptides
Author(s): Serena Ceriotti, Anna Lange Consiglio, Lavinia Casati, Fausto Cremonesi, Valeria Sibilia, Francesco Ferrucci
Increasing evidence suggests a role for ghrelin in the control of articular inflammatory diseases like osteoarthritis (OA). In the present study we examined the ability of ghrelin to counteract LPS-induced necrosis and apoptosis of chondrocytes and the involvement of GH secretagogue receptor (GHS-R)1a in the protective action of ghrelin.The effects of ghrelin (10⁻⁷–10⁻¹¹ mol/L) on equine primary cultured chondrocytes viability and necrosis in basal conditions and under LPS treatment (100 ng/ml) were detected by using both acridine orange/propidium iodide staining and annexin-5/propidium iodide staining. The presence of GHS-R1a on chondrocytes was detected by Western Blot. The involvement of the GHS-R1a in the ghrelin effect against LPS-induced cytotoxicity was examined by pretreating chondrocytes with D-Lys3-GHRP-6, a specific GHS-R1a antagonist, and by using des-acyl ghrelin (DAG, 10⁻⁷ and 10⁻⁹ mol/L) which did not recognize the GHS-R 1a.Low ghrelin concentrations reduced chondrocyte viability whereas 10⁻⁷ mol/L ghrelin protects against LPS-induced cellular damage. The protective effect of ghrelin depends on the interaction with the GHS-R1a since it is significantly reduced by D-Lys3-GHRP-6. The negative action of ghrelin involves caspase activation and could be due to an interaction with a GHS-R type different from the GHS-R1a recognized by both low ghrelin concentrations and DAG. DAG, in fact, induces a dose-dependent decrease in chondrocyte viability and exacerbates LPS-induced damage.These data indicate that ghrelin protects chondrocytes against LPS-induced damage via interaction with GHS-R1a and suggest the potential utility of local GHS-R1a agonist administration to treat articular inflammatory diseases such as OA.



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Heart Disease and Relaxin: New Actions for an Old Hormone

Publication date: Available online 8 March 2018
Source:Trends in Endocrinology & Metabolism
Author(s): Teja Devarakonda, Fadi N. Salloum
The hormone relaxin has long been recognized for its involvement in maternal adaptation during pregnancy. However, discoveries during the past two decades on the mechanism of action of relaxin, its family of receptors, and newly described roles in attenuating ischemia/reperfusion (I/R) injury, inflammation, and arrhythmias have prompted vast interest in exploring its therapeutic potential in cardiovascular disease. These observations inspired recently concluded clinical trials in patients with acute heart failure. This review discusses our current understanding of the protective signaling pathways elicited by relaxin in the heart, and highlights important new breakthroughs about relaxin signaling that may pave the way to more carefully designed future trials.



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Closed-loop intracranial stimulation alters movement timing in humans

Publication date: Available online 8 March 2018
Source:Brain Stimulation
Author(s): Bartlett D. Moore, Adam R. Aron, Nitin Tandon
BackgroundA prime objective driving the recent development of human neural prosthetics is to stimulate neural circuits in a manner time-locked to ongoing brain activity. The human supplementary motor area (SMA) is a particularly useful target for this objective because it displays characteristic neural activity just prior to voluntary movement.ObjectiveHere, we tested a method that detected activity in the human SMA related to impending movement and then delivered cortical stimulation with intracranial electrodes to influence the timing of movement.MethodsWe conducted experiments in nine patients with electrodes implanted for epilepsy localization: five patients with SMA electrodes and four control patients with electrodes outside the SMA. In the first experiment, electrocorticographic (ECoG) recordings were used to localize the electrode of interest during a task involving bimanual finger movements. In the second experiment, a real-time sense-and-stimulate (SAS) system was implemented that delivered an electrical stimulus when pre-movement gamma power exceeded a threshold.ResultsStimulation based on real-time detection of this supra-threshold activity resulted in significant slowing of motor behavior in all of the cases where stimulation was carried out in the SMA patients but in none of the patients where stimulation was performed at the control site.ConclusionsThe neurophysiological correlates of impending movement can be used to trigger a closed loop stimulation device and influence ongoing motor behavior in a manner imperceptible to the subject. This is the first report of a human closed loop system designed to alter movement using direct cortical recordings and direct stimulation.



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Digital dating abuse measures: A critical review

Publication date: Available online 8 March 2018
Source:Aggression and Violent Behavior
Author(s): Cynthia Brown, Kelsey Hegarty
Digital dating abuse is an emerging form of dating violence thought to have serious health effects on young people. In order to fully understand the nature and magnitude of the problem, a clear understanding of the measured construct, and robust measurement instruments are required. To date, a synthesis of available survey instruments and their quality has not been published, despite the existence of several instruments measuring digital dating abuse in young people's relationships. This paper describes existing instruments and their characteristics. A review of the literature from 1990 to 2016 revealed at least 17 different terms representing the digital dating abuse construct, 22 instruments measuring the phenomenon of which 16 were included in this review, and few clearly defined constructs. Definitional inconsistencies suggest that the instruments may measure various constructs including aggression and abuse, although this remains unclear. Eleven of the 16 instruments reported psychometric properties, at times limited to reliability evidence. This review highlights the need for delineation between aggressive and abusive digital dating behaviours, stringency in defining the digital dating abuse construct, and the development of a robust measurement instrument that yields both reliability and validity evidence.



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Effects of a novel neonicotinoid insecticide cycloxaprid on earthworm, Eisenia fetida

Abstract

Cycloxaprid (CYC) is a novel neonicotinoid insecticide with high activity against resistant pests but is safe for mammals. The toxic effects of CYC on earthworms (Eisenia fetida) were studied in this paper. The 14-day exposure results showed that CYC is potentially toxic to earthworms, with a 14d-LC₅₀ of 10.21 mg/kg _{dry soil}, and that it induced tissue damage to the epidermis, gut, and neurochord at sublethal doses. During a 21-day exposure, CYC induced oxidative stress in earthworms, and both enzyme activities of catalase (CAT) and superoxide dismutase (SOD) were impacted. In addition, expression of the genes Cat and Sod were down- and upregulated, respectively. The activity of the enzyme acetylcholinesterase (AChE) was increased at day 7 but decreased at day 21 after CYC exposure, while expression of the signal transduction-related genes was significantly regulated. Our study shows for the first time that negative impacts could be induced by CYC on earthworms under both acute and chronic exposure through oxidative stress and gene regulation. The present study provides a database for assessing the environmental risk to non-target organisms resulting from the use of CYC.

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Synergy between the KEAP1/NRF2 and PI3K Pathways Drives Non-Small-Cell Lung Cancer with an Altered Immune Microenvironment

Publication date: Available online 8 March 2018
Source:Cell Metabolism
Author(s): Sarah A. Best, David P. De Souza, Ariena Kersbergen, Antonia N. Policheni, Saravanan Dayalan, Dedreia Tull, Vivek Rathi, Daniel H. Gray, Matthew E. Ritchie, Malcolm J. McConville, Kate D. Sutherland
The lung presents a highly oxidative environment, which is tolerated through engagement of tightly controlled stress response pathways. A critical stress response mediator is the transcription factor nuclear factor erythroid-2-related factor 2 (NFE2L2/NRF2), which is negatively regulated by Kelch-like ECH-associated protein 1 (KEAP1). Alterations in the KEAP1/NRF2 pathway have been identified in 23% of lung adenocarcinomas, suggesting that deregulation of the pathway is a major cancer driver. We demonstrate that inactivation of Keap1 and Pten in the mouse lung promotes adenocarcinoma formation. Notably, metabolites identified in the plasma of Keap1^f/f/Pten^f/f tumor-bearing mice indicate that tumorigenesis is associated with reprogramming of the pentose phosphate pathway. Furthermore, the immune milieu was dramatically changed by Keap1 and Pten deletion, and tumor regression was achieved utilizing immune checkpoint inhibition. Thus, our study highlights the ability to exploit both metabolic and immune characteristics in the detection and treatment of lung tumors harboring KEAP1/NRF2 pathway alterations.

Graphical abstract

Teaser

Best et al. identify the tumorigenic potential of Nrf2 pathway activation in lung epithelium in the context of PI3K pathway alterations. Plasma metabolite profiling suggests that tumorigenesis is associated with reprogramming of the pentose phosphate pathway. Tumor-bearing lungs exhibit an altered immune milieu and are amenable to checkpoint inhibitor therapy.


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Oro-dental pathologies in acromegaly

Abstract

Purpose

Oro-dental pathologies (ODP) such as enlargement of the tongue, mandibular prognathism, and spaced teeth are characteristic features of acromegaly. Their frequency of occurrence during the course of the disease is largely unresolved. Purpose of this study was to assess ODP and oro-dental treatments in patients with acromegaly with regard to the length of the diagnostic process, tumor histology, and quality of life (QoL).

Methods

Single-center retrospective survey study using questionnaires on dental symptoms, diagnostic process, and treatment in patients with acromegaly operated on a growth hormone-secreting pituitary adenoma. The association between ODP and QoL was assessed using the Short-Form 36 (SF-36) Health Survey.

Results

145/314 patients completed the questionnaires. 80.7% were affected by any ODP, most frequently enlargement of the tongue (57.9%), spaced teeth (42.8%), mandibular growth (24.1%), and mandibular prognathism (22.1%). ODP were significantly more frequent in patients with sparsely vs. densely granulated adenomas (p = 0.045). Early diagnosis within 2 years was associated with significantly fewer ODP than later diagnosis (68.5 vs. 87.2%, p = 0.009). Treatments included dental crowns (16.6%), dental bridges (12.4%), dental implants (9.7%), dental prostheses (3.4%), orthodontal (i.e., braces, 6.9%), and surgical correction of the teeth (2.1%). Physical QoL was significantly lower in patients with ODP than in those without (p = 0.014).

Conclusion

In our large series of patients, four of five patients were affected by ODP at any time during the course of the disease. The results highlight the importance of early identification and treatment of oro-dental problems in patients with acromegaly as hallmarks of the disease.

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Transcriptional regulation mediated by H2A.Z via ANP32e-dependent inhibition of protein phosphatase 2A

Publication date: Available online 8 March 2018
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Hyewon Shin, Minzhen He, Zhi Yang, Yong Heui Jeon, Jessica Pfleger, Danish Sayed, Maha Abdellatif
The mechanisms that regulate H2A.Z and its requirement for transcription in differentiated mammalian cells remains ambiguous. In this study, we identified the interaction between the C-terminus of ANP32e and N-terminus of H2A.Z in a yeast two-hybrid screen. Knockdown of ANP32e resulted in proteasomal degradation and nuclear depletion of H2A.Z or of a chimeric green florescence protein fused to its N-terminus. This effect was reversed by inhibition of protein phosphatase 2A (PP2A) and, conversely, reproduced by overexpression of its catalytic subunit. Accordingly, knockdown of ANP32e inhibited phosphorylation of H2A.Z, whereas a mutation of serine-9 proved its requirement for both the protein's stability and nuclear localization, as did knockdown of the nuclear mitogen and stress-induced kinase 1. Moreover, ANP32e's knockdown also revealed its differential requirement for cell signaling and gene expression, whereas, genome-wide binding analysis confirmed its co-localization with H2A.Z at transcription start sites, as well as, gene bodies of inducible and tissue-specific genes. The data also suggest that H2A.Z restricts transcription, which is moderated by ANP32e at the promoter and gene bodies of expressed genes. Thus, ANP32e, through inhibition of PP2A, is required for nucleosomal inclusion of H2A.Z and the regulation of gene expression.



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Mapping for the management of diffuse pollution risks related to agricultural plant protection practices: case of the Etang de l’Or catchment area in France

Abstract

Faced with health, environmental, and socio-economic issues related to the heavy use of pesticides, diffuse phytosanitary pollution becomes a major concern shared by all the field actors. These actors, namely the farmers and territorial managers, have expressed the need to implement decision support tools for the territorial management of diffuse pollution resulting from the plant protection practices and their impacts. To meet these steadily increasing requests, a cartographic analysis approach was implemented based on GIS which allows the spatialization of the diffuse pollution impacts related to plant protection practices on the Etang de l'Or catchment area in the South of France. Risk mapping represents a support-decision tool that enables the different field actors to identify and locate vulnerable areas, so as to determine action plans and agri-environmental measures depending on the context of the natural environment. This work shows that mapping is helpful for managing risks related to the use of pesticides in agriculture by employing indicators of pressure (TFI) and risk on the applicator's health (IRSA) and on the environment (IRTE). These indicators were designed to assess the impact of plant protection practices at various spatial scales (field, farm, etc.). The cartographic analysis of risks related to plant protection practices shows that diffuse pollution is unequally located in the North (known for its abundant garrigues and vineyards) and in the South of the Etang de l'Or catchment area (the Mauguio-Lunel agricultural plain known for its diversified cropping systems). This spatial inequity is essentially related to land use and agricultural production system. Indeed, the agricultural lands cover about 60% of the total catchment area. Consequently, this cartographic analysis helps the territorial actors with the implementation of strategies for managing risks of diffuse pollution related to pesticides use in agriculture, based on environmental and socio-economic issues and the characteristics of the natural environment.

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New approach of ultra-focal brachytherapy for low- and intermediate-risk prostate cancer with custom-linked I-125 seeds: A feasibility study of optimal dose coverage

Publication date: Available online 7 March 2018
Source:Brachytherapy
Author(s): Thomas Brun, Jean-Marc Bachaud, Pierre Graff-Cailleaud, Bernard Malavaud, Daniel Portalez, Christian Popotte, Richard Aziza, Amélie Lusque, Thomas Filleron, Soléakhéna Ken
PurposeTo present the feasibility study of optimal dose coverage in ultra-focal brachytherapy (UFB) with multiparametric MRI for low- and intermediate-risk prostate cancer.Methods and MaterialsUFB provisional dose plans for small target volumes (<7 cc) were calculated on a prostate training phantom to optimize the seeds number and strength. Clinical UFB consisted in a contour-based nonrigid registration (MRI/Ultrasound) to implant a fiducial marker at the location of the tumor focus. Dosimetry was performed with iodine-125 seeds and a prescribed dose of 160 Gy. On CT scans acquired at 1 month, dose coverage of 152 Gy to the ultra-focal gross tumor volume was evaluated. Registrations between magnetic resonance and CT scans were assessed on the first 8 patients with three software solutions: VariSeed, 3D Slicer, and Mirada, and quantitative evaluations of the registrations were performed. Impact of these registrations on the initial dose matrix was performed.ResultsMean differences between simulated dose plans and extrapolated Bard nomogram for UFB volumes were 36.3% (26–56) for the total activity, 18.3% (10–30) for seed strength, and 22.5% (16–38) for number of seeds. Registration method implemented in Mirada performed significantly better than VariSeed and 3D Slicer (p = 0.0117 and p = 0.0357, respectively). For dose plan evaluation between Mirada and VariSeed, D100% (Gy) for ultra-focal gross tumor volume had a mean difference of 28.06 Gy, mean values being still above the objective of 152 Gy. D90% for the prostate had a mean difference of 1.17 Gy. For urethra and rectum, dose limits were far below the recommendations.ConclusionsThis UFB study confirmed the possibility to treat with optimal dose coverage target volumes smaller than 7 cc.



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Home particle repositioning maneuver to prevent the recurrence of posterior canal BPPV

To check the value of home particle repositioning maneuver in the prevention of the recurrence of posterior canal benign paroxysmal positional vertigo (pc-BPPV).

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Hydrotalcite monolayer toward high performance synergistic dual-modal imaging and cancer therapy

Publication date: May 2018
Source:Biomaterials, Volume 165
Author(s): Xuan Mei, Wei Wang, Liang Yan, Tingting Hu, Ruizheng Liang, Dan Yan, Min Wei, David G. Evans, Xue Duan
Recently, theranostic has drawn tremendous attention by virtue of the nanotechnology development and new material exploration. Herein, we reported a novel theranostic system by loading Au nanoclusters (AuNCs) and Chlorin e6 (photosensitizer, Ce6) onto the monolayer nanosheet surface of Gd-doped layered double hydroxide (Gd-LDH). The as-prepared Ce6&AuNCs/Gd-LDH exhibits a largely enhanced fluorescence quantum yield (QY) of 18.5% relative to pristine AuNCs (QY = 3.1%) as well as superior T1 magnetic resonance imaging (MRI) performance (r1 = 17.57 mM⁻¹s⁻¹) compared with commercial MRI contrast agent (Gd(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Gd-DOTA): r1 ≈ 3.4 mM⁻¹s⁻¹), resulting from a synergistic effect between AuNCs and Gd-LDH. In addition, both in vitro and in vivo therapeutic evaluations demonstrate an efficient dual-modality imaging guided anticancer performance, especially the synergetic enhanced magnetic resonance/fluorescence (MR/FL) visualization of tumor site. Therefore, this work demonstrates a successful paradigm for the design and preparation of LDHs monolayer-based theranostic material, which holds great promises in practical applications.



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Innate Antiviral Immunity in the Skin

Publication date: Available online 8 March 2018
Source:Trends in Immunology
Author(s): Chelsea Handfield, Jeffery Kwock, Amanda S. MacLeod
Barrier sites such as the skin play a critical role in immune defense. They must maintain homeostasis with commensals and rapidly detect and limit pathogen invasion. This is accomplished in part through the production of endogenous antimicrobial peptides and proteins, which can be either constitutive or inducible. Here, we focus particularly on the control of innate antiviral proteins and present the basic aspects of their regulation in the skin by interferons (IFNs), IFN-independent immunity, and environmental factors. We also discuss the activity and (dys-)function of antiviral proteins in the context of skin-tropic viruses and highlight the relevance of the innate antiviral pathway as a potential therapeutic avenue for vulnerable patient populations and skin diseases with high risk for virus infections.



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Rif1 Phosphorylation Site Analysis in Telomere Length Regulation and the Response to Damaged Telomeres

Publication date: Available online 7 March 2018
Source:DNA Repair
Author(s): Jinyu Wang, Haitao Zhang, Mohammed Al-Shibar, Belinda Willard, Alo Ray, Kurt W. Runge
Telomeres, the ends of eukaryotic chromosomes, consist of repetitive DNA sequences and their bound proteins that protect the end from the DNA damage response. Short telomeres with fewer repeats are preferentially elongated by telomerase. Tel1, the yeast homolog of human ATM kinase, is preferentially recruited to short telomeres and Tel1 kinase activity is required for telomere elongation. Rif1, a telomere-binding protein, negatively regulates telomere length by forming a complex with two other telomere binding proteins, Rap1 and Rif2, to block telomerase recruitment. Rif1 has 14 SQ/TQ consensus phosphorylation sites for ATM kinases, including 6 in a SQ/TQ Cluster Domain (SCD) similar to other DNA damage response proteins. These 14 sites were analyzed as N-terminal, SCD and C-terminal domains. Mutating some sites to non-phosphorylatable residues increased telomere length in cells lacking Tel1 while a different set of phosphomimetic mutants increased telomere length in cells lacking Rif2, suggesting that Rif1 phosphorylation has both positive and negative effects on length regulation. While these mutations did not alter the sensitivity to DNA damaging agents, inducing telomere-specific damage by growing cells lacking YKU70 at high temperature revealed a role for the SCD. Mass spectrometry of Rif1 from wild type cells or those induced for telomere-specific DNA damage revealed increased phosphorylation in cells with telomere damage at an ATM consensus site in the SCD, S1351, and non-ATM sites S181 and S1637. A phosphomimetic rif1-S1351E mutation caused an increase in telomere length at synthetic telomeres but not natural telomeres. These results indicate that the Rif1 SCD can modulate Rif1 function. As all Rif1 orthologs have one or more SCD domains, these results for yeast Rif1 have implications for the regulation of Rif1 function in humans and other organisms.



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The MLH1 ATPase Domain is needed for Suppressing Aberrant Formation of Interstitial Telomeric Sequences

Publication date: Available online 7 March 2018
Source:DNA Repair
Author(s): Pingping Jia, Weihang Chai
Genome instability gives rise to cancer. MLH1, commonly known for its important role in mismatch repair (MMR), DNA damage signaling and double-strand break (DSB) repair, safeguards genome stability. Recently we have reported a novel role of MLH1 in preventing aberrant formation of interstitial telomeric sequences (ITSs) at intra-chromosomal regions. Deficiency in MLH1, in particular its N-terminus, leads to an increase of ITSs. Here, we identify that the ATPase activity in the MLH1 N-terminal domain is important for suppressing the formation of ITSs. The ATPase activity is also needed for recruiting MLH1 to DSBs. Moreover, defective ATPase activity of MLH1 causes an increase in micronuclei formation. Our results highlight the crucial role of MLH1's ATPase domain in preventing the aberrant formation of telomeric sequences at the intra-chromosomal regions and preserving genome stability.



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Biochar application increases sorption of nitrification inhibitor 3,4-dimethylpyrazole phosphate in soil

Abstract

Biochar (BC) application to soils is of growing interest as a strategy to improve soil fertility and mitigate climate change. However, BC-induced alterations in the soil N cycle are currently under debate. BC has recently been shown to accelerate the emissions of N₂O via the biotic ammonium oxidation pathway, which results in lower nitrogen use efficiency and environmentally harmful losses of NO₃ and/ or N₂O. To avoid these potential losses, the use of nitrification inhibitor (NI) could provide a useful mitigation strategy for BC-amended agricultural fields. Here, we tested the sorption behavior of a model NI, the synthetic 3,4-dimethylpyrazole phosphate (DMPP) on 15-month-aged soil-BC mixtures. We saw that BC additions increased DMPP sorption to varying extents depending on BC feedstock type and pyrolysis temperature. The highest sorption was found for BC pyrolyzed at a lower temperature. BC effects on soil physico-chemical characteristics (i.e., hydrophobicity) seem to be important factors.

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Human IFIT3 Modulates IFIT1 RNA Binding Specificity and Protein Stability

Publication date: Available online 8 March 2018
Source:Immunity
Author(s): Britney Johnson, Laura A. VanBlargan, Wei Xu, James P. White, Chao Shan, Pei-Yong Shi, Rong Zhang, Jagat Adhikari, Michael L. Gross, Daisy W. Leung, Michael S. Diamond, Gaya K. Amarasinghe
Although interferon-induced proteins with tetratricopeptide repeats (IFIT proteins) inhibit infection of many viruses by recognizing their RNA, the regulatory mechanisms involved remain unclear. Here we report a crystal structure of cap 0 (m⁷GpppN) RNA bound to human IFIT1 in complex with the C-terminal domain of human IFIT3. Structural, biochemical, and genetic studies suggest that IFIT3 binding to IFIT1 has dual regulatory functions: (1) extending the half-life of IFIT1 and thereby increasing its steady-state amounts in cells; and (2) allosterically regulating the IFIT1 RNA-binding channel, thereby enhancing the specificity of recognition for cap 0 but not cap 1 (m⁷GpppNm) or 5′-ppp RNA. Mouse Ifit3 lacks this key C-terminal domain and does not bind mouse Ifit1. The IFIT3 interaction with IFIT1 is important for restricting infection of viruses lacking 2′-O methylation in their RNA cap structures. Our experiments establish differences in the regulation of IFIT1 orthologs and define targets for modulation of human IFIT protein activity.

Graphical abstract

Teaser

Prior studies have suggested that human IFIT1, unlike its mouse ortholog, might not recognize viral RNA molecules lacking 2′-O methylation on their cap structures. Johnson et al. report a crystal structure between cap 0 (m⁷GpppN) RNA bound to human IFIT1 in complex with the C-terminal domain (CTD) of human IFIT3. The CTD of IFIT3 bound to IFIT1 and allosterically regulated the IFIT1 RNA-binding channel and promoted selective recognition of cap 0 RNA. Functional studies demonstrated that IFIT3 interaction with IFIT1 was important for stabilizing IFIT1 expression and was required for restricting infection of viruses lacking 2′-O methylation in their RNA cap structures


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