Next generation sequencing of progressive colorectal liver metastases after portal vein embolization

Abstract

Portal vein embolization (PVE) can be required to stimulate liver regeneration before hepatectomy for colorectal liver metastasis (CRCLM), however PVE may also trigger CRCLM progression in patients initially exhibiting chemotherapy response. Using RNA-seq, we aimed to determine the molecular networks involved in metastatic progression in this context. A prospective study including all CRCLM patients undergoing PVE prior to hepatectomy was conducted. Paired biopsies of metastatic lesions were obtained prior to and after PVE and total RNA was isolated and used to prepare Illumina rRNA-depleted TruSeq stranded cDNA libraries for HiSeq 100 bp paired-end sequencing. Patients were classified with progression of disease (PD_PVE) or stable disease (SD_PVE) post-PVE using 3D-CT tumor volumetric analysis. Results: Twenty patients were included, 13 (65.0%) in the PD_PVE group (median 58.0% (18.6–234.3) increase in tumor volume) and 7 (35.0%) in the SD_PVE group exhibiting continuous chemotherapy response (median −14.3% (−40.8 to −2.8) decrease in tumor volume) (p < 0.0001). Our results showed that progressive CRCLM after PVE undergo gene expression changes that indicate activation of core cancer pathways (IL-17 (p = 5.94 × 10⁻⁰³), PI3K (p = 8.71 × 10⁻⁰³), IL6 and IGF-1 signaling pathways), consistent with changes driven by cytokines and growth factors. Differential expression analysis in a paired model of progression (EdgeR, DeSeq) identified significantly dysregulated genes in the PD_PVE group (FOS, FOSB, RAB20, IRS2). Conclusion: Differentially expressed genes and pathways with known links to cancer and metastasis were identified post-PVE in patients with disease progression. Highlighting these molecular changes is a crucial first step towards development of targeted therapeutic strategies that may mitigate the effects of PVE on tumor growth.

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Occlusal, chewing, and tasting characteristics associated with orofacial dysfunctions in children with unilateral cleft lip and palate: a case-control study

Abstract

Objective

The objective of this study is to assess the associations between orofacial dysfunctions with malocclusion, masticatory performance, and taste in children with and without unilateral cleft lip and palate (UCLP).

Material and methods

A patient-based, matched, case-control study was conducted involving 108 8- to 10-year-old children divided in UCLP and control groups. Orofacial dysfunctions were evaluated using the Nordic Orofacial Test-Screening (NOT-S). Orthodontic treatment need was evaluated using the Goslon Yardstick Index (GYI) and the Index of Orthodontic Treatment Need (IOTN) of patients and controls, respectively. Masticatory performance was assessed using a chewable test material to determine median particle size (X ₅₀) and distribution of particles in different sieves (b value). Taste perception was evaluated using four solutions (sweet, salty, bitter, or acid) in three different concentrations.

Results

More than half of the patients needed orthodontic surgery. UCLP group presented higher median particle size and needed more chewing cycles to comminute the artificial test into particles smaller than the median than those of controls. UCLP group had less perception of salty flavor than controls. There was a positive correlation between b value and NOT-S examination score for patients. In regression analysis, a significant interrelationship was observed between NOT-S examination score and b value.

Conclusions

In the UCLP patients, masticatory performance was compromised probably as a result of facial asymmetry and speech disturbance; whereas, taste was less perceived only for salty flavor.

Clinical relevance

These findings provide preliminary evidence that mastication and taste are altered in children with UCLP, so these factors must be followed up to ensure oral and general health in growing individuals.

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Keratoacanthoma management: results of a survey of UK dermatologists and surgeons

Abstract

Distinction of keratoacanthoma (KA) from squamous cell carcinoma (SCC) is challenging. Management is controversial, with some advocating prompt surgical excision and others monitoring to allow for spontaneous resolution¹. The controversy is compounded by rare reports of metastasis². And yet the benign natural history of KA is supported by various studies, including a systematic review of 455 cases with no cases of metastasis or death¹, and observational studies confirming spontaneous resolution¹.

This article is protected by copyright. All rights reserved.

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Mapping porous microstructures to yield desired mechanical properties for application in 3D printed bone scaffolds and orthopaedic implants

Publication date: 5 November 2017
Source:Materials & Design, Volume 133
Author(s): Ling Wang, Jianfeng Kang, Changning Sun, Dichen Li, Yi Cao, Zhongmin Jin
Porous design of orthopaedic implants affords the advantages of minimizing stress shielding and improving the osseointegration and long-term stability. However, the marked error in the manufactured porous structure relative to the designed model yields limited application of the porous design. This study aimed to develop a methodology to derive the relationship between the porosity, the structural characteristic parameters and the mechanical properties of a typical structural unit, to lay the foundation of a porous structural design for 3D-printed implants with gradient modulus. Mathematical expressions related to porosity were determined based on various parametrical characteristics of porous units; the effective modulus of such a porous structure was studied under variable axial loading by using finite element analysis to gain insight into the anisotropic properties of the porous structure, and to evaluate the effects of parametrical variation on the aforementioned properties. For validation purposes, samples were manufactured via selective laser melting (SLM) 3D printing technology and mechanically tested. Results indicated that porous design can reduce the effective modulus of implants by 75–80%. A general methodology was developed for evaluating BCC structural units to determine design parameter correlations, the porosity and the effective modulus of the structure.

Graphical abstract

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Dosimetric impact of intrafraction changes in MR-guided high-dose-rate (HDR) brachytherapy for prostate cancer

Publication date: Available online 29 July 2017
Source:Brachytherapy
Author(s): Alexandra Rink, Jette Borg, Anna Simeonov, Gerald O'Leary, Joelle Helou, Cynthia Ménard, Peter Chung, David A. Jaffray, Alejandro Berlin
PurposeTo assess changes in implant and treatment volumes through the course of a prostate high-dose-rate brachytherapy procedure and their impact on plan quality metrics.Methods and MaterialsSixteen MRI-guided high-dose-rate procedures included a post-treatment MR (ptMR) immediately after treatment delivery (135 min between MR scans). Target and organs at risk (OARs) were contoured, and catheters were reconstructed. The delivered treatment plan was applied to the ptMR image set. Volumes and dosimetric parameters in the ptMR were evaluated and compared with the delivered plan using a paired two-tailed t-test with p < 0.05 considered statistically significant.ResultsAn average increase of 8.9% in prostate volume was observed for whole-gland treatments, resulting in reduction in coverage for both prostate and planning target volume, reflected in decreased V100 (mean 3.3% and 4.6%, respectively, p < 0.05), and D90 (mean 7.1% and 7.6%, respectively, of prescription dose, p < 0.05). There was no significant change in doses to OARs. For partial-gland treatments, there was an increase in planning target volume (9.1%), resulting in reduced coverage and D90 (mean 3.6% and 12.4%, respectively, p < 0.05). A decrease in D0.5cc for bladder (3%, p < 0.05) was observed, with no significant changes in dose to other OARs.ConclusionsVolumetric changes were observed during the time between planning MR and ptMR. Nonetheless, treatment plans for both whole- and partial-gland therapies remained clinically acceptable. These results apply to clinical settings in which patients remain in the same position and under anesthesia during the entire treatment process.



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The Effect of Human Engagement Depicted in Contextual Photographs on the Visual Attention Patterns of Adults with Traumatic Brain Injury

Publication date: Available online 30 July 2017
Source:Journal of Communication Disorders
Author(s): Amber Thiessen, Jessica Brown, David Beukelman, Karen Hux
Photographs are a frequently employed tool for the rehabilitation of adults with traumatic brain injury (TBI). Speech-language pathologists (SLPs) working with these individuals must select photos that are easily identifiable and meaningful to their clients. In this investigation, we examined the visual attention response to camera- (i.e., depicted human figure looking toward camera) and task-engaged (i.e., depicted human figure looking at and touching an object) contextual photographs for a group of adults with TBI and a group of adults without neurological conditions. Eye-tracking technology served to accurately and objectively measure visual fixations. Although differences were hypothesized given the cognitive deficits associated with TBI, study results revealed little difference in the visual fixation patterns of adults with and without TBI. Specifically, both groups of participants tended to fixate rapidly on the depicted human figure and fixate more on objects in which a human figure was task-engaged than when a human figure was camera-engaged. These results indicate that strategic placement of human figures in a contextual photograph may modify the way in which individuals with TBI visually attend to and interpret photographs. In addition, task-engagement appears to have a guiding effect on visual attention that may be of benefit to SLPs hoping to select more effective contextual photographs for their clients with TBI. Finally, the limited differences in visual attention patterns between individuals with TBI and their age and gender matched peers without neurological impairments indicates that these two groups find similar photograph regions to be worthy of visual fixation.Learning outcomes: Readers will gain knowledge regarding the photograph selection process for individuals with TBI. In addition, readers will be able to identify camera- and task-engaged photographs and to explain why task-engagement may be a beneficial component of contextual photographs.



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Metal leachability from coal combustion residuals under different pHs and liquid/solid ratios

Publication date: 5 November 2018
Source:Journal of Hazardous Materials, Volume 341
Author(s): Evandro B. da Silva, Shiwei Li, Letúzia M. de Oliveira, Julia Gress, Xiaoling Dong, Ann C. Wilkie, Timothy Townsend, Lena Q. Ma
Coal combustion residuals (CCRs) contain variable amounts of trace metals, which can negatively impact the environment. We analyzed metal concentrations and leachability of CCRs from seven coal-fired power plants from Florida. The purpose of this study was to characterize and assess metal leachability in representative CCRs samples from coal-fired power plants, including As, Ba, Cd, Cr, Pb, and Se. The specific objectives were to: (1) measure metal leachability under different pH conditions and liquid-to-solid ratios using USEPA Leaching Environmental Assessment Framework (LEAF) Methods 1313 and 1316, and (2) compare their leachability with those obtained by the Synthetic Precipitation Leaching Procedure (SPLP). All metals excluding Cd showed amphoteric behavior, presenting higher concentrations at low and high pH using LEAF Method 1313. The highest Cd leaching was observed at pH 2–4 and decreased at pH>7. SPLP results were highly variable when compared to the LEAF data. All metals except Ba exceeded the Florida Groundwater Cleanup Target Levels at all pH levels, however, metal leaching was low at typical soil pH of 4–9. Metal concentrations in fly ash decreased in most cases with increasing LS ratio. Therefore, due to potential leaching of some metals, evaluation is needed before beneficial use of CCRs.

Graphical abstract

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Origin and chemical composition of the amorphous material from the intergrain pores of self-assembled cubic ZnS:Mn nanocrystals

Publication date: 31 December 2017
Source:Applied Surface Science, Volume 426
Author(s): Mariana Stefan, Ioana Dorina Vlaicu, Leona Cristina Nistor, Daniela Ghica, Sergiu Vasile Nistor
We have shown in previous investigations that the low temperature collective magnetism observed in mesoporous cubic ZnS:Mn nanocrystalline powders prepared by colloidal synthesis, with nominal doping concentrations above 0.2 at.%, is due to the formation of Mn²⁺ clusters with distributed antiferromagnetic coupling localized in an amorphous phase found between the cubic ZnS:Mn nanocrystals. Here we investigate the composition, origin and thermal annealing behavior of this amorphous phase in such a mesoporous ZnS:Mn sample doped with 5 at.% Mn nominal concentration. Correlated analytical transmission electron microscopy, multifrequency electron paramagnetic resonance and Fourier transform infrared spectroscopy data show that the amorphous nanomaterial consists of unreacted precursor hydrated zinc and manganese acetates trapped inside the pores and on the surface of the cubic ZnS nanocrystals. The decomposition of the acetates under isochronal annealing up to 270°C, where the mesoporous structure is still preserved, lead to changes in the nature and strength of the magnetic interactions between the aggregated Mn²⁺ ions. These results strongly suggest the possibility to modulate the magnetic properties of such transition metal ions doped II–VI mesoporous structures by varying the synthesis conditions and/or by post-synthesis thermochemical treatments.

Graphical abstract

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Quaternary schematics for property engineering of CdSe thin films

Publication date: 31 December 2017
Source:Applied Surface Science, Volume 426
Author(s): G.T. Chavan, S.T. Pawar, V.M. Prakshale, A. Sikora, S.M. Pawar, N.B. Chaure, S.S. Kamble, N.N. Maldar, L.P. Deshmukh
The synthesis of quaternary Cd1-xZnxSySe1-y (0≤x=y≤0.35) thin films was done through indigenously developed chemical solution growth process. As-obtained thin films were subjected to the physical, chemical, structural and optical characterizations. The nearly hydrophobic nature of the as-deposited films except binary CdSe was observed through the wettability studies. The colorimetric studies supported a change in physical color attributes. The elemental analysis done confirmed the formation of Cd(Zn, S)Se and the chemical states of constituent elements as Cd²⁺, Zn²⁺, S²⁻ and Se²⁻. Structural assessment suggested the formation of the polycrystalline quaternary phase of the hexagonal wurtzite structure. The Raman spectroscopy was also employed for the confirmation studies on Cd1-xZnxSySe1-y thin films. Morphological observations indicated microstructural transformation from an aggregated bunch of nano-sized globular grains into a rhomboid network of petal/flakes like crystallites. The atomic force micrographs (AFM) revealed the enhancement in the hillock structures. From advanced AFM characterizations, we observed that the CdSe thin film has leptokurtic (Sku=3.23) surface, whereas, quaternary Cd(Zn, S)Se films have platykurtic (Sku<3) surface. The orientation of the surface morphology was observed through the angular spectrum studies. The optical absorption studies revealed direct allowed transition for the films with a continuous modulation of the energy bandgap from 1.8eV to 2.31eV.



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Effects of biosolids from a wastewater treatment plant receiving manufactured nanomaterials on Medicago truncatula and associated soil microbial communities at low nanomaterial concentrations

Publication date: 31 December 2017
Source:Science of The Total Environment, Volume 609
Author(s): Chun Chen, Olga V. Tsyusko, Dave H. McNear, Jonathan Judy, Ricky W. Lewis, Jason M. Unrine
Concern has grown regarding engineered nanomaterials (ENMs) entering agricultural soils through the application of biosolids and their possible effects on agroecosystems, even though the ENMs are extensively transformed. The effects of exposure to biosolids containing transformation products of these ENMs at low concentrations remain largely unexplored. We examined the responses of Medicago truncatula and its symbiotic rhizobia Sinorhizobium meliloti exposed to soil amended with biosolids from WWTP containing low added concentrations of ENMs (ENM Low), bulk/dissolved metals (bulk/dissolved Low), or no metal additions (control). We targeted adding approximately 5mg/kg of Ag and 50mg/kg of Zn, and Ti. Measured endpoints included M. truncatula growth, nodulation, changes in the expression of stress response genes, uptake of metals (Ag, Zn and Ti) into shoots, and quantification of S. meliloti populations and soil microbial communities. After 30days exposure, no effects on root or shoot biomass were observed in ENM Low and bulk/dissolved Low treatments, whereas both treatments had a larger average number of nodules (5.7 and 5.57, respectively) compared to controls (0.33). There were no significant differences in either total accumulated metal or metal concentrations in shoots among the treatments. Expression of five stress-related genes (metal tolerance protein (MTP), metal transporter (MTR), peroxidase (PEROX), NADPH oxidase (NADPH) and 1-aminocyclopropane-1-carboxylate oxidase-like protein (ACC_Oxidase)) was significantly down-regulated in both bulk/dissolved Low and ENM Low treatments. However, a change in soil microbial community composition and a significant increase in total microbial biomass were observed in ENM Low relative to control. The ENM Low treatment had increased abundance of Gram-negative and anaerobic bacteria and reduced abundance of eukaryotes compared to control. The study demonstrated that although there were some subtle shifts in microbial community composition, plant health was minimally impacted by ENMs within the time frame and at the low exposure concentrations used in this study.

Graphical abstract

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Assessment of the bioavailability, bioaccessibility and transfer of heavy metals in the soil-grain-human systems near a mining and smelting area in NW China

Publication date: 31 December 2017
Source:Science of The Total Environment, Volume 609
Author(s): Bailin Liu, Shiwei Ai, Wenya Zhang, Dejun Huang, Yingmei Zhang
Elucidating the transfer behaviour of heavy metals from soils to grains and ultimately to humans is of great significance for both human health risk assessment and pollution control. In this study, the bioavailability of heavy metals (Cd, Cu, Pb, Zn, Cr and Ni) in farmland soils and bioaccessibility in grains (spring wheat, maize and rice) were determined to elaborate transfer dynamics in the soil-grain-human systems near a mining and smelting area in the Dongdagou watershed, Baiyin district, Gansu province, NW China. The results showed that Cd, Cu, Pb and Zn concentrations in soils were elevated compared to background levels, while Cr and Ni concentrations were relatively low throughout the region. High levels of bioavailable soil Cd were found using both EDTA and CH3COOH extraction methods. Mean concentrations of Cd, Pb and Zn in spring wheat grains and the Cd and Cr concentrations in maize grains exceeded the relevant maximum levels for pollutants according to the Chinese national standards for food safety. Except for Ni (41.90%) and Pb (31.39%), heavy metal bioaccessibility was relatively low in grains, ranging from 10.80% (Cd) to 17.18% (Zn). CH3COOH-extracted Cd, Pb and Ni, EDTA-extracted Zn, and total Cu in soils were the best indices for evaluation of uptake in grains (R²=0.54–0.91, p<0.001). Internal exposure doses of Cd and Ni in humans from spring wheat grain consumption was predicted by the linear correlations between bioaccessible and total metal concentrations (R²=0.61 and 0.67; p<0.001). The results from this study provide sufficient data and theoretical support for the use of these methods for local pollution prevention and control.

Graphical abstract

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Surface Engineering of Organic Nanoparticles for Highly Improved Bioimaging

Publication date: Available online 30 July 2017
Source:Colloids and Surfaces B: Biointerfaces
Author(s): Yanqiu Liu, Xiujuan Zhang, Mengjiao Zhou, Xianfeng Chen, Xiaohong Zhang
Surface properties of nanoparticles (NPs) have a huge influence on their biological activities. In this work, we report to use mesoporous silica nanoshell surface to regulate the cellular internalization rate and intracellular fate of fluorescent organic NPs for highly improved cellular imaging. We systematically studied the internalization of the NPs into cells, the intracellular transport pathways, the excretion from cells, and very importantly, compared the results with those from various NPs with different surface properties. It was found that the silica nanoshell coating allow the NPs to achieve strikingly improved brightness in imaging (over ten-fold enhancement) and much higher delivery efficiency than other NPs. This was attributed to their unique non-clathrin- and non-caveolae-mediated pathways which enable them to enter cells very efficiently and quickly in the cellular internalization, as well as their low cellular excretion rate. This highly effective cellular imaging effect caused by silica surface coating is much desirable for applications in sensitive imaging and long-term tracking of cells.

Graphical abstract

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A prospective study of serial imaging comparing FDG-PET and FLT PET during radical chemo-radiation for Non-Small Cell Lung Cancer: reduction of detectable proliferation associated with worse survival

Publication date: Available online 29 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Sarah Everitt, David Ball, Rodney J. Hicks, Jason Callahan, Nikki Plumridge, Jenny Trinh, Alan Herschtal, Tomas Kron, Michael Mac Manus
PurposeMonitoring tumor cell metabolism and tumor proliferation with FDG PET and FLT PET, respectively, during chemo-radiation therapy (CRT) may enable adaptive radiotherapy and provide prognostic information. We acquired serial 18F-FDG and 18F-FLT-PET/CT, during radical CRT and correlated tumor response with progression free survival (PFS) and overall survival (OS) in non-small cell lung cancer (NSCLC) patients.Methods and materialsPatients with FDG-PET/CT stage I-III NSCLC were prescribed concurrent chemotherapy and RT (60 Gy in 30 fractions). Scans were acquired at baseline [FDG-PET/CT (FDGBL) for RT planning and FLT-PET (FLTBL)], week two (FDGwk2 and FLTwk2) and week four (FDGwk4 and FLTwk4) of CRT. Tumour responses were categorised as complete or partial responses (CR, PR), stable or progressive disease (SD, PD) using EORTC criteria. Associations between response, OS and PFS were analysed with univariate Cox regressions and plotted using Kaplan-Meier curves.ResultsBetween 2009-2013, 60 patients were recruited. 37 (62%) were males and median age was 66 years (range 31-86). Two-year OS and PFS were 0.51 and 0.26, respectively. Unexpectedly, SD on FLTwk2 compared with CR/PR was associated with longer OS HR [95% CI], 2.01 [0.87, 4.65] p=0.082 and PFS 2.01 [0.92, 4.36] p=0.061. Weeks 2 and 4 FDG PET/CT were not significantly associated with survival. Study scans provided additional information to FDGBL in 21 (35%) patients. Distant metastases detected in three patients on FLTBL and in two patients on FDG/FLTwk2 changed treatment intent from curative to palliative. Loco-regional progression during RT was observed in five (8%) patients, prompting larger RT fields.ConclusionsStable uptake of 18F-FLT at week two was paradoxically associated with longer OS and PFS. This suggests that suppression of tumor cell proliferation may protect against radiation induced tumour cell killing. Baseline FLT, FLTwk2 and FDGwk2 detected rapid distant and loco-regional progression in 10 (17%) patients prompting changes in management.

Teaser

Sixty Non-Small Cell Lung Cancer (NSCLC) patients, prescribed curative intent chemo-radiation therapy, were prospectively studied. ¹⁸F-FDG and ¹⁸F-FLT-PET/CT scans were acquired at baseline, week two and week four to monitor tumor cell metabolism and proliferation, respectively. Stable uptake of ¹⁸F-FLT at week two was associated with superior overall survival compared to patients whose tumors demonstrated reduced or absent ¹⁸F-FLT uptake. This suggests that suppression of tumor cell proliferation may weaken the tumoricidal effect of chemoradiation.


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PRADO: a palliative care model for every radiation oncology practice

Publication date: Available online 29 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Timur Mitin, Charles R. Thomas, Jerry J. Jaboin




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An Update of a Prospective Study of SBRT for Post-chemoradiation Residual Disease in Stage II/III Non-small Cell Lung Cancer

Publication date: Available online 29 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Sameera Kumar, Jonathan Feddock, Xingzhe Li, Andrew J. Shearer, Logan Hall, Brent J. Shelton, Susanne Arnold, Ronald C. McGarry
Purpose/Objective(s)Chemoradiation (CRT) remains standard of care for Stage III NSCLC, although local recurrences are a significant problem. Previously, we reported prospective results of the feasibility and safety of dose escalation by the addition of a stereotactic boost (SBRT) to residual disease following standard CRT. Here we report extended term outcomes for risk of late toxicities, local control and survival.Materials/MethodsPatients with stage IIB/III NSCLC underwent CT or PET-CT screening approximately one month following completion of CRT. Limited residual disease (≤ 5 cm) within the site of the primary tumor received an SBRT boost of either 10 Gy X 2 fractions or 6.5 Gy X 3 to the primary tumor in order to achieve a total (BED10) >100 Gy.ResultsThirty-seven patients received protocol therapy. With a median follow-up of 25.2 months, the crude local control rate for the entire group was 78% (n=29), but 10 (29%) and 24 (65%) patients developed regional and metastatic disease, respectively. At last follow-up, 5 (13.5%) patients remain alive, all with no evidence of disease while twenty-seven (73%) died of disease, and the remaining 5 (13.5%) died of other causes. Median overall survival (mOS) for the entire group was 25.2 months. Predictors for Grade 3 pneumonitis included age and mean lung dose. Poorer mOS was associated with histology, mOS 15.6 months for squamous cell vs 34.8 months for other histologies (large cell neuroendocrine tumors excluded) (p=0.04). The median progression free survival (mPFS) was 6 months with IIIB disease having significantly worse mPFS (Stages IIB/IIA being 9.4 months versus 4.7 months for Stage IIIB (p=0.03)).ConclusionSBRT boost following CRT is a safe treatment resulting in improvements in local control for locally advanced NSCLC. No additional late toxicities were seen. Possible improvement in OS was found, but further study in a larger prospective trial is needed.

Teaser

Chemoradiation (CRT) remains the standard of care for Stage III NSCLC although local recurrences are a significant problem. Dose escalation of radiation has met with mixed results. Given the success and safety of SBRT in early stage NSCLC, this manuscript describes the long term safety and results of adding an SBRT boost to CRT in an effort to escalate the dose of RT to the primary mass in patients with Stage II-III NSCLC.


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Chemical characterization, toxicology and mechanism of gastric antiulcer action of essential oil from Gallesia integrifolia (Spreng.) Harms in the in vitro and in vivo experimental models

Publication date: October 2017
Source:Biomedicine & Pharmacotherapy, Volume 94
Author(s): Karuppusamy Arunachalam, Sikiru Olaitan Balogun, Eduarda Pavan, Guilherme Vieira Botelho de Almeida, Ruberlei Godinho de Oliveira, Theodoro Wagner, Valdir Cechinel Filho, Domingos Tabajara de Oliveira Martins
Gallesia integrifolia is a Brazilian Amazon tree whose bark decoction is popularly used to treat peptic ulcer. The essential oil from the inner stem bark of G. integrifolia (EOGi) was chemically characterized by GC/MS. The in vitro cytotoxicity and genotoxicity were evaluated in CHO-K1 cells, while the in vivo oral acute toxicity was performed in mice. The gastroprotective effect of EOGi was assessed in acidified ethanol and piroxicam and ulcer healing on acetic acid -induced ulcer models in rodents. Anti-secretory, mucus, K⁺-ATP channels, prostaglandins (PGs), nitric oxide (NO), TNF-α, IL-1β, IL-10, catalase (CAT) and myeloperoxidase (MPO) activities and in vitro Helicobacter pylori action by EOGi were evaluated. EOGi exhibited cytotoxic effects only at 72h and no acute toxicity. EOGi showed gastroprotective and ulcer healing effects. EOGi gastroprotection was attenuated by indomethacin pre-treatment. Gastric volume and total acidity were reduced, while gastric pH was elevated. EOGi increased mucus and NO productions and CAT activity, and inhibited MPO activity, TNF-α and IL-1β concentrations and augmented IL-10. EOGi was not active against H. pylori. These results indicated that EOGi is safe and exerts preventive and curative gastric ulcer effects by multitarget actions. Twenty compounds were identified and (−)-alpha-santalene was the main compound.

Graphical abstract

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The therapeutic effects of Yongdamsagan-tang on autoimmune hepatitis models

Publication date: October 2017
Source:Biomedicine & Pharmacotherapy, Volume 94
Author(s): Jiyoung Park, Hayeon Kim, In-Seung Lee, Kang-Hoon Kim, Yumi Kim, Yun-Cheol Na, Jang-Hoon Lee, Hyeung-Jin Jang
Autoimmune hepatitis (AIH) is an immunity disorder that is the result of antibodies in the liver tissue of the patient that are attacked by activated immune cells due to an unknown cause. In this study, we aimed to investigate the anti-inflammatory effect of Yongdamsagan-tang (YST) extracts and confirm effects on autoimmune hepatitis models as the therapeutic agent using the YST extracted by various solvents. YST, a mixture of 11 herbal extracts, is known in traditional Korean medicine as a widely used treatment for inflammatory diseases. We proposed the AIH-condition in vitro model by the addition of recombinant IL-17A and then observed several markers linked to AIH symptoms, including an increase of IL-6 expression, lipid accumulation, and fibrosis. In AIH-condition hepatic cell model, YST reduced IL-6 expression and lipid accumulation caused by treatment of IL-17 combination in hepatocyte cells. Also, YST blocked several activated fibrosis factors including transforming growth factor-β (TGF- β1), collagen type 1 (Col-α1(I)), and α-smooth muscle actin (α-SMA) in liver stellate cells. Furthermore, pretreatment with YST protected hepatic damage and reduces histological injury by suppressing apoptosis mediator and inflammatory cytokines expression in concanavalin A (Con A)-induced autoimmune hepatitis mice model. The findings here improve our understanding of YST extracted by 80% ethanol, suggesting that YST can be used as a therapeutic treatment for AIH.



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New insights into the antioxidant and apoptotic potential of Glycyrrhiza glabra L. during hydrogen peroxide mediated oxidative stress: An in vitro and in silico evaluation

Publication date: October 2017
Source:Biomedicine & Pharmacotherapy, Volume 94
Author(s): Iram Iqbal Hejazi, Rashmin Khanam, Syed Hassan Mehdi, Abdul Roouf Bhat, M. Moshahid Alam Rizvi, Asimul Islam, Sonu Chand Thakur, Fareeda Athar
Plant-derived substances (phytochemicals) are well recognized as sources of pharmacologically potent drugs in the treatment of several oxidative stress related disorders. Our study aims to evaluate the antioxidant and apoptotic effects of Glycyrrhiza glabra L. in both cell free and cell culture system. Plant fractions have been prepared with hexane, chloroform, ethyl acetate, methanol and water and their antioxidant properties are reviewed. Potent antioxidant activity has been well established in both in vitro and in silico studies which is believed to be responsible for the anticancerous nature of the plant. Results obtained indicate that methanol fraction of G. glabra L. exhibited maximum scavenging activity against DPPH and nitric oxide free radicals comparable to standard antioxidant L-AA. Administration of methanol fraction also considerably reduced the malondialdehyde produced due to lipid peroxidation in mammalian liver tissues. Moreover, the levels of antioxidant enzymes SOD, CAT, GST, GPx and GR in the oxidative stress induced tissues were refurbished significantly after treatment with plant's methanol fraction. Moreover, methanol fraction was found to be nontoxic to normal human cell line whereas it inhibited cancer cells HeLa and HepG2 considerably. Apoptosis was established by DAPI fluorescent staining and western blot analysis of pro apoptotic protein caspase-8, caspase-3 and anti-apoptotic protein Bcl-2.There is an up regulation in the levels of pro apoptotic caspase-8 and caspase-3 and down regulation of anti-apoptotic Bcl-2. Furthermore, GC–MS analysis of the methanol fraction revealed the presence of many compounds. In silico experiments using Autodock 4.2 tools showed strong affinity of plant compounds towards antioxidant enzymes (proteins) thus validating with the conclusions of antioxidant enzyme assays and establishing a role in cancer pathogenesis.

Graphical abstract

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Long intergenic noncoding RNA 00305 sponges miR-136 to regulate the hypoxia induced apoptosis of vascular endothelial cells

Publication date: October 2017
Source:Biomedicine & Pharmacotherapy, Volume 94
Author(s): Bo-Ya Zhang, Zhe Jin, Zhuo Zhao
BackgroundApoptosis in vascular endothelial cells (VECs) are closely correlated to multiple endotheliocyte-related cardiovascular diseases, for example atherosclerosis. Long non-coding RNAs (lncRNAs) have been testified to play important role in regulation of VECs. The purpose of this study is to investigate the potential regulation of lncRNA long intergenic noncoding RNA 00305 (LINC00305) on hypoxia induced VECs.MethodsHuman umbilical vein endothelial cells (HUVECs) were respectively induced with normoxia or hypoxia (1%). Expression levels of lncRNA and miRNA were detected using RT-PCR. Proliferation ability was tested by CCK-8 assay. Apoptosis assay were performed using flow cytometry and TUNEL staining. Target miRNAs prediction was performed using bioinformatics analysis.ResultsLINC00305 expression was significantly up-regulated in hypoxia induce HUVECs. Gain- and loss-of-function experiments showed that LINC00305 enhanced expression suppressed the proliferation and enhanced the apoptosis of HUVECs, while LINC00305 lower-expression exerted the opposite effect. Bioinformatics analysis revealed that miR-136 targeted LINC00305 art 3′-UTR. Moreover, rescue experiment confirmed the reversing function of miR-136 to LINC00305 on HUVECs proliferation and apoptosis.ConclusionOur study revealed the apoptosis-promoting role of LINC00305 in hypoxia-induced HUVECs via acting as miR-136 sponge, suggesting the vital function of lncRNAs on VECs apoptosis.



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Protective effects of ethanolic peel and pulp extracts of Citrus macroptera fruit against isoproterenol-induced myocardial infarction in rats

Publication date: October 2017
Source:Biomedicine & Pharmacotherapy, Volume 94
Author(s): Sudip Paul, Sagarika Das, E.M. Tanvir, Md. Sakib Hossen, Moumoni Saha, Rizwana Afroz, Md. Aminul Islam, Md. Sabir Hossain, Siew Hua Gan, Md. Ibrahim Khalil
Increases in the incidence of cardiovascular disease (CVD) have aroused strong interest in identifying antioxidants from natural sources for use in preventive medicine. Citrus macroptera (C. macroptera), commonly known as "Satkara", is an important herbal and medicinal plant reputed for its antioxidant, nutritious and therapeutic uses. The aim of the present study was to investigate the cardio-protective effects of ethanol extracts of C. macroptera peel and pulp against isoproterenol (ISO)-induced myocardial infarction (MI) in rats. Male albino Wistar rats (n=36) were pre-treated with peel and pulp extracts (500mg/kg) for 45days. They received a challenge with ISO (85mg/kg) on the 44th and 45th days. Our findings indicated that subcutaneous injection of ISO induced severe myocardial injuries associated with oxidative stress, as confirmed by elevated lipid peroxidation (LPO) and decreased cellular reduced glutathione (GSH) and anti-peroxidative enzymes, including glutathione peroxidase, glutathione reductase and glutathione-S-transferase, compared with levels observed in control animals. Pre-treatment with C. macroptera peel and pulp extracts prior to ISO administration however, significantly improved many of the investigated biochemical parameters, i.e., cardiac troponin I, cardiac marker enzymes, lipid profile and oxidative stress markers. The fruit peel extract showed stronger cardio-protective effects than the pulp extract. The biochemical findings were further confirmed by histopathological examinations. Overall, the increased endogenous antioxidant enzyme activity against heightened oxidative stress in the myocardium is strongly suggestive of the cardio-protective potential of C. macroptera.



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Berberine ameliorates methotrexate-induced liver injury by activating Nrf2/HO-1 pathway and PPARγ, and suppressing oxidative stress and apoptosis in rats

Publication date: October 2017
Source:Biomedicine & Pharmacotherapy, Volume 94
Author(s): Ayman M. Mahmoud, Walaa G. Hozayen, Shimaa M. Ramadan
Berberine (BBR) is a natural isoquinoline alkaloid with very impressive health benefits. It is one of the most effective natural supplements available; however, its ameliorative mechanism against methotrexate (MTX)-induced liver injury is not well defined. This study investigated the protective effect of BBR against MTX hepatotoxicity, focusing on its ability to attenuate oxidative stress and apoptosis and to activate nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling and peroxisome proliferator activated receptor gamma (PPARγ). Rats received BBR (25 and 50mg/kg) orally for 7days before MTX injection. Other groups received MTX followed by BBR (25 and 50mg/kg) orally for 7 days. MTX-induced rats showed significant body weight loss, increased serum liver function marker enzymes, bilirubin and tumor necrosis factor alpha (TNF-α). Liver lipid peroxidation, nitric oxide (NO) and caspase-3 were significantly increased following MTX administration. BBR supplemented either before or after MTX significantly ameliorated body weight, liver function markers, TNF-α, lipid peroxidation, NO and caspase-3. BBR increased serum albumin and liver antioxidant defenses in MTX-induced rats. Histological and immunohistochemical examination showed improved histological structure and decreased expression of Bax in liver of MTX-induced rats treated with BBR. In addition, BBR up-regulated Nrf2, HO-1 and PPARγ expression in the liver of MTX-induced rats. In conclusion, BBR attenuated MTX-induced oxidative stress and apoptosis, possibly through up-regulating Nrf2/HO-1 pathway and PPARγ. Therefore, BBR can protect against MTX-induced liver injury.

Graphical abstract

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The anti-proliferative and apoptotic effects of crocin on chemosensitive and chemoresistant cervical cancer cells

Publication date: October 2017
Source:Biomedicine & Pharmacotherapy, Volume 94
Author(s): Homa Mollaei, Reza Safaralizadeh, Esmaeil Babaei, Mohamad Reza Abedini, Reyhane Hoshyar
Cervical cancer is the fourth cause of cancer-related mortality among females worldwide. Although current therapies reduce disease symptoms, resistance of tumor cells to chemotherapy agents after a while is a serious problem. Therefore, utilization of novel adjuvant agents to increase efficiency of chemotherapy is essential. In the last two decades, botanicals with effective anticancer activities have been studied. Among them, the anticancer properties of crocin have been more attended. In this study, the molecular mechanism of crocin action was investigated in sensitive human cervical cancer cell line (OV2008) in comparison with the resistant one (C13). A 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay showed that crocin inhibits proliferation of sensitive cells (OV2008) at a time- and dose-dependent manner at 48 and 72h. Also, this inhibitory effect has been shown on resistant cells (C13) at 72h. Hoechst staining and flow cytometry assay also confirmed these results and revealed that antiproliferative effect of crocin might be due to the induction of apoptosis. Moreover, the genetic mechanism of crocin-induced apoptosis was accomplished by studying the relative expressions of P53, Bax, Bcl2 and miR-365, an upstream regulator of the last two ones. Real-time PCR analysis indicated that 1.5 and 3mg/ml crocin led to up-regulation of Bax and P53 and down-regulation of Bcl2 and miR-365 at all time intervals in both two cell lines. However, OV2008 cell line was more sensitive to crocin, and alternation of gene expretion was more obvious in this cell line. In this regard, the present study demonstrated the anti-proliferative and apoptotic activities of crocin against both sensitive and resistant cervical cancer cells that may benefit cervical cancer treatment as an adjuvant agent to decrease chemoresistance and increase the efficiency of therapy.



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Carbenoxolone reduces cyclic nucleotides level, destabilizes maturation promoting factor and induces meiotic exit from diplotene arrest in rat cumulus oocytes complexes cultured in vitro

Publication date: October 2017
Source:Biomedicine & Pharmacotherapy, Volume 94
Author(s): Meenakshi Tiwari, Shail K. Chaube
BackgroundDisruption of gap junction and transfer of cyclic nucleotides to the oocyte lead to meiotic exit from diplotene arrest (EDA) in mammals. In the present study, we examined whether a gap junction blocker, carbenoxolone (CBX) could induce EDA by reducing cyclic nucleotides level and destabilizing maturation promoting factor (MPF) in rat oocytes cultured in vitro.MethodsDiplotene-arrested cumulus oocyte complexes (COCs) were collected from ovary of immature female rats after 20 IU pregnant mare's serum gonadotropins (PMSG) for 48h. These diplotene-arrested COCs were incubated with various concentration of CBX for 3h in vitro. The morphological changes, meiotic status of oocyte, inducible nitric oxide synthase (iNOS), total nitric oxide (NO), adenosine 3′,5′-cyclic monophosphate (cAMP), guanosine 3′,5′-cyclic monophosphate (cGMP), cell division cycle 25B (Cdc25B), changes in specific phosphorylation status of cyclin-dependent kinase 1 (Cdk1) and cyclin B1 levels were analyzed.ResultsCBX induced EDA in a concentration-dependent manner. The iNOS expression, total NO and cyclic nucleotides level were significantly decreased. The reduced cyclic nucleotides level resulted in the decrease of Cdc25B expression level. The decreased Cdc25B was associated with the increased Thr14/Tyr15 phosphorylated Cdk1 level. However, Thr161 phosphorylated Cdk1 as well as cyclin B1 levels were significantly reduced leading to MPF destabilization. The destabilized MPF finally induced EDA in rat COCs cultured in vitro.ConclusionsOur results suggest that CBX blocked gap junctions interrupted the transfer of cyclic nucleotides to the oocyte. Reduction of cyclic nucleotides level destabilized MPF and induced EDA in vitro. Thus, CBX could be used to induce meiotic maturation under in vitro culture conditions during assisted reproductive technology (ART) programs.

Graphical abstract

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Diagnostic Accuracy of Clinical Decision Rules to Exclude Fractures in Acute Ankle Injuries: Systematic Review and Meta-analysis

Publication date: Available online 29 July 2017
Source:The Journal of Emergency Medicine
Author(s): Ingrid Barelds, Wim P. Krijnen, Johannes P. van de Leur, Cees P. van der Schans, Robert J. Goddard
BackgroundAnkle decision rules are developed to expedite patient care and reduce the number of radiographs of the ankle and foot. Currently, only three systematic reviews have been conducted on the accuracy of the Ottawa Ankle and Foot Rules (OAFR) in adults and children. However, no systematic review has been performed to determine the most accurate ankle decision rule.ObjectivesThe purpose of this study is to examine which clinical decision rules are the most accurate for excluding ankle fracture after acute ankle trauma.MethodsA systematic search was conducted in the databases PubMed, CINAHL, PEDro, ScienceDirect, and EMBASE. The sensitivity, specificity, likelihood ratios, and diagnostic odds ratio of the included studies were calculated. A meta-analysis was conducted if the accuracy of a decision rule was available from at least three different experimental studies.ResultsEighteen studies satisfied the inclusion criteria. These included six ankle decision rules, specifically, the Ottawa Ankle Rules, Tuning Fork Test, Low Risk Ankle Rule, Malleolar and Midfoot Zone Algorithms, and the Bernese Ankle Rules. Meta-analysis of the Ottawa Ankle Rules (OAR), OAFR, Bernese Ankle Rules, and the Malleolar Zone Algorithm resulted in a negative likelihood ratio of 0.12, 0.14, 0.39, and 0.23, respectively.ConclusionThe OAR and OAFR are the most accurate decision rules for excluding fractures in the event of an acute ankle injury.



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FDA licensure of and ACIP recommendations for vaccines

Publication date: Available online 29 July 2017
Source:Vaccine
Author(s): Larry K. Pickering, Walter A Orenstein, Wellington Sun, Carol J. Baker
Many healthcare providers are not familiar with the Food and Drug Administration (FDA) vaccine licensure process, the Advisory Committee on Immunization Practices (ACIP) vaccine recommendation process, and how FDA vaccine licensure and ACIP recommendations are related. Vaccines for use in the United States military and civilian populations are licensed by the FDA by several potential pathways but use of licensed vaccines in the civilian population should be based on recommendations made by the ACIP. In performing these distinct activities, FDA and ACIP function under different mandates. In this article, we discuss whether the FDA licensure pathways used to approve a vaccine impacts ACIP recommendation categories for vaccines licensed from 2006 to 2016.



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Data for high-throughput estimation of specific activities of enzyme/mutants in cell lysates through immunoturbidimetric assay of proteins

Publication date: October 2017
Source:Data in Brief, Volume 14
Author(s): Yiran Feng, Xiaolan Yang, Huimin Chong, Deqiang Wang, Xiaolei Hu, Chang-Guo Zhan, Fei Liao
Data in this article are associated with the research article "Highthroughput estimation of specific activities of enzyme/mutants in cell lysates through immunoturbidimetric assay of proteins" (Yang et al., 2017) [1]. This article provided data on how to develop an immunoturbidimetric assay (ITA) of enzyme/mutants as proteins in cell lysates in high-throughput (HTP) mode together with HTP assay of their activities to derive their specific activities in cell lysates for comparison, with Pseudomonas aeruginosa arylsulfatase (PAAS) and Bacillus fastidious uricase (BFU) plus their mutants as models. Data were made publicly available for further analyses.



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Validity of self-reported cancer history in the health examinees (HEXA) study: A comparison of self-report and cancer registry records

Publication date: October 2017
Source:Cancer Epidemiology, Volume 50, Part A
Author(s): Sooyoung Cho, Aesun Shin, Daesub Song, Jae Kyung Park, Yeonjung Kim, Ji-Yeob Choi, Daehee Kang, Jong-Koo Lee
PurposeTo assess the validity of the cohort study participants' self-reported cancer history via data linkage to a cancer registry database.MethodsWe included 143,965 participants from the Health Examinees (HEXA) study recruited between 2004 and 2013 who gave informed consent for record linkage to the Korean Central Cancer Registry (KCCR). The sensitivity and the positive predictive value of self-reported histories of cancer were calculated and 95% confidence intervals were estimated.ResultsA total of 4,860 participants who had at least one record in the KCCR were included in the calculation of sensitivity. In addition, 3,671 participants who reported a cancer history at enrollment were included in the calculation of positive predictive value. The overall sensitivity of self-reported cancer history was 72.0%. Breast cancer history among women showed the highest sensitivity (81.2%), whereas the lowest sensitivity was observed for liver cancer (53.7%) and cervical cancer (52.1%). The overall positive predictive value was 81.9%. The highest positive predictive value was observed for thyroid cancer (96.1%) and prostate cancer (96.1%), and the lowest was observed for cervical cancer (43.7%).ConclusionThe accuracy of self-reported cancer history varied by cancer site and may not be sufficient to ascertain cancer incidence, especially for cervical and bladder cancers.



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The Colon Revisited or The Key To Wellness, Health And Disease

Publication date: Available online 29 July 2017
Source:Medical Hypotheses
Author(s): C.A. Gonzalez-Correa, E. Mulett-Vásquez, D.A. Miranda-Mercado, C.H. Gonzalez-Correa, P.A. Gómez-Buitrago
The hypothesis being advanced in this paper is that there is a new medical paradigm emerging from the biomedical research carried out in this century, mainly due to the explosion of the so called "omics" and associated techniques. The main idea is that there is a common pathway from wellbeing and health to chronic disease ("chonopathy") and even to death, which comprises following steps: 1) unhealthy diet, sedentarism and permanent exposition to xenobiotis and all kinds of noxious stimuli, →2) intestinal dysbiosis;→ 3) alteration of the intestinal mucus layer (especially that of the colon) →4) disruption of the endothelial tight junctions →5) metabolic endotoxemia + bacterial translocation →6) inflammation → 7) exacerbation of the enteric nervous system (ENS) and consequent maladaptation and malfunctioning of the colon → 8) epigenetic manifestations → 9) "chronopathy" and premature death. Therefore, in order to maintain a good health or to improve or even reverse chronic diseases in a person, the main outcome to look for is an homeostatic balance of the intestinal microbiota (eubiosis), most of which is located in the colon. Lynn Margulis was one of the main scientists to highlight the importance of the role played by bacteria not only in the origin of all biological species now present on earth, but also on their role in global homeostasis. Bacteria do not rely on other living beings for their existence, while the latter depend completely on the former. Humans are no exemption, and new evidence emerges each day about the pivotal role of intestinal microbiota in human health, disease and, in general, in its wellbeing. The following facts about intestinal microbiota are nowadays generally accepted: there are about 10 times more bacteria in the gut than human cells in every human being; the microbioma is about 100-150 times bigger that the human genome, and there is a clear link between intestinal microbiota and many of the most common chronic diseases, from obesity and diabetes to depression and Parkinson disease and different kinds of cancer. The main implication of this theory is that we should become a sort of microbiota farmers, that is, we ought to be more conscious of our intestinal microbiota, take care of it and monitor it permanently. Thus, as part of our good life habits (healthy eating, physical exercise), we should probably undergo periodic seasons of fasting and colon cleansing, as it was common in older times.



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The Metastasis Status and Tumor Burden-Associated CA125 Level Combined with the CD4/CD8 Ratio Predicts the Prognosis of Patients with Advanced Pancreatic Cancer: A New Scoring System

Publication date: Available online 29 July 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Chao Yang, He Cheng, Guopei Luo, Yu Lu, Meng Guo, Kaizhou Jin, Zhengshi Wang, Xianjun Yu, Chen Liu
BackgroundAlthough CA125 and the tumor immune response have been reported to be associated with pancreatic cancer, their prognostic value for advanced pancreatic cancer patients undergoing chemotherapy remains uncertain. We thus studied the prognostic value of the combination of the CA125 level with the CD4/CD8 ratio.MethodsAfter excluding patients who were lost to follow-up or for whom complete clinical data were missing, 369 participants were ultimately examined. Univariate and multivariate analyses were performed using the Cox hazards model, and Kaplan-Meier methods and log-rank tests were used for the comparison of survival rates.ResultsUnivariate and multivariate analyses showed that a high CA125 level and a high CD4/CD8 ratio were independent prognosis factors (CA125≥35 U/ml, Hazard Ratio (HR)=1.90, p<0.001; CD4/CD8≥1.8, HR=1.37, p=0.004). Moreover, after combining the CA125 level and CD4/CD8 ratio to form a new scoring system, the HR was substantially elevated (CA125≥35 U/ml and CD4/CD8≥1.8, score 2, HR=2.76, 95% confidence interval: 2.04 to 3.74, p<0.001).ConclusionsA new scoring system based on the combination of the CA125 level with the CD4/CD8 ratio could further predict the prognosis of patients with advanced pancreatic cancer.



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Evidence for altered osteoclastogenesis in splenocyte cultures from VDR knockout mice

Publication date: Available online 29 July 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Daniel C. Reinke, Yolandi Starczak, Masakazu Kogawa, Kate R. Barratt, Howard A. Morris, Paul H. Anderson, Gerald J. Atkins
The indirect action of 1α,25(OH)2-vitamin-D3 (1,25D) on the osteoclast through stromal signalling is well established. The role of vitamin D in osteoclasts through direct 1,25D-VDR signalling is less well known. We showed previously that local 1,25D synthesis in osteoclasts modified osteoclastogenesis and osteoclastic resorptive activity. In this study, we hypothesised that osteoclasts lacking VDR expression would display an enhanced resorptive capacity due to the loss of 1,25D signalling. Splenocytes were cultured under osteoclast-differentiating conditions from mice with global deletion of the Vdr gene (VDRKO) and this was compared with age-matched wild-type littermate controls (WT). In VDRKO cultures, osteoclastogenesis was reduced, as indicated by fewer TRAP-positive multinucleated cells at all time points measured (p<0.05) compared to WT levels. However, VDRKO osteoclasts demonstrated greater resorption on a per cell basis than their WT counterparts. VDRKO cultures expressed greatly increased c-Fos mRNA compared to WT. In addition, the ratio of expression of the pro-apoptotic gene Bax to the pro-survival gene Bcl-2 was decreased in VDRKO cultures, implying that these osteoclasts survive longer than WT osteoclasts. Our data indicate abnormal osteoclastogenesis due to the absence of Vdr expression, consistent with direct effects of vitamin D signalling being important for regulating the maturation and resorptive activities of osteoclasts.



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JNK1 AS A SIGNALING NODE IN VDR-BRAF INDUCTION OF CELL DEATH IN AML

Publication date: Available online 29 July 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Xuening Wang, William K Beute, Jonathan S Harrison, George P Studzinski
Numerous clinical studies of vitamin D, its derivatives or analogs, have failed to clearly demonstrate sustained benefits when used for the treatment of human malignant diseases. However, given the strong preclinical evidence of anti-neoplastic activity and the epidemiological associations suggesting that vitamin D compounds may have a place in cancer therapy, attempts are continuing to devise new approaches to their therapeutic use. This laboratory has developed a strategy to enhance the effectiveness of the currently standard therapy of Acute Myeloid Leukemia (AML) by the immediate addition of the vitamin D2 analog Doxercalciferol combined with the plant polyphenol-derived Carnosic acid to AML cells previously treated with Cytarabine (AraC). Enhancement of AML cell death was noted to be dependent on VDR and BRAF kinase. Here we document that the stress-related kinase JNK is an important additional component of cell death enhancement in this protocol. Either the Knock-down or the inhibition of JNK activity reduced the enhancement of AraC-induced cell death, and we show that JNK signaling to the apoptosis regulator BIM and Caspase executioners of cell death are downstream of VDR and BRAF. A clear understanding of the molecular basis for the increased efficacy of AraC in the therapy of AML is expected to bring this regimen to a clinical trial.

Graphical abstract

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Vitamin D effects on monocyteś CCL-2, IL6 and CD14 transcription in Addison’s disease and HLA susceptibility

Publication date: Available online 29 July 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): A.U. Kraus, M. Penna-Martinez, G. Meyer, K. Badenhoop
Addisońs disease is a rare autoimmune disorder leading to adrenal insufficiency and life-long glucocorticoid dependency. Vitamin D receptor (VDR) polymorphisms and vitamin D deficiency predispose to Addisońs disease. Aim of the current study was, to investigate potential anti-inflammatory vitamin D effects on monocytes in Addisońs disease, focusing on inflammatory CCL-2 and IL6, as well on monocyte CD14 markers. Addisońs disease is genetically linked to distinct HLA susceptibility alleles. Therefore we analyzed, whether HLA genotypes differed for vitamin D effects on monocyte markers. CD14⁺ monocytes were isolated from Addisońs disease patients (AD, n=13) and healthy controls (HC, n=15) and stimulated with 1,25-dihydroxyvitamin D3 and IL1β as an inflammatory stimulant. Cells were processed for mRNA expression of CCL-2, IL6 and CD14 and DNA samples were genotyped for major histocompatibility class (MHC) class II-encoded HLA- DQA1-DQB1 haplotypes. We found a downregulation of CCL-2 after vitamin D treatment in IL1β-stimulated monocytes both from AD patients and HC (AD p<0.001; HC p<0.0001). CD14 expression however, was upregulated in both HC and AD patients after vitamin D treatment (p<0.001, respectively). HC showed higher CD14 transcription level than AD patients after vitamin D treatment (p=0.04). Compared to IL1β-induced inflammation, HC have increased CD14 levels after vitamin D treatment (p<0.001), whereas the IL1β-induced CD14 expression of AD patientś monocytes did not change after vitamin D treatment (p=0.8). AD patients carrying HLA high-risk haplotypes showed an increased CCL-2 expression after IL1β-induced inflammation compared to intermediate-risk HLA carriers (p=0.05). Also HC monocytes' CD14 transcription after IL1β and vitamin D co-stimulation differed according to HLA risk profile. We show that vitamin D can exert anti-inflammatory effects on AD patients' monocytes which may be modulated by HLA risk genotypes.



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The cortisol-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 in skeletal muscle in the pathogenesis of the metabolic syndrome

Publication date: Available online 29 July 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Christine Loerz, Edmund Maser
The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) contributes to intracellular glucocorticoid action by converting inactive cortisone to its receptor-active form cortisol (11-dehydrocorticosterone and corticosterone in mice and rats). The potential role of 11β-HSD1 in the pathogenesis of the metabolic syndrome has emerged over the past three decades. However, the precise impact of 11β-HSD1 in obesity-related diseases remains uncertain. Many studies from animal experiments to clinical studies have investigated liver and adipose tissue 11β-HSD1 in relation to obesity and its metabolic disorders including insulin resistance. But the relevance of 11β-HSD1 in skeletal muscle has been less extensively studied. On the other hand, skeletal muscle is assumed to be the main site of peripheral insulin resistance, but the biological relevance of 11β-HSD1 in skeletal muscle is unclear. This mini-review will focus on 11β-HSD1 in skeletal muscle and its postulated link to obesity and insulin-resistance.



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Synergistic Effect of 1α,25-Dihydroxyvitamin D3 and 17β-Estradiol on Osteoblast Differentiation of Pediatric MSCs

Publication date: Available online 29 July 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Jing Li, Bonnie L. Padwa, Shuanhu Zhou, Julia Mullokandova, Meryl S. LeBoff, Julie Glowacki
Vitamin D is essential for mineral homeostasis and contributes to bone metabolism by stimulating osteoblast differentiation of marrow stromal cells (MSCs). In this study, we used MSCs from pre-pubertal girls and boys to test the hypothesis that 1α,25(OH)2D and 17β-estradiol have synergistic effects on these MSCs, and what mechanism is involved. With IRB approval, we isolated MSCs from discarded excess iliac marrow graft from children undergoing alveolar cleft repair. Plasma was available from 8 female (9.3±0.2years) and 8 male (9.6±0.1years) subjects for hormone assays [25(OH)D, total testosterone, 17β-estradiol, estrone, DHEA-S, Growth Hormone, IGF-I]. RT-PCR was used for gene expression. Alkaline phosphatase (ALP) activity was used to measure osteoblast differentiation at day 7; alizarin red was used to measure matrix mineralization at day 21. All subjects were pre-pubertal based on their hormone levels. Serum 25(OH)D levels ranged from 13.1 to 26.4ng/mL, with 75% below 20ng/mL. Constitutive gene expression of VDR and ERα, β varied from subject to subject with no association with sex or serum chemistries. In osteoblastogenic medium, 1α,25(OH)2D3 (10nM) increased ALP activity by 36% (p <0.05) in MSCs; 10nM of E2 was not stimulatory but the combination of 1α,25(OH)2D3 and E2 increased ALP 151% (p <0.05 vs. control) and by 84.5% (p <0.05 vs. 1α,25(OH)2D3 alone). The combination of 1α,25(OH)2D3 and E2 significantly increased mineralization 11-fold, compared with either agent alone. Twenty-four hour treatment with 1α,25(OH)2D3 (10nM) or E2 (10nM) upregulated each other's receptor by as much as 5.8-fold for ERα and 2.9-fold for the VDR. In summary, 1α,25(OH)2D3 stimulated osteoblast differentiation and matrix mineralization with MSCs from pre-pubertal subjects, with a synergistic effect of E2, mediated by upregulated receptor levels, at least in part. These studies add new information about the regulation of human osteoblast differentiation, effects of 1α,25(OH)2D3 and E2 on MSCs, and the importance of vitamin D for skeletal health.

Graphical abstract

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Treatment of elderly patients or patients who are performance status 2 (PS2) with advanced Non-Small Cell Lung Cancer without epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations – Still a daily challenge

Publication date: September 2017
Source:European Journal of Cancer, Volume 83
Author(s): Chunxia Su, Fei Zhou, Jiqiao Shen, Jing Zhao, Mary O'Brien
Cytotoxic chemotherapy remains the core treatment strategy for patients with advanced non-small cell lung cancer (NSCLC) with tumours that do not have actionable molecular alterations, such as epidermal growth factor receptor (EGFR)-sensitising mutations, anaplastic lymphoma kinase (ALK) translocations or ROS1 translocations. Age and performance status (PS) are two pivotal factors to guide treatment decisions regarding the use of chemotherapy in lung cancer patients. Lung cancer is predominantly a disease of the elderly, with more than two-thirds of patients aged ≥65 years, the current definition of 'elderly'. The prevalence of poor PS, as estimated by patients themselves, can be as high as 50%. Both the elderly and PS2 patients are underrepresented in clinical trials. Therefore, optimising treatment strategy for the subgroup of elderly or PS2 patients with advanced NSCLC remains challenging as a result of a paucity of clinical trial data. The current review focusses on the elderly or PS2 patients without actionable oncogenic drivers and attempts to summarise current available data on recent treatments trials including angiogenesis inhibitors and immune-checkpoint inhibitors.



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Association of the oestrogen receptor beta with hormone status and prognosis in a cohort of female patients with colorectal cancer

Publication date: September 2017
Source:European Journal of Cancer, Volume 83
Author(s): Geriolda Topi, Roy Ehrnström, Karin Jirström, Ingrid Palmquist, Marie-Louise Lydrup, Anita Sjölander
BackgroundThe oestrogen receptor beta (ERβ) is the predominant oestrogen receptor in the normal colon mucosa and has been reported to exert anti-proliferative and pro-apoptotic effects. However, the role of ERβ in colorectal cancer (CRC) progression remains unclear.AimTo investigate the role of ERβ and its association with hormone status and lifestyle indicators in a female cohort of patients with CRC.MethodsTissue microarrays of primary CRC tumour samples from 320 female patients were conducted with a monoclonal anti-ERβ antibody. The staining intensity was evaluated using immunohistochemistry. The association of ERβ expression with overall survival, disease-free survival, hormone status and lifestyle was evaluated, and effect estimators with 95% confidence intervals (CIs) were reported.ResultsAmong the 314 samples with successfully detected ERβ, 182 (58%) had low expression and 132 (42%) had high expression. The Cox multivariate analysis indicated that patients with high ERβ expression had a decreased risk of overall mortality by 50% (hazard ratio [HR], 0.50; CI, 0.30–0.83) and of cancer recurrence by 76% (HR, 0.24; CI, 0.11–0.52) after adjusting for age, tumour-node-metastasis stage and tumour intravascular invasion. Furthermore, high ERβ expression was significantly correlated with shorter breastfeeding time and longer use of hormone replacement therapy. No association was found between ERβ expression and lifestyle indicators.ConclusionElevated ERβ expression is independently associated with a better prognosis and hormone status but not lifestyle indicators in female CRC patients.



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The Effect of Suspense on Brain Activation and Memory During Naturalistic Viewing

Publication date: Available online 29 July 2017
Source:Biological Psychology
Author(s): Matthew A. Bezdek, William G. Wenzel, Eric H. Schumacher
We tested the hypothesis that, during naturalistic viewing, moments of increasing narrative suspense narrow the scope of attentional focus. We also tested how changes in the emotional congruency of the music would affect brain responses to suspense, as well as subsequent memory for narrative events. In our study, participants viewed suspenseful film excerpts while brain activation was measured with functional magnetic resonance imaging. Results indicated that suspense produced a pattern of activation consistent with the attention-narrowing hypothesis. For example, we observed decreased activation in the anterior calcarine sulcus, which processes the visual periphery, and increased activity in nodes of the ventral attention network and decreased activity in nodes of the default mode network. Memory recall was more accurate for high suspense than low suspense moments, but did not differ by soundtrack congruency. These findings provide neural evidence that perceptual, attentional, and memory processes respond to suspense on a moment-by-moment basis.



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Scholar : Ειδοποίηση Μελετητή - [ ΓΛΩΣΣ

Ειδοποίηση Μελετητή:[ ΓΛΩΣΣΙΤΙΣ ]

White and Red Lesions of the Oral Mucosa

M Jessri, H Mawardi, CS Farah, SB Woo - 2017

... 13 Oral Hairy Leukoplakia . . . . . 15 Immune-Mediated and Autoimmune Conditions ..... 16 Benign
Migratory Glossitis (Geographic Tongue, Erythema Areata Migrans, Migratory Stomatitis) . . . . ...

Catatonia in children and adolescents: New perspectives

X Benarous, M Raffin, V Ferrafiat, A Consoli, D Cohen - Schizophrenia Research, 2017

Catatonia is a rare and severe psychomotor condition in children and adolescents. In the
current report, we aimed to review the recent literature.Using a PRISMA.

[PDF] GOLD-TESTING INGOLD TREATMENT OF CHRONIC POLYARTHRITIS

T SVANBERG

... I. TABLE I TYPE AND NUMBER OF COMPLICATIONS IN GOLD TREATMENT Number of Cases
with Complications During Treatment After Discharge Type of Disease-- After After After After
one several one several injection injections injection injections Stomatitis, glossitis. . ...

[PDF] IRON DEFICIENCY ANEMIA: RISK FACTORS AMONG ADULT POPULATION ROUND LMH

SR Sahu, AM Joshi

... were noted(knuckle pigmentation, greying of hair, hair fall, tachycardia, palpitation, pallor, icterus,
nail deformities, bone tenderness, headache, neuropathy, abnormal skin pigmentation, spider
nevi, petechial spots, echymosis, purpura, glossitis, splenomegaly, lymphadenopathy ...

[PDF] SEVERE MEGALOBLASTIC ANEMIA WITH MODERATE ACUTE MALNUTRITION IN AN INFANT: A RARE CASE REPORT

K Thoti, VT Madhavi, P Sravya Sruthi, P Lakshmi

... Other findings include pallor, glossitis, vomiting, diarrhoea, seizures, developmental regression
and hemorrhages.[9] Nutritional megaloblastic anemia occurs commonly in undernourished
and malnourished children; the commonest age is 3-12 months. ...

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Scholar : Scholar Alert - [ intitle:laryngeal ]

Scholar Alert: [ intitle:laryngeal ]

Influence of lateral position and pneumoperitoneum on oropharyngeal leak pressure with two types of laryngeal mask airways

S Lan, Y Zhou, JT Li, ZZ Zhao, Y Liu - Acta Anaesthesiologica Scandinavica, 2017

Background An important parameter to monitor adequate ventilation for laryngeal mask
airway (LMA) is its oropharyngeal leak pressure (OLP). This study was designed to evaluate
and compare the effect of lateral position and pneumoperitoneum on the OLP and

[PDF] The impact of lncRNA MG3 on laryngeal cancer cell growth, cycle, and apoptosis related factors

Y Li, X Zhou, C Tao, C Chen, C Cui, L Dai, H Wu, Q Wei… - Int J Clin Exp Pathol, 2017

Abstract: Laryngeal cancer is a common head and neck malignant tumor. Long non-coding
RNA (lncRNA) is a kind of RNA at the length more than 200 nucleotides that cannot code
protein. They widely exist in the human genome. Maternally expressed gene 3 (MG3) is a

Can fluid resuscitation be a risk factor for laryngeal oedema in severe dengue?

A Azim

We sincerely thank the authors for their questions. We accept that bleeding in respiratory
tract can be a complication of severe dengue, but it did not occur in our illustrated case.[1] It
is difficult to point to a single factor that is responsible, as the disease manifests with multi-

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Scholar : Ειδοποίηση Μελετητή - [ ΛΟΓΟΣ

Ειδοποίηση Μελετητή:[ ΛΟΓΟΣ ]

[PDF] λόγος and φωνή in Odyssey 10 and Plutarch's Gryllus

A Kirk - OralityandLiteracyintheAncientWorld, vol. 11, 2017

This paper examines conceptions about animal speech as reflected in the Circe episode of
Odyssey 10 and in Plutarch's moral essay Gryllus, a dialogue between Odysseus and one of
his men-turned-pigs. It focuses particularly on how these two texts treat communicative

Εναλλακτικοί τρόποι για την αποστολή και παραλαβή εταιριών μεταφοράς χρημάτων-εταιρίες μεταφοράς σε Κύπρο και εξωτερικό

Α Αντωνίου - 2017

... από την υπηρεσία. Ο κύριος λόγος για τη χρήση αυτών των υπηρεσιών είναι η παροχή
οικονομικής βοήθειας και ο λόγος επιλογής εταιρείας MT από κάποιο τραπεζικό ίδρυμα
είναι κυρίως λόγω των τελών μεταφοράς. Επιπλέον, οι ...

A NOTE ON ΤΑ ΕΣΧΑΤΑ ΕΙΔΗ AT 644A23 IN ARISTOTLE'S PART. AN. 1.4

EG Katayama - The Classical Quarterly, 2017

... 1.4 passage but also in a De Anima passage, where Aristotle states that it is ridiculous (γελοῖον)
to seek a com- mon account (τὸν κοινὸν λόγον) whether one is studying figures or souls, if we
fail to seek a distinctive account (ἴδιος λόγος) and proper properties belonging to ...

[PDF] Το παιχνίδι ως εργαλείο μάθησης σε παιδιά με αυτισμό

Ε Παχή - 2017

... επίσης και η κινητική ανάπτυξη των παιδιών. Ένας σημαντικός λόγος που η λεπτή ...
Στο τέταρτο κεφάλαιο αναφέρεται ο σκοπός της εργασίας, στο έκτο κεφάλαιο γίνεται
λόγος για τη μέθοδο που χρησιμοποιήθηκε στην συγκεκριμένη ...

[PDF] Διδακτικές προσεγγίσεις για το μνημείο του Ρώσου στρατιώτη και για το μνημείο των μαχητών του ΔΣΕ στην Φλώρινα

Χ Βασιλοπούλου - 2017

... Παρακάτω, λοιπόν, γίνεται λόγος για την ιστορία και την δομή του καθενός, με βάση πηγές και
πληροφοριακό υλικό που αποκόμισα από το διαδίκτυο, από βιβλία και από ομιλίες σημαντικών
προσώπων, και επιδιώκεται μία διδακτική προσέγγιση για το καθένα στο μάθημα της ...

[PDF] Η φύση και ο ρόλος των μοντέλων: Εξέλιξη των ιδεών των μαθητών Δημοτικού Σχολείου στο περιεχόμενο της Νανοεπιστήμης-Νανοτεχνολογίας

Ε Δαγρέ - 2017

... (Jones et al., 2013). Ο λόγος που η Νανοτεχνολογία δεν έχει έναν ορισμό που να είναι
σύμφωνος από όλη την ... νερό μέσω του φιλτραρίσματος. Ο λόγος που διαφέρουν τα
συμβατικά φίλτρα από το νανόφιλτρο LIFESAVER είναι ότι ...

[PDF] The Fragrance of the Rose: An Image of the Voice in Achilles Tatius

A Koenig - OralityandLiteracyintheAncientWorld, vol. 11, 2017

... and erotic sweetness (2.1. 2–3). Before reproducing the song, however, Clitophon
introduces it as follows: εἴ τις τὰς καμπὰς τῆς ᾠδῆς περιελὼν ψιλὸν ἔλεγεν ἁρμονίας
τὸν λόγον, οὕτως ἂν εἶχεν ὅ λόγος. 2.1. 2 If one removed ...

[PDF] Aristotle's Formal Language

M Mulhern

... A sentence (λόγος) is for Aristotle a significant utterance (φωνή σημαντική) whose parts have
independent meaning, but only the sentence as a whole makes any affirmation or denial (De
Int. 16b26-27). Every sentence is significant and signifies by convention. ...

[PDF] Comunicação e Lebenswelt, racionalidade e experiência estética: uma discussão interdisciplinar a partir de uma perspectiva pragmatista

MM Hanke - Galáxia. Revista do Programa de Pós-Graduação em …, 2017

... Enquanto a racionalidade tem sido um dos grandes temas da filosofia desde o início da
antiguidade grega – e o termo latim ratio traduz, em conjunto com oratio, o grego λόγος (lógos) –,
a atenção dada à comunicação e à experiência estética, como em Alfred Schütz e William ...

[HTML] Et l'homme tout entier devient dieu: La déification selon Origène à la lumière des nouvelles Homélies sur les Psaumes

L Perrone - Teología y vida, 2017

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