Estradiol Dimer Inhibits Tubulin Polymerization and Microtubule Dynamics

Publication date: Available online 24 May 2018
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Michal Jurášek, Markéta Černohorská, Jiří Řehulka, Vojtěch Spiwok, Tetyana Sulimenko, Eduarda Dráberová, Maria Darmostuk, Soňa Gurská, Ivo Frydrych, Renata Buriánová, Tomáš Ruml, Marián Hajdúch, Petr Bartůněk, Pavel Dráber, Petr Džubák, Pavel B. Drašar, David Sedlák
Microtubule dynamics is one of the major targets for new chemotherapeutic agents. This communication presents the synthesis and biological profiling of steroidal dimers based on estradiol, testosterone and pregnenolone bridged by 2,6-bis(azidomethyl)pyridine between D rings. The biological profiling revealed unique properties of the estradiol dimer including cytotoxic activities on a panel of 11 human cell lines, ability to arrest in the G2/M phase of the cell cycle accompanied with the attenuation of DNA/RNA synthesis. Thorough investigation precluded a genomic mechanism of action and revealed that the estradiol dimer acts at the cytoskeletal level by inhibiting tubulin polymerization. Further studies showed that estradiol dimer, but none of the other structurally related dimeric steroids, inhibited assembly of purified tubulin (IC50, 3.6 μM). The estradiol dimer was more potent than 2-methoxyestradiol, an endogenous metabolite of 17β-estradiol and well-studied microtubule polymerization inhibitor with antitumor effects that was evaluated in clinical trials. Further, it was equipotent to nocodazole (IC50, 1.5 μM), an antimitotic small molecule of natural origin. Both estradiol dimer and nocodazole completely and reversibly depolymerized microtubules in interphase U2OS cells at 2.5 μM concentration. At lower concentrations (50 nM), estradiol dimer decreased the microtubule dynamics and growth life-time and produced comparable effect to nocodazole on the microtubule dynamicity. In silico modeling predicted that estradiol dimer binds to the colchicine-binding site in the tubulin dimer. Finally, dimerization of the steroids abolished their ability to induce transactivation by estrogen receptor α and androgen receptors. Although other steroids were reported to interact with microtubules, the estradiol dimer represents a new structural type of steroid inhibitor of tubulin polymerization and microtubule dynamics, bearing antimitotic and cytotoxic activity in cancer cell lines.

Graphical abstract

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Steroid sulfatase inhibition success and limitation in breast cancer clinical assays: an underlying mechanism

Publication date: Available online 24 May 2018
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Xiaoye Sang, Hui Han, Donald Poirier, Sheng Xiang Lin
Steroid sulfatase is detectable in most hormone-dependent breast cancers. STX64, an STS inhibitor, induced tumor reduction in animal assay. Despite success in phase І clinical trial, the results of phase II trial were not that significant. Breast Cancer epithelial cells (MCF-7 and T47D) were treated with two STS inhibitors (STX64 and EM1913). Cell proliferation, cell cycle, and the concentrations of estradiol and 5α-dihydrotestosterone were measured to determine the endocrinological mechanism of sulfatase inhibition. Comparisons were made with inhibitions of reductive 17β-hydroxysteroid dehydrogenases (17β-HSDs). Proliferation studies showed that DNA synthesis in cancer cells was modestly decreased (approximately 20%), accompanied by an up to 6.5% in cells in the G0/G1 phase and cyclin D1 expression reduction. The concentrations of estradiol and 5α-dihydrotestosterone were decreased by 26% and 3% respectively. However, supplementation of 5α-dihydrotestosterone produced a significant increase (approximately 35.6%) in the anti-proliferative effect of sulfatase inhibition. This study has clarified sex-hormone control by sulfatase in BC, suggesting that the different roles of estradiol and 5α-dihydrotestosterone can lead to a reduction in the effect of sulfatase inhibition when compared with 17β-HSD7 inhibition. This suggests that combined treatment of sulfatase inhibitors with 17β-HSD inhibitors such as the type7 inhibitor could hold promise for hormone-dependent breast cancer.

Graphical abstract

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Trace element contaminants in mineral fertilizers used in Iran

Abstract

The application of mineral fertilizers which have contaminants of trace elements may impose concern regarding the entry and toxic accumulation of these elements in agro-ecosystems. In this study, 57 mineral fertilizers (nitrogen, potassium, phosphate, and compound fertilizers) distributed in Iran were analyzed for their contents of Cd, Co, Cr, Cu, Mn, Ni, Pb, Zn, and Fe. The results revealed that the contents of these trace elements varied considerably depending on the type of the element and the fertilizer. Among these elements, Fe displayed the highest average content, whereas Cd showed the lowest. Generally, the trace element contents in P-containing fertilizers were higher than those in nitrogen and potassium fertilizers. The mean values of trace elements (mg kg⁻¹) in P-containing fertilizers were 4.0 (Cd), 5.5 (Co), 35.7 (Cr), 24.4 (Cu), 272 (Mn), 14.3 (Ni), 6.0 (Pb), 226 (Zn), and 2532 (Fe). Comparing trace element contents to limit values set by the German Fertilizer Ordinance showed that the mean contents of potentially toxic trace elements, such as Cd and Pb, were lower than their limit values in all groups of fertilizers. On the other hand, while a number of fertilizers contained a high content of some essential trace elements, particularly Fe, they were not labeled as such.

https://ift.tt/2IKzl9N

The rational design of multiple molecular module-based assemblies for simultaneously improving rice yield and grain quality

Publication date: Available online 24 May 2018
Source:Journal of Genetics and Genomics
Author(s): Kun Wu, Xiaopeng Xu, Nan Zhong, Haixiang Huang, Jianping Yu, Yafeng Ye, Yuejin Wu, Xiangdong Fu




https://ift.tt/2GO1zdU

Control of flowering and inflorescence architecture in tomato by synergistic interactions between ALOG transcription factors

Publication date: Available online 25 May 2018
Source:Journal of Genetics and Genomics
Author(s): Xiaozhen Huang, Lingli Tang, Yuan Yu, Justin Dalrymple, Zachary B. Lippman, Cao Xu




https://ift.tt/2knx5qf

X chromosome gain is related to increased androgen receptor expression in male breast cancer

Abstract

X chromosome gain has been previously described in male breast cancer (MBC). Androgen receptor (AR) gene is located on X chromosome. The aim of this study was to investigate the role of the X chromosome gain in the development of MBC and its relation with AR gene copy number and expression.

The X chromosome status was assessed in 66 cases of male invasive and in situ duct breast carcinoma, in 34 cases of gynecomastia associated with cancer, and in 11 cases of tumor-free gynecomastia. Cases were tested by fluorescence in situ hybridization (FISH) to assess the X chromosome status and AR amplification. AR expression was studied by immunohistochemistry (IHC). In addition, AR methylation status was assessed.

X chromosome gain was observed in 74.7% of invasive duct carcinoma, in 20.6% of in situ duct carcinoma, and in 14.6% of gynecomastia when associated with cancer, while all cases of tumor-free gynecomastia showed wild X chromosome asset. AR gene copy number when increased paralleled the number of X chromosomes. AR IHC expression was observed in 100% of MBC tested. AR gene methylation status revealed low level or absence of methylation.

These data suggest that X chromosome can play a role in the neoplastic transformation of male breast epithelium. X chromosome gain is paralleled by AR gene polysomy. Polysomic AR genes show low methylation levels and high AR protein expression on IHC. These data should be taken into consideration for MBC treatment planning.

https://ift.tt/2xabsCZ

Improved synaptic and cognitive function in aged 3 × Tg-AD mice with reduced amyloid-β after immunotherapy with a novel recombinant 6Aβ15-TF chimeric vaccine

Publication date: Available online 24 May 2018
Source:Clinical Immunology
Author(s): Yun-Zhou Yu, Qing-Li Li, Hai-Chao Wang, Si Liu, Xiao-Bin Pang, Qing Xu, Xiao-Wei Zhou, Pei-Tang Huang
Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder impairing memory and cognition. In this study, we describe the immunogenicity and protective efficacy of the novel recombinant 6Aβ15-TF chimeric antigen as a subunit protein vaccine for AD. Recombinant 6Aβ15-TF chimeric vaccine induced strong Aβ-specific humoral immune responses without Aβ-specific T cell immunity in C57/BL6 and 3 × Tg-AD mice at different ages. As an early immunotherapy model for AD, this vaccine induced high titers of long-lasting anti-Aβ42 antibodies in aged 3 × Tg-AD mice, which led to improve behavioral performance and markedly reduced the levels of insoluble and soluble Aβ and Aβ oligomers. In agreement with these findings, immunotherapy with 6Aβ15-TF prevented the Aβ-induced decrease of presynaptic and postsynaptic proteins in aged 3 × Tg-AD mice. Our results suggest that this novel and highly immunogenic recombinant 6Aβ15-TF chimeric vaccine provides neuroprotection in AD mice and can be considered an effective AD candidate vaccine.

Graphical abstract

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Improved synaptic and cognitive function in aged 3 × Tg-AD mice with reduced amyloid-β after immunotherapy with a novel recombinant 6Aβ15-TF chimeric vaccine

Publication date: Available online 24 May 2018
Source:Clinical Immunology
Author(s): Yun-Zhou Yu, Qing-Li Li, Hai-Chao Wang, Si Liu, Xiao-Bin Pang, Qing Xu, Xiao-Wei Zhou, Pei-Tang Huang
Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder impairing memory and cognition. In this study, we describe the immunogenicity and protective efficacy of the novel recombinant 6Aβ15-TF chimeric antigen as a subunit protein vaccine for AD. Recombinant 6Aβ15-TF chimeric vaccine induced strong Aβ-specific humoral immune responses without Aβ-specific T cell immunity in C57/BL6 and 3 × Tg-AD mice at different ages. As an early immunotherapy model for AD, this vaccine induced high titers of long-lasting anti-Aβ42 antibodies in aged 3 × Tg-AD mice, which led to improve behavioral performance and markedly reduced the levels of insoluble and soluble Aβ and Aβ oligomers. In agreement with these findings, immunotherapy with 6Aβ15-TF prevented the Aβ-induced decrease of presynaptic and postsynaptic proteins in aged 3 × Tg-AD mice. Our results suggest that this novel and highly immunogenic recombinant 6Aβ15-TF chimeric vaccine provides neuroprotection in AD mice and can be considered an effective AD candidate vaccine.

Graphical abstract

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Role of DOTATATE‐PET/CT in preoperative assessment of phaeochromocytoma and paragangliomas

Clinical Endocrinology, EarlyView.


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A Role for Hypocretin/Orexin in Metabolic and Sleep Abnormalities in a Mouse Model of Non-metastatic Breast Cancer

Publication date: Available online 24 May 2018
Source:Cell Metabolism
Author(s): Jeremy C. Borniger, William H. Walker II, Surbhi, Kathryn M. Emmer, Ning Zhang, Abigail A. Zalenski, Stevie L. Muscarella, Julie A. Fitzgerald, Alexandra N. Smith, Cornelius J. Braam, Tial TinKai, Ulysses J. Magalang, Maryam B. Lustberg, Randy J. Nelson, A. Courtney DeVries
We investigated relationships among immune, metabolic, and sleep abnormalities in mice with non-metastatic mammary cancer. Tumor-bearing mice displayed interleukin-6 (IL-6)-mediated peripheral inflammation, coincident with altered hepatic glucose processing and sleep. Tumor-bearing mice were hyperphagic, had reduced serum leptin concentrations, and enhanced sensitivity to exogenous ghrelin. We tested whether these phenotypes were driven by inflammation using neutralizing monoclonal antibodies against IL-6; despite the reduction in IL-6 signaling, metabolic and sleep abnormalities persisted. We next investigated neural populations coupling metabolism and sleep, and observed altered activity within lateral-hypothalamic hypocretin/orexin (HO) neurons. We used a dual HO-receptor antagonist to test whether increased HO signaling was causing metabolic abnormalities. This approach rescued metabolic abnormalities and enhanced sleep quality in tumor-bearing mice. Peripheral sympathetic denervation prevented tumor-induced increases in serum glucose. Our results link metabolic and sleep abnormalities via the HO system, and provide evidence that central neuromodulators contribute to tumor-induced changes in metabolism.

Graphical abstract

Teaser

Cancer patients with metabolic and sleep dysfunction have worse prognoses. Using a mouse model of breast cancer, Borniger, Walker II, et al. provide evidence that tumors deregulate satiety hormones, which likely alters the activity of hypocretin/orexin neurons. Aberrant activity in these cells impairs sleep and alters glucose metabolism via the sympathetic nervous system.


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Aerobic Glycolysis Controls Myeloid-Derived Suppressor Cells and Tumor Immunity via a Specific CEBPB Isoform in Triple-Negative Breast Cancer

Publication date: Available online 24 May 2018
Source:Cell Metabolism
Author(s): Wei Li, Takashi Tanikawa, Ilona Kryczek, Houjun Xia, Gaopeng Li, Ke Wu, Shuang Wei, Lili Zhao, Linda Vatan, Bo Wen, Pan Shu, Duxin Sun, Celina Kleer, Max Wicha, Michael Sabel, Kaixiong Tao, Guobin Wang, Weiping Zou
Myeloid-derived suppressor cells (MDSCs) inhibit anti-tumor immunity. Aerobic glycolysis is a hallmark of cancer. However, the link between MDSCs and glycolysis is unknown in patients with triple-negative breast cancer (TNBC). Here, we detect abundant glycolytic activities in human TNBC. In two TNBC mouse models, 4T1 and Py8119, glycolysis restriction inhibits tumor granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF) expression and reduces MDSCs. These are accompanied with enhanced T cell immunity, reduced tumor growth and metastasis, and prolonged mouse survival. Mechanistically, glycolysis restriction represses the expression of a specific CCAAT/enhancer-binding protein beta (CEBPB) isoform, liver-enriched activator protein (LAP), via the AMP-activated protein kinase (AMPK)-ULK1 and autophagy pathways, whereas LAP controls G-CSF and GM-CSF expression to support MDSC development. Glycolytic signatures that include lactate dehydrogenase A correlate with high MDSCs and low T cells, and are associated with poor human TNBC outcome. Collectively, tumor glycolysis orchestrates a molecular network of the AMPK-ULK1, autophagy, and CEBPB pathways to affect MDSCs and maintain tumor immunosuppression.

Graphical abstract

Teaser

Tumor-derived myeloid-derived suppressor cells (MDSCs) are critical tumor immunosuppression components. Li et al. show that the high glycolytic rate in triple-negative breast cancer cells is associated with MDSC promotion through an AMPK-ULK1 and autophagy pathway. Glycolysis restriction inhibits tumor G-CSF and GM-CSF and consequently MDSC development.


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Substantial Metabolic Activity of Human Brown Adipose Tissue during Warm Conditions and Cold-Induced Lipolysis of Local Triglycerides

Publication date: Available online 24 May 2018
Source:Cell Metabolism
Author(s): Graeme Weir, Lynne E. Ramage, Murat Akyol, Jonathan K. Rhodes, Catriona J. Kyle, Alison M. Fletcher, Thomas H. Craven, Sonia J. Wakelin, Amanda J. Drake, Maria-Lena Gregoriades, Ceri Ashton, Nick Weir, Edwin J.R. van Beek, Fredrik Karpe, Brian R. Walker, Roland H. Stimson
Current understanding of in vivo human brown adipose tissue (BAT) physiology is limited by a reliance on positron emission tomography (PET)/computed tomography (CT) scanning, which has measured exogenous glucose and fatty acid uptake but not quantified endogenous substrate utilization by BAT. Six lean, healthy men underwent ¹⁸fluorodeoxyglucose-PET/CT scanning to localize BAT so microdialysis catheters could be inserted in supraclavicular BAT under CT guidance and in abdominal subcutaneous white adipose tissue (WAT). Arterial and dialysate samples were collected during warm (∼25°C) and cold exposure (∼17°C), and blood flow was measured by ¹³³xenon washout. During warm conditions, there was increased glucose uptake and lactate release and decreased glycerol release by BAT compared with WAT. Cold exposure increased blood flow, glycerol release, and glucose and glutamate uptake only by BAT. This novel use of microdialysis reveals that human BAT is metabolically active during warm conditions. BAT activation substantially increases local lipolysis but also utilization of other substrates such as glutamate.

Graphical abstract

Teaser

Weir et al., using microdialysis, have shown that human brown adipose tissue (BAT) is metabolically active in warm conditions, with higher glucose uptake and lactate release than white AT. Cold activation increased glucose and glutamate uptake and glycerol release by BAT, quantifying substrate utilization and hydrolysis of BAT triglycerides during thermogenesis.


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Neurosteroid pregnenolone sulfate, alone, and as augmentation of lurasidone or tandospirone, rescues phencyclidine-induced deficits in cognitive function and social interaction

Publication date: 17 September 2018
Source:Behavioural Brain Research, Volume 350
Author(s): L. Rajagopal, D. Soni, H.Y. Meltzer
BackgroundPregnenolone sulfate (PregS), an endogenous neurosteroid, which negatively and positively modulates gamma amino butyric acid subunit A (GABAA) and N-methyl D-aspartate (NMDA) receptors (R) respectively, among other potential neuroplastic changes on synaptic processes, has shown some beneficial effects on treating cognitive impairment associated with schizophrenia (CIAS) and negative symptoms. Lurasidone (Lur), an atypical antipsychotic drug (AAPD), and tandospirone (Tan), a 5-HT1A R partial agonist, have also been reported to improve cognitive or negative symptoms, or both, in some schizophrenia patients.MethodsWe tested whether PregS, by itself, and in combination with Lur or Tan could rescue persistent deficits produced by subchronic treatment with the NMDAR antagonist, phencyclidine (PCP)-in episodic memory, executive functioning, and social behavior, using novel object recognition (NOR), operant reversal learning (ORL), and social interaction (SI) tasks, in male C57BL/6 J mice.ResultsPregS (10, but not 3 mg/kg) significantly rescued subchronic PCP-induced NOR and SI deficits. Co-administration of sub-effective doses (SEDs) of PregS (3 mg/kg) + Lur (0.1 mg/kg) or Tan (0.03 mg/kg) rescued scPCP-induced NOR and SI deficits. Further, PregS (30, but not 10 mg/kg) rescued PCP-induced ORL deficit, as did the combination of SED PregS (10 mg/kg) +SED Lur (1 mg/kg) or Tan (1 mg/kg).ConclusionPregS was effective alone and as adjunctive treatment for treating two types of cognitive impairments and negative symptoms in this schizophrenia model. Further study of the mechanisms by which PregS alone and in combination with AAPDs and 5-HT1A R partial agonists, rescues the deficits in cognition and SI in this preclinical model is indicated.



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Predicted reach consequences drive time course of tactile suppression

Publication date: 17 September 2018
Source:Behavioural Brain Research, Volume 350
Author(s): Lindsey E. Fraser, Katja Fiehler
Sensitivity to touch is reduced during movement; this tactile suppression is likely the result of a mechanism that suppresses self-generated movement consequences. We sought to determine whether tactile suppression is modulated by naturally evoked changes in movement speed driven by task precision demands (Exp.1), and by changes in predicted movement consequences (Exp.2). We measured suppression by comparing detection thresholds for a vibration applied to the finger during reach and at rest. In Experiment 1 we varied reach target size to create a speed-accuracy tradeoff, where participants decelerated more to smaller targets to accurately hit them. We theorized that the reduction in late-reach speed associated with higher precision demands might lead to a reduction in late-reach suppression, consistent with the literature showing a positive relationship between speed and suppression. Contrary to our hypothesis, we found suppression increased towards the end of the reach in all conditions, despite a significant decrease in reaching speed. We postulated this might be a de-emphasizing of the predicted tactile feedback associated with tapping the target. To test this, in Experiment 2 we paired a vibration consequence with a target of a certain colour. We found an increase in late-reach suppression for this target compared to a target of another colour with no associated consequence. Our results indicate that tactile suppression is temporally sensitive and increases as predicted consequences become more likely. We propose the positive correlation between movement speed and suppression previously reported may be driven by the predicted somatosensory consequences associated with increased movement speed.



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Pretreated animal and human waste as a substantial nutrient source for cultivation of microalgae for biodiesel production

Abstract

The use of human and animal wastes for fertilization of aquaculture ponds has been practiced for thousands of years. In the present work, we have used the excreta (human urine, poultry waste, cow dung, and urine) as a nutrient source for the cultivation of Chlorella singularis, Micractinium pusillum, and Chlorella sorokiniana strains of microalgae. Different solid wastes were treated with 60 mM H₂SO₄ for the extraction of nutrients. After treatment, the supernatant of different solid wastes and liquid waste were diluted 5, 10, 15, and 20% to be used as a media for the cultivation of microalgae. Chlorella sorokiniana was able to grow in all concentration of excreta media. The maximum growth rate 140 ± 3.1 mg/L/day and lipid production (45.5 ± 2.3 mg/L/day) was obtained in 20% poultry. Among the different excreta media used for cultivation of microalgae, poultry media displayed the best results and thus, should be used for large scale cultivation of microalgae.

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Collision of Expanding Actin Caps with Actomyosin Borders for Cortical Bending and Mitotic Rounding in a Syncytium

Publication date: Available online 24 May 2018
Source:Developmental Cell
Author(s): Yixie Zhang, Jessica C. Yu, Tao Jiang, Rodrigo Fernandez-Gonzalez, Tony J.C. Harris
The early Drosophila embryo is a large syncytial cell that compartmentalizes mitotic spindles with furrows. Before furrow ingression, an Arp2/3 actin cap forms above each nucleus and is encircled by actomyosin. We investigated how these networks transform a flat cortex into a honeycomb-like compartmental array. The growing caps circularize and ingress upon meeting their actomyosin borders, which become the furrow base. Genetic perturbations indicate that the caps physically displace their borders and, reciprocally, that the borders resist and circularize their caps. These interactions create an actomyosin cortex arrayed with circular caps. The Rac-GEF Sponge, Rac-GTP, Arp3, and actin coat the caps as a growing material that can drive cortical bending for initial furrow ingression. Additionally, laser ablations indicate that actomyosin contraction squeezes the cytoplasm, producing counterforces that swell the caps. Thus, Arp2/3 caps form clearances of the actomyosin cortex and control buckling and swelling of these clearances for metaphase compartmentalization.

Graphical abstract

Teaser

For mitosis in the syncytial Drosophila embryo, each nucleus organizes a surface Arp2/3 actin cap encircled by an actomyosin border. Zhang et al. show that the assembling caps and borders engage each other physically to pattern the syncytial cortex in 2D and to generate compartments for mitotic spindles in 3D.


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Distant Insulin Signaling Regulates Vertebrate Pigmentation through the Sheddase Bace2

Publication date: Available online 24 May 2018
Source:Developmental Cell
Author(s): Yan M. Zhang, Milena A. Zimmer, Talia Guardia, Scott J. Callahan, Chandrani Mondal, Julie Di Martino, Toshimitsu Takagi, Myles Fennell, Ralph Garippa, Nathaniel R. Campbell, Jose Javier Bravo-Cordero, Richard M. White
Patterning of vertebrate melanophores is essential for mate selection and protection from UV-induced damage. Patterning can be influenced by circulating long-range factors, such as hormones, but it is unclear how their activity is controlled in recipient cells to prevent excesses in cell number and migration. The zebrafish wanderlust mutant harbors a mutation in the sheddase bace2 and exhibits hyperdendritic and hyperproliferative melanophores that localize to aberrant sites. We performed a chemical screen to identify suppressors of the wanderlust phenotype and found that inhibition of insulin/PI3Kγ/mTOR signaling rescues the defect. In normal physiology, Bace2 cleaves the insulin receptor, whereas its loss results in hyperactive insulin/PI3K/mTOR signaling. Insulin B, an isoform enriched in the head, drives the melanophore defect. These results suggest that insulin signaling is negatively regulated by melanophore-specific expression of a sheddase, highlighting how long-distance factors can be regulated in a cell-type-specific manner.

Graphical abstract

Teaser

Zhang et al. demonstrate that insulin signaling affects pigment patterning in zebrafish. They show that the local response to insulin signaling is regulated by Bace2, a melanocyte-enriched sheddase that cleaves the insulin receptor.


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Combination of 4-hydroperoxy cyclophosphamide and methotrexate inhibits IL-6/sIL-6R-induced RANKL expression in fibroblast-like synoviocytes via suppression of the JAK2/STAT3 and p38MAPK signaling pathway

Publication date: August 2018
Source:International Immunopharmacology, Volume 61
Author(s): Hong-Qing Niu, Wen-Peng Zhao, Xiang-Cong Zhao, Jing Luo, Kai-Li Qin, Kai-Lin Chen, Xiao-Feng Li
Although conventional combination therapy is effective for most patients with rheumatoid arthritis (RA), many still do not respond to current therapies. Therefore, novel combination regimens that better target cellular processes involved in RA pathogenesis are required. Preliminary studies have demonstrated the beneficial effects of a combination of cyclophosphamide (CTX) and methotrexate (MTX) in models of RA. Using western blotting, real-time polymerase chain reaction, enzyme-linked immunosorbent assays, and immunofluorescent staining, we demonstrated that the combination of 4-hydroperoxy CTX (4-H-CTX) and MTX inhibited the expression of receptor activator of nuclear factor-κB ligand (RANKL) in fibroblast-like synoviocytes (FLS) treated with the interleukin (IL)-6/soluble IL-6 receptor (sIL-6R) complex. To elucidate the mechanisms underlying this effect, we treated RA-FLS with the JAK2/STAT3 inhibitor AG490 or p38MAPK inhibitor SB203580. The results showed that IL-6/sIL-6R-induced RANKL upregulation required phosphorylation-mediated activation of STAT3 and p38 signaling, and that 4-H-CTX and/or MTX inhibited RANKL expression in IL-6/sIL-6R-stimulated FLS by suppressing JAK2/STAT3 and p38MAPK signaling. This study demonstrated for the first time the inhibitory effects of 4-H-CTX and MTX on RANKL expression in IL-6/sIL-6R-stimulated FLS via suppression of STAT3 and p38MAPK phosphorylation. These results identify promising therapeutic agents that might have clinical applications in patients with RA who are at high risk of bone erosion or do not respond well to conventional therapy.



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Combination of TLR8 and TLR4 agonists reduces the degrading effects of nicotine on DC-NK mediated effector T cell generation

Publication date: August 2018
Source:International Immunopharmacology, Volume 61
Author(s): Mahyar Nouri-Shirazi, Saba Tamjidi, Erika Nourishirazi, Elisabeth Guinet
The magnitude of immune responses to vaccination is a critical factor in determining protection from disease. It is known that cigarette smoke dampens the immune system and increases the risk of vaccine-preventable diseases. We reported that nicotine, the immunosuppressive component of cigarette smoke, disrupts the differentiation and functional properties of DC, which are pivotal in the initiation of immune response to vaccines. We also reported that TLR agonists act in synergy and boost DC maturation, DC-NK crosstalk and ultimately naïve T cell polarization into effector Th1 and Tc1 cells. Here, we investigated whether the combination of TLR agonists could diminish the degrading effects of nicotine on DC-NK mediated effector T cell generation.We found that none of TLR agonists, single or combined, were able to diminish completely the adverse effects of nicotine on DC. However, TLR3, TLR4, and TLR8 agonists acted as the most effective adjuvants to increase the expression levels of antigen-presenting, costimulatory molecules and production of cytokines by nicotine-exposed DC (nicDC). When combined, TLR3 + 8 and TLR4 + 8 synergistically optimized nicDC maturation and IFN-γ secretion from nicotine-exposed NK (nicNK) during co-cultures. Interestingly, in contrast to DC-NK-T, co-cultures of nicDC-nicNK-T treated with TLR3 + 8 or TLR4 + 8 agonists produced a similar frequency of effector memory Th1 and Tc1 cells. However, the effector cells from TLR4 + 8 followed by TLR3 + 8 treated nicDC-nicNK-T co-cultures produced significantly more IFN-γ when compared with aluminum salt treated co-culture. Our data suggest that addition of appropriate TLR agonists to vaccine formulation could potentially augment the immune response to vaccination in smokers.



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Editorial Board

Publication date: June 2018
Source:International Immunopharmacology, Volume 59





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Nurses Wanted-Almost Everywhere.

Author: Kennedy, Maureen Shawn MA, RN, FAAN

Page: 7

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Nutrition and Wound Healing.

Author: Bemak, Lani RN

Page: 13

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Ostomy Care.

Author: Dean, Roberta MSN, RN

Page: 13

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Simulation Training.

Author: M., Melissa via Facebook

Page: 13

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Relaxing Food Restrictions on Women in Labor.

Author: O., Jeena via ajnoffthecharts.com

Page: 13

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Colorado 'Alternative to Opioids' Pilot Project Exceeds Goals.

Author: Stockwell, Serena

Page: 14

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How Media Influences Perceptions of Suicide.

Author: Sofer, Dalia

Page: 15

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NewsCAP: Only 50% of teens with depression are diagnosed before they reach adulthood.

Author:

Page: 15

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NewsCAP: E-Cigarettes pose more harm than good as a tool to reduce smoking.

Author:

Page: 16

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Unsafe Firearm Storage in Homes with Children.

Author: Mechcatie, Elizabeth MA, BSN

Page: 17

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NewsCAP: APHA unlocks free public access to articles on firearm issues and research.

Author:

Page: 17

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Making Hospitals Less Threatening to Patients with Dementia.

Author: Sofer, Dalia

Page: 18-19

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Trump Administration Opens Division of Conscience and Religious Freedom.

Author: Kritz, Fran

Page: 20-21

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AJN On the Cover.

Author: Szulecki, Diane Editor

Page: 22

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AJN On the Web.

Author:

Page: 22

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Therapeutic perspectives for brain metastases in non-oncogene addicted non-small cell lung cancer (NSCLC): towards a less dismal future?

Publication date: Available online 24 May 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Frega Stefano, Bonanno Laura, Guarneri Valentina, Conte Pier Franco, Pasello Giulia
Risk of brain metastases (BM) affects a remarkable number of non-small cell lung cancer (NSCLC) patients, impacting on their quality of life (QoL) and prognosis.While tyrosine-kinase inhibitors (TKIs) showed interesting intracranial control rates in oncogene-addicted NSCLC, BM still represents an unmet need for the counterpart without driver gene mutations. For these patients, new treatment options include anti-angiogenic drugs and immune-checkpoint inhibitors, possibly combined with standard chemotherapy, even though the benefit on BM has not been clearly defined. A multidisciplinary team including neurosurgeons, medical and radiation oncologists is needed in order to integrate systemic and loco-regional strategies at the right time point. Ad-hoc designed clinical trials are slowly emerging for previously treated patients with uncontrolled BM.The aim of this review is to offer a detailed and updated picture of possible approaches for non oncogene-addicted NSCLC patients having BM, in order to support clinicians in their daily practice.



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Synthesis and Biological Evaluation of Irreversible EGFR Tyrosine Kinase Inhibitors Containing Pyrido[3,4-d]pyrimidine Scaffold

Publication date: Available online 24 May 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Hao Zhang, Jin Wang, Hong-Yi Zhao, Xue-Yan Yang, Hao Lei, Minhang Xin, Yong-Xiao Cao, San-Qi Zhang
In the present study, a new class of compounds containing pyrido[3,4-d]pyrimidine scaffold with an acrylamide moiety was designed as irreversible EGFR-TKIs to overcome acquired EGFR-T790M resistance. The most promising compound 25h inhibited HCC827 and H1975 cells growth with the IC50 values of 0.025 μM and 0.49 μM, respectively. Meanwhile, 25h displayed potent inhibitory activity against the EGFR^L858R (IC50 = 1.7 nM) and EGFR^L858R/T790M (IC50 = 23.3 nM). 25h could suppress EGFR phosphorylation in HCC827 and H1975 cell lines and significantly induce the apoptosis of HCC827 cells. Additionally, compound 25h could remarkably inhibit cancer growth in established HCC827 xenograft mouse model at 50 mg/kg in vivo. These results indicated that the 2,4-disubstituted 6-(5-substituted pyridin-2-amino)pyrido[3,4-d]pyrimidine derivatives can serve as effective EGFR inhibitors and potent anticancer agents.

Graphical abstract

https://ift.tt/2KUk82C

Access to new highly potent antileukemia, antiviral and antimalarial agents via hybridization of natural products (homo)egonol, thymoquinone and artemisinin

Publication date: Available online 24 May 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Aysun Çapcı Karagöz, Christoph Reiter, Ean-Jeong Seo, Lisa Gruber, Friedrich Hahn, Maria Leidenberger, Volker Klein, Frank Hampel, Oliver Friedrich, Manfred Marschall, Barbara Kappes, Thomas Efferth, Svetlana B. Tsogoeva
Hybridization of natural products has high potential to further improve their activities and may produce synergistic effects between linked pharmacophores. Here we report synthesis of nine new hybrids of natural products egonol, homoegonol, thymoquinone and artemisinin and evaluation of their activities against P. falciparum 3D7 parasites, human cytomegalovirus, sensitive and multidrug-resistant human leukemia cells. Most of the new hybrids exceed their parent compounds in antimalarial, antiviral and antileukemia activities and in some cases show higher in vitro efficacy than clinically used reference drugs chloroquine, ganciclovir and doxorubicin. Combined, our findings stress the high potency of these hybrids and encourages further use of the hybridization concept in applied pharmacological research.

Graphical abstract

https://ift.tt/2s6jCr4

Elucidating the inhibition of peptidoglycan biosynthesis in Staphylococcus aureus by albocycline, a macrolactone isolated from Streptomyces maizeus

Publication date: Available online 24 May 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Hai Liang, Guangfeng Zhou, Yunhui Ge, Elizabeth A. D'Ambrosio, Tess M. Eidem, Catlyn Blanchard, Cindy Shehatou, Vijay K. Chatare, Paul M. Dunman, Ann M. Valentine, Vincent A. Voelz, Catherine L. Grimes, Rodrigo B. Andrade
Antibiotic resistance is a serious threat to global public health, and methicillin-resistant Staphylococcus aureus (MRSA) is a poignant example. The macrolactone natural product albocycline, derived from various Streptomyces strains, was recently identified as a promising antibiotic candidate for the treatment of both MRSA and vancomycin-resistant S. aureus (VRSA), which is another clinically relevant and antibiotic resistant strain. Moreover, it was hypothesized that albocycline's antimicrobial activity was derived from the inhibition of peptidoglycan (i.e., bacterial cell wall) biosynthesis. Herein, preliminary mechanistic studies are performed to test the hypothesis that albocycline inhibits MurA, the enzyme that catalyzes the first step of peptidoglycan biosynthesis, using a combination of biological assays alongside molecular modeling and simulation studies. Computational modeling suggests albocycline exists as two conformations in solution, and computational docking of these conformations to an ensemble of simulated receptor structures correctly predicted preferential binding to S. aureus MurA—the enzyme that catalyzes the first step of peptidoglycan biosynthesis—over Escherichia coli (E. coli) MurA. Albocycline isolated from the producing organism (Streptomyces maizeus) weakly inhibited S. aureus MurA (IC50 of 480 μM) but did not inhibit E. coli MurA. The antimicrobial activity of albocycline against resistant S. aureus strains was superior to that of vancomycin, preferentially inhibiting Gram-positive organisms. Albocycline was not toxic to human HepG2 cells in MTT assays. While these studies demonstrate that albocycline is a promising lead candidate against resistant S. aureus, taken together they suggest that MurA is not the primary target, and further work is necessary to identify the major biological target.

Graphical abstract

https://ift.tt/2KSh8Uh

Experimental analysis of performance and emission on DI diesel engine fueled with diesel-palm kernel methyl ester-triacetin blends: a Taguchi fuzzy-based optimization

Abstract

The energy situation and the concerns about global warming nowadays have ignited research interest in non-conventional and alternative fuel resources to decrease the emission and the continuous dependency on fossil fuels, particularly for various sectors like power generation, transportation, and agriculture. In the present work, the research is focused on evaluating the performance, emission characteristics, and combustion of biodiesel such as palm kernel methyl ester with the addition of diesel additive "triacetin" in it. A timed manifold injection (TMI) system was taken up to examine the influence of durations of several blends induced on the emission and performance characteristics as compared to normal diesel operation. This experimental study shows better performance and releases less emission as compared with mineral diesel and in turn, indicates that high performance and low emission is promising in PKME-triacetin fuel operation. This analysis also attempts to describe the application of the fuzzy logic-based Taguchi analysis to optimize the emission and performance parameters.

https://ift.tt/2IOn685

From fish embryos to human patients: lymphangiogenesis in development and disease

Cristina Mauri | Guangxia Wang | Stefan Schulte-Merker

https://ift.tt/2LrREhq

Total sediment transport from an urbanizing watershed in the upper Yellow River, China

Abstract

For many event-based, high-sediment yield rivers draining arid zones, where erosion activities in the watershed and fluvial erosion in the stream channel are nearly equally important in sediment transport, determination of fluvial sediment dynamics are of great importance in establishing reliable strategies to manage environmental changes in watershed scale. Wash load rating curve indicating watershed characteristic changes and Ackers and White's bed load function (wash load excluded) used for determining bed load transport dynamics are distinguished for the first time to recognize the true sediment transport mode in the lower Huangshui River, which is the largest tributary of the upper Yellow River, contributing a lot to the wash load of the Inner Mongolia desert reach of the Yellow River and causing complicated water-sediment response. Based on the continuous and detailed hydrological data monitored at the Minhe gauge station, our results indicated that the sediment transport regime has altered since the 1980s in response to the eco-environmental changes mainly due to urbanization, with suspended sediment concentration (SSC) decreased by 50% on average compared with the natural state (1950–1980). The combined use of wash load rating curve and theoretical bed load function derived an estimate of total sediment transport due to comprehensive ecological management since the 2000s to be 3.43 × 107 t for the lower Huangshui River, among which the total bed load is 1.40 × 107 t, and the wash load is 2.03 × 107 t. The transport ratio of wash load to total bed load is 1.45:1.

https://ift.tt/2GMZ9fx

Sleeve Gastrectomy: Metabolic Surgical Procedure of Choice?

Publication date: Available online 24 May 2018
Source:Trends in Endocrinology & Metabolism
Author(s): Ali Aminian
Roux-en-Y gastric bypass and sleeve gastrectomy (SG) are fairly similar in terms of their long-term effects on excess body weight, cardiometabolic risk factors, and quality of life. However, SG appears to be a safer procedure with distinct metabolic advantages, which can be even better than gastric bypass in some aspects.



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The potential role of pharmacogenomics and biotransformation in hypersensitivity reactions to paracetamol

Purpose of review The aim of the present review is to discuss recent advances supporting a role of paracetamol metabolism in hypersensitivity reactions to this drug. Recent findings Recent developments in the identification of novel paracetamol metabolites, as well as in allele frequencies and functional effects of genetic variation leading to the bioavailablity of reactive paracetamol metabolites, have led to the identification of potential pharmacogenomic and metabolomic targets in studies seeking mechanisms involved in hypersensitivity reactions caused by this drug. Particularly relevant are identification of araquidonate metabolites, identification of specific-binding sequences for reactive paracetamol metabolite-protein adducts, and studies on the frequencies and the functional impact of duplication or multiduplication of genes involved in the formation of reactive metabolites, as well as complete gene deletion or deleterious mutations in genes involved in the detoxification of paracetamol reactive metabolites. In addition, recent evidence points to sex, ethnic origin and age as relevant factors in the production of reactive paracetamol metabolites. Summary High inter-individual variability in the production of reactive paracetamol metabolites exists, and factors leading to increased bioavailability of reactive paracetamol metabolites are being uncovered. Additional research is required to link these factors to paracetamol-induced hypersensitivity reactions. Correspondence to José A.G. Agúndez, University Institute of Molecular Pathology Biomarkers, UEx. ARADyAL Instituto de Salud Carlos III, Cáceres, Spain. E-mail: jagundez@unex.es Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2knGn5J

Global development of the studies focused on antibiotics in aquatic systems from 1945 to 2017

Abstract

Antibiotics are used to fight diseases in humans and farm animals. Their residues, however, can enter aquatic environments and affect the resistance of non-target microbial strains, and the prevalence of antibiotic resistance genes (ARGs) potentially poses negative impacts on human health. In order to better understand how the studies of antibiotics have been conducted, we analyzed the publications on antibiotics in aquatic systems for the period of 1945–2017. We applied a bibliometric analysis method by coupling cluster analysis and network analysis. Results indicated that early research on antibiotics in water was mostly performed in America and Europe, while, in recent years, publications for the same subject were dominated by China and the USA. The majority of the articles were published in journal Chemosphere and the most representative subject categories of the seven sections were "Environmental science and ecology," "Chemistry," "Engineering," "Biochemistry and molecular biology," "Water resources," "Agriculture," and "Pharmacology and pharmacy." The most studied class of antibiotics was tetracyclines in wastewater. Antibiotic resistance, ARGs, Escherichia coli, and some mechanistic studies such as adsorption, toxicity, degradation, and kinetics were common topics in this field. ARGs present a major public health concern and much attention should be directed at the problems with antibiotics in the future studies of water.

https://ift.tt/2Lp4nS5

Editorial Board and Contents

Publication date: June 2018
Source:Trends in Immunology, Volume 39, Issue 6





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Perioperative high-dose-rate brachytherapy in locally advanced and recurrent gynecological cancer: Final results of a Phase II trial

Publication date: Available online 24 May 2018
Source:Brachytherapy
Author(s): Rafael Martínez-Monge, Germán Valtueña Peydró, Mauricio Cambeiro, José Manuel Aramendía, Marta Gimeno, Marta Santisteban, Fernando Lecanda, Jose Angel Minguez, Juan L. Alcázar, Matías Jurado
PurposeTo determine the long-term results of a Phase II trial of perioperative high-dose-rate brachytherapy (PHDRB) in primary advanced or recurrent gynecological cancer.Methods and MaterialsFifty patients with locally advanced and recurrent gynecological cancer suitable for salvage surgery were included. Unirradiated patients (n = 25) received preoperative chemoradiation followed by surgery and PHDRB (16–24 Gy). Previously irradiated patients (n = 25) received surgery and PHDRB alone (32–40 Gy).ResultsMedian followup was 11.5 years. Eight unirradiated patients (32%) developed Grade ≥3 toxic events including two fatal events. Local and locoregional control rates at 16 years were 87.3% and 78.9%, respectively. Sixteen-year disease-free and overall survival rates were 42.9% and 46.4%, respectively. Ten previously irradiated patients (40.0%) developed Grade ≥3 adverse events, including four fatal events. Local and locoregional control rates at 14 years were 59.6% and 42.6%, respectively. Fourteen-year disease-free and overall survival rates were 16.0% and 19.2%, respectively.ConclusionsPHDRB allows effective salvage of a subset of unfavorable gynecological tumors with high-risk surgical margins. Toxicity was unacceptable at the initial dose levels but deescalation resulted in the absence of severe toxicity without a negative impact on locoregional control. A substantial percentage of patients remain alive and controlled at >10 years including a few previously irradiated cases with positive margins.



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Is alexithymia characterised by impaired interoception? Further evidence, the importance of control variables, and the problems with the Heartbeat Counting Task

Publication date: Available online 24 May 2018
Source:Biological Psychology
Author(s): Jennifer Murphy, Rebecca Brewer, Hannah Hobson, Caroline Catmur, Geoffrey Bird
Interoception, the perception of one's internal state, is commonly quantified using the heartbeat counting task (HCT) – which is thought to be a measure of cardiac interoceptive sensitivity (accuracy). Interoceptive sensitivity has been associated with a number of clinical traits and aspects of higher order cognition, including emotion processing and decision-making. It has been proposed that alexithymia (difficulties identifying and describing one's own emotions) is associated with impaired interoceptive sensitivity, but new research questions this association. Problematically, much evidence attesting to the absence of this association has been conducted using the HCT, a measure affected by various physiological and psychological factors. Here, we present novel data (N = 287) examining the relationship between alexithymia and HCT performance, controlling for a number of potential confounds. Inclusion of these control measures reveals the predicted negative relationship between alexithymia and HCT performance. Results are discussed with regard to difficulties quantifying interoceptive sensitivity using the HCT.



https://ift.tt/2s6jisi

Examining the neural correlates of active and passive forms of verbal-spatial binding in working memory

Publication date: Available online 23 May 2018
Source:Biological Psychology
Author(s): Stéphanie Grot, Marie-Eve Leclerc, David Luck
We designed an fMRI study to pinpoint the neural correlates of active and passive binding in working memory. Participants were instructed to memorize three words and three spatial locations. In the passive binding condition, words and spatial locations were directly presented as bound. Conversely, in the active binding condition, words and spatial locations were presented as separated, and participants were directed to intentionally create associations between them. Our results showed that participants performed better on passive binding relative to active binding. FMRI analysis revealed that both binding conditions induced greater activity within the hippocampus. Additionally, our analyses divulged regions specifically engaged in passive and active binding. Altogether, these data allow us to propose the hippocampus as a central candidate for working memory binding. When needed, a frontal-parietal network can contribute to the rearrangement of information. These findings may inform theories of working memory binding.



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An Intermediate Pluripotent State Controlled by MicroRNAs Is Required for the Naive-to-Primed Stem Cell Transition

Publication date: Available online 24 May 2018
Source:Cell Stem Cell
Author(s): Peng Du, Mehdi Pirouz, Jiho Choi, Aaron J. Huebner, Kendell Clement, Alexander Meissner, Konrad Hochedlinger, Richard I. Gregory
The embryonic stem cell (ESC) transition from naive to primed pluripotency is marked by major changes in cellular properties and developmental potential. ISY1 regulates microRNA (miRNA) biogenesis, yet its role and relevance to ESC biology remain unknown. Here, we find that highly dynamic ISY1 expression during the naive-to-primed ESC transition defines a specific phase of "poised" pluripotency characterized by distinct miRNA and mRNA transcriptomes and widespread poised cell contribution to mouse chimeras. Loss- and gain-of-function experiments reveal that ISY1 promotes exit from the naive state and is necessary and sufficient to induce and maintain poised pluripotency, and that persistent ISY1 overexpression inhibits the transition from the naive to the primed state. We identify a large subset of ISY1-dependent miRNAs that can rescue the inability of miRNA-deficient ESCs to establish the poised state and transition to the primed state. Thus, dynamic ISY1 regulates poised pluripotency through miRNAs to control ESC fate.

Graphical abstract

Teaser

Du et al. identify an intermediate "poised" pluripotent state characterized by specific mRNA and miRNA transcriptomes and the ability to contribute to mouse chimeras. ISY1-mediated miRNA regulation is necessary and sufficient for establishing poised pluripotency required for the naive-primed transition, providing an explanation for the early embryonic lethality of global miRNA deficiency.


https://ift.tt/2IMcqH9

Trends and mental health correlates of nonmedical opioid use among criminal justice-involved African American men

Publication date: October 2018
Source:Addictive Behaviors, Volume 85
Author(s): Joi-Sheree' Knighton, Danelle Stevens-Watkins, Michele Staton, Kevin Pangburn
BackgroundThe Centers for Disease Control and Prevention has deemed nonmedical opioid use (NMOU) an epidemic. Population-based survey data indicate high rates of NMOU among Caucasians, however, these estimates exclude incarcerated samples and may underestimate use among criminal justice-involved African Americans. Despite opioid-associated risks of co-occurring mental illness and mortality, to our knowledge, this is the first study to examine NMOU and mental health among a sample of African American men receiving corrections-based substance use disorder (SUD) treatment in jail, prison, or the community.MethodWe conducted a cross-sectional study examining trends and mental health correlates of NMOU during the year prior to each participant's incarceration, across five cohorts of African American men (N = 4021) enrolled in corrections-based SUD treatment between the years, 2010 and 2014. A series of chi-square, ANOVAs, correlations, and logistic regression models were conducted.ResultsOver 20% of our sample reported NMOU during the year prior to incarceration. On average, participants were 36-years-old, earned 13 years of education, and were generally unemployed, prior to incarceration. We found a statistically significant positive linear trend between NMOU prior to incarceration and cohort year. The final stepwise multivariate regression model was significant and revealed, older age was associated with lower odds of NMOU. More years of education and frequent mental health symptoms were associated with significantly increased odds of NMOU.DiscussionOur findings are unique in that extant literature has primarily described NMOU as a 'White suburban' problem. Culturally-adapted behavioral interventions and medication assisted therapies are discussed.



https://ift.tt/2KPuqkw

Prevalence and factors associated with use of hookah tobacco among young adults in the U.S.

Publication date: October 2018
Source:Addictive Behaviors, Volume 85
Author(s): Julia N. Soulakova, Thanh Pham, Victoria L. Owens, Lisa J. Crockett
IntroductionAmong young adults, use of hookah tobacco (HT) is an emerging health-risk behavior. The goals were to demonstrate that (1) the prevalence of ever-use and current use of HT increased among U.S. young adults (18–30 years old) in the period from 2010 to 2015 and (2) the patterns of HT use differed across diverse demographic subpopulations of young adults.MethodsWe merged and analyzed data from the 2010–2011 and 2014–2015 Tobacco Use Supplement to the Current Population Survey. The sample (n = 55,352) was representative of the young adult population in the U.S. Two binary measures were the ever and current use of HT. The significance level was 5%.ResultsThe rate of current use of HT increased from 1% in 2010–11 to 2% in 2014–15 (CI = 0.6%:1.1%). The rate of ever-use increased from 7% to 12% (CI = 4.2%:5.6%). The over-time increase was not uniform: the increase was most rapid among 26–30 year-old adults, non-Hispanic Black and African American adults, and in Northeastern and Midwestern U.S. regions. HT ever-use, overall, was associated (all p's < 0.001) with many sociodemographic factors and current tobacco-use behaviors. The rate of HT ever-use was 16% for daily and 23% for occasional cigarette smokers, 23% for users of smokeless tobacco products, 37% for cigar smokers, and 55% for smokers of regular pipe (filled with tobacco).Discussion/conclusionHT use is becoming increasingly more popular among young adults in the U.S. Methods should target not only cessation of cigarette smoking but use of all tobacco products.



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Isolation and antimicrobial drug susceptibility pattern of bacterial pathogens from pediatric patients with otitis media in selected health institutions, Addis Ababa, Ethiopia: a prospective cross-sectional study

Otitis media is inflammation of the middle ear and tympanic membrane, which often occurs after an acute upper respiratory tract infection. It is the most common episode of infection in children and the second ...

https://ift.tt/2J6BTOG

The role of gastrointestinal permeability in food allergy

The contribution of a dysfunctional intestinal barrier to the onset and progression of a variety of intestinal and extra-intestinal inflammatory diseases is well established. However, the role of the intestinal barrier function in food allergy is less evident.

https://ift.tt/2IKUzQy

High-risk drug rashes

Provide a brief overview of the clinical presentation, common offending agents, management, prognosis, and mortality of selected six high-risk drug rashes, namely Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), multiple drug hypersensitivity syndrome (MDH), acute generalized exanthematous pustulosis (AGEP), and drug-induced bullous pemphigoid (DIBP).

https://ift.tt/2LtSqLa

Subcutaneous allergen immunotherapy may be a suitable treatment for exacerbator allergic asthma

Asthma is a heterogeneous disease which is mainly linked with allergy. Allergen immunotherapy (AIT) is the only specific treatment for allergic diseases with evidence of a disease-modifying effect. Nevertheless, the safety of subcutaneous AIT (SCIT) in asthma has been of some concern since the 1980s, especially in uncontrolled asthma. In this context, our objectives were to assess the safety and efficacy of a Dermatophagoides pteronyssinus (D. pteronyssinus) cluster SCIT protocol in children with moderate to severe allergic asthma.

https://ift.tt/2xd2SU8

Dose counting and use of short-acting beta-agonist inhalers in emergency department patients with asthma exacerbation

Medication non-adherence in asthma is a well-recognized problem.1 Non-adherence includes asthma patients using run-out (empty) inhalers and incorrect inhaler techniques.2 These lead to suboptimal disease control and asthma-related emergency department (ED) visits that are potentially preventable.2 Indeed, studies have shown that patients with asthma commonly overestimate the remaining doses of their short-acting beta-agonist (SABA) in metered-dose inhalers (MDIs).3,4 Overestimating the remaining doses of SABA can cause patients to use inhalers beyond the labeled number of actuations, when the drug delivered per actuation can range from 20% to 80% of the therapeutic dose.

https://ift.tt/2xaenvH

Allergy and atopy from infancy to adulthood: Messages from the German birth cohort MAS,

Allergic diseases in early and late childhood have become a common health problem across the globe as documented by the first cross-sectional phase of the International Study on Asthma and Allergies in Childhood [ISAAC] in the mid-1990s.1,2 In many industrialized and developing countries the prevalence of asthma, allergic rhinitis and eczema has increased since then or remained at a high plateau as shown by another global ISAAC assessment a decade later.3

https://ift.tt/2Lq269k

Hypereosinophilic Syndrome in the Differential Diagnosis of Pulmonary Infiltrates with Eosinophilia

The finding of pulmonary eosinophilia elicits a broad differential diagnosis (Table 1).1–3 Attention to key differentiating histologic features combined with clinical and laboratory findings and pertinent radiologic findings are important for distinguishing among the most common entities in the differential diagnosis that include eosinophilic pneumonia, eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome), allergic bronchopulmonary aspergillosis (ABPA) or more generally allergic bronchopulmonary fungal disease (ABPFD) and isolated asthma.

https://ift.tt/2x8XtNP

Aβ dimers induce behavioral and neurochemical deficits of relevance to early Alzheimer's disease

Publication date: September 2018
Source:Neurobiology of Aging, Volume 69
Author(s): Laila Abdel-Hafiz, Andreas Müller-Schiffmann, Carsten Korth, Benedetta Fazari, Owen Y. Chao, Susanne Nikolaus, Sandra Schäble, Arne Herring, Kathy Keyvani, Valéria Lamounier-Zepter, Joseph P. Huston, Maria A. de Souza Silva
We examined behaviors and neurotransmitter levels in the tgDimer mouse, a model for early Alzheimer's disease, that expresses exclusively soluble amyloid beta (Aβ) dimers and is devoid of Aβ plaques, astrogliosis, and neuroinflammation. Seven-month-old mice were subjected to tests of motor activity, attention, anxiety, habituation learning, working memory, and depression-related behaviors. They were impaired in nonselective attention and motor learning and showed anxiety- and despair-related behaviors. In 7- and 12-month-old mice, levels of acetylcholine, dopamine, and serotonin were measured in neostriatum, ventral striatum, prefrontal cortex, hippocampus, amygdala, and entorhinal cortex by high-performance liquid chromatography. The tgDimer mice had lower serotonin turnover rates in hippocampus, ventral striatum, and amygdala relative to wild type controls. The aged tgDimer mice had less hippocampal acetylcholine than adult tgDimers. Stress-test results, based on corticosterone levels, indicated an intact hypothalamus-pituitary-adrenal axis in 12-month-old mice. Since neither Aβ plaques nor astrogliosis or neuroinflammation was responsible for these phenotypes, we conclude that Aβ dimers contribute to neurotransmitter dysfunction and behavioral impairments, characteristic for the early stages of Alzheimer's disease.



https://ift.tt/2INKbYm

Hypereosinophilic Syndrome in the Differential Diagnosis of Pulmonary Infiltrates with Eosinophilia

Publication date: Available online 24 May 2018
Source:Annals of Allergy, Asthma & Immunology
Author(s): Nives Zimmermann, Kathryn A. Wikenheiser-Brokamp




https://ift.tt/2GLPB4z

The Amish have Decreased Asthma and Allergic Diseases Compared to Old Order Mennonites

Publication date: Available online 23 May 2018
Source:Annals of Allergy, Asthma & Immunology
Author(s): Jamee C. Tantoco, Jordan Elliott Bontrager, Qianqian Zhao, James DeLine, Christine M. Seroogy




https://ift.tt/2IFrUjY

Provider Practices in Screening for Mental Health Concerns in Caregivers of Patients with Primary Immunodeficiency

Publication date: Available online 23 May 2018
Source:Annals of Allergy, Asthma & Immunology
Author(s): Amanda Page, Marni B. Jacobs, Nicole A. Herrera, Tiffany S. Henderson, Christopher Scalchunes, Michael D. Keller, Linda J. Herbert




https://ift.tt/2kpjW02

Written by Kristen A. Feemster. Vaccines—What Everyone Needs to Know, Oxford University Press, 198 Madison Avenue, New York, NY 10016, First Edition, 2018. Softcover, 186 pages, $16.95. ISBN: 978-0-19-027791-8.

Publication date: Available online 24 May 2018
Source:Annals of Allergy, Asthma & Immunology
Author(s): Peter Capucilli, Jonathan M. Spergel




https://ift.tt/2s8GXYz

Host characteristics and dynamics of Staphylococcus aureus colonization in patients with moderate-to-severe psoriasis before and after treatment: A prospective cohort study

https://ift.tt/2GQuGxi

SIOPE – Brain tumor group consensus guideline on craniospinal target volume delineation for high-precision radiotherapy

Publication date: Available online 2 May 2018
Source:Radiotherapy and Oncology
Author(s): Thankamma Ajithkumar, Gail Horan, Laetitia Padovani, Nicky Thorp, Beate Timmermann, Claire Alapetite, Lorenza Gandola, Monica Ramos, Karen Van Beek, Melissa Christiaens, Yasmin Lassen-Ramshad, Henriette Magelssen, Kristina Nilsson, Frank Saran, Barbara Rombi, Rolf Kortmann, Geert O. Janssens
ObjectiveTo develop a consensus guideline for craniospinal target volume (TV) delineation in children and young adults participating in SIOPE studies in the era of high-precision radiotherapy.Methods and materialsDuring four consensus meetings (Cambridge, Essen, Liverpool, and Marseille), conventional field-based TV has been translated into image-guided high-precision craniospinal TV by a group of expert paediatric radiation oncologists and enhanced by MRI images of liquor distribution.ResultsThe CTVcranial should include the whole brain, cribriform plate, most inferior part of the temporal lobes, and the pituitary fossa. If the full length of both optic nerves is not included, the dose received by different volumes of optic nerve should be recorded to correlate with future patterns of relapse (no consensus). The CTVcranial should be modified to include the dural cuffs of cranial nerves as they pass through the skull base foramina. Attempts to spare the cochlea by excluding CSF within the internal auditory canal should be avoided. The CTVspinal should include the entire subarachnoid space, including nerve roots laterally. The lower limit of the spinal CTV is at the lower limit of the thecal sac, best visible on MRI scan. There is no need to include sacral root canals in the spinal CTV.ConclusionThis consensus guideline has the potential to improve consistency of craniospinal TV delineation in an era of high-precision radiotherapy. This proposal will be incorporated in the RTQA guidelines of future SIOPE-BTG trials using CSI.



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Efficacy of thoracic radiotherapy in patients with stage IIIB–IV epidermal growth factor receptor-mutant lung adenocarcinomas who received and responded to tyrosine kinase inhibitor treatment

Publication date: Available online 24 April 2018
Source:Radiotherapy and Oncology
Author(s): Yu-Chun Yen, Han-Lin Hsu, Jer-Hwa Chang, Wei-Cheng Lin, Yin-Chun Chang, Chia-Lun Chang, Jyh-Ming Chow, Kevin Sheng-Po Yuan, Alexander T.H. Wu, Szu-Yuan Wu
PurposeLarge-scale, prospective, randomized studies of the efficacy of thoracic radiotherapy (RT) in patients with unresectable stage IIIB–IV epidermal growth factor receptor (EGFR)-mutant lung adenocarcinomas who received and responded to EGFR tyrosine kinase inhibitor (TKI) treatment are not currently available. Therefore, we designed a propensity score-matched, nationwide, population-based, cohort study for estimating the effects of thoracic RT on patients with EGFR-mutant lung adenocarcinomas.Patients and methodsWe analyzed patients with unresectable stage IIIB–IV EGFR mutant lung adenocarcinomas and categorized them into two groups according to treatment modality and compared their outcomes; groups 1 and 2 consisted of patients who received EGFR TKI treatment alone until tumor progression and those who received and responded to EGFR TKI treatment and subsequently received thoracic RT for lung tumors, respectively. The patients in groups 2 and 1 were matched at a ratio of 1:4.ResultsThe matching process yielded a final cohort of 1475 patients (1180 and 295 patients in groups 1 and 2, respectively) who were eligible for further analysis. According to both univariate and multivariate Cox regression analyses, the adjusted hazard ratios (aHRs) (95% confidence interval [CI]) derived for thoracic RT for lung tumor after EGFR TKI use and tumor response (group 2) compared with EGFR TKI treatment alone (group 1) was 0.72 (0.60–0.85).ConclusionsThoracic RT might be associated with overall survival in patients with unresectable stage IIIB–IV EGFR-mutant lung adenocarcinomas who received and responded to EGFR TKI treatment.



https://ift.tt/2KSDvci

Respiratory motion of lymph node stations in pancreatic cancer: Analyses using contrast-enhanced four-dimensional computed tomography

Publication date: Available online 22 May 2018
Source:Radiotherapy and Oncology
Author(s): Shigeo Takahashi, Masahide Anada, Toshifumi Kinoshita, Toru Shibata
Background and purposeData regarding respiratory motion of lymph node (LN) stations in pancreatic cancer is limited. Therefore, we assessed their respiratory motion using contrast-enhanced four-dimensional-computed tomography (CE-4DCT).Material and methodsWe evaluated respiratory motion in 18 pancreatic cancer patients. We selected LN stations around major arteries which were visible on CE-4DCT images. This included the common hepatic, celiac, splenic, and superior mesenteric stations. Two radiation oncologists individually delineated the gross tumor volume (GTV) and the LN stations as observers 1 and 2.ResultsThe respiratory motion of the celiac (median, 3.9 mm each for both observers) and superior mesenteric (median, 4.5 and 5.0 mm for observers 1 and 2, respectively) stations in the craniocaudal (CC) directions was significantly smaller than that of the GTV (median, 8.9 and 7.8 mm for observers 1 and 2, respectively). The respiratory motion of the common hepatic station (median, 3.8 and 3.6 mm for observers 1 and 2, respectively) in the anterior–posterior (AP) direction was significantly larger than that of the GTV (median, 2.8 and 2.2 mm for observers 1 and 2, respectively).ConclusionsWe observed significant differences in respiratory motion between the GTV and the LN stations in pancreatic cancer.



https://ift.tt/2GM8xzS

Local control and fracture risk following stereotactic body radiation therapy for non-spine bone metastases

Publication date: Available online 26 April 2018
Source:Radiotherapy and Oncology
Author(s): Darby Erler, Drew Brotherston, Arjun Sahgal, Patrick Cheung, Andrew Loblaw, William Chu, Hany Soliman, Hans Chung, Alex Kiss, Edward Chow, Ian Poon
AimsTo report local control and toxicity rates for patients treated with stereotactic body radiotherapy (SBRT) for non-spine bone metastases.Methods and materialsEighty-one patients with 106 non-spine bone metastases were treated between 2011 and 2014 and retrospectively reviewed. Indications included: oligometastases (63%), oligoprogression (17.3%), retreatment (2.4%) or other (17.3%). Cumulative incidence function was used to assess local recurrence and fracture probability. Bivariate relationships were investigated based on selected patient, tumour and dose–volume factors.ResultsMean follow-up was 13 months (range, 0.25–45.6) and the median patient age was 66.4 years (range, 36–86). Most patients were male (60.5%) and the predominant histology prostate cancer (32%). Bone metastases were most commonly located in the pelvis (41.5%) and almost half sclerotic. The most common prescriptions were 30 Gy/5 (30.2%) and 35 Gy/5 (42.5%). The cumulative incidence of local recurrence at 6,18 and 24 months respectively was 4.7%, 8.3% and 13.3% with a mean time to local recurrence of 11.8 months (range, 3.9–23.4). A significant association was found between local recurrence and volume of the PTV (p = 0.02), with larger PTVs having a greater risk of local failure. Fracture was observed radiographically in the treatment volume in 9/106 (8.5%) of treated lesions and the mean time to fracture was 8.4 months (range, 0.7–32.5 months). With respect to predictors, a trend was observed for lytic lesions (p = 0.11) and female gender (p = 0.09).ConclusionsThe results of this study confirm that SBRT yields high rates of long-term local control for non-spine bone metastases with a low fracture risk.



https://ift.tt/2LsheD2

Can dose outside the PTV influence the risk of distant metastases in stage I lung cancer patients treated with stereotactic body radiotherapy (SBRT)?

Publication date: Available online 22 May 2018
Source:Radiotherapy and Oncology
Author(s): André Diamant, Avishek Chatterjee, Sergio Faria, Issam El Naqa, Houda Bahig, Edith Filion, Cliff Robinson, Hani Al-Halabi, Jan Seuntjens
Background and purposeIn an era where little is known about the "abscopal" (out-of-the-field) effects of lung SBRT, we investigated correlations between the radiation dose proximally outside the PTV and the risk of cancer recurrence after SBRT in patients with primary stage I non-small cell lung cancer (NSCLC).Materials and methodsThis study included 217 stage I NSCLC patients across 2 institutions who received SBRT. Correlations between clinical and dosimetric factors were investigated. The clinical factors considered were distant metastasis (DM), loco-regional control (LRC) and radiation pneumonitis (RP). The dose (converted to EQD2) delivered to regions of varying size directly outside of the PTV was computed. For each feature, area under the curve (AUC) and odds ratios with respect to the outcome parameters DM, LRC and RP were estimated; Kaplan–Meier (KM) analysis was also performed.ResultsThirty-seven (17%) patients developed DM after a median follow-up of 24 months. It was found that the mean dose delivered to a shell-shaped region of thickness 30 mm outside the PTV had an AUC of 0.82. Two years after treatment completion, the rate of DM in patients where the mean dose delivered to this region was higher than 20.8 Gy2 was 5% compared to 60% in those who received a dose lower than 20.8 Gy2. KM analysis resulted in a hazard ratio of 24.2 (95% CI: 10.7, 54.4); p < 10⁻⁵. No correlations were found between any factor and either LRC or RP.ConclusionsThe results of this study suggest that the dose received by the region close to the PTV has a significant impact on the risk of distant metastases in stage I NSCLC patients treated with SBRT. If these results are independently confirmed, caution should be taken, particularly when a treatment plan results in a steep dose gradient extending outwards from the PTV.



https://ift.tt/2kovQHw

Tracking tumor biology with radiomics: A systematic review utilizing a radiomics quality score

Publication date: Available online 18 May 2018
Source:Radiotherapy and Oncology
Author(s): Sebastian Sanduleanu, Henry C. Woodruff, Evelyn E.C. de Jong, Janna E. van Timmeren, Arthur Jochems, Ludwig Dubois, Philippe Lambin
Introduction: In this review we describe recent developments in the field of radiomics along with current relevant literature linking it to tumor biology. We furthermore explore the methodologic quality of these studies with our in-house radiomics quality scoring (RQS) tool. Finally, we offer our vision on necessary future steps for the development of stable radiomic features and their links to tumor biology. Methods: Two authors (S.S. and H.W.) independently performed a thorough systematic literature search and outcome extraction to identify relevant studies published in MEDLINE/PubMed (National Center for Biotechnology Information, NCBI), EMBASE (Ovid) and Web of Science (WoS). Two authors (S.S, H.W) separately and two authors (J.v.T and E.d.J) concordantly scored the articles for their methodology and analyses according to the previously published radiomics quality score (RQS). Results: In summary, a total of 655 records were identified till 25-09-2017 based on the previously specified search terms, from which n = 236 in MEDLINE/PubMed, n = 215 in EMBASE and n = 204 from Web of Science. After determining full article availability and reading the available articles, a total of n = 41 studies were included in the systematic review. The RQS scoring resulted in some discrepancies between the reviewers, e.g. reviewer H.W scored 4 studies ≥50%, reviewer S.S scored 3 studies ≥50% while reviewers J.v.T and E.d.J scored 1 study ≥50%. Up to nine studies were given a quality score of 0%. The majority of studies were scored below 50%. Discussion: In this study, we performed a systematic literature search linking radiomics to tumor biology. All but two studies (n = 39) revealed that radiomic features derived from ultrasound, CT, PET and/or MR are significantly associated with one or several specific tumor biologic substrates, from somatic mutation status to tumor histopathologic grading and metabolism. Considerable inter-observer differences were found with regard to RQS scoring, while important questions were raised concerning the interpretability of the outcome of such scores.



https://ift.tt/2s6hJty

Anal and rectal function after intensity-modulated prostate radiotherapy with endorectal balloon

Publication date: Available online 30 April 2018
Source:Radiotherapy and Oncology
Author(s): Robin Krol, Gill M. McColl, Wim P.M. Hopman, Robert J. Smeenk
Background and purposeLate anorectal toxicity influences quality of life after external beam radiotherapy (EBRT) for prostate cancer. A daily inserted endorectal balloon (ERB) during EBRT aims to reduce anorectal toxicity. Our goal is to objectify anorectal function over time after prostate intensity-modulated radiotherapy (IMRT) with ERB.Material and methodsSixty men, irradiated with IMRT and an ERB, underwent barostat measurements and anorectal manometry prior to EBRT and 6 months, one year and 2 years after radiotherapy. Primary outcome measures were rectal distensibility and rectal sensibility in response to stepwise isobaric distensions and anal pressures.ResultsForty-eight men completed all measurements. EBRT reduced maximal rectal capacity 2 years after EBRT (250 ± 10 mL vs. 211 ± 10 mL; p < 0.001), area under the pressure–volume curve (2878 ± 270 mL mmHg vs. 2521 ± 305 mL mmHg; p = 0.043) and rectal compliance (NS). Sensory pressure thresholds for first sense and first urge (both p < 0.01) increased. Anal maximum pressure diminished after IMRT (p = 0.006).ConclusionsRectal capacity and sensory function are increasingly affected over time after radiotherapy. There is an indication that these reductions are affected less with IMRT + ERB compared to conventional radiation techniques.



https://ift.tt/2KTSClN

Randomized trial comparing two methods of re-irradiation after salvage surgery in head and neck squamous cell carcinoma: Once daily split-course radiotherapy with concomitant chemotherapy or twice daily radiotherapy with cetuximab

Publication date: Available online 18 May 2018
Source:Radiotherapy and Oncology
Author(s): Yungan Tao, Laura Faivre, Anne Laprie, Pierre Boisselier, Christophe Ferron, Guy Michel Jung, Séverine Racadot, Bernard Gery, Caroline Even, Ingrid Breuskin, Jean Bourhis, François Janot
BackgroundA previous randomized trial in recurrent Head and Neck squamous-cell carcinoma (HNSCC) has shown re-irradiation combined with chemotherapy after salvage surgery significantly improved disease-free survival (DFS). The objective of this randomized trial was to compare two methods of re-irradiation in terms of toxicity and survival.Patients and methodsPatients with recurrence/second primary in previously irradiated area were randomly allocated to receive either 60 Gy over 11 weeks with concomitant 5FU – hydroxyurea (VP-arm), or 60 Gy (1.2 Gy twice daily) over 5 weeks with cetuximab (HFR-arm). Primary endpoint was treatment interruption >15 days (acute toxicity).ResultsTwenty-six patients were included in VP-arm and 27 in HFR-arm. One patient in VP-arm experienced >15 days interruption due to toxicity, and none in HFR-arm. In both arms, all patients received at least 60 Gy. In VP-arm, 8/26 patients had chemotherapy delay and/or dose reduction. In HFR-arm, 4/27 patients had <6 cycles cetuximab. There was no significant difference in overall survival (Median OS: 37.4 months vs 21.9 months, p = 0.12). Toxicities and DFS were not different between 2 arms.ConclusionsTwice daily schedule of re-irradiation of 60 Gy/5 weeks with cetuximab was tolerable and no significant difference in treatment delays occurred between two arms.



https://ift.tt/2IIPr3F

Heart volume reduction during radiotherapy involving the thoracic region in children: An unexplained phenomenon

Publication date: Available online 24 April 2018
Source:Radiotherapy and Oncology
Author(s): Irma W.E.M. van Dijk, Jorrit Visser, Jan Wiersma, Jessica R. van Boggelen, Brian V. Balgobind, Elizabeth A.M. (Lieke) Feijen, Sophie C. Huijskens, Wouter E.M. Kok, Leontien C.M. Kremer, Coen R.N. Rasch, Arjan Bel
Background and purposeRadiotherapy involving the thoracic region is associated with cardiotoxicity in long-term childhood cancer survivors. We quantified heart volume changes during radiotherapy in children (<18 years) and investigated correlations with patient and treatment related characteristics.Material and methodsBetween 2010 and 2016, 34 children received radiotherapy involving the thoracic region. We delineated heart contours and measured heart volumes on 114 CBCTs. Relative volume changes were quantified with respect to the volume on the first CBCT (i.e., 100%). Cardiac radiation dose parameters expressed as 2 Gy/fraction equivalent doses were calculated from DVHs. Chemotherapy was categorized as treatment with anthracyclines, alkylating agents, vinca-alkaloids, and other.ResultsThe overall median heart volume reduction from the first to the last CBCT was 5.5% (interquartile range1.6–9.7%; p < 0.001). Heart volumes decreased significantly between the baseline measurement and the first week (Bonferroni's adjusted p = 0.002); volume changes were not significant during the following weeks. Univariate analysis showed a significant correlation between heart volume reduction and alkylating agents; however, no multivariate analyses could be done to further confirm this.ConclusionsWe found a significant heart volume reduction in children during radiotherapy. Elucidation of underlying mechanisms, clinical relevance, and possible long-term consequences of early heart volume reduction require a prospective follow-up study.



https://ift.tt/2J4ddq4

Regulation of the oxidative balance with coenzyme Q10 sensitizes human glioblastoma cells to radiation and temozolomide

Publication date: Available online 18 May 2018
Source:Radiotherapy and Oncology
Author(s): Javier Frontiñán-Rubio, Raquel María Santiago-Mora, Consuelo María Nieva-Velasco, Gustavo Ferrín, Alicia Martínez-González, María Victoria Gómez, María Moreno, Julia Ariza, Eva Lozano, Jacinto Arjona-Gutiérrez, Antonio Gil-Agudo, Manuel De la Mata, Milica Pesic, Juan Ramón Peinado, José M. Villalba, Luis Pérez-Romasanta, Víctor M. Pérez-García, Francisco J. Alcaín, Mario Durán-Prado
ObjectivesTo investigate how the modulation of the oxidative balance affects cytotoxic therapies in glioblastoma, in vitro.Material and methodsHuman glioblastoma U251 and T98 cells and normal astrocytes C8D1A were loaded with coenzyme Q10 (CoQ). Mitochondrial superoxide ion (O2⁻) and H2O2 were measured by fluorescence microscopy. OXPHOS performance was assessed in U251 cells with an oxytherm Clark-type electrode. Radio- and chemotherapy cytotoxicity was assessed by immunostaining of γH2AX (24 h), annexin V and nuclei morphology, at short (72 h) and long (15 d) time. Hif-1α, SOD1, SOD2 and NQO1 were determined by immunolabeling. Catalase activity was measured by classic enzymatic assay. Glutathione levels and total antioxidant capacity were quantified using commercial kits.ResultsCoQ did not affect oxygen consumption but reduced the level of O2⁻ and H2O2 while shifted to a pro-oxidant cell status mainly due to a decrease in catalase activity and SOD2 level. Hif-1α was dampened, echoed by a decrease lactate and several key metabolites involved in glutathione synthesis. CoQ-treated cells were twofold more sensitive than control to radiation-induced DNA damage and apoptosis in short and long-term clonogenic assays, potentiating TMZ-induced cytotoxicity, without affecting non-transformed astrocytes.ConclusionsCoQ acts as sensitizer for cytotoxic therapies, disarming GBM cells, but not normal astrocytes, against further pro-oxidant injuries, being potentially useful in clinical practice for this fatal pathology.



https://ift.tt/2sb498i

Outcomes of adjuvant treatments for resectable intrahepatic cholangiocarcinoma: Chemotherapy alone, sequential chemoradiotherapy, or concurrent chemoradiotherapy

Publication date: Available online 22 May 2018
Source:Radiotherapy and Oncology
Author(s): Yen-Kuang Lin, Mao-Chih Hsieh, Wei-Wei Wang, Yi-Chun Lin, Wei-Wen Chang, Chia-Lun Chang, Yun-Feng Cheng, Szu-Yuan Wu
BackgroundProspective randomized trials have not been used to evaluate the efficacy of adjuvant therapies after intrahepatic cholangiocarcinoma (ICC) resection.MethodsWe analyzed data from the Taiwan Cancer Registry database of ICC patients receiving resection. To compare outcomes, patients with ICC were enrolled and categorized into the following adjuvant treatment modality groups: group 1, concurrent chemoradiotherapy (CCRT); group 2, sequential chemotherapy (CT) and radiotherapy (RT); and group 3, CT alone.ResultsWe enrolled 599 patients with resectable ICC who received surgery without distant metastasis. Of these patients, 174 received adjuvant CCRT (group 1), 146 received adjuvant sequential CT and RT (group 2), and 279 received adjuvant CT alone (group 3). Multivariate Cox regression analysis indicated that pathologic stage and positive margin were significantly poor independent predictors. After adjustment for confounders, adjusted hazard ratios (95% confidence intervals) for overall mortality at advanced pathologic stages III and IV were 0.55 (0.41–0.74) and 0.92 (0.70–1.33) in groups 1 and 2, respectively, compared with group 3.ConclusionsAdjuvant CCRT improved survival in resected ICC with advanced pathologic stages or a positive margin in early pathologic stages compared with adjuvant CT alone or adjuvant sequential CT and RT.



https://ift.tt/2IHp4uW

Physician assessed and patient reported urinary morbidity after radio-chemotherapy and image guided adaptive brachytherapy for locally advanced cervical cancer

Publication date: Available online 18 May 2018
Source:Radiotherapy and Oncology
Author(s): Lars Fokdal, Richard Pötter, Kathrin Kirchheiner, Jacob Chr. Lindegaard, Nina Boje Kibsgaard Jensen, Christian Kirisits, Cyrus Chargari, Umesh Mahantshetty, Ina Maria Jürgenliemk-Schulz, Barbara Segedin, Peter Hoskin, Kari Tanderup
Background and purposeThe EMBRACE study is a prospective multi-institutional study on MRI guided adaptive brachytherapy (IGABT) in locally advanced cervix cancer (LACC). This analysis describes early to late urinary morbidity assessed by physicians and patients (PRO).Material and methodsA total of 1176 patients were analysed. Median follow up (FU) was 27 (1–83) months. Morbidity (CTCAE v.3) and PRO (EORTC QLQ-C30&CX24) was prospectively assessed at baseline (BL), and during FU.ResultsThe most frequent symptoms were frequency/urgency, incontinence, and cystitis with grade 2–4 prevalence rates of 4.3%, 5.0% and 1.7% and grade 1–4 prevalence rates of 24.5%, 16.1% and 5.8% at 3-years. The most frequent PRO endpoints were "urinary frequency" and "leaking of urine". Prevalence of "Quite a bit" or "very much" bother fluctuated from 14.0% to 21.5% for "frequency", while "leaking of urine" increased from 4.6% at BL to 9.3% at 3-years.Actuarial 3-year incidence of grade 3–4 urinary morbidity was 5.3% with most events being urinary frequency, incontinence and ureteral strictures. Grade 3–4 fistula, bleeding, spasm and cystitis were all <1.0% at 3/5-years. No grade 5 toxicity occurred.ConclusionUrinary grade 3–4 morbidity with IGABT was limited. Urinary morbidity grade 2–4 comprises mainly frequency/urgency, incontinence and cystitis and has considerable prevalence in PRO. Various urinary morbidity endpoints have different patterns of manifestation and time course.



https://ift.tt/2kricU5

SBRT for pancreatic cancer: In regard of Bohoudi et al.

Publication date: Available online 3 May 2018
Source:Radiotherapy and Oncology
Author(s): Cristina Garibaldi, Eugenia Moretti, Serenella Russo, Cinzia Talamonti, Elena Villaggi, Pietro Mancosu




https://ift.tt/2IGQbGt

A radiosensitivity gene signature and PD-L1 predict the clinical outcomes of patients with lower grade glioma in TCGA

Publication date: Available online 18 May 2018
Source:Radiotherapy and Oncology
Author(s): Bum-Sup Jang, In Ah Kim
PurposeIdentifying predictive factors for the clinical outcome of patients with lower grade gliomas following radiotherapy could help optimize patient treatments. Here, we investigate the predictive efficacy of both a previously identified "31-gene signature" and programmed death ligand-1 (PD-L1) expression.Material and methodsWe identified 511 patients with lower grade glioma (Grade 2 and 3) in The Cancer Genome Atlas dataset and divided them into two clusters: radiosensitive (RS) and radioresistant (RR). Patients were also classified as PD-L1-high or PD-L1-low based on CD274 mRNA expression. Five-year survival rates were compared across patient groups, and differentially expressed genes were identified via a gene enrichment analysis.ResultsAmong 511 patients with lower grade glioma in The Cancer Genome Atlas dataset, we identified a group that was characterized by radioresistant and high PD-L1 (the PD-L1-high-RR group). Multivariate Cox models demonstrated that the membership in the PD-L1-high-RR can predict overall survival regarding to RT. Differentially expressed genes associated with the PD-L1-high-RR group were found to play a role in the immune response, including the T-cell receptor signaling pathway.ConclusionWe tested the predictive value of a "31-gene signature" and PD-L1 expression status in a dataset of patients with lower grade glioma. Our results suggest that the patient population classified as the PD-L1-high-RR may benefit most from radiotherapy combined with anti-PD-1/PD-L1 treatment. Prospective clinical trial is necessary to validate the findings in a homogenous treated patient cohort.



https://ift.tt/2s4Q1gW

The European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology guidelines for the management of patients with cervical cancer

Publication date: Available online 1 May 2018
Source:Radiotherapy and Oncology
Author(s): David Cibula, Richard Pötter, François Planchamp, Elisabeth Avall-Lundqvist, Daniela Fischerova, Christine Haie Meder, Christhardt Köhler, Fabio Landoni, Sigurd Lax, Jacob Christian Lindegaard, Umesh Mahantshetty, Patrice Mathevet, W. Glenn McCluggage, Mary McCormack, Raj Naik, Remi Nout, Sandro Pignata, Jordi Ponce, Denis Querleu, Francesco Raspagliesi, Alexandros Rodolakis, Karl Tamussino, Pauline Wimberger, Maria Rosaria Raspollini
BackgroundDespite significant advances in the screening, detection, and treatment of preinvasive cervical lesions, invasive cervical cancer is the fifth most common cancer in European women. There are large disparities in Europe and worldwide in the incidence, management, and mortality of cervical cancer.ObjectiveThe European Society of Gynaecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) jointly develop clinically relevant and evidence-based guidelines in order to improve the quality of care for women with cervical cancer across Europe and worldwide.MethodsThe ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of cervical cancer (23 experts across Europe). To ensure that the guidelines are evidence based, the current literature identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 159 international reviewers, selected through ESGO/ESTRO/ESP and including patient representatives.ResultsThe guidelines cover comprehensively staging, management, and follow-up for patients with cervical cancer. Management includes fertility sparing treatment; stage T1a, T1b1/T2a1, clinically occult cervical cancer diagnosed after simple hysterectomy; early and locally advanced cervical cancer; primary distant metastatic disease; cervical cancer in pregnancy; and recurrent disease. Principles of radiotherapy and pathological evaluation are defined.



https://ift.tt/2KTSvqn

Risk factors for near-miss events and safety incidents in pediatric radiation therapy

Publication date: Available online 17 May 2018
Source:Radiotherapy and Oncology
Author(s): Nimrah Baig, Jiangxia Wang, Shereef Elnahal, Todd McNutt, Jean Wright, Theodore DeWeese, Stephanie Terezakis
Background and purposeFactors contributing to safety- or quality-related incidents (e.g. variances) in children are unknown. We identified clinical and RT treatment variables associated with risk for variances in a pediatric cohort.Materials and methodsUsing our institution's incident learning system, 81 patients age ≤21 years old who experienced variances were compared to 191 pediatric patients without variances. Clinical and RT treatment variables were evaluated as potential predictors for variances using univariate and multivariate analyses.ResultsVariances were primarily documentation errors (n = 46, 57%) and were most commonly detected during treatment planning (n = 14, 21%). Treatment planning errors constituted the majority (n = 16 out of 29, 55%) of near-misses and safety incidents (NMSI), which excludes workflow incidents. Therapists reported the majority of variances (n = 50, 62%). Physician cross-coverage (OR = 2.1, 95% CI = 1.04–4.38) and 3D conformal RT (OR = 2.3, 95% CI = 1.11–4.69) increased variance risk. Conversely, age >14 years (OR = 0.5, 95% CI = 0.28–0.88) and diagnosis of abdominal tumor (OR = 0.2, 95% CI = 0.04–0.59) decreased variance risk.ConclusionsVariances in children occurred in early treatment phases, but were detected at later workflow stages. Quality measures should be implemented during early treatment phases with a focus on younger children and those cared for by cross-covering physicians.



https://ift.tt/2kon3W0

Radiation dose constraints for organs at risk in neuro-oncology; the European Particle Therapy Network consensus

Publication date: Available online 17 May 2018
Source:Radiotherapy and Oncology
Author(s): Maarten Lambrecht, Daniëlle B.P. Eekers, Claire Alapetite, Neil G. Burnet, Valentin Calugaru, Ida E.M. Coremans, Piero Fossati, Morten Høyer, Johannes A. Langendijk, Alejandra Méndez Romero, Frank Paulsen, Ana Perpar, Laurette Renard, Dirk de Ruysscher, Beate Timmermann, Pavel Vitek, Damien C. Weber, Hiske L. van der Weide, Gillian A. Whitfield, Ruud Wiggenraad, Erik Roelofs, Petra Witt Nyström, Esther G.C. Troost
PurposeFor unbiased comparison of different radiation modalities and techniques, consensus on delineation of radiation sensitive organs at risk (OARs) and on their dose constraints is warranted. Following the publication of a digital, online atlas for OAR delineation in neuro-oncology by the same group, we assessed the brain OAR-dose constraints in a follow-up study.MethodsWe performed a comprehensive search to identify the current papers on OAR dose constraints for normofractionated photon and particle therapy in PubMed, Ovid Medline, Cochrane Library, Embase and Web of Science. Moreover, the included articles' reference lists were cross-checked for potential studies that met the inclusion criteria. Consensus was reached among 20 radiation oncology experts in the field of neuro-oncology.ResultsFor the OARs published in the neuro-oncology literature, we summarized the available literature and recommended dose constraints associated with certain levels of normal tissue complication probability (NTCP) according to the recent ICRU recommendations. For those OARs with lacking or insufficient NTCP data, a proposal for effective and efficient data collection is given.ConclusionThe use of the European Particle Therapy Network-consensus OAR dose constraints summarized in this article is recommended for the model-based approach comparing photon and proton beam irradiation as well as for prospective clinical trials including novel radiation techniques and/or modalities.



https://ift.tt/2GM8i7W

Quality of radiotherapy services in post-Soviet countries: An IAEA survey

Publication date: Available online 25 April 2018
Source:Radiotherapy and Oncology
Author(s): Eduardo Rosenblatt, Elena Fidarova, Sunita Ghosh, Eduardo Zubizarreta, Olga Unterkirhere, Natalia Semikoz, Valery Sinaika, Viktor Kim, Nerses Karamyan, Isa Isayev, Kamal Akbarov, Darejan Lomidze, Oksana Bondareva, Piotr Tuzlucov, Manzura Zardodkhonova, Sergey Tkachev, Marina Kislyakova, Jamshid Alimov, Tetiana Pidlubna, Michael Barton, William Mackillop
BackgroundThe quality of radiotherapy services in post-Soviet countries has not yet been studied following a formal methodology. The IAEA conducted a survey using two sets of validated radiation oncology quality indicators (ROIs).MethodsEleven post-Soviet countries were assessed. A coordinator was designated for each country and acted as the liaison between the country and the IAEA. The methodology was a one-time cross-sectional survey using a 58-question tool in Russian. The questionnaire was based on two validated sets of ROIs: for radiotherapy centres, the indicators proposed by Cionini et al., and for data at the country level, the Australasian ROIs.ResultsThe overall response ratio was 66.3%, but for the Russian Federation, it was 24%. Data were updated on radiotherapy infrastructure and equipment. 256 radiotherapy centres are operating 275 linear accelerators and 337 Cobalt-60 units. 61% of teletherapy machines are older than ten years. Analysis of ROIs revealed significant differences between these countries and radiotherapy practices in the West. Naming, task profile and education programmes of radiotherapy professionals are different than in the West.ConclusionsMost countries need modernization of their radiotherapy infrastructure coupled with adequate staffing numbers and updated education programmes focusing on evidence-based medicine, quality, and safety.



https://ift.tt/2KTSra7