Impact of pemetrexed on intracranial disease control and radiation necrosis in patients with brain metastases from non-small cell lung cancer receiving stereotactic radiation

Publication date: Available online 3 February 2018
Source:Radiotherapy and Oncology
Author(s): Daniel N. Cagney, Allison M. Martin, Paul J. Catalano, Zachary J. Reitman, Gabrielle A. Mezochow, Eudocia Q. Lee, Patrick Y. Wen, Stephanie E. Weiss, Paul D. Brown, Manmeet S. Ahluwalia, Nils D. Arvold, Shyam K. Tanguturi, Daphne A. Haas-Kogan, Brian M. Alexander, Amanda J. Redig, Ayal A. Aizer
BackgroundPemetrexed is a folate antimetabolite used in the management of advanced adenocarcinoma of the lung. We sought to assess the impact of pemetrexed on intracranial disease control and radiation-related toxicity among patients with adenocarcinoma of the lung who received stereotactic radiation for brain metastases.Materials/MethodsWe identified 149 patients with adenocarcinoma of the lung and newly diagnosed brain metastases without a targetable mutation receiving stereotactic radiation. Kaplan–Meier plots and Cox regression were employed to assess whether use of pemetrexed was associated with intracranial disease control and radiation necrosis.ResultsAmong the entire cohort, 105 patients received pemetrexed while 44 did not. Among patients who were chemotherapy-naïve, use of pemetrexed (n = 43) versus alternative regimens after stereotactic radiation (n = 24) was associated with a reduced likelihood of developing new brain metastases (HR 0.42, 95% CI 0.22–0.79, p = 0.006) and a reduced need for salvage brain-directed radiation therapy (HR 0.36, 95% CI 0.18–0.73, p = 0.005). Pemetrexed use was associated with increased radiographic necrosis. (HR 2.70, 95% CI 1.09–6.70, p = 0.03).ConclusionsPatients receiving pemetrexed after brain-directed stereotactic radiation appear to benefit from improved intracranial disease control at the possible expense of radiation-related radiographic necrosis. Whether symptomatic radiation injury occurs more frequently in patients receiving pemetrexed requires further study.



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Evaluation of clinical and endoscopic toxicity after external beam radiotherapy and endorectal brachytherapy in elderly patients with rectal cancer treated in the HERBERT study

Publication date: Available online 3 February 2018
Source:Radiotherapy and Oncology
Author(s): E.C. Rijkmans, B. van Triest, R.A. Nout, E.M. Kerkhof, J. Buijsen, T. Rozema, J.H. Franssen, L.A. Velema, M.S. Laman, A. Cats, C.A.M. Marijnen
IntroductionThe HERBERT study evaluated a high-dose-rate endorectal brachytherapy boost (HDREBT) after EBRT in medically inoperable/elderly patients with rectal cancer. The response-rates are promising but not without risk of toxicity. The current analysis provides a comprehensive overview of patient reported, physician reported and endoscopically observed toxicity.Material and methodsA brachytherapy dose finding study was performed in 38 inoperable/elderly patients with T2-T4N0-1 rectal cancer. Patients received EBRT (13 × 3 Gy) followed by three weekly HDREBT applications (5–8 Gy). Toxicity was assessed via three methods: patient and physician (CTCAEv3) reported rectal symptoms and endoscopically. Wilcoxon's signed rank test, paired t-test and Spearman's correlation were used.ResultsPatient reported bowel symptoms showed a marked increase at the end of EBRT and two weeks after HDREBT. Acute grade 2 and 3 proctitis occurred in 68.4% and 13.2% respectively while late grade 2 and ≥3 proctitis occurred in 48% and 40%. Endoscopic evaluation mainly showed erythema and telangiectasia. In three patients frank haemorrhage or ulceration occurred. Most severe toxicity was observed 12–18 months after treatment.ConclusionFor elderly patients with rectal cancer, definitive radiotherapy can provide good tumour response but has a substantial risk of toxicity. The potential benefit and risks of a HDREBT boost above EBRT alone must be further evaluated.



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A qualitative signature for predicting pathological response to neoadjuvant chemoradiation in locally advanced rectal cancers

Publication date: Available online 3 February 2018
Source:Radiotherapy and Oncology
Author(s): You Guo, Weizhong Jiang, Lu Ao, Kai Song, Huxing Chen, Qingzhou Guan, Qiao Gao, Jun Cheng, Huaping Liu, Xianlong Wang, Guoxian Guan, Zheng Guo
Background and purposeThe standard therapy for locally advanced rectal cancers (LARCs) is neoadjuvant chemoradiation (nCRT) followed by surgical resection. Pathological response to nCRT varies among patients, and it remains a challenge to predict pathological response to nCRT in LARCs.Material and methodsUsing 42 samples as the training cohort, we searched a signature by screening the gene pairs whose within-sample relative expression orderings are significantly correlated with the pathological response. The signature was validated in both a public cohort of 46 samples and a cohort of 33 samples measured at our laboratory.ResultsA signature consisting of 27 gene pairs was identified in the training cohort with an accuracy of 92.86% and an area under the receiver operating characteristic curve (AUC) of 0.95. The accuracy was 89.13% for the public test cohort and 90.91% for the private test cohort, with AUC being 0.95 and 0.91, respectively. Furthermore, the signature was used to predict disease-free survival benefits from 5Fu-based chemotherapy in 285 locally advanced colorectal cancers.ConclusionsThe signature consisting of 27 gene pairs can robustly predict clinical response of LARCs to nCRT.



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Differentiation between radiation-induced brain injury and glioma recurrence using 3D pCASL and dynamic susceptibility contrast-enhanced perfusion-weighted imaging

Publication date: Available online 2 February 2018
Source:Radiotherapy and Oncology
Author(s): Yu-Lin Wang, Si Chen, Hua-Feng Xiao, Ying Li, Yan Wang, Gang Liu, Xin Lou, Lin Ma
PurposeThis study was performed to validate the efficacy of three-dimensional pseudocontinuous arterial spin labeling (pCASL) compared with dynamic susceptibility contrast-enhanced perfusion-weighted imaging (DSC-PWI) in distinguishing radiation-induced brain injury from glioma recurrence in patients with glioma.MethodsBoth 3D pCASL and DSC-PWI were performed using a 3.0 Tesla scanner in 69 patients with previously resected and irradiated glioma who displayed newly developed abnormal contrast-enhanced lesions. The included patients were classified into a radiation-induced brain injury group (n = 34) and a glioma recurrence group (n = 35) based on subsequent pathologic analysis or clinical–radiological follow-up. Lesion perfusion parameter values (CBF and nCBF on pCASL, nrCBV and nrCBF on DSC-PWI) were measured and compared between the two groups using Student's t test. Pearson correlation analysis was performed to evaluate the correlation between pCASL (CBF and nCBF) and DSC-PWI (nrCBV and nrCBF) values in the contrast-enhanced lesions and in the perifocal edema regions.ResultsFor the contrast-enhanced lesions, the CBF, nCBF, nrCBV, and nrCBF (29.46 ± 15.08 ml/100 g/min, 1.11 ± 0.50, 1.39 ± 1.15, and 1.30 ± 0.74) in the radiation-induced brain injury group were significantly lower than those (64.52 ± 33.92 ml/100 g/min, 2.73 ± 1.71, 3.39 ± 2.12, and 3.20 ± 1.95) in the glioma recurrence group (P < 0.001). The CBF and nCBF demonstrated strong correlation with nrCBV and nrCBF in the contrast-enhanced lesions.ConclusionRadiation-induced brain injury and glioma recurrence can be reliably distinguished using both 3D pCASL and DSC-PWI. Contrast-free 3D pCASL is a suitable alternative to DSC-PWI for long-term follow-up in glioma patients with postoperative radiotherapy.



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Prognostic significance of pretreatment total lymphocyte count and neutrophil-to-lymphocyte ratio in extensive-stage small-cell lung cancer

Publication date: Available online 2 February 2018
Source:Radiotherapy and Oncology
Author(s): Ryoko Suzuki, Steven H. Lin, Xiong Wei, Pamela K. Allen, James W. Welsh, Lauren A. Byers, Ritsuko Komaki
BackgroundWe evaluated pretreatment total lymphocyte count (TLC, marker of immunosuppression), neutrophil-to-lymphocyte ratio (NLR, marker of inflammation), and overall survival (OS) in patients with extensive-stage small-cell lung cancer (ES-SCLC).MethodsPretreatment blood characteristics, age, sex, performance status, race, stage (M1a vs. M1b), number and location of metastases, weight loss, smoking status, chemotherapy cycles (<4 vs. ≥4), thoracic radiotherapy dose (<45 vs. ≥45 Gy), and receipt of prophylactic cranial irradiation (PCI) were evaluated in 252 patients with ES-SCLC treated in 1998–2015. Factors significant in univariate analysis were selected as covariates for a multivariate Cox model.ResultsPretreatment TLC was below normal (<1.0 × 10³/µL) in 58 patients (23%). Median OS time was 11.0 months and was worse for those with TLC ≤ 1.5 × 10³/µL (9.8 vs. 12.0 months) and pretreatment NLR > 4.0 (9.4 vs. 13.9 months). Multivariate analysis identified low TLC (hazard ratio [HR] 0.734, 95% confidence interval [CI] 0.565–0.955, P = 0.021) and high NLR (HR 1.521, 95% CI 1.172–1.976, P = 0.002) as predicting inferior survival. Age (>63 y), sex (male), performance status (≥2), chemotherapy cycles (<4), radiation dose (<45 Gy), and no PCI also predicted worse OS (P < 0.05).ConclusionsPretreatment TLC and NLR may be useful for stratifying patients with ES-SCLC for treatment approaches.



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Radiotherapy for prostate cancer – Does daily image guidance with tighter margins improve patient reported outcomes compared to weekly orthogonal verified irradiation? Results from a randomized controlled trial

Publication date: Available online 3 February 2018
Source:Radiotherapy and Oncology
Author(s): Hanne Tøndel, Jo-Åsmund Lund, Stian Lydersen, Anne D. Wanderås, Bjørg Aksnessæther, Christer Andre Jensen, Stein Kaasa, Arne Solberg
BackgroundNovel cancer drugs are subject to strict scientific evaluation of safety and efficacy and usually undergo a cost effectiveness analysis before approval for use in clinical practice. For new techniques in radiotherapy (RT) such as image-guided radiotherapy (IGRT), this is often not the case. We performed a randomized controlled trial to compare daily cone beam computer tomography (CBCT) IGRT with reduced planning target volume (PTV) margins vs weekly orthogonal portal imaging with conventional PTV margins. The primary aim of the study was to investigate the effect of two different image guidance techniques on patient reported outcome (PRO) using early side effects as proxy outcome of late rectal side effects in patients receiving curative RT for prostate cancer.MethodsThis open label, phase 3 trial conducted at two RT centers in Norway enrolled men aged 18 years or older with previously untreated histologically proven intermediate or high-risk adenocarcinoma of the prostate. Patients eligible for radical RT received it after 3 months of total androgen blockage and were randomly assigned to 78 Gy in 39 fractions guided either by weekly offline orthogonal portal imaging (15 mm margins to PTV) or by daily online CBCT IGRT (7 mm margins to PTV). Based on previous results indicating that acute rectal side effects are a valid proxy outcome for late rectal side effects, the primary outcome was acute rectal toxicity at end of RT as evaluated by rectal bother scale (five of the items from PRO's QUFW94). The RIC-trial is registered with ClinicalTrials.gov, number NCT01550237.FindingsBetween October 2012 and June 2015, 257 patients were randomly assigned to weekly offline portal imaging (n = 129) or daily online CBCT IGRT (n = 128). Out of 250 evaluable patients, 96% completed PROs at baseline and 97% at end of RT. Baseline analyses demonstrated balance between groups for baseline characteristics as well as for PROs. In general, patients reported a small degree of side effects at end of RT, and there was no difference between groups for primary outcome (rectal bother scale of QUFW94 1.871 vs 1.884, p = 0.804). In addition, there were no significant differences between groups for any other gastrointestinal or urinary symptom as reported by QUFW94. Health related quality of life analyses (EORTC QLQ 30) demonstrated no differences between groups.InterpretationIn radical RT for prostate cancer, daily CBCT IGRT with reduced PTV margins demonstrated no advantage with respect to patient reported side effects at end of RT as compared to weekly orthogonal offline portal imaging with standard PTV margins.



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Preventive radioecological assessment of territory for optimization of monitoring and countermeasures after radiation accidents

Publication date: Available online 3 February 2018
Source:Journal of Environmental Radioactivity
Author(s): B.S. Prister, V.D. Vinogradskaya, T.D. Lev, M.M. Talerko, E.K. Garger, Y. Onishi, O.G. Tischenko
A methodology of a preventive radioecological assessment of the territory has been developed for optimizing post-emergency monitoring and countermeasure implementation in an event of a severe radiation accident. Approaches and main stages of integrated radioecological zoning of the territory are described. An algorithm for the assessment of the potential radioecological criticality (sensitivity) of the area is presented. The proposed approach is validated using data of the dosimetric passportization in Ukraine after the Chernobyl accident for the test site settlements.



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Mapping potassium and thorium concentrations in Belgian soils

Publication date: Available online 2 February 2018
Source:Journal of Environmental Radioactivity
Author(s): Giorgia Cinelli, Francois Tondeur, Boris Dehandschutter
The European Atlas of Natural Radiation developed by the Joint Research Centre (JRC) of the European Commission includes maps of potassium K and thorium Th. With several different databases available, including data (albeit not calibrated) from an airborne survey, Belgium is a favourable case for exploring the methodology of mapping for these natural radionuclides. Harmonized databases of potassium and thorium in soil were built by radiological (not airborne) and geochemical data. Using this harmonized database it was possible to calibrate the data from the airborne survey. Several methods were used to perform spatial interpolation and to smooth the data: moving average (MA) without constraint, or constrained by soil class and by geological unit. Overall, there was a reasonable agreement between the maps on a 1 × 1 km² grid obtained with the two datasets (airborne data and harmonized soil data) with all the methods. The agreement was better when the maps are reduced to a 10 km × 10 km grid used for the European Atlas of Natural Radiation. The best agreement was observed with the MA constrained by geological unit.



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Development and validation of an MRI-based model to predict response to chemoradiotherapy for rectal cancer

To safely implement organ preserving treatment strategies for patients with rectal cancer, well-considered selection of patients with favourable response is needed. In this study, we develop and validate an MRI-based response predicting model.

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Review of the patient positioning reproducibility in head-and-neck radiotherapy using Statistical Process Control

A remarkable improvement in patient positioning was observed after the implementation of various process changes aiming to increase the consistency of patient positioning throughout the radiotherapy treatment chain. However, no tool was available to describe these changes over time in a standardised way. This study reports on the feasibility of Statistical Process Control (SPC) to highlight changes in patient positioning accuracy and facilitate correlation of these changes with the underlying process changes.

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ROS and redox signaling in myocardial ischemia-reperfusion injury and cardioprotection

Publication date: March 2018
Source:Free Radical Biology and Medicine, Volume 117
Author(s): Susana Cadenas
Ischemia-reperfusion (IR) injury is central to the pathology of major cardiovascular diseases, such as stroke and myocardial infarction. IR injury is mediated by several factors including the elevated production of reactive oxygen species (ROS), which occurs particularly at reperfusion. The mitochondrial respiratory chain and NADPH oxidases of the NOX family are major sources of ROS in cardiomyocytes. The first part of this review discusses recent findings and controversies on the mechanisms of superoxide production by the mitochondrial electron transport chain during IR injury, as well as the contribution of the NOX isoforms expressed in cardiomyocytes, NOX1, NOX2 and NOX4, to this damage. It then focuses on the effects of ROS on the opening of the mitochondrial permeability transition pore (mPTP), an inner membrane non-selective pore that causes irreversible damage to the heart. The second part analyzes the redox mechanisms of cardiomyocyte mitochondrial protection; specifically, the activation of the hypoxia-inducible factor (HIF) pathway and the antioxidant transcription factor Nrf2, which are both regulated by the cellular redox state. Redox mechanisms involved in ischemic preconditioning, one of the most effective ways of protecting the heart against IR injury, are also reviewed. Interestingly, several of these protective pathways converge on the inhibition of mPTP opening during reperfusion. Finally, the clinical and translational implications of these cardioprotective mechanisms are discussed.

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Mitochondrial rescue prevents glutathione peroxidase-dependent ferroptosis

Publication date: March 2018
Source:Free Radical Biology and Medicine, Volume 117
Author(s): Anja Jelinek, Lukas Heyder, Michael Daude, Matthias Plessner, Sylvia Krippner, Robert Grosse, Wibke E. Diederich, Carsten Culmsee
Research into oxidative cell death is producing exciting new mechanisms, such as ferroptosis, in the neuropathologies of cerebral ischemia and hemorrhagic brain insults. Ferroptosis is an oxidative form of regulated necrotic cell death featuring glutathione (GSH) depletion, disrupted glutathione peroxidase-4 (GPX4) redox defense and detrimental lipid reactive oxygen species (ROS) formation. Further, our recent findings identified mitochondrial damage in models of oxidative glutamate toxicity, glutathione peroxidase depletion, and ferroptosis. Despite knowledge on the signaling pathways of ferroptosis increasing, the particular role of mitochondrial damage requires more in depth investigation in order to achieve effective treatment options targeting mitochondria.In the present study, we applied RSL3 to induce ferroptosis in neuronal HT22 cells and mouse embryonic fibroblasts. In both cell types, RSL3 mediated concentration-dependent inhibition of GPX4, lipid peroxidation, enhanced mitochondrial fragmentation, loss of mitochondrial membrane potential, and reduced mitochondrial respiration. Ferroptosis inhibitors, such as deferoxamine, ferrostatin-1 and liproxstatin-1, but also CRISPR/Cas9 Bid knockout and the BID inhibitor BI-6c9 protected against RSL3 toxicity. We found compelling new information that the mitochondria-targeted ROS scavenger mitoquinone (MitoQ) preserved mitochondrial integrity and function, and cell viability despite significant loss of GPX4 expression and associated increases in general lipid peroxidation after exposure to RSL3. Our data demonstrate that rescuing mitochondrial integrity and function through the inhibition of BID or by the mitochondria-targeted ROS scavenger MitoQ serves as a most effective strategy in the prevention of ferroptosis in different cell types. These findings expose mitochondria as promising targets for novel therapeutic intervention strategies in oxidative cell death.

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Nrf2/ARE pathway attenuates oxidative and apoptotic response in human osteoarthritis chondrocytes by activating ERK1/2/ELK1-P70S6K-P90RSK signaling axis

Publication date: 20 February 2018
Source:Free Radical Biology and Medicine, Volume 116
Author(s): Nazir M. Khan, Imran Ahmad, Tariq M. Haqqi
Nrf2, a redox regulated transcription factor, has recently been shown to play a role in cartilage integrity but the mechanism remains largely unknown. Osteoarthritis (OA) is a multifactorial disease in which focal degradation of cartilage occurs. Here, we studied whether Nrf2 exerts chondroprotective effects by suppressing the oxidative stress and apoptosis in IL-1β stimulated human OA chondrocytes. Expression of Nrf2 and its target genes HO-1, NQO1 and SOD2 was significantly high in OA cartilage compared to normal cartilage and was also higher in damaged area compared to smooth area of OA cartilage of the same patient. Human chondrocytes treated with IL-1β resulted in robust Nrf2/ARE reporter activity, which was inhibited by pretreatment with antioxidants indicating that Nrf2 activity was due to IL-1β-induced ROS generation. Ectopic expression of Nrf2 significantly suppressed the IL-1β-induced generation of ROS while Nrf2 knockdown significantly increased the basal as well as IL-1β-induced ROS levels in OA chondrocytes. Further, Nrf2 activation significantly inhibited the IL-1β-induced activation of extrinsic and intrinsic apoptotic pathways as determined by inhibition of DNA fragmentation, activation of Caspase-3,−8,−9, cleavage of PARP, release of cytochrome-c, suppression of mitochondrial dysfunction and mitochondrial ROS production in OA chondrocytes. Nrf2 over-expression in OA chondrocytes increased the expression of anti-apoptotic proteins while pro-apoptotic proteins were suppressed. Importantly, Nrf2 over-expression activated ERK1/2 and its downstream targets-ELK1, P70S6K and P90RSK and suppressed the IL-1β-induced apoptosis whereas inhibition of ERK1/2 activation abrogated the protective effects of Nrf2 in OA chondrocytes. Taken together, our data demonstrate that Nrf2 is a stress response protein in OA chondrocytes with anti-oxidative and anti-apoptotic function and acts via activation of ERK1/2/ELK1-P70S6K-P90RSK signaling axis. These activities of Nrf2 make it a promising candidate for the development of novel therapies for the management of OA.

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Deletion of NADPH oxidase 4 reduces severity of traumatic brain injury

Publication date: March 2018
Source:Free Radical Biology and Medicine, Volume 117
Author(s): Merry W. Ma, Jing Wang, Krishnan M. Dhandapani, Darrell W. Brann
Traumatic brain injury (TBI) contributes to over 30% of injury-related deaths and is a major cause of disability without effective clinical therapies. Oxidative stress contributes to neurodegeneration, neuroinflammation, and neuronal death to amplify the primary injury after TBI. NADPH oxidase (NOX) is a major source of reactive oxygen species following brain injury. Our current study addresses the functional role of the NOX4 isoform in the damaged cortex following TBI. Adult male C57BL/6 J and NOX4^-/- mice received a controlled cortical impact and lesion size, NOX4 expression, oxidative stress, neurodegeneration, and cell death were assessed in the injured cerebral cortex. The results revealed that NOX4 mRNA and protein expression were significantly upregulated at 1–7 days post-TBI in the injured cerebral cortex. Expression of the oxidative stress markers, 8-OHdG, 4-HNE, and nitrotyrosine was upregulated at 2 and 4 days post-TBI in the WT injured cerebral cortex, and nitrotyrosine primarily colocalized with neurons. In the NOX4^-/- mice, expression of these oxidative stress markers, 8-OHdG, 4-HNE, and nitrotyrosine were significantly attenuated at both timepoints. In addition, examination of NOX4^-/- mice revealed a reduced number of apoptotic (TUNEL⁺) and degenerating (FJB⁺) cells in the perilesional cortex after TBI, as well as a smaller lesion size compared with the WT group. The results of this study implicate a functional role for NOX4 in TBI induced oxidative damage and neurodegeneration and raise the possibility that targeting NOX4 may have therapeutic efficacy in TBI.

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Hsp90 inhibition renders iNOS aggregation and the clearance of iNOS aggregates by proteasomes requires SPSB2

Publication date: March 2018
Source:Free Radical Biology and Medicine, Volume 117
Author(s): Tingting Wang, Suxin Luo, Honghua Qin, Yong Xia
Inducible nitric oxide synthase (iNOS) plays important roles in cell injury and host defense. Our early study demonstrated that heat shock protein 90 (Hsp90) interacts with iNOS and this interaction enhances iNOS function. Recently, we reported that Hsp90 is also essential for iNOS gene transactivation. In the present study, we investigate the role of Hsp90 in controlling iNOS protein stability. In mouse macrophages, Hsp90 inhibition dissociated Hsp90 from iNOS and the latter subsequently formed aggregates. Aggregation deactivated iNOS. iNOS aggregates were cleared by the ubiquitin-proteasome system (UPS) inside cells. CHIP, an Hsp90-dependent E3 ligase, was previously implicated in iNOS turnover. However, CHIP knockdown had little effect on iNOS degradation in Hsp90-inhibited cells, indicating that other E3 ligases accounted for the clearance of iNOS aggregates. Further studies revealed that the SPRY domain-containing SOCS box protein 2 (SPSB2), an E3 ligase-recruiting protein, was essential for the ubiquitination of iNOS aggregates. SPSB2 knockdown or deleting the SPSB2-interacting domain on iNOS prevented the clearance of iNOS aggregates in Hsp90-inhibited cells. Thus, besides modulating iNOS function and gene transcription, Hsp90 is also essential for the protein stability of iNOS. Hsp90 blockade induces iNOS aggregation and SPSB2 is required for UPS degradation of iNOS aggregates.

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Extracellular redox state shift: A novel approach to target prostate cancer invasion

Publication date: March 2018
Source:Free Radical Biology and Medicine, Volume 117
Author(s): Weixiong Zhong, Heidi L. Weiss, Rani D. Jayswal, Patrick J. Hensley, Laura M. Downes, Daret K. St. Clair, Luksana Chaiswing
AimExtracellular superoxide dismutase (ECSOD) and the cysteine/glutamate transporter (Cys)/(xCT) are tumor microenvironment (TME) redox state homeostasis regulators. Altered expression of ECSOD and xCT can lead to imbalance of the TME redox state and likely have a profound effect on cancer invasion. In the present study, we investigated whether ECSOD and xCT could be therapeutic targets for prostate cancer (PCa) invasion.ResultsImmunohistochemistry of tumor microarray PCa tissues (N = 165) with high Gleason scores indicated that xCT protein expression is significantly increased while ECSOD protein expression is significantly decreased. Metastatic PCa indicated ECSOD protein expression is significantly decreased in epithelial area whereas xCT protein expression is significantly increased in stromal area. Furthermore, inhibition of extracellular O2^•- by overexpression of ECSOD or alteration of the extracellular Cys/CySS ratio by knockdown of xCT protein inhibited PCa cell invasion. Simultaneous overexpression of ECSOD and knockdown xCT inhibited PCa cell invasion more than overexpression of ECSOD or knockdown of xCT alone. In the co-culturing system, simultaneous overexpression of ECSOD and knockdown of xCT in prostate stromal WPMY-1 cells inhibited PCa cell invasiveness more than overexpression of ECSOD alone. The decrease in PCa invasion correlated with increased of extracellular H2O2 levels. Notably, overexpression of catalase in TME reversed the inhibitory effect of ECSOD on cancer cell invasion.ConclusionImpaired ECSOD activity and an upregulated of xCT protein expression may be clinical features of an aggressive PCa, particularly metastatic cancers and/or those with a high Gleason score. Therefore, shifting the extracellular redox state toward an oxidizing status by targeted modulation of ECSOD and xCT, in both cancer and stromal cells, may provide a greater strategy for potential therapeutic interventions of aggressive PCa.

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Modulation of the rod outer segment aerobic metabolism diminishes the production of radicals due to light absorption

Publication date: March 2018
Source:Free Radical Biology and Medicine, Volume 117
Author(s): Daniela Calzia, Paolo Degan, Federico Caicci, Maurizio Bruschi, Lucia Manni, Luca A. Ramenghi, Giovanni Candiano, Carlo Enrico Traverso, Isabella Panfoli
Oxidative stress is a primary risk factor for both inflammatory and degenerative retinopathies. Our previous data on blue light-irradiated retinas demonstrated an oxidative stress higher in the rod outer segment (OS) than in the inner limb, leading to impairment of the rod OS extra-mitochondrial aerobic metabolism.Here the oxidative metabolism and Reactive Oxygen Intermediates (ROI) production was evaluated in purified bovine rod OS in function of exposure to different illumination conditions. A dose response was observed to varying light intensities and duration in terms of both ROI production and ATP synthesis. Pretreatment with resveratrol, inhibitor of F1Fo-ATP synthase, or metformin, inhibitor of the respiratory complex I, significantly diminished the ROI production. Metformin also diminished the rod OS Complex I activity and reduced the maximal OS response to light in ATP production.Data show for the first time the relationship existing in the rod OS between its -aerobic- metabolism, light absorption, and ROI production. A beneficial effect was exerted by metformin and resveratrol, in modulating the ROI production in the illuminated rod OS, suggestive of their beneficial action also in vivo. Data shed new light on preventative interventions for cone loss secondary to rod damage due to oxidative stress.

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Quantification of light-induced miniSOG superoxide production using the selective marker, 2-hydroxyethidium

Publication date: 20 February 2018
Source:Free Radical Biology and Medicine, Volume 116
Author(s): Miriam E. Barnett, Timothy M. Baran, Thomas H. Foster, Andrew P. Wojtovich
Genetically-encoded photosensitizers produce reactive oxygen species (ROS) in response to light. Transgenic expression of fusion proteins can target the photosensitizers to specific cell regions and permit the spatial and temporal control of ROS production. These ROS-generating proteins (RGPs) are widely used for cell ablation, mutagenesis and chromophore-assisted light inactivation of target proteins. However, the species produced by RGPs are unclear due to indirect measures with confounding interpretations. Recently, the RGP mini “Singlet Oxygen Generator” (miniSOG) was engineered from Arabidopsis thaliana phototropin 2. While miniSOG produces singlet oxygen (¹O2), the contribution of superoxide (O2^•-) to miniSOG-generated ROS remains unclear. We measured the light-dependent O2^•- production of purified miniSOG using HPLC separation of dihydroethidium (DHE) oxidation products. We demonstrate that DHE is insensitive to ¹O2 and establish that DHE is a suitable indicator to measure O2^•- production in a system that produces both ¹O2 and O2^•-. We report that miniSOG produces both ¹O2 and O2^•-, as can its free chromophore, flavin mononucleotide. miniSOG produced O2^•- at a rate of ~4.0µmol O2^•-/min/µmol photosensitizer for an excitation fluence rate of 5.9mW/mm² at 470 ± 20nm, and the rate remained consistent across fluences (light doses). Overall, the contribution of O2^•- to miniSOG phenotypes should be considered.

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Crosstalk between Rac1-mediated actin regulation and ROS production

Publication date: 20 February 2018
Source:Free Radical Biology and Medicine, Volume 116
Author(s): Alejandro Acevedo, Christian González-Billault
The small RhoGTPase Rac1 is implicated in a variety of events related to actin cytoskeleton rearrangement. Remarkably, another event that is completely different from those related to actin regulation has the same relevance; the Rac1-mediated production of reactive oxygen species (ROS) through NADPH oxidases (NOX). Each outcome involves different Rac1 downstream effectors; on one hand, events related to the actin cytoskeleton require Rac1 to bind to WAVEs proteins and PAKs that ultimately promote actin branching and turnover, on the other, NOX-derived ROS production demands active Rac1 to be bound to a cytosolic activator of NOX. How Rac1-mediated signaling ends up promoting actin-related events, NOX-derived ROS, or both is poorly understood. Rac1 regulators, including scaffold proteins, are known to exert tight control over its functions. Hence, evidence of Rac1 regulatory events leading to both actin remodeling and NOX-mediated ROS generation are discussed. Moreover, cellular functions linked to physiological and pathological conditions that exhibit crosstalk between Rac1 outcomes are analyzed, while plausible roles in neuronal functions (and dysfunctions) are highlighted. Together, discussed evidence shed light on cellular mechanisms which requires Rac1 to direct either actin- and/or ROS-related events, helping to understand crucial roles of Rac1 dual functionality.

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Roles of mammalian glutathione peroxidase and thioredoxin reductase enzymes in the cellular response to nitrosative stress

Publication date: Available online 3 February 2018
Source:Free Radical Biology and Medicine
Author(s): Moran Benhar
Mammalian cells employ elaborate antioxidant systems to effectively handle reactive oxygen and nitrogen species (ROS and RNS). At the heart of these systems operate two selenoprotein families consisting of glutathione peroxidase (GPx) and thioredoxin reductase (TrxR) enzymes. Although mostly studied in the context of oxidative stress, considerable evidence has amassed to indicate that these selenoenzymes also play important roles in nitrosative stress responses. GPx and TrxR, together with their redox partners, metabolize nitrosothiols and peroxynitrite, two major RNS. As such, these enzymes play active roles in the cellular defense against nitrosative stress. However, under certain conditions, these enzymes are inactivated by nitrosothiols or peroxynitrite, which may exacerbate oxidative and nitrosative stress in cells. The selenol groups in the active sites of GPx and TrxR enzymes are critically involved in these beneficial and detrimental processes. Further elucidation of the biochemical interactions between distinct RNS and GPx/TrxR will lead to a better understanding of the roles of these selenoenzymes in cellular homeostasis and disease.

Graphical abstract

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Update of the systematic review of palliative radiation therapy fractionation for bone metastases

Radiation therapy is an effective modality for pain management of symptomatic bone metastases. We update the previous meta-analyses of randomized trials comparing single fraction to multiple fractions of radiation therapy in patients with uncomplicated bone metastases.

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Surgical indications or inclusion/exclusion criteria of explorative tympanotomy on sudden sensorineural hearing

We read with great interest the work described in the article entitled, “The role of explorative tympanotomy (EXT) in patients with sudden sensorineural hearing loss with and without perilymphatic fistula,” by Prenzler et al. [1]. Sudden sensorineural hearing loss (SSNHL) is a medical emergency frequently seen in patients presenting in the otology clinic. With increasing productivity at work, increased psychological pressure of modern life, and frequent use of headphones, SSNHL has become increasingly common in recent years.

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Non-Contrast MDCT For Ureteral Calculi and Alternative Diagnoses: Yield in Adult Women Versus in Adult Men

Publication date: Available online 2 February 2018
Source:Current Problems in Diagnostic Radiology
Author(s): Parisa Fani, Michael N. Patlas, Sandra Monteiro, Douglas S. Katz
PurposeTo determine the yield of non-contrast Multi-Detector Computed Tomography (MDCT) of the abdomen and pelvis in diagnosing the ureteral calculus as well as other alternative acute conditions in male versus in female patients presenting to the emergency department with new onset symptoms.MethodsOur institutional review board approved a retrospective review of the official reports of the non-contrast MDCT examination of the abdomen and pelvis performed on adults (18 years and older) presenting to our emergency department with suspected ureteral calculus from October 1, 2011 to Oct 30, 2013. Patients with recently documented ureteral calculi, known urinary tract infection, malignancy and trauma were excluded from the study. From a total of 1097 non-contrast MDCT examinations of the abdomen and pelvis over the 2-year period, 400 randomly selected cases were reviewed (approximately one-third of all the examinations). We compared the prevalence of ureteral calculi between the male and female population. P value and confidence intervals were determined using software Stata 14. Other acute intra-abdominal findings amenable to prompt medical care were also documented and analyzed separately.ResultsThe mean age was 55.2 years, with a range of 19 to 90 years. This included 170 female (mean age 56.8 years) and 230 male patients (mean age 54.2 years). Ureteral calculi were detected in 170 (42.5%) of the patients [111 male (48%) and 59 female (34.7%)] with prevalence significantly higher in the male patients compared to in female patients (p<0.01, confidence level of 95% and CI of 13.2–13.4). Alternative diagnosis was made in 49 cases (12.25 %), including 26 females (15.29%) and 23 males (10.00%). There was no significant difference in alternative acute findings in male compared to in female patients (p > 0.05). This was with the exception of acute pyelonephritis, which was significantly higher in the female patients (p<0.01).ConclusionOur study determined that the likelihood of making the diagnosis of a ureteral calculus on non-contrast MDCT of the abdomen and pelvis was significantly higher in male patients compared with female patients presenting to our emergency department. However, there was no statistically significant difference in the alternative diagnoses, with the exception of pyelonephritis, which was more common in women.



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Pancreatic Walled-Off Necrosis Eroding into the Inferior Vena Cava: A Case Report

Publication date: Available online 2 February 2018
Source:Current Problems in Diagnostic Radiology
Author(s): Anupama Ramachandran, Sanchit Sharma, Shalimar, Raju Sharma, Kumble Seetharama Madhusudhan
Walled off necrosis (WON) is a well-known delayed local complication of acute necrotizing pancreatitis. Occasionally, WON may spontaneously rupture into the gastrointestinal tract or peritoneal cavity. However, erosion of a WON to a systemic vein has not been reported in literature so far. We report an unusual case of a 63-year-old male with acute necrotizing pancreatitis in whom WON was eroding into the inferior vena cava resulting in its thrombosis. Our patient also had a bunch of other well described complications of pancreatitis including splanchnic venous thrombosis.



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Assess, manage and prevent cancer-related neutropenia in your patients. Start our free module today!… https://t.co/JYlUsVTfJu

Assess, manage and prevent cancer-related neutropenia in your patients. Start our free module today!… https://t.co/JYlUsVTfJu

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New perspectives to improve critical care benchmarking

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Effects of processing parameters on the caffeine extraction yield during decaffeination of black tea using pilot-scale supercritical carbon dioxide extraction technique

Abstract

In this pilot-scale study supercritical carbon dioxide (SCCO₂) extraction technique was used for decaffeination of black tea. Pressure (250, 375, 500 bar), extraction time (60, 180, 300 min), temperature (55, 62.5, 70 °C), CO₂ flow rate (1, 2, 3 L/min) and modifier quantity (0, 2.5, 5 mol%) were selected as extraction parameters. Three-level and five-factor response surface methodology experimental design with a Box–Behnken type was employed to generate 46 different processing conditions. 100% of caffeine from black tea was removed under two different extraction conditions; one of which was consist of 375 bar pressure, 62.5 °C temperature, 300 min extraction time, 2 L/min CO₂ flow rate and 5 mol% modifier concentration and the other was composed of same temperature, pressure and extraction time conditions with 3 L/min CO₂ flow rate and 2.5 mol% modifier concentration. Results showed that extraction time, pressure, CO₂ flow rate and modifier quantity had great impact on decaffeination yield.

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Antibacterial activity and mode of action of totarol against Staphylococcus aureus in carrot juice

Abstract

Food contaminated with pathogenic bacteria such as Staphylococcus aureus (S. aureus), represents a serious health risk to human beings. Totarol is an antibacterial novel phenolic diterpenes. In present study, the antibacterial activity of totarol against S. aureus was investigated in a food system. The antibacterial activity of totarol was determined by measuring the zones of inhibition and minimum inhibitory concentrations (MICs). The MICs for S. aureus strains were in the range of 2–4 μg/ml. The probable antibacterial mechanism of totarol was the alteration in cell membranes integrity and permeability, which leading to the leakage of cellular materials. The electric conductivity showed a time- and dose-dependent increasing manner, and we utilized totarol to induce the production of cytoplasmic β-galactosidase in S. aureus. Scanning electron microscopy and transmission electron microscopy analysis further confirmed that S. aureus cell membranes were damaged by totarol. The time-kill assay and detection of the kinetics of S. aureus deactivation in situ indicated that totarol has good preservative activities in a food model. Totarol successfully inhibited S. aureus development in carrot juice, at room temperature (25 °C) and in refrigerator (4 °C) respectively. Our works provided not only additional evidences in support of totarol being regarded as a natural antibacterial food preservative but also fundamental understanding on the mode of antibacterial action. It is necessary to consider that totarol will become a promising antibacterial additive for food preservative.

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Analysis of NO–suppressing activity of Strawberry Wine supplemented with ball-milled achenes

Abstract

Inflammation is generally thought to be involved in the development of several chronical diseases, therefore, phytochemicals to modulate immune responses has attracted great interests. The objective of the present study was to evaluate the potential anti-inflammatory effects of wine supplemented using ball-milled achene on modulating NO production and inducible nitric oxide synthase (iNOS) expression. Ball-milled achenes were added in strawberry must prior to fermentation, and the wine samples were then concentrated and extracted with water and/or ethanol prior to analysis. Bioactivities of wine extracts were evaluated using the cell viability assay, cell cycle measurements, NO production and iNOS expression in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Treatments of achenes supplemented strawberry wine extract up to 100 μg/mL inhibited the proliferation of LPS-stimulated RAW264.7 cell via affecting the progression of cell cycle. Moreover, no detectable cytotoxicity in RAW264.7 cells was observed. The supplemented wine extract suppressed the action of LPS and led to a decreased NO production in stimulated cells. The inhibitory effect of the wine extract on NO production was determined to be a 25–40% decrease in the level of 25–100 μg/mL, in contrast to a 10% decrease for conventional wine samples. Additionally, an alcoholic wine extract (100 μg/mL) led to a 40.31% decrease in iNOS expression in LPS-stimulated cells, which was more effective than the same dose of tocopherol. The results show that strawberry wine supplemented with ball-milled achenes causes a substantial inhibition of NO production, and this biofunction is exerted via the down-regulation of iNOS expression.

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Effects of packaging and pre-storage treatments on aflatoxin production in peanut storage under controlled conditions

Abstract

This study reports on aflatoxin production and peanut (Bailey’s variety) quality, for four peanut pre-storage treatments; [(Raw clean (Raw-Cl), Raw inoculated with Aspergillus flavus NRRL 3357 (Raw-Inf), inoculated partially roasted but not-blanched (PRN-blanch); and inoculated partially roasted, blanched with discolored nuts sorted out (PR-blanched)]. All four treated samples were packaged in four different packaging systems [polypropylene woven sacks (PS), hermetic packs (HP), hermetic packs with oxygen absorbers (HPO), and vacuumed hermetic packs (HPV)] and stored under controlled conditions at a temperature of 30 ± 1 °C and water activity of 0.85 ± 0.02, for 14 weeks. Raw-Inf samples in PS had a higher fungal growth with a mean value of 8.01 × 10⁴ CFU/g, compared to the mean values of samples in hermetic packs: 1.07 × 10³ CFU/g for HP, 14.55 CFU/g for HPO, and 57.82 CFU/g for HPV. Similarly, the hermetic bags were able to reduce aflatoxin level of the Raw-Inf samples by 50.6% (HP), 63.0% (HPV), and 66.8% (HPO). Partial roasting and blanching in PS also reduced aflatoxin level by about 74.6%. Quality maintenance was the best for peanuts in HPO, recording peroxide value (PV) of 10.16 meq/kg and p-Anisidine (p-Av) of 3.95 meq/kg compared to samples in polypropylene woven sacks which had PV of 19.25 meq/kg and p-Av of 6.48 meq/kg. These results indicate that using zero-oxygen hermetic packaging, instead of the conventional polypropylene woven sacks, helped to suppress aflatoxin production and quality deterioration. Also, partially roasted, blanched and sorted peanuts showed a potential for reducing aflatoxin presence during storage.

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Assessing the fatty acid, essential oil composition, their radical scavenging and antibacterial activities of Schinus terebinthifolius Raddi leaves and twigs

Abstract

The fatty acid, essential oil compositions and their respective antioxidant and antibacterial activities was determined in Schinus terebinthifolius Raddi leaves and twigs. The lipid content ranged from 1.75 to 4.65% in twigs and leaves, respectively. Thirteen fatty acids were identified with α-linolenic (C18:3), palmitic (C16:0) and linoleic (C18:2) acids being the main components. The essential oils of both organs were characterized by a high amount of monoterpene hydrocarbons (68.91–74.88%) with α-phellandrene (33.06–36.18%), α-pinene (14.85–15.18%) and limonene (6.62–8.79%) being the chief components. The DPPH˙ radical scavenging assay revealed that both oils have a very weak antiradical activity. In contrast, they showed an appreciable antibacterial activity against the gram-positive Enterococcus feacium (ATCC 19434) and Streptococcus agalactiae (ATCC 13813) bacteria. These results suggest that leaves and twigs of S. terebinthifolius could be considered as an important dietary source of health promoting phytochemicals and has a good potential for use in food industry and pharmacy.

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Treatment of extensive post tonsillectomy oropharyngeal stenosis secondary to fibromatosis

Aggressive fibromatosis is an uncommon, benign tumor of fibroblastic origin with high potential for local invasion. Less than a quarter of these lesions are located in the head and neck, and although extremely rare, associations have been demonstrated with physical trauma. We describe a unique case of oropharyngeal fibromatosis with traumaticetiology, managed successfully with surgical excision of the lesion with negative surgical margins. A 5-year old patient was found to have an aggressive fibromatosis causing oropharyngeal stenosis following tonsillectomy.

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IJMS, Vol. 19, Pages 462: Influence of Graded Levels of l-Theanine Dietary Supplementation on Growth Performance, Carcass Traits, Meat Quality, Organs Histomorphometry, Blood Chemistry and Immune Response of Broiler Chickens

IJMS, Vol. 19, Pages 462: Influence of Graded Levels of l-Theanine Dietary Supplementation on Growth Performance, Carcass Traits, Meat Quality, Organs Histomorphometry, Blood Chemistry and Immune Response of Broiler Chickens

International Journal of Molecular Sciences doi: 10.3390/ijms19020462

Authors: Muhammad Saeed Xu Yatao Faiz-ul Hassan Muhammad Arain Mohamed Abd El-Hack Ahmed Noreldin Chao Sun

l-theanine is a water-soluble non-proteinous amino acid mainly found in green tea leaves. Despite the availability of abundant literature on green tea, studies on the use of l-theanine as a feed additive in animals, and especially broilers are limited. The objective of this study was, therefore, to evaluate the effect of different dietary levels of l-theanine on meat quality, growth performance, immune response, and blood metabolites in broilers. A total of 400 day-old broiler chicks were randomly divided into four treatment groups using a completely randomized design; C-control, basal diet; 100LT-basal diet + 100 mg l-theanine/kg diet; 200LT-basal diet + 200 mg l-theanine/kg diet; and 300LT-basal diet + 300 mg l-theanine/kg diet. Results revealed that the intermediate level of l-theanine (200 mg/kg diet) showed better results in terms of body weight gain (BWG), feed consumed (FC), and feed conversion ratio (FCR) as compared with the other supplemented groups and the control. The live weight eviscerated weight and gizzard weight were higher in all l-theanine levels as compared to those of the control group. Increased weight (p ≤ 0.05) of spleen and bursa were found in group 200LT (200 mg l-theanine/kg diet). Concerning meat color parameters, values for yellowness (b*), and redness (a*) were greater in l-theanine-supplemented groups than the control. Supplementing broiler diet with l-theanine reduced (p = 0.02) total serum cholesterol contents while increased HDL. Further analysis revealed lower relative serum cytokines (IL-2 and INF-γ) and reduced mRNA expression of TNF-α and IL-6 in thymus, and IFN-γ and IL-2 in spleen in the treated group. Moreover, supplementation with 200 mg/kg of l-theanine improved antioxidant status in blood by increasing SOD, GSH-Px, and relative CAT levels. It is concluded that the optimum supplementation level of l-theanine is 200 mg/kg of diet because it resulted in improved performance parameters in broilers. However, higher levels of l-theanine (300 mg/kg diet) may have deleterious effects on performance and health of broiler chickens.

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Impact of pollution on Allergy/immunology

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Hereditary Angioedema with Normal C1 Inhibitor: Four Types and Counting

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Single-cell Transcriptome Analyses Reveal Molecular Signals to Intrinsic and Acquired Paclitaxel Resistance in Esophageal Squamous Cancer Cells

Paclitaxel is widely used in the combination chemotherapy for many cancers including esophageal squamous cell carcinoma (ESCC). However, the paclitaxel resistance occurs frequently in treating ESCC and the mechanism is not fully understood yet. The heterogeneity of gene expression within the drug-resistant cancer cells may be one of the major factors contributing to its resistance. In the present study, we successfully induced paclitaxel resistance in ESCC cell line KYSE-30 through low dose and long-term treatment of paclitaxel.

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The 5T4 oncofetal glycoprotein does not act as a general organizer of the CXCL12 system in cancer cells

Publication date: Available online 2 February 2018
Source:Experimental Cell Research
Author(s): Malte Puchert, Christian Koch, Jürgen Engele
The chemokine, CXCL12, promotes cancer growth and metastasis through interaction with either CXCR4 and/or CXCR7. This tumor-specific organization of the CXCL12 system obscures current therapeutic approaches, aiming at the selective inactivation of CXCL12 receptors. Since it has been previously suggested that the cellular use of CXCR4 or CXCR7 is dictated by the 5T4 oncofetal glycoprotein, we have now tested whether 5T4 would represent a general and reliable marker for the organization of the CXCL12 system in cancer cells. The CXCR4 antagonist, AMD3100, as well as the CXCR7 antagonist, CCX771, demonstrated that the cancer cell lines A549, C33A, DLD-1, MDA-231, and PC-3 use either CXCR7 and/or CXCR4 for mediating CXCL12-induced chemotaxis and cell proliferation. The use of CXCL12 receptors as well as their subcellular localization remained unchanged in most cell lines following siRNA-mediated depletion of 5T4. In distinct cell lines, inhibition of 5T4 expression, however, modulated tumor cell migration and proliferation per se. Collectively our analyses fail to demonstrate general organizational influences of 5T4 of the CXCL12 system in different cancer cell lines, and, hence, dismiss its future use as a diagnostic marker.



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EMT-related Transcription Factor Snail up-regulates FAPα in Malignant Melanoma Cells

Publication date: Available online 2 February 2018
Source:Experimental Cell Research
Author(s): Yanmei Yi, Zhaotong Wang, Yanqin Sun, Junhu Chen, Biao Zhang, Minhua Wu, Tianyu Li, Li Hu, Jun Zeng
FAPα is a cell surface serine protease, mainly expressed in tumor stromal fibroblasts in more than 90% of human epithelial carcinomas. Due to its almost no expression in normal tissues and its tumor-promoting effects, FAPα has been studied as a novel potential target for antitumor therapy. However, the regulation mechanism on FAPα expression is poorly understood. In this study, we found that overexpression of snail significantly increased the mRNA and protein expression levels of FAPα in malignant melanoma B16 and SK-MEL-28 cells. Overexpression of snail increased FAPα promoter activity remarkably. Snail could directly bind to FAPα promoter to regulate FAPα expression. Moreover, snail expression was positively correlated to FAPα expression in human cutaneous malignant melanoma. Furthermore, knockdown of FAPα markedly reduced snail-induced cell migration. Overall, our findings provide a novel regulation mechanism on FAPα expression and highlight the role of snail/FAPα axis as a novel target for melanoma treatment.



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Vasoactive intestinal peptide inhibits airway smooth muscle cell proliferation in a mouse model of asthma via the ERK1/2 signaling pathway

Publication date: Available online 2 February 2018
Source:Experimental Cell Research
Author(s): Juan Wang, Yun-Xiao Shang, Xu-Xu Cai, Li-Yun Liu
Asthma is a heterogeneous clinical syndrome characterized by airway inflammation, hyper-responsiveness and remodeling. Airway remodeling is irreversible by current antiasthmatic drugs, and it is the main cause of severe asthma. Airway smooth muscle cells (ASMCs) act as the main effector cells for airway remodeling; the proliferation and hypertrophy of which are involved in airway remodeling. Caveolin (Cav)−1 is present on the surface of ASMCs, which is involved in cell cycle and signal transduction regulation, allowing ASMCs to change from proliferation to apoptosis. The extracellular signal-regulated kinase (ERK)1/2 signaling pathway is a common pathway regulated by various proliferative factors, which demonstrates a regulatory role in airway remodeling of asthma. There have been many studies on the correlation between vasoactive intestinal peptide (VIP) and airway reactivity and inflammation in asthma, but the functions and related mechanisms of ASMCs remain unclear. In this study, we established an airway remodeling model in asthmatic mice, and concluded that VIP inhibits airway remodeling in vivo. The in vitro effect of VIP on interleukin-13-induced proliferation of ASMCs was studied by examining the effects of VIP on expression of ERK1/2, phospho-ERK1/2 and Cav-1 in ASMCs, as well as changes in cell cycle distribution. VIP inhibited phosphorylation of the ERK1/2 signaling pathway and expression of Cav-1 on ASMCs and decreased the proportion of S phase cells in the cell cycle, thus inhibiting the proliferation of ASMCs. This study provides a novel therapeutic mechanism for the treatment of asthma.



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Elongation factor-2 kinase acts downstream of p38 MAPK to regulate proliferation, apoptosis and autophagy in human lung fibroblasts

Publication date: Available online 3 February 2018
Source:Experimental Cell Research
Author(s): Yanni Wang, Guojin Huang, Zhixia Wang, Huiping Qin, Biwen Mo, Changming Wang
Idiopathic pulmonary fibrosis (IPF) is a chronic, fatal and progressive fibro-proliferative lung disease, and fibroblast-to-myofibroblast differentiation is a crucial process in the development of IPF. Elongation factor-2 kinase (eEF2K) has been reported to play an important role in various disease types, but the role of eEF2K in IPF is unknown. In this study, we investigated the role of eEF2K in normal lung fibroblast (NHLF) proliferation, differentiation, apoptosis, and autophagy as well as the interaction between eEF2K and p38 MAPK signaling through in vitro experiments. We found that the inhibition of eEF2K markedly augmented cell proliferation and differentiation, suppressed apoptosis and autophagy, and reversed the anti-fibrotic effects of a p38 MAPK inhibitor. Together, our results indicate that eEF2K might inhibit TGF-β1-induced NHLF proliferation and differentiation and activate NHLF cell apoptosis and autophagy through p38 MAPK signaling, which might ameliorate lung fibroblast-to-myofibroblast differentiation.



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IJMS, Vol. 19, Pages 461: Evaluation of Polyphenol Anthocyanin-Enriched Extracts of Blackberry, Black Raspberry, Blueberry, Cranberry, Red Raspberry, and Strawberry for Free Radical Scavenging, Reactive Carbonyl Species Trapping, Anti-Glycation, Anti-β-Amyloid Aggregation, and Microglial Neuroprotective Effects

IJMS, Vol. 19, Pages 461: Evaluation of Polyphenol Anthocyanin-Enriched Extracts of Blackberry, Black Raspberry, Blueberry, Cranberry, Red Raspberry, and Strawberry for Free Radical Scavenging, Reactive Carbonyl Species Trapping, Anti-Glycation, Anti-β-Amyloid Aggregation, and Microglial Neuroprotective Effects

International Journal of Molecular Sciences doi: 10.3390/ijms19020461

Authors: Hang Ma Shelby Johnson Weixi Liu Nicholas DaSilva Susan Meschwitz Joel Dain Navindra Seeram

Glycation is associated with several neurodegenerative disorders, including Alzheimer’s disease (AD), where it potentiates the aggregation and toxicity of proteins such as β-amyloid (Aβ). Published studies support the anti-glycation and neuroprotective effects of several polyphenol-rich fruits, including berries, which are rich in anthocyanins. Herein, blackberry, black raspberry, blueberry, cranberry, red raspberry, and strawberry extracts were evaluated for: (1) total phenolic and anthocyanins contents, (2) free radical (DPPH) scavenging and reactive carbonyl species (methylglyoxal; MGO) trapping, (3) anti-glycation (using BSA-fructose and BSA-MGO models), (4) anti-Aβ aggregation (using thermal- and MGO-induced fibrillation models), and, (5) murine microglia (BV-2) neuroprotective properties. Berry crude extracts (CE) were fractionated to yield anthocyanins-free (ACF) and anthocyanins-enriched (ACE) extracts. The berry ACEs (at 100 μg/mL) showed superior free radical scavenging, reactive carbonyl species trapping, and anti-glycation effects compared to their respective ACFs. The berry ACEs (at 100 μg/mL) inhibited both thermal- and MGO-induced Aβ fibrillation. In addition, the berry ACEs (at 20 μg/mL) reduced H2O2-induced reactive oxygen species production, and lipopolysaccharide-induced nitric oxide species in BV-2 microglia as well as decreased H2O2-induced cytotoxicity and caspase-3/7 activity in BV-2 microglia. The free radical scavenging, reactive carbonyl trapping, anti-glycation, anti-Aβ fibrillation, and microglial neuroprotective effects of these berry extracts warrant further in vivo studies to evaluate their potential neuroprotective effects against AD.

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Optimization of ultrasound-assisted extraction (UAE) of phenolic compounds from olive cake

Abstract

The use of ultrasound in ultrasound-assisted extraction (UAE) is one of the main applications of this technology in food industry. This study aimed to optimize UAE conditions for olive cake extract (OCE) through response surface methodology (RSM). The optimal UAE conditions were obtained with extraction temperature of 56 °C, extraction time of 3 min, duty cycle of 0.6 s, and solid to solvent ratio of 3.6%. At the optimum conditions, the total phenolic compounds (TPC) content and antioxidant activity (AA) were measured 4.04 mg/g and 68.9%, respectively. The linear term of temperature had the most effect on TPC content and AA of OCE prepared by UAE. Protocatechuic acid and cinnamic acid were characterized as the highest (19.5%) and lowest (1.6%) phenolic compound measured in OCE extracted by UAE. This research revealed that UAE is an effective method to extract phenolic compounds from olive cake. RSM successfully optimized UAE conditions for OCE.

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Storage quality of walnut oil containing lycopene during accelerated oxidation

Abstract

The purpose of investigation was to assess the effect of lycopene on the peroxide value, acid value, fatty acids, total phenolic content and ferric-reducing antioxidant power of walnut oil. Walnut oil was extracted from Xinjiang walnut variety using cold pressing method. Our study reported that after 45 days of accelerated oxidation at 60 °C (Schaal oven test), 0.005% lycopene exhibited the greatest antioxidant effect than other addition levels of lycopene. Therefore, under ambient storage conditions, the shelf-life of walnut oil could be extended up to 16 months by 0.005% lycopene. Moreover, 0.005% lycopene added to walnut oil had a significantly higher content of saturated fatty acid, unsaturated fatty acid, total phenol, reducing ability of the polar and non-polar components than the blank sample (walnut oil without any addition of lycopene). In conclusion, lycopene improved the quality of walnut oil because of its antioxidant effect against lipid oxidation.

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A Phase II trial of 8 weeks of degarelix for prostate volume reduction: Efficacy and hormonal recovery

Publication date: Available online 2 February 2018
Source:Brachytherapy
Author(s): M.A. Korzeniowski, J.M. Crook, D. Bowes, M. Gaztañaga, A. Ots, J. Jazwal, J. Rose, A. Tétreault-Laflamme, L. Pilote, R. Halperin, D. Kim, D. Petrik, C. Araujo, F. Bachand
PurposeThe purpose of this study was to determine the efficacy of 8 weeks of degarelix for prostate downsizing before interstitial brachytherapy. We also report associated toxicity and the time course of endocrine recovery over the following 12 months.Methods and MaterialsFifty patients were accrued to an open-label Phase II clinical trial (www.clinicaltrials.gov ID NCT01446991). Baseline prostate transrectal ultrasound (TRUS) was performed on all patients followed by degarelix administration and a repeat TRUS at Week 8. Brachytherapy was performed within 4 weeks of the 8-week TRUS for all patients who achieved suitable downsizing.ResultsThe median prostate volume was reduced from 65.0 cc (interquartile range [IQR]: 55.2–80.0 cc) to 48.2 cc at 8 weeks (IQR: 41.2–59.3 cc), representing a median decrease of 26.2% (IQR: 21–31%). Functional recovery of testosterone within an age-adjusted normal range occurred at a median of 34.1 weeks (IQR: 28.2–44.5 weeks) from the date of the final injection. Despite this recovery, follicle-stimulating hormone and luteinizing hormone levels remained abnormally elevated throughout 12 months. Quality-of-life implications are discussed.ConclusionsDegarelix is effective for prostate downsizing before prostate brachytherapy with a median volume decrease of 26.2% by 8 weeks. Despite the short course of treatment and eventual testosterone recovery, follicle-stimulating hormone and luteinizing hormone remain elevated beyond 12 months. Further investigation with randomized comparisons to other hormonal agents is warranted.



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Masthead

Publication date: January–February 2018
Source:Brachytherapy, Volume 17, Issue 1





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Table of Contents

Publication date: January–February 2018
Source:Brachytherapy, Volume 17, Issue 1





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Editorial Board

Publication date: January–February 2018
Source:Brachytherapy, Volume 17, Issue 1





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Treatment delivery verification in brachytherapy: Prospects of technology innovation

Publication date: January–February 2018
Source:Brachytherapy, Volume 17, Issue 1
Author(s): Kari Tanderup, Christian Kirisits, Antonio L. Damato




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Comparing the RTOG/EORTC and LENT-SOMA scoring systems for the evaluation of late skin toxicity after 125I seed brachytherapy for parotid gland cancer

Publication date: January–February 2018
Source:Brachytherapy, Volume 17, Issue 1
Author(s): Ming-hui Mao, Jie Zhang, Jian-Guo Zhang




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Technique adaptation, strategic replanning, and team learning during implementation of MR-guided brachytherapy for cervical cancer

Publication date: January–February 2018
Source:Brachytherapy, Volume 17, Issue 1
Author(s): Julia Skliarenko, Marco Carlone, Kari Tanderup, Kathy Han, Akbar Beiki-Ardakani, Jette Borg, Kitty Chan, Jennifer Croke, Alexandra Rink, Anna Simeonov, Reem Ujaimi, Jason Xie, Anthony Fyles, Michael Milosevic
PurposeMR-guided brachytherapy (MRgBT) with interstitial needles is associated with improved outcomes in cervical cancer patients. However, there are implementation barriers, including magnetic resonance (MR) access, practitioner familiarity/comfort, and efficiency. This study explores a graded MRgBT implementation strategy that included the adaptive use of needles, strategic use of MR imaging/planning, and team learning.Methods and MaterialsTwenty patients with cervical cancer were treated with high-dose-rate MRgBT (28 Gy in four fractions, two insertions, daily MR imaging/planning). A tandem/ring applicator alone was used for the first insertion in most patients. Needles were added for the second insertion based on evaluation of the initial dosimetry. An interdisciplinary expert team reviewed and discussed the MR images and treatment plans.ResultsDosimetry-trigger technique adaptation with the addition of needles for the second insertion improved target coverage in all patients with suboptimal dosimetry initially without compromising organ-at-risk (OAR) sparing. Target and OAR planning objectives were achieved in most patients. There were small or no systematic differences in tumor or OAR dosimetry between imaging/planning once per insertion vs. daily and only small random variations. Peer review and discussion of images, contours, and plans promoted learning and process development.ConclusionsTechnique adaptation based on the initial dosimetry is an efficient approach to implementing MRgBT while gaining comfort with the use of needles. MR imaging and planning once per insertion is safe in most patients as long as applicator shifts, and large anatomical changes are excluded. Team learning is essential to building individual and programmatic competencies.



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IJMS, Vol. 19, Pages 459: Epigenetics and MicroRNAs in Cancer

IJMS, Vol. 19, Pages 459: Epigenetics and MicroRNAs in Cancer

International Journal of Molecular Sciences doi: 10.3390/ijms19020459

Authors: Alice Ramassone Sara Pagotto Angelo Veronese Rosa Visone

The ability to reprogram the transcriptional circuitry by remodeling the three-dimensional structure of the genome is exploited by cancer cells to promote tumorigenesis. This reprogramming occurs because of hereditable chromatin chemical modifications and the consequent formation of RNA-protein-DNA complexes that represent the principal actors of the epigenetic phenomena. In this regard, the deregulation of a transcribed non-coding RNA may be both cause and consequence of a cancer-related epigenetic alteration. This review summarizes recent findings that implicate microRNAs in the aberrant epigenetic regulation of cancer cells.

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IJMS, Vol. 19, Pages 458: Molecular Pharmacology of Rosmarinic and Salvianolic Acids: Potential Seeds for Alzheimer’s and Vascular Dementia Drugs

IJMS, Vol. 19, Pages 458: Molecular Pharmacology of Rosmarinic and Salvianolic Acids: Potential Seeds for Alzheimer’s and Vascular Dementia Drugs

International Journal of Molecular Sciences doi: 10.3390/ijms19020458

Authors: Solomon Habtemariam

Both caffeic acid and 3,4-dihydroxyphenyllactic acid (danshensu) are synthesized through two distinct routs of the shikimic acid biosynthesis pathway. In many plants, especially the rosemary and sage family of Lamiaceae, these two compounds are joined through an ester linkage to form rosmarinic acid (RA). A further structural diversity of RA derivatives in some plants such as Salvia miltiorrhiza Bunge is a form of RA dimer, salvianolic acid-B (SA-B), that further give rise to diverse salvianolic acid derivatives. This review provides a comprehensive perspective on the chemistry and pharmacology of these compounds related to their potential therapeutic applications to dementia. The two common causes of dementia, Alzheimer’s disease (AD) and stroke, are employed to scrutinize the effects of these compounds in vitro and in animal models of dementia. Key pharmacological mechanisms beyond the common antioxidant and anti-inflammatory effects of polyphenols are highlighted with emphasis given to amyloid beta (Aβ) pathologies among others and neuronal regeneration from stem cells.

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IJMS, Vol. 19, Pages 460: MicroRNAs as New Biomarkers for Diagnosis and Prognosis, and as Potential Therapeutic Targets in Acute Myeloid Leukemia

IJMS, Vol. 19, Pages 460: MicroRNAs as New Biomarkers for Diagnosis and Prognosis, and as Potential Therapeutic Targets in Acute Myeloid Leukemia

International Journal of Molecular Sciences doi: 10.3390/ijms19020460

Authors: Stefania Trino Daniela Lamorte Antonella Caivano Ilaria Laurenzana Daniela Tagliaferri Geppino Falco Luigi Del Vecchio Pellegrino Musto Luciana De Luca

Acute myeloid leukemias (AML) are clonal disorders of hematopoietic progenitor cells which are characterized by relevant heterogeneity in terms of phenotypic, genotypic, and clinical features. Among the genetic aberrations that control disease development there are microRNAs (miRNAs). miRNAs are small non-coding RNAs that regulate, at post-transcriptional level, translation and stability of mRNAs. It is now established that deregulated miRNA expression is a prominent feature in AML. Functional studies have shown that miRNAs play an important role in AML pathogenesis and miRNA expression signatures are associated with chemotherapy response and clinical outcome. In this review we summarized miRNA signature in AML with different cytogenetic, molecular and clinical characteristics. Moreover, we reviewed the miRNA regulatory network in AML pathogenesis and we discussed the potential use of cellular and circulating miRNAs as biomarkers for diagnosis and prognosis and as therapeutic targets.

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"Otolaryngol Head Neck Surg"[jour]; +31 new citations

31 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Otolaryngol Head Neck Surg"[jour]

These pubmed results were generated on 2018/02/03

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

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Utility of Neutrophil-to-Lymphocyte Ratio (NLR) as a Predictor of Acute Infarction in New-Onset Acute Vertigo Patients Without Neurologic and Computed Tomography Abnormalities

Publication date: Available online 2 February 2018
Source:The Journal of Emergency Medicine
Author(s): Sun Hwa Lee, Seong Jong Yun, Seokyong Ryu, Seung Woon Choi, Hye Jin Kim, Tae Kyung Kang, Sung Chan Oh, Suk Jin Cho
BackgroundNeutrophil-to-lymphocyte ratio (NLR) has been used as a predictive marker for various conditions. However, there are no previous studies about NLR as a prognostic marker for acute infarction.ObjectiveTo evaluate the potential utility of NLR as a predictor of acute infarction in acute vertigo patients without neurologic and computed tomography (CT) abnormalities.MethodsWe conducted a prospective, observational study in the Emergency Department (ED) between January 2015 and December 2016. All patients underwent physical examination, laboratory tests, CT, and magnetic resonance imaging (MRI). Results of the initial and follow-up MRI with clinical progress note were considered as the reference standard. Statistically, multivariate logistic regression analysis and receiver operating characteristic (ROC) curve were used.ResultsThirty-five (25.9%) patients were diagnosed with acute infarction and 100 (74.1%) patients were diagnosed with peripheral vertigo. Horizontal nystagmus (p = 0.03; odds ratio 0.22) and NLR (p = 0.03; odds ratio 5.4) were significant factors for the differential diagnosis of acute infarction and peripheral vertigo. NLR > 2.8 showed the greatest area under the ROC curve (AUC; 0.819), optimal sensitivity (85.7%), and specificity (78.0%). NLR > 1.4 showed the highest sensitivity (97.1%) and relatively low specificity (41%). The absence of horizontal nystagmus increased the specificity (81.0%) and AUC (0.844).ConclusionsA combination of NLR > 2.8 and the absence of horizontal nystagmus is sufficiently specific for acute infarction in an ED patient with acute vertigo; thus, further testing with MRI is indicated. NLR < 2.8 by itself or combined with the presence of horizontal nystagmus is not sufficiently sensitive to rule out the need for further testing.



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Diagnosis of Prostate Cancer with Noninvasive Estimation of Prostate Tissue Composition by Using Hybrid Multidimensional MR Imaging: A Feasibility Study.

Diagnosis of Prostate Cancer with Noninvasive Estimation of Prostate Tissue Composition by Using Hybrid Multidimensional MR Imaging: A Feasibility Study.

Radiology. 2018 Feb 02;:171130

Authors: Chatterjee A, Bourne RM, Wang S, Devaraj A, Gallan AJ, Antic T, Karczmar GS, Oto A

Abstract
Purpose To evaluate whether compartmental analysis by using hybrid multidimensional magnetic resonance (MR) imaging can be used to diagnose prostate cancer and determine its aggressiveness. Materials and Methods Twenty-two patients with prostate cancer underwent preoperative 3.0-T MR imaging. Axial images were obtained with hybrid multidimensional MR imaging by using all combinations of echo times (47, 75, 100 msec) and b values of 0, 750, 1500 sec/mm2, resulting in a 3 × 3 array of data associated with each voxel. Volumes of the tissue components stroma, epithelium, and lumen were calculated by fitting the hybrid data to a three-compartment signal model, with distinct, paired apparent diffusion coefficient (ADC) and T2 values associated with each compartment. Volume fractions and conventional ADC and T2 were measured for regions of interest in sites of prostatectomy-verified malignancy (n = 28) and normal tissue (n = 71). Receiver operating characteristic (ROC) analysis was used to evaluate the performance of various parameters in differentiating prostate cancer from benign tissue. Results Compared with normal tissue, prostate cancer showed significantly increased fractional volumes of epithelium (23.2% ± 7.1 vs 48.8% ± 9.2, respectively) and reduced fractional volumes of lumen (26.4% ± 14.1 vs 14.0% ± 5.2) and stroma (50.5% ± 15.7 vs 37.2% ± 9.1) by using hybrid multidimensional MR imaging. The fractional volumes of tissue components show a significantly higher Spearman correlation coefficient with Gleason score (epithelium: ρ = 0.652, P = .0001; stroma: ρ = -0.439, P = .020; lumen: ρ = -0.390, P = .040) compared with traditional T2 values (ρ = -0.292, P = .132) and ADCs (ρ = -0.315, P = .102). The area under the ROC curve for differentiation of cancer from normal prostate was highest for fractional volume of epithelium (0.991), followed by fractional volumes of lumen (0.800) and stroma (0.789). Conclusion Fractional volumes of prostatic lumen, stroma, and epithelium change significantly when cancer is present. These parameters can be measured noninvasively by using hybrid multidimensional MR imaging and have the potential to improve the diagnosis of prostate cancer and determine its aggressiveness. © RSNA, 2018 Online supplemental material is available for this article.

PMID: 29393821 [PubMed - as supplied by publisher]

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Brachytherapy of Intracranial Gliomas.

Brachytherapy of Intracranial Gliomas.

Prog Neurol Surg. 2018;31:72-86

Authors: Nachbichler SB, Kreth FW

Abstract
Interstitial implantation of radioactive materials (brachytherapy [BT]) has been designed to protractedly deliver a high radiation dose to a well-defined target volume, while minimizing irradiation of the adjacent normal tissues. Even though promising results have been reported over time, the role of this treatment modality in the management of brain tumors is still poorly defined, and only a few centers worldwide apply it in clinical practice. Nevertheless, temporary or permanent interstitial implantation of low activity (<20 mCi) and low dose rate (≤10 cGy/h) iodine-125 (125I) seeds as possible therapy of intracranial gliomas is currently undergoing a definite revival, and several indications for its use have been identified. Generally, 125I-BT may be considered a reasonable option in cases of unresectable, well-circumscribed, either newly diagnosed or recurrent tumors with a diameter of ≤4 cm, virtually in any location within the brain. Importantly, this treatment does not narrow down the spectrum of the possible subsequent salvage therapeutic options, since neither repeated interstitial nor additional external beam irradiation at the time of tumor progression after BT is associated with a significantly increased risk of radiogenic complications. Using correct patient selection criteria, appropriate surgical technique, and established treatment parameters, would make BT a truly minimally invasive procedure with a low risk of complications and reasonable efficacy.

PMID: 29393178 [PubMed - in process]

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National disparities in treatment package time for resected locally advanced head and neck cancer and impact on overall survival.

National disparities in treatment package time for resected locally advanced head and neck cancer and impact on overall survival.

Head Neck. 2018 Feb 02;:

Authors: Guttmann DM, Kobie J, Grover S, Lin A, Lukens JN, Mitra N, Rhodes KV, Feng W, Swisher-McClure S

Abstract
BACKGROUND: The purpose of this study was to determine national disparities in head and neck cancer treatment package time (the time interval from surgery through the completion of radiation) and the associated impact on survival.
METHODS: We conducted an observational cohort study using the National Cancer Database of 15 234 patients with resected head and neck cancer who underwent adjuvant radiotherapy from 2004-2012. Predictors of prolonged package time were identified by multivariable linear regression. Survival outcomes were assessed using a multivariable Cox model.
RESULTS: Mean package time was 100 days (SD 23). Package time was 7.52 days (95% confidence interval [CI] 6.23-8.81; P < .001) longer with Medicaid versus commercial insurance. Low income and African American race also predicted for longer package times. All-cause mortality increased an average of 4% with each 1 week increase in treatment package time (hazard ratio [HR] 1.04; 95% CI 1.03-1.05; P < .001).
CONCLUSION: Significant national socioeconomic disparities exist in treatment package time. Treatment delays in this setting may contribute to worse survival outcomes.

PMID: 29394465 [PubMed - as supplied by publisher]

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Primary orbital melanoma treated with orbital exenteration and postoperative radiotherapy: A case report and review of the literature.

Primary orbital melanoma treated with orbital exenteration and postoperative radiotherapy: A case report and review of the literature.

Head Neck. 2018 Feb 02;:

Authors: Haskins CP, Nurkic S, Fredenburg KM, Dziegielewski PT, Mendenhall WM

Abstract
BACKGROUND: We report on a patient with human immunodeficiency virus (HIV)-positive disease with a primary orbital melanoma treated with surgery and adjuvant radiation.
METHODS: A 53-year-old woman with HIV-positive disease presented with left-sided progressive ipsilateral vision loss and proptosis. An MRI scan revealed a mass-enhancing lesion measuring 2.1 × 2.6 × 2.5 cm abutting the optic nerve. The patient underwent left orbital exenteration with temporalis flap reconstruction, pathology revealing malignant melanoma, stage T1N0M0. Posterior margins were positive and lymphovascular invasion was present; therefore, the patient received adjuvant radiation to a total dose of 70 Gy in 35 fractions.
RESULTS: The patient remains with no evidence of disease (NED) at a follow-up time of 3.5 years.
CONCLUSION: Surgery remains the mainstay of treatment in patients with primary orbital melanomas, and adjuvant radiotherapy should be considered for those with positive margins or other risk factors for recurrence. We present a patient with significant risk factors with NED at 3.5-year follow-up.

PMID: 29394463 [PubMed - as supplied by publisher]

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Prognostic value of lymph node ratio in head and neck squamous cell carcinoma.

Prognostic value of lymph node ratio in head and neck squamous cell carcinoma.

Head Neck. 2018 Feb 02;:

Authors: Talmi YP, Takes RP, Alon EE, Nixon IJ, López F, de Bree R, Rodrigo JP, Shaha AR, Halmos GB, Rinaldo A, Ferlito A

Abstract
BACKGROUND: Lymph node ratio (LNR) is increasingly reported as a potential prognostic tool. The purpose of this review was to analyze the available literature on the prognostic significance of LNR in head and neck squamous cell carcinoma (HNSCC).
METHODS: A PubMed internet search was performed and articles meeting selection criteria were reviewed.
RESULTS: Twenty-eight studies were identified in the literature dealing with the prognostic value of LNR. The published results are variable with a range of cutoff values of LNR associated with prognosis (overall survival [OS] and/or disease-specific survival [DSS]) between 0.02 and 0.20, with an average of 0.09.
CONCLUSION: The LNR is reported to be of value in assessing prognosis in the patients with HNSCC. Although it is easy to calculate and could be considered in the staging of these patients, the currently available evidence in the literature does not yet provide a solid base for implementation.

PMID: 29394461 [PubMed - as supplied by publisher]

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Integrated Beam Orientation and Scanning-Spot Optimization in Intensity Modulated Proton Therapy for Brain and Unilateral Head and Neck Tumors.

Integrated Beam Orientation and Scanning-Spot Optimization in Intensity Modulated Proton Therapy for Brain and Unilateral Head and Neck Tumors.

Med Phys. 2018 Feb 02;:

Authors: Gu W, O'Connor D, Nguyen D, Yu VY, Ruan D, Dong L, Sheng K

Abstract
PURPOSE: Intensity Modulated Proton Therapy (IMPT) is the state-of-the-art method of delivering proton radiotherapy. Previous research has been mainly focused on optimization of scanning spots with manually selected beam angles. Due to the computational complexity, the potential benefit of simultaneously optimizing beam orientations and spot pattern could not be realized. In this study, we developed a novel integrated beam orientation optimization (BOO) and scanning-spot optimization algorithm for intensity modulated proton therapy (IMPT).
METHODS: A brain chordoma and three unilateral head-and-neck patients with a maximal target size of 112.49 cm3 were included in this study. 1162 non-coplanar candidate beams evenly distributed across 4π steradians were included in the optimization. For each candidate beam, the pencil-beam doses of all scanning-spots covering the PTV and a margin were calculated. The beam angle selection and spot intensity optimization problem was formulated to include three terms: a dose fidelity term to penalize the deviation of PTV and OAR doses from ideal dose distribution; an L1-norm sparsity term to reduce the number of active spots and improve delivery efficiency; a group sparsity term to control the number of active beams to between 2 and 4. For the group sparsity term, convex L2,1-norm and nonconvex L2,1/2-norm were tested. For the dose fidelity term, both quadratic function and linearized equivalent uniform dose (LEUD) cost function were implemented. The optimization problem was solved using the Fast Iterative Shrinkage-Thresholding Algorithm (FISTA). The IMPT BOO method was tested on three head-and-neck patients and one skull base chordoma patient. The results were compared with IMPT plans created using column generation selected beams or manually selected beams.
RESULTS: The L2,1-norm plan selected spatially aggregated beams, indicating potential degeneracy using this norm. L2,1/2-norm was able to select spatially separated beams and achieve smaller deviation from the ideal dose. In the L2,1/2-norm plans, the [mean dose, maximum dose] of OAR were reduced by an average of [2.38%, 4.24%] and[2.32%, 3.76%] of the prescription dose for the quadratic and LEUD cost function, respectively, compared with the IMPT plan using manual beam selection while maintaining the same PTV coverage. The L2,1/2 group sparsity plans were dosimetrically superior to the column generation plans as well. Besides beam orientation selection, spot sparsification was observed. Generally, with the quadratic cost function, 30%~60% spots in the selected beams remained active. With the LEUD cost function, the percentages of active spots were in the range of 35%~85%.The BOO-IMPT run time was approximately 20 minutes.
CONCLUSION: This work shows the first IMPT approach integrating non-coplanar BOO and scanning-spot optimization in a single mathematical framework. This method is computationally efficient, dosimetrically superior and produces delivery-friendly IMPT plans. This article is protected by copyright. All rights reserved.

PMID: 29394454 [PubMed - as supplied by publisher]

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Neck Injury Response in High Vertical Accelerations and its Algorithmical Formalization to Mitigate Neck Injuries.

Neck Injury Response in High Vertical Accelerations and its Algorithmical Formalization to Mitigate Neck Injuries.

Stapp Car Crash J. 2017 Nov;61:211-225

Authors: Klima J, Kang J, Meldrum A, Pankiewicz S

Abstract
Tank Automotive Research, Development and Engineering Center (TARDEC) conducted a comprehensive analysis of data collected during the evaluation of head and neck impact during injurious and non-injurious loading. This evaluation included impact velocity, helmet to roof clearance, and neck angle using a fully instrumented Hybrid III head and neck assembly. The results of this effort were compared against post mortem human subject (PMHS) data from similar testing conducted in conjunction with the Warrior Injury Assessment Manikin (WIAMan) program. The results identified the most severe helmet to roof clearance and neck angles. TARDEC used this knowledge as the foundation for continued research into head and neck impact injury mitigation through the use of passive technology and interior vehicle design.

PMID: 29394440 [PubMed - in process]

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Commentary on "Development and Implementation of an Inpatient Otolaryngology Consultation Service at an Academic Medical Center".

Commentary on "Development and Implementation of an Inpatient Otolaryngology Consultation Service at an Academic Medical Center".

South Med J. 2018 Feb;111(2):123-124

Authors: Chen PG

PMID: 29394431 [PubMed - in process]

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Development and Implementation of an Inpatient Otolaryngology Consultation Service at an Academic Medical Center.

Development and Implementation of an Inpatient Otolaryngology Consultation Service at an Academic Medical Center.

South Med J. 2018 Feb;111(2):118-122

Authors: Huddle MG, London NR, Stewart CM

Abstract
OBJECTIVES: To design and implement a formal otolaryngology inpatient consultation service that improves satisfaction of consulting services, increases educational opportunities, improves the quality of patient care, and ensures sustainability after implementation.
METHODS: This was a retrospective cohort study in a large academic medical center encompassing all inpatient otolaryngology service consultations from July 2005 to June 2014. Staged interventions included adding fellow coverage (July 2007 onward), intermittent hospitalist coverage (July 2010 onward), and a physician assistant (October 2011 onward). Billing data were collected for incidences of new patient and subsequent consultation charges. The 2-year preimplementation period (July 2005-June 2007) was compared with the postimplementation periods, divided into 2-year blocks (July 2007-June 2013). Outcome measures of patient encounters and work relative value units were compared between pre- and postimplementation blocks.
RESULTS: Total encounters increased from 321 preimplementation to 1211, 1347, and 1073 in postimplementation groups (P < 0.001). Total work relative value units increased from 515 preimplementation to 2090, 1934, and 1273 in postimplementation groups (P < 0.001).
CONCLUSIONS: A formal inpatient consultation service was designed with supervisory oversight by non-Accreditation Council for Graduate Medical Education fellows and then expanded to include intermittent hospitalist management, followed by the addition of a dedicated physician assistant. These additions have led to the formation of a sustainable consultation service that supports the mission of high-quality care and service to consulting teams.

PMID: 29394430 [PubMed - in process]

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Vision Screening in Adults Across the Life Span.

Vision Screening in Adults Across the Life Span.

South Med J. 2018 Feb;111(2):109-112

Authors: Cohen HS, Stitz J, Sangi-Haghpeykar H, Williams SP

Abstract
OBJECTIVES: The goal of this study was to determine whether adults across the life span differ in responses to quick vision screening and how those responses relate to adults' use of specialized eye care.
METHODS: Subjects were 363 community-dwelling ambulatory adults, 21 to 95 years old, who were tested while they wore their corrective lenses during routine visits to a tertiary care facility. No subjects had known neurological impairments, age-related macular degeneration, or other significant eye disease. A wall-mounted Early Treatment in Diabetic Retinopathy Study chart was used.
RESULTS: Older adults 58 years old or older had significantly worse scores than younger adults. Scores did not differ between subjects who had been tested within or prior to the last 10 months. Older subjects had their vision tested significantly more recently than younger subjects.
CONCLUSIONS: Vision screening is quick, inexpensive, and easily performed by ancillary staff, and it may provide the physician with useful additional information for treatment planning.

PMID: 29394428 [PubMed - in process]

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