bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of deep neural network for individualized hepatobiliary toxicity prediction after liver SBRT
Authors: Ibragimov Bulat , Toesca Diego , Chang Daniel , Yuan Yixuan , Koong Albert , Xing Lei 
Published: August 2018

BackgroundAccurate prediction of radiation toxicity of healthy organs‐at‐risks (OARs) critically determines the radiation therapy (RT) success. The existing dose–volume histogram‐based metric may grossly under/overestimate the therapeutic toxicity after 27% in liver RT and 50% in head‐and‐neck RT. We propose the novel paradigm for toxicity prediction by leveraging the enormous potential of deep learning and go beyond the existing dose/volume histograms.Experimental DesignWe employed a database of 125 liver stereotactic body RT (SBRT) cases with follow‐up data to train deep learning‐based toxicity predictor. Convolutional neural networks (CNNs) were applied to discover the consistent patterns in 3D dose plans associated with toxicities. To enhance the predicting power, we first pretrain the CNNs with transfer learning from 3D CT images of 2644 human organs. CNNs were then trained on liver SBRT cases. Furthermore, nondosimetric pretreatment features, such as patients’ demographics, underlying liver diseases, liver‐directed therapies, were inputted into the fully connected neural network for more comprehensive prediction. The saliency maps of CNNs were used to estimate the toxicity risks associated with irradiation of anatomical regions of specific OARs. In addition, we applied machine learning solutions to map numerical pretreatment features with hepatobiliary toxicity manifestation.ResultsAmong 125 liver SBRT patients, 58 were treated for liver metastases, 36 for hepatocellular carcinoma, 27 for cholangiocarcinoma, and 4 for other histologies. We observed that CNN we able to achieve accurate hepatobiliary toxicity prediction with the AUC of 0.79, whereas combining CNN for 3D dose plan analysis and fully connected neural networks for numerical feature analysis resulted in AUC of 0.85. Deep learning produces almost two times fewer false‐positive toxicity predictions in comparison to DVH‐based predictions, when the number of false negatives, i.e., missed toxicities, was minimized. The CNN saliency maps automatically estimated the toxicity risks for portal vein (PV) regions. We discovered that irradiation of the proximal portal vein is associated with two times higher toxicity risks (risk score: 0.66) that irradiation of the left portal vein (risk score: 0.31).ConclusionsThe framework offers clinically accurate tools for hepatobiliary toxicity prediction and automatic identification of anatomical regions that are critical to spare during SBRT.
Benchmarking the DACS‐integrated Radiation Dose Monitor® skin dose mapping software using XR‐RV3 Gafchromic® films
Authors: Habib Geryes Bouchra , Hadid‐Beurrier Lama , Waryn Marie‐Joséphine , Jean‐Pierre Antonella , Farah Jad 
Published: August 2018

PurposeTo perform a benchmark of a new DACS‐integrated patient skin dose mapping solution using on‐phantom measurements with Gafchromic® films.Materials and methodsTo calculate cumulative patient skin dose distribution with 1‐cm2 resolution, a Radiation Dose Monitor (RDM, Medsquare), using the Radiation Dose Structured Report (RDSR), tabulated backscatter and mass energy absorption coefficients together with site‐specific corrections for table, mattress attenuation, and air kerma calibration factor. Peak skin dose (PSD) and two‐dimensional (2D) skin dose distributions calculated with RDM were compared against on‐phantom measurements with XR‐RV3 Gafchromic® films considering two widely used x‐ray equipment. Seventeen different settings which include simple and multiple beam projections with extreme angulations (up to 75°), all available fields‐of‐view (FOVs 48–11 cm), additional collimation, variable table height and lateral positions, and variable phantom thickness (12, 20, and 30 cm) were involved.ResultsDue to a careful calibration of films using clinical beam qualities, 22.8% (k = 2) overall measurement uncertainty was achieved. Calculated and measured PSD values agreed with an average difference of 10% ± 7% and 9% ± 7% for 34 test conditions performed on Siemens Artis Zee and GEMS Innova IGS interventional systems, respectively. Finally, RDM's 2D skin dose maps closely matched those registered on XR‐RV3 films considering the 1‐cm2 resolution. While RDM correctly reproduced beam overlapping due to variable tube projections, FOV, table positions, etc., few challenges were identified related to conversion of rectangular fields to square areas in the RDSR and a stair‐step effect visible for large tube projections (>45°).ConclusionThe accuracy of RDM's DACS‐integrated skin dose mapping software was acceptable considering measurement uncertainties associated with Gafchromic® films.
Predicting lesion size by accumulated thermal dose in MR‐guided focused ultrasound for essential tremor
Authors: Huang Yuexi , Lipsman Nir , Schwartz Michael L. , Krishna Vibhor , Sammartino Francesco , Lozano Andres M. , Hynynen Kullervo 
Published: August 2018

PurposeTo correlate the accumulated thermal dose (ATD) with lesion size in magnetic resonance (MR)‐guided focused ultrasound (MRgFUS) thalamotomy to help guide future clinical treatments.Materials and MethodsThirty‐six patients with medication‐refractory essential tremor were treated using a commercial MRgFUS brain system (ExAblate 4000, InSightec) in a 3T MR scanner (MR750, GE Healthcare). Intraoperative MR‐thermometry was performed to measure the induced temperature and thermal dose distributions (thermal coefficient = −0.00909 ppm/°C). The ATD was calculated over multiple sonications with appropriate corrections for spatial‐shifting artifacts. The ATD profile sizes obtained for dose values of 17, 40, 100, 200, and 240 cumulative equivalent minutes at 43°C (CEM) were correlated with the corresponding lesion sizes measured via axial T1‐ and T2‐weighted MR images acquired 1 day post‐treatment.ResultsOf a total of 232 included sonications, 83 required corrections for off‐resonance‐induced spatial‐shifting artifacts (correction range = [1.1,2.2] mm). The mean lesion sizes measured on T2‐weighted MR images (6.2 ± 1.3 mm, mean ± SD) were 15% larger than those measured on corresponding T1‐weighted MR images (5.3 ± 1.2 mm, mean ± SD). The ATD values that provided the best correlations with the measured lesion sizes on T2‐ and T1‐weighted MR images were 100 and 200 CEM, respectively.ConclusionThe ATD was correlated with lesion size measured 1 day following MRgFUS thalamotomy for essential tremor. These data provide useful information for predicting brain lesion size and determining treatment endpoints in future clinical MRgFUS procedures.
Gene alterations and expression spectrum of SPATA33 in nonobstructive azoospermic Iranian men
Authors: Monsef Ladan , Borjian Boroujeni Parnaz , Totonchi Mehdi , Sabbaghian Marjan , Mohseni Meybodi Anahita 
Published: August 2018

AbstractGenetic abnormalities have been considered a significant cause of male infertility. Increased expression of SPATA33 during the first wave of spermatogenesis indicates its possible association with the meiotic process. The aim of the current study was to investigate the genetic variations in the SPATA33 gene and its expression in patients with nonobstructive azoospermia (NOA). A total of 100 Iranian NOA men with idiopathic infertility were taken as the case group. The control group comprised 100 fertile men who had at least one child. The presence of nucleotide variations was analyzed in both groups using the standard polymerase chain reaction (PCR) sequencing technique. For mRNA and protein expression studies, testicular biopsy specimens from 27 patients were subdivided into three groups: nine obstructive azoospermic patients with hypospermatogenesis as control; nine maturation arrest (MA) and nine Sertoli cell‐only syndromes (SCOS) as case groups. The expression of SPATA33 at both mRNA and protein levels was compared among these three groups using the reverse transcription PCR technique, the realtime‐PCR technique, and immunohistochemistry. Mutation analysis of the
SPATA33 gene revealed five nucleotide changes among the population studied. All but one showed no significant differences between the groups. The genotype distributions of rs112536073A > T in the transcription factor binding site region with heterozygote and homozygote genotypes were significantly different (
p < 0.05) between the two groups. More heterozygotes of this polymorphism were observed in patients, whereas more homozygotes were detected in controls. Accordingly, the current study illustrated that alterations in
SPATA33 gene, at least those found in this study, may not impair spermatogenesis in patients with NOA. Reduction of gene expression at the level of mRNA in patients with SCOS can be interpreted by the absence of germ cells in the testicular tissue of these patients.
Estimation of visceral fat in 9‐ to 13‐year‐old girls using dual‐energy X‐ray absorptiometry (DXA) and anthropometry
Authors: Lee V. , Blew R. , Hetherington‐Rauth M. , Blew D. , Galons J.‐P. , Hagio T. , Bea J. , Lohman T. , Going S. 
Published: August 2018

SummaryObjectivesAccumulation of visceral fat (VF) in children increases the risk of cardiovascular disease and type 2 diabetes, and measurement of VF in children using computed tomography and magnetic resonance imaging (MRI) is expensive. Dual‐energy X‐ray absorptiometry (DXA) may provide a low‐cost alternative. This study aims to determine if DXA VF estimates can accurately estimate VF in young girls, determine if adding anthropometry would improve the estimate and determine if other DXA fat measures, with and without anthropometry, could be used to estimate VF in young girls.MethodsVisceral fat was measured at lumbar intervertebral sites (L1–L2, L2–L3, L3–L4 and L4–L5) using 3.0T MRI on 32 young girls (mean age 11.3 ± 1.3 years). VF was estimated using the GE CoreScan application. Measurement of DXA android and total body fat was performed. Weight, height and waist circumference (WC) measurements were also obtained.ResultsWaist circumference and body mass index were both strongly correlated with MRI, although WC was the best anthropometric covariate. Per cent fat (%fat) variables had the strongest correlation and did best in regression models. DXA %VF (GE CoreScan) and DXA android %fat and total body %fat accounted for 65% to 74% of the variation in MRI VF.ConclusionWaist circumference predicted MRI VF almost as well as DXA estimates in this population, and a combination of WC and DXA fat improves the predictability of VF. DXA VF estimate was improved by the addition of WC; however, DXA android %fat with WC was better at predicting MRI VF.
Association between Development of Dementia and Use of Benzodiazepines: A Systematic Review and Meta‐Analysis
Authors: Lucchetta Rosa Camila , da Mata Barbara Paes Miglioli , Mastroianni Patricia de Carvalho 
Published: August 2018

Study ObjectiveThe use of benzodiazepines and the development of dementia is controversial, with studies indicating that benzodiazepines could be either a protective factor or a risk factor for dementia, or no association may exist between the two. Our objective was to identify whether such an association exists.DesignSystematic review and meta‐analysis of 12 prospective and retrospective cohort studies and case‐control studies.ParticipantsA total of 981,133 (in the systematic review) and 980,860 (in the meta‐analysis) adults or elderly individuals.Measurements and Main ResultsA search of the PubMed, LILACS, and Cochrane Central Register of Controlled Trials databases, as well as a manual search of the reference lists of the included publications and reviews, was performed. We included studies that reported the incidence of dementia and in ever users of benzodiazepines. Data were analyzed by using a random effects model in R software. Quality of the evidence was assessed with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) certainty ratings system. The results of the main meta‐analysis suggest that benzodiazepines can be a risk factor for developing dementia (odds ratio 1.38, 95% confidence interval 1.07–1.77; I2 = 98%; 95% prediction interval 0.58–3.25; very low certainty).ConclusionOur results suggest an association between the use of benzodiazepines and the development of dementia. However, the current evidence lacks the power to infer differences between the effects of Alzheimer's disease and vascular dementias, long‐acting and short‐acting benzodiazepines, and various exposure loads (duration and dose). Future long‐term prospective cohort studies are necessary, with adequate adjustments for confounding variables, strategies to minimize reverse causality, reporting of subgroups aimed at greater homogeneity of findings, adequate statistical power to identify high‐magnitude effects, and defined daily dose analyses for dose‐response gradient.
Flavin oxidation in flavin‐dependent N‐monooxygenases
Authors: Robinson Reeder M. , Klancher Catherine A. , Rodriguez Pedro J. , Sobrado Pablo 
Published: August 2018

AbstractSiderophore A (SidA) from Aspergillus fumigatus is a flavin‐containing monooxygenase that hydroxylates ornithine (Orn) at the amino group of the side chain. Lysine (Lys) also binds to the active site of SidA; however, hydroxylation is not efficient and H2O2 is the main product. The effect of pH on steady‐state kinetic parameters was measured and the results were consistent with Orn binding with the side chain amino group in the neutral form. From the pH dependence on flavin oxidation in the absence of Orn, a pKa value >9 was determined and assigned to the FAD‐N5 atom. In the presence of Orn, the pH dependence displayed a pKa value of 6.7 ±0.1 and of 7.70 ±0.10 in the presence of Lys. Q102 interacts with NADPH and, upon mutation to alanine, leads to destabilization of the C4a‐hydroperoxyflavin (FADOOH). Flavin oxidation with Q102A showed a pKa value of ~8.0. The data are consistent with the pKa of the FAD N5‐atom being modulated to a value >9 in the absence of Orn, which aids in the stabilization of FADOOH. Changes in the FAD‐N5 environment lead to a decrease in the pKa value, which facilitates elimination of H2O2 or H2O. These findings are supported by solvent kinetic isotope effect experiments, which show that proton transfer from the FAD N5‐atom is rate limiting in the absence of a substrate, however, is significantly less rate limiting in the presence of Orn and or Lys.
Trade secrets and innovation: Evidence from the “inevitable disclosure” doctrine
Authors: Contigiani Andrea , Hsu David H. , Barankay Iwan 
Published: August 2018

Research Summary: Does heightened employer‐friendly trade secrecy protection help or hinder innovation? By examining U.S. state‐level legal adoption of a doctrine allowing employers to curtail inventor mobility if the employee would “inevitably disclose” trade secrets, we investigate the impact of a shifting trade secrecy regime on individual‐level patenting outcomes. Using a difference‐in‐differences design taking unaffected U.S. inventors as the comparison group, we find strengthening employer‐friendly trade secrecy adversely affects innovation. We then investigate why. We do not find empirical support for diminished idea recombination from suppressed inventor mobility as the operative mechanism. While shifting intellectual property protection away from patenting into trade secrecy has some explanatory power, our results are consistent with reduced individual‐level incentives to signaling quality to the external labor market.Managerial Summary: While managers often list trade secrecy protection as their most important appropriation mechanism form and basis of competitive advantage (even more often than formal intellectual property protection), researchers have a hard time studying the effect of such secrets. We use a changing trade secrecy legal environment in some U.S. states (the introduction of the inevitable disclosure doctrine [IDD]) to study its effect on inventor‐level innovation. We find that a strengthened employer‐friendly trade secrecy regime adversely affects inventor‐level innovation. While part of the effect is due to substituting trade secrecy protection for patents, we also find that inventors’ diminished external labor market prospects may dampen their innovation output. Consequently, while employers may wish for strengthened trade secrecy protections, the results may paradoxically be against their innovation interests.
Glucose suppresses IL‐1β‐induced MMP‐1 expression through the FAK, MEK, ERK, and AP‐1 signaling pathways
Authors: Wu Tsung‐Ju , Lin Chih‐Yang , Tsai Chun‐Hao , Huang Yuan‐Li , Tang Chih‐Hsin 
Published: August 2018

AbstractOsteoarthritis (OA) commonly affects the synovial joint and is characterized by degradation of articular cartilage. Increased matrix metalloproteinase (MMP) activity plays a major role in this degradation. Dextrose (D‐glucose) prolotherapy has shown promising activity in the treatment of different musculoskeletal disorders, including OA. However, little is known about the role of glucose on MMP inhibition in OA therapy. We found that stimulating chondrocytes with the proinflammatory cytokine interleukin‐1β (IL‐1β) increased the expression of MMP‐1, MMP‐3, and MMP‐13. Glucose reduced this increase in MMP‐1 expression, but had no effect upon MMP‐3 or MMP‐13 expression. Analyses using a focal adhesion kinase (FAK) inhibitor, MEK inhibitors (U0126 and PD98059), an ERK inhibitor, AP‐1 inhibitors (curcumin and tanshinone), or siRNAs demonstrated that the FAK, MEK, ERK, and AP‐1 pathways mediate IL‐1β‐induced increases in MMP‐1 expression. Glucose antagonized IL‐1β‐promoted phosphorylation of FAK, MEK, ERK, and c‐Jun. Thus, glucose decreased IL‐1β‐induced MMP‐1 expression through the FAK, MEK, ERK, and AP‐1 signaling cascades. These findings may provide a better understanding of the mechanisms of prolotherapy on inhibiting MMP expression.
Anti‐carcinogenic effect of hesperidin against renal cell carcinoma by targeting COX‐2/PGE2 pathway in Wistar rats
Authors: Siddiqi Aisha , Saidullah Bano , Sultana Sarwat 
Published: August 2018

AbstractThe present study was designed to evaluate the protective effects of hesperidin, a flavonoid on DEN initiated and Fe‐NTA promoted renal carcinogenesis in Wistar rats. Renal cancer was initiated by a single i.p. injection of DEN (200 mg/kg b.wt.) and promoted with Fe‐NTA (9 mg Fe/kg b.wt. i.p.) twice a week for 16 weeks. Rats were simultaneously administered with hesperidin (100 and 200 mg/kg b.wt.) for 16 consecutive weeks. The chemopreventive effect of hesperidin was assessed in terms of antioxidant activities, renal function, PGE2 level, and the expressions of COX‐2 and VEGF. Hesperidin decreased the DEN and Fe‐NTA induced lipid peroxidation, improved the renal function (by decreasing the levels of BUN, creatinine, and KIM‐1) and restored the renal antioxidant armory (GSH, GPx, GR, SOD, and catalase). Hesperidin was also found to decrease the level of PGE2 and downregulate the expressions of COX‐2 and VEGF. Histological findings further revealed the protective effects of hesperidin against DEN and Fe‐NTA induced kidney damage. The result of our present findings suggest that hesperidin may be a promising modulator in preventing renal cancer possibly by virtue of its ability to alleviate oxidative stress and inhibit COX‐2/PGE2 pathway.
In vitro evaluation of the toxicity and underlying molecular mechanisms of Janus Fe3O4‐TiO2 nanoparticles in human liver cells
Authors: Su Hong , Li Zhou , Lazar Lissy , Alhamoud Yasmin , Song Xin , Li Juan , Wang Yafei , Fiati kenston Samuel Selorm , Lqbal Muhammad Zubair , Wu Aiguo , Li Zhen , Hua Qihang , Ding Min , Zhao Jinshun 
Published: August 2018

AbstractRecent studies show that Janus Fe3O4‐TiO2 nanoparticles (NPs) have potential applications as a multifunctional agent of magnetic resonance imaging (MRI) and photodynamic therapy (PDT) for the diagnosis and therapy of cancer. However, little work has been done on their biological effects. To evaluate the toxicity and underlying molecular mechanisms of Janus Fe3O4‐TiO2 nanoparticles, an in vitro study using a human liver cell line HL‐7702 cells was conducted. For comparison, the Janus Fe3O4‐TiO2 NPs parent material TiO2 NPs was also evaluated. Results showed that both Fe3O4‐TiO2 NPs and TiO2 NPs decreased cell viability and ATP levels when applied in treatment, but increased malonaldehyde (MDA) and reactive oxygen species (ROS) generation. Mitochondria JC‐1 staining assay showed that mitochondrial membrane permeability injury occurred in both NPs treated cells. Cell viability analysis showed that TiO2 NPs induced slightly higher cytotoxicity than Fe3O4‐TiO2 NPs in HL7702 cells. Western blotting indicated that both TiO2 NPs and Fe3O4‐TiO2 NPs could induce apoptosis, inflammation, and carcinogenesis related signal protein alterations. Comparatively, Fe3O4‐TiO2 NPs induced higher signal protein expressions than TiO2 NPs under a high treatment dose. However, under a low dose (6.25 μg/cm2), neither NPs had any significant toxicity on HL7702 cells. In addition, our results suggest both Fe3O4‐TiO2 NPs and TiO2 NPs could induce oxidative stress and have a potential carcinogenetic effect in vitro. Further studies are needed to elaborate the detailed mechanisms of toxicity induced by a high dose of Fe3O4‐TiO2 NPs.
Effects of novel brominated flame retardant TBBPA on human airway epithelial cell (A549) in vitro and proteome profiling
Authors: Wu Shijin , Wu Mei , Qi Mengting , Zhong Li , Qiu Lequan 
Published: August 2018

AbstractThe cellular toxicity response of human airway epithelial cells (A549) to tetrabromobisphenol (TBBPA) was assessed in vitro. Cell viability, levels of intracellular reactive oxygen species (ROS), lipid peroxidation (MDA), and caspase‐3 activity were determined after A549 treated with varying concentrations of TBBPA. A comparative proteomic analysis was performed in cells treated with different concentrations of TBBPA (0, 10, and 40 μg/mL). Two‐way anova analysis showed that cell viability was significantly decreased after treatment by TBBPA with a concentration of 16 μg/mL for 48 hr, however, the caspase‐3 activities, ROS generation, and MDA content increased. Ultrastructural observation revealed that the cell was morphological damaged after exposure to 64 μg/mL TBBPA, with mitochondria seriously injured and the smooth endoplasmic reticulum dilated. There was a good correlation between ROS generation and mitochondrial dysfunction. Seventeen differentially expressed proteins involved in various biological processes were identified. These findings provide a basis for understanding the mechanisms of cell dysfunction and perturbation of antioxidant status induced by additive flame retardant on airway epithelial cells.