bluuebunny/crossref_metadata_2025_split huggingface dataset:
TP53, STK11, and EGFR Mutations Predict Tumor Immune Profile and the Response to Anti–PD-1 in Lung Adenocarcinoma
Authors: Biton Jérôme , Mansuet-Lupo Audrey , Pécuchet Nicolas , Alifano Marco , Ouakrim Hanane , Arrondeau Jennifer , Boudou-Rouquette Pascaline , Goldwasser François , Leroy Karen , Goc Jeremy , Wislez Marie , Germain Claire , Laurent-Puig Pierre , Dieu-Nosjean Marie-Caroline , Cremer Isabelle , Herbst Ronald , Blons Hélène , Damotte Diane 
Published: May 2018

Abstract
Purpose: By unlocking antitumor immunity, antibodies targeting programmed cell death 1 (PD-1) exhibit impressive clinical results in non–small cell lung cancer, underlining the strong interactions between tumor and immune cells. However, factors that can robustly predict long-lasting responses are still needed.
Experimental Design: We performed in-depth immune profiling of lung adenocarcinoma using an integrative analysis based on immunohistochemistry, flow-cytometry, and transcriptomic data. Tumor mutational status was investigated using next-generation sequencing. The response to PD-1 blockers was analyzed from a prospective cohort according to tumor mutational profiles and PD-L1 expression, and a public clinical database was used to validate the results obtained.
Results: We showed that distinct combinations of STK11, EGFR, and TP53 mutations were major determinants of the tumor immune profile (TIP) and of the expression of PD-L1 by malignant cells. Indeed, the presence of TP53 mutations without co-occurring STK11 or EGFR alterations (TP53-mut/STK11-EGFR-WT), independently of KRAS mutations, identified the group of tumors with the highest CD8 T-cell density and PD-L1 expression. In this tumor subtype, pathways related to T-cell chemotaxis, immune cell cytotoxicity, and antigen processing were upregulated. Finally, a prolonged progression-free survival (PFS: HR = 0.32; 95% CI, 0.16–0.63, P &lt; 0.001) was observed in anti–PD-1-treated patients harboring TP53-mut/STK11-EGFR-WT tumors. This clinical benefit was even more remarkable in patients with associated strong PD-L1 expression.
Conclusions: Our study reveals that different combinations of TP53, EGFR, and STK11 mutations, together with PD-L1 expression by tumor cells, represent robust parameters to identify best responders to PD-1 blockade. Clin Cancer Res; 24(22); 5710–23. ©2018 AACR.
Combined HDAC and Bromodomain Protein Inhibition Reprograms Tumor Cell Metabolism and Elicits Synthetic Lethality in Glioblastoma
Authors: Zhang Yiru , Ishida Chiaki Tsuge , Ishida Wataru , Lo Sheng-Fu L. , Zhao Junfei , Shu Chang , Bianchetti Elena , Kleiner Giulio , Sanchez-Quintero Maria J. , Quinzii Catarina M. , Westhoff Mike-Andrew , Karpel-Massler Georg , Canoll Peter , Siegelin Markus D. 
Published: May 2018

Abstract
Purpose: Glioblastoma remains a challenge in oncology, in part due to tumor heterogeneity.
Experimental Design: Patient-derived xenograft and stem-like glioblastoma cells were used as the primary model systems.
Results: Based on a transcriptome and subsequent gene set enrichment analysis (GSEA), we show by using clinically validated compounds that the combination of histone deacetylase (HDAC) inhibition and bromodomain protein (BRD) inhibition results in pronounced synergistic reduction in cellular viability in patient-derived xenograft and stem-like glioblastoma cells. Transcriptome-based GSEA analysis suggests that metabolic reprogramming is involved with synergistic reduction of oxidative and glycolytic pathways in the combination treatment. Extracellular flux analysis confirms that combined HDAC inhibition and BRD inhibition blunts oxidative and glycolytic metabolism of cancer cells, leading to a depletion of intracellular ATP production and total ATP levels. In turn, energy deprivation drives an integrated stress response, originating from the endoplasmic reticulum. This results in an increase in proapoptotic Noxa. Aside from Noxa, we encounter a compensatory increase of antiapoptotic Mcl-1 protein. Pharmacologic, utilizing the FDA-approved drug sorafenib, and genetic inhibition of Mcl-1 enhanced the effects of the combination therapy. Finally, we show in orthotopic patient-derived xenografts of GBM, that the combination treatment reduces tumor growth, and that triple therapy involving the clinically validated compounds panobinostat, OTX015, and sorafenib further enhances these effects, culminating in a significant regression of tumors in vivo.
Conclusions: Overall, these results warrant clinical testing of this novel, efficacious combination therapy. Clin Cancer Res; 24(16); 3941–54. ©2018 AACR.
Temporal Efficacy of a Sulforaphane-Based Broccoli Sprout Diet in Prevention of Breast Cancer through Modulation of Epigenetic Mechanisms
Authors: Li Yuanyuan , Buckhaults Phillip , Li Shizhao , Tollefsbol Trygve 
Published: May 2018

Abstract
Breast cancer is the most common cancer and the second leading cause of cancer-related death among women. An important risk factor for breast cancer is individual genetic background, which is initially generated early in human life, for example, during the processes of embryogenesis and fetal development in utero. Bioactive dietary components such as sulforaphane (SFN), an isothiocyanate from cruciferous vegetables including broccoli sprouts (BSp), cabbage, and kale, has been shown to reduce the risk of developing many common cancers through regulation of epigenetic mechanisms. Our study indicates a prenatal/maternal BSp dietary treatment exhibited maximal preventive effects in inhibiting breast cancer development compared with postnatal early-life and adult BSp treatments in two transgenic mouse models that can develop breast cancer. Postnatal early-life BSp treatment starting prior to puberty onset showed protective effects in prevention of breast cancer but was not as effective as the prenatal/maternal BSp treatment. However, adulthood-administered BSp diet did not reduce mammary tumorigenesis. Our results suggest that the prenatal/maternal BSp bioactive natural plant product may impact early embryonic development by regulating global differential gene expression through affecting epigenetic profiles resulting in differential susceptibility to breast cancer later in life. These results suggest that a temporal exposure to epigenetic-modulating dietary components such as cruciferous vegetables could be a key factor for maximizing chemopreventive effects on human breast cancer. This study may lead to translational breast cancer chemopreventive potential by appropriate administration of key dietary components leading to early breast cancer prevention in humans. Cancer Prev Res; 11(8); 451–64. ©2018 AACR.
A common heritage of behaviour systems
Authors: Bowers Robert Ian 
Published: May 2018

AbstractBehaviour systems theory had its beginnings with Nikolaas Tinbergen’s “hierarchical systems”, an aspect of his thinking and writing that he conspicuously left out of his very memorable 1963 manifesto. This starting point has since been developed within psychology, where it has provided numerous advances. Tinbergen’s aspiration for behaviour systems had been principled integration of ethology with physiology, but the bridge among sciences it ultimately provided led to psychology. To an ethology audience, this paper attempts to reintroduce behaviour systems as a part of Tinbergen’s legacy to make accessible the theoretical developments of behaviour systems theory that have occurred outside of ethology over the last several decades. To a psychology audience, the paper serves as a reminder of the ethological origins of behaviour systems. Both sciences and their integration stand to benefit from recognising this point of common heritage.
A Global Climatology of Tropical Cyclone Eyes
Authors: Knapp Kenneth R. , Velden Christopher S. , Wimmers Anthony J. 
Published: May 2018

Abstract
Intense tropical cyclones (TCs) generally produce a cloud-free center with calm winds, called the eye. The Automated Rotational Center Hurricane Eye Retrieval (ARCHER) algorithm is used to analyze Hurricane Satellite (HURSAT) B1 infrared satellite imagery data for storms occurring globally from 1982 to 2015. HURSAT B1 data provide 3-hourly observations of TCs. The result is a 34-yr climatology of eye location and size. During that time period, eyes are identified in about 13% of all infrared images and slightly more than half of all storms produced an eye. Those that produce an eye have (on average) 30 h of eye scenes. Hurricane Ioke (1992) had the most eye images (98, which is 12 complete days with an eye). The median wind speed of a system with an eye is 97 kt (50 m s−1) [cf. 35 kt (18 m s−1) for those without an eye]. Eyes are much more frequent in the Northern Hemisphere (particularly in the western Pacific) but eyes are larger in the Southern Hemisphere. The regions where eyes occur are expanding poleward, thus expanding the area at risk of TC-related damage. Also, eye scene occurrence can provide an objective measure of TC activity in place of those based on maximum wind speeds, which can be affected by available observations and forecast agency practices.
Alginate Ototoxicity in the Mouse Model
Authors: Alvi Sameer A. , Nelson‐Brantley Jennifer , Staecker Hinrich 
Published: May 2018

ObjectiveTo determine whether alginate exposure to the round window of the mouse causes any measurable ototoxicity.Study DesignProspective animal study.SettingBasic science laboratory affiliated with a tertiary care university medical center.Subjects and MethodsAfter Institutional Animal Care and Use Committee approval, 5 adult mice were obtained and underwent bullostomy and round window niche application of alginate. Auditory brainstem response (ABR) tests were completed at baseline prior to the procedure and also 5, 14, and 30 days postprocedure. Results were compared. At termination of procedure, the mice were sacrificed with harvest of the cochleae, which were viewed under histologic section.ResultsThere were no significant increases in ABR thresholds in any of the test animals at all test periods after alginate exposure compared to baseline. There were also no observable behavioral changes after the procedure to indicate vestibular dysfunction. Cochlear sectioning revealed no evidence of histologic damage.ConclusionExposure of alginate to the round window does not cause any obvious ototoxicity in the mouse model. Further clinical trials will be needed to elucidate the effect of alginate in the human middle ear.
Raman Spectroscopy for Inverted Papilloma: A Proof‐of‐Concept Study
Authors: Mascarella Marco A. , Alrasheed Abdulaziz , Fnais Naif , Gourgas Ophelie , Jalani Ghulam , Cerruti Marta , Tewfik Marc A. 
Published: May 2018

Inverted papillomas are tumors of the sinonasal tract with a propensity to recur. Raman spectroscopy can potentially identify inverted papillomas from other tissue based on biochemical signatures. A pilot study comparing Raman spectroscopy to histopathology for 3 types of sinonasal tissue was performed. Spectral data of biopsies from patients with normal sinonasal mucosa, chronic rhinosinusitis, and inverted papillomas are compared to histopathology using principal component analysis and linear discriminant analysis after data preprocessing. A total of 18 normal, 15 chronic rhinosinusitis, and 18 inverted papilloma specimens were evaluated. The model distinguished normal sinonasal mucosa, chronic rhinosinusitis, and inverted papilloma tissue with an overall accuracy of 90.2% (95% confidence interval, 0.86‐0.94). In conclusion, Raman spectroscopy can distinguish inverted papilloma, normal sinonasal mucosa, and chronically rhinosinusitis tissue with acceptable accuracy.
Patterns of malignant non-mass enhancement on 3-T breast MRI help predict invasiveness: using the BI-RADS lexicon fifth edition
Authors: Lee Seung Min , Nam Kyung Jin , Choo Ki Seok , Kim Jin You , Jeong Dong Wook , Kim Hyun Yul , Kim Jee Yeon 
Published: May 2018

Background Non-mass enhancements (NME) with invasive components account for 10–42% of total malignant NMEs. The factors associated with invasiveness on magnetic resonance imaging (MRI) could be useful for clinical assessment and treatment. Purpose To evaluate the clinical significances of the distributions and internal enhancement patterns (IEP) of malignant NMEs on 3-T breast MRI. Material and Methods A total of 448 consecutive women with newly diagnosed breast cancer that had undergone preoperative MRI and surgery between February 2013 and March 2016 were identified. After exclusions, 72 malignant NMEs without a mass in 72 women (mean age = 51.5 years) were included. Two readers independently assessed distributions and IEPs of NME, according to the Breast Imaging Reporting and Data System lexicon fifth edition. Collected data included the presence of invasion and histopathologic factors. Results A clustered ring IEP was significantly associated with invasive cancer (75.0%, P = 0.001, Reader1; 72.9%, P < 0.001, Reader 2), absence of necrosis (79.0%, P < 0.001; 72.1%, P < 0.001, respectively), and high Ki-67 expression (74.2%, P = 0.048; 74.2%, P = 0.003, respectively). A clumped IEP was related to ductal carcinoma in situ (33.3%, P = 0.025; 50.0%, P = 0.001, respectively), absence of lymph node metastasis (24.1%, P = 0.029; 31.5%, P = 0.030, respectively), and presence of necrosis (34.5%, P = 0.003; 44.8%, P = 0.001, respectively). Conclusion The presence of a clustered ring IEP in patients with breast cancer was found to be significantly associated with invasive breast cancer and high Ki-67 expression.
Association between serum S100A1 level and Global Registry of Acute Coronary Events score in patients with non-ST-segment elevation acute coronary syndrome
Authors: Li Yuanmin , Han Chenjun , Zhang Peng , Zang Wangfu , Guo Rong 
Published: May 2018

Objective Acute coronary syndrome (ACS) is associated with several clinical syndromes, one of which is acute non-ST-segment ACS (NSTE-ACS). S100A1 is a calcium-dependent regulator of heart contraction and relaxation. We investigated the association between the serum S100A1 level and the Global Registry of Acute Coronary Events (GRACE) risk score in patients with NSTE-ACS and the potential of using the serum S100A1 level to predict the 30-day prognosis of NSTE-ACS. Methods The clinical characteristics of 162 patients with NSTE-ACS were analyzed to determine the GRACE score. The serum S100A1 concentration was determined using fasting antecubital venous blood. The patients were divided into different groups according to the serum S100A1 level, and the 30-day NSTE-ACS prognosis was evaluated using Kaplan–Meier analysis. Results The serum S100A1 levels differed significantly among the groups. Correlation analysis showed that the serum S100A1 level was positively correlated with the GRACE score. Kaplan–Meier analysis revealed that the number of 30-day cardiac events was significantly higher in patients with an S100A1 level of >3.41 ng/mL. Conclusions S100A1 is a potential biomarker that can predict the progression of NSTE-ACS and aid in its early risk stratification and prognosis.
Bone Marrow Stimulation Technique Augmented by an Ultrapurified Alginate Gel Enhances Cartilage Repair in a Canine Model
Authors: Baba Rikiya , Onodera Tomohiro , Matsuoka Masatake , Hontani Kazutoshi , Joutoku Zenta , Matsubara Shinji , Homan Kentaro , Iwasaki Norimasa 
Published: May 2018

Background: The optimal treatment for a medium- or large-sized cartilage lesion is still controversial. Since an ultrapurified alginate (UPAL) gel enhances cartilage repair in animal models, this material is expected to improve the efficacy of the current treatment strategies for cartilage lesions. Hypothesis: The bone marrow stimulation technique (BMST) augmented by UPAL gel can induce hyaline-like cartilage repair. Study Design: Controlled laboratory study. Methods: Two cylindrical osteochondral defects were created in the patellar groove of 27 beagle dogs. A total of 108 defects were divided into 3 groups: defects without intervention (control group), defects with the BMST (microfracture group), and defects with the BMST augmented by implantation of UPAL gel (combined group). At 27 weeks postoperatively, macroscopic and histological evaluations, micro–computed tomography assessment, and mechanical testing were performed for each reparative tissue. Results: The defects in the combined group were almost fully covered with translucent reparative tissues, which consisted of hyaline-like cartilage with well-organized collagen structures. The macroscopic score was significantly better in the combined group than in the control group ( P < .05). The histological scores in the combined group were significantly better than those in the control group ( P < .01) and microfracture group ( P < .05). Although the repaired subchondral bone volumes were not influenced by UPAL gel augmentation, the mechanical properties of the combined group were significantly better than those of the microfracture group ( P < .05). Conclusion: The BMST augmented by UPAL gel elicited hyaline-like cartilage repair that had characteristics of rich glycosaminoglycan and matrix immunostained by type II collagen antibody in a canine osteochondral defect model. The present results suggest that the current technique has the potential to be one of the autologous matrix-induced chondrogenesis techniques of the future and to expand the operative indications for the BMST without loss of its technical simplicity. Clinical Relevance: The data support the clinical reality of 1-step minimally invasive cartilage-reparative medicine with UPAL gel without harvesting donor cells.
Adjustable-Loop Femoral Cortical Suspensory Fixation for Patellar Tendon Anterior Cruciate Ligament Reconstruction: A Time Zero Biomechanical Comparison With Interference Screw Fixation
Authors: Mickelson Dayne T. , Lefebvre Thomas , Gall Ken , Riboh Jonathan C. 
Published: May 2018

Background: Adjustable-loop cortical buttons for femoral fixation of bone-tendon-bone grafts have potential advantages over interference screw fixation; however, these devices have not been benchmarked biomechanically against interference screws. Purpose/Hypothesis: The purpose was to compare the time zero biomechanical properties of commercially available, adjustable-loop cortical button and metallic interference screws for femoral fixation of bone-tendon-bone grafts. It was hypothesized that no significant differences would be found in biomechanical properties between fixation techniques. Study Design: Controlled laboratory study. Methods: Adjustable-loop cortical buttons (n = 8) and metallic interference screws (n = 8) were used to fix matched pairs of human bone-tendon-bone allografts in porcine distal femurs. These constructs were preconditioned (10 N to 50 N at 1 Hz, 10 cycles), subjected to cyclic loading (50 N to 250 N at 1 Hz, 500 cycles), and then pulled to failure at 20 mm/min. Results: The loads to failure (mean ± SD, 700 ± 256 N vs 688 ± 215 N, P = .92) and linear stiffnesses (219 ± 48 N/mm vs 218 ± 49 N/mm, P = .97) for the adjustable-loop cortical button and metallic interference screws, respectively, were not significantly different. Cyclic displacement was higher in the adjustable-loop cortical button group (2.1 ± 0.6 mm vs 1.3 ± 0.4 mm, P = .01). The mechanism of failure was different between groups, with bone block slippage occurring most commonly in the interference screw group (n = 5) and fracture of the bone block through the suture hole occurring most commonly in the adjustable-loop cortical button group (n = 6). Conclusion: Adjustable-loop cortical buttons and interference screws have similar time zero failure loads, although cyclic displacement was higher with the adjustable-loop cortical buttons. The mean difference in displacement was less than 1 mm compared with the interference screw. Clinical Relevance: Adjustable-loop cortical buttons may be an acceptable alternative to an interference screw for femoral fixation of bone-tendon-bone grafts in anterior cruciate ligament reconstruction. The clinical relevance of the observed differences in cyclic displacement is unknown and should be evaluated in future studies.
Les représentations visuelles des biens et des services par leurs marquages : les fondements sémiotiques d’un langage des marques
Authors: Bobrie François 
Published: May 2018

Alors que la littérature marketing s’est abondamment intéressée au concept de « Marque » ( brand), elle a délaissé l’étude du marquage ( branding) dans ses dimensions figuratives les plus concrètes. Cet article est dédié à une enquête sémiotique sur la nature des marquages et sur les principes théoriques qui rendent compte de leurs constructions visuelles. Après avoir décrit les outils conceptuels mobilisés, nous montrons à partir d’exemples que le marquage est avant tout la source d’un récit de l’objet marqué et qu’il ne peut pas se résumer à une somme de stimuli, même codés. Puis à partir d’un échantillon de bouteilles de différents crus de Bordeaux et du Beaujolais, nous montrons comment les marquages comme langage visuel permettent de raconter toutes les nuances d’un positionnement et d’une segmentation à l’intérieur d’une même catégorie puis de se différencier entre catégories. En conclusion, nous soulignons l’intérêt heuristique d’une étude sémiotique pour comprendre et maîtriser l’efficacité d’une stratégie de marquage.
Effectiveness of the SIME Program for Infants and Toddlers in Center-Based Settings
Authors: Zhang Xiao , Chan Wai Ling 
Published: May 2018

Objective: This study evaluates the effectiveness of a center-based childcare program, namely, the stimulation, interaction, motivation, and experience (SIME) program for infants and toddlers. Method: Fifty-eight children between 1 and 2 years of age and their parents and childcare workers were recruited from two childcare centers in Hong Kong and participated in the SIME program over a 1-year period. Eighty-seven children from four other childcare centers served as controls. All children were grouped by age (1- vs. 2-year-old class). Results: The SIME program had positive effects on motor, language, cognitive and social development, parenting practices, and the quality of relationships with parents and childcare workers, especially for 1-year-old children and children from the center that served mainly families with a lower socioeconomic status (SES). Conclusion: The outcomes in 1-year-old children and children from the lower SES center confirm the success of this type of center-based infant–toddler program.
Changes in Hindfoot Alignment After High or Low Tibial Osteotomy
Authors: Choi Jun Young , Song Si Jung , Kim Sung Jung , Kim Sang Hee , Park Ji Soo , Suh Jin Soo 
Published: May 2018

Background: We aimed to determine the change in hindfoot alignment after high (HTO) or low tibial osteotomy (LTO), which is commonly performed to prevent the progression of arthritis of the knee or ankle. Methods: We retrospectively reviewed the radiographic findings of patients who underwent HTO or LTO for arthritis with varus deformity of the knee or ankle joint. The hindfoot alignment view angle (HAVA), hindfoot alignment ratio (HAR), and hindfoot moment arm (HMA) were measured using the hindfoot alignment radiographs. All radiographic parameters were measured at 3, 6, and 12 months postoperatively to assess serial changes. Results: In the HTO group, the HAVA and HMA were significantly increased at 12 months postoperatively compared to preoperatively ( P = .03 and .001, respectively). Similarly, the HAR increased from 0.23 preoperatively to 0.44 at 12 months postoperatively, which was a statistically significant change ( P = .001). In the LTO group, the 12-month postoperative HAVA, HAR, and HMA were significantly decreased ( P = .001 for each), which represented a hindfoot alignment change to the valgus position. Conclusions: After HTO, preoperative hindfoot valgus deviation was significantly decreased at 12 months and approached normal values, while the preoperative mild hindfoot varus alignment was changed to valgus deviation after LTO. Level of Evidence: Level III, comparative series.