bluuebunny/crossref_metadata_2025 huggingface dataset:
CasCP: Efficient and Secure Certificateless Authentication Scheme for Wireless Body Area Networks with Conditional Privacy-Preserving
Authors: Xie Yong , Zhang Songsong , Li Xiang , Li Yanggui , Chai Yuan
Published: June 2019

As the aging population of society continues to intensify, the series of problems brought about by aging is becoming more and more serious. Because the health problem of the elderly brings many social problems, people have paid close attention to it. Fortunately, as a typical smart healthcare system, wireless body area networks (WBANs) present quit nice medical care for people, especially the aged. However, personal health information is very sensitive. But, the common communication channel is used in WBANs and any malicious entity can initiate a security attack on WBANs. To ensure secure communication and privacy-preserving which are the premise of the sound development of WBANs, an improved and efficient certificateless authentication scheme with conditional privacy-preserving is proposed in this paper on the basis of analyzing the most recent presented certificateless authentication scheme for WBANs. The proposed scheme also provides batch authentication to decrease authentication and communication cost. A rigid security proof demonstrates that our proposed scheme resists every type of security attack and can provide condition privacy-preserving. The performance analysis shows that our proposed scheme has some advantages in computation and communication cost.
Stable Copper Tin Sulfide Nanoflower Modified Carbon Quantum Dots for Improved Supercapacitors
Authors: Bi Zhen , Huang Lanyan , Shang Chaoqun , Wang Xin , Zhou Guofu
Published: June 2019

Copper tin sulfides (CTSs) have widely been investigated as electrode materials for supercapacitors owing to their high theoretical pseudocapacitances. However, the poor intrinsic conductivity and volume change during redox reactions hindered their electrochemical performances and broad applications. In this study, carbon quantum dots (CQDs) were employed to modify CTSs. The structures and morphologies of obtained materials were characterized by X-ray diffraction (XRD) and transmission electron microscopy (TEM). XRD revealed CTSs were composed of Cu2SnS3 and Cu4SnS4, and TEM suggested the decoration of CQDs on the surface of CTSs. With the decoration of CQDs, CTSs@CQDs showed a remarkable specific capacitance of 856 F·g−1 at 2 mV·s−1 and a high rate capability of 474 F·g−1 at 50 mV·s−1, which were superior to those of CTSs (851 F·g−1 at 2 mV·s−1 and 192 F·g−1 at 50 mV·s−1, respectively). This was mainly ascribed to incorporation of carbon quantum dots, which improved the electrical conductivity and alleviated volume change of CTSs during charge/discharge processes.
Tailoring Immunotherapy Treatment of Synchronous Renal Cell Carcinoma (RCC) and Triple-Negative Breast Cancer (TNBC)
Authors: Sheng Iris Y. , Kruse Megan , Leininger Kathryn M. , Ornstein Moshe C.
Published: June 2019

Synchronous tumors are defined as two tumors arising concurrently or within six months of each other. Reports of synchronous RCC and breast cancer are limited to nonmetastatic renal cell carcinoma (RCC) and hormone receptor-positive infiltrative ductal carcinoma. We present the first case of synchronous metastatic renal cell carcinoma and metastatic triple-negative breast cancer, managed with a novel combination of immunotherapy and chemotherapy.
Resolvin D1 Alleviates Ventilator-Induced Lung Injury in Mice by Activating PPARγ/NF-κB Signaling Pathway
Authors: Xia Haifa , Wang Jingxu , Sun Shujun , Wang Fuquan , Yang Yiyi , Chen Lin , Sun Zhipeng , Yao Shanglong
Published: June 2019

As one of the basic treatment modalities in the intensive care unit (ICU), mechanical ventilation can cause or aggravate acute lung injury or ventilator-induced lung injury (VILI). Resolvin D1 (RvD1) is an endogenous polyunsaturated fatty acid derivative with strong anti-inflammatory action. In this study, we explored if RvD1 possesses a protective effect on VILI. Mice were ventilated with high tidal volume (40 mL/kg, HVT) for 4 h and were then intraperitoneally administered RvD1 at the beginning of high tidal volume ventilation and given GW9662 (a PPAR-γ antagonist) intraperitoneally 30 min before ventilation. RvD1 attenuated VILI, as evidenced by improved oxygenation and reduced histological injury, compared with HVT -induced lung injury. Similarly, it could ameliorate neutrophil accumulation and production of proinflammatory cytokines in lung tissue. In contrast, the protective effect of RvD1 on lung tissue could be reversed by GW9662. RvD1 mitigated VILI by activating peroxisome proliferator-activated receptor gamma (PPAR-γ) and inhibiting nuclear factor-kappa B (NF-κB) signaling pathways in mice. In conclusion, RvD1 could reduce the inflammatory response in VILI by activating PPAR-γ and inhibiting NF-κB signaling pathways.
Modification of the Intrastromal Ring Position according to Postimplant Visual and Refractive Failure: Report of Two Cases
Authors: Izquierdo Luis , Mejías Smith Josefina A. , Lievano Jose R. , Sarquis Ramón , Henriquez Maria A.
Published: June 2019

Objective. The following report presents the adaptation of an existing technique of intrastromal corneal ring (ICRS) implantation enabling repositioning of the ring position postoperatively to manage a refractive failure in two patients with keratoconus. Methods. In two cases, KeraRing and Ferrara nomograms had suggested different ring positions. To manage with the differences between the two nomograms, a longer corneal tunnel was created followed by the classic intervention to move the ring through the initial intrastromal corneal tunnel according to the topographic values. Once the first ring position has failed, the ring segment was repositioned along the longer corneal tunnel according to the postoperative outcome. Results. Significant improvement in both cases was observed in the best corrected visual acuity (BCVA), uncorrected visual acuity (UCVA), and root mean square (RMS) measured with Scheimpflug imaging (Pentacam; Oculus GmBH, Wetzlar, Germany). The participants were followed for one year. Conclusion. In patients with keratoconus which exhibit significant differences between KeraRing and Ferrara nomograms, a longer tunnel should be created to enable repositioning of the ring postoperatively if necessary, to avoid extracting the ring or changing it.
Blow-Up of Solutions with High Energies of a Coupled System of Hyperbolic Equations
Authors: Esquivel-Avila Jorge A.
Published: June 2019

We consider an abstract coupled evolution system of second order in time. For any positive value of the initial energy, in particular for high energies, we give sufficient conditions on the initial data to conclude nonexistence of global solutions. We compare our results with those in the literature and show how we improve them.
Investigating the Practices of Project Governance in Public Sector Infrastructure Program in Pakistan
Authors: Khan Asadullah , Waris Muhammad , Ismail Ishak , Sajid Mirza Rizwan , Ali Zaigham , Ullah Mahfooz , Hussain Ammar
Published: June 2019

The governance of public sector infrastructure projects became an important area of interest in the literature on project management. Today, it is a focal point for policymakers to ensure successful appraisal and implementation of government‐sponsored programs. This paper aims to investigate the current practices of project governance (PG) for steering the public sector infrastructure program in Pakistan. An empirical investigation was carried out among professionals of public sector organizations involved in different infrastructure development projects. Latent construct of PG was validated through second‐order confirmatory factor analysis (CFA) and quantified the three dimensions of PG, i.e., portfolio direction (PD), sponsorship, effectiveness, and efficiency (SEE), and disclosure and reporting (DR) through the relative importance index (RII) method. The result showed that DR is among the least practicing dimension having RII = 0.55, while PD and SEE have shown similar prevalence with RII = 0.70 and 0.69, respectively. Overall, the most practicing item in the PG was “the alignment of portfolios with objectives and strategy” whereas the lowest practicing item relates to the “completeness of project information distribution due to the multi‐layered bureaucratic system.” The findings of this study will guide the decision makers to take appropriate measures for enhancing the effectiveness of PG in Pakistan.
Destruction of the Dorsal Motor Nucleus of the Vagus Aggravates Inflammation and Injury from Acid-Induced Acute Esophagitis in a Rat Model
Authors: Zhao Li , Xie Pengyan , Geng Bin , Wang Zheng , Xu Le
Published: June 2019

Background/Aims. The aim of this study is to examine the protective effect of the cholinergic anti-inflammatory pathway (CAP) in experimental esophagitis in rats. Methods. A total of 40 male Sprague-Dawley (SD) rats were randomly divided into five groups as follows: control group, sham + saline group, sham + acid group, operation + saline group, and operation + acid group. Two weeks after the dorsal motor nucleus of the vagus (DMV) destruction, hydrochloric acid with pepsin was perfused into the lower part of the esophagus for 90 min. The rats were sacrificed 60 min after perfusion. The esophagus was prepared for hematoxylin and eosin (HE) staining, and the degree of inflammation and NF-κB activation in the esophagus was measured. Inflammatory cytokines (TNF-α, IL-6, IL-1β, and PGE2) in the esophagus were measured by ELISA. The brain was removed and processed for c-fos immunohistochemistry staining. The c-fos-positive neurons were counted and analyzed. Results. The TNF-α, IL-1β, IL-6, and PGE2 concentrations in the esophageal tissue increased after acid perfusion. The microscopic esophagitis scores and the activation of NF-κB p65 in the esophagus were significantly higher in the operation + acid group than in the operation + saline group. c-fos-positive neurons significantly increased in rats receiving acid perfusion in the amygdala (AM), the paraventricular nucleus of the hypothalamus (PVN), the parabrachial nucleus (PBN), the nucleus of the solitary tract (NTS)/DMV, the nucleus ambiguous (NA), the reticular nucleus of the medulla (RNM), and the area postrema (AP). After DMV destruction, c-fos expression was reduced in the AM, PVN, PBN, NTS/DMV, NA, RNM, and AP, especially in the AM, PVN, NTS/DMV, RNM, and AP. Conclusions. The DMV is an important nucleus of the CAP. The DMV lesion can aggravate esophageal inflammation and injury from acid-induced acute esophagitis in a rat model. The CAP has a protective effect on the acute esophagitis rat model and could be a new therapy for reflux esophagitis (RE).
Treatment Outcomes of Hepatitis C-Infected Patients in Specialty Clinic vs. Primary Care Physician Clinic: A Comparative Analysis
Authors: Syed Taseen Ahmed , Bashir Muhammad Hassaan , Farooqui Samid Muhammad , Chen Allshine , Chen Sixia , Nusrat Salman , Fazili Javid
Published: June 2019

Background. Oral direct-acting antivirals (DAAs) provide an exceptional opportunity to treat hepatitis C virus (HCV) infection. Goals. We compared the treatment outcomes between specialty and primary care physician (PCP) clinics for patients treated with DAAs. Methods. We performed a retrospective analysis of patients treated for HCV in our PCP clinics and specialty; liver and gastroenterology clinics and gastroenterology clinics. We used the two-sided t-test and the chi-square test to compare the means of continuous and categorical variables, respectively. Results. Data from a total of 377 patients was analyzed (PCP clinic: n=185 and specialty clinic: n=192). There was no significant difference between age, race, and gender. Model for End-Stage Liver Disease (MELD) and Child-Turcotte-Pugh (CTP) scores were comparable at baseline. Greater than 90% of the patients achieved sustained virological response (SVR) with no difference between the groups. Conclusions. Uncomplicated patients can be treated for hepatitis C by their PCPs with DAAs with similar treatment outcomes to specialty clinics. There should be explicit guidelines on patient eligibility for treatment by PCPs vs. specialists.
Robot-Assisted Removal of a Broken Scalpel Blade following Discectomy
Authors: Koutserimpas Christos , Ioannidis Argyrios , Konstantinidis Michael , Athanasopoulos Panagiotis , Antonakopoulos Fotios , Konstantinidis Konstantinos
Published: June 2019

The risk of a broken scalpel blade during discectomy is considered extremely rare, while no guidelines exist regarding this complication. We report a case of a robotic broken blade removal following lumbar discectomy. A 52-year-old female was subjected to L4-L5 discectomy. During the annulus resection, the scalpel blade broke and was retained within the disc space. The broken blade migrated towards the abdominal cavity and viscera. Emergency CT angiography scan revealed that the main vessels were intact, while the broken surgical knife was located anterior to the lumbar spine at the L4/L5 level, to the left of the aorta and superiorly of the left common iliac artery. At that point, robot-assisted laparoscopy was performed. The broken instrument was located and carefully removed. It seems more proper that such foreign bodies should be removed, while robotic surgery may play a significant role in cases that the foreign body is near major vessels.
Implications of Aging Quality of Oak Shaving on Kyoho Wine Immersed with Residue of Cabernet Sauvignon
Authors: Nan Lijun , Zhang Xiaofang , Zhong Yingxue , Cui Changwei , Ning Na , Xu Chengdong , Li Yashan , Huang Jing
Published: June 2019

In order to study effect of oak sawdust on the quality of Kyoho wine immersed by fermented Cabernet Sauvignon residual, Kyoho wine aged without oak sawdust (KWO), including KWO1 and KWO2 according to immersed orders by fermented Cabernet Sauvignon residual, was taken as control to compare the effect of oak sawdust on quality of Kyoho wine (KO), including KO1 and KO2 according to aged orders by oak sawdust. During the 15 days of aging, physical and chemical indicators, such as chroma, tonality, and total phenol in wine were determined simultaneously by using a spectrophotometer, including tannin content by KMnO4titration, once every 3 days. The results showed that the chromaticities of Kyoho wine were 3.21, 3.02, 4.46, and 3.71 for KO1, KO2, KWO1, and KWO2, respectively. Similarly, the hues were in turn 0.73, 0.68, 0.97, and 0.72, respectively. Tannin contents were 1601.5 mg/L, 1517.3 mg/L, 337.2 mg/L, and 115.6 mg/L; total phenol contents were 277.67 mg/L, 222.1 mg/L, 64 mg/L, and 79.8 mg/L. Therefore, the contents of tannin and total phenol from KO1 wine were all the highest values. The chroma and tone of the four types of wine showed an upward trend of “S.” The chromaticity and tone were the lowest for the KO2 wine and the highest for the KWO1 wine with the larger difference between KO2 and KWO1.
Frequency‐Hopping Signal Network‐Station Sorting Based on Maxout Network Model and Generative Method
Authors: Li Hongguang , Guo Ying , Sui Ping , Yu Xinyong , Yang Xin , Wang Shaobo
Published: June 2019

Automatic frequency‐hopping (FH) signal network‐station sorting is one of the most difficult and import problems in the field of electronic warfare, especially in a complex electromagnetic environment. In this paper, an automatic and reliable network‐station sorting method of FH signal with maxout network feature extraction and generative‐based classification method is proposed. Experiments on real FH data sets demonstrate that the proposed method not only outperforms the competitive feature extraction methods with a higher accuracy of FH signal network‐station sorting but also has a better robustness against noise, especially Gaussian noise.
The Mechanism of Compound Anshen Essential Oil in the Treatment of Insomnia Was Examined by Network Pharmacology
Authors: Ren Guilin , Zhong Yu , Ke Gang , Liu Xiaoli , Li Huiting , Li Xiaofang , Zheng Qin , Yang Ming
Published: June 2019

The active component-target network and protein-protein interaction network of Compound Anshen essential oil were constructed. The target functions and related pathways were analyzed to explore the mechanism of Compound Anshen essential oil in the treatment of insomnia. GC-MS was used to detect the chemical composition of Compound Anshen essential oil, and the TCMSP, STITCH, TTD, and DrugBank databases were searched to predict and screen the targets of Compound Anshen essential oil in the treatment of insomnia. Cytoscape software was used to construct the network diagrams of the active component-action target and protein-protein interaction networks, ClueGO software was used to analyze the GO enrichment and KEGG pathway of the target, and the systemsDock website database was used for molecular docking. The analysis of the network results showed that the activity of Compound Anshen essential oil mainly involves biological processes such as the phospholipase C-activating G protein-coupled receptor signaling pathway, response to ammonium ions, calcium ion transport into the cytosol, and chloride transport. The results of molecular docking showed that linalool, caryophyllene, dibutyl phthalate, (-)-4-terpineol, and (-)-α-terpineol have good binding activity with ADRB2, DRD2, ESR1, KCNH2, NR1H4, NR1I2, NR1I3, and TRPV1 targets. This study demonstrates the multicomponent, multitarget, and multichannel characteristics of Compound Anshen essential oil and provides a new therapeutic idea and method for further research on the mechanism of Compound Anshen essential oil in the treatment of insomnia.
A Model System for Studying the DNMT3A Hotspot Mutation (DNMT3AR882) Demonstrates a Causal Relationship between Its Dominant-Negative Effect and Leukemogenesis
Authors: Lu Rui , Wang Jun , Ren Zhihong , Yin Jiekai , Wang Yinsheng , Cai Ling , Wang Gang Greg
Published: June 2019

Mutation of DNA methyltransferase 3A at arginine 882 (DNMT3AR882mut) is prevalent in hematologic cancers and disorders. Recently, DNMT3AR882mut has been shown to have hypomorphic, dominant-negative, and/or gain-of-function effects on DNA methylation under different biological contexts. However, the causal role for such a multifaceted effect of DNMT3AR882mut in leukemogenesis remains undetermined. Here, we report TF-1 leukemia cells as a robust system useful for modeling the DNMT3AR882mut-dependent transformation and for dissecting the cause–effect relationship between multifaceted activities of DNMT3AR882mut and leukemic transformation. Ectopic expression of DNMT3AR882mut and not wild-type DNMT3A promoted TF-1 cell transformation characterized by cytokine-independent growth, and induces CpG hypomethylation predominantly at enhancers. This effect was dose dependent, acted synergistically with the isocitrate dehydrogenase 1 (IDH1) mutation, and resembled what was seen in human leukemia patients carrying DNMT3AR882mut. The transformation- and hypomethylation-inducing capacities of DNMT3AR882mut relied on a motif involved in heterodimerization, whereas its various chromatin-binding domains were dispensable. Mutation of the heterodimerization motif that interferes with DNMT3AR882mut binding to endogenous wild-type DNMT proteins partially reversed the CpG hypomethylation phenotype caused by DNMT3AR882mut, thus supporting a dominant-negative mechanism in cells. In mice, bromodomain inhibition repressed gene-activation events downstream of DNMT3AR882mut-induced CpG hypomethylation, thereby suppressing leukemogenesis mediated by DNMT3AR882mut. Collectively, this study reports a model system useful for studying DNMT3AR882mut, shows a requirement of the dominant-negative effect by DNMT3AR882mut for leukemogenesis, and describes an attractive strategy for the treatment of leukemias carrying DNMT3AR882mut.

Significance:

These findings highlight a model system to study the functional impact of a hotspot mutation of DNMT3A at R882 in leukemia.
Plasma Metabolomic Signatures Associated with Long-term Breast Cancer Risk in the SU.VI.MAX Prospective Cohort
Authors: Lécuyer Lucie , Dalle Céline , Lyan Bernard , Demidem Aicha , Rossary Adrien , Vasson Marie-Paule , Petera Mélanie , Lagree Marie , Ferreira Thomas , Centeno Delphine , Galan Pilar , Hercberg Serge , Deschasaux Mélanie , Partula Valentin , Srour Bernard , Latino-Martel Paule , Kesse-Guyot Emmanuelle , Druesne-Pecollo Nathalie , Durand Stéphanie , Pujos-Guillot Estelle , Touvier Mathilde
Published: June 2019

Background:

Breast cancer is a major cause of death in occidental women. The role of metabolism in breast cancer etiology remains unclear. Metabolomics may help to elucidate novel biological pathways and identify new biomarkers to predict breast cancer long before symptoms appear. The aim of this study was to investigate whether untargeted metabolomic signatures from blood draws of healthy women could contribute to better understand and predict the long-term risk of developing breast cancer.

Methods:

A nested case–control study was conducted within the SU.VI.MAX prospective cohort (13 years of follow-up) to analyze baseline plasma samples of 211 incident breast cancer cases and 211 matched controls by LC/MS. Multivariable conditional logistic regression models were computed.

Results:

A total of 3,565 ions were detected and 1,221 were retained for statistical analysis. A total of 73 ions were associated with breast cancer risk (P < 0.01; FDR ≤ 0.2). Notably, we observed that a lower plasma level of O-succinyl-homoserine (OR = 0.70, 95%CI = [0.55-0.89]) and higher plasma levels of valine/norvaline [1.45 (1.15–1.83)], glutamine/isoglutamine [1.33 (1.07–1.66)], 5-aminovaleric acid [1.46 (1.14–1.87)], phenylalanine [1.43 (1.14–1.78)], tryptophan [1.40 (1.10–1.79)], γ-glutamyl-threonine [1.39 (1.09–1.77)], ATBC [1.41 (1.10–1.79)], and pregnene-triol sulfate [1.38 (1.08–1.77)] were associated with an increased risk of developing breast cancer during follow-up.

Conclusion: Several prediagnostic plasmatic metabolites were associated with long-term breast cancer risk and suggested a role of microbiota metabolism and environmental exposure.

Impact:

After confirmation in other independent cohort studies, these results could help to identify healthy women at higher risk of developing breast cancer in the subsequent decade and to propose a better understanding of the complex mechanisms involved in its etiology.
Clinical Efficacy and Safety of Nivolumab: Results of a

M

ulticenter, Op

e

n-label, Single-a

r

m, Japanese Phase II study in Mal

i

gnant Pleural Meso

t

helioma (MERIT)
Authors: Okada Morihito , Kijima Takashi , Aoe Keisuke , Kato Terufumi , Fujimoto Nobukazu , Nakagawa Kazuhiko , Takeda Yuichiro , Hida Toyoaki , Kanai Kuninobu , Imamura Fumio , Oizumi Satoshi , Takahashi Toshiaki , Takenoyama Mitsuhiro , Tanaka Hiroshi , Hirano Jun , Namba Yoshinobu , Ohe Yuichiro
Published: June 2019

Purpose:

Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy with poor prognosis. Patients with MPM who do not respond to standard first-line chemotherapy have limited treatment options. We evaluated the efficacy and safety of nivolumab, an immune checkpoint inhibitor, for the treatment of advanced or metastatic MPM.

Patients and Methods:

Japanese patients with unresectable, advanced, or metastatic MPM resistant or intolerant to ≤2 regimens of chemotherapy and ≥1 measurable lesion(s) were enrolled. Patients received nivolumab 240 mg intravenously every 2 weeks until progressive disease or unacceptable toxicity. The primary endpoint was objective response rate by central assessment according to the Modified Response Evaluation Criteria in Solid Tumors. Adverse events (AEs) and treatment-related AEs (TRAEs) were evaluated.

Results:

Thirty-four patients were enrolled between July 2016 and October 2016. Median follow-up was 16.8 (range: 1.8–20.2) months. Ten (29%, 95% confidence interval, 16.8–46.2) patients showed a centrally assessed objective response. The objective response rates were 26% (7/27), 67% (2/3), and 25% (1/4) patients for epithelioid, sarcomatoid, and biphasic histologic subtypes, respectively. Median duration of response was 11.1 months with a 68% disease control rate. Median overall survival and progression-free survival were 17.3 and 6.1 months, respectively. The objective response rate was 40% with programmed death-ligand 1 expression ≥1% and 8% with <1%. Thirty-two patients (94%) experienced AEs and 26 (76%) experienced TRAEs.

Conclusions:

Nivolumab met the primary endpoint as second- or third-line treatment for patients with MPM and showed promising efficacy with manageable toxicity.

See related commentary by Mansfield and Zauderer, p. 5438
T-Cell Deletion of MyD88 Connects IL17 and IκBζ to RAS Oncogenesis
Authors: Cataisson Christophe , Salcedo Rosalba , Michalowski Aleksandra M. , Klosterman Mary , Naik Shruti , Li Luowei , Pan Michelle J. , Sweet Amalia , Chen Jin-Qiu , Kostecka Laurie G. , Karwan Megan , Smith Loretta , Dai Ren-Ming , Stewart C. Andrew , Lyakh Lyudmila , Hsieh Wang-Ting , Khan Asra , Yang Howard , Lee Maxwell , Trinchieri Giorgio , Yuspa Stuart H.
Published: June 2019

Cancer development requires a favorable tissue microenvironment. By deleting Myd88 in keratinocytes or specific bone marrow subpopulations in oncogenic RAS-mediated skin carcinogenesis, we show that IL17 from infiltrating T cells and IκBζ signaling in keratinocytes are essential to produce a permissive microenvironment and tumor formation. Both normal and RAS-transformed keratinocytes respond to tumor promoters by activating canonical NF-κB and IκBζ signaling, releasing specific cytokines and chemokines that attract Th17 cells through MyD88-dependent signaling in T cells. The release of IL17 into the microenvironment elevates IκBζ in normal and RAS-transformed keratinocytes. Activation of IκBζ signaling is required for the expression of specific promoting factors induced by IL17 in normal keratinocytes and constitutively expressed in RAS-initiated keratinocytes. Deletion of Nfkbiz in keratinocytes impairs RAS-mediated benign tumor formation. Transcriptional profiling and gene set enrichment analysis of IκBζ−deficient RAS-initiated keratinocytes indicate that IκBζ signaling is common for RAS transformation of multiple epithelial cancers. Probing The Cancer Genome Atlas datasets using this transcriptional profile indicates that reduction of IκBζ signaling during cancer progression associates with poor prognosis in RAS-driven human cancers.

Implications:

The paradox that elevation of IκBζ and stimulation of IκBζ signaling through tumor extrinsic factors is required for RAS-mediated benign tumor formation while relative IκBζ expression is reduced in advanced cancers with poor prognosis implies that tumor cells switch from microenvironmental dependency early in carcinogenesis to cell-autonomous pathways during cancer progression.
Tumor Cells Hijack Macrophage-Produced Complement C1q to Promote Tumor Growth
Authors: Roumenina Lubka T. , Daugan Marie V. , Noé Rémi , Petitprez Florent , Vano Yann A. , Sanchez-Salas Rafaël , Becht Etienne , Meilleroux Julie , Clec'h Bénédicte Le , Giraldo Nicolas A. , Merle Nicolas S. , Sun Cheng-Ming , Verkarre Virginie , Validire Pierre , Selves Janick , Lacroix Laetitia , Delfour Olivier , Vandenberghe Isabelle , Thuilliez Celine , Keddani Sonia , Sakhi Imene B. , Barret Eric , Ferré Pierre , Corvaïa Nathalie , Passioukov Alexandre , Chetaille Eric , Botto Marina , de Reynies Aurélien , Oudard Stephane Marie , Mejean Arnaud , Cathelineau Xavier , Sautès-Fridman Catherine , Fridman Wolf H.
Published: June 2019

Clear-cell renal cell carcinoma (ccRCC) possesses an unmet medical need, particularly at the metastatic stage, when surgery is ineffective. Complement is a key factor in tissue inflammation, favoring cancer progression through the production of complement component 5a (C5a). However, the activation pathways that generate C5a in tumors remain obscure. By data mining, we identified ccRCC as a cancer type expressing concomitantly high expression of the components that are part of the classical complement pathway. To understand how the complement cascade is activated in ccRCC and impacts patients' clinical outcome, primary tumors from three patient cohorts (n = 106, 154, and 43), ccRCC cell lines, and tumor models in complement-deficient mice were used. High densities of cells producing classical complement pathway components C1q and C4 and the presence of C4 activation fragment deposits in primary tumors correlated with poor prognosis. The in situ orchestrated production of C1q by tumor-associated macrophages (TAM) and C1r, C1s, C4, and C3 by tumor cells associated with IgG deposits, led to C1 complex assembly, and complement activation. Accordingly, mice deficient in C1q, C4, or C3 displayed decreased tumor growth. However, the ccRCC tumors infiltrated with high densities of C1q-producing TAMs exhibited an immunosuppressed microenvironment, characterized by high expression of immune checkpoints (i.e., PD-1, Lag-3, PD-L1, and PD-L2). Our data have identified the classical complement pathway as a key inflammatory mechanism activated by the cooperation between tumor cells and TAMs, favoring cancer progression, and highlight potential therapeutic targets to restore an efficient immune reaction to cancer.
Inhibition of the NKp44-PCNA Immune Checkpoint Using a mAb to PCNA
Authors: Kundu Kiran , Ghosh Susmita , Sarkar Rhitajit , Edri Avishay , Brusilovsky Michael , Gershoni-Yahalom Orly , Yossef Rami , Shemesh Avishai , Soria Jean-Charles , Lazar Vladimir , Joshua Ben-Zion , Campbell Kerry S. , Elkabets Moshe , Porgador Angel
Published: June 2019

mAb-based blocking of the immune checkpoints involving the CTLA4-B7 and PD1-PDL1 inhibitory axes enhance T-cell–based adaptive immune responses in patients with cancer. We show here that antitumor responses by natural killer (NK) cells can be enhanced by a checkpoint-blocking mAb, 14-25-9, which we developed against proliferating cell nuclear antigen (PCNA). PCNA is expressed on the surface of cancer cells and acts as an inhibitory ligand for the NK-cell receptor, NKp44-isoform1. We tested for cytoplasmic- and membrane-associated PCNA by FACS- and ImageStream-based staining of cell lines and IHC of human cancer formalin fixed, paraffin embedded tissues. The mAb, 14-25-9, inhibited binding of chimeric NKp44 receptor to PCNA and mostly stained the cytoplasm and membrane of tumor cells, whereas commercial antibody (clone PC10) stained nuclear PCNA. NK functions were measured using ELISA-based IFNγ secretion assays and FACS-based killing assays. The NK92-NKp44-1 cell line and primary human NK cells showed increased IFNγ release upon coincubation with mAb 14-25-9 and various solid tumor cell lines and leukemias. Treatment with 14-25-9 also increased NK cytotoxic activity. In vivo efficacy was evaluated on patient-derived xenografts (PDX)-bearing NSG mice. In PDX-bearing mice, intravenous administration of mAb 14-25-9 increased degranulation (CD107a expression) of intratumorally injected patient autologous or allogeneic NK cells, as well as inhibited tumor growth when treated long term. Our study describes a mAb against the NKp44-PCNA innate immune checkpoint that can enhance NK-cell antitumor activity both in vitro and in vivo.
SEC11A Expression Is Associated with Basal-Like Bladder Cancer and Predicts Patient Survival
Authors: Shigematsu Yoshinori , Oue Naohide , Sekino Yohei , Sakamoto Naoya , Sentani Kazuhiro , Uraoka Naohiro , Hayashi Tetsutaro , Teishima Jun , Matsubara Akio , Yasui Wataru
Published: June 2019

Objectives: Bladder cancer (BC) is a common malignancy worldwide. Signal peptidase complex 18 (SPC18) protein, which is encoded by the SEC11A gene, is one of the subunits of the signal peptidase complex and induces transforming growth factor-α secretion. In the present study, we analyzed the expression and function of SPC18 protein in human BC. Methods: Expression of SPC18 was analyzed by immunohistochemistry. RNA interference was used to inhibit SEC11A expression in BC cell lines. For constitutive expression of the SEC11A gene, a SEC11A expression vector was transfected into BC cell lines. To examine cell viability, we performed 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Modified Boyden chamber assays were used to examine cell invasiveness. Results: SPC18 was upregulated in 54% of 81 BC cases. SPC18 expression served as an independent prognostic classifier of patients with BC. SPC18-positive BC cases frequently expressed cytokeratin 5/6, a marker of basal-like BC. Cell growth and invasiveness were inhibited by SEC11A knockdown and enhanced by forced expression of SEC11A. Conclusion: These results indicate that SPC18 plays an important role in the progression of BC. Specific inhibitors of SPC18 may be promising anticancer drugs for patients with basal-like BC.
MicroRNA-26a: An Emerging Regulator of Renal Biology and Disease
Authors: Li Xiaoyan , Pan Xiao , Fu Xianghui , Yang Yi , Chen Jianghua , Lin Weiqiang
Published: June 2019

MicroRNAs (miRNAs) are short, single-stranded, noncoding RNAs that modulate many key biological processes by simultaneously suppressing multiple target genes. Among them, miR-26a, a conserved miRNA among vertebrates, is highly expressed in various tissues. Accumulating evidence demonstrates that miR-26a plays pivotal roles in cellular differentiation, cell growth, apoptosis, and metastasis, thereby participating in the initiation and development of various human diseases, such as metabolic disease and cancer. More recently, miR-26a was found as a versatile regulator of renal biology and disease. miR-26a is intensively involved in the maintenance of podocyte homeostasis and the actin cytoskeleton. It is also able to modulate the homeostasis and function of mesangial cells. In addition, miR-26a affects the expansion of regulatory T cells in the context of ischemia-reperfusion injury and autoimmune diabetes and thus protects the renal system from immune attack. These available data strongly suggest that renal miR-26a possesses critical pathological functions and represents a potential target for renal disease therapies. This review summarizes current knowledge of miR-26a in renal biology and disease, laying the foundation for exploring its previously unknown functions and mechanisms in the renal system.
A Case-Control Study of the Association of the Polymorphisms of MTHFR and APOE with Risk Factors and the Severity of Coronary Artery Disease
Authors: Long Yan , Zhao Xiao-Tao , Liu Chang , Sun Yuan-Yuan , Ma Yin-Ting , Liu Xin-Yu , Liu Ji-Xuan
Published: June 2019

Objectives: To explore the association between single-nucleotide polymorphisms (SNPs) in MTHFR and APOE and the risk of CAD and, more importantly, the severity of CAD and the profile of serum lipids, we performed a case-control study in a Chinese Han population. Methods: A total of 1,207 cases of consecutive CAD-suspected inpatients were recruited, and 406 CAD cases and 231 non-CAD controls were enrolled for the final analysis after screening for exclusion criteria. All subjects had undergone coronary angiography, and the severity of CAD was evaluated by 2 cardiologists according to the Gensini scores. The genotypes of MTHFR and APOEwere detected using real-time PCR, and then verified by Sanger sequencing. Environmental risk factors, such as age, sex, smoking, alcohol consumption, hypertension, diabetes, dyslipidemia, and BMI were collected. Statistical analyses (the χ2 test, binary logistic regression analysis, and ordinal polytomous logistic regression analysis) were performed with SPSS v16.0. Results: The genotypes ofall the subjects included in the CAD and non-CAD groups in this study were successfully detected, with an agreement of 100% with Sanger sequencing. The distributions of genotypes CT and TT at MTHFR C667T were higher in CAD cases than in non-CAD controls (OR 1.99, 95% CI 1.34–2.95; OR 1.77, 95% CI 1.18–2.67; p < 0.05), whereas genotype AC at MTHFR A1298Cwas lower in CAD cases (OR 0.71, 95% CI 0.50–1.02; p < 0.05). A significant association was observed in genotypes CT and TT at MTHFR C667T and the risk of CAD (OR 1.44, 95% CI 1.27–3.67; OR 1.56, 95% CI 0.88–2.78; p < 0.05). Both genotypes and alleles of APOE were comparable in the CAD cases and non-CAD controls (p > 0.05). The genotype TT at MTHFR C667T and ε4+ at APOE were more likely to be found in the CAD subgroup with a Gensini score ≥72 (p = 0.040 and p = 0.028, respectively). Meanwhile, in the patients with genotype TT,a higher level of serum Hcy was detected, while genotype ε4+ patients possessed higher levels of serum apolipoprotein E (ApoE) and low-density lipoprotein cholesterol (LDL-C) than other genotypes. Conclusion: This study revealed that the SNP site of MTHFR C667Tis associatedwith the risk of CAD in this Chinese Han population. In addition, the genotypes of TT in MTHFR C667T and ε4+in APOE may increase the severity of CAD, and higher Hcy, LDL-C, and ApoE levels may be involved in this pathogenic process.
Relevance of Collaterals for the Success of Neuroprotective Therapies in Acute Ischemic Stroke: Insights from the Randomized URICO-ICTUS Trial
Authors: Amaro Sergio , Renú Arturo , Laredo Carlos , Castellanos Mar , Arenillas Juan F. , Llull Laura , Rudilloso Salvatore , Urra Xabier , Obach Victor , Chamorro Ángel ,   on behalf of the URICO-ICTUS investigators
Published: June 2019

Background: Collateral circulation may modify the effect of neuroprotective therapies. We report a post hoc analysis of the URICO-ICTUS trial (NCT00860366) assessing the modifying treatment effect of pretreatment collaterals on clinical and radiological outcomes in patients with large-vessel acute ischemic stroke receiving uric acid therapy or placebo. Methods: URICO-ICTUS was a randomized clinical trial where 411 alteplase-treated patients also received uric acid 1,000 mg (n = 211) or placebo (n = 200) before the end of alteplase infusion. Herein, we included a nested study of 84 patients (placebo = 40, uric acid = 44) who had a pretreatment CT-angiography (CTA) showing a proximal arterial occlusion in the carotid territory. Excellent collaterals were defined as 100% collateral supply on pretreatment CTA. Regression models assessed the interaction between therapy (uric acid/placebo) and collaterals on the main outcome (ordinal modified Rankin Scale [mRS] shift at 90 days). Results: Overall, excellent collaterals were associated with improved outcome. There was a significant interaction between therapy and pretreatment collaterals (p interaction = 0.02) for the prediction of improved mRS shift. The largest treatment contrast in favor of uric acid was found in patients with excellent collaterals (adjusted OR 9.2; 95% CI 1.23–68.6; p = 0.03). Conclusions: Collectively, the study found that collaterals were associated with the neuroprotective effect of uric acid therapy highlighting the importance of assessing collateral status in neuroprotection trials.
Positive Association between Basal Total Testosterone Circulating Levels and Tumor Grade Groups at the Time of Diagnosis of Prostate Cancer
Authors: Porcaro Antonio B. , Tafuri Alessandro , Sebben Marco , Pirozzi Marco , Processali Tania , Rizzetto Riccardo , Amigoni Nelia , Shakir Aliasger , Tiso Leone , Cerrato Clara , Panunzio Andrea , De Michele Mario , Cerruto Maria Angela , Brunelli Matteo , Migliorini Filippo , Siracusano Salvatore , Artibani Walter
Published: June 2019

Introduction: To test the hypothesis that basal total testosterone (TT) levels are associated with International Society of Urologic Pathology (ISUP) tumor grade groups at the time of diagnosis of prostate cancer (PCA). Methods: From November 2014 to March 2018, preoperative TT and PSA were measured in 601 consecutive patients who were not under androgen deprivation and undergoing surgery for PCA. Patients were classified into low (ISUP 1; reference group), intermediate (ISUP 2/3), and high (ISUP 4/5) tumor grade groups. The association of TT and other clinical factors with tumor groups was evaluated by multinomial multivariate regression analysis. Results: 218 patients (36.3%) were biopsy low grade (ISUP 1), 297 (49.4%) intermediate grade (ISUP 2/3), and 86 (14.3) high grade (ISUP 4/5). Median basal circulating TT levels progressively increased as tumor grade groups increased. On multivariate models, TT, among other clinical factors, was positively associated with the risk of intermediate (OR 1.001; p = 0.023) and high tumor grades (OR 1.002, p = 0.022) compared to low-grade cancers. Conclusions: Increased endogenous circulating basal TT levels were positively associated with ISUP tumor grade groups at the time of diagnosis indicating a close association with tumor biology. Basal TT levels may reflect the heterogeneity of the cancer population.
Multimodal Intraoperative Spinal Cord Monitoring during Spinal Deformity Surgery: Efficacy, Diagnostic Characteristics, and Algorithm Development
Authors: Tsirikos Athanasios I. , Duckworth Andrew D. , Henderson Lindsay E. , Michaelson Ciara
Published: June 2019

Objective: This study aims to present the diagnostic characteristics of multimodal intraoperative monitoring (IOM) in spinal deformity surgery and to define and categorise the neuromonitoring events, as well as propose an algorithm of action. Materials and Methods: We reviewed 1,155 consecutive patients (807 female, 348 male) who underwent deformity correction using standardised perioperative care, cortical/cervical somatosensory evoked potentials (SSEPs), and upper/lower limb transcranial electrical motor evoked potential (MEPs) by a single surgeon. The mean age at surgery was 13.8 years (range 10–23.3). We categorised IOM events as true, transient true, and false positive or negative. Diagnostic performance criteria were calculated. Results: The most common diagnosis was adolescent idiopathic scoliosis in 717 (62%) patients. We identified 3 true positive monitoring events occurring in 2 patients (0.17%), 8 transient true positive (0.69%), and 8 transient false positive events (0.69%). There were no false negative events and no patient had postoperative neurological complications. The multimodal IOM technique had a sensitivity of 100%, specificity of 99.3%, positive predictive value of 55.6%, and negative predictive value of 100%. Sensitivity was 100% for MEPs and multimodal monitoring compared to 20% for cortical or cervical SSEPs. The frequency of true or transient true positive events was higher (p = 0.07) in Scheuermann’s kyphosis (3/91 patients, 3.3%) compared to adolescent idiopathic scoliosis (6/717 patients, 0.84%). Conclusion: Multimodal IOM is highly sensitive and specific for spinal cord injury. This technique is reliable for the assessment of the condition of the spinal cord during major deformity surgery. We propose an algorithm of intraoperative action to allow close cooperation between the surgical, anaesthetic, and neurophysiology teams and to prevent neurological deficits.
Après la Physique Ionienne et la Physique du XXe siècle
Authors: Pin Víctor Gomez
Published: June 2019

In lieu of an abstract, here is a brief excerpt of the content:

"Pour mettre en relief la difficulté que l’on a parfois à cataloguer la philosophie dans le cadre des disciplines académiques, j’ai souvent utilisé un apologue : si on demande à un étudiant de chimie ou de philologie latine de décrire ce que l’on fait concrètement pendant son heure de cours, il s’en tirera sans trop de trouble. Demandons la même chose à l’étudiant qui se dirige vers son cours d’Ontologie ou même de Théorie de la Connaissance. Il aura la plus grande difficulté à expliquer au profane curieux à quoi il va occuper son temps, quelle sera non seulement sa propre tâche mais aussi celle de son professeur."
Le Langage est un Monde
Authors: Santos Luiz Henrique Lopes dos
Published: June 2019

In lieu of an abstract, here is a brief excerpt of the content:

"Il est déjà passé le temps où la philosophie s’occupait fièrement des choses elles-mêmes. Cette constatation (d’ailleurs historiquement incontestable), le diagnostic de la situation à laquelle elle se réfère et la soumission volontaire à ses conséquences jettent les bases du programme philosophique que Francis Wolff s’est proposé d’accomplir dans Dire le monde."
Comprendre Pourquoi J’Agis
Authors: Malinge Yoann
Published: June 2019

In lieu of an abstract, here is a brief excerpt of the content:

"'De deux choses l’une : ou [la personne qui agit] est une personne, elle demeure la même, et ses actes expliquent entièrement ce qu’elle est ; ou ses actes peuvent toujours être interrogés comme des événements du monde, et elle n’est jamais la même qu’elle-même. Car inversement, l’acte est d’autant plus un vrai acte (et non un simple événement naturel du monde) qu’il ne surgit pas de ce que sont les choses, mais change la face du monde. Il est lui-même cette face changée du monde' [Francis Wolff, Dire le monde].

Telle est l’antinomie de la relation de l’agent à son action que décrit Francis Wolff dans le troisième chapitre de Dire le monde.Pour penser l’action, il faut concevoir dans le même mouvement un agent qui soit la cause de l’action sans que cette action soit l’effet de ce qu’est l’agent. La solution que Francis Wolff fournit à l’antinomie, dans le quatrième chapitre de Dire le monde, repose sur le « je » et sur le concept de « j’agis ». Il ne s’agit pas ici d’en faire le commentaire, mais de trouver dans cette résolution une source d’inspiration pour envisager la conscience de l’agent lorsqu’il agit."
Un Monde Contradictoire est-il Possible ?
Authors: Moulines Carlos Ulises
Published: June 2019

In lieu of an abstract, here is a brief excerpt of the content:

"Dans Dire le monde, Francis Wolff développe une conception ontologique qui combine, de manière originale, quelques catégories traditionnelles de la métaphysique avec des notions et principes de la philosophie analytique contemporaine, et tout particulièrement de la philosophie du langage. Je connais très peu de philosophes contemporains qui soient capables de combiner ces deux grandes traditions philosophiques d’une manière si prometteuse pour analyser (et résoudre !) quelques- unes des questions ontologiques les plus difficiles. Francis Wolff en est capable, d’abord parce que, par sa formation, il connaît très bien les deux traditions, mais surtout parce qu’il ne veut pas se limiter à une exégèse plus ou moins bien fondée des idées d’autres auteurs du passé ou du présent : il veut surtout établir et défendre sa propre réponse à la question ontologique de toujours : « Qu’y a-t-il ? »."
Réflexion et Réflexivité
Authors: Recanati François
Published: June 2019

In lieu of an abstract, here is a brief excerpt of the content:

"Étymologiquement, pour autant que je sache, la notion première de réflexion est la notion physique ; une vitre, par exemple, réfléchit les rayons du soleil. La physique étudie cela, comme elle étudie la trajectoire mécanique d’une boule de billard qui sert ici de modèle. Quel rapport entre cette réflexion (la réflexion optique) et celle qui nous importe à nous, philosophes ? Je pense que le lien est fourni par un type particulier de réflexion optique, à savoir la réflexion spéculaire. Les miroirs réfléchissent la lumière, et quand ils le font, le miroir renvoie à l’observateur l’image symétrique inversée de ce qui se trouve devant le miroir (typiquement l’observateur lui-même). Je regarde dans le miroir, et je me vois ! Dans le phénomène spéculaire, nous trouvons ce qui est au cœur de la ou des notion(s) non plus physique(s) mais mentale(s) de réflexion : la notion philosophique, et aussi la notion ordinaire (comme lorsqu’on dit de quelqu’un qu’il réfléchit, ou lorsqu’on propose des réflexions sur un sujet donné). Ce qui caractérise la réflexion mentale, sous toutes ses formes, est quelque chose que l’on retrouve aussi dans la réflexion spéculaire et qui fait que celle-ci sert souvent de modèle pour la réflexion mentale : c’est la réflexivité."