bluuebunny/crossref_metadata_2025 huggingface dataset:
Geochemical Fingerprinting of Rising Deep Endogenous Gases in an Active Hypogenic Karst System
Authors: Fernandez-Cortes A. , Perez-Lopez R. , Cuezva S. , Calaforra J. M. , Cañaveras J. C. , Sanchez-Moral S.
Published: December 2018

The hydrothermal caves linked to active faulting can potentially harbour subterranean atmospheres with a distinctive gaseous composition with deep endogenous gases, such as carbon dioxide (CO2) and methane (CH4). In this study, we provide insight into the sourcing, mixing, and biogeochemical processes involved in the dynamic of deep endogenous gas formation in an exceptionally dynamic hypogenic karst system (Vapour Cave, southern Spain) associated with active faulting. The cave environment is characterized by a prevailing combination of rising warm air with large CO2outgassing (>1%) and highly diluted CH4with an endogenous origin. Theδ13CCO2data, which ranges from −4.5 to −7.5‰, point to a mantle-rooted CO2that is likely generated by the thermal decarbonation of underlying marine carbonates, combined with degassing from CO2-rich groundwater. A pooled analysis ofδ13CCO2data from exterior, cave, and soil indicates that the upwelling of geogenic CO2has a clear influence on soil air, which further suggests a potential for the release of CO2along fractured carbonates. CH4molar fractions and theirδD andδ13C values (ranging from −77 to −48‰ and from −52 to −30‰, respectively) suggest that the methane reaching Vapour Cave is the remnant of a larger source of CH4, which was likely generated by microbial reduction of carbonates. This CH4has been affected by a postgenetic microbial oxidation, such that the gas samples have changed in both molecular and isotopic composition after formation and during migration through the cave environment. Yet, in the deepest cave locations (i.e., 30 m below the surface), measured concentration values of deep endogenous CH4are higher than in atmospheric with lighterδ13C values with respect to those found in the local atmosphere, which indicates that Vapour Cave may occasionally act as a net source of CH4to the open atmosphere.
A Case of Myeloproliferative Neoplasm with BCR-FGFR1 Rearrangement: Favorable Outcome after Haploidentical Allogeneic Transplantation
Authors: Villafuerte-Gutiérrez Paola , López Rubio Montserrat , Herrera Pilar , Arranz Eva
Published: December 2018

Hematopoietic myeloproliferative neoplasms with FGFR1 rearrangement result in the 8p11 myeloproliferative syndrome that in the current Word Health Organization classification is designated as “myeloid and lymphoid neoplasm with FGFR1 abnormalities.” We report the case of a 66-year-old man who had clinical features that resembled chronic myeloid leukaemia (CML), but bone marrow cytogenetic and fluorescent in situ hybridization (FISH) studies showed t(8;22)(p11;q11) and BCR-FGFR1 fusion gene. He was initially managed with hydroxyurea, and given the aggressive nature of this disease, four months later, the patient underwent an allogeneic hematopoietic stem-cell transplantation (HSCT) from an HLA-haploidentical relative. Currently, HSCT may be the only therapeutic option for long-term survival at least until more efficacious tyrosine kinase inhibitors (TKIs) become available.
Coordination of Pheromone Deposition Might Solve Time‐Constrained Travelling Salesman Problem
Authors: Sakiyama Tomoko , Arizono Ikuo
Published: December 2018

In this study, we develop two Ant Colony Optimization (ACO) models as new metaheuristic models for solving the time‐constrained Travelling Salesman Problem (TSP). Here, the time‐constrained TSP means a TSP in which several cities have constraints that the agents have to visit within prescribed time limits. In our ACO models, only agents that achieved tour under certain conditions defined in respective ACO models are allowed to modulate pheromone deposition. The agents in one model are allowed to deposit pheromone only if they achieve a tour satisfying strictly the above purpose. The agents in the other model is allowed to deposit pheromone not only if they achieve a tour satisfying strictly the above purpose, but also if they achieve a tour satisfying the above purpose in some degree. We compare performance of two developed ACO models by focusing on pheromone deposition. We confirm that the later model performs well to some TSP benchmark datasets from TSPLIB in comparison to the former and the traditional AS (Ant System) models. Furthermore, the agent exhibits critical properties; i.e., the system exhibits complex behaviors. These results suggest that the agents perform adaptive travels by coordinating some complex pheromone depositions.
Facile Synthesis of Tin Oxide Hollow Nanoflowers Interfering with Quorum Sensing-Regulated Functions and Bacterial Biofilms
Authors: Al-Shabib Nasser A. , Husain Fohad Mabood , Ahmad Naushad , Qais Faizan Abul , Khan Aslam , Khan Altaf , Khan Mohammad Shavez , Khan Javed Masood , Shahzad Syed Ali , Ahmad Iqbal
Published: December 2018

Monophasic tin dioxide nanoflowers (TONFs) assembled by rod-like nanostructures were prepared by coprecipitation method using tin chloride and ammonia precipitators, as the starting materials, without using any surfactants or templates. The structural, compositional, optical, and morphological properties of TONFs were investigated by XRD, FT-IR, UV-vis, SEM-EDX, and TEM techniques. Synthesized TONFs demonstrated inhibition of quorum sensing- (QS-) regulated virulence in pathogens, viz., Chromobacterium violaceum, Pseudomonas aeruginosa, and Serratia marcescens. Significant reduction in biofilm formation in all test pathogens was also observed which was further validated by CLSM images illustrating disturbed biofilm architecture. Vital functions like EPS, swarming motility, and cell surface hydrophobicity that contribute to successful biofilm formation were reduced after addition of sub-MICs of TONFs. Significant eradication of preformed biofilms was recorded upon addition of subinhibitory concentrations of TONFs in all test pathogens. The study highlights the broad-spectrum QS and biofilm inhibition by TONFs that can be exploited in future to protect food from contamination and combatting persistent drug-resistant infections.
Endophytic FungusAspergillus japonicusMediates Host Plant Growth under Normal and Heat Stress Conditions
Authors: Ismail  , Hamayun Muhammad , Hussain Anwar , Iqbal Amjad , Khan Sumera Afzal , Lee In-Jung
Published: December 2018

We have isolated an endophytic fungus with heat stress alleviation potential from wild plantEuphorbia indicaL. The phylogenetic analysis and 18S rDNA sequence homology revealed that the designated isolate wasAspergillus japonicusEuR-26. Analysis ofA. japonicusculture filtrate displayed higher concentrations of salicylic acid (SA), indoleacetic acid (IAA), flavonoids, and phenolics. Furthermore,A. japonicusassociation with soybean and sunflower had improved plant biomass and other growth features under high temperature stress (40°C) in comparison to endophyte-free plants. In fact, endophytic association mitigated heat stress by negotiating the activities of abscisic acid, catalase, and ascorbic acid oxidase in both soybean and sunflower. The nutritional quality (phenolic, flavonoids, soluble sugars, proteins, and lipids) of theA. japonicus-associated seedlings has also improved under heat stress in comparison to endophyte-free plants. From the results, it is concluded thatA. japonicuscan modulate host plants growth under heat stress and can be used as thermal stress alleviator in arid and semiarid regions of the globe (where mean summer temperature exceeds 40°C) to sustain agriculture.
Multifocal Pigmented Villonodular Synovitis in the Noonan Syndrome
Authors: Miri Othmane , Bonnet Nicolas , Lysy Philippe , Loucheur Naima , Gayito René , Docquier Pierre Louis
Published: December 2018

Noonan-like/multiple giant cell lesion (NS/MGCL) is a rare condition overlapping with Noonan syndrome. Once thought to be a specific and separate entity, it is now suggested to be a variant of the Noonan syndrome spectrum. We report the case of an 8-year-old boy with a typical clinical picture of Noonan syndrome with a de novo germline mutation of PTPN11 (c.854 T>C). During his follow-up, the patient developed multifocal pigmented villonodular synovitis which first affected the left knee and shortly after both elbows.
Novel Registration and Fusion Algorithm for Multimodal Railway Images with Different Field of Views
Authors: Guo Baoqing , Zhou Xingfang , Lin Yingzi , Zhu Liqiang , Yu Zujun
Published: December 2018

Objects intruding high-speed railway clearance do great threat to running trains. In order to improve accuracy of railway intrusion detection, an automatic multimodal registration and fusion algorithm for infrared and visible images with different field of views is presented. The ratio of the nearest to next nearest distance, geometric, similar triangle, and RANSAC constraints are used to refine the matching SURF feature points successively. Correct matching points are accumulated with multiframe to overcome the insufficient matching points in single image pair. After being registered, an improved Contourlet transform fusion algorithm combined with total variation and local region energy is proposed. Inverse Contourlet transform to low frequency subband coefficient fused with total variation model and high frequency subband coefficients fused with local region energy is used to reconstruct the fused image. The comparison to other 4 popular fusion methods shows that our algorithm has the best comprehensive performance for multimodal railway image fusion.
Importance of High-Risk Human Papillomavirus Infection Detection in Female Renal Transplant Recipients in the First Year after Transplantation
Authors: Cistjakovs Maksims , Sultanova Alina , Jermakova Olga , Sokolovska Liba , Chapenko Svetlana , Lesina-Korne Baiba , Rozental Rafail , Murovska Modra , Ziedina Ieva
Published: December 2018

Objectives. Most of human papillomavirus (HPV) infections are “cleared” by the immune system; however, in cases of immune system suppression, infections could lead to development of malignancies. The aim of this study was to find out the frequency of HR-HPV infection in early period after renal transplantation in recipients receiving immunosuppressive therapy and to follow the progression of the infection up to one year. Methods. 43 female renal transplant recipients and 79 healthy female individuals as a control group were enrolled in this investigation. For the detection of HPV infection, patients’ samples (blood and vaginal swabs) were collected two weeks after transplantation with following collection of six months and one year. Different polymerase chain reactions for HR-HPV genomic sequences detection and ELISA kit for detection of anti-HPV IgG antibodies were used. Results. In this study, we show that frequency rate of HR-HPV infection has increased in the first year after transplantation from early stage of immunosuppressive therapy (from 24% to 36%). Also an increase of HR-HPV load was detected over time, showing the highest median viral load at sixth month after transplantation. Conclusions. From the obtained data, it follows that it is very important to carefully monitor patients receiving immunosuppression therapy on progression of HR-HPV.
The ColoCare Study: A Paradigm of Transdisciplinary Science in Colorectal Cancer Outcomes
Authors: Ulrich Cornelia M. , Gigic Biljana , Böhm Jürgen , Ose Jennifer , Viskochil Richard , Schneider Martin , Colditz Graham A. , Figueiredo Jane C. , Grady William M. , Li Christopher I. , Shibata David , Siegel Erin M. , Toriola Adetunji T. , Ulrich Alexis
Published: December 2018

Background:

Colorectal cancer is a leading cause of cancer death. Biomarkers to predict treatment outcomes are needed, as is evidence whether postdiagnosis diet and lifestyle can affect well-being and clinical outcomes. The international ColoCare Consortium aims to identify new biologic markers (e.g., metabolomic, transcriptomic, metagenomic, genetic, epigenetic, proteomic markers) that predict clinical outcomes, and to characterize associations between modifiable risk factors (e.g., diet, supplement use, physical activity) with short-term and long-term patient-reported and clinical outcomes among patients with colorectal cancer.

Methods/Results: ColoCare is recruiting newly diagnosed patients with colorectal cancer across six sites in the United States and one site in Germany. As of April 2018, we have recruited >2,000 patients across all sites. Our projected enrollment is >4,000 multiethnic patients with colorectal cancer. The study includes uniformly collected, comprehensive sets of data and biospecimens at multiple time points up to 5 years after diagnosis. Treatment and clinical data are abstracted from medical records and centrally harmonized. Biospecimens are archived according to standardized procedures. Our initial studies demonstrated metabolic differences in adipose tissue types. We further reported on associations of biological factors (e.g., inflammation, DNA methylation, metabolomics) with lifestyle factors (e.g., adiposity, smoking, physical activity, dietary supplement use) or joint associations with clinical outcomes.

Conclusions:

ColoCare is a consortium for the investigation of multilevel factors relevant to colorectal cancer survivorship.

Impact:

The combination of a comprehensive set of biospecimens collected at multiple time points, jointly with detailed assessments of health behaviors and other prognostic factors, results in a unique resource that facilitates wide-ranging, innovative, and impactful research on colorectal cancer.
The Secretome Engages STAT3 to Favor a Cytokine-rich Microenvironment in Mediating Acquired Resistance to FGFR Inhibitors
Authors: Wang Xinyi , Ai Jing , Liu Hongyan , Peng Xia , Chen Hui , Chen Yi , Su Yi , Shen Aijun , Huang Xun , Ding Jian , Geng Meiyu
Published: December 2018

Acquired resistance severely hinders the application of small-molecule inhibitors. Our understanding of acquired resistance related to FGFRs is limited. Here, to explore the underlying mechanism of acquired resistance in FGFR-aberrant cancer cells, we generated cells resistant to multiple FGFR inhibitors (FGFRi) and investigated the potential mechanisms underlying acquired resistance. We discovered that reprogramming of the secretome is closely associated with acquired resistance to FGFRi. The secretome drives acquired resistance by activating the transcription factor STAT3 via its cognate receptors. Moreover, macrophages and fibroblasts could interact with cancer cells to enhance acquired resistance by promoting exaggerated and dynamic cytokine secretion, as well as STAT3 activation. We also found that Hsp90 and HDAC inhibitors could substantially and simultaneously suppress the proliferation of resistant cells, the secretion of multiple cytokines, and the activation of STAT3. Our study offers translational insights concerning the poor efficacy observed in patients with macrophage- and fibroblast-rich lung cancers and breast tumors after treatment with FGFRi in clinical trials.
KDM5B Promotes Drug Resistance by Regulating Melanoma-Propagating Cell Subpopulations
Authors: Liu Xiaoni , Zhang Shang-Min , McGeary Meaghan K. , Krykbaeva Irina , Lai Ling , Jansen Daniel J. , Kales Stephen C. , Simeonov Anton , Hall Matthew D. , Kelly Daniel P. , Bosenberg Marcus W. , Yan Qin
Published: December 2018

Tumor heterogeneity is a major challenge for cancer treatment, especially due to the presence of various subpopulations with stem cell or progenitor cell properties. In mouse melanomas, both CD34+p75− (CD34+) and CD34−p75− (CD34−) tumor subpopulations were characterized as melanoma-propagating cells (MPC) that exhibit some of those key features. However, these two subpopulations differ from each other in tumorigenic potential, ability to recapitulate heterogeneity, and chemoresistance. In this study, we demonstrate that CD34+ and CD34− subpopulations carrying the BRAFV600E mutation confer differential sensitivity to targeted BRAF inhibition. Through elevated KDM5B expression, melanoma cells shift toward a more drug-tolerant, CD34− state upon exposure to BRAF inhibitor or combined BRAF inhibitor and MEK inhibitor treatment. KDM5B loss or inhibition shifts melanoma cells to the more BRAF inhibitor–sensitive CD34+ state. These results support that KDM5B is a critical epigenetic regulator that governs the transition of key MPC subpopulations with distinct drug sensitivity. This study also emphasizes the importance of continuing to advance our understanding of intratumor heterogeneity and ultimately develop novel therapeutics by altering the heterogeneous characteristics of melanoma.
Genome-Wide Sequencing of Cell-Free DNA Identifies Copy-Number Alterations That Can Be Used for Monitoring Response to Immunotherapy in Cancer Patients
Authors: Jensen Taylor J. , Goodman Aaron M. , Kato Shumei , Ellison Christopher K. , Daniels Gregory A. , Kim Lisa , Nakashe Prachi , McCarthy Erin , Mazloom Amin R. , McLennan Graham , Grosu Daniel S. , Ehrich Mathias , Kurzrock Razelle
Published: December 2018

Inhibitors of the PD-1/PD-L1/CTLA-4 immune checkpoint pathway have revolutionized cancer treatment. Indeed, some patients with advanced, refractory malignancies achieve durable responses; however, only a subset of patients benefit, necessitating new biomarkers to predict outcome. Interrogating cell-free DNA (cfDNA) isolated from plasma (liquid biopsy) provides a promising method for monitoring response. We describe the use of low-coverage, genome-wide sequencing of cfDNA, validated extensively for noninvasive prenatal testing, to detect tumor-specific copy-number alterations, and the development of a new metric—the genome instability number (GIN)—to monitor response to these drugs. We demonstrate how the GIN can be used to discriminate clinical response from progression, differentiate progression from pseudoprogression, and identify hyperprogressive disease. Finally, we provide evidence for delayed kinetics in responses to checkpoint inhibitors relative to molecularly targeted therapies. Overall, these data demonstrate a proof of concept for using this method for monitoring treatment outcome in patients with cancer receiving immunotherapy.
Neuropsychiatric Manifestations of Cognitively Advanced Idiopathic Normal Pressure Hydrocephalus
Authors: Mathew Robert , Pavithran Sauda , Byju P.
Published: December 2018

Background: Neuropsychiatric manifestations of patients with idiopathic normal pressure hydrocephalus (iNPH) have not been studied in a systematic way. Aim: To study the spectrum of neuropsychiatric abnormalities in patients with iNPH. Patient Selection and Evaluation: Patients attending 3 different tertiary care centers during three consecutive time periods spanning from 2010 to 2015 were analyzed for neuropsychiatric manifestations. Patients diagnosed as having probable or possible iNPH as per the consensus criteria were included in the study. Neuropsychiatric manifestations were captured by a comprehensive inventory (Cambridge Behavioral Inventory, CBI). Results: The CBI score was available for 41 patients. The mean Mini-Mental State Examination score was 15.37 (SD 7.2) and the Addenbrooke’s Cognitive Examination score was 34.95 (SD 19.67), thereby indicating cognitively advanced iNPH. All patients had impairment in one or more items on the CBI. The mean score was 55.46 (SD 27) out of 180, thereby indicating a mild degree of impairment. Among the subscores, impairment with motivation was the most observed abnormality followed by memory impairment. When the CBI total score and subscores were compared, all of them (except motivation) were higher for Alzheimer’s disease; however, none was statistically significant. Even though the motivation score was higher for iNPH, the difference did not reach statistical significance. Conclusions: It can be concluded that neurobehavioral abnormalities are common in patients with cognitively advanced normal pressure hydrocephalus. However, the intensity of involvement appeared less when compared to Alzheimer’s disease. Apathy appears to be the most common impairment.
Development and Application of a New PCR Method for Detection of Blumeria graminis f. sp. tritici
Authors: Kuzdraliński Adam , Szczerba Hubert , Kot Anna , Ostrowska Agnieszka , Nowak Michał , Muszyńska Marta
Published: December 2018

We developed new PCR assays that target beta-tubulin (TUB2) and 14 alpha-demethylase (CYP51) genes and used them for the species-specific detection of Blumeria graminis f. sp. tritici (Bgt). Based on fungi DNA sequences available in the NCBI (National Center for Biotechnology Information) GenBank database we developed simplex and duplex PCR assays. The specificities of the primer sets were evaluated using environmental samples of wheat leaves collected during the 2015/2016 growing season across Poland. Primer sets LidBg17/18 and LidBg21/22 strongly amplified fragments of the expected length for all 67 tested samples. Primer specificity was confirmed using field samples of Zymoseptoria tri­tici, Puccinia triticina (syn. P. recondita f. sp. tritici), P. striiformis f. sp. tritici, and Pyrenophora tritici-repentis.
Photoinactivation of the Staphylococcus aureus Lactose-Specific EIICB Phosphotransferase Component with p-azidophenyl-β-D-Galactoside and Phosphorylation of the Covalently Bound Substrate
Authors: Sossna-Wunder Gina , Hengstenberg Wolfgang , Briozzo Pierre , Deutscher Josef
Published: December 2018

Background: The phosphoenolpyruvate (PEP):lactose phosphotransferase system of Staphylococcus aureus transports and phosphorylates lactose and various phenylgalactosides. Their phosphorylation is catalyzed by the Cys476-phosphorylated EIIB domain of the lactose-specific permease enzyme IICB (EIICBLac). Phosphorylation causes the release of galactosides bound to the EIIC domain into the cytoplasm by a mechanism not yet understood. Results: Irradiation of a reaction mixture containing the photoactivatable p-azidophenyl-β-D-galactopyranoside and EIICBLac with UV light caused a loss of EIICBLac activity. Nevertheless, photoinactivated EIICBLac could still be phosphorylated with [32P]PEP. Proteolysis of photoinactivated [32P]P-EIICBLac with subtilisin provided an 11-kDa radioactive peptide. Only the sequence of its first three amino acids (-H-G-P-, position 245–247) could be determined. They are part of the substrate binding pocket in EIICs of the lactose/cellobiose PTS family. Surprisingly, while acid treatment caused hydrolysis of the phosphoryl group in active [32P]P∼EIICBLac, photoinactivated [32P]P-EIICBLac remained strongly phosphorylated. Conclusion: Phosphorylation of the –OH group at C6 of p-nitrenephenyl-β-D-galactopyranoside covalently bound to EIICLac by the histidyl-phosphorylated [32P]P∼EIIBLac domain is a likely explanation for the observed acid resistance. Placing p-nitrenephenyl-β-D-galactopyranoside into the active site of modelled EIICLac suggested that the nitrene binds to the -NH- group of Ser248, which would explain why no sequence data beyond Pro247could be obtained.
Developing a Process for Returning Medically Actionable Genomic Variants to Latino Patients in a Federally Qualified Health Center
Authors: Shaibi Gabriel Q. , Kullo Iftikhar J. , Singh Davinder P. , Sharp Richard R. , De Filippis Eleanna , Cuellar Idali , Hernandez Valentina , Levey Sharon , Radecki Breitkopf Carmen , Olson Janet E. , Cerhan James R. , Mandarino Lawrence J. , Thibodeau Stephen N. , Lindor Noralane M.
Published: December 2018

Aim: To develop a process for returning medically actionable genomic variants to Latino patients receiving care in a Federally Qualified Health Center. Methods: Prior to recruitment, researchers met with primary care providers to (1) orient clinicians to the project, (2) establish a process for returning actionable and nonactionable results to participants and providers through the electronic health record, and (3) develop a process for offering clinical decision support for follow-up education and care. A Community Advisory Board was engaged to provide input on recruitment strategies and materials for conveying results to participants. Participants in the Sangre Por Salud (Blood for Health) Biobank with hyperlipidemia or colon polyps represented the pool of potentially eligible participants. Results: A total of 1,621 individuals were invited to participate and 710 agreed to an in- person consenting visit (194 no-showed and 16 declined). Over 12-months, 500 participants were enrolled. Participants were primarily Spanish-speaking (81.6%), female (74.2%), and enrolled because of hyperlipidemia (95.4%). All but 2 participants opted to receive primary (i.e., related to enrollment phenotypes) as well as secondary actionable results. Conclusion: Efforts to bring precision medicine to community-based health centers serving minority patients may require multilevel engagement activities to include individuals, providers, health systems, and the community.
Bilateral Lateral Rectus Recession for the Treatment of Recurrent Exotropia after Bilateral Medial Rectus Resection
Authors: Wang Xi , Chen Xiaohang , Liu Longqian
Published: December 2018

Purpose: To evaluate the efficacy of bilateral lateral rectus muscle recession (BLR) to treat recurrent exotropia after bilateral medial rectus muscle resection (BMR). Methods: Twenty-four patients who underwent BLR for recurrent exotropia and were followed up for more than 6 months were included in this retrospective study. All of them had prior BMR. The angle of deviation, success rates, near stereopsis, and surgical effect of BLR were evaluated. Surgical success was defined as postoperative deviations ≤10 prism diopters (PD). Results: The overall mean follow-up time after reoperation for patients was 24.13 ± 15.01 months (range 6–60 months). The mean angle of deviation at distance was significantly reduced from –37.75 ± 14.93 PD to +1.50 ± 6.43 PD (p < 0.001). Twenty-two (91.6%) of 24 patients had successful outcomes, 1 (4.2%) had overcorrection, and 1 (4.2%) had undercorrection at the last follow-up. Improved stereopsis after reoperation was observed in 78.3% (18/23) of the patients. The mean surgical effect was 2.78 ± 0.71 PD/mm. Conclusion: Based on our results, BLR could be an effective and safe method for treating recurrent exotropia after a moderate to large amount of BMR.
Elevated Hemidiaphragm and Shortness of Breath: Challenges in Clinicoradiologic Integration
Authors: Podder Vivek , Biswas Rakesh , Sehgal Nidhi
Published: December 2018

Unilateral diaphragmatic paralysis is often suspected when a hemidiaphragm is found abnormally elevated on chest radiography. Chest radiography has a high sensitivity for diaphragmatic palsy. A 67-year-old male presented to the hospital with a history of 4 months of exertional breathlessness that improved after taking a rest. The patient had normal cardiac and respiratory physical function. He also had a normal electrocardiogram and good systolic function on echocardiography. A treadmill test revealed ST-segment changes during peak exercise and recovery phases. On chest X-ray, his right hemidiaphragm was shown to be significantly elevated. Further investigation was conducted to rule out diaphragmatic paralysis, and the findings took a surprising turn to an entirely different diagnosis.
Taxifolin Inhibits Receptor Activator of NF-κB Ligand-Induced Osteoclastogenesis of Human Bone Marrow-Derived Macrophages in vitro and Prevents Lipopolysaccharide-Induced Bone Loss in vivo
Authors: Zhang Hong-Qi , Wang Yun-Jia , Yang Guan-Teng , Gao Qi-Le , Tang Ming-Xing
Published: December 2018

It has been reported that taxifolin inhibit osteoclastogenesis in RAW264.7 cells. In our research, the inhibition effects of taxifolin on the osteoclastogenesis of human bone marrow-derived macrophages (BMMs) induced by receptor activator of NF-κB ligand (RANKL) as well as the protection effects in lipopolysaccharide-induced bone lysis mouse model have been demonstrated. In vitro, taxifolin inhibited RANKL-induced osteoclast differentiation of human BMMs without cytotoxicity. Moreover, taxifolin significantly suppressed RANKL-induced gene expression, including tartrate-resistant acid phosphatase, matrix metalloproteinase-9 nuclear factor of activated T cells 1 and cathepsin K, and F-actin ring formation. Further studies showed that taxifolin inhibit osteoclastogenesis via the suppression of the NF-κB signaling pathway. In vivo, taxifolin prevented bone loss in mouse calvarial osteolysis model. In conclusion, the results suggested that taxifolin has a therapeutic potential for osteoclastogenesis-related diseases such as osteoporosis, osteolysis, and rheumatoid arthritis.
Inhibition of Erythrocyte Cell Membrane Scrambling Following Energy Depletion and Hyperosmotic Shock by Alectinib
Authors: Al Mamun Bhuyan Abdulla  , Lang Florian
Published: December 2018

Background/Aims: The anaplastic lymphoma kinase (ALK) inhibitor alectinib is clinically used for the treatment of ALK positive non-small-cell lung cancer. At least in part the substance is effective by triggering suicidal death or apoptosis of tumor cells. Erythrocytes are lacking mitochondria and nuclei, key organelles of apoptosis but are, similar to apoptosis of nucleated cells, able to enter suicidal erythrocyte death or eryptosis. Stimulators of eryptosis include energy depletion, hyperosmotic shock, oxidative stress, and increase of cytosolic Ca2+ activity ([Ca2+]i). The present study explored, whether alectinib influences eryptosis. Methods: Flow cytometry was employed to quantify phosphatidylserine exposure at the cell surface from annexin-V-binding and cell volume from forward scatter. Measurements were made without or with energy depletion (glucose deprivation for 48 hours), hyperosmotic shock (+550mM sucrose for 6 hours), oxidative stress (50 min exposure to 0.3 mM tert-butylhydroperoxide), and Ca2+ loading (60 minutes treatment with 1 µM Ca2+ ionophore ionomycin). Results: A 48 hours exposure of human erythrocytes to alectinib (150-600 ng/ml) did not significantly modify the percentage of annexin-V-binding cells and forward scatter. Energy depletion, hyperosmotic shock, oxidative stress and Ca2+ loading were each followed by profound and significant increase of the percentage annexin-V-binding erythrocytes and a significant decrease of forward scatter. The effects of energy depletion and hyperosmotic shock, but not of oxidative stress or Ca2+ loading on annexin-V-binding were significantly blunted in the presence of alectinib (150-600 ng/ml). In none of the conditions was forward scatter significantly modified by alectinib. Conclusion: Alectinib inhibits cell membrane scrambling following energy depletion and hyperosmotic shock.
Potential Role of microRNA-183 as a Tumor Suppressor in Hepatocellular Carcinoma
Authors: Bian Wei , Zhang Hongfei , Tang Miao , Zhang Shaojun , Wang Lichao , Liu Longlong , Wang Wenyao
Published: December 2018

Background/Aims: Disseminated tumors, known as metastases, are responsible for ninety-percent of mortality due to cancer. Epithelial to mesenchymal transition, a phenomenon required for morphological conversion of non-motile discoid shaped epithelial cells to highly motile spindle-shaped mesenchymal cells, is thought to be a pre-requisite for metastatic progression. Metastasis-associated 1 (MTA1) protein is a prime inducer of EMT and metastatic progression in all solid tumors including hepatocellular carcinoma (HCC). However, the molecular mechanisms that regulate the expression and function of MTA1 in HCC have not been elucidated. Methods: In silico prediction algorithms were used to find microRNAs (miRNAs) that may target MTA1. We examined the relationship between the expression of MTA1 and miR-183 using quantitative real time PCR. We also determined the levels of the MTA1 protein using immunohistochemistry. Reporter assays, in the presence and absence of the miR-183 mimic, were used to confirm MTA1 as a bona fide target of miR183. The effect of miR-183 on HCC pathogenesis was determined using a combination of in vitro migration and invasion assay, together with in vivo xenograft experiments. The correlation between miR-183 and MTA1 expression was also studied in samples from HCC patients, and in The Cancer Genome Atlas dataset. Results: Analysis of the sequence database revealed that MTA1 is a putative target of miR-183. MTA1 protein and RNA expression showed opposite trends to miR-183 expression in breast, renal, prostate, and testicular tissue samples from cancer patients, and in the metastatic HCC cell line HepG2. An inverse correlation was also observed between MTA1 (high) and miR-183 (low) expression within samples from HHC patients and in the TCGA dataset. Reporter assays in HepG2 cells showed that miR-183 could inhibit translation of a reporter harboring the wild-type, but not the mutant miR-183 3’-untranslated region (UTR). In addition, miR-183 significantly inhibited in vitro migration and invasion in HepG2 cells, and in vivo hepatic metastasis. Conclusion: Our results reveal a novel post-transcriptional regulatory mechanism for MTA1 expression via miR-183, which is suppressed during HCC pathogenesis.
Blocking TRPA1 and TNF-α Signal Improves Bortezomib-Induced Neuropathic Pain
Authors: Li Chunrui , Deng Taoran , Shang Zhen , Wang Di , Xiao Yi
Published: December 2018

Background/Aims: Bortezomib (BTZ) is largely used as a chemotherapeutic agent for the treatment of multiple myeloma. However, one of the significant limiting complications of BTZ is painful peripheral neuropathy during BTZ therapy. The purpose of this study was to examine the underlying mechanisms leading to neuropathic pain induced by BTZ. Methods: ELISA and western blot analysis were used to examine the levels of tumor necrosis factor alpha (TNF-α) and its receptor, transient receptor potential ankyrin 1 (TRPA1) and intracellular p38-MAPK and JNK signal in the lumbar dorsal root ganglion. Behavioral test was performed to determine mechanical pain and cold sensitivity in a rat model. Results: Systemic injection of BTZ significantly increased mechanical pain and cold sensitivity as compared with control animals (P< 0.05 vs. control rats). Our data also showed that protein expression of TRPA1 was upregulated in the dorsal root ganglion of BTZ rats and blocking TRPA1 attenuated mechanical pain and cold sensitivity in control rats and BTZ rats (P< 0.05 vs. vehicle control). Notably, the inhibitory effect of blocking TRPA1 on mechanical pain and cold sensitivity was smaller in BTZ rats than that in control rats. In addition, a blockade of TNF-α attenuated intracellular p38-MAPK and JNK signal in the dorsal root ganglion. This also decreased TRPA1 expression and alleviated mechanical hyperalgesia and cold hypersensitivity in BTZ rats. Conclusion: We revealed specific signaling pathways leading to neuropathic pain induced by chemotherapeutic BTZ. The data also suggest that blocking TRPA1 and tumor necrosis factor alpha is beneficial to alleviate neuropathic pain during BTZ intervention.
Microbial Intervention as a Novel Target in Treatment of Non-Alcoholic Fatty Liver Disease Progression
Authors: Zhou Youlian , Zheng Tiying , Chen Huiting , Li Yongqiang , Huang Hongli , Chen Wenji , Du Yanlei , He Jie , Li Yuyuan , Cao Jie , Nie Yuqiang , Zhou Yongjian
Published: December 2018

Background/Aims: Emerging evidence suggests a close link between gut microbiota and non-alcoholic fatty liver disease (NAFLD). In this study, we aimed to investigate the association between gut microbiota and the DNA methylation of adiponectin (an adipocyte-specific adipocytokine) in rats, following diet-induced NAFLD. Methods: 50 male SD rats were randomly divided into five groups with or without a high fat diet (HFD), antibiotics, and probiotics, in order to establish an imbalanced gut microbiota and probiotic treatment model in NAFLD rats. After 13 weeks of treatment, blood, liver, and cecal tissue samples were collected. Serum lipids, liver function indexes by biochemical analyzers, and changes in liver pathology with hematoxylin-eosin (HE) and masson staining were detected. Furthermore, the serum adiponectin by enzyme-linked immunosorbent assay (ELISA) and liver adiponectin methylation levels in the promoter regions by pyrophosphate sequencing were determined. High throughput Illumina sequencing targeted microbial 16S genes, bioinformatics and statistical analysis identified cecal-associated gut microbiota. Results: HFD with antibiotic exposure showed the most severe steatohepatitis and a severe gut microbiota alteration. Reduced bacterial diversity was also seen and the abundances of Firmicutes, Lactobacillus, Cyanobacteria, Acidobacteria, Chlamydiae, Chlamydiales, Rubrobacteria, Verrucomicrobia, Blautia, Shewanella, Bacteroides, Bacteroides acidifaciens, and Bacteroides uniformis, were shown to be partly reversed by probiotic treatment. Decreased serum adiponectin levels and increased DNA methylation levels of adiponectin promoter regions were also markedly associated with the NAFLD progression during gut microbiota alteration. Conclusion: Our results suggested that both gut microbiota alteration and adiponectin variability may be drivers of NAFLD progression and that targeting the gut microbiota, such as via administration of a probiotic, may delay NAFLD progression via adiponectin.
miR-122 Targets X-Linked Inhibitor of Apoptosis Protein to Sensitize Oxaliplatin-Resistant Colorectal Cancer Cells to Oxaliplatin-Mediated Cytotoxicity
Authors: Hua Yongqiang , Zhu Yaodong , Zhang Jijie , Zhu Zhenfeng , Ning Zhouyu , Chen Hao , Liu Luming , Chen Zhen , Meng Zhiqiang 
Published: December 2018

Background/Aims: Although oxaliplatin is one of the most effective chemotherapeutic drugs used to treat colorectal cancer (CRC), long-term administration usually induces acquired drug resistance during the course of treatment. Thus, there is an urgent need to explore novel strategies to improve the efficiency of cancer therapy. The aim of this study was to explore the effect of microRNA-122 (miR-122) on reversing oxaliplatin resistance in CRC. Methods: The expression of miR-122 in CRC cells was examined by quantitative reverse transcriptase real-time PCR. The cytotoxicity of oxaliplatin against CRC cells was evaluated by Cell Counting Kit-8 assays. Mitochondrial membrane potentials and cell apoptotic rates were measured by flow cytometry. Cellular protein expression and interactions were detected by western blot and co-immunoprecipitation. Results: Established oxaliplatin-resistant SW480 and HT29 cells (SW480/OR and HT29/OR) expressed significantly higher levels of X-linked inhibitor of apoptosis protein (XIAP) and lower levels of miR-122 compared with normal SW480 and HT29 cells, respectively. Our results showed that the downregulation of miR-122 was responsible for the overexpression of XIAP in these oxaliplatin-resistant CRC cells. We then found that the recovery of miR-122 expression can sensitize SW480/OR and HT29/OR cells to oxaliplatin-mediated apoptosis through the inhibition of XIAP expression. Conclusion: Upregulation of XIAP in CRC cells is responsible for the acquired resistance to oxaliplatin. Furthermore, miR-122 reversed oxaliplatin resistance in CRC by targeting XIAP.
miR-202 Enhances the Anti-Tumor Effect of Cisplatin on Non-Small Cell Lung Cancer by Targeting the Ras/MAPK Pathway
Authors: Sun Wei , Ping Wei , Tian Yitao , Zou Wenbin , Liu Jiawei , Zu Yukun
Published: December 2018

Background/Aims: KRas is usually mutated in non-small cell lung cancer (NSCLC). The mutated KRas gene is a negative prognostic indicator that promotes tumor proliferation, metastasis, and drug resistance in NSCLC, and thus has become a target for cancer therapy. This study is focused on the effects of the microRNA (miR)-202/KRas axis in regulating chemosensitivity in NSCLC. Methods: Quantitative reverse transcriptase real-time PCR analysis was performed to examine the expression of miR-202. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays were performed to evaluate the sensitivity of cisplatin against NSCLC cells. The miR-202/KRas axis was confirmed by western blot and luciferase reporter assays. Cell apoptosis was measured by flow cytometry. KRas expression, MEK1/2 and ERK1/2 phosphorylation, and activation of caspase-9 and caspase-3 were detected by western blot. Results: A significant decrease in miR-202 expression was observed in NSCLC cells both in vivo and in vitro. In addition, miR-202 expression was associated with drug resistance. Recovery of miR-202 expression levels was found to increase the sensitivity of both NCI-H441 and A549 NSCLC cells to cisplatin treatment. Mechanically, as the Ras/mitogen-activated protein kinase (MAPK) pathway was aberrantly activated in NCI-H441 and A549 NSCLC cells, the overexpression of miR-202 was found to inhibit the Ras/MAPK pathway by targeting the KRas gene. As a result, increased miR-202 expression expanded apoptosis signaling induced by cisplatin in NSCLC cells. Conclusion: The miR-202/KRas axis controlled the chemosensitivity of NSCLC by mediating the Ras/MAPK pathway. Thus, the combination of platinum-based drugs with miR-202 may represent a novel strategy to enhance the anti-tumor effect against NSCLC.
Serum Beta Carotene and Overall and Cause-Specific Mortality
Authors: Huang Jiaqi , Weinstein Stephanie J. , Yu Kai , Männistö Satu , Albanes Demetrius
Published: December 2018

Rationale:

Although the health effects of beta carotene have been studied extensively, a systematic examination of serum concentrations and long-term mortality, including cardiovascular disease mortality, has not been reported.

Objective:

Explore whether serum beta carotene is associated with overall and cause-specific mortality and to elucidate the strength and dose-response of the association.

Methods and Results:

We conducted a prospective serological analysis of 29 103 men in the ATBC study (Alpha-Tocopherol, Beta-Carotene Cancer Prevention). During 31 years of follow-up, 23 796 deaths occurred, including deaths because of cardiovascular disease (9869), cancer (7692), respiratory disease (2161), diabetes mellitus (119), injuries and accidents (1255), and other causes (2700). Serum beta carotene was assayed using high-performance liquid chromatography. Adjusting for major risk factors measured, men with higher serum beta carotene had significantly lower all-cause mortality (hazard ratios=0.81, 0.71, 0.69, and 0.64 for quintile 2 (Q2)-Q5 versus Q1, respectively;
P
trend
<0.0001). Serum beta carotene was significantly associated with risk of death from cardiovascular disease, heart disease, stroke, cancer, respiratory disease, diabetes mellitus, injuries and accidents, and other causes (Q5 versus Q1, hazard ratio=0.21–0.73, all
P
trend
<0.0001). The all-cause mortality association was not materially impacted by adjustment for fruit and vegetable consumption (albeit, estimated with some measurement error) and was generally similar across subgroups of smoking intensity, alcohol consumption, trial supplementation, and duration of follow-up, but was significantly modified by age, years of smoking, and body mass index, with stronger inverse associations among men who were younger, smoked fewer years, and had a lower body mass index (all
P
interaction
≤0.0025).

Conclusions:

This study provides evidence that higher beta carotene biochemical status is associated with lower overall, cardiovascular disease, heart disease, stroke, cancer, and other causes of mortality. The dose-response associations over a 30-year period were not attenuated by adjustment for other important risk factors and support greater fruit and vegetable consumption as a means to increase beta carotene status and promote longevity.
Myonectin Is an Exercise-Induced Myokine That Protects the Heart From Ischemia-Reperfusion Injury
Authors: Otaka Naoya , Shibata Rei , Ohashi Koji , Uemura Yusuke , Kambara Takahiro , Enomoto Takashi , Ogawa Hayato , Ito Masanori , Kawanishi Hiroshi , Maruyama Sonomi , Joki Yusuke , Fujikawa Yusuke , Narita Shingo , Unno Kazumasa , Kawamoto Yoshiyuki , Murate Takashi , Murohara Toyoaki , Ouchi Noriyuki
Published: December 2018

Rationale:

Physical exercise provides benefits for various organ systems, and some of systemic effects of exercise are mediated through modulation of muscle-derived secreted factors, also known as myokines. Myonectin/C1q (complement component 1q)/TNF (tumor necrosis factor)-related protein 15/erythroferrone is a myokine that is upregulated in skeletal muscle and blood by exercise.

Objective:

We investigated the role of myonectin in myocardial ischemic injury.

Methods and Results:

Ischemia-reperfusion in myonectin-knockout mice led to enhancement of myocardial infarct size, cardiac dysfunction, apoptosis, and proinflammatory gene expression compared with wild-type mice. Conversely, transgenic overexpression of myonectin in skeletal muscle reduced myocardial damage after ischemia-reperfusion. Treadmill exercise increased circulating myonectin levels in wild-type mice, and it reduced infarct size after ischemia-reperfusion in wild-type mice, but not in myonectin-knockout mice. Treatment of cultured cardiomyocytes with myonectin protein attenuated hypoxia/reoxygenation-induced apoptosis via S1P (sphingosine-1-phosphate)-dependent activation of cAMP/Akt cascades. Similarly, myonectin suppressed inflammatory response to lipopolysaccharide in cultured macrophages through the S1P/cAMP/Akt-dependent signaling pathway. Moreover, blockade of S1P-dependent pathway reversed myonectin-mediated reduction of myocardial infarct size in mice after ischemia-reperfusion.

Conclusions:

These data indicate that myonectin functions as an endurance exercise-induced myokine which ameliorates acute myocardial ischemic injury by suppressing apoptosis and inflammation in the heart, suggesting that myonectin mediates some of the beneficial actions of exercise on cardiovascular health.
Abstract 002: Macula Densa SGLT1-NOS1-TGF Pathway -- A New Mechanism for Glomerular Hyperfiltration in Diabetes
Authors: Zhang Jie , Jiang Shan , Wei Jin , Wang Lei , Liu Ruisheng
Published: December 2018

Glomerular hyperfiltration is a common observation in early diabetes and considered as risk factor for diabetic nephropathy. The mechanisms underlying glomerular hyperfiltration have not been fully clarified. In the present study, we tested a novel SGLT1-NOS1 -TGF (sodium-glucose cotransporter 1 - neuronal nitric oxide synthase – tubuloglomerular feedback) pathway with a hypothesis that tubular glucose is sensed by SGLT1 of the macula densa, which enhances macula densa NOS1 activity and blunts TGF response, therefore increasing glomerular filtration rate (GFR). NO generation by the macula densa, measured by DAF-2 DA in isolated perfused juxtaglomerular apparatus (JGA), increased by 78.4±9.1% when tubular glucose (glucose) was increased from 100 mg/dl to 300 mg/dl (n=4, p<0.01 vs 100 mg/dl). A selective SGLT1 inhibitor KGA-2727 (10
-6
M) blocked this glucose-induced NO generation. Human kidney biopsy tissues were cultured in normal glucose (100 mg/dl) and high glucose (300 mg/dl) media for 30 minutes with hanging drop technique. Protein levels of P-NOS1
ser1417
increased by 63.1±9.2% and P-NOS1
ser847
decreased by 47.4±5.9% (n=4, p<0.01 vs normal glucose) with high glucose. TGF response was significantly reduced from 3.8±0.2 μm to 2.4±0.2 μm (n=4, p<0.05 vs 100 mg/dl), measured in isolated and double perfused JGAs when tubular glucose was increased from 100 mg/dl to 300 mg/dl. The glucose-induced TGF inhibition was blocked in the presence of SGLT1 inhibition (n=4). GFR, measured in conscious mice with a single bolus injection of FITC-inulin, increased by 19.1±3.5% in response to an acute intravenous injection of 50 μl 2M glucose in C57BL/6 mice (n=4, p<0.01 vs baseline). Then, we repeated the experiments in macula densa specific NOS1 KO (KO) mice. Both glucose-induced TGF (ΔP
sf
was from 7.8±1.3 to 7.3±2.1 mmHg) and GFR (from 223±15.7 to 240±6.9 μl/min) (n=5) were blocked in the KO mice. We conclude that increase of tubular glucose concentration activates NOS1 by phosphorylation of NOS1
ser1417
via SGLT1 in the macula densa, which increases GFR by inhibiting TGF response.