bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combination therapy with BYL719 and LEE011 is synergistic and causes a greater suppression of p-S6 in triple negative breast cancer
Authors: Yuan Yuan , Wen Wei , Yost Susan E. , Xing Quanhua , Yan Jin , Han Ernest S. , Mortimer Joanne , Yim John H. 
Published: May 2019

AbstractA third of patients with triple negative breast cancer (TNBC) have relapsed disease within 2–5 years from initial diagnosis, leaving an unmet need for therapeutic targets. TNBC frequently harbors alterations of the PI3K/AKT/mTOR pathway, but single agent PI3K/AKT/mTOR inhibitors have not shown marked efficacy. In this study, we investigated a strategy to improve efficacy of PI3K-α inhibitor BYL719 (alpelisib) in TNBC. While BYL719 is effective at inhibiting cell proliferation in T47D, a triple positive cell line, it had limited activity in TNBC. This may be partially due to persistent phosphorylation of RB, and incomplete inhibition of p-S6 in TNBC, since the inhibitory effect of BYL719 on p-RB and p-S6 was significantly reduced in TNBC compared to T47D cells. Addition of the CDK4/6 inhibitor LEE011 to BYL719 caused a simultaneous reduction of p-RB and p-S6, and a more complete inhibition of p-S6, leading to decreased expression of the pro-survival protein MCL-1, an induction of apoptosis, and an enhanced reduction of tumor growth in a PDX model of TNBC. These findings suggest that inhibition of p-RB and p-S6 is important for an effective response to the treatment of TNBC, and provides a strong rationale for clinical development of combination therapy with BYL719 and LEE011 for treatment of metastatic TNBC with intact RB.Presentation: This study was presented in part as an abstract at the 2016 San Antonio Breast Cancer Symposium (P3-03-15) and the 2018 Cancer Research and Targeted Therapy in London.
Transcriptome profiles revealed the mechanisms underlying the adaptation of yak to high-altitude environments
Authors: Xin Jin-Wei , Chai Zhi-Xin , Zhang Cheng-Fu , Zhang Qiang , Zhu Yong , Cao Han-Wen , Ji Qiu-Mei , Zhong Jin-Cheng 
Published: May 2019

AbstractThe yak is a valuable species in the Qinghai-Tibet Plateau of China. Nevertheless, the molecular mechanisms underlying its adaptation to high-altitude environments remain largely unknown. In the present study, comparative transcriptome sequencing was performed for lung and gluteus tissues from two species of low-altitude cattle (Sanjiang and Holstein cattle), Tibetan cattle (living at a moderate altitude), and yak (living at a high altitude) and the differentially expressed genes were validated using real-time quantitative PCR. The results showed that CD36 antigen was up-regulated and CD59 antigen was down-regulated in yak in comparison to the other animals, which might promote the development of red blood cells and inhibit the development of lymphocytes in yak. In addition, thrombospondin type 1, coagulation factor 5/8, and fibronectin were all down-regulated, but serpin and alpha 2-macroglobulin (A2M) were up-regulated. These differences would inhibit blood coagulation, thus reducing the risk of pulmonary edema. The expression levels of the calcium-release, potassium, and transient receptor potential channels decreased in yak, minimizing membrane depolarization and the harmful effects of pulmonary edema. Eleven KEGG pathways associated with innate immunity were more activated in yak and Tibetan cattle than in other cattle strains, which should reduce their risk of infection and disease. These changes together might facilitate the adaptation of yak and Tibetan cattle to live in high-altitude habitats.
CRISPR/Cas9-mediated ablation of elovl2 in Atlantic salmon (Salmo salar L.) inhibits elongation of polyunsaturated fatty acids and induces Srebp-1 and target genes
Authors: Datsomor Alex K. , Zic Nikola , Li Keshuai , Olsen Rolf E. , Jin Yang , Vik Jon Olav , Edvardsen Rolf B. , Grammes Fabian , Wargelius Anna , Winge Per 
Published: May 2019

AbstractAtlantic salmon can synthesize polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (20:5n-3), arachidonic acid (20:4n-6) and docosahexaenoic acid (22:6n-3) via activities of very long chain fatty acyl elongases (Elovls) and fatty acyl desaturases (Fads), albeit to a limited degree. Understanding molecular mechanisms of PUFA biosynthesis and regulation is a pre-requisite for sustainable use of vegetable oils in aquafeeds as current sources of fish oils are unable to meet increasing demands for omega-3 PUFAs. By generating CRISPR-mediated elovl2 partial knockout (KO), we have shown that elovl2 is crucial for multi-tissue synthesis of 22:6n-3 in vivo and that endogenously synthesized PUFAs are important for transcriptional regulation of lipogenic genes in Atlantic salmon. The elovl2-KOs showed reduced levels of 22:6n-3 and accumulation of 20:5n-3 and docosapentaenoic acid (22:5n-3) in the liver, brain and white muscle, suggesting inhibition of elongation. Additionally, elovl2-KO salmon showed accumulation of 20:4n-6 in brain and white muscle. The impaired synthesis of 22:6n-3 induced hepatic expression of sterol regulatory element binding protein-1 (srebp-1), fatty acid synthase-b, Δ6fad-a, Δ5fad and elovl5. Our study demonstrates key roles of elovl2 at two penultimate steps of PUFA synthesis in vivo and suggests Srebp-1 as a main regulator of endogenous PUFA synthesis in Atlantic salmon.
Affimer reagents as tools in diagnosing plant virus diseases
Authors: Hesketh Emma L. , Tiede Christian , Adamson Hope , Adams Thomas L. , Byrne Matthew J. , Meshcheriakova Yulia , Kruse Inga , McPherson Michael J. , Lomonossoff George P. , Tomlinson Darren C. , Ranson Neil A. 
Published: May 2019

AbstractPlant viruses can cause devastating losses to agriculture and are therefore a major threat to food security. The rapid identification of virally-infected crops allowing containment is essential to limit such threats, but plant viral diseases can be extremely challenging to diagnose. An ideal method for plant virus diagnosis would be a device which can be implemented easily in the field. Such devices require a binding reagent that is specific for the virus of interest. We chose to investigate the use of Affimer reagents, artificial binding proteins and a model plant virus Cowpea Mosaic virus (CPMV) empty virus like particles (eVLPs). CPMV-eVLP mimic the morphology of wild-type (WT) CPMV but lack any infectious genomic material and so do not have biocontainment issues. We have produced and purified an Affimer reagent selected for its ability to bind to CPMV-eVLP and have shown that the selected Affimer also specifically binds to WT CPMV. We have produced a 3.4 Å structure of WT CPMV bound to the Affimer using cryo-electron microscopy. Finally, we have shown that this Affimer is capable of reliably detecting the virus in crude extracts of CPMV-infected leaves and can therefore form the basis for the future development of diagnostic tests.
Loss of Disabled-2 Expression in Pancreatic Cancer Progression
Authors: Hocevar Barbara A. 
Published: May 2019

AbstractPancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer type characterized by rapid metastasis and resistance to chemotherapy, properties that are shared by cancer stem cells (CSCs). In pancreatic cancer, tumor cells which possess the properties of CSCs also phenotypically resemble cells that have undergone epithelial-to-mesenchymal transition or EMT. Disabled-2 (Dab2) is a multifunctional scaffold protein frequently downregulated in cancer that has been linked to the process of EMT. However, the role of Dab2 in pancreatic cancer development and progression remains unclear. Downregulation of Dab2 expression in pancreatic cancer cell lines was found to trigger induction of genes characteristic of EMT and the CSC phenotype, while overexpression of Dab2 in the Panc1 cell line blocked the process of TGFβ-stimulated EMT. In addition, selective inhibition of the TGFβRI/RII receptors was found to reverse genes altered by Dab2 downregulation. Dab2 mRNA expression was found to be decreased in PDAC tumor samples, as compared to levels observed in normal pancreatic tissue. Methylation of the Dab2 gene promoter was demonstrated in Stage I PDAC tumors and in the MiaPaCa2 cell line, suggesting that promoter methylation may silence Dab2 expression early in pancreatic cancer progression. These results suggest that Dab2 may function as a tumor suppressor in pancreatic cancer by modulation of the TGFβ-stimulated EMT and CSC phenotype.
Periodontitis is associated with an increased risk for proximal colorectal neoplasms
Authors: Kim Gun Woo , Kim Young-Sang , Lee Soo Hyun , Park Seung Geon , Kim Duk Hwan , Cho Joo Young , Hahm Ki Baik , Hong Sung Pyo , Yoo Jun-Hwan 
Published: May 2019

AbstractInterval colorectal cancers detected after colonoscopy are known to be highly associated with proximal colorectal neoplasms (CRNs). This cross-sectional study investigated whether periodontitis could be a risk factor for proximal CRNs in healthy individuals. A total of 2504 subjects who received a colonoscopy and dental exam were enrolled in this study. We divided the subjects into the periodontitis group (n = 216) and the control group (n = 2288). The periodontitis group was defined as subjects who had one or more teeth with a probing pocket depth (PPD) ≥4 mm. The prevalence of proximal CRNs was significantly higher in the periodontitis group (25.0%) than in the control group (12.3%) (P < 0.001). Independent risk factors for proximal CRNs in the multivariate analysis were periodontitis, smoking, age, waist circumference, and triglycerides, and those for proximal advanced CRNs were periodontitis, age, and family history of CRC. However, periodontitis was not a risk factor for overall CRNs and advanced CRNs. Periodontitis was associated with an increased risk of proximal CRNs (odds ratio [OR], 1.525; 95% confidence intervals [95% CI], 1.071–2.172) and proximal advanced CRNs (OR, 2.671; 95% CI, 1.088–6.560). Periodontitis might be associated with proximal CRNs and proximal advanced CRNs.
Effect of mycalolides isolated from a marine sponge Mycale aff. nullarosette on actin in living cells
Authors: Hayashi-Takanaka Yoko , Kina Yuto , Nakamura Fumiaki , Yamazaki Shota , Harata Masahiko , Soest Rob W. M. van , Kimura Hiroshi , Nakao Yoichi 
Published: May 2019

AbstractDiscovery of novel bioactive compounds is important not only for therapeutic purposes but also for understanding the mechanisms of biological processes. To screen bioactive compounds that affect nuclear morphology in marine organism extracts, we employed a microscopy-based assay using DNA staining of human cancer cells. A crude extract from a marine sponge Mycale aff. nullarosette, collected from the east coast of Japan, induced cellular binucleation. Fractionation of the extract led to the isolation of mycalolides A and B, and 38-hydroxymycalolide B as the active components. Mycalolides have been identified as marine toxins that induce depolymerization of the actin filament. Live cell imaging revealed that low concentrations of mycalolide A produce binucleated cells by inhibiting the completion of cytokinesis. At higher concentrations, however, mycalolide A causes immediate disruption of actin filaments and changes in cell morphology, yielding rounded cells. These results suggest that the completion of cytokinesis is a process requiring high actin polymerization activity. Furthermore, luciferase reporter assays with mycalolide A treatments support the view that the level of globular actin can affect transcription of a serum response gene.
15-deoxy-Δ12,14-Prostaglandin J2 inhibits human soluble epoxide hydrolase by a dual orthosteric and allosteric mechanism
Authors: Abis Giancarlo , Charles Rebecca L. , Kopec Jolanta , Yue Wyatt W. , Atkinson R. Andrew , Bui Tam T. T. , Lynham Steven , Popova Simona , Sun Yin-Biao , Fraternali Franca , Eaton Philip , Conte Maria R. 
Published: May 2019

AbstractHuman soluble epoxide hydrolase (hsEH) is an enzyme responsible for the inactivation of bioactive epoxy fatty acids, and its inhibition is emerging as a promising therapeutical strategy to target hypertension, cardiovascular disease, pain and insulin sensitivity. Here, we uncover the molecular bases of hsEH inhibition mediated by the endogenous 15-deoxy-Δ12,14-Prostaglandin J2 (15d-PGJ2). Our data reveal a dual inhibitory mechanism, whereby hsEH can be inhibited by reversible docking of 15d-PGJ2 in the catalytic pocket, as well as by covalent locking of the same compound onto cysteine residues C423 and C522, remote to the active site. Biophysical characterisations allied with in silico investigations indicate that the covalent modification of the reactive cysteines may be part of a hitherto undiscovered allosteric regulatory mechanism of the enzyme. This study provides insights into the molecular modes of inhibition of hsEH epoxy-hydrolytic activity and paves the way for the development of new allosteric inhibitors.
The impact of clothing on ozone and squalene ozonolysis products in indoor environments
Authors: Lakey Pascale S. J. , Morrison Glenn C. , Won Youngbo , Parry Krista M. , von Domaros Michael , Tobias Douglas J. , Rim Donghyun , Shiraiwa Manabu 
Published: May 2019

AbstractMultiphase reactions of ozone with human skin oils impact indoor air quality by depleting ozone and forming semi-volatile organic compounds, which can be respiratory and skin irritants. Here we demonstrate the impact of clothing on indoor air composition and human exposure by integrating indoor chemistry modeling over a wide range of different spatial and temporal scales. Constrained by molecular dynamics simulations that provide key kinetic parameters, the kinetic model reproduces experimental measurements and predicts that squalene could persist in clothing for several hours to over a day depending on ozone concentrations. Soiled clothing protects skin from ozone exposure even with high concentrations, but can enhance concentrations of oxidation products to a ppb level depending on air exchange rates. Computational fluid dynamics simulations reveal that primary products have ~1.6–2.0 times higher concentrations in the breathing zone than in bulk room air, while secondary products are distributed more uniformly throughout a room.
End-to-end capacities of a quantum communication network
Authors: Pirandola Stefano 
Published: May 2019

AbstractIn quantum mechanics, a fundamental law prevents quantum communications to simultaneously achieve high rates and long distances. This limitation is well known for point-to-point protocols, where two parties are directly connected by a quantum channel, but not yet fully understood in protocols with quantum repeaters. Here we solve this problem bounding the ultimate rates for transmitting quantum information, entanglement and secret keys via quantum repeaters. We derive single-letter upper bounds for the end-to-end capacities achievable by the most general (adaptive) protocols of quantum and private communication, from a single repeater chain to an arbitrarily complex quantum network, where systems may be routed through single or multiple paths. We analytically establish these capacities under fundamental noise models, including bosonic loss which is the most important for optical communications. In this way, our results provide the ultimate benchmarks for testing the optimal performance of repeater-assisted quantum communications.
Rapid increase in transparency of biological organs by matching refractive index of medium to cell membrane using phosphoric acid
Authors: Umezawa Masakazu , Haruguchi Shinsuke , Fukushima Rihito , Sekiyama Shota , Kamimura Masao , Soga Kohei 
Published: May 2019

Tissue clearing effect of phosphoric acid is fast and needs only 60 min incubation.
A novel method for the absolute end-to-end calibration of the Auger fluorescence telescopes
Authors: Mathes Hermann-Josef 
Published: May 2019

The fluorescence detector technique is using the atmosphere as a calorimeter. Besides the precise monitoring of the parameters of the atmosphere a proper knowledge of the optical properties in the UV range of all optical components involved in the measurements of the fluorescence light is vital.
Until now, the end-to-end calibration was performed with a 4.5 m2 large, uniformly lit light source attached to the aperture of the telescopes. To improve the maintainability we propose an alternative setup where a small and lightweight light source of known optical properties re-samples the measurement of the big light source piece by piece. This will be achieved by moving the light source based on an integrating sphere in two dimensions in front of the aperture. A prototype setup has been installed and we are currently optimizing the parameters of the system and the procedures. The aim is to reduce the effort for the procedure without diminishing the quality of the measurement.
First measurements with this setup have already been performed and the measurements of the geometrical and optical properties of the light source are an ongoing activity. We present our calibration scheme and the first, preliminary results.
Psychosoziale Betreuung und Homöopathie für eine Dolmetscherin für Flüchtlinge
Authors: Hoffmann-Durben Marita 
Published: May 2019

ZusammenfassungDer Fallbericht dokumentiert die psychosoziale Betreuung einer aus dem Iran stammenden Dolmetscherin durch traumatherapeutische und akuttherapeutische homöopathische Interventionen. Die Dolmetscherin, die bei einem Betreuungsprojekt für Flüchtlinge mitarbeitete, litt darunter, dass durch ihre Übersetzungen traumatischer Erfahrungen der Flüchtlinge eigene traumatische Erfahrungen getriggert wurden. Die psychische und körperliche Stabilität war nach 10 Sitzungen innerhalb eines Jahres wieder gegeben.
Häufige Erkrankungen durch Reisen homöopathisch behandelt
Authors: Albrecht Daniela 
Published: May 2019

ZusammenfassungDas Vorgehen und die Möglichkeiten einer homöopathischen Reiseberatung werden neben einer konventionellen Reiseberatung in der ärztlichen Praxis beschrieben. Zur Verdeutlichung wird ein Fall einer Kinetose dargestellt und aufgezeigt, wie im Vorfeld beraten und versorgt wurde. Als weiterer Fall wird die Erkrankung einer Reiserückkehrerin mit einer anhaltenden postinfektiösen Diarrhö beschrieben, die erfolgreich homöopathisch behandelt wurde. Neben einer individuellen Behandlung von Reiserückkehrern in der Praxis sollte während der Reise auch die Gabe von homöopathischen Mittel nach vereinfachten individualisierten Indikationen durch die Reisenden selbst in Betracht gezogen und entsprechend beraten werden.
Muskuloskelettale Beschwerden mit internistischem oder
viszeralem Hintergrund
Authors: Zalpour Christoff 
Published: May 2019

ZusammenfassungUm den Anforderungen eines Erstkontaktes in der Physiotherapie gerecht zu werden,
ist es unerlässlich, internistische oder viszerale Erkrankungen zu (er)kennen,
die sich hinter muskuloskelettalen Symptomen verbergen können. Dr. Christoff
Zalpour stellt die häufigsten Erkrankungen und ihre Symptome vor.
Novel telemetric sensor capsule for EGD urgency triage: a feasibility study
Authors: Schmidt Arthur , Zimmermann Melanie , Bauder Markus , Kuellmer Armin , Caca Karel 
Published: May 2019

Abstract
Background and study aims Upper gastrointestinal bleeding (UGIB) is a frequent cause of hospitalization. Because of the lack of reliable noninvasive diagnostic tools, the decision to proceed with emergency endoscopy in these cases is made based on clinical parameters. A novel non-imaging telemetric real-time sensor capsule (HemoPill Acute, Ovesco Endoscopy AG) has shown promising results for noninvasive detection of UGIB in preclinical studies.
Patients and methods We conducted a prospective non-randomized, single center, open-label study to investigate feasibility and safety of the novel sensor capsule in patients with symptoms of UGIB. The primary aim of the first clinical study was to investigate feasibility and safety of the device in a clinical setting. All patients underwent endoscopy within 12 hours after capsule ingestion. Sensor data from the capsule within 10 minutes after ingestion were compared with endoscopic findings.
Results From April 2015 to February 2016, 30 consecutive patients with symptoms of acute UGIB were included; 27 were eligible for analysis. Capsule ingestion was well tolerated in all patients and there were no device-related adverse events. Endoscopy showed blood or hematin in the upper gastrointestinal tract of 10 of 27 patients; in 2 of 10 patients it was estimated to be more than 20 mL; in 4 of 8 patients it was between 5 and 20 mL and in 4 of 8 it was estimated to < 5 mL. The sensor capsule was positive in 2 of 2 patients (100 %) with > 20 mL of blood or hematin and in 1 of 8 patients (12.5 %) between 5 and 20 mL. All patients (17/17; 100 %) were correctly identified as non-bleeders.
Conclusion Both device and procedure proved to be safe and feasible. Larger studies will be necessary to evaluate the role of the sensor capsule in risk stratification of patients with acute UGIB.
Retrospektive Studie über die Anwendung der tiefen kontinuierlichen Sedierung bis zum Tod auf einer spezialisierten Palliativabteilung in der Schweiz
Authors: Camartin Cristian 
Published: May 2019

Zusammenfassung
Einleitung In der Palliative Care steht die Behandlung von belastenden Symptomen im Vordergrund. Im Falle einer ungenügenden Symptomkontrolle kann die Durchführung einer tiefen kontinuierlichen Sedierung bis zum Tod in Erwägung gezogen werden. Ziel dieser Maßnahme ist das Bewusstsein des Patienten in therapierefraktären Situationen zu reduzieren um so das Leiden mindern zu können.
Fragestellungen
1. Wie viele Patienten benötigten am Lebensende zur Symptomkontrolle eine tiefe kontinuierliche Sedierung bis zum Tod?2. Bei welchen Erkrankungen wurde am häufigsten eine tiefe kontinuierliche Sedierung bis zum Tod benötigt?3. Welche belastenden Symptome wurden angegangen?4. Welche Medikation und Dosierung wurde angewendet?5. Wie lange wurde eine Sedierung durchgeführt?
Methodik Retrospektive Studie mit Auswertung der Todesfälle auf der Palliativstation des Kantonsspitals Graubünden vom 01.01.2013 – 31.12.2016. Aus den Akten wurden die Diagnosen, Indikation sowie Dosierungen mit Dauer der tiefen kontinuierlichen Sedierung bis zum Tod und die Symptome, welche zur Indikation und Einleitung einer kontinuierlichen Sedierung bis zum Tod geführt haben, ausgewertet.
Resultate In diesem Zeitrahmen gab es insgesamt 560 Todesfälle. Eine tiefe kontinuierliche Sedierung bis zum Tod musste bei 59 Patienten (10,5 %) durchgeführt werden. Diese Maßnahme wurde häufiger bei Patienten mit einem Tumorleiden eingesetzt. Es zeigte sich, dass insbesondere Patienten mit einem Lungentumor (in 17,5 % der Fälle) eine tiefe kontinuierliche Sedierung bis zum Tod brauchten. Einen hohen Anteil von tiefen kontinuierlichen Sedierungen bis zum Tod gab es bei Patienten mit Tumoren im Hals-Nasen-Ohren-Bereich sowie bei nicht onkologischen Patienten mit einer amyotrophen Lateralsklerose. Die tiefe kontinuierliche Sedierung bis zum Tod konnte fast ausschließlich mit Midazolam durchgeführt werden, mit einer mittleren Dosis von 5,5 mg/h (SD 5,0 mg/h). Die Dauer der Sedierung betrug im Mittelwert 29,2 h (SD 41,0 h).
Diskussion Eine tiefe kontinuierliche Sedierung bis zum Tod wird bei refraktären Symptomen eingesetzt. Die hauptsächlichen Beschwerden sind Unruhe und Atemnot. Patienten mit Lungentumoren benötigen zur Symptomlinderung anteilsmäßig am häufigsten eine tiefe kontinuierliche Sedierung bis zum Tod. Diese wird in einem begrenzten Zeitraum von 26,6 h im Durchschnitt (SD 41,0 h) angewendet. Als Standardmedikament wird Midazolam eingesetzt, um das Ziel einer tiefen kontinuierlichen Sedierung bis zum Tod erreichen zu können.