bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of Therapeutic Senescence in Vemurafenib-Resistant Melanoma by Extended Inhibition of CDK4/6
Authors: Yoshida Akihiro , Lee Eric K. , Diehl J. Alan 
Published: March 2016

Abstract
Dysregulation of the p16–cyclin D1–CDK4/6–Rb pathway occurs frequently in melanoma; however, the therapeutic efficacy of CDK4/6 inhibition remains to be critically evaluated. We demonstrate that CDK4/6 inhibition inhibits melanoma progression through induction of senescence. Palbociclib, a specific CDK4/6 inhibitor, rapidly induces cell cycle arrest within 24 hours and continued exposure for 8 days or longer induces senescence. The induction of senescence correlates with inhibition of mTOR and more specifically mTORC1 signaling. Vemurafenib, a specific BRAFV600E inhibitor, has significant clinical efficacy in BRAFV600E-positive melanomas, but its impact is hampered by a rapid acquisition of resistance. Strikingly, we found that vemurafenib-resistant tumors remain sensitive to palbociclib, suggesting that initial treatment with vemurafenib followed by palbociclib with or without mTOR inhibitors might provide an avenue to overcome recurrence of vemurafenib-resistant metastatic disease. Taken together, these results support palbociclib as a promising therapeutic for treatment of melanoma. Cancer Res; 76(10); 2990–3002. ©2016 AACR.
FBW7 (F-box and WD Repeat Domain-Containing 7) Negatively Regulates Glucose Metabolism by Targeting the c-Myc/TXNIP (Thioredoxin-Binding Protein) Axis in Pancreatic Cancer
Authors: Ji Shunrong , Qin Yi , Liang Chen , Huang Run , Shi Si , Liu Jiang , Jin Kaizhou , Liang Dingkong , Xu Wenyan , Zhang Bo , Liu Liang , Liu Chen , Xu Jin , Ni Quanxing , Chiao Paul J. , Li Min , Yu Xianjun 
Published: March 2016

Abstract
Purpose: FBW7 functions as a tumor suppressor by targeting oncoproteins for destruction. We previously reported that the oncogenic mutation of KRAS inhibits the tumor suppressor FBW7 via the Ras–Raf–MEK–ERK pathway, which facilitates the proliferation and survival of pancreatic cancer cells. However, the underlying mechanism by which FBW7 suppresses pancreatic cancer remains unexplored. Here, we sought to elucidate the function of FBW7 in pancreatic cancer glucose metabolism and malignancy.
Experimental Design: Combining maximum standardized uptake value (SUVmax), which was obtained preoperatively via a PET/CT scan, with immunohistochemistry staining, we analyzed the correlation between SUVmax and FBW7 expression in pancreatic cancer tissues. The impact of FBW7 on glucose metabolism was further validated in vitro and in vivo. Finally, gene expression profiling was performed to identify core signaling pathways.
Results: The expression level of FBW7 was negatively associated with SUVmax in pancreatic cancer patients. FBW7 significantly suppressed glucose metabolism in pancreatic cancer cells in vitro. Using a xenograft model, MicroPET/CT imaging results indicated that FBW7 substantially decreased 18F-fluorodeoxyglucose (18F-FDG) uptake in xenograft tumors. Gene expression profiling data revealed that TXNIP, a negative regulator of metabolic transformation, was a downstream target of FBW7. Mechanistically, we demonstrated that TXNIP was a c-Myc target gene and that FBW7 regulated TXNIP expression in a c-Myc–dependent manner.
Conclusions: Our results thus reveal that FBW7 serves as a negative regulator of glucose metabolism through regulation of the c-Myc/TXNIP axis in pancreatic cancer. Clin Cancer Res; 22(15); 3950–60. ©2016 AACR.
Reduced Proteolytic Shedding of Receptor Tyrosine Kinases Is a Post-Translational Mechanism of Kinase Inhibitor Resistance
Authors: Miller Miles A. , Oudin Madeleine J. , Sullivan Ryan J. , Wang Stephanie J. , Meyer Aaron S. , Im Hyungsoon , Frederick Dennie T. , Tadros Jenny , Griffith Linda G. , Lee Hakho , Weissleder Ralph , Flaherty Keith T. , Gertler Frank B. , Lauffenburger Douglas A. 
Published: March 2016

Abstract
Kinase inhibitor resistance often involves upregulation of poorly understood “bypass” signaling pathways. Here, we show that extracellular proteomic adaptation is one path to bypass signaling and drug resistance. Proteolytic shedding of surface receptors, which can provide negative feedback on signaling activity, is blocked by kinase inhibitor treatment and enhances bypass signaling. In particular, MEK inhibition broadly decreases shedding of multiple receptor tyrosine kinases (RTK), including HER4, MET, and most prominently AXL, an ADAM10 and ADAM17 substrate, thus increasing surface RTK levels and mitogenic signaling. Progression-free survival of patients with melanoma treated with clinical BRAF/MEK inhibitors inversely correlates with RTK shedding reduction following treatment, as measured noninvasively in blood plasma. Disrupting protease inhibition by neutralizing TIMP1 improves MAPK inhibitor efficacy, and combined MAPK/AXL inhibition synergistically reduces tumor growth and metastasis in xenograft models. Altogether, extracellular proteomic rewiring through reduced RTK shedding represents a surprising mechanism for bypass signaling in cancer drug resistance.
Significance: Genetic, epigenetic, and gene expression alterations often fail to explain adaptive drug resistance in cancer. This work presents a novel post-translational mechanism of such resistance: Kinase inhibitors, particularly targeting MAPK signaling, increase tumor cell surface receptor levels due to widely reduced proteolysis, allowing tumor signaling to circumvent intended drug action. Cancer Discov; 6(4); 382–99. ©2016 AACR.
This article is highlighted in the In This Issue feature, p. 331
Total carotenoids of the copepod Acartia clausi Giesbrecht, 1889 from the Caspian Sea at different growth stages fed different microalgal diets
Authors: Nobakht Maryam , Khalesi Mohammadkazem , Esmaeili Fereidouni Abolghasem , Khalili Khosrow Jani 
Published: March 2016

In the Caspian Sea, the calanoid copepod Acartia clausi, a potential food for fish fry, obtains its carotenoids from plant sources. To determine the effects of microalgal diets containing Isochrysis galbana and Chaetoceros calcitrans on total carotenoids of nauplii, copepodites and adults of A. clausi, they were cultured under three microalgal treatments: I. galbana, C. calcitrans, and a mixture of these microalgae (5000, 15 000 and 30 000 cells/ml). Total carotenoids were measured separately using methanol and ethanol. The highest level of total carotenoids was observed in the copepodites fed 30 000 cells/ml of both C. calcitrans and the microalgal mixture, which were different from nauplii and adults fed 5000 and 15 000 cells/ml (). The nauplii fed I. galbana showed higher total carotenoids than copepodites and adults (). Ethanol and methanol worked differently for carotenoid extraction from A. clausi fed C. calcitrans compared with the other treatments (). These solvents showed dissimilarities with 5000 cells/ml of C. calcitrans and I. galbana, as well as with 30 000 cells/ml of I. galbana and mixed microalgal diets. A mixed microalgal diet of 30 000 cells/ml is recommended for mass production of this species. The use of methanol is suitable for optimized extraction of total carotenoids.
H. Paul Grice’s Lecture Notes on Charles S. Peirce’s Theory of Signs
Authors: Pietarinen Ahti-Veikko , Bellucci Francesco 
Published: March 2016

This document provides a transcription of a significant unpublished manuscript by Paul Grice on Charles Peirce’s Theory of Signs, deposited in the H. Paul Grice Papers, BANC MSS 90/135, The Bancroft Library, University of California, Berkeley. Grice’s notes concern the theory of signs, semeiotic, of the American logician, scientist and philosopher Charles Sanders Peirce (1839–1914). The material was probably intended as the text for lectures. The MS consists of 46 non-numbered sheets. The editors have prepared the transcription from a copy of the original manuscript located in the Bancroft Library.
Engaging parents with sex and relationship education: A UK primary school case study
Authors: Alldred Pam , Fox Nick , Kulpa Robert 
Published: March 2016

Objective: To assess an intervention to familiarise parents with children’s books for use in primary (5–11 years) sex and relationship education (SRE) classes. Method: Case study of a 7-week programme in one London primary school, using ethnographic observation, semi-structured interviews and focus groups with parents ( n = 7) and key stakeholders ( n = 4), and pre- and post-programme self-completion questionnaires ( n = 9). Results: Parents reported increased understanding of the SRE curriculum and awareness of relevant children’s books, enhanced interactions with their children on SRE topics and some positive effects on partners and attitudes towards the school. There was increased confidence in addressing issues in the SRE curriculum for parents of 8- to 10-year-olds, although reduced confidence for one mother. Conclusions: Familiarising parents with materials has the potential to enhance SRE, by improving coherence between educators’ and parents’ messages to children about sex and relationships, increased discussion of SRE topics in parent–child conversations and reduced parental anxiety about topics such as sexual orientation. Future challenges of involving fathers, scalability and sustainability highlight the dilemma of how best to enable parental choice or make equalities interventions.
Controlling Dicopper Protein Functions
Authors: Fujieda Nobutaka , Itoh Shinobu 
Published: March 2016

Abstract
Maturation processes of dinuclear copper proteins such as tyrosinase, catechol oxidase, and hemocyanin have been a long-standing mystery in copper protein chemistry. Until now, several crystal structures have revealed that these copper proteins share a similar dinuclear copper active site, where each copper ion is ligated by three histidine imidazoles, and binds molecular oxygen in a side-on fashion to form a (µ-η2:η2-peroxido)dicopper(II) species not only as the dioxygen-adduct in oxy-hemocyanins but also as the key reactive intermediate for the hydroxylation of phenols to catechols (phenolase reaction) and the oxidation of catechols to o-quinones (catecholase reaction) in tyrosinases and catechol oxidases. Recently, we have succeeded in determining the high-resolution crystal structures of the recombinant pro-form of yellow koji mold tyrosinase to find the existence of a distinct C-terminal domain containing a –CXXC– unit, that is the common sequence motif of the copper chaperons. Thus, the C-terminal domain apparently acts as a copper chaperon, helping construction of the dinuclear copper active site of tyrosinase. Furthermore, we have found that the proteolytic cleavage of the C-terminal domain from the pro-form (inactive-form) of tyrosinase greatly enhances the tyrosinase activity, thus suggesting that the C-terminal domain also acts as a shielding domain to regulate the enzymatic activity. In fact, overall structure of the pro-form resembles the structure of one of the functional units of octopus hemocyanin (oxygen carrier protein), which also has a similar C-terminal domain prohibiting the monooxygenase activity. On the basis of these results together with the detailed kinetic and spectroscopic analyses, the maturation process of the dinuclear copper proteins is discussed to provide new insights into the regulation mechanism of the dicopper protein functions; dioxygen binding and activation. We have also succeeded in evolving phenolase activity from molluscan and arthropod hemocyanins by treating them with a hydrolytic enzyme or an acid, and demonstrated that the reaction mechanism of their phenolase activity is the same to that of tyrosinase itself, that is the electrophilic aromatic substitution mechanism. Furthermore, we have developed an artificial dicopper protein exhibiting catecholase activity using metallo-β-lactamase, a dinuclear zinc enzyme, as a metal binding platform.
Enoxaparin and rivaroxaban have different effects on human mesenchymal stromal cells in the early stages of bone healing
Authors: Pilge H. , Fröbel J. , Prodinger P. M. , Mrotzek S. J. , Fischer J. C. , Zilkens C. , Bittersohl B. , Krauspe R. 
Published: March 2016

Objectives Venous thromboembolism (VTE) is a major potential complication following orthopaedic surgery. Subcutaneously administered enoxaparin has been used as the benchmark to reduce the incidence of VTE. However, concerns have been raised regarding the long-term administration of enoxaparin and its possible negative effects on bone healing and bone density with an increase of the risk of osteoporotic fractures. New oral anticoagulants such as rivaroxaban have recently been introduced, however, there is a lack of information regarding how these drugs affect bone metabolism and post-operative bone healing. Methods We measured the migration and proliferation capacity of mesenchymal stem cells (MSCs) under enoxaparin or rivaroxaban treatment for three consecutive weeks, and evaluated effects on MSC mRNA expression of markers for stress and osteogenic differentiation. Results We demonstrate that enoxaparin, but not rivaroxaban, increases the migration potential of MSCs and increases their cell count in line with elevated mRNA expression of C-X-C chemokine receptor type 4 (CXCR4), tumor necrosis factor alpha (TNFα), and alpha-B-crystallin (CryaB). However, a decrease in early osteogenic markers (insulin-like growth factors 1 and 2 (IGF1, IGF2), bone morphogenetic protein2 (BMP2)) indicated inhibitory effects on MSC differentiation into osteoblasts caused by enoxaparin, but not by rivaroxaban. Conclusions Our findings may explain the adverse effects of enoxaparin treatment on bone healing. Rivaroxaban has no significant impact on MSC metabolism or capacity for osteogenic differentiation in vitro. Cite this article: Dr H. Pilge. Enoxaparin and rivaroxaban have different effects on human mesenchymal stromal cells in the early stages of bone healing. Bone Joint Res 2016;5:95–100. DOI: 10.1302/2046-3758.53.2000595.
La inclusión de la «cuestión ecológica» en el currículo de los/as graduados/as en Relaciones Laborales y Recursos Humanos
Authors: Lerma Montero Ignasi 
Published: March 2016

La crisis ecológica continúa acumulando indicadores cada vez más alarmantes. Su resolución reclama un nuevo modelo de desarrollo humano, fundamentado en los principios de equidad y limitación del crecimiento a la capacidad de sustentación del planeta, que implica la necesidad de profundas modificaciones en los procesos de producción y en las relaciones sociales de producción. Requiere pues, resolver y decidir —de forma consciente— sobre el dilema que plantea la sostenibilidad para el futuro de nuestras sociedades tanto a nivel local como global.En este trabajo se formula un marco teórico del campo de interacciones entre la «cuestión ecológica» y los sistemas de relaciones laborales, a partir del cual se desarrolla una propuesta de contenidos curriculares mediante núcleos temáticos y su articulación docente, atendiendo al perfil profesional de los futuros Graduados en Relaciones Laborales y Recursos Humanos.
Una Historia de las relaciones laborales para no historiadores en un contexto de crisis
Authors: Galán García Agustín , Martínez Rodríguez Susana 
Published: March 2016

La mayoría de las universidades españolas han concluido ya el proceso de implantación de los nuevos grados. En unos casos, este proceso ha supuesto, además de una mayor carga de trabajo para los docentes, un mero cambio nominal con escasas manifestaciones prácticas. En otros, por el contrario, las modificaciones han sido más profundas y de mayor aplicación. Incluso tenemos numerosas publicaciones que a modo de balance van ofreciendo los resultados alcanzados y las percepciones obtenidas (Iglesias de Ussel y otros, 2009).No tenemos constancia, sin embargo, de que los contenidos de las distintas asignaturas se hayan adaptado a la nueva orientación que el grado que nos ocupa ha querido incorporar. Proponemos en esta comunicación una revisión de los programas que se están impartiendo en las asignaturas de historia de las relaciones laborales, al margen de la denominación concreta que reciba en cada una de las universidades. En segundo lugar presentaremos una propuesta de conjunto de cuáles, a nuestro juicio, deben ser los contenidos y las orientaciones que debe incorporar un programa que no tiene como destinatarios a futuros historiadores pero que se ha revelado esencial para contextualizar y comprender el carácter realmente complejo y dinámico de las relaciones laborales. En cuarto y último lugar abordaremos el papel explicativo de nuestra materia en el contexto de crisis en el que nos encontramos y nuestra participación, en calidad de docentes de esta materia, en el debate social del momento.En definitiva, reivindicamos en esta comunicación una actualización de los contenidos atendiendo, al menos, a dos cuestiones que deberían de haberlos condicionado: la llegada el Espacio Europeo de Educación superior y, en segundo lugar, al contexto social y económico en el que nos encontramos.
JENIS TINDAK TUTUR YANG MENGIKUTI INTERJEKSI PANGGILAN DALAM BAHASA JEPANG
Authors: Ratna Maharani Patria 
Published: March 2016

[Types of Speech Acts Following Calling Interjection In Japanese] In speaking, there are times when a calling interjection can be followed by more than one type of speech acts. This research discusses the calling interjection which are used by male speakers in the film Brother Beat. In addition, this study also discussed what kind of speech acts that may follow the call in a speech interjection. The data in this study is a narrative that contains interjection calling spoken by male speakers in the Brother Beat movie. The method used is descriptive qualitative method. To get the data, the researcher usesscrutinize technique and tapping notes method. The results obtained in this research are, calling interjection, such as Anosa, oi, Anona, nee, you, and ano, are often used by male speakers to call the addressees. After the calling interjection, directive speech act and assertive speech act are speech act which appear to follow the calling interjection. Interjection ano sa, oi, anona, and ano, are types of calling interjection which can be followed by a directive speech acts and assertive speech act. In the other hand, calling interjection of nee, can be only followed by a directive speech act, while calling interjection of you can be followed by a ssertives speech act.
Perbedaan Harga Lahan Sebagai Akibat Terjadinya Fenomena Percampuran Ruang Bermukim di Wilayah Pinggiran Kota Semarang (Studi Kasus Perumahan Formal dan Informal di Kelurahan Pedalangan & Bulusan)
Authors: Gustiana Wily Alfi 
Published: March 2016

<p class="Abstract"><em>Suburbanization is a process to shape built areas as an impact urban development expansion (Wiratmaja, 2002:33). The real form of suburbanization is shift settlements activity towards suburban area. Therefore, many new development settlements are made to accommodate city core inhabitants at this time. Pedalangan Subdistrict and Bulusan which are part of Banyumanik District also Tembalang has been filled by new formal settlements such as Graha Estetika, Graha Sapta Asri, Grand Tembalang Regency, Villa Tembalang, and Korpri. Whereas, urban settlements in Pedalangan Subdistrict also Bulusan is not only consist of estate that is part of formal settlements but also Kampong which is a part of informal settlements. Mostly, new developments of formal settlements build nearby informal settlements that have been there first. These things have a potential thing to emerge disparity related social, economic, cultural, physical, and spatial aspect. One of the most spatial impacts that will appear is the land price differentiation between formal and informal settlements. Based on that phenomenon is formulated statement research “There was land price differentiation as an impact of mix urban settlements between formal and informal settlements in suburban area.” This research aims to identify land price differentiation that occurred as an impact of mix urban settlements in suburban area. In order to achieve that purpose, the process of identification and analysis need to carry on towards factors that could affect the land price such as land physic characteristic, accessibility, facility and infrastructure availability, ownership status, and environmental quality. This research will use quantitative descriptive analysis with descriptive statistics based on the results of questionnaires and observation. Based on findings, that indicate there are only two factors that can be land price differentiation between formal and informal settlements is the ease of accessibility and facility and infrastructure availability. The land physic characteristic, ownership status, and environmental quality can not to identify land price differentiation because of these characteristics of each these factors are almost equally between formal and informal settlements. Based on the results of the study findings it can be concluded that there are land price differentiation between formal and informal settlements caused by mix urban settlements. It also need a form of problem solve such as zoning regulation, land conversion regulation, land transaction regulation, land taxation, and regulation of new building that aims to control development of suburban areas to be more focused by considering the integration process physical, social, and economic community.</em></p><em></em>
Zwischen dem Großen Erwählten und Westminster Überlegungen zum Demokratieverständnis von Aung San Suu Kyi
Authors: Zöllner Hans-Bernd 
Published: March 2016

Abstract
Between the Great Elect and Westminster – Some Reflections on Aung San Suu Ky’s Concept of Democracy. In view of the elections in Myanmar held on November 8, 2015, the article investigates the concept of democracy set forth by the country’s best known politician, Nobel Laureate Aung San Suu Kyi. She invokes two traditions of “democracy” that contradict each other in terms of the role of the opposition. The Buddhist concept of the Maha-sammata, the Great Select, that the Burmese leader invokes as a Burmese model of democracy is elected unanimously and for life. The relevance of this model for Burma’s and Myanmar’s political culture is substantiated by empirical evidence like the outcome of elections since the beginning of the twentieth century until the recent elections held in 2015. On the other hand, the leader of Myanmar’s most successful party looks at a Westminster style democracy based on the idea that a loyal opposition controls the government as a model for the country’s future political development. Even after the free and fair elections in 2015, it will be one of the most important tasks of Myanmar politics to solve this “opposition dilemma”.
Myanmarforschung 2015: Interdisziplinäre Tagung zur Vernetzung der deutschsprachigen Myanmarforschenden
Authors: Winterberger Georg 
Published: March 2016

Abstract
Myanmar is facing a phase of change. The opening of the country in 2011 has consequences on the political, economic and social level. This phase is very complex and not yet thoroughly explored and understood, therefore, there is a growing number of scientists who do or plan research in Myanmar. The conference “Myanmarforschung 2015 – Interdisziplinäre Tagung zur Vernetzung der deutschsprachigen Myanmarforschenden” (Myanmar research 2015 – interdisciplinary conference for networking of German speaking Myanmar researchers), which was held from July 23th to 25th 2015 at the University of Zurich, had the aim to give a platform to these scientists for sharing their knowledge. This paper gives an overview and background information about this conference and it reports about the presentations, which were held in Zurich.