bluuebunny/crossref_metadata_2025_split huggingface dataset:
Emerging Opportunities and Challenges in Cancer Immunotherapy
Authors: Whiteside Theresa L. , Demaria Sandra , Rodriguez-Ruiz Maria E. , Zarour Hassane M. , Melero Ignacio 
Published: April 2016

AbstractImmunotherapy strategies against cancer are emerging as powerful weapons for treatment of this disease. The success of checkpoint inhibitors against metastatic melanoma and adoptive T-cell therapy with chimeric antigen receptor T cells against B-cell–derived leukemias and lymphomas are only two examples of developments that are changing the paradigms of clinical cancer management. These changes are a result of many years of intense research into complex and interrelated cellular and molecular mechanisms controling immune responses. Promising advances come from the discovery of cancer mutation-encoded neoantigens, improvements in vaccine development, progress in delivery of cellular therapies, and impressive achievements in biotechnology. As a result, radical transformation of cancer treatment is taking place in which conventional cancer treatments are being integrated with immunotherapeutic agents. Many clinical trials are in progress testing potential synergistic effects of treatments combining immunotherapy with other therapies. Much remains to be learned about the selection, delivery, and off-target effects of immunotherapy used alone or in combination. The existence of numerous escape mechanisms from the host immune system that human tumors have evolved still is a barrier to success. Efforts to understand the rules of immune cell dysfunction and of cancer-associated local and systemic immune suppression are providing new insights and fuel the enthusiasm for new therapeutic strategies. In the future, it might be possible to tailor immune therapy for each cancer patient. The use of new immune biomarkers and the ability to assess responses to therapy by noninvasive monitoring promise to improve early cancer diagnosis and prognosis. Personalized immunotherapy based on individual genetic, molecular, and immune profiling is a potentially achievable future goal. The current excitement for immunotherapy is justified in view of many existing opportunities for harnessing the immune system to treat cancer. Clin Cancer Res; 22(8); 1845–55. ©2016 AACR.See all articles in this CCR Focus section, “Opportunities and Challenges in Cancer Immunotherapy.”
Strategic Combinations: The Future of Oncolytic Virotherapy with Reovirus
Authors: Zhao Xing , Chester Cariad , Rajasekaran Narendiran , He ZhiXu , Kohrt Holbrook E. 
Published: April 2016

AbstractThe dominant cancer treatment modalities such as chemotherapy, radiotherapy, and even targeted kinase inhibitors and mAbs are limited by low efficacy, toxicity, and treatment-resistant tumor subclones. Oncolytic viral therapy offers a novel therapeutic strategy that has the potential to dramatically improve clinical outcomes. Reovirus, a double-stranded benign human RNA virus, is a leading candidate for therapeutic development and currently in phase III trials. Reovirus selectively targets transformed cells with activated Ras signaling pathways; Ras genes are some of the most frequently mutated oncogenes in human cancer and it is estimated that at least 30% of all human tumors exhibit aberrant Ras signaling. By targeting Ras-activated cells, reovirus can directly lyse cancer cells, disrupt tumor immunosuppressive mechanisms, reestablish multicellular immune surveillance, and generate robust antitumor responses. Reovirus therapy is currently being tested in combination with radiotherapy, chemotherapy, immunotherapy, and surgery. In this review, we discuss the current successes of these combinatorial therapeutic strategies and emphasize the importance of prioritizing combination oncolytic viral therapy as reovirus-based treatments progress in clinical development. Mol Cancer Ther; 15(5); 767–73. ©2016 AACR.
Isorhapontigenin (ISO) Inhibits Invasive Bladder Cancer Formation In Vivo and Human Bladder Cancer Invasion In Vitro by Targeting STAT1/FOXO1 Axis
Authors: Jiang Guosong , Wu Amy D. , Huang Chao , Gu Jiayan , Zhang Liping , Huang Haishan , Liao Xin , Li Jingxia , Zhang Dongyun , Zeng Xingruo , Jin Honglei , Huang Haojie , Huang Chuanshu 
Published: April 2016

Abstract
Although our most recent studies have identified Isorhapontigenin (ISO), a novel derivative of stilbene that isolated from a Chinese herb Gnetum cleistostachyum, for its inhibition of human bladder cancer growth, nothing is known whether ISO possesses an inhibitory effect on bladder cancer invasion. Thus, we addressed this important question in current study and discovered that ISO treatment could inhibit mouse-invasive bladder cancer development following bladder carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) exposure in vivo. We also found that ISO suppressed human bladder cancer cell invasion accompanied by upregulation of the forkhead box class O 1 (FOXO1) mRNA transcription in vitro. Accordingly, FOXO1 was profoundly downregulated in human bladder cancer tissues and was negatively correlated with bladder cancer invasion. Forced expression of FOXO1 specifically suppressed high-grade human bladder cancer cell invasion, whereas knockdown of FOXO1 promoted noninvasive bladder cancer cells becoming invasive bladder cancer cells. Moreover, knockout of FOXO1 significantly increased bladder cancer cell invasion and abolished the ISO inhibition of invasion in human bladder cancer cells. Further studies showed that the inhibition of Signal transducer and activator of transcription 1 (STAT1) phosphorylation at Tyr701 was crucial for ISO upregulation of FOXO1 transcription. Furthermore, this study revealed that metalloproteinase-2 (MMP-2) was a FOXO1 downstream effector, which was also supported by data obtained from mouse model of ISO inhibition BBN-induced mouse-invasive bladder cancer formation. These findings not only provide a novel insight into the understanding of mechanism of bladder cancer's propensity to invasion, but also identify a new role and mechanisms underlying the natural compound ISO that specifically suppresses such bladder cancer invasion through targeting the STAT1–FOXO1–MMP-2 axis. Cancer Prev Res; 9(7); 567–80. ©2016 AACR.
Wilhelm Tell vor Schiller
Authors: Jurt Joseph 
Published: April 2016

Na Suíça, a figura de Guilherme Tell representava duas tradições, por um lado o herói que expressa o orgulho dos confederados, por outro, a encarnação dos oprimidos em geral. Na peça ‘Grisler ou l’Helvétie délivrée’ (1748) do autor de Berna Samuel Henzi, a figura central é a do déspota Grisler, a quem Guilherme Tell se opõe. Após a deposição do tirano é introduzido um programa republicano que se baseia na idéia de igualdade frente à lei. Na tragédia ‘Guillaume Tell’ (1766) de Antoine-Marin Lemierre virtude e senso de liberdade são postos em relação com o motivo topológico das montanhas. Tell não aparece aqui mais como um solitário e sim como um dos confederados. Na época da revolução francesa, Guilherme Tell aparece ao lado de Brutus como uma figura emblemática da resistência do povo contra a tirania, e a peça de Lemierre obteve então grande sucesso. Schiller também associou em seu ‘Wilhelm Tell’ (1804) a idéia de liberdade suíça à representação da natureza sublime, como era propagado nos relatos de viagem. Sua peça, no entanto, se contrapunha à usurpação da figura de Tell pelos jacobinos e invocava uma comunidade baseada na fraternidade que deveria substituir o velho modelo social marcado pela figura do super-pai.
Vom Theater als moralischer Anstalt zum Dichter als Gewissen der Nation oder: Von Friedrich Schiller zu Elfriede Jelineks historischem Drama Burgtheater
Authors: Herzmann Herbert 
Published: April 2016

Mesmo usando elementos da realidade, o drama histórico permanence ficção. A literatura “mente”, ou, em outras palavras, cria sua própria realidade e sua própria verdade. O Burgtheater de Viena como instituição histórica e lugar de ficção dramática é a matéria prima do drama histórico de Jelinek. É fácil reconhecer nas dramatis personae - que falam uma linguagem artificial, cheia de estereótipos nazistas - membros da família Hörbiger, uma dinastia de atores do Burgtheater. O argumento de que os Hörbiger não precisariam se sentir agredidos, já que se trata de ficção, não é irrefutável. A autora acusa na peça especialmente Käthe de ser responsável pelos crimes cometidos pelos nazistas. Em uma entrevista telefônica, Jelinek levanta as mesmas acusações também contra a real Paula Wessely, revelando uma grande proximidade entre a personagem ficcional e a opinião da autora sobre a pessoa real. O caráter artificial da peça parece ser uma proteção que permite que a autora diga coisas pelas quais, ditas em outras circunstâncias, poderia ser processada. Segundo Harald Weinrich, uma literatura, que não quer mais “mentir”, mas pretende contar a “verdade real” e a “realidade verdadeira”, corre o risco de servir à mentira real. Ao assumir, na peça Burgtheater, o papel de consciência da nação, em vez de se limitar simplesmente a contribuir para a elevação moral da nação através da ficção, Jelinek corre esse risco.
A tradução para a criança e para o jovem: a prática como base da reflexão e da relação profissional
Authors: Azenha Junior João 
Published: April 2016

Die vorliegende Arbeit stellt den Versuch dar, meine Erfahrungen als Übersetzer von Kinder- und Jugendliteratur zu systematisieren. Von Aspekten ausgehend, die sowohl für die Produktion als auch für die Übersetzung von Kinder- und Jugendliteratur von entscheidender Bedeutung sind, werden Begriffe wie Interaktion und Kreativität bei der Übersetzung dieser Textsorte kurz erörtert. Dies geschieht anhand von Beispielen, die vom Deutschen ins brasilianische Portugiesische übersetzt wurden. Forderungen nach einer systematischeren Berücksichtigung dieser Frage seitens der Übersetzungstheorie und nach einer besonderen, noch zu definierenden Stelle für diese Übersetzungsart in der Berufspraxis liegen dem Beitrag zugrunde.
A língua como pátria
Authors: Aron Irene 
Published: April 2016

Die Beispiele von Paul Celan und Rose Ausländer zeigen einige dramatische Aspekte des komplexen Verhältnisses zwischen Sprache und Identität, bzw. zwischen der deutschen Sprache im Dritten Reich und der literarischen Identität beider Dichter jüdischer Herkunft. Viktor Klemperer ist das Beispiel eines assimilierten Juden, der stets sein Deutschtum und seine tiefe Zugehörigkeit zu Deutschland und der deutschen Kultur unterstreicht. Ruth Klüger gehört zu einer späteren Generation, die sich eigentlich heimatlos fühlt, aber auch in der deutschen Sprache eine literarische Heimat findet. Canetti, Nobelpreisträger, ein sephardischer Jude, der in Bulgarien geboren ist, wählt für sich als Kosmopolit, als Mensch und Dichter eine Heimat, wo die deutsche Sprache und Kultur die Grenzen bilden.
“Continuação a seguir...”: Günter Grass e a Arte da Narrativa
Authors: Mazzari Marcus 
Published: April 2016

Der Artikel verfolgt die Entwicklung des Werks von Günter Grass mit Blick auf die Rezeption in Deutschland und die Vergabe des Nobelpreises. Es wird gezeigt, dass Grass traditionelle Erzählstrategien – z. B. die des Märchens – gebraucht, um im Gestus des scheinbar Irrealen das Groteske der historischen Realität im 20. Jahrhundert herauszustellen.
“Ich kann mein Name mit letra junta und letra solta schreib”: deutsch-portugiesisches Code-Switching in einer Grundschule im südbrasilianischen Immigrationsgebiet
Authors: Fritzen Maristela Pereira 
Published: April 2016

O presente artigo tem por objetivo contribuir para a compreensão de aspectos do bilingüismo social de um grupo de língua minoritária, localizado em área de imigração alemã no sul do Brasil. Utilizando como base uma pesquisa etnográfica, o estudo descreve o uso das línguas em interação face a face por alunos bilíngües em escola monolíngüe português do ensino fundamental. O foco da análise está no code-switching alemão-português visto sob uma perspectiva sócio-funcional. Os resultados sugerem que o code-switching não deveria relacionar-se a um suposto deficit lingüístico, mas ser considerado parte constitutiva do discurso de crianças bilíngües, que tanto podem empregar a mudança de código como uma estratégia conversacional ou como importante recurso no processo de aprendizagem.
Goethe e Brecht em diálogo
Authors: Heise Eloa 
Published: April 2016

O propósito desse trabalho é tecer um paralelo entre os prólogos do Faust I, o “prólogo no céu” de Goethe e o prólogo da peça de Brecht Der gute Mensch von Sezuan. A análise comparativa dos dois textos oferece subsídios para se afirmar que Brecht cria uma paródia do prólogo goethiano, procedimento que será interpretado como uma das características da literatura do século XX. Tal recurso de intert extualidade e de recriação será visto como uma forma de caracterizar o presente amorfo a partir do confronto e da analogia, com visão crítica, de uma obra consagrada da tradição.
MicroRNA-155 Promotes the Directional Migration of Resident Smooth Muscle Progenitor Cells by Regulating Monocyte Chemoattractant Protein 1 in Transplant Arteriosclerosis
Authors: Sun Yuan , Wang Ke , Ye Ping , Wu Jie , Ren Lingyun , Zhang Anchen , Huang Xiaofan , Deng Peng , Wu Chuangyan , Yue Zhang , Chen Zhaolei , Ding Xiangchao , Chen Jiuling , Xia Jiahong 
Published: April 2016

Objective—
Smooth muscle–like cells are major cell components of transplant arteriosclerosis lesions. This study investigated the origin of the smooth muscle–like cells, the mechanisms responsible for their accumulation in the neointima, and the factors that drive these processes.

Approach and Results—

A murine aortic transplantation model was established by transplanting miR-155
−/−
bone marrow cells into miR-155
+/+
mice. MicroRNA-155 was found to play a functional role in the transplant arteriosclerosis. Moreover, we found that the nonbone marrow–derived progenitor cells with markers of both early differentiated smooth muscles and stem cells in the allograft adventitia were smooth muscle progenitor cells. Purified smooth muscle progenitor cells expressed a mature smooth muscle cell marker when induced by platelet-derived growth factor-BB in vitro. In vivo, these cells could migrate into the intima from the adventitia and could contribute to the neointimal hyperplasia. The loss of microRNA-155 in bone marrow–derived cells decreased the concentration gradient of monocyte chemoattractant protein 1 between the intima and the adventitia of the allografts, which reduced the migration of smooth muscle progenitor cells from the adventitia into the neointima.

Conclusions—
This study demonstrated that microRNA-155 promoted the directional migration of smooth muscle progenitor cells from the adventitia by regulating the monocyte chemoattractant protein 1 concentration gradient, which aggravated transplant arteriosclerosis.
Intracellular Trafficking, Localization, and Mobilization of Platelet-Borne Thiol Isomerases
Authors: Crescente Marilena , Pluthero Fred G. , Li Ling , Lo Richard W. , Walsh Tony G. , Schenk Michael P. , Holbrook Lisa M. , Louriero Silvia , Ali Marfoua S. , Vaiyapuri Sakthivel , Falet Hervé , Jones Ian M. , Poole Alastair W. , Kahr Walter H.A. , Gibbins Jonathan M. 
Published: April 2016

Objective—
Thiol isomerases facilitate protein folding in the endoplasmic reticulum, and several of these enzymes, including protein disulfide isomerase and ERp57, are mobilized to the surface of activated platelets, where they influence platelet aggregation, blood coagulation, and thrombus formation. In this study, we examined the synthesis and trafficking of thiol isomerases in megakaryocytes, determined their subcellular localization in platelets, and identified the cellular events responsible for their movement to the platelet surface on activation.

Approach and Results—

Immunofluorescence microscopy imaging was used to localize protein disulfide isomerase and ERp57 in murine and human megakaryocytes at various developmental stages. Immunofluorescence microscopy and subcellular fractionation analysis were used to localize these proteins in platelets to a compartment distinct from known secretory vesicles that overlaps with an inner cell-surface membrane region defined by the endoplasmic/sarcoplasmic reticulum proteins calnexin and sarco/endoplasmic reticulum calcium ATPase 3. Immunofluorescence microscopy and flow cytometry were used to monitor thiol isomerase mobilization in activated platelets in the presence and absence of actin polymerization (inhibited by latrunculin) and in the presence or absence of membrane fusion mediated by Munc13-4 (absent in platelets from Unc13d
Jinx
mice).

Conclusions—
Platelet-borne thiol isomerases are trafficked independently of secretory granule contents in megakaryocytes and become concentrated in a subcellular compartment near the inner surface of the platelet outer membrane corresponding to the sarco/endoplasmic reticulum of these cells. Thiol isomerases are mobilized to the surface of activated platelets via a process that requires actin polymerization but not soluble N-ethylmaleimide–sensitive fusion protein attachment receptor/Munc13-4–dependent vesicular–plasma membrane fusion.
Regional Variation in Out-of-Hospital Cardiac Arrest Survival in the United States
Authors: Girotra Saket , van Diepen Sean , Nallamothu Brahmajee K. , Carrel Margaret , Vellano Kimberly , Anderson Monique L. , McNally Bryan , Abella Benjamin S. , Sasson Comilla , Chan Paul S. 
Published: April 2016

Background—
Although previous studies have shown marked variation in out-of-hospital cardiac arrest survival across US regions, factors underlying this survival variation remain incompletely explained.

Methods and Results—

Using data from the Cardiac Arrest Registry to Enhance Survival, we identified 96 662 adult patients with out-of-hospital cardiac arrest in 132 US counties. We used hierarchical regression models to examine county-level variation in rates of survival and survival with functional recovery (defined as Cerebral Performance Category score of 1 or 2) and examined the contribution of demographics, cardiac arrest characteristics, bystander cardiopulmonary resuscitation, automated external defibrillator use, and county-level sociodemographic factors in survival variation across counties. A total of 9317 (9.6%) patients survived to discharge, and 7176 (7.4%) achieved functional recovery. At a county level, there was marked variation in rates of survival to discharge (range, 3.4%–22.0%; median odds ratio, 1.40; 95% confidence interval, 1.32–1.46) and survival with functional recovery (range, 0.8%–21.0%; median odds ratio, 1.53; 95% confidence interval, 1.43–1.62). County-level rates of bystander cardiopulmonary resuscitation and automated external defibrillator use were positively correlated with both outcomes (
P
<0.0001 for all). Patient demographic and cardiac arrest characteristics explained 4.8% and 27.7% of the county-level variation in survival, respectively. Additional adjustment of bystander cardiopulmonary resuscitation and automated external defibrillator explained 41% of the survival variation, and this increased to 50.4% after adjustment of county-level sociodemographic factors. Similar findings were noted in analyses of survival with functional recovery.

Conclusions—
Although out-of-hospital cardiac arrest survival varies significantly across US counties, a substantial proportion of the variation is attributable to differences in bystander response across communities.
Global Electric Heterogeneity Risk Score for Prediction of Sudden Cardiac Death in the General Population
Authors: Waks Jonathan W. , Sitlani Colleen M. , Soliman Elsayed Z. , Kabir Muammar , Ghafoori Elyar , Biggs Mary L. , Henrikson Charles A. , Sotoodehnia Nona , Biering-Sørensen Tor , Agarwal Sunil K. , Siscovick David S. , Post Wendy S. , Solomon Scott D. , Buxton Alfred E. , Josephson Mark E. , Tereshchenko Larisa G. 
Published: April 2016

Background—
Asymptomatic individuals account for the majority of sudden cardiac deaths (SCDs). Development of effective, low-cost, and noninvasive SCD risk stratification tools is necessary.

Methods and Results—

Participants from the Atherosclerosis Risk in Communities study and Cardiovascular Health Study (n=20 177; age, 59.3±10.1 years; age range, 44–100 years; 56% female; 77% white) were followed up for 14.0 years (median). Five ECG markers of global electric heterogeneity (GEH; sum absolute QRST integral, spatial QRST angle, spatial ventricular gradient [SVG] magnitude, SVG elevation, and SVG azimuth) were measured on standard 12-lead ECGs. Cox proportional hazards and competing risks models evaluated associations between GEH electrocardiographic parameters and SCD. An SCD competing risks score was derived from demographics, comorbidities, and GEH parameters. SCD incidence was 1.86 per 1000 person-years. After multivariable adjustment, baseline GEH parameters and large increases in GEH parameters over time were independently associated with SCD. Final SCD risk scores included age, sex, race, diabetes mellitus, hypertension, coronary heart disease, stroke, and GEH parameters as continuous variables. When GEH parameters were added to clinical/demographic factors, the C statistic increased from 0.777 to 0.790 (
P
=0.008), the risk score classified 10-year SCD risk as high (>5%) in 7.2% of participants, 10% of SCD victims were appropriately reclassified into a high-risk category, and only 1.4% of SCD victims were inappropriately reclassified from high to intermediate risk. The net reclassification index was 18.3%.

Conclusions—
Abnormal electrophysiological substrate quantified by GEH parameters is independently associated with SCD in the general population. The addition of GEH parameters to clinical characteristics improves SCD risk prediction.
Temporal Frequency Tuning Reveals Interactions between the Dorsal and Ventral Visual Streams
Authors: Kristensen Stephanie , Garcea Frank E. , Mahon Bradford Z. , Almeida Jorge 
Published: April 2016

Abstract
Visual processing of complex objects is supported by the ventral visual pathway in the service of object identification and by the dorsal visual pathway in the service of object-directed reaching and grasping. Here, we address how these two streams interact during tool processing, by exploiting the known asymmetry in projections of subcortical magnocellular and parvocellular inputs to the dorsal and ventral streams. The ventral visual pathway receives both parvocellular and magnocellular input, whereas the dorsal visual pathway receives largely magnocellular input. We used fMRI to measure tool preferences in parietal cortex when the images were presented at either high or low temporal frequencies, exploiting the fact that parvocellular channels project principally to the ventral but not dorsal visual pathway. We reason that regions of parietal cortex that exhibit tool preferences for stimuli presented at frequencies characteristic of the parvocellular pathway receive their inputs from the ventral stream. We found that the left inferior parietal lobule, in the vicinity of the supramarginal gyrus, exhibited tool preferences for images presented at low temporal frequencies, whereas superior and posterior parietal regions exhibited tool preferences for images present at high temporal frequencies. These data indicate that object identity, processed within the ventral stream, is communicated to the left inferior parietal lobule and may there combine with inputs from the dorsal visual pathway to allow for functionally appropriate object manipulation.