bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expressed Gene Fusions as Frequent Drivers of Poor Outcomes in Hormone Receptor–Positive Breast Cancer
Authors: Matissek Karina J. , Onozato Maristela L. , Sun Sheng , Zheng Zongli , Schultz Andrew , Lee Jesse , Patel Kristofer , Jerevall Piiha-Lotta , Saladi Srinivas Vinod , Macleay Allison , Tavallai Mehrad , Badovinac-Crnjevic Tanja , Barrios Carlos , Beşe Nuran , Chan Arlene , Chavarri-Guerra Yanin , Debiasi Marcio , Demirdögen Elif , Egeli Ünal , Gökgöz Sahsuvar , Gomez Henry , Liedke Pedro , Tasdelen Ismet , Tolunay Sahsine , Werutsky Gustavo , St. Louis Jessica , Horick Nora , Finkelstein Dianne M. , Le Long Phi , Bardia Aditya , Goss Paul E. , Sgroi Dennis C. , Iafrate A. John , Ellisen Leif W. 
Published: December 2017

Abstract
We sought to uncover genetic drivers of hormone receptor–positive (HR+) breast cancer, using a targeted next-generation sequencing approach for detecting expressed gene rearrangements without prior knowledge of the fusion partners. We identified intergenic fusions involving driver genes, including PIK3CA, AKT3, RAF1, and ESR1, in 14% (24/173) of unselected patients with advanced HR+ breast cancer. FISH confirmed the corresponding chromosomal rearrangements in both primary and metastatic tumors. Expression of novel kinase fusions in nontransformed cells deregulates phosphoprotein signaling, cell proliferation, and survival in three-dimensional culture, whereas expression in HR+ breast cancer models modulates estrogen-dependent growth and confers hormonal therapy resistance in vitro and in vivo. Strikingly, shorter overall survival was observed in patients with rearrangement-positive versus rearrangement-negative tumors. Correspondingly, fusions were uncommon (&lt;5%) among 300 patients presenting with primary HR+ breast cancer. Collectively, our findings identify expressed gene fusions as frequent and potentially actionable drivers in HR+ breast cancer.
Significance: By using a powerful clinical molecular diagnostic assay, we identified expressed intergenic fusions as frequent contributors to treatment resistance and poor survival in advanced HR+ breast cancer. The prevalence and biological and prognostic significance of these alterations suggests that their detection may alter clinical management and bring to light new therapeutic opportunities. Cancer Discov; 8(3); 336–53. ©2017 AACR.
See related commentary by Natrajan et al., p. 272.
See related article by Liu et al., p. 354.
This article is highlighted in the In This Issue feature, p. 253
Factors Associated with Chronic Kidney Disease and Their Clinical Utility in Primary Care Clinics in a Multi-Ethnic Southeast Asian Population
Authors: Lew Quan Lan J. , Allen John C. , Nguyen Francis , Tan Ngiap Chuan , Jafar Tazeen H. 
Published: December 2017

<b><i>Background:</i></b> Chronic kidney disease (CKD) is a major global public health challenge. We investigated determinants of CKD and their clinical utility in an ethnically diverse Southeast Asian population. <b><i>Methods:</i></b> Electronic health records (EHR) of adults ≥40 years who visited any one of 4 government polyclinics in Singapore from January 1, 2012 to ­December 31, 2015 were analyzed. CKD was defined as an estimated glomerular filtration rate &#x3c;60 mL/min/1.73 m<sup>2</sup> or 1+ dipstick proteinuria excretion, based on 2 measurements ≥3 months apart. CKD-associated factors and their clinical utility for predicting odds of CKD were investigated using multiple logistic regression analysis. <b><i>Results:</i></b> Based on the study criteria, 25.9% (95% CI 25.6–26.2) of the 88,765 eligible study individuals had CKD. The factors (OR and 95% CI) independently associated with CKD were older age ≥65 years (2.54 [2.44–2.64] vs. ≤65 years), respectively; men (1.13 [1.09–1.18]); Malay (1.27 [1.20–1.33]) and Indian (0.77 [0.71–0.83]) vs. Chinese ethnicity; overweight (body mass index [BMI] ≥27.5 kg/m<sup>2</sup>; 1.10 [1.04–1.16]) vs. normal weight (BMI 18 to &#x3c;23 kg/m<sup>2</sup>); government (1.22 [1.15–1.31]) vs. private housing; and with hypertension (3.32 [3.09–3.56]), diabetes (6.93 [6.67–7.20]) or stroke (1.46 [1.36–1.56]) vs. without each co-morbidity, respectively. The area under the receiver operating characteristic curve (95% CI) for the model to predict the probability of CKD using hypertension, diabetes, and age was 0.808 (0.805–0.811). Only 28.5% (27.9–29.1%) of individuals with CKD had physician documentation of their CKD status. However, documentation of CKD status was associated with age ≥65 years (1.11 [1.04–1.20] vs. &#x3c;65 years), men (1.35 [1.26–1.44]) vs. women, with vs. without hypertension (1.24 [1.07–1.44]), Indian (0.80 [0.69–0.92]) compared to Chinese ethnicity, ever smokers (0.89 [0.81–0.99]) vs. non-smokers, and those with vs. without stroke (0.83 [0.75–0.93]). <b><i>Conclusions:</i></b> CKD prevalence in our Southeast Asian population is high and under-documented even in high-risk patients. Our findings highlight factors associated with CKD, and the predictive value of hypertension, diabetes, and advancing age as EHR-based screening targets for CKD. Our results also suggest that complementary educational efforts will be needed to increase physician detection and optimize the management of CKD, especially in high risk and marginalized groups across all clinics in Singapore, and possibly in the region.
Memórias de rios e de lagos na ficção amazônica
Authors: Vidal Elizabete De Lemos 
Published: December 2017

A pesquisa sobre memórias de rios e lagos amazônicos possibilitou um encontro entre dois escritores - Dalcídio Jurandir e Benedicto Monteiro - traduzindo, do universo literário criado por esses dois autores, vivências do mundo amazônico. Nesse sentido, é possível afirmar que no romance Marajó, de Dalcídio Jurandir e no conto O peixe, de Benedicto Monteiro, há uma representação do “médico popular“ que atua nos espaços da Amazônia ribeirinha. As especificidades e funções atribuídas a esse personagem, no plano do enunciado e da enunciação, auxiliam na reconstituição das memórias amazônicas traduzidas no plano da ficção. O tom de oralidade presente no conto O peixe, enriquece o convencional papel do narrador, refletindo as vivências e experiências do autor em prestadas à angústia de um homem dividido entre as coisas de Deus e as tentações do Diabo: águas, peixes, plantas, musgos, cores, cheiros e sabores, elementos de um mundo particular, se agregam à geografia dos rios, lagos, furos, igarapés, que materializam constelação de signos amazônicos
Cardiac-Specific Bdh1 Overexpression Ameliorates Oxidative Stress and Cardiac Remodeling in Pressure Overload–Induced Heart Failure
Authors: Uchihashi Motoki , Hoshino Atsushi , Okawa Yoshifumi , Ariyoshi Makoto , Kaimoto Satoshi , Tateishi Shuhei , Ono Kazunori , Yamanaka Ryoetsu , Hato Daichi , Fushimura Yohei , Honda Sakiko , Fukai Kuniyoshi , Higuchi Yusuke , Ogata Takehiro , Iwai-Kanai Eri , Matoba Satoaki 
Published: December 2017

Background
Energy starvation and the shift of energy substrate from fatty acids to glucose is the hallmark of metabolic remodeling during heart failure progression. However, ketone body metabolism in the failing heart has not been fully investigated.

Methods and Results

Microarray data analysis and mitochondrial isobaric tags for relative and absolute quantification proteomics revealed that the expression of D-β-hydroxybutyrate dehydrogenase I (Bdh1), an enzyme that catalyzes the NAD
+
/NADH coupled interconversion of acetoacetate and β-hydroxybutyrate, was increased 2.5- and 2.8-fold, respectively, in the heart after transverse aortic constriction. In addition, ketone body oxidation was upregulated 2.2-fold in transverse aortic constriction hearts, as determined by the amount of
14
CO
2
released from the metabolism of [1-
14
C] β-hydroxybutyrate in isolated perfused hearts. To investigate the significance of this augmented ketone body oxidation, we generated heart-specific Bdh1-overexpressing transgenic mice to recapitulate the observed increase in basal ketone body oxidation. Bdh1 transgenic mice showed a 1.7-fold increase in ketone body oxidation but did not exhibit any differences in other baseline characteristics. When subjected to transverse aortic constriction, Bdh1 transgenic mice were resistant to fibrosis, contractile dysfunction, and oxidative damage, as determined by the immunochemical detection of carbonylated proteins and histone acetylation. Upregulation of Bdh1 enhanced antioxidant enzyme expression. In our in vitro study, flow cytometry revealed that rotenone-induced reactive oxygen species production was decreased by adenovirus-mediated Bdh1 overexpression. Furthermore, hydrogen peroxide–induced apoptosis was attenuated by Bdh1 overexpression.

Conclusions
We demonstrated that ketone body oxidation increased in failing hearts, and increased ketone body utilization decreased oxidative stress and protected against heart failure.
Running a Religious Philanthropic Enterprise
Authors: Lu Wei-Hsu 
Published: December 2017

AbstractReligious philanthropy is now in a new age. In 2012, the State Bureau of Religious Affairs and other 5 state agencies published a document to encourage and regulate religious philanthropic activities. It means that the central government’s new religious policy is to cultivate religious philanthropy. However, many religious groups, since their engagement in philanthropy, have encountered a series of problems, such as the immaturity of theory, the inefficiency of resource use and search, the shortage of organizations and staff with experience, and the unclear division between serving and preaching. Even if the religious environment in Taiwan is different from that in Mainland, the success of the waste sorting and recycling program of Tzu Chi, the largest Humanistic Buddhist group in Taiwan, still brings some valuable experience to religious groups doing philanthropy in Mainland. First, Tzu Chi’s leader, Cheng Yen, was good at linking Buddha’s teachings with recognized environmental issues. Her style of speech might be learned by other religious leaders who intend to generate philanthropic discourses. Second, Tzu Chi’s waste sorting and recycling program always made use of contingent opportunities and resources outside it to develop itself. This way of expansion should be noted by religious groups that want to establish philanthropic organizations. Third, the division of labor among Tzu Chi’s leader, volunteers, and professionals and their high level of autonomy could be taken by other religious philanthropic organizations. Finally, Tzu Chi’s religious philanthropic practices prioritize public interests and set an example for the separation between serving and preaching.
On Legitimacy of WISEs
Authors: Chen Tingming , Weng Yichun 
Published: December 2017

AbstractAmid the increasing diversification of social development, the services provided by the government hardly satisfy all sorts of needs. The establishment of non-profit organizations (npos) timely addresses the government’s deficiency in handling public affairs. As a result, thenpos almost turn into private enterprises and social enterprises aim to deliver public benefits, which has aroused disputes and doubts like “mission drift” and “for-profits in disguise.” This article adopts Suchman’s pragmatic, moral and cognitive legitimacy analysis to reexamine the work integration social enterprises (WISEs) which enable the disadvantaged or those with disabilities to join in the labor market after training, coaching and professional practice. Based on literature review and in-depth interview, this article makes a case study of CANYOU, an exemplary social enterprise set by persons with disabilities by leveraging advanced technologies.
Lithic Production Strategies in the Oldowan Assemblages from Sterkfontein Member 5 and Swartkrans Member 1, Gauteng Province, South Africa
Authors: Caruana Matthew V. 
Published: December 2017

AbstractSterkfontein Member 5 East (Oldowan Infill) and Swartkrans Member 1 (Lower Bank) represent the largest concentrations of Oldowan artefacts in southern Africa, and yet they vary significantly in terms of raw material use and typological frequencies. While previous research has described these differences in detail, questions remain as to the cause and implications of this variability. To increase resolution on this matter, this study implements quantitative methods to investigate lithic production strategies at these sites. Results expand upon previous findings concerning differences in raw material use and knapping methods and how these patterns relate to core reduction and flake production. Explanations for these patterns focus on a dichotomy between efficiency and expediency in lithic production, which differ from previous interpretations. As such, variability between these assemblages may relate more to mobility patterns in early hominins within this region and immediate needs for tool use.
Identification of the integrin-binding site on coagulation factor VIIa required for proangiogenic PAR2 signaling
Authors: Rothmeier Andrea S. , Liu Enbo , Chakrabarty Sagarika , Disse Jennifer , Mueller Barbara M. , Østergaard Henrik , Ruf Wolfram 
Published: December 2017

Key PointsThe FVIIa integrin-binding motif is required for TF-FVIIa complex formation with integrin β1 and proangiogenic signaling. The arf6 integrin recycling pathway controls TF-FVIIa signaling and cell surface availability for procoagulant activity.
Delivery of Global Cancer Care: An International Study of Medical Oncology Workload
Authors: Fundytus Adam , Sullivan Richard , Vanderpuye Verna , Seruga Bostjan , Lopes Gilberto , Hammad Nazik , Sengar Manju , Hopman Wilma M. , Brundage Michael D. , Booth Christopher M. 
Published: December 2017

Background To our knowledge, there is no literature that has described medical oncology (MO) workload in the global context. Here, we report results of an international study of global MO workload. Methods An online survey was distributed through a snowball method via national oncology societies to chemotherapy-prescribing physicians in 65 countries. Countries were classified into low- or low-middle–income countries (LMICs), upper-middle–income countries (UMICs), and high-income countries (HICs) on the basis of World Bank criteria. Workload was measured as the annual number of new consultations provided to patients with cancer per oncologist. Results A total of 1,115 physicians completed the survey: 13% (147 of 1,115) from LMICs, 17% (186 of 1,115) from UMICs, and 70% (782 of 1,115) from HICs. Eighty percent (897 of 1,115) of respondents were medical oncologists, 10% (109 of 1,115) were clinical oncologists, and 10% (109 of 1,115) were other. The median number of annual consults per oncologist was 175 (interquartile range, 75 to 275); 13% (140 of 1,103) saw ≥ 500 new patients in a year. Annual case volume in LMICs (median consults, 425; 40% of respondents seeing > 500 consults) was substantially higher than in UMICs (median consults, 175; 14% > 500) and HICs (median consults, 175; 7% > 500; P < .001). Among LMICs, UMICs, and HICs, median working days per week were 6, 5, and 5, respectively ( P < .001). The highest annual case volumes per oncologist were in Pakistan (median consults, 950; 73% > 500 consults), India (median consults, 475; 43% > 500), and Turkey (median consults, 475; 27% > 500). Conclusion There is substantial global variation in medical oncology case volumes and clinical workload; this is most striking among LMICs, where huge deficits exist. Additional work is needed, particularly detailed country-level mapping, to quantify activity-based global MO practice and workload to inform training needs and the design of new pathways and models of care.
Directional vibration sensing in the leafcutter ant Atta sexdens
Authors: Hager Felix A. , Kirchner Lea , Kirchner Wolfgang H. 
Published: December 2017

ABSTRACT
Leafcutter ants communicate with the substrate-borne component of the vibratory emission produced by stridulation. Stridulatory signals in the genus Atta have been described in different behavioural contexts, such as foraging, alarm signalling and collective nest building. Stridulatory vibrations are employed to recruit nestmates, which can localize the source of vibration, but there is little information about the underlying mechanisms. Our experiments reveal that time-of-arrival delays of the vibrational signals are used for tropotactic orientation in Atta sexdens. The detected time delays are in the same range as the time delays detected by termites. Chemical communication is also of great importance in foraging organization, and signals of different modalities may be combined in promoting the organization of collective foraging. Here we show that the tropotactic orientation to vibrational signals interacts with chemical communication signals.
Paracrine brassinosteroid signaling at the stem cell niche controls cellular regeneration
Authors: Lozano-Elena Fidel , Planas-Riverola Ainoa , Vilarrasa-Blasi Josep , Schwab Rebecca , Caño-Delgado Ana I. 
Published: December 2017

ABSTRACT
Stem cell regeneration is crucial for both cell turnover and tissue healing in multicellular organisms. In Arabidopsis roots, a reduced group of cells known as the quiescent center (QC) act as a cell reservoir for surrounding stem cells during both normal growth and in response to external damage. Although cells of the QC have a very low mitotic activity, plant hormones such as brassinosteroids (BRs) can promote QC divisions. Here, we used a tissue-specific strategy to investigate the spatial signaling requirements of BR-mediated QC divisions. We generated stem cell niche-specific receptor knockout lines by placing an artificial microRNA against BRI1 (BRASSINOSTEROID INSENSITIVE 1) under the control of the QC-specific promoter WOX5. Additionally, QC-specific knock-in lines for BRI1 and its downstream transcription factor BES1 (BRI1-EMS-SUPPRESOR1) were also created using the WOX5 promoter. By analyzing the roots of these lines, we show that BES1-mediated signaling cell-autonomously promotes QC divisions, that BRI1 is essential for sensing nearby inputs and triggering QC divisions and that DNA damage promotes BR-dependent paracrine signaling in the stem cell niche as a prerequisite to stem cell replenishment.
Dynamic changes in the interchromosomal interaction of early histone gene loci during development of sea urchin
Authors: Matsushita Masaya , Ochiai Hiroshi , Suzuki Ken-ichi T. , Hayashi Sayaka , Yamamoto Takashi , Awazu Akinori , Sakamoto Naoaki 
Published: December 2017

ABSTRACT
The nuclear positioning and chromatin dynamics of eukaryotic genes are closely related to the regulation of gene expression, but they have not been well examined during early development, which is accompanied by rapid cell cycle progression and dynamic changes in nuclear organization, such as nuclear size and chromatin constitution. In this study, we focused on the early development of the sea urchin Hemicentrotus pulcherrimus and performed three-dimensional fluorescence in situ hybridization of gene loci encoding early histones (one of the types of histone in sea urchin). There are two non-allelic early histone gene loci per sea urchin genome. We found that during the morula stage, when the early histone gene expression levels are at their maximum, interchromosomal interactions were often formed between the early histone gene loci on separate chromosomes and that the gene loci were directed to locate to more interior positions. Furthermore, these interactions were associated with the active transcription of the early histone genes. Thus, such dynamic interchromosomal interactions may contribute to the efficient synthesis of early histone mRNA during the morula stage of sea urchin development.
The EGFR odyssey – from activation to destruction in space and time
Authors: Bakker Jeroen , Spits Menno , Neefjes Jacques , Berlin Ilana 
Published: December 2017

ABSTRACT
When cell surface receptors engage their cognate ligands in the extracellular space, they become competent to transmit potent signals to the inside of the cell, thereby instigating growth, differentiation, motility and many other processes. In order to control these signals, activated receptors are endocytosed and thoroughly curated by the endosomal network of intracellular vesicles and proteolytic organelles. In this Review, we follow the epidermal growth factor (EGF) receptor (EGFR) from ligand engagement, through its voyage on endosomes and, ultimately, to its destruction in the lysosome. We focus on the spatial and temporal considerations underlying the molecular decisions that govern this complex journey and discuss how additional cellular organelles – particularly the ER – play active roles in the regulation of receptor lifespan. In summarizing the functions of relevant molecules on the endosomes and the ER, we cover the order of molecular events in receptor activation, trafficking and downregulation, and provide an overview of how signaling is controlled at the interface between these organelles.
BMSCs ameliorate septic coagulopathy by suppressing inflammation in cecal ligation and puncture-induced sepsis
Authors: Xu Shunyao , Zhou Zhen , Li Hao , Liu Ziying , Pan Xiaojun , Wang Fen , Huang Yueyue , Li Xiaogang , Xiao Yunbei , Pan Jingye , Wang Cong , Li Dequan 
Published: December 2017

ABSTRACT
Sepsis is an aggressive and life-threatening systemic inflammatory response with a high mortality. Inflammation and coagulation play crucial roles in the pathogenesis of sepsis in a mutually promoting manner. Unlike other single-target molecular therapies that have no obvious effects on clinical sepsis, bone marrow stromal cell (BMSC) therapy offers a broader spectrum of activities ranging from immune and inflammation suppression to tissue regeneration. In this report, we demonstrate that BMSC injection attenuates septic coagulopathy. It decreased the mortality, mitigated lung injury and reduced the surge of proinflammatory factors in mice with sepsis induced by cecal ligation and puncture (CLP). An in vitro cell model also revealed that co-culture with BMSCs reduced secretion of proinflammatory factors and injury of endothelial cells in response to lipopolysaccharide (LPS), an endotoxin of gram-negative bacteria. Together, our results demonstrate that BMSCs suppress sepsis-induced inflammation, endothelial dysfunction and defective coagulation.
The Value of Dynamic Pricing in Large Queueing Systems
Authors: Kim Jeunghyun , Randhawa Ramandeep S. 
Published: December 2017

We study the value of dynamic pricing to maximize revenues in queueing systems with price- and delay-sensitive customers. The system queue length is visible so that upon arrival, customers decide to join the system based on the congestion and the price at that time. We analyze this problem in the asymptotic regime of large customer market size and capacity. We find that dynamic pricing performs significantly better than static pricing at mitigating the effect of uncertainty. Asymptotically, the revenue in such systems consists of a positive deterministic component and a negative stochastic component, the latter representing the impact of variability. Static pricing leads to the n1/2-scale effect of variability, i.e., the expected steady-state queue length is Kn1/2 for some K > 0, where n represents the system size. However, dynamic pricing can lower this effect of variability to the n1/3-scale. We further show that a simple policy of using only two prices can achieve most of the benefits of dynamic pricing. We also discuss how our results can apply to other dynamic control problems in queueing systems. The e-companion is available at https://doi.org/10.1287/opre.2017.1668 .