bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neddylation Inhibition Activates the Extrinsic Apoptosis Pathway through ATF4–CHOP–DR5 Axis in Human Esophageal Cancer Cells
Authors: Chen Ping , Hu Tao , Liang Yupei , Li Pei , Chen Xiaoyu , Zhang Jingyang , Ma Yangcheng , Hao Qianyun , Wang Jinwu , Zhang Ping , Zhang Yanmei , Zhao Hu , Yang Shengli , Yu Jinha , Jeong Lak Shin , Qi Hui , Yang Meng , Hoffman Robert M. , Dong Ziming , Jia Lijun 
Published: March 2016

Abstract
Purpose: Targeting the protein neddylation pathway has become an attractive anticancer strategy; however, the role of death receptor–mediated extrinsic apoptosis during treatment remained to be determined.
Experimental Design: The activation of extrinsic apoptosis and its role in MLN4924 treatment of human esophageal squamous cell carcinoma (ESCC) were evaluated both in vitro and in vivo. The expression of the components of extrinsic apoptotic pathway was determined by immunoblotting analysis and downregulated by siRNA silencing for mechanistic studies.
Results: Pharmaceutical or genetic inactivation of neddylation pathway induced death receptor 5 (DR5)–mediated apoptosis and led to the suppression of ESCC in murine models. Mechanistically, neddylation inhibition stabilized activating transcription factor 4 (ATF4), a Cullin-Ring E3 ubiquitin ligases (CRL) substrate. Transcription factor CHOP was subsequently transactivated by ATF4 and further induced the expression of DR5 to activate caspase-8 and induce extrinsic apoptosis. Moreover, the entire neddylation pathway was hyperactivated in ESCC and was negatively associated with patient overall survival.
Conclusions: Our findings highlight a critical role of ATF4–CHOP–DR5 axis-mediated extrinsic apoptosis in neddylation-targeted cancer therapy and support the clinical investigation of neddylation inhibitors (e.g., MLN4924) for the treatment of ESCC, a currently treatment-resistant disease with neddylation hyperactivation. Clin Cancer Res; 22(16); 4145–57. ©2016 AACR.
Differential Effects of PI3K and Dual PI3K/mTOR Inhibition in Rat Prolactin-Secreting Pituitary Tumors
Authors: Chanal Marie , Chevallier Pascale , Raverot Véronique , Fonteneau Guillaume , Lucia Kristin , Monteserin Garcia Jose Luis , Rachwan Alexa , Jouanneau Emmanuel , Trouillas Jacqueline , Honnorat Jérôme , Auger Carole , Theodoropoulou Marily , Raverot Gérald 
Published: March 2016

Abstract
Aggressive pituitary tumors are rare but difficult to manage, as there is no effective chemotherapy to restrict their growth and cause their shrinkage. Within these tumors, growth-promoting cascades, like the PI3K/mTOR pathway, appear to be activated. We tested the efficacy of two inhibitors of this pathway, NVP-BKM120 (Buparlisib; pan-PI3K) and NVP-BEZ235 (dual PI3K/mTOR), both in vitro on immortalized pituitary tumor cells (GH3) and on primary cell cultures of human pituitary tumors and in vivo on a rat model of prolactin (PRL) tumors (SMtTW3). In vitro, NVP-BEZ235 had a potent apoptotic and cytostatic effect that was characterized by decreased cyclin D/E and Cdk4/2 protein levels and subsequent accumulation of cells in G1. In vivo, the effect was transient, with a decrease in mitotic index and increase in apoptosis; long-term treatment had no significant inhibitory effect on tumor growth. In contrast, while NVP-BKM120 had little effect in vitro, it dramatically limited tumor growth in vivo. Increased Akt phosphorylation observed only in the NVP-BEZ235–treated tumors may explain the differential response to the two inhibitors. Primary cell cultures of human PRL pituitary tumors responded to NVP-BEZ235 with reduced cell viability and decreased hormone secretion, whereas NVP-BKM120 had little effect. Altogether, these results show a potential for PI3K inhibitors in the management of aggressive pituitary tumors. Mol Cancer Ther; 15(6); 1261–70. ©2016 AACR.
Kinase-Dependent and -Independent Roles for PTK6 in Colon Cancer
Authors: Mathur Priya S. , Gierut Jessica J. , Guzman Grace , Xie Hui , Xicola Rosa M. , Llor Xavier , Chastkofsky Michael I. , Perekatt Ansu O. , Tyner Angela L. 
Published: March 2016

Abstract
Disruption of the gene encoding Protein Tyrosine Kinase 6 (Ptk6) delayed differentiation and increased growth in the mouse intestine. However, Ptk6-null mice were also resistant to azoxymethane-induced colon tumorigenesis. To further explore functions of PTK6 in colon cancer, expression of epithelial and mesenchymal markers, as well as proliferation, migration, and xenograft tumor growth, was examined in human colon tumor cell lines with knockdown or overexpression of PTK6. PTK6 protein, transcript, and activation were also examined in a human colon tumor tissue array, using immunohistochemistry and qRT-PCR. Knockdown of PTK6 led to the epithelial–mesenchymal transition (EMT) in SW480 and HCT116 cells, whereas overexpression of PTK6 in SW620 cells restored an epithelial phenotype in a kinase-independent manner. PTK6 knockdown also increased xenograft tumor growth of SW480 cells, suggesting tumor suppressor functions. In clinical specimens, PTK6 expression was highest in normal differentiated epithelial cells and reduced in tumors. In contrast, overexpression of constitutively active PTK6 promoted STAT3 and ERK5 activation in colon cancer cells, and endogenous PTK6 promoted cell survival and oncogenic signaling in response to DNA-damaging treatments. These data indicate that PTK6 has complex, context-specific functions in colon cancer; PTK6 promotes the epithelial phenotype to antagonize the EMT in a kinase-independent manner, whereas activation of PTK6 promotes oncogenic signaling.
Implications: Understanding context-specific functions of PTK6 is important, because although it promotes cell survival and oncogenic signaling after DNA damage, expression of PTK6 in established tumors may maintain the epithelial phenotype, preventing tumor progression. Mol Cancer Res; 14(6); 563–73. ©2016 AACR.
Metropolitan Poverty: The Case of New York City
Authors: Mogull Robert G. 
Published: March 2016

This study serves two purposes. First, it demonstrates a method of estimating and projecting annual poverty at sub-national levels. Data obtained from decennial censuses provide the benchmarks from which poverty is estimated and projected for various demographic groups. Projections are based upon curvilinear trends of rates and counts for each group. The methodology can be easily applied in a variety of jurisdictional settings and levels. The second objective is to provide a specific portrait of poverty by demographic group within the New York City metropolitan region. The evidence indicates a substantial increase over the next decade both in the incidence of poverty and in the number of impoverished residents. There will also be major shifts among population segments in their shares of total area poverty.
Monetary Trends in the United States and the United Kingdom
Authors: Friedman Milton 
Published: March 2016

Editor’s Introduction Originally published in Volume 16, Number 1, Spring 1972, pages 4-17. At the 1971 annual conference of the American Economic Association, Milton Friedman (1912-2006) delivered this paper as the fourth John R. Commons Lecture. It is a summary of research he was conducting with Anna Schwartz intended as a follow-up to their seminal work published nearly a decade earlier, A Monetary History of the United States, 1867-1960. Over his lengthy career, Professor Friedman became his generation’s leading proponent of the Chicago School of economic thought and the founder of modern monetarism. In 1976 he received the Nobel Prize in Economic Sciences, “for his achievements in the fields of consumption analysis, monetary history and theory and for his demonstration of the complexity of stabilization policy.” Professor Friedman was one of those rare economists whose work was as widely known by the general public as it was respected by his academic peers. In this paper, Friedman identifies, examines, and compares a variety of trends in the monetary bases of the United States and the United Kingdom using nearly a century of data. His observations on the impact of technology, such as “automatic computers” on the velocity of money and the early movements toward a “checkless society” are prescient given that they were written more than forty years before today’s age of digital commerce. The paper concludes with a transcription of Professor Friedman’s responses to questions from the lecture’s audience.
Replacing the Autarky Factor Prices with the Corresponding Post-Trade Prices: An Extension of Deardorff's Factor-Proportions Theory of Trade
Authors: Madresehee Mehrdad 
Published: March 2016

A generalized version of the Heckscher-Ohlin model of trade (factor-proportions theory of the pattern of trade) has been developed by A. V. Deardorff for the ℓ-factor, m-commodity, and n-country case. Even though Deardorffs model does not add to the unrealistic assumptions of the simple version of the model, it seems to have a basic problem—it is untestable. One of the reasons that Deardorffs model is not testable is due to the fact that the model measures the relative abundance of factors in a country by comparing their relative autarky prices in that country with those of the same factor in other trading countries. Since the autarky factor prices are not observable, this model cannot be tested unless further assumptions are made about the relationship between pre-trade and post-trade factor prices. To overcome the problem concerning the unobservability of autarky factor prices, I have proved two theorems which make it possible to conduct tests to support the Deardorff model by allowing for the replacement of the autarky factor prices with the corresponding post-trade prices whenever the former ones should be used in the test. According to the corollaries which follow from these two theorems, any positive test result which is conducted based on post-trade factor prices can be used as supportive evidence to validate Deardorffs model which was formulated based on pre-trade factor price. However, unsatisfactory results cannot be used to falsify Deardorffs model due to the fact that the proved conditions are sufficient but not necessary.
External Debt, Growth and Debt-Service Capacity in Sub-Saharan Africa: A Theoretical and Empirical Analysis
Authors: Scott Gerald 
Published: March 2016

First the paper uses a simple neoclassical production function to show how capital imports can increase output in a low income nation. Secondly the paper shows how the increased output resulting from capital imports can potentially be distributed between debt service payments and consumption. Thirdly the paper uses data from 1980–87 for 31 countries in SSA, to provide empirical estimates of the elasticity of output with respect to capital imports, and the elasticity of the surplus with respect to output. The theoretical model suggests that the actual surplus available for debt service may be much smaller than that suggested by the productivity of capital imports alone. The empirical estimates for SSA indicate that although capital imports into SSA have been very unproductive the marginal propensity to save seems sufficient to permit the region to generate a surplus for debt service.
Do Japanese Automakers Maximize Profits? A Systems Analysis of the Pricing of Automobile Inventories
Authors: Langlois Catherine C. 
Published: March 2016

This article investigates Japanese automaker pricing practices on the U.S. market and finds them compatible with short run profit maximization. The short run is here the selling time of a typical inventory holding and short run profit is defined as average per unit of time profit made over this selling time. Maximizing this concept of short run profit implies setting markup over the average cost of goods equal to the inverse of the price sensitivity of inventory selling time. To test for short run profit maximizing behavior, estimates of this price sensitivity for each firm are compared to the actual markups applied by U.S. and Japanese automakers.
The Effect of Risk-Aversion on the Portfolio Allocation between Taxable Bonds and Non-Taxable Bonds of the Same Risk
Authors: Mantell Edmund H. 
Published: March 2016

A well-known proposition found in numerous textbooks, as well as in marketing materials distributed by bond salesmen, asserts that a lower-yielding municipal bond can provide the same after-tax return as a higher-yielding corporate bond, ceteris paribus. A simple algebraic “equivalence relation” is sometimes adduced to illustrate what the before-tax yield on the corporate must be if its after-tax yield to the investor is to be equal to the yield on a municipal. A portfolio policy implication frequently suggested is that if the after-tax yield on the corporate is equal to the yield on the municipal, ceteris paribus, the “rational” investor should be indifferent to his allocation between the two. This paper constructs a theory to demonstrate the dubious validity of that investment policy. The theory in this paper relies on the assumptions respecting the risk-aversive attitude of investors as well as the presence of risky taxable income statistically independent of the income from the bonds. The main results of the analysis are expressed by two propositions that establish that the risk-averse investor will choose a specific allocation of his bond portfolio and will require a risk premium to induce him to hold municipals of the same risk as corporates.
Prothrombin Time Tests for the Monitoring of Direct Oral Anticoagulants and Their Evaluation as Indicators of the Reversal Effect
Authors: Nagakari Kunihiko , Emmi Mari , Iba Toshiaki 
Published: March 2016

Introduction: The prompt assessment and the reversal of direct oral anticoagulants (DOACs) are urgent matters in the emergency care setting. Thus, we planned to elucidate the adequate prothrombin time (PT) test for the evaluation of the anticoagulant effects of various DOACs. Methods: The anticoagulant effects of rivaroxaban, apixaban, and edoxaban were measured with 3 PT tests (Triniclot PT Excel S, Neoplastin R, and Thromborel S). Human plasma was spiked with each DOAC at a range of 0 to 1000 ng/mL, and the PT was measured using each PT test. In another series, the reversal effect of either 4-factor prothrombin complex concentrate (PCC) or activated PCC (aPCC) was evaluated with each PT test. Results: All PT reagents correlated with the concentrations of each DOAC, however, the reactivity was considerably different between the DOACs and the PT tests. A prolonged PT with DOACs was reversed both by PCC and aPCC in a dose-dependent manner; however, Triniclot PT Excel S showed reprolongation of the PT with a higher dose of PCC. Conclusion: The proper choice of PT test is necessary for the assessments of the anticoagulant activity of DOACs. It is also important to understand the different characteristics of each PT test for the assessment of the reversal effects of PCC.
Observational study of trastuzumab-related cardiotoxicity in early and metastatic breast cancer
Authors: Grazziotin LR , Picon PD 
Published: March 2016

Introduction Trastuzumab-related cardiotoxicity has been a major concern in clinical practice, since observational studies have shown higher incidences than that reported in clinical trials. We aim to measure the incidence of trastuzumab-related cardiotoxicity in patients with early and metastatic breast cancer in the south of Brazil. Methods Multicenter prospective observational study, which included 109 patients with early or metastatic HER-2+ breast cancer undergoing any trastuzumab-based regimen. Cardiac events were measured by transthoracic echocardiography assessments and by signs and symptoms of heart failure. Results Trastuzumab-related cardiotoxicity was observed in 58 patients (53.2%). Emergency and hospitalization admissions were necessary in seven and three patients, respectively, due to symptoms of heart failure. One patient died in consequence of trastuzumab-related cardiotoxicity. In total, trastuzumab was discontinued in 31.2% of patients, of which almost a third could not return to treatment. In this study, no risk factors were significantly associated with the development of cardiotoxicity. Discussion The incidence of TRC and trastuzumab's early discontinuation observed was significantly higher in comparison with other studies. These findings endorse the fact that trastuzumab-related cardiotoxicity is a relevant adverse reaction, and therefore, cardiac dysfunction's monitoring must be highlighted in order to allow a safe use of trastuzumab in this population.
Social work doctoral education: Are doctoral students being prepared to teach?
Authors: Maynard Brandy R , Labuzienski Elizabeth M , Lind Kristina S , Berglund Andrew H , Albright David L 
Published: March 2016

Summary Longstanding tensions exist around the purpose of social work doctoral programs, particularly around the extent to which doctoral program should prepare their students to teach. Indeed, social work programs in the United States have been criticized for failing to prepare graduates for teaching; however, it has been a number of years since doctoral curricula have been reviewed. The purpose of this study was to examine the extent to which US social work doctoral programs are training their students to teach by assessing the extent to which pedagogical training is explicitly integrated into doctoral curricula and examining the scope and content of required doctoral courses on teaching. Content analysis of social work doctoral program curricula ( n = 72) and teaching and learning related course syllabi ( n = 24) was conducted by two coders. Syllabi were coded and analyzed to produce a profile of course objectives, readings, teaching strategies, assessment methods, and course content. Findings Of the 72 PhD programs, 90% included a goal related to the preparation of their students for teaching; however, only 37 (51%) required a course on teaching. Course content, teaching, and assessment methods were found to vary across courses. Applications Training the next generation of social work practitioners to engage in effective social work practice is critical to the profession; however, the preparation of doctoral students to provide quality education to future social work practitioners seems to be largely neglected. Implications for doctoral education are discussed.
First occurrence of moskvinite-(Y) in the Ilímaussaq alkaline complex, South Greenland – implications for rare-earth element mobility
Authors: Friis Henrik 
Published: March 2016

AbstractMoskvinite-(Y), Na2K(Y,REE)Si6O15, is a rare mineral, which until now has only been described from its type locality Dara-i-Pioz, Tajikistan. At Ilímaussaq moskvinite-(Y) was discovered in a drill core from Kvanefjeld, where it occurs as a replacement mineral associated with a mineral belonging to the britholite group. The composition was determined by a combination of electron probe microanalysis and laser ablation inductively coupled plasma mass spectrometry analyses. The empirical formula based on 15 oxygens is Na1.94K0.99(Y0.94Yb0.03Er0.03Dy0.03Ho0.01Gd0.01)∑1.05Si5.98O15. The coexistence of an almost pure Y and a light rare-earth element (REE) mineral is interpreted as fractionation ofREEand Y during the replacement of an earlier formedREEmineral. Theoretical calculations of the observed replacement of feldspathoids by natrolite show that the generated fluid would have pH > 8, which inhibits large scale mobility ofREE. In addition, a K-Fe sulfide member of the chlorbartonite-bartonite group is for the first time observed in Ilímaussaq where it occurs where sodalite is replaced by natrolite and arfvedsonite by aegirine. The sulfide incorporates the S and some of the Cl generated by the alteration of sodalite, whereas the K and Fe originates from the replacement of arfvedsonite by aegirine.
GNA13 loss in germinal center B cells leads to impaired apoptosis and promotes lymphoma in vivo
Authors: Healy Jane A. , Nugent Adrienne , Rempel Rachel E. , Moffitt Andrea B. , Davis Nicholas S. , Jiang Xiaoyu , Shingleton Jennifer R. , Zhang Jenny , Love Cassandra , Datta Jyotishka , McKinney Matthew E. , Tzeng Tiffany J. , Wettschureck Nina , Offermanns Stefan , Walzer Katelyn A. , Chi Jen-Tsan , Rasheed Suhail A. K. , Casey Patrick J. , Lossos Izidore S. , Dave Sandeep S. 
Published: March 2016

Key Points
In mice, loss of GNA13 in GC B cells protects against cell death and may promote genetic instability via ongoing somatic hypermutation. Gna13 loss, in combination with MYC overexpression, promotes lymphoma in mice.
Behavioural and psychological symptoms in dementia and the
challenges for family carers: Systematic review
Authors: Feast Alexandra , Orrell Martin , Charlesworth Georgina , Melunsky Nina , Poland Fiona , Moniz-Cook Esme 
Published: March 2016

BackgroundTailored psychosocial interventions can help families to manage
behavioural and psychological symptoms in dementia (BPSD), but carer
responses to their relative's behaviours contribute to the success of
support programmes.AimsTo understand why some family carers have difficulty in dealing with
BPSD, in order to improve the quality of personalised care that is
offered.MethodA systematic review and meta-ethnographic synthesis was conducted of
high-quality quantitative and qualitative studies between 1980 and
2012.ResultsWe identified 25 high-quality studies and two main reasons for behaviours
being reported as challenging by family carers: changes in communication
and relationships, resulting in ‘feeling bereft’; and perceptions of
transgressions against social norms associated with ‘misunderstandings
about behaviour’ in the relative with dementia. The underlying belief
that their relative had lost, or would inevitably lose, their identity to
dementia was a fundamental reason why family carers experienced behaviour
as challenging.ConclusionsFamily carers' perceptions of BPSD as challenging are associated with a
sense of a declining relationship, transgressions against social norms
and underlying beliefs that people with dementia inevitably lose their
‘personhood’. Interventions for the management of challenging behaviour
in family settings should acknowledge unmet psychological need in family
carers.
TAK1 determines susceptibility to endoplasmic reticulum stress and leptin resistance in the hypothalamus
Authors: Sai Kazuhito , Morioka Sho , Takaesu Giichi , Muthusamy Nagendran , Ghashghaei H. Troy , Hanafusa Hiroshi , Matsumoto Kunihiro , Ninomiya-Tsuji Jun 
Published: March 2016

ABSTRACT
Sustained endoplasmic reticulum (ER) stress disrupts normal cellular homeostasis and leads to the development of many types of human diseases, including metabolic disorders. TAK1 (also known as MAP3K7) is a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family and is activated by a diverse set of inflammatory stimuli. Here, we demonstrate that TAK1 regulates ER stress and metabolic signaling through modulation of lipid biogenesis. We found that deletion of Tak1 increased ER volume and facilitated ER-stress tolerance in cultured cells, which was mediated by upregulation of sterol-regulatory-element-binding protein (SREBP)-dependent lipogenesis. In the in vivo setting, central nervous system (CNS)-specific Tak1 deletion upregulated SREBP-target lipogenic genes and blocked ER stress in the hypothalamus. Furthermore, CNS-specific Tak1 deletion prevented ER-stress-induced hypothalamic leptin resistance and hyperphagic obesity under a high-fat diet (HFD). Thus, TAK1 is a crucial regulator of ER stress in vivo, which could be a target for alleviation of ER stress and its associated disease conditions.