4,087 research outputs found
Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma: A Physiopathologic and Pharmacologic Review
No full textPancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a poor prognosis and inadequate response to treatment. Many factors contribute to this therapeutic failure: lack of symptoms until the tumor reaches an advanced stage, leading to late diagnosis; early lymphatic and hematic spread; advanced age of patients; important development of a pro-tumoral and hyperfibrotic stroma; high genetic and metabolic heterogeneity; poor vascular supply; a highly acidic matrix; extreme hypoxia; and early development of resistance to the available therapeutic options. In most cases, the disease is silent for a long time, andwhen it does become symptomatic, it is too late for ablative surgery; this is one of the major reasons explaining the short survival associated with the disease. Even when surgery is possible, relapsesare frequent, andthe causes of this devastating picture are the low efficacy ofand early resistance to all known chemotherapeutic treatments. Thus, it is imperative to analyze the roots of this resistance in order to improve the benefits of therapy. PDAC chemoresistance is the final product of different, but to some extent, interconnected factors. Surgery, being the most adequate treatment for pancreatic cancer and the only one that in a few selected cases can achieve longer survival, is only possible in less than 20% of patients. Thus, the treatment burden relies on chemotherapy in mostcases. While the FOLFIRINOX scheme has a slightly longer overall survival, it also produces many more adverse eventsso that gemcitabine is still considered the first choice for treatment, especially in combination with other compounds/agents. This review discusses the multiple causes of gemcitabine resistance in PDAC
ko-ax photo [Selected by Tate Curator of Photography, Simon Baker]
No full textko-ax photo was an open submission competition selected by Simon Baker (Curator of Photography, Tate), Sue Steward (Photography critic, Telegraph, Observer, Guardian, BBC) and John Gill (Curator Brighton Photo Biennial and Founder Photoworks). The 10 artists selected all presented fascinating artworks that conceal narratives and ask questions of the viewer. Questions of beauty, family, decay and fantasy were all explored across over 50 works.</p
The Role of Sodium Hydrogen Exchanger 1 in Dysregulation of Proton Dynamics and Reprogramming of Cancer Metabolism as a Sequela.
No full textCancer cells have an unusual regulation of hydrogen ion dynamics that are driven by poor vascularity perfusion, regional hypoxia, and increased glycolysis. All these forces synergize/orchestrate together to create extracellular acidity and intracellular alkalinity. Precisely, they lead to extracellular pH (pHe) values as low as 6.2 and intracellular pH values as high as 8. This unique pH gradient (∆pHi to ∆pHe) across the cell membrane increases as the tumor progresses, and is markedly displaced from the electrochemical equilibrium of protons. These unusual pH dynamics influence cancer cell biology, including proliferation, metastasis, and metabolic adaptation. Warburg metabolism with increased glycolysis, even in the presence of Oxygen with the subsequent reduction in Krebs’ cycle, is a common feature of most cancers. This metabolic reprogramming confers evolutionary advantages to cancer cells by enhancing their resistance to hypoxia, to chemotherapy or radiotherapy, allowing rapid production of biological building blocks that support cellular proliferation, and shielding against damaging mitochondrial free radicals. In this article, we highlight the interconnected roles of dysregulated pH dynamics in cancer initiation, progression, adaptation, and in determining the programming and re-programming of tumor cell metabolism
The people behind the papers – Jason Ko and Daniel Lobo
No full textPlanarians grow when they are fed and shrink during periods of starvation. However, it is unclear how they maintain appropriate body proportions as their size changes. A new paper in Development investigates the differences between growth and shrinkage dynamics and builds a mathematical model to explore the mechanisms underpinning these two processes. To learn more about the story behind the paper, we caught up with first author, Jason Ko, and corresponding author, Daniel Lobo, Associate Professor at the University of Maryland.https://doi.org/10.1242/dev.20298
Organizational Learning and Marketing Capability Development: A Study of Charity Retailing Operation of British Social Enterprises
No full textSocial enterprise is a hybrid form of profit- and social benefit-seeking organization whereby traditional nonprofit organizations pursue both their social mission and business opportunities. To embrace this new strategic direction shift, the nonprofit organizations need to develop new competences that will enable them to respond to the changes in the business model. The article investigates the learning mechanisms through which social enterprises develop a marketing capability to deploy their resources in the marketplace as the drivers of competitive advantage in their commercial practice. We study eight cases of UK-based charity retailers, in order to address the role of knowledge accumulation, articulation and codification process in the evolution of marketing capability development. We identify, amongst other things that the critical process of organizational learning for social enterprise is to transfer the experience into organization specific knowledge under the social aspects of constraints
Ko au te whenua, te whenua ko au – I am the land, the land is me: An autoethnographic investigation of a secondary school teacher’s experience seeking to enrich learning in outdoor education for Māori students.
No full textThis thesis is my story as an outdoor educator, as a researcher, and a co-participant reflecting on my own actions and experiences as well as those of my students. In this autoethnography I share my revelations and tensions in my role as an outdoor education teacher seeking to enrich the experiences of Māori students. Māori culture and history have largely been ignored in the outdoor education classrooms and environments of Aotearoa New Zealand. After teaching the subject for ten years I didn’t perceive that I was perpetuating the same invisibility in my own outdoor education course. Over this time a number of questions that had fermented at the back of my mind came to the fore; ‘why are so few Māori students opting to take outdoor education as a senior secondary school subject?’ and ‘how can I make the subject of outdoor education more desirable and appealing to Māori?’ A place-responsive approach incorporates and values traditional ways of learning through the notion of place and the stories attached to them. The cultural context of learning about and through place has the potential to provide learning opportunities that are relevant and meaningful to all learners but particularly Māori. Place-responsive pedagogies allow outdoor educators to create an environment where language, knowledge, culture and values are normal, valid and legitimate – contexts where Māori students can be themselves. Through this research I have found that the implementation of a place responsive approach has had significant implications for Year twelve outdoor education at Mount Maunganui College. The improvement in Māori student achievement and numbers selecting the subject have been affirming.
Ko au te whenua, te whenua ko au – I am the land, the land is m
Glycolysis, Tumor Metabolism, Cancer Growth and Dissemination. A new pH-based Etiopathogenic Perspective and Therapeutic Approach to an old Cancer Question
No full textCancer cells acquire an unusual glycolytic behavior to a large extent relative to an intracellular alkaline (pHi). This effect is part of the metabolic alterations found in most, if not all, cancer cells to deal with unfavorable conditions, mainly hypoxia and low nutrient supply, in order to preserve its evolutionary trajectory with the production of lactate after ten steps of glycolysis. Thus, cancer cells reprogram their cellular metabolism in a way that gives them their evolutionary and thermodynamic advantage. Tumors exist within a highly heterogeneous microenvironment, and cancer cells survive within any of the different habitats that lie within tumors thanks to the overexpression of different membrane-bound proton transporters. This creates a highly abnormal and selective proton reversal in cancer cells and tissues that is involved in local cancer growth and in the metastatic process. Because of this environmental heterogeneity, cancer cells within one part of the tumor may have a different genotype and phenotype than within another part. This phenomenon has frustrated the potential of single-target therapy of this type of reductionist therapeutic approach over the last decades. Here, we present a detailed biochemical framework on every step of tumor glycolysis and then propose a new paradigm and therapeutic strategy based upon the dynamics of the hydrogen ion in cancer cells and tissues in order to overcome the old paradigm of one enzyme-one target approach to cancer treatment. Finally, a new and integral explanation of the Warburg effect is advanced
KNOWLEDGE ACCUMULATION IN ASIAN PUBLIC ADMINISTRATION RESEARCH: A CRITICAL REVIEW
No full textGiven the growing controversy over the relevance of Anglo-Saxon style public administration to developing countries and a greater demand for more context-relevant theories of public administration in Asia, we should expect that Asian scholars achieve a certain level of knowledge growth in line with this controversy and demand. On the basis of the review of 8810 articles published in nine major international journals during 1990-2011, the author found that the number of articles on Asian public administration is very small, and there is no strong pattern of growth in this regard. In addition, there are very few studies adopting a comparative approach covering multiple Asian countries. Copyright (c) 2013 John Wiley & Sons, Ltd.N
Book-in-Common Conversation - Lisa Ko
No full textLisa Ko, author of The Leavers, will speak about her book and writing career in a virtual presentation on Tuesday, March 23 at 7 pm. Lisa Ko is the recipient of the 2016 PEN/Bellwether Prize and the 2017 Barnes and Noble Discover Great New Writers Award. The Leavers was also named best book of the year by NPR
Differentially altered social dominance- and cooperative-like behaviors in Shank2- and Shank3-mutant mice
No full textBackground: Recent progress in genomics has contributed to the identification of a large number of autism spectrum disorder (ASD) risk genes, many of which encode synaptic proteins. Our understanding of ASDs has advanced rapidly, partly owing to the development of numerous animal models. Extensive characterizations using a variety of behavioral batteries that analyze social behaviors have shown that a subset of engineered mice that model mutations in genes encoding Shanks, a family of excitatory postsynaptic scaffolding proteins, exhibit autism-like behaviors. Although these behavioral assays have been useful in identifying deficits in simple social behaviors, alterations in complex social behaviors remain largely untested. Methods: Two syndromic ASD mouse models—Shank2 constitutive knockout [KO] mice and Shank3 constitutive KO mice—were examined for alterations in social dominance and social cooperative behaviors using tube tests and automated cooperation tests. Upon naïve and salient behavioral experience, expression levels of c-Fos were analyzed as a proxy for neural activity across diverse brain areas, including the medial prefrontal cortex (mPFC) and a number of subcortical structures. Findings: As previously reported, Shank2 KO mice showed deficits in sociability, with intact social recognition memory, whereas Shank3 KO mice displayed no overt phenotypes. Strikingly, the two Shank KO mouse models exhibited diametrically opposed alterations in social dominance and cooperative behaviors. After a specific social behavioral experience, Shank mutant mice exhibited distinct changes in number of c-Fos+ neurons in the number of cortical and subcortical brain regions. Conclusions: Our results underscore the heterogeneity of social behavioral alterations in different ASD mouse models and highlight the utility of testing complex social behaviors in validating neurodevelopmental and neuropsychiatric disorder models. In addition, neural activities at distinct brain regions are likely collectively involved in eliciting complex social behaviors, which are differentially altered in ASD mouse models. © 2020, The Author(s).1
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