312 research outputs found
Exploring the endocannabinoidome in genetically obese (ob/ob) and diabetic (db/db) mice: Links with inflammation and gut microbiota
Background: Obesity and type 2 diabetes are two interrelated metabolic disorders characterized by insulin resistance and a mild chronic inflammatory state. We previously observed that leptin (ob/ob) and leptin receptor (db/db) knockout mice display a distinct inflammatory tone in the liver and adipose tissue. The present study aimed at investigating whether alterations in these tissues of the molecules belonging to the endocannabinoidome (eCBome), an extension of the endocannabinoid (eCB) signaling system, whose functions are important in the context of metabolic disorders and inflammation, could reflect their different inflammatory phenotypes. Results: The basal eCBome lipid and gene expression profiles, measured by targeted lipidomics and qPCR transcriptomics, respectively, in the liver and subcutaneous or visceral adipose tissues, highlighted a differentially altered eCBome tone, which may explain the impaired hepatic function and more pronounced liver inflammation remarked in the ob/ob mice, as well as the more pronounced inflammatory state observed in the subcutaneous adipose tissue of db/db mice. In particular, the levels of linoleic acid-derived endocannabinoid-like molecules, of one of their 12-lipoxygenase metabolites and of Trpv2 expression, were always altered in tissues exhibiting the highest inflammation. Correlation studies suggested the possible interactions with some gut microbiota bacterial taxa, whose respective absolute abundances were significantly different between ob/ob and the db/db mice. Conclusions: The present findings emphasize the possibility that bioactive lipids and the respective receptors and enzymes belonging to the eCBome may sustain the tissue-dependent inflammatory state that characterizes obesity and diabetes, possibly in relation with gut microbiome alterations
A Many-body Problem with Point Interactions on Two Dimensional Manifolds
A non-perturbative renormalization of a many-body problem, where
non-relativistic bosons living on a two dimensional Riemannian manifold
interact with each other via the two-body Dirac delta potential, is given by
the help of the heat kernel defined on the manifold. After this renormalization
procedure, the resolvent becomes a well-defined operator expressed in terms of
an operator (called principal operator) which includes all the information
about the spectrum. Then, the ground state energy is found in the mean field
approximation and we prove that it grows exponentially with the number of
bosons. The renormalization group equation (or Callan-Symanzik equation) for
the principal operator of the model is derived and the function is
exactly calculated for the general case, which includes all particle numbers.Comment: 28 pages; typos are corrected, three figures are adde
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Phase II study of olaparib in patients with refractory Ewing sarcoma following failure of standard chemotherapy
Background: Preclinical studies have documented antitumor activity of PARP inhibition both in vitro and in vivo, against Ewing sarcoma cells. This study aimed to translate that observation into a clinical trial to assess the efficacy and tolerability of olaparib, a PARP inhibitor, in patients with advanced Ewing sarcoma (EWS) progressing after prior chemotherapy. Methods: In this nonrandomized phase II trial, adult participants with radiographically measureable metastatic EWS received olaparib tablets, 400 mg orally twice daily, until disease progression or drug intolerance. Tumor measurements were determined by CT or MRI at 6 and 12 weeks after starting olaparib administration, and then every 8 weeks thereafter. Tumor response determinations were made according to RECIST 1.1, and adverse event determinations were made according to CTCAE, version 4.0. A total of 22 participants were planned to be enrolled using a conventional 2-step phase II study design. If no objective responses were observed after 12 participants had been followed for at least 3 months, further accrual would be stopped. Results: 12 participants were enrolled, and all were evaluable. There were no objective responses (PR/CR), 4 SD (duration 10.9, 11.4, 11.9, and 17.9 wks), and 8 PD as best response. Of the SD, 2 had minor responses (−9% and −11.7% by RECIST 1.1). The median time to disease progression was 5.7 weeks. Further enrollment was therefore discontinued. No significant or unexpected toxicities were observed with olaparib, with only a single case each of grade 3 anemia and grade 3 thrombocytopenia observed. Conclusions: This study is the first report of a prospective phase II trial to evaluate the safety and efficacy of a PARP inhibitor in patients with advanced Ewing sarcoma after failure of standard chemotherapy. Olaparib administration was safe and well tolerated when administered to this small heavily pre-treated cohort at the 400 mg BID dose, although the median duration of dosing was for only 5.7 weeks. No significant responses or durable disease control was seen, and the short average interval to disease progression underscores the aggressiveness of this disease. Other studies to combine cytotoxic chemotherapy with PARP inhibition in EWS are actively ongoing. Trial registration ClinicalTrials.gov Identifier: NCT0158354
The opposite of Dante's hell? The transfer of ideas for social housing at international congresses in the 1850s–1860s
With the advent of industrialization, the question of developing adequate housing for the emergent working classes became more pressing than before. Moreover, the problem of unhygienic houses in industrial cities did not stop at the borders of a particular nation-state; sometimes literally as pandemic diseases spread out 'transnationally'. It is not a coincidence that in the nineteenth century the number of international congresses on hygiene and social topics expanded substantially. However, the historiography about social policy in general and social housing in particular, has often focused on individual cases because of the different pace of industrial and urban development and is thus dominated by national perspectives. In this paper, I elaborate on transnational exchange processes and local adaptations and transformations. I focus on the transfer of the housing model of SOMCO in Mulhouse, (a French house building association) during social international congresses. I examine whether cross-national networking enabled and facilitated the implementation of ideas on the local scale. I will elaborate on the transmission and the local adaptation of the Mulhouse-model in Belgium. Convergences, divergences, and different factors that influenced the local transformations (personal choice, political situation, socioeconomic circumstances) will be taken into accoun
Induced pseudoscalar coupling of the proton weak interaction
The induced pseudoscalar coupling is the least well known of the weak
coupling constants of the proton's charged--current interaction. Its size is
dictated by chiral symmetry arguments, and its measurement represents an
important test of quantum chromodynamics at low energies. During the past
decade a large body of new data relevant to the coupling has been
accumulated. This data includes measurements of radiative and non radiative
muon capture on targets ranging from hydrogen and few--nucleon systems to
complex nuclei. Herein the authors review the theoretical underpinnings of
, the experimental studies of , and the procedures and uncertainties
in extracting the coupling from data. Current puzzles are highlighted and
future opportunities are discussed.Comment: 58 pages, Latex, Revtex4, prepared for Reviews of Modern Physic
A simple blood test expedites the diagnosis of GLUT1 deficiency syndrome
published_or_final_versio
Dendritic cells loaded with killed breast cancer cells induce differentiation of tumor-specific cytotoxic T lymphocytes
BACKGROUND: Early clinical trials, mostly in the setting of melanoma, have shown that dendritic cells (DCs) expressing tumor antigens induce some immune responses and some clinical responses. A major difficulty is the extension to other tumors, such as breast carcinoma, for which few defined tumor-associated antigens are available. We have demonstrated, using both prostate carcinoma and melanoma as model systems, that DCs loaded with killed allogeneic tumor cell lines can induce CD8(+ )T cells to differentiate into cytotoxic T lymphocytes (CTLs) specific for shared tumor antigens. METHODS: The present study was designed to determine whether DCs would capture killed breast cancer cells and present their antigens to autologous CD4(+ )and CD8(+ )T cells. RESULTS: We show that killed breast cancer cells are captured by immature DCs that, after induced maturation, can efficiently present MHC class I and class II peptides to CD8(+ )and CD4(+ )T lymphocytes. The elicited CTLs are able to kill the target cells without a need for pretreatment with interferon gamma. CTLs can be obtained by culturing the DCs loaded with killed breast cancer cells with unseparated peripheral blood lymphocytes, indicating that the DCs can overcome any potential inhibitory effects of breast cancer cells. CONCLUSION: Loading DCs with killed breast cancer cells may be considered a novel approach to breast cancer immunotherapy and to identification of shared breast cancer antigens
Twenty-Five Years of Convoluted Health Reforms in Mexico
Núria Homedes and Antonio Ugalde discuss 25 years of reform to the Mexican health care system and argue that although costs and accessibility have increased, health inequities, efficiency, productivity, and quality of care have not improved
The changing culture of silviculture
Changing climates are altering the structural and functional components of forest ecosystems at an unprecedented rate. Simultaneously, we are seeing a diversification of public expectations on the broader sustainable use of forest resources beyond timber production. As a result, the science and art of silviculture needs to adapt to these changing realities. In this piece, we argue that silviculturists are gradually shifting from the application of empirically derived silvicultural scenarios to new sets of approaches, methods and practices, a process that calls for broadening our conception of silviculture as a scientific discipline. We propose a holistic view of silviculture revolving around three key themes: observe, anticipate and adapt. In observe, we present how recent advances in remote sensing now enable silviculturists to observe forest structural, compositional and functional attributes in near-real-time, which in turn facilitates the deployment of efficient, targeted silvicultural measures in practice that are adapted to rapidly changing constraints. In anticipate, we highlight the importance of developing state-of-the-art models designed to take into account the effects of changing environmental conditions on forest growth and dynamics. In adapt, we discuss the need to provide spatially explicit guidance for the implementation of adaptive silvicultural actions that are efficient, cost-effective and socially acceptable. We conclude by presenting key steps towards the development of new tools and practical knowledge that will ensure meeting societal demands in rapidly changing environmental conditions. We classify these actions into three main categories: reexamining existing silvicultural trials to identify key stand attributes associated with the resistance and resilience of forests to multiple stressors, developing technological workflows and infrastructures to allow for continuous forest inventory updating frameworks, and implementing bold, innovative silvicultural trials in consultation with the relevant communities where a range of adaptive silvicultural strategies are tested. In this holistic perspective, silviculture can be defined as the science of observing forest condition and anticipating its development to apply tending and regeneration treatments adapted to a multiplicity of desired outcomes in rapidly changing realities
The changing culture of silviculture
Changing climates are altering the structural and functional components of forest ecosystems at an unprecedented rate. Simultaneously, we are seeing a diversification of public expectations on the broader sustainable use of forest resources beyond timber production. As a result, the science and art of silviculture needs to adapt to these changing realities. In this piece, we argue that silviculturists are gradually shifting from the application of empirically derived silvicultural scenarios to new sets of approaches, methods and practices, a process that calls for broadening our conception of silviculture as a scientific discipline. We propose a holistic view of silviculture revolving around three key themes: observe, anticipate and adapt. In observe, we present how recent advances in remote sensing now enable silviculturists to observe forest structural, compositional and functional attributes in near-real-time, which in turn facilitates the deployment of efficient, targeted silvicultural measures in practice that are adapted to rapidly changing constraints. In anticipate, we highlight the importance of developing state-of-the-art models designed to take into account the effects of changing environmental conditions on forest growth and dynamics. In adapt, we discuss the need to provide spatially explicit guidance for the implementation of adaptive silvicultural actions that are efficient, cost-effective and socially acceptable. We conclude by presenting key steps towards the development of new tools and practical knowledge that will ensure meeting societal demands in rapidly changing environmental conditions. We classify these actions into three main categories: re-examining existing silvicultural trials to identify key stand attributes associated with the resistance and resilience of forests to multiple stressors, developing technological workflows and infrastructures to allow for continuous forest inventory updating frameworks, and implementing bold, innovative silvicultural trials in consultation with the relevant communities where a range of adaptive silvicultural strategies are tested. In this holistic perspective, silviculture can be defined as the science of observing forest condition and anticipating its development to apply tending and regeneration treatments adapted to a multiplicity of desired outcomes in rapidly changing realities
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