Showing papers by "University of Louisville published in 2012"
Daniel J. Klionsky1, Fábio Camargo Abdalla2, Hagai Abeliovich3, Robert T. Abraham4 +1284 more•Institutions (463)
TL;DR: These guidelines are presented for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
4,316 citations
Johns Hopkins University1, University of Alabama at Birmingham2, University of Birmingham3, Oklahoma Medical Research Foundation4, Laval University5, University of Manchester6, University College London7, University of California, Los Angeles8, Lund University9, Northwestern University10, Hanyang University11, Dalhousie University12, University of Toronto13, McGill University14, North Shore-LIJ Health System15, Allegheny General Hospital16, University of California, San Diego17, University of Pennsylvania18, Monklands Hospital19, University of the Basque Country20, St Thomas' Hospital21, University of Copenhagen22, New York University23, University of North Carolina at Chapel Hill24, Karolinska Institutet25, SUNY Downstate Medical Center26, University of Manitoba27, Wake Forest University28, University of Louisville29, Emory University30, Istanbul University31, Medical University of South Carolina32, University of Texas Health Science Center at San Antonio33, Cedars-Sinai Medical Center34, University of Maryland, Baltimore35
TL;DR: The Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) classification criteria in order to improve clinical relevance, meet stringent methodology requirements, and incorporate new knowledge regarding the immunology of SLE.
Abstract: Objective The Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) classification criteria in order to improve clinical relevance, meet stringent methodology requirements, and incorporate new knowledge regarding the immunology of SLE. Methods The classification criteria were derived from a set of 702 expert-rated patient scenarios. Recursive partitioning was used to derive an initial rule that was simplified and refined based on SLICC physician consensus. The SLICC group validated the classification criteria in a new validation sample of 690 new expert-rated patient scenarios. Results Seventeen criteria were identified. In the derivation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (49 versus 70; P = 0.0082) and had greater sensitivity (94% versus 86%; P < 0.0001) and equal specificity (92% versus 93%; P = 0.39). In the validation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (62 versus 74; P = 0.24) and had greater sensitivity (97% versus 83%; P < 0.0001) but lower specificity (84% versus 96%; P < 0.0001). Conclusion The new SLICC classification criteria performed well in a large set of patient scenarios rated by experts. According to the SLICC rule for the classification of SLE, the patient must satisfy at least 4 criteria, including at least one clinical criterion and one immunologic criterion OR the patient must have biopsy-proven lupus nephritis in the presence of antinuclear antibodies or antidouble-stranded DNA antibodies. (Less)
3,609 citations
University of Louisville1, Rush University Medical Center2, University of North Carolina at Chapel Hill3, University of Amsterdam4, University of Pennsylvania5, Mayo Clinic6, University of Göttingen7, Columbia University Medical Center8, University of Cambridge9, Stavanger University Hospital10, Autonomous University of Barcelona11, Ikerbasque12, Newcastle University13, Istanbul University14
TL;DR: These diagnostic criteria will support future research efforts to identify at the earliest stage those PD patients at increased risk of progressive cognitive decline and dementia who may benefit from clinical interventions at a predementia stage.
Abstract: Mild cognitive impairment is common in nondemented Parkinson's disease (PD) patients and may be a harbinger of dementia. In view of its importance, the Movement Disorder Society commissioned a task force to delineate diagnostic criteria for mild cognitive impairment in PD. The proposed diagnostic criteria are based on a literature review and expert consensus. This article provides guidelines to characterize the clinical syndrome and methods for its diagnosis. The criteria will require validation, and possibly refinement, as additional research improves our understanding of the epidemiology, presentation, neurobiology, assessment, and long-term course of this clinical syndrome. These diagnostic criteria will support future research efforts to identify at the earliest stage those PD patients at increased risk of progressive cognitive decline and dementia who may benefit from clinical interventions at a predementia stage.
1,867 citations
La Trobe University1, Harvard University2, German Cancer Research Center3, Yale University4, Morehouse School of Medicine5, Autonomous University of Barcelona6, University of Massachusetts Medical School7, Semmelweis University8, Cardiff University9, Ikerbasque10, Karolinska Institutet11, Pohang University of Science and Technology12, Allahabad University13, Ghent University14, University of Melbourne15, London Metropolitan University16, Erasmus University Rotterdam17, University of Mainz18, National University of Singapore19, University of Oslo20, University of Gothenburg21, University of Valencia22, Umeå University23, University of Freiburg24, University of Amsterdam25, Utrecht University26, Johns Hopkins University27, Mayo Clinic28, Ohio State University29, University of Cambridge30, University of Zurich31, Curie Institute32, Michigan State University33, Autonomous University of Madrid34, University of Helsinki35, Aalborg University36, University of Louisville37, Carlos III Health Institute38, Centre national de la recherche scientifique39, Heidelberg University40
TL;DR: Vesiclepedia is a community-annotated compendium of molecular data on extracellular vesicles that aims to provide a single authoritative source for information on vesicle structure and function.
Abstract: Extracellular vesicles (EVs) are membraneous vesicles released by a variety of cells into their microenvironment. Recent studies have elucidated the role of EVs in intercellular communication, pathogenesis, drug, vaccine and gene-vector delivery, and as possible reservoirs of biomarkers. These findings have generated immense interest, along with an exponential increase in molecular data pertaining to EVs. Here, we describe Vesiclepedia, a manually curated compendium of molecular data (lipid, RNA, and protein) identified in different classes of EVs from more than 300 independent studies published over the past several years. Even though databases are indispensable resources for the scientific community, recent studies have shown that more than 50% of the databases are not regularly updated. In addition, more than 20% of the database links are inactive. To prevent such database and link decay, we have initiated a continuous community annotation project with the active involvement of EV researchers. The EV research community can set a gold standard in data sharing with Vesiclepedia, which could evolve as a primary resource for the field.
1,146 citations
TL;DR: The metabolic responses of a MYC-inducible human Burkitt lymphoma model P493 cell line to aerobic and hypoxic conditions, and to glucose deprivation, are determined using stable isotope-resolved metabolomics to demonstrate an alternative energy-generating glutaminolysis pathway involving a glucose-independent TCA cycle.
915 citations
TL;DR: A new model of pathogenesis according to which periodontitis is initiated by a synergistic and dysbiotic microbial community rather than by select 'periopathogens', such as the 'red complex' is described.
Abstract: Recent advancements in the periodontal research field are consistent with a new model of pathogenesis according to which periodontitis is initiated by a synergistic and dysbiotic microbial community rather than by select 'periopathogens', such as the 'red complex'. In this polymicrobial synergy, different members or specific gene combinations within the community fulfill distinct roles that converge to shape and stabilize a disease-provoking microbiota. One of the core requirements for a potentially pathogenic community to arise involves the capacity of certain species, termed 'keystone pathogens', to modulate the host response in ways that impair immune surveillance and tip the balance from homeostasis to dysbiosis. Keystone pathogens also elevate the virulence of the entire microbial community through interactive communication with accessory pathogens. Other important core functions for pathogenicity require the expression of diverse molecules (e.g. appropriate adhesins, cognate receptors, proteolytic enzymes and proinflammatory surface structures/ligands), which in combination act as community virulence factors to nutritionally sustain a heterotypic, compatible and proinflammatory microbial community that elicits a non-resolving and tissue-destructive host response. On the basis of the fundamental concepts underlying this model of periodontal pathogenesis, that is, polymicrobial synergy and dysbiosis, we term it the PSD model.
841 citations
TL;DR: In this article, the BaBar data sample was used to investigate the sensitivity of BaBar ratios to new physics contributions in the form of a charged Higgs boson in the type II two-Higgs doublet model.
Abstract: Based on the full BaBar data sample, we report improved measurements of the ratios R(D(*)) = B(B -> D(*) Tau Nu)/B(B -> D(*) l Nu), where l is either e or mu. These ratios are sensitive to new physics contributions in the form of a charged Higgs boson. We measure R(D) = 0.440 +- 0.058 +- 0.042 and R(D*) = 0.332 +- 0.024 +- 0.018, which exceed the Standard Model expectations by 2.0 sigma and 2.7 sigma, respectively. Taken together, our results disagree with these expectations at the 3.4 sigma level. This excess cannot be explained by a charged Higgs boson in the type II two-Higgs-doublet model. We also report the observation of the decay B -> D Tau Nu, with a significance of 6.8 sigma.
660 citations
TL;DR: The interesting duality of c-Myc effects places it in the mainstream of transformational changes and gives it a very important role in regulating the “transformed phenotype.”
Abstract: The processes of cellular growth regulation and cellular metabolism are closely interrelated. The c-Myc oncogene is a "master regulator" which controls many aspects of both of these processes. The metabolic changes which occur in transformed cells, many of which are driven by c-Myc overexpression, are necessary to support the increased need for nucleic acids, proteins, and lipids necessary for rapid cellular proliferation. At the same time, c-Myc overexpression results in coordinated changes in level of expression of gene families which result in increased cellular proliferation. This interesting duality of c-Myc effects places it in the mainstream of transformational changes and gives it a very important role in regulating the "transformed phenotype." The effects induced by c-Myc can occur either as a "primary oncogene" which is activated by amplification or translocation or as a downstream effect of other activated oncogenes. In either case, it appears that c-Myc plays a central role in sustaining the changes which occur with transformation. Although efforts to use c-Myc as a therapeutic target have been quite frustrating, it appears that this may change in the next few years.
634 citations
TL;DR: A small, intrapericardially positioned, continuous-flow, centrifugal pump was noninferior to contemporaneously implanted, commercially available ventricular assist devices and functional capacity and quality of life improved markedly, and the adverse event profile was favorable.
Abstract: Background—Contemporary ventricular assist device therapy results in a high rate of successful heart transplantation but is associated with bleeding, infections, and other complications. Further reductions in pump size, centrifugal design, and intrapericardial positioning may reduce complications and improve outcomes. Methods and Results—We studied a small, intrapericardially positioned, continuous-flow centrifugal pump in patients requiring an implanted ventricular assist device as a bridge to heart transplantation. The course of investigational pump recipients was compared with that of patients implanted contemporaneously with commercially available devices. The primary outcome, success, was defined as survival on the originally implanted device, transplantation, or explantation for ventricular recovery at 180 days and was evaluated for both noninferiority and superiority. Secondary outcomes included a comparison of survival between groups and functional and quality-of-life outcomes and adverse events i...
601 citations
TL;DR: The results suggest that the metabolic profiles of tumors are likely to depend on both the genotype and tissue of origin and have implications regarding the design of therapies targeting tumor metabolism.
554 citations
University of Washington1, Cleveland Clinic2, University of Pittsburgh3, Children's Memorial Hospital4, North York General Hospital5, University of Louisville6, Sacred Heart Hospital7, Boston Children's Hospital8, Rutgers University9, Dalhousie University10, University of Michigan11, Group Health Cooperative12, Izaak Walton Killam Health Centre13, Rush University Medical Center14, State University of New York Upstate Medical University15, Memorial Hospital of South Bend16, Rhode Island Hospital17, Carolinas Medical Center18, Nemours Foundation19, University of New Mexico20
TL;DR: It is found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo.
Abstract: Background Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management. Methods We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization. Results Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copy-number variant...
07 Oct 2012
TL;DR: This work extracts semi-local features called random occupancy pattern ROP features, which employ a novel sampling scheme that effectively explores an extremely large sampling space and utilizes a sparse coding approach to robustly encode these features.
Abstract: We study the problem of action recognition from depth sequences captured by depth cameras, where noise and occlusion are common problems because they are captured with a single commodity camera. In order to deal with these issues, we extract semi-local features called random occupancy pattern ROP features, which employ a novel sampling scheme that effectively explores an extremely large sampling space. We also utilize a sparse coding approach to robustly encode these features. The proposed approach does not require careful parameter tuning. Its training is very fast due to the use of the high-dimensional integral image, and it is robust to the occlusions. Our technique is evaluated on two datasets captured by commodity depth cameras: an action dataset and a hand gesture dataset. Our classification results are superior to those obtained by the state of the art approaches on both datasets.
Tokyo Institute of Technology1, Kogakuin University2, Goddard Space Flight Center3, Osaka University4, University of Louisville5, University of Cincinnati6, Space Science Institute7, University of Hawaii8, The Aerospace Corporation9, Valparaiso University10, Subaru11, Academia Sinica12, Ibaraki University13, Kanagawa University14, Nagoya University15, Princeton University16, University of Nice Sophia Antipolis17, Max Planck Society18, College of Charleston19, University of Tokyo20, Kyoto University21, Graduate University for Advanced Studies22, Instituto Nacional de Técnica Aeroespacial23, California Institute of Technology24, University of Amsterdam25, Institute for the Physics and Mathematics of the Universe26, Hokkaido University27, University of Washington28, Tohoku University29
TL;DR: In this article, high-resolution, H-band, imaging observations, collected with Subaru/HiCIAO, of the scattered light from the transitional disk around SAO 206462 (HD 135344B), reveal the presence of scattered light components as close as 0.2 (approx 28 AU).
Abstract: We present high-resolution, H-band, imaging observations, collected with Subaru/HiCIAO, of the scattered light from the transitional disk around SAO 206462 (HD 135344B). Although previous sub-mm imagery suggested the existence of the dust-depleted cavity at r approximates 46 AU, our observations reveal the presence of scattered light components as close as 0".2 (approx 28 AU) from the star. Moreover, we have discovered two small-scale spiral structures lying within 0".5 (approx 70 AU). We present models for the spiral structures using the spiral density wave theory, and derive a disk aspect ratio of h approx 0.1, which is consistent with previous sub-mm observations. This model can potentially give estimates of the temperature and rotation profiles of the disk based on dynamical processes, independently from sub-mm observations. It also predicts the evolution of the spiral structures, which can be observable on timescales of 10-20 years, providing conclusive tests of the model. While we cannot uniquely identify the origin of these spirals, planets embedded in the disk may be capable of exciting the observed morphology. Assuming that this is the case, we can make predictions on the locations and, possibly, the masses of the unseen planets. Such planets may be detected by future multi-wavelengths observations.
TL;DR: EMT-ATFs have been shown to cooperate in oncogenic transformation, regulate cancer cell stemness, override safeguard programs against cancer like apoptosis and senescence, determine resistance to chemotherapy and promote tumor angiogenesis.
Abstract: Cancer is a complex multistep process involving genetic and epigenetic changes that eventually result in the activation of oncogenic pathways and/or inactivation of tumor suppressor signals. During cancer progression, cancer cells acquire a number of hallmarks that promote tumor growth and invasion. A crucial mechanism by which carcinoma cells enhance their invasive capacity is the dissolution of intercellular adhesions and the acquisition of a more motile mesenchymal phenotype as part of an epithelial-to-mesenchymal transition (EMT). Although many transcription factors can trigger it, the full molecular reprogramming occurring during an EMT is mainly orchestrated by three major groups of transcription factors: the ZEB, Snail and Twist families. Upregulated expression of these EMT-activating transcription factors (EMT-ATFs) promotes tumor invasiveness in cell lines and xenograft mice models and has been associated with poor clinical prognosis in human cancers. Evidence accumulated in the last few years indicates that EMT-ATFs also regulate an expanding set of cancer cell capabilities beyond tumor invasion. Thus, EMT-ATFs have been shown to cooperate in oncogenic transformation, regulate cancer cell stemness, override safeguard programs against cancer like apoptosis and senescence, determine resistance to chemotherapy and promote tumor angiogenesis. This article reviews the expanding portfolio of functions played by EMT-ATFs in cancer progression.
TL;DR: Isolation of CSCs from cardiac tissue obtained in the operating room is feasible and does not alter practices during CABG surgery, and interim cardiac magnetic resonance results show that CSC infusion produces a striking improvement in both global and regional LV function, a reduction in infarct size, and an increase in viable tissue that persist at least 1 year and are consistent with cardiac regeneration.
Abstract: Background—SCIPIO is a first-in-human, phase 1, randomized, open-label trial of autologous c-kit+ cardiac stem cells (CSCs) in patients with heart failure of ischemic etiology undergoing coronary artery bypass grafting (CABG). In the present study, we report the surgical aspects and interim cardiac magnetic resonance (CMR) results. Methods and Results—A total of 33 patients (20 CSC-treated and 13 control subjects) met final eligibility criteria and were enrolled in SCIPIO. CSCs were isolated from the right atrial appendage harvested and processed during surgery. Harvesting did not affect cardiopulmonary bypass, cross-clamp, or surgical times. In CSC-treated patients, CMR showed a marked increase in both LVEF (from 27.5±1.6% to 35.1±2.4% [P=0.004, n=8] and 41.2±4.5% [P=0.013, n=5] at 4 and 12 months after CSC infusion, respectively) and regional EF in the CSC-infused territory. Infarct size (late gadolinium enhancement) decreased after CSC infusion (by manual delineation: −6.9±1.5 g [−22.7%] at 4 months [P...
TL;DR: Mixed chimerism and tolerance without the negative side effects of GVHD or engraftment syndrome is reported in a phase 2 clinical trial of combined kidney and hematopoietic transplantation and is suggested to free some patients from the difficulties associated with lifelong immunosuppression and add transplantation as a viable option for patients for whom no matched donors exist.
Abstract: The toxicity of chronic immunosuppressive agents required for organ transplant maintenance has prompted investigators to pursue approaches to induce immune tolerance. We developed an approach using a bioengineered mobilized cellular product enriched for hematopoietic stem cells (HSCs) and tolerogenic graft facilitating cells (FCs) combined with nonmyeloablative conditioning; this approach resulted in engraftment, durable chimerism, and tolerance induction in recipients with highly mismatched related and unrelated donors. Eight recipients of human leukocyte antigen (HLA)-mismatched kidney and FC/HSC transplants underwent conditioning with fludarabine, 200-centigray total body irradiation, and cyclophosphamide followed by posttransplant immunosuppression with tacrolimus and mycophenolate mofetil. Subjects ranged in age from 29 to 56 years. HLA match ranged from five of six loci with related donors to one of six loci with unrelated donors. The absolute neutrophil counts reached a nadir about 1 week after transplant, with recovery by 2 weeks. Multilineage chimerism at 1 month ranged from 6 to 100%. The conditioning was well tolerated, with outpatient management after postoperative day 2. Two subjects exhibited transient chimerism and were maintained on low-dose tacrolimus monotherapy. One subject developed viral sepsis 2 months after transplant and experienced renal artery thrombosis. Five subjects experienced durable chimerism, demonstrated immunocompetence and donor-specific tolerance by in vitro proliferative assays, and were successfully weaned off all immunosuppression 1 year after transplant. None of the recipients produced anti-donor antibody or exhibited engraftment syndrome or graft-versus-host disease. These results suggest that manipulation of a mobilized stem cell graft and nonmyeloablative conditioning represents a safe, practical, and reproducible means of inducing durable chimerism and donor-specific tolerance in solid organ transplant recipients.
TL;DR: The catalytic performance of zeolitic imidazole framework-8 and amine-functionalized ZIF-8 catalysts in the synthesis of chloropropene carbonate from CO2 and epichlorohydrin is demonstrated in this article.
Abstract: The catalytic activity of zeolitic imidazole framework-8 (ZIF-8) and amine-functionalized ZIF-8 catalysts in the synthesis of chloropropene carbonate from CO2 and epichlorohydrin is demonstrated. In contrast to hitherto known catalysts, ZIF-8 catalysts displayed high epoxide conversions and moderate to high selectivities to chloropropene carbonate at reaction temperatures as low as 70 °C. No cocatalysts or solvents were required during the reaction. The incorporation of ethylenediamine in ZIF-8 enhanced its catalytic performance as a result of the higher CO2 adsorption capacity of the amine-functionalized samples. The ZIF-8 catalysts, however, lost their distinctive crystalline structure and superior catalytic performance when attempts were made to recycle them after use.
TL;DR: Using MYC-inducible human Burkitt lymphoma model P493 and PC3 human prostate cancer cells, it is shown that MYC suppressed POX/PRODH expression primarily through up-regulating miR-23b*.
Abstract: In addition to glycolysis, the oncogenic transcription factor c-MYC (MYC) stimulates glutamine catabolism to fuel growth and proliferation of cancer cells through up-regulating glutaminase (GLS). Glutamine is converted to glutamate by GLS, entering the tricarboxylic acid cycle as an important energy source. Less well-recognized, glutamate can also be converted to proline through Δ1-pyrroline-5-carboxylate (P5C) and vice versa. This study suggests that some MYC-induced cellular effects are due to MYC regulation of proline metabolism. Proline oxidase, also known as proline dehydrogenase (POX/PRODH), the first enzyme in proline catabolism, is a mitochondrial tumor suppressor that inhibits proliferation and induces apoptosis. MiR-23b* mediates POX/PRODH down-regulation in human kidney tumors. MiR-23b* is processed from the same transcript as miR-23b; the latter inhibits the translation of GLS. Using MYC-inducible human Burkitt lymphoma model P493 and PC3 human prostate cancer cells, we showed that MYC suppressed POX/PRODH expression primarily through up-regulating miR-23b*. The growth inhibition in the absence of MYC was partially reversed by POX/PRODH knockdown, indicating the importance of suppression of POX/PRODH in MYC-mediated cellular effects. Interestingly, MYC not only inhibited POX/PRODH, but also markedly increased the enzymes of proline biosynthesis from glutamine, including P5C synthase and P5C reductase 1. MYC-induced proline biosynthesis from glutamine was directly confirmed using 13C,15N-glutamine as a tracer. The metabolic link between glutamine and proline afforded by MYC emphasizes the complexity of tumor metabolism. Further studies of the relationship between glutamine and proline metabolism should provide a deeper understanding of tumor metabolism while enabling the development of novel therapeutic strategies.
TL;DR: The integration and interpretation of cellular bioenergetics in the context of mitochondrial quality control and genetics is the theme of this review.
Abstract: Bioenergetic dysfunction is emerging as a cornerstone for establishing a framework for understanding the pathophysiology of cardiovascular disease, diabetes,cancer and neurodegeneration. Recent advances in cellular bioenergetics have shown that many cells maintain a substantial bioenergetic reserve capacity, which is a prospective index of ‘ healthy ’ mitochondrial populations.The bioenergetics of the cell are likely regulated by energy requirements and substrate availability. Additionally,the overall quality of the mitochondrial population and the relative abundance of mitochondria in cells and tissues also impinge on overall bioenergetic capacity and resistance to stress. Because mitochondria are susceptible to damage mediated by reactive oxygen/nitrogen and lipid species, maintaining a ‘ healthy ’ population of mitochondria through quality control mechanisms appears to be essential for cell survival under conditions of pathological stress. Accumulating evidence suggest that mitophagy is particularly important for preventing amplification of initial oxidative insults, which otherwise would further impair the respiratory chain or promote mutations in mitochondrial DNA (mtDNA). The processes underlying the regulation of mitophagy depend on several factors, including the integrity of mtDNA, electron transport chain activity, and the interaction and regulation of the autophagic machinery. The integration and interpretation of cellular bioenergetics in the context of mitochondrial quality control and genetics is the theme of this review.
TL;DR: It is recommended that cross-sectional imaging be used for the assessment of all dental implant sites and that CBCT is the imaging method of choice for gaining this information.
Abstract: A Position Paper Subcommittee of the American Academy of Oral and Maxillofacial Radiology (AAOMR) reviewed the literature since the original position statement on selection criteria for radiology in dental implantology, published in 2000. All current planar modalities, including intraoral, panoramic, and cephalometric, as well as cone beam computed tomography (CBCT) are discussed, along with radiation dosimetry and anatomy considerations. We provide research-based, consensus-derived clinical guidance for practitioners on the appropriate use of specific imaging modalities in dental implant treatment planning. Specifically, the AAOMR recommends that cross-sectional imaging be used for the assessment of all dental implant sites and that CBCT is the imaging method of choice for gaining this information. This document will be periodically revised to reflect new evidence.
TL;DR: Del-1 suppressed LFA-1-dependent recruitment of neutrophils and IL-17-triggered inflammatory pathology and may thus be a promising therapeutic agent for inflammatory diseases.
Abstract: Aging is linked to greater susceptibility to chronic inflammatory diseases, several of which, including periodontitis, involve neutrophil-mediated tissue injury. Here we found that aging-associated periodontitis was accompanied by lower expression of Del-1, an endogenous inhibitor of neutrophil adhesion dependent on the integrin LFA-1, and by reciprocal higher expression of interleukin 17 (IL-17). Consistent with that, IL-17 inhibited gingival endothelial cell expression of Del-1, thereby promoting LFA-1dependent recruitment of neutrophils. Young Del-1-deficient mice developed spontaneous periodontitis that featured excessive neutrophil infiltration and IL-17 expression; disease was prevented in mice doubly deficient in Del-1 and LFA-1 or in Del-1 and the IL-17 receptor. Locally administered Del-1 inhibited IL-17 production, neutrophil accumulation and bone loss. Therefore, Del-1 suppressed LFA-1-dependent recruitment of neutrophils and IL-17-triggered inflammatory pathology and may thus be a promising therapeutic agent for inflammatory diseases.
TL;DR: It is shown that pro‐inflammatory cytokines promote glycolysis in breast cancer cells, and that the inflammation‐induced miR‐155 functions as an important mediator in this process, and it is suggested that the miR-155/miR‐143/HK2 axis may represent a common mechanism linking inflammation to the altered metabolism in cancer cells.
Abstract: Cancer cells preferentially metabolize glucose through aerobic glycolysis. This phenomenon, known as the Warburg effect, is an anomalous characteristic of glucose metabolism in cancer cells. Chronic inflammation is a key promoting factor of tumourigenesis. It remains, however, largely unexplored whether and how pro-tumourigenic inflammation regulates glucose metabolism in cancer cells. Here, we show that pro-inflammatory cytokines promote glycolysis in breast cancer cells, and that the inflammation-induced miR-155 functions as an important mediator in this process. We further show that miR-155 acts to upregulate hexokinase 2 (hk2), through two distinct mechanisms. First, miR-155 promotes hk2 transcription by activation of signal transducer and activator of transcription 3 (STAT3), a transcriptional activator for hk2. Second, via targeting C/EBPβ (a transcriptional activator for mir-143), miR-155 represses mir-143, a negative regulator of hk2, thus resulting in upregulation of hk2 expression at the post-transcriptional level. The miR-155-mediated hk2 upregulation also appears to operate in other types of cancer cells examined. We suggest that the miR-155/miR-143/HK2 axis may represent a common mechanism linking inflammation to the altered metabolism in cancer cells.
University of Michigan1, University of Texas Southwestern Medical Center2, American Society of Clinical Oncology3, Peter MacCallum Cancer Centre4, University of California, Los Angeles5, University of Texas MD Anderson Cancer Center6, National Coalition for Cancer Survivorship7, University of Louisville8, University of Utah9, University of Pennsylvania10, Thomas Jefferson University11, University of Vermont12, Duke University13
TL;DR: The evidence review demonstrated that SLN biopsy is an acceptable method for lymph node staging of most patients with newly diagnosed melanoma, and completion lymph node dissection (CLND) is recommended for all patients with a positive SLNBiopsy and achieves good regional disease control.
Abstract: Purpose
The American Society of Clinical Oncology (ASCO) and Society of Surgical Oncology (SSO) sought to provide an evidence-based guideline on the use of lymphatic mapping and sentinel lymph node (SLN) biopsy in staging patients with newly diagnosed melanoma.
TL;DR: This review focuses on the pathogenic T cells and discusses how these T cells are activated and involved in the disease pathogenesis and the recent progress on the T cell and its related cytokine-targeted therapy for psoriasis treatment.
Abstract: Psoriasis is one of the most common immune-mediated chronic, inflammatory skin diseases characterized by hyperproliferative keratinocytes and infiltration of T cells, dendritic cells, macrophages and neutrophils. Although the pathogenesis of psoriasis is not fully understood, there is ample evidence suggesting that the dysregulation of immune cells in the skin, particularly T cells, plays a critical role in psoriasis development. In this review, we mainly focus on the pathogenic T cells and discuss how these T cells are activated and involved in the disease pathogenesis. Newly identified ‘professional' IL-17-producing dermal γδ T cells and their potential role in psoriasis will also be included. Finally, we will briefly summarize the recent progress on the T cell and its related cytokine-targeted therapy for psoriasis treatment.
Vanderbilt University1, Ohio State University2, University of California, Santa Barbara3, Las Cumbres Observatory Global Telescope Network4, University of Louisville5, Harvard University6, Geological Museum7, University of Copenhagen8, Swarthmore College9, California Institute of Technology10, University of Notre Dame11, Fisk University12, Texas A&M University13, University of Hawaii14, University of Arizona15, Max Planck Society16
TL;DR: The first transiting low-mass companion from the wide-field Kilodegree Extremely Little Telescope-North (KELT-North) transit survey was discovered in this paper.
Abstract: We present the discovery of KELT-1b, the first transiting low-mass companion from the wide-field Kilodegree Extremely Little Telescope-North (KELT-North) transit survey. A joint analysis of the spectroscopic, radial velocity, and photometric data indicates that the V = 10.7 primary is a mildly evolved mid-F star with Teff = 6516±49 K, log g = 4.228 +0.014 −0.021, and [Fe/H] = 0.052±0.079, with an inferred mass M∗ = 1.335 ± 0.063 M� and radius R∗ = 1.471 +0.045 −0.035 R� . The companion is a low-mass brown dwarf or a super-massive planet with mass MP = 27.38 ± 0.93 MJup and radius RP = 1.116 +0.038 −0.029 RJup. The companion is on a very short (∼29 hr) period circular orbit, with an ephemeris Tc(BJDTDB) = 2455909.29280 ± 0.00023 and P = 1.217501 ± 0.000018 days. KELT-1b receives a large amount of stellar insolation, resulting in an estimated equilibrium temperature assuming zero albedo and perfect redistribution of Teq = 2423 +3427 K. Comparison with standard evolutionary models suggests that the radius of KELT-1b is likely to be significantly inflated. Adaptive optics imaging reveals a candidate stellar companion to KELT-1 with a separation of 588 ± 1 mas, which is consistent with an M dwarf if it is at the same distance as the primary. Rossiter–McLaughlin measurements during transit imply a projected spin–orbit alignment angle λ = 2 ± 16 deg, consistent with a zero obliquity for KELT-1. Finally, the v sin I∗ = 56 ± 2k m s −1 of the primary is consistent at ∼2σ with tidal synchronization. Given the extreme parameters of the KELT-1 system, we expect it to provide an important testbed for theories of the emplacement and evolution of short-period companions, as well as theories of tidal dissipation and irradiated brown dwarf atmospheres.
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TL;DR: The results show that the proposed interfirm IT capability profiles and interfirm communications have both a direct and an interaction effect on relational value.
Abstract: This study seeks to identify the means by which information technology helps cocreate relational value in the context of interfirm relationships in the logistics industry — a large and information-intensive industry. We identify a set of IT functionalities — single-location shipping, multilocation shipping, supply chain visibility, and financial settlement — that can be used to manage the flows of physical goods, information, and finances across locations in interfirm logistics processes. Progressively more advanced sets of IT functionalities, when implemented and used in the interfirm relationship to execute logistics processes, are proposed to form four distinct IT capability profiles of increased sophistication. Interfirm IT capability profiles of higher sophistication are proposed to help cocreate greater relational value by facilitating the flows of physical goods, information, and finances across locations in the interfirm logistics process. Besides their direct role in helping cocreate relational value, these interfirm IT capability profiles are proposed to further enhance relational value cocreation when complemented by interfirm communications for business development and IT development.Our empirical study was situated in one of the world’s largest logistics suppliers and over 2,000 of its interfirm relationships with buyers across industries. Integrated data from four archival sources on the IT functionalities implemented and used in interfirm logistics relationships, interfirm communications, relational value (share of wallet and loyalty), and multiple control variables were collected. The results show that the proposed interfirm IT capability profiles and interfirm communications have both a direct and an interaction effect on relational value. Implications for cocreating relational value in interfirm relationships with the aid of IT are discussed.
TL;DR: The role of growth factors, cytokines, chemokines and bioactive lipids and microvesicles released from cells employed as cellular therapeutics in regenerative medicine are discussed and it is suggested that paracrine effects make major contributions in most of the currently reported positive results in clinical trials employing adult stem cells.
Abstract: Although regenerative medicine is searching for pluripotent stem cells that could be employed for therapy, various types of more differentiated adult stem and progenitor cells are in meantime being employed in clinical trials to regenerate damaged organs (for example, heart, kidney or neural tissues). It is striking that, for a variety of these cells, the currently observed final outcomes of cellular therapies are often similar. This fact and the lack of convincing documentation for donor-recipient chimerism in treated tissues in most of the studies indicates that a mechanism other than transdifferentiation of cells infused systemically into peripheral blood or injected directly into damaged organs may have an important role. In this review, we will discuss the role of (i) growth factors, cytokines, chemokines and bioactive lipids and (ii) microvesicles (MVs) released from cells employed as cellular therapeutics in regenerative medicine. In particular, stem cells are a rich source of these soluble factors and MVs released from their surface may deliver RNA and microRNA into damaged organs. Based on these phenomena, we suggest that paracrine effects make major contributions in most of the currently reported positive results in clinical trials employing adult stem cells. We will also present possibilities for how these paracrine mechanisms could be exploited in regenerative medicine to achieve better therapeutic outcomes. This approach may yield critical improvements in current cell therapies before true pluripotent stem cells isolated in sufficient quantities from adult tissues and successfully expanded ex vivo will be employed in the clinic.
TL;DR: This research provides a clearer understanding of how ligands influence each of the three stages in the gold catalytic cycle and proposes a ligand design protocol for each category of gold-catalyzed reactions.
Abstract: Gold catalysis is considered one of the most important breakthroughs in organic synthesis during the past decade, but a rational understanding of ligand effects in gold catalysis is lacking. Most gold-catalyzed reactions go through three major stages: (i) electronic activation of alkyne (or allene) to generate a vinyl gold intermediate; (ii) protodeauration to generate the product and regenerate the cationic gold catalyst; (iii) decay of the active gold catalyst. Our research provides a clearer understanding of how ligands influence each of the three stages in the gold catalytic cycle. What is even more important, by not focusing on a particular gold-catalyzed reaction, we have been able to categorize most gold-catalyzed reactions and propose a ligand design protocol for each category of gold-catalyzed reactions.
University of Texas MD Anderson Cancer Center1, Hoffmann-La Roche2, University of Basel3, Aalborg University4, Memorial Sloan Kettering Cancer Center5, Cornell University6, Houston Methodist Hospital7, Columbia University8, University of North Carolina at Chapel Hill9, Cleveland Clinic10, University of Maryland, Baltimore11, University of Hong Kong12, Zhejiang University13, Radboud University Nijmegen14, City of Hope National Medical Center15, University of Ulsan16, University of California, San Francisco17, Southwest Washington Medical Center18, University of Wisconsin-Madison19, Northwestern University20, Nanjing Medical University21, University of Louisville22, University of Southern Denmark23
TL;DR: Assessment of TP53 mutation status is important for stratifying R-CHOP-treated patients into distinct prognostic subsets and has significant value in the design of future therapeutic strategies.
TL;DR: Ireversible electroporation ablation of locally advanced pancreatic cancer tumors is a safe and feasible primary local treatment in unresectable, locally advanced disease.
Abstract: Background Locally advanced pancreatic cancer patients have limited options for disease control. Local ablation technologies based on thermal damage have been used but are associated with major complications in this region of the pancreas. Irreversible electroporation (IRE) is a nonthermal ablation technology that we have shown is safe near vital vascular and ductal structures. The aim of this study was to evaluate the safety and efficacy of IRE as a therapy in the treatment of locally advanced pancreatic cancer. Study Design We performed a prospective multi-institutional pilot evaluation of patients undergoing IRE for locally advanced pancreatic cancer from December 2009 to March 2011. These patients were evaluated for 90-day morbidity, mortality, and local disease control. Results Twenty-seven patients (13 women and 14 men) underwent IRE, with median age of 61 years (range 45 to 80 years). Eight patients underwent margin accentuation with IRE in combination with left-sided resection (n = 4) or pancreatic head resection (n = 4). Nineteen patients had in situ IRE. All patients underwent successful IRE, with intraoperative imaging confirming effective delivery of therapy. All 27 patients demonstrated nonclinically relevant elevation of their amylase and lipase, which peaked at 48 hours and returned to normal at 72 hour postprocedure. There has been one 90-day mortality. No patient has shown evidence of clinical pancreatitis or fistula formation. After all patients have completed 90-day follow-up, there has been 100% ablation success. Conclusions IRE ablation of locally advanced pancreatic cancer tumors is a safe and feasible primary local treatment in unresectable, locally advanced disease. Confirming these early results must occur in a planned phase II investigational device exemption (IDE) study to be initiated in 2012.