tbuckley/cabot-search huggingface dataset:
Cell entry, efficient RNA replication, and production of infectious hepatitis C virus progeny in mouse liver-derived cells
Authors: Anne Frentzen, None Anggakusuma, Engin Gürlevik, Kathrin Hueging, Sarah Knocke, Corinne Ginkel, Richard J.P. Brown, Markus Heim, Michael T. Dill, Andrea Kröger, Ulrich Kalinke, Lars Kaderali, Florian Kuehnel, Thomas Pietschmann
Journal: Hepatology (2013)

Only humans and chimpanzees are susceptible to chronic infection by hepatitis C virus (HCV). The restricted species tropism of HCV is determined by distinct host factor requirements at different steps of the viral life cycle. In addition, effective innate immune targeting precludes efficient propagation of HCV in nonhuman cells. Species-specificity of HCV host factor usage for cell entry and virus release has been explored. However, the reason for inefficient HCV RNA replication efficiency in mouse liver cells remains elusive. To address this, we generated novel mouse liver-derived cell lines with specific lesions in mitochondrial antiviral signaling protein (MAVS), interferon regulatory factor 3 (IRF3), or Interferon-α/β receptor (IFNAR) by in vivo immortalization. Blunted innate immune responses in these cells modestly increased HCV RNA replication. However, ectopic expression of liver-specific human microRNA 122 (miR-122) further boosted RNA replication in all knockout cell lines. Remarkably, MAVS−/−miR-122 cells sustained vigorous HCV RNA replication, attaining levels comparable to the highly permissive human hepatoma cell line Huh-7.5. RNA replication was dependent on mouse cyclophilin and phosphatidylinositol-4 kinase III alpha (PI4KIIIα) and was also observed after transfection of full-length viral RNA. Additionally, ectopic expression of either human or mouse apolipoprotein E (ApoE) was sufficient to permit release of infectious particles. Finally, expression of human entry cofactors rendered these cells permissive to HCV infection, thus confirming that all steps of the HCV replication cycle can be reconstituted in mouse liver-derived cells. Conclusion: Blunted innate immunity, abundant miR-122, and HCV entry factor expression permits propagation of HCV in mouse liver-derived cell lines. (Hepatology 2014;58:78–88)
Impressions of Clinical Allergy in China
Authors: Judith S. Rubenstein
Journal: JAMA (1984)

<h3>To the Editor.—</h3> In May 1984, we were part of a delegation of allergists and clinical immunologists to be invited by the Chinese Medical Association to the People's Republic of China. We describe some of our impressions of clinical allergy there. The manifestations of allergic diseases in China and in the West appear similar in some respects, yet strikingly different in others. As in the West, the principal perennial allergens or irritants are house dust, dust mites, molds, animal danders, and cigarette smoke. However, urticaria, not a common allergic illness in the West, is considered the leading allergic illness in China.<sup>1</sup>Although IgE levels are somewhat elevated in Chinese patients with urticaria, no specific allergic meaning may be attached to this since the levels are not different from presumably normal Chinese—nor from other Asians. This elevation has been ascribed to the greater incidence of parasitic infestation in Asia.
Evaluation of Treatment-Effect Heterogeneity Using Biomarkers Measured on a Continuous Scale: Subpopulation Treatment Effect Pattern Plot
Authors: Ann A. Lazar, Bernard F. Cole, Marco Bonetti, Richard D. Gelber
Journal: Journal of Clinical Oncology (2010)

The discovery of biomarkers that predict treatment effectiveness has great potential for improving medical care, particularly in oncology. These biomarkers are increasingly reported on a continuous scale, allowing investigators to explore how treatment efficacy varies as the biomarker values continuously increase, as opposed to using arbitrary categories of expression levels resulting in a loss of information. In the age of biomarkers as continuous predictors (eg, expression level percentage rather than positive v negative), alternatives to such dichotomized analyses are needed. The purpose of this article is to provide an overview of an intuitive statistical approach-the subpopulation treatment effect pattern plot (STEPP)-for evaluating treatment-effect heterogeneity when a biomarker is measured on a continuous scale. STEPP graphically explores the patterns of treatment effect across overlapping intervals of the biomarker values. As an example, STEPP methodology is used to explore patterns of treatment effect for varying levels of the biomarker Ki-67 in the BIG (Breast International Group) 1-98 randomized clinical trial comparing letrozole with tamoxifen as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer. STEPP analyses showed patients with higher Ki-67 values who were assigned to receive tamoxifen had the poorest prognosis and may benefit most from letrozole.
β2 integrins are required for skin homing of primed T cells but not for priming naive T cells
Authors: Stephan Grabbe, Georg Varga, Stefan Beissert, Meike Steinert, Gunther Pendl, Stephan Seeliger, Wilhelm Bloch, Thorsten Peters, Thomas Schwarz, Cord Sunderkötter, Karin Scharffetter-Kochanek
Journal: Journal of Clinical Investigation (2002)

Beta2 integrins are of critical importance for leukocyte extravasation through vascular endothelia and for T cell activation. To elucidate the role of beta2 integrins in T cell-mediated immune responses, allergic contact dermatitis (ACD), irritant dermatitis, and delayed-type hypersensitivity (DTH) were assessed in mice lacking the beta2 integrin subunit, CD18. ACD and DTH responses, but not edema formation, were severely suppressed in CD18(-/-) mice. Extravasation of CD18(-/-) T cells into eczematous skin lesions was greatly impaired, whereas migration of Langerhans cell precursors and dendritic cells was normal in CD18(-/-) mice. CD18(-/-)lymph nodes (LNs) contained an abnormal population of CD3(-)CD44(high) lymphocytes and showed evidence of widespread T cell activation. T cells from regional LNs of sensitized CD18(-/-) mice proliferated in response to hapten challenge, and subcutaneous injection of sensitized syngeneic LN cells directly into ears of hapten-challenged naive recipients restored the defective ACD in CD18(-/-) mice, suggesting that CD18 is not required for priming of naive T cells but is indispensable for T cell extravasation. Thus, a dysfunction of T cells, in addition to granulocytes, may contribute to the pathophysiology of leukocyte adhesion deficiency type I, which arises from mutations in the human CD18 gene.
Distinct TRAIL Resistance Mechanisms Can Be Overcome by Proteasome Inhibition but not Generally by Synergizing Agents
Authors: Christina Menke, Lianghua Bin, Jacqueline Thorburn, Kian Behbakht, Heide L. Ford, Andrew Thorburn
Journal: Cancer Research (2011)

Abstract One impediment to the use of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-targeted agents as antitumor drugs is the evolution of resistance, a common problem in cancer. On the contrary, many different kinds of drugs synergize with TRAIL in TRAIL-sensitive tumor cells, raising the question whether one can overcome resistance with the same drugs producing synergy. This is an important question, because recent clinical trials suggest that combination treatments with cytotoxic drugs and TRAIL receptor-targeted agents do not provide additional benefit compared with cytotoxic agents on their own. Such results might be expected if drug combinations that synergize in sensitive tumor cells but cannot overcome TRAIL resistance are used in patients whose tumors were not selected for retention of TRAIL sensitivity. We tested this idea by creating isogenic tumor cells with acquired TRAIL resistance or defined mechanisms of resistance that occur in human tumors and then comparing them to the TRAIL-sensitive parental cell line. Although diverse classes of anticancer drugs were all able to synergize with TRAIL in sensitive cells, most agents were unable to overcome resistance and there was no relationship between the amount of synergy seen with a particular agent and its ability to overcome acquired resistance. An important exception was proteasome inhibitors, which were, however, able to overcome diverse resistance mechanisms. Our findings suggest that one should select drugs for TRAIL receptor agonist combination therapy based not just on their ability to synergize, but rather on their ability to overcome resistance as well as synergize. Cancer Res; 71(5); 1883–92. ©2011 AACR.
Community based outpatient treatment of multidrug-resistant tuberculosis
Authors: K Dheda
Journal: Thorax (2003)

▴ Mitnick C, Bayona J, Palacios E, et al . Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru. N Engl J Med2003;348:119–28 [OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] Treatment for multidrug-resistant tuberculosis (MDR-TB) is virtually non-existent in developing countries because of limited resources and infrastructure. This study assesses treatment feasibility and identifies predictors of poor outcome in patients receiving community based outpatient treatment for MDR-TB in a poor section of Lima. Seventy … [1]: {openurl}?query=rft.jtitle%253DNew%2BEngland%2BJournal%2Bof%2BMedicine%26rft.stitle%253DNEJM%26rft.issn%253D0028-4793%26rft.aulast%253DMitnick%26rft.auinit1%253DC.%26rft.volume%253D348%26rft.issue%253D2%26rft.spage%253D119%26rft.epage%253D128%26rft.atitle%253DCommunity-Based%2BTherapy%2Bfor%2BMultidrug-Resistant%2BTuberculosis%2Bin%2BLima%252C%2BPeru%26rft_id%253Dinfo%253Adoi%252F10.1056%252FNEJMoa022928%26rft_id%253Dinfo%253Apmid%252F12519922%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1056/NEJMoa022928&link_type=DOI [3]: /lookup/external-ref?access_num=12519922&link_type=MED&atom=%2Fthoraxjnl%2F58%2F4%2F347.atom [4]: /lookup/external-ref?access_num=000180263900004&link_type=ISI
Sex chromosomes and genetic association studies
Authors: David G Clayton
Journal: Genome Medicine (2009)

Although the literature concerning statistical testing for genotype-phenotype association in family-based and population-based studies is very extensive, until recently the sex chromosomes have received little attention. Here it is shown that the X chromosome in particular presents special problems with respect to efficient analysis of mixed-sex population studies, and as a result of X inactivation. This paper reviews recent developments in approaching these problems.
IgG subclass, IgE, and IgA anti-trinitrophenyl antibody production within trinitrophenyl-Ficoll-responsive B cell clones. Evidence in support of three distinct switching pathways.
Authors: P K Mongini, W E Paul, E S Metcalf
Journal: The Journal of Experimental Medicine (1983)

The IgM, IgG subclass, IgE, and IgA anti-trinitrophenyl (TNP) antibody (Ab) response of B cells to the type 2 antigen TNP-Ficoll was studied in athymic nude mice and in the in vitro splenic focus assay. Results from the splenic focus assay in which purified B lymphocyte preparations had been transferred to irradiated nu/nu recipients indicate that many TNP-Ficoll stimulated B cell clones secrete multiple isotypes and hence appear to be undergoing intraclonal isotype switching. Although the frequency of clones secreting each of the IgG subclasses was found to correlate with 5' to 3' Igh-gamma gene order, the frequency of IgE and IgA-secreting clones did not appear to be influenced by the respective position of Igh-epsilon and Igh-alpha on the chromosome. Unlike clones that secreted anti-TNP Ab of the IgG subclasses, IgE and IgA anti-TNP Ab-secreting clones did not have a high propensity for coexpression of isotypes encoded by 5' Igh-C genes. These data suggest that three distinct switching pathways may be employed by B cells responding to TNP-Ficoll: a common IgG pathway, an IgE pathway, and an IgA pathway. The presence of T cells resulted in a preferential enhancement of the production of anti-TNP Ab of those IgG subclasses which were least represented in the absence of T cells, i.e., IgG2b and IgG2a. No significant enhancement of IgE anti-TNP clonal frequency was found in the presence of T lymphocytes, but T cells were found to significantly enhance the clonal expression of IgA anti-TNP Ab. Although a relatively large number of B cell clones were found to synthesize IgE and IgA anti-TNP Ab in the splenic focus assay, relatively little or no secretion of these isotypes was detected in immune mice. Possible explanations for this apparent discrepancy are discussed.
Assessment of erlotinib pharmacodynamics in tumors and skin of patients with head and neck cancer
Authors: E. Calvo, S.N. Malik, L.L. Siu, G.M. Baillargeon, J. Irish, S.F. Chin, P. Santabarbara, J.I. Kreisberg, E.K. Rowinsky, M. Hidalgo
Journal: Annals of Oncology (2007)
Real-Time Continuous Glucose Monitoring Significantly Reduces Severe Hypoglycemia in Hypoglycemia-Unaware Patients With Type 1 Diabetes
Authors: Pratik Choudhary, Sharmin Ramasamy, Louisa Green, Geraldine Gallen, Siobhan Pender, Anna Brackenridge, Stephanie A. Amiel, John C. Pickup
Journal: Diabetes Care (2013)

To evaluate the effect of continuous glucose monitoring (CGM) on the frequency of severe hypoglycemia (SH) in patients with established hypoglycemia unawareness.We conducted a retrospective audit of 35 patients with type 1 diabetes and problematic hypoglycemia unawareness, despite optimized medical therapy (continuous subcutaneous insulin infusion/multiple daily insulin injections), who used CGM for >1 year.Over a 1-year follow-up period, the median rates of SH were reduced from 4.0 (interquartile range [IQR] 0.75-7.25) episodes/patient-year to 0.0 (0.0-1.25) episodes/patient-year (P < 0.001), and the mean (±SD) rates were reduced from 8.1 ± 13 to 0.6 ± 1.2 episodes/year (P = 0.005). HbA1c was reduced from 8.1 ± 1.2% to 7.6 ± 1.0% over the year (P = 0.005). The mean Gold score, measured in 19 patients, did not change: 5.1 ± 1.5 vs. 5.2 ± 1.9 (P = 0.67).In a specialist experienced insulin pump center, in carefully selected patients, CGM reduced SH while improving HbA1c but failed to restore hypoglycemia awareness.
Thomas Willis and the background to Cerebri Anatome
Authors: J. P B O'Connor
Journal: Journal of the Royal Society of Medicine (2003)

In 1664 Thomas Willis (1621-1675) published a text on the brain and nerves that was to be deeply influential for the next two centuries. Initially, Cerebri Anatome had little impact on English medical practice, though it enhanced Willis's reputation to the extent that he was able to become a prosperous London physician1.

Primitive descriptions of the arterial anastomosis at the base of the brain already existed in 1664. Willis improved on these accounts, and made the first attempt to attribute a function to the anatomy that he described. In the eighteenth century his description of the brain became accepted as definitive, appearing in the Bibliotheca Anatomica of 1774-1777 for the first time as the famous ‘circle of Willis’. Modern historical scholarship has highlighted the contribution that Willis made to neuroanatomy, which had been previously eclipsed by contemporaries such as Thomas Browne2.

Although his description of the anatomy of the brain remains important for contemporary neurological science, Willis's understanding of the brain was very different from that of modern scientific thought. Willis wrote Cerebri Anatome while Professor of Natural Philosophy in Oxford, where he used the anatomy of the brain as a tool to investigate the nature of the soul. He wrote at a time when England was in great political and religious turmoil, following the Civil War and the execution of Charles I, and his work reflects his allegiances during this turbulent period. In this paper, I discuss the dependence of Willis's description of anatomy upon his concept of the human soul. By considering Cerebri Anatome as a product of the life that Willis led, it is possible to understand his anatomical descriptions as a reflection of beliefs and practices in the mid-seventeenth century.
Nephro-Ureteral Anastomosis after Complete Avulsion of the Ureter
Authors: R. C. Begg
Journal: BMJ (1926)

described above.I submit the following proposals for further invsstigation:1.The preparation of suitable media of human and bovine material containing unheated blood serum.2. The evolving of a vigorous strain of tubercle bacilli which will grow on human and bovine media which are not sterilized by heat.3. The elimination of autolysis in such media and investigation into the possible action of autolytic enzymes on the tubercle bacillus.4. The preparation of a tuberculin by the method described above.5. Preliminary investigations to be carried out with bovine tubercle bacilli on media of bovine material.In conclusion I lhave to express my thanks to Professor
Protein C and S levels in acute leukemia
Authors: Kevin Troy, David Essex, Jacob Rand, Myra Lema, Janet Cuttner
Journal: American Journal of Hematology (1991)

Abstract Patients with acute leukemia undergoing remission induction chemotherapy occasionally develop venous thrombosis despite severe thrombocytopenia and in the absence of disseminated intravascular coagulation. This observation prompted us to study the levels of the naturally occurring anticoagulant proteins C and S prospectively in patient sundergoing remission induction chemotherapy for acute leukemia. Plasma samples from 50 adult patients with acute leukemia (34 AML, 16 ALL) were analyzed for protein C antigen, functional protein C, immunologic total and free protein S as well as levels of C4b binding protein (C4bBP). Plasma levels of immunolgic protein C were significantly lower in patients with active acute myelocytic leukemia (mean = 77.9) than in controls (mean = 123.6) or patients in remission (mean = 132). Functional protein C levels were also significantly lower in AML patients with active disease (mean = 58.5) than controls (mean = 95.5) or patients in remission (mean = 98.5). Patients with acute lymphocytic leukemia (ALL) had normal levels of immunologic and functional protein C. Although total protein S levels were normal in all patients studied, levels of free protein Swere significantly decreased in patients with active AML (mean = 29.3) compared with patients in remission (mean = 42.0) or controls (mean = 42.4). In contrast, patients with ALL, both with active disease and in remission had normal free protein S levels. This decrease in free protein S seen in active AML was not associated with liver disease, white cell count or an increase in C4bBP. These findings provide a possible explanation for the occasional occurrence of venous thrombosis in patients with acute myelocytic leukemia.
LEVEL 1 SHOCK TEAM-EARLY EXPERIENCE IN EMCO USE AS A RESCUE DEVICE IN CARDIAC ARREST FROM STEMI IN THE CARDIAC CATHETERIZATION LABORATORY
Authors: Michael R. Mooney, David Hildebrandt, David Feldman, Benjamin Sun, Dirck Rilla, Yale Wang, Ivan Chavez, M. Nicholas Burke, Timothy Henry
Journal: Journal of the American College of Cardiology (2013)
Infliximab failure in cap polyposis
Authors: V Maunoury
Journal: Gut (2005)

Cap polyposis is a rare condition that predominantly affects the rectosigmoid with distinctive clinicopathological features. The common symptoms are mucoid and bloody diarrhoea with abdominal pain and tenesmus. At endoscopy, polyps are red, sessile, and located at the apices of enlarged transverse mucosal folds with a normal intervening mucosa. Microscopic features include elongated hyperplastic looking glands with a mixed inflammatory infiltrate in the lamina propria. A cap of fibrinopurulent exudate covers the polyps. Treatment of this condition remains empiric. Metronidazole and steroids have been effective in some cases. Symptoms are often relieved by polypectomy but rectosigmoid resection may be required …
Mutation of Vps54 causes motor neuron disease and defective spermiogenesis in the wobbler mouse
Authors: Thomas Schmitt-John, Carsten Drepper, Anke Mußmann, Phillip Hahn, Melanie Kuhlmann, Cora Thiel, Martin Hafner, Andreas Lengeling, Peter Heimann, Julie M Jones, Miriam H Meisler, Harald Jockusch
Journal: Nature Genetics (2005)
Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials
Authors: M.J. Sorich, M.D. Wiese, A. Rowland, G. Kichenadasse, R.A. McKinnon, C.S. Karapetis
Journal: Annals of Oncology (2014)
Mesoporous Silica Nanoparticles as Drug Delivery Systems for Targeted Inhibition of Notch Signaling in Cancer
Authors: Veronika Mamaeva, Jessica M Rosenholm, Laurel Tabe Bate-Eya, Lotta Bergman, Emilia Peuhu, Alain Duchanoy, Lina E Fortelius, Sebastian Landor, Diana M Toivola, Mika Lindén, Cecilia Sahlgren
Journal: Molecular Therapy (2011)

Notch signaling, a key regulator of stem cells, is frequently overactivated in cancer. It is often linked to aggressive forms of cancer, evading standard treatment highlighting Notch as an exciting therapeutic target. Notch is in principle "druggable" by γ-secretase inhibitors (GSIs), inhibitory peptides and antibodies, but clinical use of Notch inhibitors is restricted by severe side effects and there is a demand for alternative cancer-targeted therapy. Here, we present a novel approach, using imagable mesoporous silica nanoparticles (MSNPs) as vehicles for targeted delivery of GSIs to block Notch signaling. Drug-loaded particles conjugated to targeting ligands induced cell-specific inhibition of Notch activity in vitro and exhibited enhanced tumor retainment with significantly improved Notch inhibition and therapeutic outcome in vivo. Oral administration of GSI-MSNPs controlled Notch activity in intestinal stem cells further supporting the in vivo applicability of MSNPs for GSI delivery. MSNPs showed tumor accumulation and targeting after systemic administration. MSNPs were biocompatible, and particles not retained within the tumors, were degraded and eliminated mainly by renal excretion. The data highlights MSNPs as an attractive platform for targeted drug delivery of anticancer drugs with otherwise restricted clinical application, and as interesting constituents in the quest for more refined Notch therapies.
Electroporated DNA Vaccine Clears Away Multifocal Mammary Carcinomas in Her-2/<b><i>neu</i></b>Transgenic Mice
Authors: Elena Quaglino, Manuela Iezzi, Cristina Mastini, Augusto Amici, Federica Pericle, Emma Di Carlo, Serenella M. Pupa, Carla De Giovanni, Michela Spadaro, Claudia Curcio, Pier Luigi Lollini, Piero Musiani, Guido Forni, Federica Cavallo
Journal: Cancer Research (2004)

Abstract The transforming rat Her-2/neu oncogene embedded into the genome of virgin transgenic BALB/c mice (BALB-neuT) provokes the development of an invasive carcinoma in each of their 10 mammary glands. i.m. vaccination with DNA plasmids coding for the extracellular and transmembrane domains of the protein product of the Her-2/neu oncogene started when mice already display multifocal in situ carcinomas temporarily halts neoplastic progression, but all mice develop a tumor by week 43. By contrast, progressive clearance of neoplastic lesions and complete protection of all 1-year-old mice are achieved when the same plasmids are electroporated at 10-week intervals. Pathological findings, in vitro tests, and the results from the immunization of both IFN-γ and immunoglobulin gene knockout BALB-neuT mice, and of adoptive transfer experiments, all suggest that tumor clearance rests on the combination of antibodies and IFN-γ-releasing T cells. These findings show that an appropriate vaccine effectively inhibits the progression of multifocal preneoplastic lesions.