tbuckley/cabot-search huggingface dataset:
Construction of T cell hybridomas secreting allogeneic effect factor.
Authors: D H Katz, T E Bechtold, A Altman
Journal: The Journal of Experimental Medicine (1980)

T cell hybridoma lines were constructed by fusion of DBA/2 alloantigen-activated T cell blasts with the AKR thymoma line BW5147. Certain of the hybridomas prepared in this manner secreted spontaneously into their culture supernates biologically active molecules that displayed B cell- and T cell-activating properties characteristic of allogeneic effect factor (AEF). Cell surface phenotype analysis documented that the hybridomas were, indeed, somatic cell hybrids between the two respective partner cells used for fusion. The B cell-activating properties of these hybridoma supernates was demonstrated by their capacity to stimulate T cell-depleted spleen cells to respond in vitro to T-dependent antigens. The T cell-activating properties of these hybridoma supernates was verified by their capacity to stimulate autonomous development of self-specific cytotoxic T lymphocytes and by their capacity to exert mitogenic effects on unprimed T cells. The biologically active molecules secreted by these hybridomas were, like conventional AEF, inhibitable by specific anti-Ia antibodies thus indicating the presence of Ia determinants on the relevant hybridoma products. Finally, these AEF-secreting hybridomas could be stimulated to proliferate and to secrete increased quantities of AEF when exposed to the specific alloantigen-bearing target cells to which the T cell blasts had been originally sensitized.
An EGFR–Src–Arg–Cortactin Pathway Mediates Functional Maturation of Invadopodia and Breast Cancer Cell Invasion
Authors: Christopher C. Mader, Matthew Oser, Marco A. O. Magalhaes, Jose Javier Bravo-Cordero, John Condeelis, Anthony J. Koleske, Hava Gil-Henn
Journal: Cancer Research (2011)

Invasive carcinoma cells use specialized actin polymerization-driven protrusions called invadopodia to degrade and possibly invade through the extracellular matrix (ECM) during metastasis. Phosphorylation of the invadopodium protein cortactin is a master switch that activates invadopodium maturation and function. Cortactin was originally identified as a hyperphosphorylated protein in v-Src-transformed cells, but the kinase or kinases that are directly responsible for cortactin phosphorylation in invadopodia remain unknown. In this study, we provide evidence that the Abl-related nonreceptor tyrosine kinase Arg mediates epidermal growth factor (EGF)-induced cortactin phosphorylation, triggering actin polymerization in invadopodia, ECM degradation, and matrix proteolysis-dependent tumor cell invasion. Both Src and Arg localize to invadopodia and are required for EGF-induced actin polymerization. Notably, Arg overexpression in Src knockdown cells can partially rescue actin polymerization in invadopodia while Src overexpression cannot compensate for loss of Arg, arguing that Src indirectly regulates invadopodium maturation through Arg activation. Our findings suggest a novel mechanism by which an EGFR-Src-Arg-cortactin pathway mediates functional maturation of invadopodia and breast cancer cell invasion. Furthermore, they identify Arg as a novel mediator of invadopodia function and a candidate therapeutic target to inhibit tumor invasion in vivo.
Recurrent methicillin-resistant <i>Staphylococcus aureus</i> septicaemia and pacemaker-lead-associated endocarditis following diagnostic gastroscopy
Authors: Debabrata Majumdar, Jyothi G Rao, Kapil Kapur, Basil T Saeed, Ashraf Soliman
Journal: Gut (2010)

We read with interest the recent guidelines for antibiotic prophylaxis produced by the British Society of Gastroenterology which do not support the routine use of antibiotic prophylaxis even for high-risk patients having an endoscopy.1 We would like to present a case which suggests that these guidelines may be underplaying the possible risk in certain patients.

We experienced a 67-year-old patient with recurrent Methicillin resistant Staphylococcus aureus (MRSA) septicaemia due to pacemaker-lead endocarditis, as a complication of a gastroscopy. He had a past medical history of coronary artery bypass grafting and permanent pacemaker implant, and was admitted with a 2-day history of melaena. A day after endoscopy, he developed features of sepsis, complicated by ventricular tachyarrythmia necessitating treatment in the intensive care unit. Blood cultures were positive for MRSA, …
Peripheral lung remodelling in asthma and chronic obstructive pulmonary disease
Authors: J. Hogg
Journal: European Respiratory Journal (2004)

In this issue of the European Respiratory Journal , Vignola et al. 1 report an association between high-resolution computed tomography (HRCT) scan abnormalities of the conducting airways and an analysis of markers of the tissue remodelling process. They demonstrate an association between the level of HRCT abnormality in the airways and increased levels of active elastase with overproduction of tissue-inhibitor metalloproteinase-1 over metalloproteinase-9 in the sputum. The study design is cross-sectional in nature and based on small numbers of patients collected into three groups, according to whether they had newly diagnosed and untreated asthma, treated asthma or chronic obstructive pulmonary disease (COPD). The design does not include a control group with normal lung function and lacks longitudinal data collection to ensure that the sputum markers and HRCT abnormalities change in the expected directions with disease progression. After the first reading, the notion that editorial writers have been described as “the sort of people who come down from …
Cytotoxic Markers and Frequency Predict Functional Capacity of Natural Killer Cells Infiltrating Renal Cell Carcinoma
Authors: Julia S. Schleypen, Nicole Baur, Robert Kammerer, Peter J. Nelson, Karl Rohrmann, Elisabeth F. Gröne, Markus Hohenfellner, Axel Haferkamp, Heike Pohla, Dolores J. Schendel, Christine S. Falk, Elfriede Noessner
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Renal cell carcinoma harbors high numbers of infiltrating lymphocytes with apparent limited efficacy in tumor control. This study focused on the natural killer (NK) cells infiltrating renal cell carcinoma. Experimental Design: Tumor-infiltrating lymphocytes (TIL) were isolated from renal cell carcinoma and analyzed for NK cell frequency and phenotype (n = 34). NK cells were enriched and tested for effector function. Results: Two renal cell carcinoma subtypes were identified, one containing high (&amp;gt;20% of the lymphocyte population, n = 14), the other low (&amp;lt;20%, n = 20), NK cell numbers. NK cells of both groups were noncytolytic ex vivo but differed in CD16 and cytotoxic effector molecule expression as well as in their capacity to acquire cytotoxic activity: The majority of NK cells from tumors with high NK cell content (high NK-TIL) were CD16bright, whereas few CD16bright NK cells were found in tumors with low NK cell frequencies (low NK-TIL). The CD16 dichotomy correlated with different capacities to develop cytotoxicity after short-term activation with interleukin-2 ex vivo: Low NK-TIL remained noncytolytic against K562 and unresponsive to signals via the activating receptor NKp46 despite expression of receptor and adaptor molecules. In contrast, high NK-TIL acquired cytotoxic function. As described for peripheral CD16bright NK cells, NK cells from high-NK tumors showed high per cell expression of granzyme A, granzyme B, and perforin. NK cells from low NK-TIL resembled CD16neg/dim peripheral NK cells with few cytotoxin+ cells and lower expression of perforin. Conclusion: The extent of NK cell infiltration and the expression of markers (CD16 and cytotoxins) predict the functional capacity of NK cells infiltrating renal cell carcinoma and can be used to characterize subgroups of renal cell carcinoma.
Endothelial-Specific Notch Blockade Inhibits Vascular Function and Tumor Growth through an eNOS-Dependent Mechanism
Authors: Alexandre Patenaude, Megan Fuller, Linda Chang, Fred Wong, Grigorios Paliouras, Rebecca Shaw, Alastair H. Kyle, Patricia Umlandt, Jennifer H.E. Baker, Erika Diaz, Jade Tong, Andrew I. Minchinton, Aly Karsan
Journal: Cancer Research (2014)

Notch signaling is important for tumor angiogenesis induced by vascular endothelial growth factor A. Blockade of the Notch ligand Dll4 inhibits tumor growth in a paradoxical way. Dll4 inhibition increases endothelial cell sprouting, but vessels show reduced perfusion. The reason for this lack of perfusion is not currently understood. Here we report that inhibition of Notch signaling in endothelial cell using an inducible binary transgenic system limits VEGFA-driven tumor growth and causes endothelial dysfunction. Neither excessive endothelial cell sprouting nor defects of pericyte abundance accompanied the inhibition of tumor growth and functional vasculature. However, biochemical and functional analysis revealed that endothelial nitric oxide production is decreased by Notch inhibition. Treatment with the soluble guanylate cyclase activator BAY41-2272, a vasorelaxing agent that acts downstream of endothelial nitric oxide synthase (eNOS) by directly activating its soluble guanylyl cyclase receptor, rescued blood vessel function and tumor growth. We show that reduction in nitric oxide signaling is an early alteration induced by Notch inhibition and suggest that lack of functional vessels observed with Notch inhibition is secondary to inhibition of nitric oxide signaling. Coculture and tumor growth assays reveal that Notch-mediated nitric oxide production in endothelial cell requires VEGFA signaling. Together, our data support that eNOS inhibition is responsible for the tumor growth and vascular function defects induced by endothelial Notch inhibition. This study uncovers a novel mechanism of nitric oxide production in endothelial cells in tumors, with implications for understanding the peculiar character of tumor blood vessels.
PHYSIOLOGICAL ONTOGENY
Authors: Alfred E. Cohn
Journal: The Journal of Experimental Medicine (1925)

In these experiments we have shown that, with the technique adopted, differences in behavior are exhibited by fragments of the heart taken from different localities. The different localities behave in a more or less uniform manner. The pace-making function, for instance, is found at first throughout the cardiac tube but later it is restricted and comes to reside in a special small area at the back of the right auricle near the center. The pace-making system is able to develop a rate comparable to that shown by the whole intact heart, irrespective of the size of the fragment in which it is contained. Later, under the circumstances of the study, the ventricular structures lose the power of spontaneous contraction, and later still, the auricular ones also. It need scarcely be pointed out, however, that this loss refers only to the function of pace making. In its place, the various localities of the heart undoubtedly take on other capabilities. This is what is meant after all by differentiation. The question whether the pace-making and conduction systems reside in the remains of primitive portions of the cardiac tube in an undifferentiated form, or whether on the other hand these primitive portions develop into differentiated structures which preside over these functions may be reviewed afresh. Obviously the tube in its early state possesses these functions; obviously also the major part of the heart loses them during the course of development. A knowledge of the changes in form paralleling changes in function would have great interest. On this phase of the problem we hope to report later. On the basis of these observations, differentiation from the point of view of stimulus production may be viewed perhaps in this manner. Pace making, the conduction of impulses, and contraction are the primitive functions of the tube. As the tube develops into the adult structure, pace making and conduction are supposedly served by tissues resembling in structure the original ones. Whether as a matter of fact a structural change takes place is an interesting and important problem. Those portions of the heart which require to develop greater degrees of energy lose the primitive functions of pace making and conduction, and, in the transformation, take on a differentiated structure. It is, then, not the structures in which the primitive functions of pace making and conduction reside which are differentiated, but the greater mass of ventricular muscle. These reflections have their origin not only from our own work but they grow out of observations to be found in the writings of those (A. Keith and I. Mc-Kenzie) who call the nodal and conduction tissues in the heart, embryonic. But whether from the point of view developed here the use of this term is completely descriptive remains an interesting problem.
ON THE RENAL SITE AND MODE OF ACTION OF GLUCOCORTICOID IN CIRRHOSIS*
Authors: Hershel Jick, Julian G. Snyder, Elliot M. Finkelstein, Joseph L. Cohen, Edward W. Moore, Robert S. Morrison
Journal: Journal of Clinical Investigation (1963)

in cirrhotics, patients with cirrhosis on a low-salt diet were studied. The data indicate that these agents given acutely cause increased reabsorption of sodium in the ascending loop of Henle, a segment of the tubule that is relatively impermeable to water, and thus increase the capacity of the kidney of these patients to conserve free water.
The relationship between facial annular erythema and anti-SS-A/Ro antibodies in three East Asian women
Authors: None KAWAKAMI, None SAITO
Journal: British Journal of Dermatology (1999)

A distinct annular erythema developed on the cheeks of three East Asian women who had anti-SS-A/Ro (SSA) antibodies. The erythema was characterized by a wide, elevated border and central pallor. Histologically, there was a coat-sleeve-like infiltration of lymphocytes around the blood vessels, appendages, and secretory gland cells in the dermis. Immunohistological analysis clarified that the majority of infiltrating lymphocytes were CD4-positive T cells. Abnormal expression of HLA-DR antigens in the perivascular, appendage, and secretory gland cells in the dermis was also observed. The differential diagnosis of the three patients lay between Sjögren syndrome (SjS), Sjögren/systemic lupus erythematosus overlap syndrome and an asymptomatic clinical state. These results are consistent with recent findings of major histocompatibility complex class II expression on target organs in various autoimmune diseases. Based on these findings, erythema appears to represent a broad cutaneous manifestation of these diseases. Furthermore, the presence of SSA antibodies, aberrant HLA-DR expression, and sun exposure may be responsible for the development of erythema.
Donepezil for Irradiated Brain Tumor Survivors: A Phase III Randomized Placebo-Controlled Clinical Trial
Authors: Stephen R. Rapp, L. Doug Case, Ann Peiffer, Michelle M. Naughton, Michael D. Chan, Volker W. Stieber, Dennis F. Moore, Steven C. Falchuk, James V. Piephoff, William J. Edenfield, Jeffrey K. Giguere, Monica E. Loghin, Edward G. Shaw
Journal: Journal of Clinical Oncology (2015)

Neurotoxic effects of brain irradiation include cognitive impairment in 50% to 90% of patients. Prior studies have suggested that donepezil, a neurotransmitter modulator, may improve cognitive function.A total of 198 adult brain tumor survivors ≥ 6 months after partial- or whole-brain irradiation were randomly assigned to receive a single daily dose (5 mg for 6 weeks, 10 mg for 18 weeks) of donepezil or placebo. A cognitive test battery assessing memory, attention, language, visuomotor, verbal fluency, and executive functions was administered before random assignment and at 12 and 24 weeks. A cognitive composite score (primary outcome) and individual cognitive domains were evaluated.Of this mostly middle-age, married, non-Hispanic white sample, 66% had primary brain tumors, 27% had brain metastases, and 8% underwent prophylactic cranial irradiation. After 24 weeks of treatment, the composite scores did not differ significantly between groups (P = .48); however, significant differences favoring donepezil were observed for memory (recognition, P = .027; discrimination, P = .007) and motor speed and dexterity (P = .016). Significant interactions between pretreatment cognitive function and treatment were found for cognitive composite (P = .01), immediate recall (P = .05), delayed recall (P = .004), attention (P = .01), visuomotor skills (P = .02), and motor speed and dexterity (P < .001), with the benefits of donepezil greater for those who were more cognitively impaired before study treatment.Treatment with donepezil did not significantly improve the overall composite score, but it did result in modest improvements in several cognitive functions, especially among patients with greater pretreatment impairments.
Impaired skin microvascular function in children, adolescents, and young adults with type 1 diabetes.
Authors: F Khan, T A Elhadd, S A Greene, J J Belch
Journal: Diabetes Care (2000)

Vascular disease in type 1 diabetes is a complex and multifactorial process, which probably begins in childhood in association with the onset of diabetes. To determine the possible factors involved, we measured microvascular responses to endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitroprusside) vasodilators in 56 patients with type 1 diabetes (aged 9-22 years) and 22 control subjects.Skin perfusion was measured at the dorsum of the foot using laser Doppler flowmetry during low-current iontophoresis of acetylcholine and sodium nitroprusside. Maximum vasodilator function was measured during local 44 degrees C skin heating.Vascular responses were significantly reduced in patients with type 1 diabetes compared with responses in control subjects: acetylcholine (P<0.01, analysis of variance [ANOVA]), sodium nitroprusside (P<0.01, ANOVA), and local heating (P<0.02. Mann-Whitney U test). Endothelium-dependent responses were related to duration of diabetes (r = -0.38, P<0.01) and to glycemic control (r = 0.37, P<0.01). Significant correlations were found in the patient group between responses to acetylcholine and sodium nitroprusside (r = 0.28, P<0.05) but not to heating, suggesting that a common factor (e.g., nitric oxide activity) may be responsible for the abnormal vascular responses to these chemicals.Early changes in microvascular function are present in young patients with type 1 diabetes, long before the initial clinical presentation. These abnormalities may be related to complex interactions between structural abnormalities and functional changes in the endothelium, smooth muscle, and nitric oxide activity.
Meeting the Needs of Intensive Care Unit Patient Families
Authors: ELIE AZOULAY, FRÉDÉRIC POCHARD, SYLVIE CHEVRET, FRANÇOIS LEMAIRE, MUSTAFA MOKHTARI, JEAN-ROGER LE GALL, JEAN FRANÇOIS DHAINAUT, BENOÎT SCHLEMMER
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Intensive care unit (ICU) caregivers should seek to develop collaborative relationships with their patients' family members, based on an open exchange of information and aimed at helping family members cope with their distress and allowing them to speak for the patient if necessary. We conducted a prospective multicenter study of family member satisfaction evaluated using the Critical Care Family Needs Inventory. Forty-three French ICUs participated in the study. ICU characteristics, patient and family member demographics, and data on satisfaction were collected. Factors associated with satisfaction were identified using a Poisson regression model. A total of 637 patients were included in the study, and 920 family members completed the questionnaire. Seven predictors of family satisfaction were found: one family-related factor, namely, family of French descent and six caregiver-related factors, namely, no perceived contradictions in information given by caregivers; information provided by a junior physician; patient to nurse ratio ⩽ 3; knowledge of the specific role of each caregiver; help from the family's own doctor; and sufficient time spent giving information. Predictors of satisfaction are amenable to intervention and deserve to be investigated further with the goal of improving the satisfaction of ICU patients' family members.
Passive Smoking on Commercial Airlines-Reply
Authors: Margaret E. Mattson
Journal: JAMA (1989)

<h3>In Reply.—</h3> Concerning the comments of Mr Jones, the intention of the study was not to demonstrate the hazardous nature of passive smoke exposure, which has been amply documented elsewhere.<sup>1,2</sup>Our study demonstrated exposure during the flight to cigarette smoke, which was absorbed and later excreted in the form of cotinine, a metabolite of nicotine. Furthermore, both the degree of exposure to nicotine and the levels of cotinine subsequently excreted were correlated with symptoms of physical irritation as well as annoyance. Second, the purpose of measuring nicotine in the air was because it is a marker of exposure to cigarette smoke. It was not to imply that particular levels of nicotine per se are deleterious. Environmental tobacco smoke contains several thousand chemicals, of which at least 40 are demonstrated carcinogens. These carcinogens are the species of interest for risk-assessment studies. Third, although health information on environmental tobacco smoke is
Defining and Assessing Professional Competence
Authors: Ronald M. Epstein
Journal: JAMA (2002)

ContextCurrent assessment formats for physicians and trainees reliably test core knowledge and basic skills. However, they may underemphasize some important domains of professional medical practice, including interpersonal skills, lifelong learning, professionalism, and integration of core knowledge into clinical practice.ObjectivesTo propose a definition of professional competence, to review current means for assessing it, and to suggest new approaches to assessment.Data SourcesWe searched the MEDLINE database from 1966 to 2001 and reference lists of relevant articles for English-language studies of reliability or validity of measures of competence of physicians, medical students, and residents.Study SelectionWe excluded articles of a purely descriptive nature, duplicate reports, reviews, and opinions and position statements, which yielded 195 relevant citations.Data ExtractionData were abstracted by 1 of us (R.M.E.). Quality criteria for inclusion were broad, given the heterogeneity of interventions, complexity of outcome measures, and paucity of randomized or longitudinal study designs.Data SynthesisWe generated an inclusive definition of competence: the habitual and judicious use of communication, knowledge, technical skills, clinical reasoning, emotions, values, and reflection in daily practice for the benefit of the individual and the community being served. Aside from protecting the public and limiting access to advanced training, assessments should foster habits of learning and self-reflection and drive institutional change. Subjective, multiple-choice, and standardized patient assessments, although reliable, underemphasize important domains of professional competence: integration of knowledge and skills, context of care, information management, teamwork, health systems, and patient-physician relationships. Few assessments observe trainees in real-life situations, incorporate the perspectives of peers and patients, or use measures that predict clinical outcomes.ConclusionsIn addition to assessments of basic skills, new formats that assess clinical reasoning, expert judgment, management of ambiguity, professionalism, time management, learning strategies, and teamwork promise a multidimensional assessment while maintaining adequate reliability and validity. Institutional support, reflection, and mentoring must accompany the development of assessment programs.