tbuckley/cabot-search huggingface dataset:
Chemokines control naive CD8+ T cell selection of optimal lymph node antigen presenting cells
Authors: Heather D. Hickman, Lily Li, Glennys V. Reynoso, Erica J. Rubin, Cara N. Skon, Jacqueline W. Mays, James Gibbs, Owen Schwartz, Jack R. Bennink, Jonathan W. Yewdell
Journal: The Journal of Experimental Medicine (2011)

Naive antiviral CD8+ T cells are activated in the draining LN (DLN) by dendritic cells (DCs) presenting viral antigens. However, many viruses infect LN macrophages, which participate in initiation of innate immunity and B cell activation. To better understand how and why T cells select infected DCs rather than macrophages, we performed intravital microscopy and ex vivo analyses after infecting mice with vaccinia virus (VV), a large DNA virus that infects both LN macrophages and DCs. Although CD8+ T cells interact with both infected macrophages and DCs in the LN peripheral interfollicular region (PIR), DCs generate more frequent and stable interactions with T cells. VV infection induces rapid release of CCR5-binding chemokines in the LN, and administration of chemokine-neutralizing antibodies diminishes T cell activation by increasing T cell localization to macrophages in the macrophage-rich region (MRR) at the expense of PIR DCs. Similarly, DC ablation increases both T cell localization to the MRR and the duration of T cell–macrophage contacts, resulting in suboptimal T cell activation. Thus, virus-induced chemokines in DLNs enable antiviral CD8+ T cells to distinguish DCs from macrophages to optimize T cell priming.
Inhibition of Fatty Acid Synthase Induces Endoplasmic Reticulum Stress in Tumor Cells
Authors: Joy L. Little, Frances B. Wheeler, Diane R. Fels, Constantinos Koumenis, Steven J. Kridel
Journal: Cancer Research (2007)

Abstract Fatty acid synthase (FAS), the cellular enzyme that synthesizes palmitate, is expressed at high levels in tumor cells and is vital for their survival. Through the synthesis of palmitate, FAS primarily drives the synthesis of phospholipids in tumor cells. In this study, we tested the hypothesis that the FAS inhibitors induce endoplasmic reticulum (ER) stress in tumor cells. Treatment of tumor cells with FAS inhibitors induces robust PERK-dependent phosphorylation of the translation initiation factor eIF2α and concomitant inhibition of protein synthesis. PERK-deficient transformed mouse embryonic fibroblasts and HT-29 colon carcinoma cells that express a dominant negative PERK (ΔC-PERK) are hypersensitive to FAS inhibitor–induced cell death. Pharmacologic inhibition of FAS also induces the processing of X-box binding protein-1, indicating that the IRE1 arm of the ER stress response is activated when FAS is inhibited. Induction of ER stress is further confirmed by the increased expression of the ER stress–regulated genes CHOP, ATF4, and GRP78. FAS inhibitor–induced ER stress is activated prior to the detection of caspase 3 and PARP cleavage, primary indicators of cell death, whereas orlistat-induced cell death is rescued by coincubation with the global translation inhibitor cycloheximide. Lastly, FAS inhibitors cooperate with the ER stress inducer thapsigargin to enhance tumor cell killing. These results provide the first evidence that FAS inhibitors induce ER stress and establish an important mechanistic link between FAS activity and ER function. [Cancer Res 2007;67(3):1262–9]
Purification of human interleukin 2 to apparent homogeneity and its molecular heterogeneity.
Authors: K Welte, C Y Wang, R Mertelsmann, S Venuta, S P Feldman, M A Moore
Journal: The Journal of Experimental Medicine (1982)

Interleukin 2 (IL-2), produced with and without co-stimulation by the Burkitt's lymphoma line Daudi, was purified 37,000-fold to apparent homogeneity from lymphocyte conditioned medium by (NH4)2SO4 precipitation, DEAE-cellulose ion-exchange chromatography, gel filtration, and chromatography on blue agarose and on Procion-red agarose. The purified IL-2 showed a 10(6) U/mg protein sp act. IL-2 produced in the absence of Daudi cells had a mol wt of 26,000 as measured by gel filtration and an isoelectric point of 6.7. This IL-2 showed a 16,000 and 17,000 mol wt in sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). IL-2, produced in the presence of Daudi cells (10(6)/ml), showed a mol wt of approximately 14,000, as measured by both gel filtration and SDS-PAGE, and an isoelectric point of 8.1. The purified IL-2 lacked detectable interferon (alpha and gamma), granulocyte-macrophage colony-stimulating factor, B cell growth factor, T cell-replacing factor, and thymocyte-differentiating activity and was free of any contaminating proteins as judged by silver staining in SDS-PAGE. All three molecular forms of IL-2 were biologically active at concentrations of 10(-11) - 10(-10) M, supporting the growth of human and murine cytotoxic T cell lines.
Liver biopsy under ultrasound control Reply
Authors: R J ASPINALL;
Journal: Gut (2000)

Editor,—I read the recent occasional viewpoint by Shah et al ((1999) Gut 45:628–629.[OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4]) with much interest. The authors describe their regional practice of mandatory real time ultrasound guidance for percutaneous liver biopsy in all cases of suspected diffuse liver disease. However, the published literature does not convincingly support the universal adoption of such a policy. The only prospective randomised study cited in support of their protocol, by Lindor and colleagues,1 is open to a number of methodological criticisms. In particular, in an unspecified proportion of the patents randomised to ultrasound guidance, the procedure was not actually performed under direct guidance and was instead immediately preceded by a “biopsy room” ultrasound scan. The net result of this may have been to selectively raise the pre-biopsy scanning rates in the “ultrasound” cohort who were already more likely to have been previously scanned than the “blind” patients (76–78% v 67–68% in the respective groups). In terms of the reduction in post-biopsy complications claimed by Lindor et al , the major impact was a reduction in hospitalisation due to pain. There was no statistically significant difference in the rates of bleeding or hypotension. The reduction in … [1]: {openurl}?query=rft.jtitle%253DHepatology%2B%2528Baltimore%252C%2BMd.%2529%26rft.stitle%253DHepatology%26rft.aulast%253DLindor%26rft.auinit1%253DK.%26rft.volume%253D23%26rft.issue%253D5%26rft.spage%253D1079%26rft.epage%253D1083%26rft.atitle%253DThe%2Brole%2Bof%2Bultrasonography%2Band%2Bautomatic-needle%2Bbiopsy%2Bin%2Boutpatient%2Bpercutaneous%2Bliver%2Bbiopsy%26rft_id%253Dinfo%253Adoi%252F10.1002%252Fhep.510230522%26rft_id%253Dinfo%253Apmid%252F8621137%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=10.1002/hep.510230522&link_type=DOI [3]: /lookup/external-ref?access_num=8621137&link_type=MED&atom=%2Fgutjnl%2F47%2F3%2F455.1.atom [4]: /lookup/external-ref?access_num=A1996UJ44300022&link_type=ISI
Pulmonary endocrine cells in anthracosilicotic lungs
Authors: None Gosney, J Peers, C Beesley, E Gradwell
Journal: European Respiratory Journal (1997)

It has been suggested by some studies of human and animal lungs that the products of pulmonary endocrine cells, particularly gastrin-releasing peptide, might play a role in fibrogenesis, but more recent detailed studies of fibrotic human lungs have failed to confirm this. We have made a detailed quantitative examination of a series of fibrotic human lungs to see if we could determine whether there was any relationship between endocrine cells and fibrosis. Using immunocytochemistry, we investigated the morphology, content, distribution and number of pulmonary endocrine cells in 15 pairs of fibrotic lungs from coal miners, and compared their features with those of equivalent cells in age-matched controls. Proliferation of endocrine cells was seen in the lungs of just two miners, in which it was focal and associated with acute bronchitis and bronchopneumonia. There was no difference between the miners and controls in the appearance (mostly solitary cells), content (predominantly gastrin-releasing peptide and calcitonin), distribution (mainly in small bronchi and bronchioles), or number (4.5 vs 4.1 cells per 10,000 epithelial cells, respectively) of endocrine cells. It seems unlikely that the substances secreted by these cells play any role in stimulating fibrosis in human lungs, but rather that they have a function in the inflammatory response to pulmonary injury.
Nitric Oxide Is a Key Component in Inflammation-Accelerated Tumorigenesis
Authors: S. Perwez Hussain, Peijun He, Jeffery Subleski, Lorne J. Hofseth, Glenwood E. Trivers, Leah Mechanic, Anne B. Hofseth, Mark Bernard, Jonathan Schwank, Giang Nguyen, Ewy Mathe, Draginja Djurickovic, Diana Haines, Jonathan Weiss, Timothy Back, Eilene Gruys, Victor E. Laubach, Robert H. Wiltrout, Curtis C. Harris
Journal: Cancer Research (2008)

Nitric oxide (NO(*)), an important signaling molecule and a component of inflammatory response, is involved in tumorigenesis. However, the quantity of NO(*) and the cellular microenvironment influences the role of NO(*) in tumor development. We used a genetic strategy to test the hypothesis that an inflammatory microenvironment with an enhanced level of NO(*) accelerates spontaneous tumor development. C. parvum-induced inflammation and increased NO(*) synthase-2 (NOS2) expression coincided with accelerated spontaneous tumor development, mostly lymphomas, in p53-/-NOS2+/+ C57BL6 mice when compared with the controls (P = 0.001). However, p53-/-NOS2-/- mice did not show any difference in tumor latency between C. parvum-treated and control groups. In C. parvum-treated p53-/-NOS2+/+ mice, tumor development was preceded by a higher expression of NOS2 and phosphorylated Akt-Ser(473) (pAkt-Ser473) in spleen, increased cell proliferation measured by Ki-67 IHC in spleen and thymus, and a lower apoptotic index and CD95-L expression in spleen and thymus. C. parvum-treated p53-/-NOS2+/+ mice showed an increase in the number of Foxp3(+) T-reg cells, dendritic cells (DC), as well as increased CD80(+), CD86(+), CD40(+), and CD83(+) on DC in the spleen. Regulatory T-cells (T-reg) and the maturation of DC may modulate tumorigenesis. An increase in the FoxP3(+)T-reg cells in C. parvum-treated p53-/-NOS2+/+ mice indicates a role of NO(*) in the regulation of T-reg cells that may contribute to a protumor shift of the immune environment favoring an accelerated tumor development. These data provide genetic and mechanistic evidence that an inflammatory microenvironment and an increased level of NO(*) can accelerate tumor development.
Comparative analysis of the vaginal microbiome in health and disease
Authors: Bryan A White, Andres M Gomez, Mengfei Ho, Margret Berg Miller, Susan M Thomas, Carl J Yeoman, Suleyman Yildirim, Douglas J Creedon, Tony L Goldberg, Steven R Leigh, Karen E Nelson, Rebecca M Stumpf, Brenda A Wilson
Journal: Genome biology (2011)

Deep exome resequencing is a powerful approach for delineating patterns of protein-coding variation among genes, pathways, individuals and populations.We analyzed exome data from 2,440 individuals of European and African ancestry as part of the National Heart, Lung, and Blood Institute's Exome Project, the aim of which is to discover novel genes and mechanisms that contribute to heart, lung and blood disorders.Each exome was sequenced to a mean coverage of 116×, allowing detailed inferences about the population genomic patterns of both common variation and rare coding variation.We identifi ed more than 500,000 single nucleotide variations, the majority of which were novel and rare (76% of variants had a minor allele frequency of less than 0.1%), refl ecting the recent dramatic increase in the size of the human population.The unprecedented magnitude of this dataset allowed us to rigorously characterize the large variation in nucleotide diversity among genes (ranging from 0 to 1.32%), as well as the role of positive and purifying selection in shaping patterns of proteincoding variation and the diff erential signatures of population structure from rare and common variation.This dataset provides a framework for personal genomics and is an important resource that will allow inferences of broad importance to human evolution and health.
THE DEVELOPMENT AND CLINICAL UTILITY OF THE TAXANE CLASS OF ANTIMICROTUBULE CHEMOTHERAPY AGENTS
Authors: Eric K. Rowinsky, MD
Journal: Annual Review of Medicine (1997)

▪ Abstract The taxane class of antimicrotubule anticancer agents is perhaps the most important addition to the chemotherapeutic armamentarium against cancer over the past several decades. After only a brief period, the taxanes have not only demonstrated a unique ability to palliate the symptoms of many types of advanced cancers, including carcinoma of the ovary, lung, head and neck, bladder, and esophagus, they have also demonstrated effectiveness in the initial therapy of earlier stages of cancer, a setting in which any new therapy is likely to make its greatest impact. The challenge now facing investigators is to develop strategies to maximize therapeutic benefits with the taxanes in the early stages, as well as the advanced stages, of many cancers. This review describes the preclinical features and clinical results of the two major taxanes, paclitaxel (Taxol®, Bristol-Myers Squibb) and docetaxel (Taxotere®, Rhone-Poulenc Rhorer).
Effects of Lipid-Lowering by Simvastatin on Human Atherosclerotic Lesions
Authors: Roberto Corti, Zahi A. Fayad, Valentin Fuster, Stephen G. Worthley, Gerard Helft, James Chesebro, Michele Mercuri, Juan J. Badimon
Journal: Circulation (2001)

Background This study was designed to investigate the effects of lipid-lowering by simvastatin on human atherosclerotic lesions. Methods and Results Eighteen asymptomatic hypercholesterolemic patients with documented aortic and/or carotid atherosclerotic plaques were selected for the study. A total of 35 aortic and 25 carotid artery plaques were detected. Serial black-blood MRI of the aorta and carotid artery of the patients was performed at baseline and 6 and 12 months after lipid-lowering therapy with simvastatin. The effects of the treatment on atherosclerotic lesions were measured as changes in lumen area, vessel wall thickness, and vessel wall area, a surrogate of atherosclerotic burden. Simvastatin induced a significant ( P &lt;0.01) reduction in total and LDL cholesterol levels at 6 weeks that was maintained thereafter. At 6 months, no changes in lumen area, vessel wall thickness, or vessel wall area were observed. However, at 12 months, significant reductions in vessel wall thickness and vessel wall area, without changes in lumen area, were observed in both aortic and carotid arteries ( P &lt;0.001). Conclusions This in vivo human study demonstrates that effective and maintained lipid-lowering therapy by simvastatin is associated with a significant regression of atherosclerotic lesions. Our observation suggests that statins induce vascular remodeling, as manifested by reduced atherosclerotic burden without changes in the lumen.
THE REMOVAL OF CARTILAGE MATRIX BY PAPAIN
Authors: J. L. Potter, R. T. McCluskey, G. Weissmann, L. Thomas
Journal: The Journal of Experimental Medicine (1960)

In rabbits, the depletion of cartilage matrix which occurs following intravenous administration of papain treated with iodacetamide is attributable to a portion of the enzyme in the disulfide form which has not undergone alkylation. It is this portion that is reactivated in cartilage in vivo and initiates the enzymatic breakdown of the protein-polysaccharide complex which forms a major component of the matrix. Evidence presented in support of these conclusions indicates that, contrary to an earlier hypothesis, papain acetamide is not reactivated in vivo. Following intravenous injection in amounts up to 4 mg./kg., active and inactive papain leaves the circulation at a rate proportional to the concentration, and it is likely that the initial rate of disappearance represents equilibration with the extracellular space. Following injection in the active or inactive form, a high proportion of papain in serum is bound to protein in the alpha globulin fraction. It is believed that in the case of fully active papain, the proportion which is not bound to alpha globulin becomes attached to other proteins of serum in extracellular fluid, such as albumin, by a process of enzyme substrate combination, and is thus prevented from diffusing into cartilage. In the case of inactive papain, a comparable excess remains free to enter cartilage, where it initiates depletion of matrix following reactivation within the tissue. These conclusions provide an explanation for the failure of fully active papain to cause depletion of cartilage matrix in vivo; the widespread changes seen after the injection of papain inactivated by iodoacetamide or by simple reversible oxidation are attributable to a small proportion of the injected material which enters cartilage in the disulfide form in a concentration of approximately 2 micrograms/gm. wet weight. The possibility that such a small amount of protease, when reactivated, can produce changes in cartilage matrix has been confirmed by studies on the effects of papain on isolated cartilage and chondromucoprotein in vitro. It has been shown that severe local injury results when active papain is injected into the skin of a rabbit in low concentrations. Since a much higher concentration of papain can be attained in the circulation without obvious adverse effects, it is evident that binding of the protease by alpha globulin and possibly other serum proteins may exemplify a mechanism whereby the tissues are protected from injury following entry into the circulation of other potentially harmful agents, such as proteolytic enzymes derived from cells or bacteria.
Z-type alpha 1-antitrypsin is less competent than M1-type alpha 1-antitrypsin as an inhibitor of neutrophil elastase.
Authors: F Ogushi, G A Fells, R C Hubbard, S D Straus, R G Crystal
Journal: Journal of Clinical Investigation (1987)

Alpha 1-antitrypsin (alpha 1AT) deficiency resulting from homozygous inheritance of the Z-type alpha 1AT gene is associated with serum alpha 1AT levels of less than 50 mg/dl and the development of emphysema in the third to fourth decades. Despite the overwhelming evidence that the emphysema of PiZZ individuals develops because of a "deficiency" of alpha 1AT and hence an insufficient antineutrophil elastase defense of the lung, epidemiologic evidence has shown that levels of alpha 1AT of only 80 mg/dl protect the lung from an increased risk of emphysema. With this background, we hypothesized that homozygous inheritance of the Z-type may confer an added risk beyond a simple deficiency of alpha 1AT by virtue of an inability of the Z-type alpha 1AT molecule to inhibit neutrophil elastase as effectively as the common M1-type molecule. To evaluate this hypothesis, the functional status of alpha 1AT from PiZZ individuals (n = 10) was compared with that of alpha 1AT from PiM1M1 individuals (n = 7) for its ability to inhibit neutrophil elastase (percent inhibition) as well as its association rate constant for neutrophil elastase (K association). Plasma alpha 1AT concentration, measured by radial immunodiffusion, was 34 +/- 1 mg/dl in PiZZ patients vs. 237 +/- 14 mg/dl for PiM1M1 plasma, a sevenfold difference. When titrated against neutrophil elastase, the present inhibition of PiZZ plasma was significantly less than Pi M1M1 plasma (ZZ 78 +/- 1% vs. M1M1 95 +/- 1%, P less than 0.001) as was purified Z type alpha 1AT (ZZ, 63 +/- 2% vs. M1M1 86 +/- 2%, P less than 0.001). Sodium dodecyl sulfate (SDS) gel comparisons of the complexes formed with M1-type alpha 1AT and Z-type alpha 1AT with elastase demonstrated the Z alpha 1AT-elastase complexes were less stable than the M1 alpha 1AT-elastase complexes, thus releasing some of the enzyme to continue to function as a protease. Consistent with these observations, the K association of purified Z-type alpha 1AT for neutrophil elastase was lower than that of M1-type alpha 1AT (ZZ 4.5 +/- 0.3 X 10(6) M-1s-1 vs. M1M1 9.7 +/- 0.4 X 10(6) M-1s-1, P less than 0.001), suggesting that for the population of alpha 1AT molecules, the active Z-type molecules take more than twice as long as the active M1-type alpha 1AT to inhibit neutrophil elastase. Consequently, not only is there less alpha1AT in PiZZ individuals, but the population of Z-type alpha1AT molecules is less competent as an inhibitor of neutrophil elastase than M1-type alpha1AT molecules. This combination of defects suggests that PiZZ individuals have far less functional antielastase protection than suggested by the reduced concentrations of alpha1AT alone, further explaining their profound risk for development of emphysema.
Middle aged medicine
Authors: D. Spence
Journal: BMJ (2014)

The greatest joy of youth is the lack of insight. We think we know everything because we have so little life experience we don’t know any better. But life experience isn’t optional. We age, uncertainty replaces certainty, confidence is replaced by insecurity, invincibility is replaced by vulnerability, and what was once important is now unimportant. We realise that intellectual vanity is the worst vanity of all, with people intent on a kind of social plastic surgery to pretend they are something they are not. The only things we really want are the very things we can’t possess. …
Chronic lung disease in the Papua New Guinea Highlands.
Authors: H R Anderson
Journal: Thorax (1979)

In the Eastern Highlands of Papua New Guinea 46 men and 24 women with chronic lung disease underwent clinical and lung function investigations. In all cases the sole or predominant abnormality was irreversible airways obstruction, probably from chronic bronchitis with variable amounts of acompanying emphysema. There were close similarities to chronic obstructife lung disease in European populations in terms of symptoms, airways obstruction, transfer factor, and radiographic emphysema and inflammatory changes. Bronchiectasis and local fibrosis were present in a few subjects, but previous reports that pulmonary and pleural fibrosis are features of the disease were not confirmed. Possibly environmental and genetic factors may increase the associated blood gas disturbances leading to pulmonary hypertension. Unlike chronic obstructive lung disease in European populations, tobacco smoking is not an important aetiological factor. Although there is no direct evidence, the most likely possibilities are domestic wood smoke and acute chest infections.