tbuckley/cabot-search huggingface dataset:
Differential Regulation of Cathepsin S and Cathepsin L in Interferon γ–treated Macrophages
Authors: Courtney Beers, Karen Honey, Susan Fink, Katherine Forbush, Alexander Rudensky
Journal: The Journal of Experimental Medicine (2003)

Cathepsin S (catS) and cathepsin L (catL) mediate late stages of invariant chain (Ii) degradation in discrete antigen-presenting cell types. Macrophages (Mϕs) are unique in that they express both proteases and here we sought to determine the relative contribution of each enzyme. We observe that catL plays no significant role in Ii cleavage in interferon (IFN)-γ–stimulated Mϕs. In addition, our studies show that the level of catL activity is significantly decreased in Mϕs cultured in the presence of IFN-γ whereas catS activity increases. The decrease in catL activity upon cytokine treatment occurs despite the persistence of high levels of mature catL protein, suggesting that a specific inhibitor of the enzyme is up-regulated in IFN-γ–stimulated peritoneal Mϕs. Similar inhibition of activity is observed in dendritic cells engineered to overexpress catL. Such enzymatic inhibition in Mϕs exhibits only partial dependence upon Ii and therefore, other mechanisms of catL inhibition are regulated by IFN-γ. Thus, during a T helper cell type 1 immune response catL inhibition in Mϕs results in preferential usage of catS, such that major histocompatibility complex class II presentation by all bone marrow–derived antigen-presenting cell is regulated by catS.
Recurrence of hepatitis B and delta hepatitis after orthotopic liver transplantation.
Authors: M R Lucey, D M Graham, P Martin, A Di Bisceglie, S Rosenthal, J G Waggoner, R M Merion, D A Campbell, T T Nostrant, H D Appelman
Journal: Gut (1992)

The clinical course of 10 liver transplant recipients who had hepatitis B virus (HBV) and five recipients with HBV and D (delta) infection before transplantation is described. Six patients who underwent eight transplants died. The estimated one and two year survival rates in patients with HBV only before transplantation were 74% and 67% respectively. The estimated one and two year survival in patients with HBV and HDV infection beforehand was 100%. Graft infection by HBV occurred in 8 of 10 patients infected with HBV only; and in 4 of 5 patients with previous HBV and HDV infection. There was a widely variable time from transplantation to the appearance of HBV markers in liver or serum, ranging from 6-331 days. Hepatitis D antigen (HDAg) appeared in three grafts very rapidly after transplantation at 4, 8, and 37 days respectively. Graft infection by HBV was accompanied by significant liver injury in six allografts in five recipients. In particular, there was a striking morphological appearance in five infected livers in which the hepatocytes became progressively enlarged and distorted as they accumulated huge amounts of hepatitis B surface and core antigens (HBsAg, HBcAg). These features were accompanied by pericellular fibrosis and cholestasis but little associated inflammation. This syndrome carried a poor prognosis. A gradual progression to cirrhosis occurred in one additional liver. Finally, recurrent HBV infection was a principal or a contributing factor in all deaths. The presence of HBcAg and inflammation in he native liver increased the risk of HBV induced tissue damaged in the graft whereas HDV infection in the host liver seemed to reduce the risk of significant HBV induced tissue damage in the allograft. These data suggest that post transplant HBV infection is accompanied by a variety of changes in the liver allograft, some of which are unique to the transplanted liver and may result in impaired allograft function.
Overhaul US licensing process for devices, urges Institute of Medicine
Authors: D. Cohen
Journal: BMJ (2011)

The US Food and Drug Administration needs to overhaul the process by which medium risk devices such as hip implants and x ray machines reach the market, an Institute of Medicine report has concluded.

The so called “510(k)” process, introduced by Congress in 1976 when regulation of medical devices began, is one of two regulatory pathways through which medical devices reach the market in the United States.

It requires manufacturers only to show that their product is “substantially equivalent” to another. Currently companies do not have to prove the safety and effectiveness of their product in clinical studies.

Thousands …
Insulin-Like Growth Factor-I: a Key Regulator of Human Cancer Risk?
Authors: K. D. Burroughs, S. E. Dunn, J. C. Barrett, J. A. Taylor
Journal: JNCI Journal of the National Cancer Institute (1999)

In this issue of the Journal, Ma et al. (1) report the results of a nested case–control study that show an association between colorectal cancer risk in men and elevated plasma levels of insulin-like growth factor-I (IGF-I) and decreased plasma levels of IGF-binding protein-3 (IGFBP-3). Importantly, this study demonstrates these effects by using plasma samples drawn years before the clinical appearance of the tumor, thus minimizing the chance that plasma levels are influenced by the disease process. This study follows reports demonstrating associations between levels of IGF-I and/or IGFBP-3 and the risk for cancers of the breast, prostate, and lung, suggesting that IGF-I is an important indicator of risk for the most prevalent forms of cancer in Western society (2–5). In fact, IGF-I levels appear to have a stronger association than most other risk factors for these common cancers. IGF-I is unique as a peptide growth factor. In addition to autocrine/paracrine functions demonstrated in numerous tissues, it serves as an endocrine hormone promoting postnatal somatic growth and maintaining lean tissue mass (6). IGF-I effects are modulated by a family of high-affinity BPs. IGF-I and its principal carrier protein, IGFBP-3, are produced primarily by the liver. Hepatic IGF-I synthesis is regulated by growth hormone (GH) and caloric intake and serves to integrate anabolic signals from the pituitary with signals related to nutritional status. In contrast to insulin, which is involved in short-term regulation of energy metabolism, changes in IGF-I levels occur over a longer term of days to weeks. Dietary restriction, which decreases the serum concentration of IGF-I in both humans and rodents, reduces the incidence of cancer in many rodent models (7,8). Caloric excess, on the other hand, may increase plasma IGF-I in humans (9). Perhaps part of the link between diet and cancer risk might be due to IGF-I and IGFBP-3. Although Ma et al. find little evidence of an association between cancer risk and plasma measures of either total IGF-I or IGFBP-3 alone, they show by a number of different analyses
Peutz Jeghers syndrome polyps are polyclonal with expanded progenitor cell compartment
Authors: W W J de Leng, M Jansen, J J Keller, M de Gijsel, A N A Milne, F H M Morsink, M A J Weterman, C A Iacobuzio-Donahue, H C Clevers, F M Giardiello, G J A Offerhaus
Journal: Gut (2007)

Peutz–Jeghers syndrome (PJS) is an autosomal dominant cancer susceptibility syndrome characterised by mucocutaneous melanin pigmentation, hamartomatous polyps, and an 18-fold increase in intestinal and extraintestinal cancer risk.1 PJS is caused by a germline mutation in LKB1 , a gene that plays a role in cellular polarity.2 Proper cellular polarity is critical for accurate asymmetrical stem cell division.3 The pathogenesis and neoplastic risk, if any, of hamartomatous Peutz–Jeghers polyps remain unclear.

Based on rare observations of neoplastic changes in PJS polyps and the finding of biallelic inactivation of the gene involved in PJS, the existence of a unique hamartoma–carcinoma sequence has been proposed in this disorder.4,5 This concept suggests that PJS polyps are clonal premalignant lesions responsible, at least in part, for the high rates of gastrointestinal cancer in these patients. However, dysplastic changes have been found rarely. Clarification of the risk of neoplastic transformation in PJS polyps would assist …
Transfer of a point mutation in Mycobacterium tuberculosis inhA resolves the target of isoniazid
Authors: Catherine Vilchèze, Feng Wang, Masayoshi Arai, Manzour Hernando Hazbón, Roberto Colangeli, Laurent Kremer, Torin R Weisbrod, David Alland, James C Sacchettini, William R Jacobs
Journal: Nature Medicine (2006)
S125 Ly6Chi circulating monocytes direct alternatively activated, pro-fibrotic, lung macrophage regulation of pulmonary fibrosis
Authors: M. A. Gibbons, A. C. MacKinnon, P. Ramachandran, R. Duffin, K. Dhaliwal, C. Haslett, S. E. M. Howie, A. J. Simpson, N. Hirani, J. Gauldie, J. P. Iredale, T. Sethi, S. J. Forbes
Journal: Thorax (2010)

<h3>Introduction and objectives</h3> Idiopathic pulmonary fibrosis (IPF) remains one of the few respiratory conditions for which there are <i>no</i> effective therapies. The role of monocytes and macrophages in IPF has been disputed as anti-inflammatory therapies produce questionable benefit. Corticosteroids, however, actually induce an alternatively activated, pro-fibrotic, macrophage phenotype. We sought to determine whether monocytes and macrophages play a role in disease pathogenesis in an attempt to explain why current hypotheses and anti-inflammatory therapies have produced limited clinical benefit despite years of research. <h3>Methods</h3> Using multiple in vivo depletional strategies, backed up by an adoptive transfer technique, we extensively investigated the role of monocytes and macrophages during lung fibrogenesis. We performed studies on samples from patients with IPF in an attempt to determine the translational importance of our findings. <h3>Results</h3> Depletion of lung macrophages during fibrogenesis <i>reduced</i> pulmonary fibrosis as measured by lung collagen (p=0.0079), fibrosis score (p=0.0051), and qPCR for surrogate markers of fibrosis <i>Col1</i> (p=0.0083) and <i>a-smooth muscle actin</i> (p=0.0349). There was an associated reduction in expression of markers of alternative macrophage activation, <i>Ym1</i> (p=0.0179), and <i>Arginase1</i>. This reduction was confirmed by immunohistochemistry (IHC) for Ym1 (p=0.0233). IHC on lung macrophages from patients with IPF demonstrated the novel finding of expression of the human alternative macrophage marker CD163. Depletion of Ly6C<sup>hi</sup> circulating monocytes reduced pulmonary fibrosis (p=0.0052). Adoptive transfer of Ly6C<sup>hi</sup> BMDMS during fibrogenesis exacerbated pulmonary fibrosis (p=0.0304). Furthermore, depletion of <i>circulating</i> Ly6C<sup>hi</sup> monocytes lead to a subsequent reduction in the number of Ym1-positive alternatively activated <i>lung</i> macrophages (p=0.0310) with a concomitant reduction in the expression of <i>Ym1</i> and <i>Arginase1</i>. <h3>Conclusions</h3> We have demonstrated that monocytes and macrophages <i>do</i> modulate pulmonary fibrosis and suggest that Ly6C<sup>hi</sup> monocytes (possible fibrocyte precursors) are precursors of alternatively activated, pro-fibrotic, lung macrophages. These findings could link the ‘inflammatory’ and aberrant wound healing hypotheses and explain the lack of effectiveness of corticosteroids in treating IPF. By enhancing our understanding of the pathogenesis of this dreadful disease, our results may enable new therapeutic targets to be developed, facilitate targeted cell-based therapy, and bring hope to one of the longstanding enigmas of respiratory medicine.
mTOR Inhibitor RAD001 Promotes Metastasis in a Rat Model of Pancreatic Neuroendocrine Cancer
Authors: Stefan E. Pool, Sander Bison, Stuart J. Koelewijn, Linda M. van der Graaf, Marleen Melis, Eric P. Krenning, Marion de Jong
Journal: Cancer Research (2012)

Inhibition of mTOR is commonly considered a valid target in cancer treatment, but this assertion does not address effects on the immune microenvironment that may be detrimental to cancer treatment. Here we show how administration of the mTOR inhibitor RAD001 (everolimus) results in the occurrence of distant metastasis in a rat model of pancreatic cancer. RAD001 was administered twice weekly for 4.5 weeks as a single treatment or combined with [(177)Lu-DOTA,Tyr3]octreotate ((177)Lu-DOTATATE), where the latter targets the somatostatin receptor-2. The hypothesized synergistic therapeutic effect of RAD001 combined with (177)Lu-DOTATATE was, however, not observed in our experiments. The combination was shown to be less effective than (177)Lu-DOTATATE alone. Unexpectedly, tumor metastasis was observed in 77% of the subjects treated with RAD001, either alone or as part of the combination treatment. This was a striking effect, because metastasis did not occur in control or (177)Lu-DOTATATE-treated animals, including those where the primary tumor was surgically removed. These findings may be important clinically among noncompliant patients or patients that discontinue RAD001 therapy because of adverse effects.
Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells
Authors: Takashi Yahata, Tomomi Takanashi, Yukari Muguruma, Abd Aziz Ibrahim, Hideyuki Matsuzawa, Tomoko Uno, Yin Sheng, Makoto Onizuka, Mamoru Ito, Shunichi Kato, Kiyoshi Ando
Journal: Blood (2011)
Two Cases of Ovarian Cyst in Childhood
Authors: P. T. Bray, L. P. Thomas
Journal: BMJ (1954)

MEDICAL MEMORANDA course in the hope that the gastric haemorrhage, which was presumed to have come from the fundus, where adherent clot was found, would not recur.The patient's condition improved for several days, though intermittent melaena occurred.On April 1 I passed an oesophagoscope into the stomach and found no evidence of bleeding or lesion in the oesophagus, but there was old clot in the stomach.Shortly after this lie started to bleed severely, and as the consulting haematologist again found no evidence of blood dyscrasia I decided to do a total gastrectomy.Second Operation.-OnApril 1, under a similar anaes- thetic, the old incision was opened up and extended.There was a good deal of mild peritonitis due to the previous gastrotomy.Total gastrectomy was performed and a retro- colic jejunal loop was anastomosed to the oesophagus without entero-anastomosis (operative time two hours).Recovery was uneventful and the patient was discharged on April 26 on an unrestricted diet.
Elevated Plasma Free Fatty Acid Concentrations in Patients with Pheochromocytoma
Authors: Karl Engelman, Peter S. Mueller, Albert Sjoerdsma
Journal: New England Journal of Medicine (1964)

THE catechol amines, norepinephrine and epinephrine, have been found to stimulate the release of free fatty acids from adipose tissue. In 1956 Dole1 and Gordon and Cherkes2 reported a rise in plasma free fatty acids after intravenous administration of epinephrine to human beings. Havel and Goldfien3 showed that norepinephrine was also potent in elevating plasma free fatty acids, and in 1962 Mueller and Horwitz4 related the fatty acid mobilizing capacity of primary and secondary amine derivatives of phenylethylamine to the presence of hydroxyl groups at the para-carbon and beta-carbon positions. An enzymatic basis for these effects has been offered by . . .
Striking Increase of Survival of Mice Bearing M 109 Madison Carcinoma Treated With a Novel Protein From With a Novel Protein From Amphibian Embryos
Authors: S M Mikulski, W Ardelt, K Shogen, E H Bernstein, H Menduke
Journal: JNCI Journal of the National Cancer Institute (1990)

Journal Article Striking Increase of Survival of Mice Bearing M 109 Madison Carcinoma Treated With a Novel Protein From With a Novel Protein From Amphibian Embryos Get access STANISLAW M. MIKULSKI, STANISLAW M. MIKULSKI Alfacell Corporation 225 Belleville Ave. Bloomfield, NJ 07003PA Search for other works by this author on: Oxford Academic PubMed Google Scholar WOJCIECH ARDELT, WOJCIECH ARDELT Alfacell Corporation 225 Belleville Ave. Bloomfield, NJ 07003PA Search for other works by this author on: Oxford Academic PubMed Google Scholar KUSLIMA SHOGEN, KUSLIMA SHOGEN Alfacell Corporation 225 Belleville Ave. Bloomfield, NJ 07003PA Search for other works by this author on: Oxford Academic PubMed Google Scholar EUGENE H. BERNSTEIN, EUGENE H. BERNSTEIN University Laboratories, Inc. Hoghland Park, NJPA Search for other works by this author on: Oxford Academic PubMed Google Scholar HYMAN MENDUKE HYMAN MENDUKE Department of Pharmacology Jefferson Medical College PhiladelphiaPA 1 We thank Joyce H. Smoyak of University Laboratories, Inc., for her devotion and commitment in conducting the animal studies. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 82, Issue 2, 17 January 1990, Pages 151–153, https://doi.org/10.1093/jnci/82.2.151-a Published: 17 January 1990
Are Chemotherapy Response Rates Related to Treatment-Induced Survival Prolongations in Patients With Advanced Cancer?
Authors: Tait D. Shanafelt, Charles Loprinzi, Randolph Marks, Paul Novotny, Jeff Sloan
Journal: Journal of Clinical Oncology (2004)

Purpose Patients with incurable cancer are faced with difficult decisions regarding whether to take chemotherapy in an attempt to preserve the quality and/or prolong the quantity of their lives. The average prolongation in survival with chemotherapy compared with best supportive care has not been well described. Methods We performed a literature search using PUBMED combined with expert inquiry to identify trials comparing cytotoxic chemotherapy with best supportive care. Twenty-five randomized, controlled clinical trials comparing cytotoxic chemotherapy with best supportive care were identified. Sixteen trials (64%) were in patients with non–small-cell lung cancer (NSCLC). Data were extracted and analyzed. Results Sufficient data for statistical modeling were available for NSCLC trials. The mean sample size of the NSCLC trials was 175 patients. Response rates in the treatment arms for NSCLC ranged from 7% to 42%. A relationship between response rate and survival was observed for NSCLC. The estimated relationship for NSCLC suggested that each 3.3% increase in response rate correlated, on average, with a 1-week increase in median survival, and each 2% increase in response rate correlated, on average, with a 1% increase in 1-year survival. The mean increase in 1-year survival for trials of agents with at least a 20% response rate in NSCLC was 16%. Formulas are provided to help estimate how a given response rate may effect median and 1-year survival relative to best supportive care alone for NSCLC. Conclusion We found a relationship between response rate and both median and 1-year survival in NSCLC. This information may help oncologists estimate how an NSCLC chemotherapy regimen with a given response rate can, on average, impact survival relative to supportive care alone.
N-acetylcysteine and clotrimazole inhibit sickle erythrocyte dehydration induced by 1-chloro-2,4-dinitrobenzene
Authors: Archil Shartava, Arvind K. Shah, Steven R. Goodman
Journal: American Journal of Hematology (1999)

Clotrimazole, a specific inhibitor of the Ca(2+) activated potassium (Gardos) channel, and the antioxidant N-acetylcysteine were found to inhibit the in vitro formation of high-density sickle cells induced by treatment with 1-chloro-2,4-dinitrobenzene (CDNB). The CDNB induced leakage of K(+) can be inhibited by treatment of SS erythrocytes with 20 mM N-acetylcysteine. We conclude that the effect of N-acetylcysteine in preventing K(+) efflux and formation of high-density sickle cells is related to its ability to protect the Gardos channel from oxidative damage caused by diminished levels of reduced glutathione. This effect is due to the ability of N-acetylcysteine to maintain an appropriate level of reduced glutathione and its direct antioxidant activity.
CONTEMPORARY NATIONAL TRENDS AND OUTCOMES OF INFERIOR VENA CAVA FILTER PLACEMENT IN HIGH BLEEDING RISK PATIENTS WITH PROXIMAL LOWER EXTREMITY DEEP VEIN THROMBOSIS
Authors: Michael Andrew Lashner, Chad Zack, Huaqing Zhao, Eric Choi, Grayson Wheatley, Riyaz Bashir
Journal: Journal of the American College of Cardiology (2014)
UK will launch European health insurance card in September
Authors: Rory Watson
Journal: BMJ (2005)

The standardised European health insurance card, launched last year, has quickly established itself as an essential item for people travelling to, or working temporarily in, countries in the European Union other than their own. The card, which entitles the visitor to urgent medical treatment as if they were insured in the host country, is now carried by 30 million EU citizens.

The United Kingdom will start issuing the card, which is valid for five years, to residents in September. This will replace the E111 form, the traditional certificate for non-private health insurance when abroad. Thirteen of the EU's …
Catecholamine release from bovine adrenal chromaffin cells during anoxia or metabolic inhibition.
Authors: K L Dry, J H Phillips, A M Dart
Journal: Circulation Research (1991)

A significant release of catecholamines within the heart has been observed during myocardial ischemia. Because this can be markedly inhibited by amine-uptake-blocking agents, it has been suggested that its mechanism is a carrier-mediated efflux from neurons, which is not operative under normal conditions. The present work examined this release process in chromaffin cells isolated from the bovine adrenal medulla, a model system for studying the sympathetic nervous system. Chromaffin cells in primary culture retained normal secretory responses for up to 7 days. Conditions designed to mimic ischemia, that is, anoxia or metabolic inhibition, resulted in a significant release of catecholamines. This release was shown to be independent of extracellular calcium but, in contrast to the release observed in ischemic hearts, was not inhibited by amine-uptake blockers. Electrophoresis with immunoblotting demonstrated that significant levels of the chromaffin granule protein, chromogranin A, were released during metabolic inhibition, indicative of an exocytotic mechanism. However, there was no release of the cytosolic protein, lactate dehydrogenase, indicating that there was no concomitant breakdown of the cell membrane. These results provide evidence for an exocytotic release of catecholamines mediated by the direct action of conditions of metabolic inhibition.
A Comparison of Accuracy and Estimated Cost of Methods for Home Blood Glucose Monitoring
Authors: Brahm Shapiro, Peter J Savage, Diane Lomatch, Thomas Gniadek, Ray Forbes, Rebecca Mitchell, Karla Hein, Renate Starr, Marie Nutter, Betty Scherdt
Journal: Diabetes Care (1981)

Venous serum glucose concentrations determined by a laboratory hexokinase technique were compared over a wide range of glucose concentrations with concentrations of capillary blood glucose determined by three reflectance meter techniques currently available in the United States (Eyetone and Dextrometer, Ames Company; StatTek, Bio-Dynamics BMC) and by visual interpretation of reagent strips (Chemstrip bG, Bio-Dynamics BMC). The Chemstrip bG reagent strip was read by patients, nurses, and a physician. In all cases, there was an excellent correlation between laboratory serum glucose concentrations and reflectance meter blood glucose determinations (r = 0.90–0.94, P &amp;lt; 0.0001) or visual interpretation of Chemstrip bG (r = 0.85–0.92, P &amp;lt; 0.0001). Chemstrip bG appears to be the least expensive method of glucose measurement. This method offers additional advantages in not requiring a reflectance meter, which needs frequent recalibration and other ancillary equipment for blood glucose determination.
Changes in atopy over 25 years: Allergy epidemic has spread to old age
Authors: Allan Linneberg
Journal: BMJ (2005)

EDITOR—The data presented by Law et al on changes in atopy over 25 years seem to challenge the idea that respiratory allergies affect mainly young people.1 They present evidence that atopy (detectable serum IgE antibodies against inhalant allergens) has increased in middle aged men over recent decades.

Furthermore, their results support the notion that atopy is …