tbuckley/cabot-search huggingface dataset:
Absence of trauma-induced leukocyte rolling in mice deficient in both P-selectin and intercellular adhesion molecule 1.
Authors: E J Kunkel, U Jung, D C Bullard, K E Norman, B A Wolitzky, D Vestweber, A L Beaudet, K Ley
Journal: The Journal of Experimental Medicine (1996)

Leukocyte recruitment during inflammation is achieved through a multistep paradigm that includes margination, selectin-mediated rolling, beta 2 integrin-mediated firm adhesion, emigration, and migration into the site of inflammation. We have used the mouse cremaster muscle as a model of trauma- and cytokine-induced inflammation to study the possible role of intercellular adhesion molecule (ICAM) 1 in leukocyte rolling using gene-targeted mice deficient in ICAM-1, P-selectin, and a combination of P-selectin and ICAM-1. Rolling flux and average leukocyte rolling velocity in ICAM-1-deficient mice was not different from wild-type mice, but P-selectin/ICAM-1-deficient mice showed a total absence of rolling for at least 2 h after surgical trauma. Rolling in both wild-type and ICAM-1-deficient mice 60-120 min after trauma was significantly inhibited by a P-selectin monoclonal antibody (mAb) (RB40.34). In contrast, an mAb (KAT-1) blocking ICAM-1 binding to leukocyte function-associated antigen 1 did not block residual rolling in P-selectin-deficient mice. TNF-alpha induced leukocyte rolling in P-selectin/ICAM-1-deficient mice, but the rolling flux fraction was significantly lower than in TNF-alpha-treated ICAM-1-deficient mice. Leukocyte rolling in P-selectin/ICAM-1-deficient mice treated with TNF-alpha for 3 h was completely blocked by an E-selectin mAb (9A9E3), and partially by an L-selectin mAb (MEL-14). This clearly demonstrates E-selectin-dependent rolling in vivo. Leukocyte rolling velocities were significantly reduced after TNF-alpha treatment and were similar in wild-type and gene-targeted strains. We conclude that the residual trauma-induced leukocyte rolling seen in P-selectin-deficient mice is completely abolished by concomitant ICAM-1 deficiency. This severe defect in leukocyte rolling may explain the absence of leukocyte recruitment into the inflamed peritoneal cavity of P-selectin/ICAM-1-deficient mice at early time points (&amp;lt; or = 4 h).
Attenuation of exercise induced asthma by local hyperthermia.
Authors: S L Johnston, D Perry, S O'Toole, Q A Summers, S T Holgate
Journal: Thorax (1992)

BACKGROUND: Prior treatment with local hyperthermia has been shown to prevent mast cell degranulation and leucocyte histamine release, and to reduce mortality and cellular infiltrates in a model of acute lung injury. Local hyperthermia is effective in reducing the symptoms of the common cold and perennial and seasonal allergic rhinitis, nasal patency also being improved in rhinitis. It is possible that these effects are mediated by common anti-inflammatory mechanisms, and that this treatment may be effective in the treatment of asthma. The effect of prior local hyperthermia on the response to exercise challenge and histamine bronchoprovocation was therefore examined. METHODS: In a randomised, double blind, placebo controlled, crossover study, 10 asthmatic subjects with exercise induced asthma used machines delivering 40 1/minute of fully humidified air at either 42 degrees C (active treatment) or 31 degrees C (placebo treatment) for 30 minutes9 tidal breathing. For each pretreatment, at two week intervals they underwent exercise challenges starting one and 24 hours after starting the inhalations. After a further two weeks the protocol was repeated with histamine substituted for the exercise challenges. RESULTS: The mean (SE) maximum percentage fall in forced expiratory volume in one second (FEV1) was significantly lower one hour after treatment with air at 42 degrees C (30.8% (3.1%)) than after treatment with air at 31 degrees C (22.3% (2.9%)). There was no significant effect on exercise challenge at 24 hours, or on histamine challenge at either time point, though there were nonsignificant trends towards protection with exercise at 24 hours and with histamine at one hour. CONCLUSION: In asthmatic subjects the response to exercise challenge is significantly attenuated one hour after treatment with local hyperthermia. This treatment warrants further investigation in the treatment of clinical asthma and other inflammatory disorders.
Neutral metalloproteases and age related changes in human articular cartilage.
Authors: J Martel-Pelletier, J P Pelletier
Journal: Annals of the Rheumatic Diseases (1987)

A decrease in proteoglycan (Pg) content and disturbances in the collagen network have been reported in aging cartilage. This study aims to determine whether these changes are associated with proteolytic enzymes such as neutral metalloproteases. Eighty lateral tibial plateaus were collected from subjects after death. The age, topographical area, and lesion severity (macroscopic grading) of each specimen were noted and the effects of neutral metallo-Pg-degrading and collagenolytic enzymes on these specimens were compared. The specimens were divided into two age groups: 20-50 years (group 1) and greater than 50 years (group 2). They were selected from both weight bearing and non-weight bearing areas. In some cartilage tissues the superficial layer was separated from the deep zone. Our data for the two neutral metalloenzymes examined showed: no correlation between enzyme activity and age when the specimens were of the same grade and a statistically significant rise in the enzyme levels of the older specimens, which increased as the lesions progressed. Neutral metallo-Pg-degrading enzyme activity was higher in non-weight bearing areas than in weight bearing areas, and this reached a statistical difference in the older cartilage with advanced lesions. The Pg-degrading enzyme activity was raised in the superficial layers of damaged cartilage tissue. Our data suggest that neutral metalloproteases are closely associated with the appearance and progression of the changes seen in aging cartilage.
Potassium Efflux from Amphibian Atrium during the Cardiac Cycle: A REEXAMINATION
Authors: DAVID F. JUNCKER, ERNEST A. GREENE, RICHARD STISH, VICTOR LORBER
Journal: Circulation Research (1972)

Fine fibers from amphibian atrium were mounted in a microperfusion chamber and loaded with 42 K, followed by a rapid, nonisotopic wash during which the preparation was stimulated electrically. The stimulus was triggered and the "cold" effluent collected by a high-speed rotary fraction collector. Thus effluent corresponding to the same time interval in the cardiac cycle was always collected in the same tube. Large numbers of cycles were thus summed, decreasing the error in the tracer assay. Mechanical systole, previously shown to produce an artifact in the tracer efflux profile, was suppressed or prevented by various means. Under these conditions, a prolonged decrease in 42 K efflux was observed, corresponding in time to the plateau of the action potential. Experiments were also carried out with 22 Na, 45 Ca, and 82 Br, all of which showed primarily a single, positive efflux peak with its maximum within the first 50 msec of the action potential. Cell membrane permeability to K + appears to be markedly voltage dependent; and a diminished membrane permeability to K + apparently plays an important part in the generation of the plateau of the cardiac action potential.
Androgen Causes Growth Suppression and Reversion of Androgen-Independent Prostate Cancer Xenografts to an Androgen-Stimulated Phenotype in Athymic Mice
Authors: Chih-pin Chuu, Richard A. Hiipakka, Junichi Fukuchi, John M. Kokontis, Shutsung Liao
Journal: Cancer Research (2005)

Abstract Most prostate cancer patients develop androgen-independent recurrent prostate tumors a few years after androgen ablation therapy. No therapy, however, has been shown to substantially extend survival in these patients. Previously, we reported that androgen suppresses the growth of androgen-independent LNCaP prostate tumor cells both in vitro and in vivo. In cell culture, androgen receptor (AR)–rich androgen-independent LNCaP 104-R1 cells adapt to growth suppression by androgen and then their growth is androgen stimulated. Because maintaining androgen dependency of prostate tumor cells should prolong the usefulness of androgen ablation therapy, we determined if androgen-independent prostate tumors would revert to an androgen-stimulated phenotype in vivo upon androgen treatment. Growth of the LNCaP 104-R1 tumors was suppressed by androgen, but tumors then adapted to suppression by androgen and growth became androgen stimulated. Tumor AR and prostate-specific antigen mRNA and protein were initially high in 104-R1 tumors but decreased during adaptation. Subsequent removal of androgen decreased the serum prostate-specific antigen level further and stopped the growth of the adapted tumors. Because androgen caused growth suppression and then reversion of androgen-independent tumors to an androgen-stimulated phenotype and because the growth of androgen-stimulated tumors could be restrained by androgen ablation, these results suggest a novel therapy for AR-positive androgen-independent prostate cancer.
Carbon monoxide stimulates the apical 70-pS K+ channel of the rat thick ascending limb
Authors: HuaJun Liu, David B. Mount, Alberto Nasjletti, WenHui Wang
Journal: Journal of Clinical Investigation (1999)

We have investigated the expression of heme oxygenase (HO) in the rat kidney and the effects of HO-dependent heme metabolites on the apical 70-pS K+ channel in the thick ascending limb (TAL). Reverse transcriptase–PCR (RT-PCR) and Western blot analyses indicate expression of the constitutive HO form, HO-2, in the rat cortex and outer medulla. Patch-clamping showed that application of 10 μM chromium mesoporphyrin (CrMP), an inhibitor of HO, reversibly reduced the activity of the apical 70-pS K+ channel, defined by NPo, to 26% of the control value. In contrast, addition of 10 μM magnesium protoporphyrin had no significant effect on channel activity. HO involvement in regulation of the apical 70-pS K+ channel of the TAL, was further indicated by the addition of 10 μM heme-L-lysinate, which significantly stimulated the channel activity in cell-attached patches by 98%. The stimulatory effect of heme on channel activity was also observed in inside-out patches in the presence of 0.5–1 mM reduced nicotinamide adenine dinucleotide phosphate. This was completely abolished by 10 μM CrMP, suggesting that a HO-dependent metabolite of heme mediated the effect. This was further supported by exposure of the cytosolic membrane of inside-out patches to a carbon monoxide–bubbled bath solution, which increased channel activity. Moreover, carbon monoxide completely abolished the effect of 10 μM CrMP on the channel activity. In contrast, 10 μM biliverdin, another HO-dependent metabolite of heme, had no effect. We conclude that carbon monoxide produced from heme via an HO-dependent metabolic pathway stimulates the apical 70-pS K+ channel in the rat TAL.
Prospective Study of Adult Onset Diabetes Mellitus (Type 2) and Risk of Colorectal Cancer in Women
Authors: F. B. Hu, J. E. Manson, S. Liu, D. Hunter, G. A. Colditz, K. B. Michels, F. E. Speizer, E. Giovannucci
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: The remarkable similarity of lifestyle and environmental risk factors for type 2 (non-insulin-dependent) diabetes mellitus and colon cancer has led to the hypothesis that diabetes may increase the risk of this cancer. We prospectively examined the relationship between diabetes and risk of colorectal cancer in a cohort of 118 403 women aged 30 through 55 years who were without previously diagnosed cancer at baseline in 1976. METHODS: The women, who were enrolled in the Nurses' Health Study, were assessed for history of diabetes at baseline and during follow-up by use of biennial questionnaires. Self-reported diabetes was validated by information obtained from a supplemental questionnaire on symptoms and treatment and was confirmed by medical record review in a sample of the participants. Incident cases of colorectal cancer were ascertained through medical record review. All reported P values are two-sided. RESULTS: During 18 years of follow-up (2 001 061 person-years), we documented 892 new cases of colorectal cancer. After adjustment for age, body mass index (weight in kg/height in m 2 ), physical activity, and other covariates, relative risks (RRs) were 1.43 (95% confidence interval [ CI] = 1.10-1.87; P = .009) for colorectal cancer, 1.49 (95% CI = 1.09-2.06; P = .01) for colon cancer, 1.11 (95% CI = 0.56-2.21; P = .76) for rectal cancer, 1.56 (95% CI = 1.07-2.28; P = .02) for advanced colorectal cancer, and 2.39 (95% CI = 1.46-3.92; P = .0005) for fatal colorectal cancer. CONCLUSION: Our data provide support for the hypothesis that diabetes is associated with an increased risk of colorectal cancer in women.
The Missing Link between Clinical States and Biomarkers in Mental Disorders
Authors: Giovanni A. Fava, Jenny Guidi, Silvana Grandi, Gregor Hasler
Journal: Psychotherapy and Psychosomatics (2014)

Current diagnostic definitions of psychiatric disorders based on collections of symptoms encompass very heterogeneous populations and are thus likely to yield spurious results when exploring biological correlates of mental disturbances. It has been suggested that large studies of biomarkers across diagnostic entities may yield improved clinical information. Such a view is based on the concept of assessment as a collection of symptoms devoid of any clinical judgment and interpretation. Yet, important advances have been made in recent years in clinimetrics, the science of clinical judgment. The current clinical taxonomy in psychiatry, which emphasizes reliability at the cost of clinical validity, does not include effects of comorbid conditions, timing of phenomena, rate of progression of an illness, responses to previous treatments, and other clinical distinctions that demarcate major prognostic and therapeutic differences among patients who otherwise seem to be deceptively similar since they share the same psychiatric diagnosis. Clinimetrics may provide the missing link between clinical states and biomarkers in psychiatry, building pathophysiological bridges from clinical manifestations to their neurobiological counterparts.
The failing malignant liver
Authors: B C SMITH, O F W JAMES
Journal: Gut (1998)

See article on page 576 

Acute liver failure, defined as hepatic encephalopathy developing within 12 weeks of jaundice in the absence of a previous history of symptomatic liver disease,1 is a medical emergency. Accurate recognition of the underlying disease is crucial to enable specific therapy, when available, to be instituted. Rowbotham et al (see page 576), in the most comprehensive examination of this topic to date, discuss the importance of malignant hepatic infiltration as a cause of acute liver failure. This is, however, an undoubtedly rare cause for this presentation in the UK, responsible for only 0.44% of all cases of liver failure admitted to the King’s Unit since 1978.

This syndrome can occur in a number of scenarios. Firstly and most importantly, patients with no previous history of malignancy may develop fulminant liver failure and present as a diagnostic problem. Secondly, acute liver failure may develop in a patient with previously diagnosed malignancy but without known liver involvement. Finally, fulminant liver failure may be seen as a terminal event in a patient already known to have primary or secondary hepatic malignancy. Such patients, although not fulfilling the strict diagnostic criteria for acute liver failure, may provide further insight into the likely mechanisms of liver failure in malignancy.

In a patient presenting with acute liver failure with no cause apparent, the diagnosis of hepatic infiltration should be considered but may be surprisingly difficult to …
Imaging Intratumor Heterogeneity: Role in Therapy Response, Resistance, and Clinical Outcome
Authors: James P.B. O'Connor, Chris J. Rose, John C. Waterton, Richard A.D. Carano, Geoff J.M. Parker, Alan Jackson
Journal: Clinical Cancer Research (2014)

Abstract Tumors exhibit genomic and phenotypic heterogeneity, which has prognostic significance and may influence response to therapy. Imaging can quantify the spatial variation in architecture and function of individual tumors through quantifying basic biophysical parameters such as CT density or MRI signal relaxation rate; through measurements of blood flow, hypoxia, metabolism, cell death, and other phenotypic features; and through mapping the spatial distribution of biochemical pathways and cell signaling networks using PET, MRI, and other emerging molecular imaging techniques. These methods can establish whether one tumor is more or less heterogeneous than another and can identify subregions with differing biology. In this article, we review the image analysis methods currently used to quantify spatial heterogeneity within tumors. We discuss how analysis of intratumor heterogeneity can provide benefit over more simple biomarkers such as tumor size and average function. We consider how imaging methods can be integrated with genomic and pathology data, instead of being developed in isolation. Finally, we identify the challenges that must be overcome before measurements of intratumoral heterogeneity can be used routinely to guide patient care. Clin Cancer Res; 21(2); 249–57. ©2014 AACR.
No effects of PRP on ultrasonographic tendon structure and neovascularisation in chronic midportion Achilles tendinopathy
Authors: R J de Vos, A Weir, J L Tol, J A N Verhaar, H Weinans, H T M van Schie
Journal: British Journal of Sports Medicine (2010)

Objective To assess whether a platelet-rich plasma (PRP) injection leads to an enhanced tendon structure and neovascularisation, measured with ultrasonographic techniques, in chronic midportion Achilles tendinopathy. Design Double-blind, randomised, placebo-controlled clinical trial. Setting Sports medical department of The Hague medical centre. Patients 54 patients with chronic midportion Achilles tendinopathy were included. Interventions Patients were randomised to eccentric exercise therapy with either a PRP injection (PRP group) or a saline injection (placebo group). Main outcome measurements Tendon structure was evaluated by ultrasonographic tissue characterisation, a novel technique which quantifies tendon structure into four echo-types: echo-types I+II represent organised tendon bundles, whereas echo-types III+IV represent a disorganised tendon structure. Colour Doppler ultrasonography was used to measure the degree of neovascularisation. Follow-up was at 6, 12 and 24 weeks. Results A significant improvement in echo-types I+II was found after 24 weeks within both the PRP group (n=27) and the placebo group (n=27), but there was no significant between-group difference (95% CI −1.6 to 7.8, p=0.169). After 6 weeks, the neovascularisation score increased within the PRP group (p=0.001) and the placebo group (p=0.002), but there was no significant between-group difference in change in neovascularisation score at any point in time. Conclusion Injecting PRP for the treatment of chronic midportion Achilles tendinopathy does not contribute to an increased tendon structure or alter the degree of neovascularisation, compared with placebo. Funding Biomet Biologics LLC, Warsaw, Indiana.
Determining Prognosis in Patients With Pancreatic Endocrine Neoplasms: Can the WHO Classification System Be Simplified?
Authors: Cristina R. Ferrone, Laura H. Tang, James Tomlinson, Mithat Gonen, Steven N. Hochwald, Murray F. Brennan, David S. Klimstra, Peter J. Allen
Journal: Journal of Clinical Oncology (2007)

Purpose The WHO classification for well-differentiated pancreatic endocrine neoplasms (PENs) incorporates both stage and grade. This study compares the prognostic value of a simplified staging and grading system with the WHO system in a large single-institution study. Patients and Methods A prospective database (1982 to 2005) identified 183 patients who underwent operative treatment for PENs. Tumors were staged (&lt; 2 cm primary, ≥ 2 cm primary, or metastases) and graded (low grade: no necrosis and &lt; two mitoses/50 high-powered fields [HPF]; or intermediate grade: necrosis and/or ≥ two mitoses/50 HPF) with a simplified schema. Influence of stage and grade on recurrence and disease-specific survival (DSS) was determined. Prognostic strength was assessed with the concordance index (CI). Results Median age of the 183 patients was 56 years, and 53% were women. Median follow-up time was 44 months (range, 1 to 226 months). Classification identified 28 patients (15%) with WHO 1.1 disease, 74 (41%) with 1.2 disease, and 81 (44%) with 2.0 disease. Classification by stage identified 35 patients (19%) with tumors less than 2 cm, 96 (52%) with tumors ≥ 2 cm, and 52 (29%) with nodal or distant metastases. Tumors were low grade in 102 patients (56%). Earlier stage tumors were more likely to be low grade (&lt; 2 cm, 83%; ≥ 2 cm, 61%; metastases, 28%; P &lt; .001). The WHO classification, tumor stage, and grade were associated with 5-year DSS (P &lt; .001). Tumors ≥ 2 cm or metastases are stratified by grade (5-year DSS rate for low v intermediate grade: ≥ 2 cm, 97% v 80%, respectively; P &lt; .001; metastases, 93% v 62%, respectively; P = .05). The CI was 0.72 for WHO, 0.71 for stage, 0.66 for grade, and 0.76 for stage combined with grade. Conclusion Accurate prognostic information can be obtained by combining tumor size and metastases with simple grading information based on necrosis and mitotic rate.
Functional Protection by Acute Phase Proteins α <sub>1</sub> -Acid Glycoprotein and α <sub>1</sub> -Antitrypsin Against Ischemia/Reperfusion Injury by Preventing Apoptosis and Inflammation
Authors: Marc A. R. C. Daemen, Vincent H. Heemskerk, Cornelis van ’t Veer, Geertrui Denecker, Tim G. A. M. Wolfs, Peter Vandenabeele, Wim A. Buurman
Journal: Circulation (2000)

Ischemia followed by reperfusion (I/R) causes apoptosis, inflammation, and tissue damage leading to organ malfunction. Ischemic preconditioning can protect against such injury. This study investigates the contribution of the acute phase proteins alpha(1)-acid glycoprotein (AGP) and alpha(1)-antitrypsin (AAT) to the protective effect of ischemic preconditioning in the kidney.Exogenous AGP and AAT inhibited apoptosis and inflammation after 45 minutes of renal I/R in a murine model. AGP and AAT administered at reperfusion prevented apoptosis at 2 hours and 24 hours, as evaluated by the presence of internucleosomal DNA cleavage, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling, and the determination of renal caspase-1- and caspase-3-like activity. AGP and AAT exerted anti-inflammatory effects, as reflected by reduced renal tumor necrosis factor-alpha expression and neutrophil influx after 24 hours. In general, these agents improved renal function. Similar effects were observed when AGP and AAT were administered 2 hours after reperfusion but to a lesser extent and without functional improvement. Moreover, I/R elicited an acute phase response, as reflected by elevated serum AGP and serum amyloid P (SAP) levels after 24 hours, and increased hepatic acute phase protein mRNA levels after 18 hours of renal reperfusion.We propose that the antiapoptotic and anti-inflammatory effects of AGP and AAT contribute to the delayed type of protection associated with ischemic preconditioning and other insults. This mechanism is potentially involved in the course of many clinical conditions associated with I/R injury. Moreover, exogenous administration of these proteins may provide new therapeutic means of treatment.