tbuckley/cabot-search huggingface dataset:
Sn-protoporphyrin lowers serum bilirubin levels, decreases biliary bilirubin output, enhances biliary heme excretion and potently inhibits hepatic heme oxygenase activity in normal human subjects
Authors: Lars Berglund, Bo Angelin, Rolf Blomstrand, George Drummond, Attallah Kappas
Journal: Hepatology (1988)

Sn-protoporphyrin, a potent competitive inhibitor of heme oxygenase, the rate-limiting enzyme in the degradation of heme to bile pigment, was administered to 10 normal volunteers: 8 males and 2 females. A significant decrease in the levels of serum (mean decrease; 38%) and biliary bilirubin (mean decrease: 47%) was demonstrated in all 10 subjects. The decrease in these parameters lasted for a minimum of 4 days after administration of the metalloporphyrin. Sn-protoporphyrin also facilitated the excretion of endogenous heme in bile during the 24- to 48-hr period following administration of the compound. The metalloporphyrin was rapidly cleared from plasma with a half-life of 3.4 hr. A small amount (3 to 6%) of Sn-protoporphyrin was excreted in both urine and bile. The activity of microsomal heme oxygenase was measured in five human liver samples freshly obtained at the time of cholecystectomy and varied from ˜2 to 4 nmoles bilirubin formed per mg protein per hour. The addition of Sn-protoporphyrin to microsomal heme oxygenase isolated from these liver samples resulted in a dose-dependent decrease in the activity of this enzyme at concentrations of the metalloporphyrin in the range of 10 −7 to 10 −9 M . The findings reported here provide strong evidence that the suppression of biliary and serum bilirubin levels and the enhancement of heme excretion in the bile of the normal volunteers examined in this study were due to inhibition of physiological rates of heme oxidation activity by the synthetic heme analog, Sn-protoporphyrin.
Ang II–stimulated migration of vascular smooth muscle cells is dependent on LR11 in mice
Authors: Meizi Jiang, Hideaki Bujo, Kenji Ohwaki, Hiroyuki Unoki, Hiroyuki Yamazaki, Tatsuro Kanaki, Manabu Shibasaki, Kazuhiko Azuma, Kenichi Harigaya, Wolfgang J. Schneider, Yasushi Saito
Journal: Journal of Clinical Investigation (2008)

Medial-to-intimal migration of SMCs is critical to atherosclerotic plaque formation and remodeling of injured arteries. Considerable amounts of the shed soluble form of the LDL receptor relative LR11 (sLR11) produced by intimal SMCs enhance SMC migration in vitro via upregulation of urokinase-type plasminogen activator receptor (uPAR) expression. Here, we show that circulating sLR11 is a novel marker of carotid intima-media thickness (IMT) and that targeted disruption of the LR11 gene greatly reduces intimal thickening of arteries through attenuation of Ang II-induced migration of SMCs. Serum concentrations of sLR11 were positively correlated with IMT in dyslipidemic subjects, and multivariable regression analysis suggested sLR11 levels as an index of IMT, independent of classical atherosclerosis risk factors. In Lr11-/- mice, femoral artery intimal thickness after cuff placement was decreased, and Ang II-stimulated migration and attachment of SMCs from these mice were largely abolished. In isolated murine SMCs, sLR11 caused membrane ruffle formation via activation of focal adhesion kinase/ERK/Rac1 accompanied by complex formation between uPAR and integrin alphavbeta3, a process accelerated by Ang II. Overproduction of sLR11 decreased the sensitivity of Ang II-induced activation pathways to inhibition by an Ang II type 1 receptor blocker in mice. Thus, we demonstrate a requirement for sLR11 in Ang II-induced SMC migration and propose what we believe is a novel role for sLR11 as a biomarker of carotid IMT.
HOW TCRS BIND MHCS, PEPTIDES, AND CORECEPTORS
Authors: Markus G. Rudolph, Robyn L. Stanfield, Ian A. Wilson
Journal: Annual Review of Immunology (2006)

Since the first crystal structure determinations of alphabeta T cell receptors (TCRs) bound to class I MHC-peptide (pMHC) antigens in 1996, a sizable database of 24 class I and class II TCR/pMHC complexes has been accumulated that now defines a substantial degree of structural variability in TCR/pMHC recognition. Recent determination of free and bound gammadelta TCR structures has enabled comparisons of the modes of antigen recognition by alphabeta and gammadelta T cells and antibodies. Crystal structures of TCR accessory (CD4, CD8) and coreceptor molecules (CD3epsilondelta, CD3epsilongamma) have further advanced our structural understanding of most of the components that constitute the TCR signaling complex. Despite all these efforts, the structural basis for MHC restriction and signaling remains elusive as no structural features that define a common binding mode or signaling mechanism have yet been gleaned from the current set of TCR/pMHC complexes. Notwithstanding, the impressive array of self, foreign (microbial), and autoimmune TCR complexes have uncovered the diverse ways in which antigens can be specifically recognized by TCRs.
Syndecan-1 regulates αvβ3 and αvβ5 integrin activation during angiogenesis and is blocked by synstatin, a novel peptide inhibitor
Authors: DeannaLee M. Beauvais, Brian J. Ell, Andrea R. McWhorter, Alan C. Rapraeger
Journal: The Journal of Experimental Medicine (2009)

Syndecan-1 (Sdc1) is a matrix receptor shown to associate via its extracellular domain with the αvβ3 and αvβ5 integrins, potentially regulating cell adhesion, spreading, and invasion of cells expressing these integrins. Using Sdc1 deletion mutants expressed in human mammary carcinoma cells, we identified the active site within the Sdc1 core protein and derived a peptide inhibitor called synstatin (SSTN) that disrupts Sdc1's interaction with these integrins. Because the αvβ3 and αvβ5 integrins are critical in angiogenesis, a process in which a role for Sdc1 has been uncertain, we used human vascular endothelial cells in vitro to show that the Sdc1 regulatory mechanism is also required for integrin activation on these cells. We found Sdc1 expressed in the vascular endothelium during microvessel outgrowth from aortic explants in vitro and in mouse mammary tumors in vivo. Moreover, we show that SSTN blocks angiogenesis in vitro or when delivered systemically in a mouse model of angiogenesis in vivo, and impairs mammary tumor growth in an orthotopic mouse tumor model. Thus, Sdc1 is a critical regulator of these two important integrins during angiogenesis and tumorigenesis, and is inhibited by the novel SSTN peptide.
Immunohistological findings in lip biopsy specimens from patients with Crohn's disease and healthy subjects.
Authors: G Crama-Bohbouth, F T Bosman, B J Vermeer, A M van der Wal, I Biemond, I T Weterman, A S Pena
Journal: Gut (1983)

Biopsies of apparently normal buccal mucosa were taken from 14 patients with Crohn's disease and 13 healthy controls who were matched for dental status. Most patients had an increased number of lymphocytes around vessels in the subepithelial tissue and two showed fibrosis with moderate atrophy of minor glands. Plasma cells which contained immunoglobulin, predominantly IgA, were only found around minor salivary glands in both patients and controls. Quantitative studies showed a significant increase in the number of cells containing IgA in patients compared with controls. No correlation was found between immunoglobulin pattern and disease activity, age, sex, or duration of Crohn's disease. A significant correlation was found between the activity of the disease, as defined by the Crohn's Disease Activity Index, and the number of plasma cells containing IgM.
RESEARCH IN PRIVATE PRACTICE
Authors: FLANDERS DUNBAR
Journal: American Journal of Psychiatry (1951)

1. On the basis of material presented, it would appear that the psychiatrist in private practice may increase his therapeutic success and add materially to the general fund of medical knowledge if he takes advantage of his assets and trains himself, as an integral part of his therapeutic procedure, to make and record the kind of careful observation required of the research scientist. 2. In so doing, he will find himself more and more in the rôle of the doctor of the family or the social group and an active participant in such public health programs as are focussed on preventive medicine. The cure of one person may mean the elimination of a focus of infection, and the prevention of illness in one or many persons more or less intimately associated with this patient. 3. The busy psychiatrist may well select from among the many who consult him those who are parents of young children, or in positions of authority that give them control over the destiny of groups. But every therapist who studies the patient in his family and cultural setting, and looks at him as a part of a series of patients with similar complaints, will make his contribution to research.
Comparative Impact of Multiple Biomarkers and N-Terminal Pro-Brain Natriuretic Peptide in the Context of Conventional Risk Factors for the Prediction of Recurrent Cardiovascular Events in the Heart Outcomes Prevention Evaluation (HOPE) Study
Authors: Stefan Blankenberg, Matthew J. McQueen, Marek Smieja, Janice Pogue, Cynthia Balion, Eva Lonn, Hans J. Rupprecht, Christoph Bickel, Laurence Tiret, Francois Cambien, Hertzel Gerstein, Thomas Münzel, Salim Yusuf
Journal: Circulation (2006)

Background— Individual markers of inflammation may add incremental predictive value in the context of conventionally available risk factors. We evaluated the ability of 9 inflammatory biomarkers, microalbuminuria, and N-terminal pro-brain natriuretic peptide (Nt-proBNP) to improve cardiovascular risk prediction beyond that obtained from traditional risk factors in a secondary-prevention population. Methods and Results— We measured biomarkers representing the acute-phase reaction (C-reactive protein, fibrinogen, and interleukin-6), proinflammatory pathways (soluble tumor necrosis factor receptor-1 and -2, soluble interleukin-1 receptor antagonist, and interleukin-18), endothelial activation (soluble vascular adhesion molecule-1 and soluble intercellular adhesion molecule-1), Nt-proBNP, and microalbuminuria in 3199 study individuals of the Heart Outcomes Prevention Evaluation (HOPE) Study and assessed their association with risk of myocardial infarction, stroke, or cardiovascular death (primary outcome, n=501) over 4.5 years of follow-up. In a backward Cox regression procedure that included risk factors and biomarkers, Nt-proBNP (hazard ratio [HR] 1.72 per increment SD, 95% CI 1.39 to 2.12; P &lt;0.0001), soluble intercellular adhesion molecule-1 (HR 1.46, 95% CI 1.19 to 1.80; P =0.0003), microalbuminuria (HR 1.55, 95% CI 1.22 to 1.98; P =0.0004), soluble interleukin-1 receptor antagonist (HR 1.30, 95% CI 1.05 to 1.61; P =0.02), and fibrinogen (HR 1.31, 95% CI 1.05 to 1.62; P =0.02) remained significantly related to the primary outcome. Only inclusion of Nt-proBNP provided incremental information above that obtained by models of traditional risk factors. Conclusions— Although levels of various inflammatory biomarkers are significantly related to future cardiovascular risk, their incremental predictive value is modest. A model consisting of simple traditional risk factors and Nt-proBNP provided the best clinical prediction in the secondary-prevention population.
Transforming Growth Factor-β and Breast Cancer Risk in Women With Mammary Epithelial Hyperplasia
Authors: Helenice Gobbi, William D. Dupont, Jean F. Simpson, W.Dale Plummer, Peggy A. Schuyler, Sandra J. Olson, Carlos L. Arteaga, David L. Page
Journal: JNCI Journal of the National Cancer Institute (1999)

Transforming growth factors-beta (TGF-betas) regulate mammary epithelial cell division. Loss of expression of TGF-beta receptor II (TGF-beta-RII) is related to cell proliferation and tumor progression. Breast epithelial hyperplastic lesions lacking atypia (EHLA) are associated with a mild elevation in breast cancer risk. We investigated the expression of TGF-beta-RII in EHLA and the risk of subsequent invasive breast cancer.We conducted a nested case-control study of women with biopsy-confirmed EHLA who did not have a history of breast cancer or atypical hyperplasia of the breast. Case patients (n = 54) who subsequently developed invasive breast cancer were matched with control patients (n = 115) who did not. Formalin-fixed, paraffin-embedded sections of breast biopsy specimens of all 169 patients with EHLA were studied by immunohistochemical analysis with antibodies against TGF-beta-RII. All P values are two-sided.Women with breast EHLA and 25%-75% TGF-beta-RII-positive cells or less than 25% TGF-beta-RII-positive cells had odds ratios of invasive breast cancer of 1.98 (95% confidence interval [CI] = 0.95-4.1) or 3.41 (95% CI = 1.2-10.0), respectively (P for trend =.008). These risks are calculated with respect to women with EHLA that had greater than 75% TGF-beta-RII expression. Women with a heterogeneous pattern of TGF-beta-RII expression in their normal breast lobular units and either greater than 75%, 25%-75%, or less than 25% positive cells in their EHLA had odds ratios for breast cancer risk of 0.742 (95% CI = 0.3-1.8), 2.85 (95% CI = 1.1-7.1), or 3.55 (95% CI = 1.0-10.0), respectively (P for trend =.003). These risks are relative to women with a homogeneous pattern of expression in their normal lobular units and greater than 75% positive cells in their EHLA.This study indicates that loss of TGF-beta-RII expression in epithelial cells of EHLA is associated with increased risk of invasive breast cancer.
Taking Risks with Translational Research
Authors: Ian G. Mills, Richard B. Sykes
Journal: Science Translational Medicine (2010)

The recent bankruptcy filing by deCODE, a company with an exceptional pedigree in associating genetic variance with disease onset, highlights the commercial risks of translational research. Indeed, deCODE's approach was similar to that adapted by academic researchers who seek to connect genetics and disease. We argue here that neither a purely corporate nor purely academic model is entirely appropriate for such research. Instead, we suggest that the private sector undertake the high-throughput elements of translational research, while the public sector and governments assume the role of providing long-term funding to develop gifted scientists with the confidence to attempt to use genetic data as a stepping stone to a truly mechanistic understanding of complex disease.
Vascular Effects of Hypertonic Solutions
Authors: RAYMOND C. READ, JOHN A. JOHNSON, JAMES A. VICK, MAURICE W. MEYER
Journal: Circulation Research (1960)

During the course of an investigation into the treatment of metabolic acidosis arising from total body perfusion, it was noticed that the intra-arterial administration of concentrated alkalies resulted in a fall in arteriovenous pressure difference at constant flow. A similar decline in peripheral resistance could be produced by hypertonic sugar and salt solutions. This response was found to be independent of the central nervous system. The role of the vasodilatation in the complex vasomotor reaction to the rapid intravenous injection of hyperosmotic agents was then investigated in the intact and vagotomized dog. It was found that when concentrations of up to 1,500 mOsm./L. were used, the predominant response was a delayed hypotension consistent with peripheral vasodilatation. This reaction was complicated by preliminary pulmonary hypertension when solutions containing more than 2,000 mOsm./L. were administered. Twenty per cent NaCl produced such a severe initial phase that the animals frequently died from acute cor pulmonale. The site of obstruction to blood flow through the lungs was variable. Fifty percent glucose could incite pulmonary hypertension, but urea was anomalous in that it was never observed to produce pulmonary vascular effects. Studies in the isolated perfused lung indicated that, again with the exception of urea, all solutions with an osmolarity equal or greater than 5 per cent NaCl evoked pulmonary hypertension. The increase in pulmonary vascular resistance was transitory in spite of recirculation. No response could be elicited when red cells were absent from the perfusate even though, under these conditions, the lung was still sensitive to serotonin. Microscopic examination of the circulation through the brain, lung, mesentery and thigh of both cat and dog demonstrated that intravascular red-cell agglutination occurred after regional arterial injection of highly concentrated salt and sugar solutions. This alteration in the stability of the red-cell stream is considered to be responsible for the obstructive effects of hyperosmotic agents previously attributed to vasospasm.
The Anaplastic Lymphoma Kinase Controls Cell Shape and Growth of Anaplastic Large Cell Lymphoma through Cdc42 Activation
Authors: Chiara Ambrogio, Claudia Voena, Andrea D. Manazza, Cinzia Martinengo, Carlotta Costa, Tomas Kirchhausen, Emilio Hirsch, Giorgio Inghirami, Roberto Chiarle
Journal: Cancer Research (2008)

Abstract Anaplastic large cell lymphoma (ALCL) is a non-Hodgkin's lymphoma that originates from T cells and frequently expresses oncogenic fusion proteins derived from chromosomal translocations or inversions of the anaplastic lymphoma kinase (ALK) gene. The proliferation and survival of ALCL cells are determined by the ALK activity. Here we show that the kinase activity of the nucleophosmin (NPM)-ALK fusion regulated the shape of ALCL cells and F-actin filament assembly in a pattern similar to T-cell receptor–stimulated cells. NPM-ALK formed a complex with the guanine exchange factor VAV1, enhancing its activation through phosphorylation. VAV1 increased Cdc42 activity, and in turn, Cdc42 regulated the shape and migration of ALCL cells. In vitro knockdown of VAV1 or Cdc42 by short hairpin RNA, as well as pharmacologic inhibition of Cdc42 activity by secramine, resulted in a cell cycle arrest and apoptosis of ALCL cells. Importantly, the concomitant inhibition of Cdc42 and NPM-ALK kinase acted synergistically to induce apoptosis of ALCL cells. Finally, Cdc42 was necessary for the growth as well as for the maintenance of already established lymphomas in vivo. Thus, our data open perspectives for new therapeutic strategies by revealing a mechanism of regulation of ALCL cell growth through Cdc42. [Cancer Res 2008;68(21):8899–907]
Prostaglandin F2α-F-Prostanoid Receptor Signaling Promotes Neutrophil Chemotaxis via Chemokine (C-X-C Motif) Ligand 1 in Endometrial Adenocarcinoma
Authors: Alison E. Wallace, Kurt J. Sales, Roberto D. Catalano, Richard A. Anderson, Alistair R.W. Williams, Martin R. Wilson, Jurgen Schwarze, Hongwei Wang, Adriano G. Rossi, Henry N. Jabbour
Journal: Cancer Research (2009)

Abstract The prostaglandin F2α (PGF2α) receptor (FP) is elevated in endometrial adenocarcinoma. This study found that PGF2α signaling via FP regulates expression of chemokine (C-X-C motif) ligand 1 (CXCL1) in endometrial adenocarcinoma cells. Expression of CXCL1 and its receptor, CXCR2, are elevated in cancer tissue compared with normal endometrium and localized to glandular epithelium, endothelium, and stroma. Treatment of Ishikawa cells stably transfected with the FP receptor (FPS cells) with 100 nmol/L PGF2α increased CXCL1 promoter activity, mRNA, and protein expression, and these effects were abolished by cotreatment of cells with FP antagonist or chemical inhibitors of Gq, epidermal growth factor receptor, and extracellular signal-regulated kinase. Similarly, CXCL1 was elevated in response to 100 nmol/L PGF2α in endometrial adenocarcinoma explant tissue. CXCL1 is a potent neutrophil chemoattractant. The expression of CXCR2 colocalized to neutrophils in endometrial adenocarcinoma and increased neutrophils were present in endometrial adenocarcinoma compared with normal endometrium. Conditioned media from PGF2α-treated FPS cells stimulated neutrophil chemotaxis, which could be abolished by CXCL1 protein immunoneutralization of the conditioned media or antagonism of CXCR2. Finally, xenograft tumors in nude mice arising from inoculation with FPS cells showed increased neutrophil infiltration compared with tumors arising from wild-type cells or following treatment of mice bearing FPS tumors with CXCL1-neutralizing antibody. In conclusion, our results show a novel PGF2α-FP pathway that may regulate the inflammatory microenvironment in endometrial adenocarcinoma via neutrophil chemotaxis. [Cancer Res 2009;69(14):5726–33]
Outcome of orthotopic liver transplantation in patients with haemophilia
Authors: F H Gordon, P K Mistry, C A Sabin, C A Lee
Journal: Gut (1998)

Background —Many patients with haemophilia have developed cirrhosis or hepatocellular carcinoma due to transfusion acquired chronic viral hepatitis. Aims —To assess the long term outcome of all haemophilic patients reported to have undergone orthotopic liver transplantation. Methods —Transplant centres of patients identified by medical database search were contacted and survival data assessed by Kaplan-Meier analysis. Results —Twenty six haemophilic men (median age 46 years, range 5–63 years) underwent orthotopic liver transplantation in 16 centres between 1982 and 1996. Indications for transplantation were hepatitis C cirrhosis (69%), hepatitis B with or without C cirrhosis (15%), viral hepatitis related hepatocellular carcinoma (12%), and biliary atresia (4%). Six patients (23%) were infected with human immunodeficiency virus (HIV). Postoperatively, the median time to normal clotting factor levels was 24 hours (range 0–48 hours) and exogenous clotting factors were stopped at a median of 24 hours (range 0–480 hours). Four patients (15%) had bleeding complications. The one and three year survival of HIV positive recipients (67% and 23%) was significantly poorer (p=0.0003) than that of HIV negative recipients (90% and 83%). Coagulopathy was cured in all patients surviving more than 12 days post-transplant. Six of the 20 patients (30%) with hepatitis C cirrhosis pretransplant had evidence of disease recurrence at a mean of nine months post-transplant. Conclusions —Hepatitis C cirrhosis is the most common indication for orthotopic liver transplantation in patients with haemophilia. Transplantation results in long term cure of haemophilia but may be complicated by the effects of HIV infection or recurrent viral hepatitis.
Vision-Based Navigation in Image-Guided Interventions
Authors: Daniel J. Mirota, Masaru Ishii, Gregory D. Hager
Journal: Annual Review of Biomedical Engineering (2011)

The trend toward minimally invasive surgical interventions has created new challenges for visualization during surgical procedures. However, at the same time, the introduction of high-definition digital endoscopy offers the opportunity to apply methods from computer vision to provide visualization enhancements such as anatomic reconstruction, surface registration, motion tracking, and augmented reality. This review provides a perspective on this rapidly evolving field. It first introduces the clinical and technical background necessary for developing vision-based algorithms for interventional applications. It then discusses several examples of clinical interventions where computer vision can be applied, including bronchoscopy, rhinoscopy, transnasal skull-base neurosurgery, upper airway interventions, laparoscopy, robotic-assisted surgery, and Natural Orifice Transluminal Endoscopic Surgery (NOTES). It concludes that the currently reported work is only the beginning. As the demand for minimally invasive procedures rises, computer vision in surgery will continue to advance through close interdisciplinary work between interventionists and engineers.