tbuckley/cabot-search huggingface dataset:
Loss of SPARC in bladder cancer enhances carcinogenesis and progression
Authors: Neveen Said, Henry F. Frierson, Marta Sanchez-Carbayo, Rolf A. Brekken, Dan Theodorescu
Journal: Journal of Clinical Investigation (2013)

Secreted protein acidic and rich in cysteine (SPARC) has been implicated in multiple aspects of human cancer. However, its role in bladder carcinogenesis and metastasis are unclear,with some studies suggesting it may be a promoter and others arguing the opposite. Using a chemical carcinogenesis model in Sparc-deficient mice and their wild-type littermates, we found that loss of SPARC accelerated the development of urothelial preneoplasia (atypia and dysplasia), neoplasia, and metastasis and was associated with decreased survival. SPARC reduced carcinogen-induced inflammation and accumulation of reactive oxygen species as well as urothelial cell proliferation. Loss of SPARC was associated with an inflammatory phenotype of tumor-associated macrophages and fibroblasts, with concomitant increased activation of urothelial and stromal NF-κB and AP1 in vivo and in vitro. Syngeneic spontaneous and experimental metastasis models revealed that tumor- and stroma-derived SPARC reduced tumor growth and metastasis through inhibition of cancer-associated inflammation and lung colonization. In human bladder tumor tissues, the frequency and intensity of SPARC expression were inversely correlated with disease-specific survival. These results indicate that SPARC is produced by benign and malignant compartments of bladder carcinomas where it functions to suppress bladder carcinogenesis, progression, and metastasis.
Therapeutic Inhibition of the Complement System
Authors: Savvas C. Makrides
Journal: Pharmacological Reviews (1998)

The use of powerful methodologies in molecular biology, biochemistry, and physiology in the last 2 decades had led to impressive progress in our understanding of the mechanisms of complement activation and its role as either a protective or a pathogenic factor in human disease. With respect to disease pathogenesis, the complexity of the complement cascade provides opportunities for several different therapeutic targets within the complement pathways. More than a century after complement was first described, we are about to witness in the near future the availability of a variety of complement inhibitors for specific therapies. Progress in the area of xenotransplantation has been substantial, but formidable obstacles remain to selective inhibition of the factors that block successful clinical xenotransplantation. Bispecific antibodies, designed to enhance rather than inhibit existing complement pathways, hold strong promise for the clearance of viral and bacterial pathogens from the circulation.
Organic Anion Transporting Polypeptide 1B1: a Genetically Polymorphic Transporter of Major Importance for Hepatic Drug Uptake
Authors: Mikko Niemi, Marja K. Pasanen, Pertti J. Neuvonen
Journal: Pharmacological Reviews (2011)

The importance of membrane transporters for drug pharmacokinetics has been increasingly recognized during the last decade. Organic anion transporting polypeptide 1B1 (OATP1B1) is a genetically polymorphic influx transporter expressed on the sinusoidal membrane of human hepatocytes, and it mediates the hepatic uptake of many endogenous compounds and xenobiotics. Recent studies have demonstrated that OATP1B1 plays a major, clinically important role in the hepatic uptake of many drugs. A common single-nucleotide variation (coding DNA c.521T&gt;C, protein p.V174A, rs4149056) in the <i>SLCO1B1</i> gene encoding OATP1B1 decreases the transporting activity of OATP1B1, resulting in markedly increased plasma concentrations of, for example, many statins, particularly of active simvastatin acid. The variant thereby enhances the risk of statin-induced myopathy and decreases the therapeutic indexes of statins. However, the effect of the <i>SLCO1B1</i> c.521T&gt;C variant is different on different statins. The same variant also markedly affects the pharmacokinetics of several other drugs. Furthermore, certain <i>SLCO1B1</i> variants associated with an enhanced clearance of methotrexate increase the risk of gastrointestinal toxicity by methotrexate in the treatment of children with acute lymphoblastic leukemia. Certain drugs (e.g., cyclosporine) potently inhibit OATP1B1, causing clinically significant drug interactions. Thus, OATP1B1 plays a major role in the hepatic uptake of drugs, and genetic variants and drug interactions affecting OATP1B1 activity are important determinants of individual drug responses. In this article, we review the current knowledge about the expression, function, substrate characteristics, and pharmacogenetics of OATP1B1 as well as its role in drug interactions, in parts comparing with those of other hepatocyte-expressed organic anion transporting polypeptides, OATP1B3 and OATP2B1.
Cost-Effectiveness Analysis of Regorafenib for Metastatic Colorectal Cancer
Authors: Daniel A. Goldstein, Bilal B. Ahmad, Qiushi Chen, Turgay Ayer, David H. Howard, Joseph Lipscomb, Bassel F. El-Rayes, Christopher R. Flowers
Journal: Journal of Clinical Oncology (2015)

Regorafenib is a standard-care option for treatment-refractory metastatic colorectal cancer that increases median overall survival by 6 weeks compared with placebo. Given this small incremental clinical benefit, we evaluated the cost-effectiveness of regorafenib in the third-line setting for patients with metastatic colorectal cancer from the US payer perspective.We developed a Markov model to compare the cost and effectiveness of regorafenib with those of placebo in the third-line treatment of metastatic colorectal cancer. Health outcomes were measured in life-years and quality-adjusted life-years (QALYs). Drug costs were based on Medicare reimbursement rates in 2014. Model robustness was addressed in univariable and probabilistic sensitivity analyses.Regorafenib provided an additional 0.04 QALYs (0.13 life-years) at a cost of $40,000, resulting in an incremental cost-effectiveness ratio of $900,000 per QALY. The incremental cost-effectiveness ratio for regorafenib was > $550,000 per QALY in all of our univariable and probabilistic sensitivity analyses.Regorafenib provides minimal incremental benefit at high incremental cost per QALY in the third-line management of metastatic colorectal cancer. The cost-effectiveness of regorafenib could be improved by the use of value-based pricing.
Finasteride and High-Grade Prostate Cancer in the Prostate Cancer Prevention Trial
Authors: M. S. Lucia, J. I. Epstein, P. J. Goodman, A. K. Darke, V. E. Reuter, F. Civantos, C. M. Tangen, H. L. Parnes, S. M. Lippman, F. G. La Rosa, M. W. Kattan, E. D. Crawford, L. G. Ford, C. A. Coltman, I. M. Thompson
Journal: JNCI Journal of the National Cancer Institute (2007)

BackgroundThe Prostate Cancer Prevention Trial (PCPT) reported a decreased incidence of prostate cancer overall but an increase in the incidence of high-grade prostate cancer with finasteride compared with placebo. We assessed whether the increased high-grade prostate cancer associated with finasteride in the PCPT was due to finasteride's potential effects on tumor morphology or prostate size.
Establishment of Patient-Derived Non–Small Cell Lung Cancer Xenografts as Models for the Identification of Predictive Biomarkers
Authors: Iduna Fichtner, Jana Rolff, Richie Soong, Jens Hoffmann, Stefanie Hammer, Anette Sommer, Michael Becker, Johannes Merk
Journal: Clinical Cancer Research (2008)

Abstract Purpose: It was the aim of our study to establish an extensive panel of non-small cell lung cancer (NSCLC) xenograft models useful for the testing of novel compounds and for the identification of biomarkers. Experimental Design: Starting from 102 surgical NSCLC specimens, which were obtained from primarily diagnosed patients with early-stage tumors (T2/T3), 25 transplantable xenografts were established and used for further investigations. Results: Early passages of the NSCLC xenografts revealed a high degree of similarity with the original clinical tumor sample with regard to histology, immunohistochemistry, as well as mutation status. The chemotherapeutic responsiveness of the xenografts resembled the clinical situation in NSCLC with tumor shrinkage obtained with paclitaxel (4 of 25), gemcitabine (3 of 25), and carboplatin (3 of 25) and lower effectiveness of etoposide (1 of 25) and vinorelbine (0 of 11). Twelve of 25 NSCLC xenografts were &amp;gt;50% growth inhibited by the anti-epidermal growth factor receptor (EGFR) antibody cetuximab and 6 of 25 by the EGFR tyrosine kinase inhibitor erlotinib. The response to the anti-EGFR therapies did not correlate with mutations in the EGFR or p53, but there was a correlation of K-ras mutations and erlotinib resistance. Protein analysis revealed a heterogeneous pattern of expression. After treatment with cetuximab, we observed a down-regulation of EGFR in 2 of 6 sensitive xenograft models investigated but never in resistant models. Conclusion: An extensive panel of patient-derived NSCLC xenografts has been established. It provides appropriate models for testing marketed as well as novel drug candidates. Additional expression studies allow the identification of stratification biomarkers for targeted therapies.
Use of injections in healthcare settings worldwide, 2000: literature review and regional estimates
Authors: Y. J F Hutin
Journal: BMJ (2003)

To describe injection practices worldwide in terms of frequency and safety.Literature review. The global burden of disease project of the World Health Organization defined 14 regions on the basis of geography and mortality patterns. Data sources included published studies and unpublished WHO reports. Studies were reviewed by using a standardised decision making algorithm to generate region specific estimates.Healthcare facilities, both formal and informal.General population and users of healthcare facilities.Annual number of injections per person and proportion of injections administered with syringes or needles, or both, reused in the absence of sterilisation.The analysis excluded four regions (predominantly affluent, developed nations) where reuse of injection equipment in the absence of sterilisation was assumed to be negligible. In the 10 other regions, the annual ratio of injections per person ranged from 1.7 to 11.3. Of these, the proportion administered with equipment reused in the absence of sterilisation ranged from 1.2% to 75.0%. Reuse was highest in the South East Asia region "D" (seven countries, mostly located in South Asia), the eastern Mediterranean region "D" (nine countries, mostly located in the Middle East crescent), and the western Pacific region "B" (22 countries). No information regarding injection safety was available for Latin America.Overuse of injections and unsafe practices are still common in developing and transitional countries. An urgent need exists to use injections safely and appropriately, to prevent healthcare associated infections with HIV and other bloodborne pathogens.
P1 Quality of life related to COPD and occupational exposures
Authors: A. Darby, J. Waterhouse, V. Stevens, C. Billings, S. Hickman, A. Seriki, J. Wight, D. Fishwick
Journal: Thorax (2010)

<b>Background: </b> Saccades are fast eye movements that conjugately shift the point of fixation between distant features of interest in the visual environment. Several disorders, affecting sites from brainstem to extraocular muscle, may cause horizontal saccades to become disconjugate. Prior techniques for detection of saccadic disconjugacy, especially in internuclear ophthalmoparesis (INO), have compared only one point in abducting vs adducting saccades, such as peak velocity. <b>Methods: </b> We applied a phase-plane technique that compared each eye’s velocity as a function of change in position (normalized displacement) in 22 patients with disease variously affecting the brainstem reticular formation, the abducens nucleus, the medial longitudinal fasciculus, the oculomotor nerve, the abducens nerve, the neuromuscular junction, or the extraocular muscles; 10 age-matched subjects served as controls. <b>Results: </b> We found three different patterns of disconjugacy throughout the course of horizontal saccades: early abnormal velocity disconjugacy during the first 10% of the displacement in patients with INO, oculomotor or abducens nerve palsy, and advanced extraocular muscle disease; late disconjugacy in patients with disease affecting the neuromuscular junction; and variable middle-course disconjugacy in patients with pontine lesions. When normal subjects made disconjugate saccades between two targets aligned on one eye, the initial part of the movement remained conjugate. <b>Conclusions: </b> Along with conventional measures of saccades, such as peak velocity, phase planes provide a useful tool to determine the site, extent, and pathogenesis of disconjugacy. We hypothesize that the pale global extraocular muscle fibers, which drive the high-acceleration component of saccades, receive a neural command that ensures initial ocular conjugacy.
A regulatory role for the C5a anaphylatoxin in type 2 immunity in asthma
Authors: J. Kohl
Journal: Journal of Clinical Investigation (2006)

Complement component 5 (C5) has been described as either promoting or protecting against airway hyperresponsiveness (AHR) in experimental allergic asthma, suggesting pleomorphic effects of C5. Here we report that local pharmacological targeting of the C5a receptor (C5aR) prior to initial allergen sensitization in murine models of inhalation tolerance or allergic asthma resulted in either induction or marked enhancement of Th2-polarized immune responses, airway inflammation, and AHR. Importantly, C5aR-deficient mice exhibited a similar, increased allergic phenotype. Pulmonary allergen exposure in C5aR-targeted mice resulted in increased sensitization and accumulation of CD4+CD69+ T cells associated with a marked increase in pulmonary myeloid, but not plasmacytoid, DC numbers. Pulmonary DCs from C5aR-targeted mice produced large amounts of CC chemokine ligand 17 (CCL17) and CCL22 ex vivo, suggesting a negative impact of C5aR signaling on pulmonary homing of Th2 cells. In contrast, C5aR targeting in sensitized mice led to suppressed airway inflammation and AHR but was still associated with enhanced production of Th2 effector cytokines. These data suggest a dual role for C5a in allergic asthma, i.e., protection from the development of maladaptive type 2 immune responses during allergen sensitization at the DC/T cell interface but enhancement of airway inflammation and AHR in an established inflammatory environment.
Vicious circle: systemic autoreactivity in Ro52/TRIM21-deficient mice
Authors: Silvia Bolland, Adolfo Garcia-Sastre
Journal: The Journal of Experimental Medicine (2009)

Dysregulated innate responses, particularly excessive activation of interferon (IFN) pathways, have been implicated in the development of autoimmune pathologies. Autoreactivity frequently targets IFN-inducible genes such as the Ro autoantigens, which ubiquitinate and inhibit interferon regulatory factors (IRFs). A new study validates the role of these common autoantigens in preventing autoimmunity. The findings reveal that injury-induced systemic autoimmune disease is exacerbated in the absence of Ro52/Trim21 and is driven by the IL-23–Th17 pathway.
Outcomes of cardiopulmonary resuscitation in dialysis patients.
Authors: A H Moss, J L Holley, M B Upton
Journal: Journal of the American Society of Nephrology (1992)

Patients with renal failure are believed to have a poor survival rate after cardiopulmonary resuscitation, but there is little specific information about the outcomes of cardiopulmonary resuscitation in dialysis patients. To be better able to inform dialysis patients and assist them in decision making about cardiopulmonary resuscitation, the eight-year experience with cardiopulmonary resuscitation in dialysis patients at a university dialysis program was analyzed and outcomes were compared with those of a control group of nondialysis patients undergoing cardiopulmonary resuscitation during the same time period in the same hospital. Of 221 dialysis patients experiencing cardiopulmonary arrest, 74 (34%) had CPR compared with 247 (21%) of 1,201 control patients (P = 0.0002). Six of 74 (8%; 95% confidence interval, 2 to 14%) dialysis patients survived to hospital discharge compared with 30 of 247 (12%; 95% confidence interval, 8 to 16%) control patients (P = not significant). At 6 months after CPR, 2 (3%) of 74 dialysis patients were still alive compared with 23 (9%) of 247 controls (P = 0.044); this difference was not explained by age or comorbid conditions. Twenty-one (78%) of the 27 successfully resuscitated dialysis patients died a mean of 4.4 days later; 95% were on mechanical ventilation in an intensive care unit at the time of death. It was concluded that cardiopulmonary resuscitation is a procedure that rarely results in extended survival for dialysis patients. In discussions about cardiopulmonary resuscitation with dialysis patients, nephrologists should provide this information.
Src-Induced Cisplatin Resistance Mediated by Cell-to-Cell Communication
Authors: Elizabeth Peterson-Roth, Cathleen M. Brdlik, Peter M. Glazer
Journal: Cancer Research (2009)

Cisplatin-induced cell death can be triggered by cell-to-cell communication through gap junctions. Here, we show that activated src produces tyrosine phosphorylation of the gap junction protein connexin 43, decreases gap junction communication, and increases cell survival in response to cisplatin. Experiments with mixed cell populations show that src activity in one cell can confer increased cisplatin survival on neighboring cells, even when the neighboring cells lack such src activity. This work is the first demonstration that expression of an oncogene in one cell can affect the survival of a neighboring cell not expressing the oncogene in response to a chemotherapeutic drug. The trans-acting effect of activated src on neighboring cells can be blocked by inhibitors of src kinase or by siRNA-mediated knockdown of src expression, and it can be counteracted by forced up-regulation of connexin 43, via either gene transfer or proteasome inhibition. These results identify a novel pathway of cisplatin resistance that may be amenable to therapeutic intervention.
Accelerated Wound Healing by In vivo Application of Keratinocytes Overexpressing KGF
Authors: Jürgen Kopp, Guang Y. Wang, Peter Kulmburg, Stefan Schultze-Mosgau, Jing N. Huan, Kang Ying, Harun Seyhan, Mark D. Jeschke, Ulrich Kneser, Alexander D. Bach, Sheng D. Ge, Steven Dooley, Raymund E. Horch
Journal: Molecular Therapy (2004)

Epidermal regeneration is a complex process, strongly influenced by growth factors, including keratinocyte growth factor (KGF). The objective of this study was to establish immortalized HaCaT keratinocytes and KMST-6-fibroblasts stably expressing KGF. Transfection efficiency, genomic integration, and functionality of the transgene were determined by ELISA and PCR, and KGF-expressing clones were selected using an air–liquid interface test system. HaCaT cells displayed stronger transgene expression compared to transfected fibroblasts, and the most effective HaCaT clone was incubated on a membrane carrier to form a "membrane cell graft." Twenty-one superficial second-degree burn wounds were created in each of three pigs, and wound healing capacity of the generated "polypeptide cell delivery system" after grafting was examined. Untransfected HaCaT keratinocytes and membrane-covered and untreated burn wounds served as controls. Histological and macroscopical follow-up revealed that grafting of transfected HaCaT cells resulted in complete reepithelialization within 5 days, while wounds covered with untransfected cells needed 2 days longer. At untreated sites, a thin epithelium was detectable after 10 days. The results indicate that wound healing processes can be stimulated distinctly by growth factors secreted from HaCaT cells, with a prominent role for transgenic KGF.
Problem-based learning in sports medicine: the way forward or a backward step?
Authors: Andrew Franklyn-Miller, Eanna Falvey, Paul McCrory
Journal: British Journal of Sports Medicine (2007)

Self-directed problem-based learning vs traditional didactic courses

As sports and exercise medicine (SEM) develops as a postgraduate specialty, training curricula are increasingly becoming sophisticated and developing along the principles of current educational theory. We have a problem, however, that at the present time the majority of sports physicians are graduates of “traditional” didactic medical courses, whereas the future generation of trainees will come from a more progressive learning environment with self-directed “problem-based learning” (PBL) principles in their undergraduate courses. The usefulness of this approach in postgraduate SEM education remains both problematic and unproven.

Medical schools as we know them began in the early Renaissance period in southern Europe and were under the jurisdiction of the Roman Catholic Church. In later centuries, medicine was taught by a lengthy apprenticeship system with various medical colleges arising in order to provide primitive training (eg, anatomical dissection) and a form of licensure.

Sir William Osler (1849–1919) was a Canadian-born physician who is largely responsible for many of the things that we take for granted in medicine today: university-based medical education, a strong underpinning of basic science for clinicians and an emphasis on bedside learning. Perhaps his greatest contribution to medicine was to insist that students learned from seeing and talking to patients, and this approach led to the establishment of the medical residency programme within hospitals. He himself liked to say, “ He who studies medicine without books sails an uncharted sea, whereas he who studies medicine without patients does not go to sea at all .”1

Osler’s textbook, The Principles and Practice of Medicine ,2 became the standard text of internal medicine following its publication in 1892 and the basis of most medical education. He stressed that the derivation of the word diagnosis comes from the Greek words dia , which …
Effect of upper-airway stimulation for obstructive sleep apnoea on airway dimensions
Authors: Faiza Safiruddin, Olivier M. Vanderveken, Nico de Vries, Joachim T. Maurer, Kent Lee, Quan Ni, Kingman P. Strohl
Journal: European Respiratory Journal (2014)

Upper-airway stimulation (UAS) using a unilateral implantable neurostimulator for the hypoglossal nerve is an effective therapy for obstructive sleep apnoea patients with continuous positive airway pressure intolerance. This study evaluated stimulation effects on retropalatal and retrolingual dimensions during drug-induced sedation compared with wakefulness to assess mechanistic relationships in response to UAS. Patients with an implanted stimulator underwent nasal video endoscopy while awake and/or during drug-induced sedation in the supine position. The cross-sectional area, anterior–posterior and lateral dimensions of the retropalatal and retrolingual regions were measured during baseline and stimulation. 15 patients underwent endoscopy while awake and 12 underwent drug-induced sedation endoscopy. Increased levels of stimulation were associated with increased area of both the retropalatal and retrolingual regions. During wakefulness, a therapeutic level of stimulation increased the retropalatal area by 56.4% (p=0.002) and retrolingual area by 184.1% (p=0.006). During stimulation, the retropalatal area enlarged in the anterior–posterior dimension while retrolingual area enlarged in both anterior–posterior and lateral dimensions. During drug-induced sedation endoscopy, the same stimulation increased the retropalatal area by 180.0% (p=0.002) and retrolingual area by 130.1% (p=0.008). Therapy responders had larger retropalatal enlargement with stimulation than nonresponders. UAS increases both the retropalatal and retrolingual areas. This multilevel enlargement may explain reductions of the apnoea–hypopnoea index in selected patients receiving this therapy.