tbuckley/cabot-search huggingface dataset:
Specific and Sensitive Tumor Imaging Using Biostable Oligonucleotide Aptamer Probes
Authors: Zihua Zeng, Parag Parekh, Zheng Li, Zheng-Zheng Shi, Ching-Hsuan Tung, Youli Zu
Journal: Theranostics (2014)

Although several imaging modalities are widely used for tumor imaging, none are tumor type-specific.Different types of cancer exhibit differential therapeutic responses, thus necessitating development of an imaging modality able to detect various tumor types with high specificity.To illustrate this point, CD30-specific oligonucleotide aptamer in vivo imaging probes were conjugated to the near-infrared IRD800CW reporter.Mice bearing xenografted CD30-positive or control CD30-negative lymphoma tumors on contralateral sides of the same mouse were developed.Following a systemic administration of aptamer probes, whole body imaging of tumor-bearing mice was performed.Imaging signal from tumor sites was analyzed and imaging specificity confirmed by tissue immunostaining.The in vivo biodistribution of aptamer probes was also evaluated.Whole body scans revealed that the RNA-based aptamer probes selectively highlighted CD30-expressing lymphoma tumors immediately after systemic administration, but did not react with control tumors in the same mouse.The resultant imaging signal lasted up to 1 hr and the aptamer probes were rapidly eliminated from the body through urinary and lower intestinal tracts.For more sensitive imaging, biostable CD30-specific ssDNA-based aptamer probes were also generated.Systemic administration of these probes also selectively highlighted the CD30-positive lymphoma tumors, with imaging signal detected 4-5 folds higher than that derived from control tumors in the same animal, and lasted for up to 24hr.This study demonstrates that oligonucleotide aptamer probes can provide tumor type-specific imaging with high sensitivity and a long-lasting signal, indicating their potential for clinical applications.
Multidrug resistance-associated protein 4 regulates cAMP-dependent signaling pathways and controls human and rat SMC proliferation
Authors: Yassine Sassi, Larissa Lipskaia, Grégoire Vandecasteele, Viacheslav O. Nikolaev, Stéphane N. Hatem, Fleur Cohen Aubart, Frans G. Russel, Nathalie Mougenot, Cédric Vrignaud, Philippe Lechat, Anne-Marie Lompré, Jean-Sébastien Hulot
Journal: Journal of Clinical Investigation (2008)

The second messengers cAMP and cGMP can be degraded by specific members of the phosphodiesterase superfamily or by active efflux transporters, namely the multidrug resistance-associated proteins (MRPs) MRP4 and MRP5. To determine the role of MRP4 and MRP5 in cell signaling, we studied arterial SMCs, in which the effects of cyclic nucleotide levels on SMC proliferation have been well established. We found that MRP4, but not MRP5, was upregulated during proliferation of isolated human coronary artery SMCs and following injury of rat carotid arteries in vivo. MRP4 inhibition significantly increased intracellular cAMP and cGMP levels and was sufficient to block proliferation and to prevent neointimal growth in injured rat carotid arteries. The antiproliferative effect of MRP4 inhibition was related to PKA/CREB pathway activation. Here we provide what we believe to be the first evidence that MRP4 acts as an independent endogenous regulator of intracellular cyclic nucleotide levels and as a mediator of cAMP-dependent signal transduction to the nucleus. We also identify MRP4 inhibition as a potentially new way of preventing abnormal VSMC proliferation.
Solvent Toxicology: Recent Advances in the Toxicology of Benzene, The Glycol Ethers, and Carbon Tetrachloride
Authors: G F Kalf, G B Post, R Snyder
Journal: The Annual Review of Pharmacology and Toxicology (1987)

Heme oxygenases (HO) catabolize free heme, that is, iron (Fe) protoporphyrin (IX), into equimolar amounts of Fe2+, carbon monoxide (CO), and biliverdin. The stress-responsive HO-1 isoenzyme affords protection against programmed cell death. The mechanism ...Read More
Highlights on pulmonary hypertension: a commentary
Authors: T Higenbottam, R Rodriguez-Roisin
Journal: European Respiratory Journal (1993)

Physiological description of the pulmonary vascular response to hypoxia and to disease has clarified the func­ tion of pulmonary arteries. The understanding of the cellular regulation of vascular tone has proceeded at a rapid pace, with the discovery of endothelium-derived relaxing factor (EDRF) [11], and its identification as the gas nitric oxide (NO) [12]. Also, endothelin-1, a polypep­ tide elaborated by endothelium, has been found to be the most powerful natural vasoconstriction [13]. Production of endothelium-derived nitric oxide (EDNO) and endothelin1 are influenced by hypoxia. EDNO may be reduced in COLD [14], whilst endothelin-1 [15] can be increased by hypoxia. These observations not only provide insight into the possible role of endothelium in pulmonary hyper­ tension but have led to radically new treatments. Inhaled NO is a selective pulmonary vasodilator [16], and may have an important action in improving gas exchange in patients with acute respiratory distress syndrome (ARDS) [17]. Finally, the vascular smooth muscle cells of the pul­ monary arteries may be particularly important in deter­ mining hypoxic vasoconstriction [ 18]. The articles included in the series on Pulmonary Hypertension published in this and future issues of the Journal provide new insights into major areas of growth of knowledge in the pulmonary vasculature. For brevity, much has been omitted, particularly the description of the pulmonary vasculitides or the involvement of the blood vessels in systemic disease. These will, no doubt, be covered by future symposia; by which time, the struc­ tural and functional consequences of chronic hypoxia on pulmonary vas~ulature are likely to have been fully elu­ cidated.
Cyclophosphamide, Methotrexate, and Fluorouracil Versus Tamoxifen Plus Ovarian Suppression as Adjuvant Treatment of Estrogen Receptor–Positive Pre-/Perimenopausal Breast Cancer Patients: Results of the Italian Breast Cancer Adjuvant Study Group 02 Randomized Trial
Authors: F. Boccardo, A. Rubagotti, D. Amoroso, M. Mesiti, D. Romeo, P. Sismondi, M. Giai, F. Genta, P. Pacini, V. Distante, A. Bolognesi, D. Aldrighetti, A. Farris
Journal: Journal of Clinical Oncology (2000)

To compare the efficacy of chemotherapy versus that of tamoxifen plus ovarian suppression in pre-/perimenopausal estrogen receptor-positive patients with early breast cancer.Patients were randomly assigned to receive either six cycles of a standard regimen of cyclophosphamide 100 mg/m(2) orally days 1 to 14, methotrexate 40 mg/m(2) intravenously (IV) days 1 and 8, and fluorouracil 600 mg/m(2) IV days 1 and 8 (CMF), with all drugs restarted on day 29, or 5 years of tamoxifen, 30 mg/d, plus ovarian suppression with surgical oophorectomy, ovarian irradiation, or monthly goserelin 3.6-mg injections. Disease-free survival was the main study end point. Overall survival and toxicity were additional end points.Between 1989 and 1997, 120 patients were assigned to CMF and 124 to tamoxifen and ovarian suppression (oophorectomy, n = 6; ovarian irradiation, n = 31; and goserelin injections, n = 87). At the time of analysis (median follow-up time, 76 months; range, 9 to 121 months), 82 patients had relapsed and 39 had died. No difference between groups had emerged with respect to either disease-free or overall survival. Treatments were comparable even in respect to age, tumor size, and nodal status, although a nonsignificant trend favored patients with poorly differentiated tumors treated with CMF. Leukopenia, nausea, vomiting, stomatitis, and alopecia were significantly more common in patients treated with CMF. There were few patients who developed benign gynecologic changes in either group, and numbers were comparable.The combination of tamoxifen with ovarian suppression seems to be safe and to yield comparable results relative to standard CMF.
Renal Tubular Reabsorption of Folate Mediated by Folate Binding Protein 1
Authors: Henrik Birn, Ofer Spiegelstein, Erik I. Christensen, Richard H. Finnell
Journal: Journal of the American Society of Nephrology (2005)

Renal tubular reabsorption of filtered folate is essential for the conservation and normal homeostasis of this important vitamin. Different molecular mechanisms have been implicated in epithelial folate transport, including folate receptors. Defective expression or antibody inactivation of these is associated with embryonic defects also correlated with low folate intake; however, their contribution to renal tubular folate reabsorption has not been established. With the use of targeted inactivation of the folate binding protein 1 (folbp1) and folate binding protein 2 (folbp2) genes in mice, the role of folate receptors in renal epithelial folate reabsorption was evaluated during low and normal folate intake. Inactivation of folbp1 was associated with (1) loss of (3)H-folic acid binding to crude kidney membranes, (2) increase in renal folate clearance, and (3) increase in urinary excretion and decrease in renal uptake of injected (3)H-methyltetrahydrofolate. No changes in renal folate handling were observed as a result of folbp2 inactivation. Thus, folbp1 is essential for normal renal tubular folate reabsorption, preventing excessive urinary folate loss. Folbp1 is heavily expressed in choroid plexus, yolk sac, and placenta, supporting a role of folbp1 in folate transport in other tissues. The greatest significance of folbp1 for renal folate uptake was observed at conditions of low folate intake, providing a possible explanation for the ability of folate supplementation to prevent developmental defects associated with folbp1 inactivation.
Signal Transducer and Activator of Transcription (STAT)5 Activation by BCR/ABL Is Dependent on Intact Src Homology (SH)3 and SH2 Domains of BCR/ABL and Is Required for Leukemogenesis
Authors: Malgorzata Nieborowska-Skorska, Mariusz A. Wasik, Artur Slupianek, Paolo Salomoni, Toshio Kitamura, Bruno Calabretta, Tomasz Skorski
Journal: The Journal of Experimental Medicine (1999)

Signal transducer and activator of transcription (STAT)5 is constitutively activated in BCR/ ABL-expressing cells, but the mechanisms and functional consequences of such activation are unknown. We show here that BCR/ABL induces phosphorylation and activation of STAT5 by a mechanism that requires the BCR/ABL Src homology (SH)2 domain and the proline-rich binding site of the SH3 domain. Upon expression in 32Dcl3 growth factor-dependent myeloid precursor cells, STAT5 activation-deficient BCR/ABL SH3+SH2 domain mutants functioned as tyrosine kinase and activated Ras, but failed to protect from apoptosis induced by withdrawal of interleukin 3 and/or serum and did not induce leukemia in severe combined immunodeficiency mice. In complementation assays, expression of a dominant-active STAT5B mutant (STAT5B-DAM), but not wild-type STAT5B (STAT5B-WT), in 32Dcl3 cells transfected with STAT5 activation-deficient BCR/ABL SH3+SH2 mutants restored protection from apoptosis, stimulated growth factor-independent cell cycle progression, and rescued the leukemogenic potential in mice. Moreover, expression of a dominant-negative STAT5B mutant (STAT5B-DNM) in 32Dcl3 cells transfected with wild-type BCR/ABL inhibited apoptosis resistance, growth factor-independent proliferation, and the leukemogenic potential of these cells. In retrovirally infected mouse bone marrow cells, expression of STAT5B-DNM inhibited BCR/ABL-dependent transformation. Moreover, STAT5B-DAM, but not STAT5B-WT, markedly enhanced the ability of STAT5 activation-defective BCR/ABL SH3+SH2 mutants to induce growth factor-independent colony formation of primary mouse bone marrow progenitor cells. However, STAT5B-DAM did not rescue the growth factor-independent colony formation of kinase-deficient K1172R BCR/ABL or the triple mutant Y177F+R522L+ Y793F BCR/ABL, both of which also fail to activate STAT5. Together, these data demonstrate that STAT5 activation by BCR/ABL is dependent on signaling from more than one domain and document the important role of STAT5-regulated pathways in BCR/ABL leukemogenesis.
Measurement of scapula upward rotation: a reliable clinical procedure
Authors: L Watson, S M Balster, C Finch, R Dalziel
Journal: British Journal of Sports Medicine (2005)

Background: It is important to deal with the scapula when developing rehabilitation strategies for the shoulder complex. This requires clinical measurement tools that are readily available and easy to apply and which provide a reliable evaluation of scapula motion. Aim: To determine the reliability of the Plurimeter-V gravity inclinometer for the measurement of scapular upward rotation positions during humeral elevation in coronal abduction in a group of patients with shoulder pathology. Method: Twenty six patients were assessed in two repeat tests within a single testing session. Patients exhibiting a wide spectrum of shoulder pathology were selected. The angle of scapular upward rotation was measured during total shoulder abduction. The measurement protocol was performed twice during a single testing session by a single tester. Results of the two tests were compared and the reliability assessed by intraclass correlation coefficients (ICCs). Results: There was no significant difference in the scapula measurements taken during the two tests at each testing position. Overall, there was very good intrarater reliability (ICC = 0.88). The ICC ranged from 0.81 (at 135°) to 0.94 (at both resting and end of total shoulder abduction range). Conclusion: The Plurimeter-V gravity inclinometer can be used effectively and reliably for measuring upward rotation of the scapula in all ranges of shoulder abduction in the coronal plane.
Seeing you through London 2012: eye care at the Paralympics
Authors: Clare M Wilson, W David Thomson, Penny J D'Ath
Journal: British Journal of Sports Medicine (2013)

The provision of eye care services for competitors and support teams is integral to the modern Olympic Games. The eye clinic for the London 2012 Paralympic Games employed a multidisciplinary team of eye care professionals using state-of-the-art instrumentation to provide the highest level of eye care. The detailed organisation of the eye care clinic at London 2012 is described in a companion paper which summarises the eye care clinic during the London 2012 Olympic Games. These two reports will aid in planning eye care clinics at future Games.This paper summarises the organisation of the eye clinic and provides outline audit data relating to eye conditions encountered during the Paralympic Games.A total of 870 patients representing 102 countries attended the eye clinic. 274 (31.5%) were competitors; the remainder were trainers and support staff. No serious ocular injuries resulted from competitor injury in the field of play during the Paralympic Games, although seven patients were referred urgently to hospital eye services for conditions including orbital cellulitis, retinal detachment, exudative macular degeneration, corneal ulcer, Stevens-Johnson syndrome and macular oedema. A total of 749 spectacles, 14 pairs of contact lenses and 7 low vision aids were dispensed.By combining excellent facilities and equipment with a multidisciplinary team of eye care professionals, we feel we provided the highest level of eye care, providing a legacy for future Games.
Anaplastic Lymphoma Kinase Inhibition in Non–Small-Cell Lung Cancer
Authors: Eunice L. Kwak, Yung-Jue Bang, D. Ross Camidge, Alice T. Shaw, Benjamin Solomon, Robert G. Maki, Sai-Hong I. Ou, Bruce J. Dezube, Pasi A. Jänne, Daniel B. Costa, Marileila Varella-Garcia, Woo-Ho Kim, Thomas J. Lynch, Panos Fidias, Hannah Stubbs, Jeffrey A. Engelman, Lecia V. Sequist, WeiWei Tan, Leena Gandhi, Mari Mino-Kenudson, Greg C. Wei, S. Martin Shreeve, Mark J. Ratain, Jeffrey Settleman, James G. Christensen, Daniel A. Haber, Keith Wilner, Ravi Salgia, Geoffrey I. Shapiro, Jeffrey W. Clark, A. John Iafrate
Journal: New England Journal of Medicine (2010)

Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase.After screening tumor samples from approximately 1500 patients with non-small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy.Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects.The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).
Decision analysis in the management of duodenal adenomatosis in familial adenomatous polyposis.
Authors: H F Vasen, S Bulow, T Myrhoj, L Mathus-Vliegen, G Griffioen, E Buskens, B G Taal, F Nagengast, J F Slors, P de Ruiter
Journal: Gut (1997)

Patients with familial adenomatous polyposis are not only at high risk of developing adenomas in the colorectum but a substantial number of patients also develop polyps in the duodenum. Because treatment of duodenal polyps is extremely difficult and it is unknown how many patients ultimately develop duodenal cancer, the value of surveillance of the upper digestive tract is uncertain.(1) To assess the cumulative risk of duodenal cancer in a large series of polyposis patients. (2) To develop a decision model to establish whether surveillance would lead to increased life expectancy.Risk analysis was performed in 155 Dutch polyposis families including 601 polyposis patients, and 142 Danish families including 376 patients. Observation time was from birth until date of last contact, death, diagnosis of duodenal cancer, or closing date of the study.Seven Dutch and five Danish patients developed duodenal cancer. The lifetime risk of developing this cancer by the age of 70 was 4% (95% confidence interval 1-7%) in the Dutch series and 3% (95% confidence interval 0-6%) in the Danish series. Decision analysis showed that surveillance led to an increase in life expectancy by seven months.Surveillance of the upper digestive tract led to a moderate gain in life expectancy. Future studies should evaluate whether this increase in life expectancy outweighs the morbidity of endoscopic examination and proximal pancreaticoduodenectomy.
Effect of HLA type and hypocomplementaemia on the expression of parvovirus arthritis: one year follow up of an outbreak.
Authors: N S Gendi, K Gibson, B P Wordsworth
Journal: Annals of the Rheumatic Diseases (1996)

To determine the effect of HLA type and hypocomplementaemia on the duration and severity of joint involvement in parvovirus infection (HPV).Forty seven patients were selected on a geographical basis from 83 with proven HPV infection during an outbreak that occurred in Oxfordshire in 1993. They were contacted by questionnaire a year later. Thirty five patients were available for examination and blood sampling. Subjects were typed for HLA-DRB1 alleles and HLA-B27 status. Immunological profiles, including C3 and C4 complement components, were determined.Joint symptoms occurred in all patients. They resolved within a week in 12 patients and persisted beyond one year in 19. On review, none had a picture of rheumatoid arthritis, but three patients had developed carpal tunnel syndrome. Decreased C4 was found in four. The HLA frequencies were similar to those in controls; however, joint symptoms persisted for more than one week in all HLA-DR4 positive patients (p = 0.009). There was no relation between the severity of joint symptoms and either HLA type, or hypocomplementaemia.Joint symptoms are common in parvovirus infection and the presence of HLA-DR4 may be associated with persistence of joint symptoms beyond one week. This study revealed no evidence of progression to rheumatoid arthritis.
Th17 cells play a critical role in the development of experimental Sjögren's syndrome
Authors: Xiang Lin, Ke Rui, Jun Deng, Jie Tian, Xiaohui Wang, Shengjun Wang, King-Hung Ko, Zhijun Jiao, Vera Sau-Fong Chan, Chak Sing Lau, Xuetao Cao, Liwei Lu
Journal: Annals of the Rheumatic Diseases (2014)

Although Th17 cells have been increasingly recognised as an important effector in various autoimmune diseases, their function in the pathogenesis of Sjögren's syndrome (SS) remains largely uncharacterised. This study aims to determine the role of Th17 cells in the development of experimental SS (ESS).The ESS was induced in wildtype and IL-17A knockout (IL-17 KO) C57BL/6 mice immunised with salivary glands (SG) proteins. Phenotypic analysis of immune cells in the draining cervical lymph nodes (CLN) and SG was performed by flow cytometry and immunofluorescence microscopy. To determine the role of Th17 cells in ESS, immunised IL-17 KO mice were adoptively transferred with in vitro-generated Th17 cells and monitored for SS development. The salivary flow rate was measured, whereas inflammatory infiltration and tissue destruction in SG were assessed by histopathology.SG protein-immunised mice developed overt SS symptoms with increased Th17 cells detected in CLN and within lymphocytic foci in inflamed SG. Notably, immunised IL-17 KO mice were completely resistant for SS induction, showing no evidence of disease symptoms and histopathological changes in SG. Adoptive transfer of Th17 cells rapidly induced the onset of ESS in immunised IL-17 KO mice with markedly reduced saliva secretion, elevated autoantibody production and pronounced inflammation and tissue damage in SG.Our findings have defined a critical role of Th17 cells in the pathogenesis of ESS. Further studies may validate Th17 cell as a potential target for treating SS.