tbuckley/cabot-search huggingface dataset:
US Food and Drug Administration Approval Overview in Metastatic Breast Cancer
Authors: Patricia Cortazar, Robert Justice, John Johnson, Rajeshwari Sridhara, Patricia Keegan, Richard Pazdur
Journal: Journal of Clinical Oncology (2012)

Article Tools REVIEW ARTICLE Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2011.39.2613 Journal of Clinical Oncology - published online before print March 19, 2012 PMID: 22430273 US Food and Drug Administration Approval Overview in Metastatic Breast Cancer Patricia CortazarxPatricia CortazarSearch for articles by this author , Robert JusticexRobert JusticeSearch for articles by this author , John JohnsonxJohn JohnsonSearch for articles by this author , Rajeshwari SridharaxRajeshwari SridharaSearch for articles by this author , Patricia KeeganxPatricia KeeganSearch for articles by this author , Richard PazdurxRichard PazdurSearch for articles by this author Show More All authors: US Food and Drug Administration, Silver Spring, MD. https://doi.org/10.1200/JCO.2011.39.2613 First Page Full Text PDF Figures and Tables © 2012 by American Society of Clinical Oncology
Craniosynostosis in transgenic mice overexpressing Nell-1
Authors: Xinli Zhang, Shun’ichi Kuroda, Dale Carpenter, Ichiro Nishimura, Chia Soo, Rex Moats, Keisuke Iida, Eric Wisner, Fei-Ya Hu, Steve Miao, Steve Beanes, Catherine Dang, Heleni Vastardis, Michael Longaker, Katsuyuki Tanizawa, Norihiro Kanayama, Naoaki Saito, Kang Ting
Journal: Journal of Clinical Investigation (2002)

Previously, we reported NELL-1 as a novel molecule overexpressed during premature cranial suture closure in patients with craniosynostosis (CS), one of the most common congenital craniofacial deformities. Here we describe the creation and analysis of transgenic mice overexpressing Nell-1. Nell-1 transgenic animals exhibited CS-like phenotypes that ranged from simple to compound synostoses. Histologically, the osteogenic fronts of abnormally closing/closed sutures in these animals revealed calvarial overgrowth and overlap along with increased osteoblast differentiation and reduced cell proliferation. Furthermore, anomalies were restricted to calvarial bone, despite generalized, non-tissue-specific overexpression of Nell-1. In vitro, Nell-1 overexpression accelerated calvarial osteoblast differentiation and mineralization under normal culture conditions. Moreover, Nell-1 overexpression in osteoblasts was sufficient to promote alkaline phosphatase expression and micronodule formation. Conversely, downregulation of Nell-1 inhibited osteoblast differentiation in vitro. In summary, Nell-1 overexpression induced calvarial overgrowth resulting in premature suture closure in a rodent model. Nell-1, therefore, has a novel role in CS development, perhaps as part of a complex chain of events resulting in premature suture closure. On a cellular level, Nell-1 expression may modulate and be both sufficient and required for osteoblast differentiation.
Urinary oestriol excretion in pregnant patient given large doses of prednisone.
Authors: A. M. Driscoll
Journal: BMJ (1969)

JOURNALon oral contraception longer-that is, 18 months (unpublished data).Brakman and Astrup (1964) reported raised fibrinogen levels in women on oral contraceptives.A FIG. 2.-Thromboelastographic patterns.A, a normal pattern after three months on chlormadinone acetate.B, hypercoagul- ability after 12 months on B a conventional oestrogenprogesterone compound.C, extreme hypercoagulability pattern of a patient suffering from a deep-vein thrombosis after oral con- traceptive administration. CThe normal thromboelastographic pattern so far also con- trasts with our findings during the administration of conven- tional preparations, as Fig. 2 shows.An extreme form of thromboelastographic hypercoagulability pattern in a patient who had been receiving an oestrogen-progestin compound and suffered a deep-vein thrombosis is illustrated for comparison.The absence so far of changes in platelet aggregation is likewise reassuring, as in parallel studies we have shown significant shortening of the platelet aggregation with the Chandler tube in women taking both high-dose and low-dose forms of combined preparations (Poller and Priest, 1969).We should emphasize that these results, though extremely encouraging, reflect only the first three cycles of administra- tion, and a long-term study must of course be performed to exclude a delayed or cumulative action.In so far as it is possible to be certain at this stage the investigation does suggest that the thrombogenic constituent of conventional oral contraception may have been eliminated by the use of progesterone alone.
Mantle-cell lymphoma genotypes identified with CGH to BAC microarrays define a leukemic subgroup of disease and predict patient outcome
Authors: Fanny Rubio-Moscardo, Joan Climent, Reiner Siebert, Miguel A Piris, Jose I Martín-Subero, Inga Nieländer, Javier Garcia-Conde, Martin J S Dyer, Maria Jose Terol, Daniel Pinkel, Jose A Martinez-Climent
Journal: Blood (2005)
High knee abduction moments are common risk factors for patellofemoral pain (PFP) and anterior cruciate ligament (ACL) injury in girls: Is PFP itself a predictor for subsequent ACL injury?
Authors: Gregory D Myer, Kevin R Ford, Stephanie L Di Stasi, Kim D Barber Foss, Lyle J Micheli, Timothy E Hewett
Journal: British Journal of Sports Medicine (2014)

Identifying risk factors for knee pain and anterior cruciate ligament (ACL) injury can be an important step in the injury prevention cycle.
The largest systematic and prospective evaluation of seronegative villous atrophy
Authors: I. Aziz, K. E. Evans, N. R. Lewis, M. Peerally, M. Imran, J. Whiteley, D. S. Sanders
Journal: Gut (2011)

<h3>Introduction</h3> Villous atrophy (VA) in the presence of positive coeliac serology (EMA and tTG) is highly predictive of coeliac disease (CD). However, diagnostic challenges may arise in those where VA is associated with a negative serology. <h3>Aims</h3> To study the aetiology of seronegative VA. <h3>Methods</h3> Patients presenting with seronegative VA (both EMA negative and tTG &lt; 30) were prospectively recruited and investigated in a systematic and rigorous manner – initially, by means of revisiting the patient9s history and histopathology, followed by immunoglobulins, HLA typing, repeat duodenal biopsies and coeliac serology, CLO test, small bowel aspirate, anti-enterocyte antibodies, HIV status, TB quantiferon, PCR for Whipple9s disease, stool cultures +/− colonoscopy. <h3>Results</h3> 91 patients, female 52 (57%), median age 55, age range (16–92). A history of autoimmune disorders, dermatitis herpitiformis or family history was significantly associated with a diagnosis of coeliac disease (p = 0.0006, exact fisher test). Patients from an ethnic background (p = 0.01) or with a negative HLA typing for DQ2 or DQ8 (p &lt; 0.0001) were significantly associated with a non-coeliac cause for their VA. There was no statistical difference in age, gender, baseline bloods or clinical symptoms between the coeliac and non-coeliac group (p &gt; 0.05). <h3>Conclusion</h3> By taking a systematic approach, we were able to identify a cause for seronegative VA in up to 75% of cases. Coeliac disease accounted for almost half of all the cases investigated. Despite growing interest in drugs and <i>H. pylori</i> causing small bowel enteropathy, there are minimal data to suggest an association with VA. In those where a cause for VA was not found, 57% (13/23) subsequently normalised their small bowel histology on repeat biopsies – we speculate a transient post infective phenomena in this group. Of those with persisting VA of unknown cause (n 10), the outcome is not yet clear, and they remain under active follow-up. This is the largest study investigating patients with seronegative VA – based on these data; we would suggest caution in commencing a gluten-free diet in this group of patients without further investigation and supportive evidence for coeliac disease.
Voltage-shift of the current activation in HERG S4 mutation (R534C) in LQT2
Authors: T Nakajima
Journal: Cardiovascular Research (1999)

Objective: Recently, a novel missense mutation (R534C) in the S4 region of human ether-a-go-go-related gene (HERG) was identified in one Japanese LQT2 family. The S4 region presumably functions as a voltage sensor. However, it has not yet been addressed whether the S4 region of HERG indeed functions as a voltage sensor, and whether these residues play any role in abnormal channel function in cardiac repolarization. Methods: We characterized the electrophysiological properties of the R534C mutation using the heterologous expression system in Xenopus oocytes. Whole cell currents were recorded in oocytes injected with wild-type cRNA, R534C cRNA, or a combination of both. Results: Clinical features – QTc intervals of all affected patients with R534C mutation in HERG are prolonged ranging from 460 to 680 ms (averaged QTc interval>540 ms). One member of this family had experienced sudden cardiac arrest, and other suffered from recurrent palpitation. Electrophysiology – Oocytes injected with R534C cRNA did express functional channels with altered channel gating. Kinetic analyses revealed that the R534C mutation shifted the voltage-dependence of HERG channel activation to a negative direction, accelerated activation and deactivation time course, and reduced steady-state inactivation. Quantitative analyses revealed that this mutation did not cause apparent dominant-negative suppression. Computer simulation – Incorporating the kinetic alterations of R534C, however, did not reproduce prolonged action potential duration (APD). Conclusions: The data revealed that arginine at position 534 in the S4 region of HERG is indeed involved in voltage-dependence of channel activation as a voltage sensor. Our examination indicated that HERG current suppression in R534C mutation was the least severe among other mutations that have been electrophysiologicaly examined, while affected patients did show significant QT prolongation. This suggest that another unidentified factor(s) that prolong APD might be present.
Calmodulin-Dependent Protein Kinase II: Linking Heart Failure and Arrhythmias
Authors: Paari Dominic Swaminathan, Anil Purohit, Thomas J. Hund, Mark E Anderson
Journal: Circulation Research (2012)

Understanding relationships between heart failure and arrhythmias, important causes of suffering and sudden death, remains an unmet goal for biomedical researchers and physicians. Evidence assembled over the past decade supports a view that activation of the multifunctional Ca 2+ and calmodulin-dependent protein kinase II (CaMKII) favors myocardial dysfunction and cell membrane electrical instability. CaMKII activation follows increases in intracellular Ca 2+ or oxidation, upstream signals with the capacity to transition CaMKII into a Ca 2+ and calmodulin-independent constitutively active enzyme. Constitutively active CaMKII appears poised to participate in disease pathways by catalyzing the phosphorylation of classes of protein targets important for excitation–contraction coupling and cell survival, including ion channels and Ca 2+ homeostatic proteins, and transcription factors that drive hypertrophic and inflammatory gene expression. This rich diversity of downstream targets helps to explain the potential for CaMKII to simultaneously affect mechanical and electrical properties of heart muscle cells. Proof-of-concept studies from a growing number of investigators show that CaMKII inhibition is beneficial for improving myocardial performance and for reducing arrhythmias. We review the molecular physiology of CaMKII and discuss CaMKII actions at key cellular targets and results of animal models of myocardial hypertrophy, dysfunction, and arrhythmias that suggest CaMKII inhibition may benefit myocardial function while reducing arrhythmias.
Correlation between spirometry, six minute walk test and HRCT characteristics of patients with interstitial lung diseases in a tertiary care center in Sri Lanka
Authors: Anoma Siribaddana, M.T. Muthunayake, D.L.B. Dassanayake, Nimojan Nadesan, Srinath Ileperuma, Lalith Gamage
Journal: European Respiratory Journal (2012)

Background  High Resolution Computed Tomography of Chest (HRCT) is a robust tool in the diagnosis of interstitial lung diseases (ILD), but its role as a tool of assessment of functional disability in ILD has not been assessed in Sri Lanka.  Objectives  To find out the correlation between spirometry, six minute walk test and HRCT characteristics of patients with ILDs  Methods  Study was done in chest unit, General Hospital, Kandy (GHK) from 1/ 2011 to 12/2011. Ethical clearance was granted by Ethical Committee of GHK. Patients with suspected ILDs on chest radiography and showed restrictive lung defect on spirometry underwent HRCT scan of the chest. Pathological findings of HRCT (parenchymal nodules, fibrosis, ground glass and mosaic perfusion) were given a score using the scoring system used by Ziora et al (Ann Agric Environ Med 2005, 12, 31–34). Six minute walking test was performed. Correlations were analyzed using Pearsons and Spearmans correlation coefficient.  Results  Twenty one patients {5 (23.8%) males, 16 (76.2%) females} with ILD were studied. There was a significant positive correlation between resting saturation and forced vital capacity (FVC) (r = 0.52, p = 0.02), resting saturation and forced expiratory volume in 1 second (FEV1) (r = 0.549, p = 0.012), six minute walk distance and FVC (r = 0.505, p = 0.023). There were no correlations between HRCT scores with spirometry, and six minute walk test parameters.  Conclusion  Although there was a correlation between spirometry and six minute walk test, pathological distribution described by HRCT showed no correlation with spirometry or six minute walk test in patients with ILD.
Inhibitors of oxidative ATP production cause transient vasoconstriction and block subsequent pressor responses in rat lungs.
Authors: S Rounds, I F McMurtry
Journal: Circulation Research (1981)

We wondered if depression of oxidative adenosine triphosphate (ATP) production caused pulmonary vasoconstriction. If so, then several chemically different inhibitors of oxidative ATP production all should cause pulmonary pressor responses. The vascular reactivity of isolated, blood-perfused rat lungs was established by eliciting pressor responses to airway hypoxia and to intraarterial angiotensin II. Then, during normoxia, we added to perfusate one of five chemical inhibitors of oxidative ATP production: 10 mM azide, 1 mM cyanide, 1 mM dinitrophenol, 5 or 10 microM antimycin A, or 0.5 microM rotenone. Each of the five chemical inhibitors, but not their solvents, caused a transient pressor response, followed by loss of vascular reactivity to hypoxia, angiotensin II, and chemical inhibitors. The inhibitor pressor responses were not due to an effect on blood cells, since they also were seen in lungs perfused with plasma. The magnitudes of pressor responses to all metabolic inhibitors except azide correlated with the magnitudes of preceding pressor responses to hypoxia, but not to the preceding angiotensin II responses. When verapamil or calcium chloride was added to perfusate, the hypoxic and inhibitor pressor responses were blunted more than was the angiotensin II response. Thus, five chemically different substances, inhibiting different steps of oxidative ATP production, all caused pressor responses that were blocked readily by verapamil and by increased perfusate calcium chloride. These results support the possibility that depression of oxidative ATP production elicits pulmonary vasoconstriction that is dependent on influx of extracellular calcium. Hypoxia might also be sensed in the pulmonary circulation by decreased oxidative ATP production in some as yet unidentified lung cell.
Vascular endothelial growth factor measured in platelet poor plasma allows optimal separation between cancer patients and volunteers: A key to study an angiogenic marker in vivo?
Authors: W. Wynendaele, R. Derua, M.F. Hoylaerts, A. Pawinski, E. Waelkens, E.A. de Bruijn, R. Paridaens, W. Merlevede, A.T. van Oosterom
Journal: Annals of Oncology (1999)
Immunocytology of synovial fluid cells may be of diagnostic and prognostic value in arthritis.
Authors: L W Poulter, H A Al-Shakarchi, E D Campbell, A J Goldstein, A T Richardson
Journal: Annals of the Rheumatic Diseases (1986)

Cells of the synovial fluid (SF) have been examined by immunocytochemical methods. Samples were aspirated from four groups of patients with knee effusions: (a) seropositive inflammatory arthritis (n = 9); (b) seronegative inflammatory arthritis (n = 9); (c) osteoarthritic patients (n = 5); and (d) patients with traumatised knees (n = 4). The proportions of lymphocyte and macrophage subsets within the SF were determined with a panel of monoclonal antibodies. Patients with inflammatory arthritis had significantly larger proportions of activated T cells (RFT2+) and macrophages with the phenotype of interdigitating cells (RFD1+). No significant difference between groups could be found on differential count or when T4+/T8+ subset ratios were calculated. No significant difference in proportions of lymphocyte or macrophage subsets was found between the groups with seropositive and seronegative inflammatory arthritis. In two of three patients, where immunocytochemical analysis was performed before and after intra-articular steroids, reductions in the proportions of RFT2+ T cells and RFD1+ macrophage like cells were seen. It is suggested that such analysis may be of diagnostic or prognostic value.
Nitric oxide regulates vascular calcification by interfering with TGF-β signalling
Authors: Yosuke Kanno, Takeshi Into, Charles J. Lowenstein, Kenji Matsushita
Journal: Cardiovascular Research (2007)

Vascular calcification often occurs with advancing age, atherosclerosis, and metabolic disorders such as diabetes mellitus and end-stage renal disease. Vascular calcification is associated with cardiovascular events and increased mortality. Nitric oxide (NO) is crucial for maintaining vascular function, but little is known about how NO affects vascular calcification. The aim of this study was to examine the effect of NO on vascular calcification.In this study, we examined the inhibitory effects of NO on calcification of murine vascular smooth muscle cells (VSMCs) in vitro. We measured calcium concentration, alizarin red staining, and alkaline phosphatase activity to examine the effect of NO on calcification of VSMCs and differentiation of VSMCs into osteoblastic cells. We also determined gene expression and levels of phosphorylation of Smad2/3 by RT-PCR and western blotting. NO inhibited calcification of VSMCs and differentiation of VSMCs into osteoblastic cells. An inhibitor of cyclic guanosine monophosphate (cGMP)-dependent protein kinase restored the inhibition by NO of osteoblastic differentiation and calcification of VSMCs. NO inhibited transforming growth factor-beta (TGF-beta)-induced phosphorylation of Smad2/3 and expression of TGF-beta-induced genes such as plasminogen activator inhibitor-1. In addition, NO inhibited expression of the TGF-beta receptor ALK5.Our data show that NO prevents differentiation of VSMCs into osteoblastic cells by inhibiting TGF-beta signalling through a cGMP-dependent pathway. Our findings suggest that NO may play a beneficial role in atherogenesis in part by limiting vascular calcification.
Interferon gamma drastically modifies the regulation of interleukin 1 genes by endotoxin in U937 cells.
Authors: C Ucla, P Roux-Lombard, S Fey, J M Dayer, B Mach
Journal: Journal of Clinical Investigation (1990)

IL-1 alpha, IL-1 beta, and tumor necrosis factor alpha (TNF-alpha) gene expression is induced by LPS (endotoxin) in monocytes/macrophages and in some monocytic cell lines. IFN gamma and 1 alpha,25-dihydroxyvitamin D3 (1,25[OH]2D3) are important macrophage-activating factors. They induce changes in the human monocyte cell line U937 that reflect cellular differentiation. We have studied the effect of IFN-gamma and of 1,25(OH)2D3 on the expression of IL-1 and TNF-alpha messenger RNA in response to LPS. The induction of these genes by LPS is immediate and transient, with a maximum in 3 h. Preincubation of the cells with IFN-gamma or with 1,25(OH)2D3 increases these mRNA responses to LPS about fourfold. More importantly, cells exposed to IFN-gamma for 72 h exhibit a drastically different and unexpected pattern of IL-1 alpha and IL-1 beta gene response to LPS. Instead of the normal transient response, one then observes a sustained increase in IL-1 alpha and IL-1 beta gene expression over at least 16 h after LPS stimulation. This was measured both at the level of mRNA and by direct transcription assays (run-off). This striking effect of IFN-gamma on the kinetics of IL-1 gene response does not apply to the TNF-alpha gene. Interestingly, 1,25(OH)2D3, which shares with IFN-gamma a number of important effects on monocytes/macrophages, does not affect the kinetics of IL-1 gene response to LPS. In view of the biological relevance of endotoxin as a macrophage activator, the potential clinical implication of this prolonged induction of IL-1 gene expression is discussed.
Synthesis and transport of lipoprotein particles by intestinal absorptive cells in man
Authors: Guido N. Tytgat, Cyrus E. Rubin, David R. Saunders
Journal: Journal of Clinical Investigation (1971)

The site of synthesis and some new details of lipoprotein particle transport have been demonstrated within the jejunal mucosa of man. In normal fasting volunteers, lipoprotein particles (88%, 150-650 A diameter) were visualized within the smooth endoplasmic reticulum and Golgi cisternae of absorptive cells covering the tips of jejunal villi. Electron microscopic observations suggested that these particles exited through the sides and bases of absorptive cells by reverse pinocytosis and then passed through the extracellular matrix of the lamina propria to enter lacteal lumina. When these lipid particles were isolated from fasting intestinal biopsies by preparative ultracentrifugation, their size distribution was similar to that of very low density (S(f) 20-400) lipoprotein (VLDL) particles in plasma. After a fatty meal, jejunal absorptive cells and extracts of their homogenates contained lipid particles of VLDL-size as well as chylomicrons of various sizes. The percentage of triglyceride in isolated intestinal lipid particles increased during fat absorption. Our interpretation of these data is that chylomicrons are probably derived from intestinal lipoprotein particles by addition of triglyceride.
Trend of incidence, subsite distribution and staging of colorectal neoplasms in the 15-year experience of a specialised cancer registry
Authors: M. Ponz de Leon, M. Marino, P. Benatti, G. Rossi, M. Menigatti, M. Pedroni, C. Di Gregorio, L. Losi, F. Borghi, A. Scarselli, G. Ponti, B. Roncari, G. Zangardi, G. Abbati, E. Ascari, L. Roncucci
Journal: Annals of Oncology (2004)