tbuckley/cabot-search huggingface dataset:
Abstract 2049: Preclinical profile of AMG900 in combination with HDACIs in prostate cancer
Authors: Channing Paller, Michel Wissing, Eugene Kim, Hans Hammers, Charles Rudin, Michael Carducci, Sushant Kachhap
Journal: Cancer Research (2012)

Abstract Background: Histone deacetylase (HDAC) enzymes maintain the structural conformation of chromatin. Inhibition of HDACs induces G1 arrest and differentiation. Previous microarray analysis demonstrated downregulation of the aurora kinase-pathway in prostate cancer cell lines treated with HDAC-inhibitors (HDACIs) vorinostat and valproic acid (VPA). Hence we sought to combine these HDACIs with AMG900, a pan-Aurora kinase inhibitor, to assess potential additive or synergistic effects, hypothesizing that low-dose combinations will have a proapoptotic effect comparable to a higher dose of AMG900 as a single agent. Methods: We used MTS assays, clonogenic assays, beta-galactosidase staining and western blot analyses to investigate differences in proliferation and molecular markers with combinations of AMG900 and HDACIs compared to AMG900 alone. Results: In vitro treatment of a panel of prostate cancer cell lines with low-dose combinations of AMG900 with HDACIs revealed enhanced antiproliferative responses compared to single agent use. Short term MTS assays only demonstrated moderate synergism in DU-145 and LNCaP cells co-treated with VPA and synergism in PC3 cells co-treated with vorinostat, based on the Chou-Talalay-method (CalcuSyn). However, all cell lines demonstrated significant decreased long term survival when combining low-dose AMG900 (1nM) with HDACIs. In DU-145 and PC3 cells lines, the low-dose AMG900 (1nM) combinations demonstrated equivalent clonogenic survival to high dose AMG900 treatment (5nM), either alone or in combination with HDACIs. We noted morphologic changes in treated cell lines and explored senescence with beta-galactosidase staining. DU-145 and PC3 cells, when treated with a combination of AMG900 and HDACIs, demonstrated a significant increase in beta-galactosidase positive cells, suggesting cell senescence (10-20% in single agent vs 50% in low-dose combinations). We also explored the mechanisms associated with decreased clonogenic survival at low doses and found a significant increase in cleaved PARP in DU-145 cells with both combinations, and with Vorinostat in LNCaP cells, but not PC3 cells which have a baseline level of ongoing apoptosis. In addition, western blot analysis showed significant differences in ACH3, pH3 and Cyclin B1 in combination treatment compared to single agent use. Conclusions: A combination of low-dose AMG900 with HDACIs in prostate cancer cell lines demonstrates synergy and efficacy equivalent to high doses of AMG900 alone, confirming our hypothesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2049. doi:1538-7445.AM2012-2049
Sympathectomy alters acetylcholinesterase expression in adult rat heart
Authors: C. N. Battie, N. Moran
Journal: Cardiovascular Research (1990)

Study objective – The aim of the study was to determine the significance of adrenergic nerve associated acetylcholinesterase for the pool of total acetylcholinesterase molecules. Design – Acetylcholinesterase was analysed after destruction of adrenergic nerves by 6-hydroxy-dopamine or bilateral stellate sympathectomy. Effectiveness of treatment was verified by determining noradrenaline concentrations in right ventricle. Acetylcholinesterase activity was assayed in homogenates of atria and portions of left ventricular free wall. Subjects – Adult male Sprague-Dawley rats were used, weight 225-260 g, n = 5 per experimental group. Main results – Sympathectomy caused a small decrease in acetylcholinesterase activity, due to a decrease in the activity of the tetrameric globular form of the enzyme. Choline acetylcholinesterase activity was not altered by sympathectomy, which is an indication that cholinergic nerves were not affected. Conclusions – The contribution of adrenergic neurones to the cardiac pool of acetylcholinesterase is measurable and consists primarily of the tetrameric globular form of the enzyme.
The Subsequent Risk of Internal Cancer With Bowen's Disease
Authors: C. G. Chute, Tsu-Yi Chuang, E. J. Bergstralh, W.-P. D. Su
Journal: JAMA (1991)

To address the subsequent risk of internal cancer in a population-based cohort of patients with Bowen's disease.Incident cases of skin cancers other than malignant melanoma occurring in a defined population were classified as basal cell carcinoma, squamous cell carcinoma, or Bowen's disease. Through medical records, all patients were followed up for the development of subsequent internal cancer until they died, moved from Rochester, Minn, or January 1, 1986, whichever came first. Incidence rates of skin cancer and subsequent cancer were computed; the subsequent rate of internal cancer was compared with that prevailing in the community.Enrolled were all permanent residents in the population base of Rochester, Minn, who developed basal cell carcinoma (n = 657), squamous cell carcinoma (n = 169), or Bowen's disease (n = 71) on the basis of pathologic examination and clinical presentation from 1976 through 1984.The relative risk of subsequent internal cancer among patients with Bowen's disease compared with that of the population base from which they arose was 1.1 (95% confidence limits, 0.5, 1.6).Annual incidence rates, adjusted to the 1980 US white population, were 14.9 per 100,000 for Bowen's disease, 38.8 for squamous cell carcinoma, and 146 for basal cell carcinoma. The estimated relative risk for subsequent cancer was 0.9 (95% confidence limits, 0.5, 1.6) among patients with squamous cell carcinoma and 1.0 (95% confidence limits, 0.7, 1.3) for patients with basal cell carcinoma. These risks were not significantly different for various durations of follow-up or for sun-exposed vs sun-protected sites.We find no evidence in these population-based cohort data of and increased risk of subsequent internal cancer associated with Bowen's disease or other forms of nonmelanomatous skin cancer.
Antimycin A-induced defenestration in rat hepatic sinusoidal endothelial cells
Authors: Filip Braet, Michael Muller, Katrien Vekemans, Eddie Wisse, David G. Le Couteur
Journal: Hepatology (2003)

Liver sinusoidal endothelial cells (LSECs) possess fenestrae arranged in sieve plates. Hepatic endothelial fenestrae are open pores approximately 100 to 200 nm in diameter. Alterations in their number or diameter by hormones, xenobiotics, and diseases have important implications for hepatic microcirculation and function. Numerous reports of hepatotoxin–induced defenestration suggest that the cytoskeleton and the energy status of hepatic endothelial cells play a key role in the regulation of fenestrae. Therefore, we investigated the effect of antimycin A, an inhibitor of mitochondrial energy production, on the number of fenestrae in cultured LSECs using high–resolution microscopy and immunocytochemistry. Prolonged incubation (greater than 30 min) with antimycin A resulted in defenestrated cells and coincided with the appearance of F–actin dots, whereas the distribution of G–actin remained unchanged. Adenosine triphosphate (ATP) was depleted dramatically to less than 5% within 30 minutes within the LSECs. After treatment with antimycin A, unusual elevated fenestrated complexes were apparent, organized as a meshwork of anastomosing fenestrae at the center of and above the sieve plates. The position and appearance of these novel structures and their association with defenestration suggest that they are implicated in the process of defenestration. In conclusion, the results of experiments with antimycin A suggest that ATP is needed to maintain fenestrae and the underlying fenestrae–associated cytoskeleton rings that maintain fenestrae patency. Antimycin A–induced defenestration of LSECs is associated with the development of a structure in the sieve plate that appears to be intrinsically involved in defenestration.
Abstract 1395: Identification of genes and pathways related to lymphovascular invasion in axillary-node negative breast cancer: A bioinformatic analysis of gene expression data
Authors: Mathieu Blais, Dushanthi Pinnaduwage, Sheley Bull, Irene L. Andrulis
Journal: Cancer Research (2014)

Abstract Breast Cancer patients whose disease has not spread to the lymph nodes (axillary node-negative breast cancer, ANNBC) generally have a good prognosis; however, 20-30% will experience a recurrence. We previously reported that the presence of Lymphovascular invasion (LVI) is an independent predictor of recurrence in ANNBC. Given that breast cancers generally metastasize through LVI, identification of genes with altered expression when comparing LVI+ from LVI- tumors is relevant from both the fundamental and the clinical perspective. To discover genes and pathways involved in LVI and recurrence in ANNBC we performed differential gene expression microarray analysis of LVI+ (n = 37) and LVI- (n=68) ANNBC tumors and assessed pathway enrichment using Ingenuity IPA. We also analysed differences within the LVI+ group designed to compare genes for their association with early recurrence (n = 14; ≤ 4 years) versus free of recurrence for at least 10 years (n = 23). The biofunctions predicted to be activated that distinguish LVI+ from LVI- tumors are largely related to cell movement and invasion. Those enriched in the subset of patients with early recurrence were mostly related to cell fate. In addition, we observed that inflammation related pathways are enriched in the LVI+ subgroup that undergoes early recurrence. TGF-β1 was predicted to be an upstream regulator in the LVI+ vs LVI- dataset and also highly ranked in the early recurrence vs. late recurrence analysis. Our bioinformatics analyses are consistent with a migratory phenotype for cancer cells associated with LVI. The results suggest important pathways as well as upstream regulators associated with LVI and recurrence that are involved in invasion and cell fate biofunctions. The findings are currently being evaluated through validation and functional studies. Note: This abstract was not presented at the meeting. Citation Format: Mathieu Blais, Dushanthi Pinnaduwage, Sheley Bull, Irene L. Andrulis. Identification of genes and pathways related to lymphovascular invasion in axillary-node negative breast cancer: A bioinformatic analysis of gene expression data. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1395. doi:10.1158/1538-7445.AM2014-1395
Towards primary care groups Managing the future in Bradford
Authors: S R Proctor, J L Campbell
Journal: BMJ (1999)

This is the first of four articles showing how primary care groups have been set up in various areas in Britain This paper describes the processes and experiences of key players in Bradford, West Yorkshire, of setting up primary care groups (PCGs)—from initial reactions to the government's white paper,1 through configuration and establishing the boards, to planning and delivering the main tasks before going live on 1 April 1999. Bradford is one of the 10 largest cities in England. Bradford Health Authority serves the population of the city and surrounding areas. It is an area of great diversity, which incorporates some moderately affluent suburban communities as well as areas of substantial deprivation, poor housing, and high unemployment (box). The area is lively and culturally rich and includes some of the most beautiful countryside in England. The diversity of the area is also reflected in its primary care provision. This includes two total purchasing pilots (groups of general practitioners who purchase hospital and community health services outside fundholding).1 A range of fundholding practices have collaborated to develop joint contracts for commissioning a range of services. The district also has a substantial number of singlehanded practices, particularly in the inner city, and many of these have collaborated to form a support organisation for small practices. Despite the diverse needs of the communities served by primary care services in Bradford, sharing ideas between practices and working collaboratively is, in certain parts of the district, established. The district has recently become a health action zone and aims to build on existing partnerships across agencies and to work to reduce health inequalities. #### Summary points
Cell Targeting: Transferrin‐Mediated Rapid Targeting, Isolation, and Detection of Circulating Tumor Cells by Multifunctional Magneto‐Dendritic Nanosystem (Adv. Healthcare Mater. 6/2013)
Authors: Shashwat S. Banerjee, Archana Jalota‐Badhwar, Sneha D. Satavalekar, Sujit G. Bhansali, Naval D. Aher, Russel R. Mascarenhas, Debjani Paul, Somesh Sharma, Jayant J. Khandare
Journal: Advanced Healthcare Materials (2013)

A multicomponent magneto-dendritic nanosystem (MDNS) is designed for rapid tumor cell targeting, isolation, and high-resolution imaging by a facile bioconjugation approach. Jayant J. Khandare and co-workers show on page 800 that the MDNS system is capable of capturing circulating tumors cells rapidly from the mixture of peripheral blood cells. This approach is envisioned for the early diagnosis of metastatic cancer.
18F-Choline PET/CT Pitfalls in Image Interpretation
Authors: Ferdinando Calabria, Agostino Chiaravalloti, Orazio Schillaci
Journal: Clinical Nuclear Medicine (2013)

F-choline PET/CT is an important diagnostic tool in the management of patients with prostate cancer (PC). The aim of this study was to describe and discuss some abnormal sites of uptake that we observed, not due to PC recurrence.Three hundred patients were submitted to F-choline PET/CT for staging or restaging of PC. Whole-body PET/CT was acquired 40 minutes after the F-choline administration.We found abnormal uptake of the tracer, not related to PC, in 48/300 patients (16%). Most of these findings were due to inflammatory processes. Furthermore, some malignant conditions, such as a case of colon cancer, a case of bladder carcinoma, and a multiple myeloma, were diagnosed. Mild uptake was also detected in some benign diseases, such as thymoma, adrenal adenoma, and sarcoidosis. Six patients showed focal brain uptake in correspondence to a meningioma.It is necessary for nuclear physicians, during clinical practice, to consider the possibility of F-choline uptake in some benign or malignant conditions for the intrinsic pharmacologic property of the tracer. An accurate medical investigation, correlative imaging with CT and/or MRI with contrast agents, laboratory data, and above all, histologic examination are often necessary for correct diagnosis.
IN-HOSPITAL HEMOGLOBIN A1C TESTING AND ITS RELATION TO INITIATION OF GLUCOSE LOWERING THERAPY IN HYPERGLYCEMIC PATIENTS WITH ACUTE MYOCARDIAL INFARCTION
Authors: Joshua Stolker, John A. Spertus, Darren K. McGuire, Silvio E. Inzucchi, Saif S. Rathore, Thomas M. Maddox, Frederick A. Masoudi, Fengming Tang, Philip G. Jones, Mikhail Kosiborod
Journal: Journal of the American College of Cardiology (2010)
Morphometric Assessment of the Heteromodal Association Cortex in Schizophrenia
Authors: Robert W. Buchanan, Alan Francis, Celso Arango, Karl Miller, David M. Lefkowitz, Robert P. McMahon, Patrick E. Barta, Godfrey D. Pearlson
Journal: American Journal of Psychiatry (2004)

The heteromodal association cortex has been hypothesized to be selectively involved in the pathophysiology of schizophrenia. To test this hypothesis, the authors measured prefrontal, inferior parietal, and superior temporal gyrus volumes and examined the pattern of connections among these regions.Forty-four patients with schizophrenia or schizoaffective disorder and 34 healthy comparison subjects were included in the study. A spoiled gradient recall acquisition in the steady-state three-dimensional magnetic resonance imaging sequence was used for morphometric assessment of the heteromodal association cortex.Patients with schizophrenia had significantly smaller inferior prefrontal region volumes and significant reversal of the normal asymmetry of the inferior parietal cortex. No significant group differences were found in superior temporal gyrus volume. The groups differed significantly in the correlation between inferior prefrontal region volumes and angular gyrus volumes.The results suggest that patients with schizophrenia may be characterized by selective abnormalities of the heteromodal regions involved in the neuroanatomy of language.
Cerebral Embolization in Atrial Fibrillation Complicating Hyperthyroidism
Authors: Herman B. Giddings
Journal: JAMA (1978)

ATRIAL fibrillation occurs in 10% of patients with thyrotoxicosis. Although embolization is frequently associated with atrial fibrillation in patients with organic cardiac disease, hyperthyroid patients with this arrhythmia are generally not considered at risk for this complication. Indeed, standard texts do not mention the possibility of systemic embolization in hyperthyroidism. We describe a patient with Graves' disease and atrial fibrillation whose otherwise typical course was complicated by a cerebral embolus and severe neurologic deficit. Underlying cardiac disease could not be demonstrated by noninvasive techniques. <h3>Report of a Case</h3> A 50-year-old woman was admitted for the second time to the Montefiore Hospital and Medical Center on Feb 8, 1976, for evaluation of purpura. Four months before admission she was admitted to another hospital because of shortness of breath, palpitations, and increased restlessness. The 24-hour radioactive iodine uptake was 71%; the serum thyroxine (T<sub>4</sub>) concentration was 18.6 μg/dl, and the ECG
Poor response to erythropoietin
Authors: I. C Macdougall
Journal: BMJ (1995)

and would permit some uses that otherwise seem to be prohibited.Significantly, in the debate over property rights in human bodies or parts thereof the conclusion is that there may be some property rights in human body parts but that, as with all such rights, constraints will nevertheless exist on how such rights can be exercised and the uses to which human tissue can be put.Property, in addition, might be a useful concept, but not to the extent that it involves commercialism.In an effort to clarify the legal status ofbody parts the report proposes that two presumptions should be taken as standard: firstly, that tissue removed in the course oftreatment should be presumed to have been abandoned and, secondly, that if tissue is removed in other circumstances and donated voluntarily it may also be used if consent to the intended use is given.If adopted, these proposals would simplify what is otherwise an extremely complex question.
Changes in red cell ion transport, reduced intratumoral neovascularization, and some mild motor function abnormalities accompany targeted disruption of the Mouse Kell gene (<i>Kel</i>)
Authors: Xiang Zhu, Alicia Rivera, Mari S. Golub, Jianbin Peng, Quan Sha, Xu Wu, Xiaoling Song, Prem Kumarathasan, Mac Ho, Colvin M. Redman, Soohee Lee
Journal: American Journal of Hematology (2009)

Kell (ECE-3), a highly polymorphic blood group glycoprotein, displays more than 30 antigens that produce allo-antibodies and, on red blood cells (RBCs), is complexed through a single disulfide bond with the integral membrane protein, XK. XK is a putative membrane transporter whose absence results in a late onset form of neuromuscular abnormalities known as the McLeod syndrome. Although Kell glycoprotein is known to be an endothelin-3-converting enzyme, the full extent of its physiological function is unknown. To study the functions of Kell glycoprotein, we undertook targeted disruption of the murine Kel gene by homologous recombination. RBCs from Kel(-/-) mice lacked Kell glycoprotein, Kell/XK complex, and endothelin-3-converting enzyme activity and had reduced levels of XK. XK mRNA levels in spleen, brain, and testis were unchanged. In Kel(-/-) mice RBC Gardos channel activity was increased and the normal enhancement by endothelin-3 was blunted. Analysis of the microvessels of tumors produced from LL2 cells indicated that the central portion of tumors from wild-type mice were populated with many mature blood vessels, but that vessels in tumors from Kel(-/-) mice were fewer and smaller. The absence of Kell glycoprotein mildly affected some motor activities identified by foot splay on the drop tests. The targeted disruption of Kel in mouse enabled us to identify phenotypes that would not be easily detected in humans lacking Kell glycoprotein. In this regard, the Kell knockout mouse provides a good animal model for the study of normal and/or pathophysiological functions of Kell glycoprotein.
Echocardiographic Diagnosis of Idiopathic Hypertrophic Cardiomyopathy without Outflow Obstruction
Authors: A S. ABBASI, R. N. MACALPIN, L. M. EBER, M. L. PEARCE
Journal: Circulation (1972)

The echocardiographic findings of eight patients with hypertrophic cardiomyopathy without outflow obstruction (HMC) and of 15 normal (Norm) individuals are presented. The characteristic features in HMC were: (1) interventricular septal width much greater than normal (HMC = 2.5 ± 0.3 cm, Norm = 1.0 ± 0.2 cm, P &lt; 0.005); (2) normal or only slightly increased posterior left ventricular wall thickness; (3) the ratio of interventricular septal to posterior wall thickness ≧2.0; (4) ejection fraction greater than normal (HMC = 0.76 ± 0.08, Norm = 0.68 ± 0.06, P &lt; 0.025); (5) reduced velocity of the early diastolic closing motion of the anterior mitral leaflet (HMC = 60 ± 23 mm/sec, Norm = 124 ± 29 mm/sec, P &lt; 0.005); (6) absence of abnormal systolic movement of the anterior mitral valve, as seen in hypertrophic obstructive cardiomyopathy. The diagnosis of hypertrophic cardiomyopathy can be made with echocardiography, even when outflow tract obstruction of the left ventricle is absent.
Acute aortic dissection and medial degeneration in patients with 'floppy' mitral valves.
Authors: R McKay, M H Yacoub
Journal: Thorax (1976)

Mitral regurgitation due to 9floppy9 valves is frequently associated with areas of medical necrosis in the ascending aorta. Application of the aortic clamp to such an area during valve replacement may produce an intimal tear followed by acute dissection. This complication occurred in three patients and was treated successfully by repair of the tear in the two cases where the dissection was observed at the time of operation. Is is suggested that infrequent clamping of the aorta and careful control of the pefusion pressure may decrease the risk of intimal trauma and acute dissection.
Has the BMJ discovered an end to ageing?
Authors: E. S Kilpatrick
Journal: BMJ (1998)

EDITOR—Having deliberated over using the word “ageing” or “aging” in a manuscript,1 I was interested to see that the BMJ preferred to use the spelling without the “e” in their “aging issue” (25 October 1997). Given that the Concise Oxford Dictionary 2 gives credence to both spellings, I wished to establish if a consensus existed within …
FIBROUS ANKYLOSIS OF THE HAND DUE TO PROLONGED SWELLING
Authors: A. BRUCE GILL
Journal: JAMA (1924)

The hand is essentially a prehensile organ, and loss of the power to pick up objects, to grasp firmly and to execute fine movements constitutes its most common and most serious disability. Loss of function of the hand may be due to stiffness or ankylosis of the joints of the fingers; to imperfect or lost tendon action from adhesions or loss of tendon substance or contracture of muscles, such as Volkmann's contracture; to Dupuytren's and cicatricial contractures of fascia, and to lesions of nerves which supply the muscles of the hand and the forearm. Of these causes of acquired deformity and disability, the most common is the first, the limitation or absence of motion of the joints of the fingers due to conditions within or about the joints themselves. This stiffness and ankylosis may result from active joint disease, as in various types of arthritis, or from prolonged passive congestion