tbuckley/cabot-search huggingface dataset:
Somatic Mutation Screening: Identification of Individuals Harboring K-ras Mutations With the Use of Plasma DNA
Authors: M. S. Kopreski
Journal: JNCI Journal of the National Cancer Institute (2000)

Background: Many cancers are attributed to somatic mutation of DNA. We investigated whether it is feasible to detect cancer-associated somatic mutations in patients with neoplasms by using plasma DNA. Methods: Plasma samples were prospectively collected from 240 patients undergoing colonoscopy. Colorectal biopsies were performed as clinically indicated in 135 patients, and risk factor information was available from 232 patients. DNA was extracted from plasma and colorectal tissue and was amplified by use of a polymerase chain reaction method that enriches for mutations in codon 12 of the K-ras oncogene. Molecular, histologic, and clinical data were compared by use of two-sided Fisher's exact test. Results: Mutations in the K-ras gene detected in the plasma of 64 (28%) of 232 patients were statistically significantly associated with colorectal cancer risk factors (P = .0002). Of those patients having tissue available for comparison (n = 135), mutations in the K-ras gene were found in the tissues of 35 patients, and 29 (83%) of these 35 showed mutations in plasma samples. In contrast, the plasma assay was negative in 93 of the 100 patients whose tissue K-ras was wild-type. Among patients without biopsies (n = 105), 28 had mutated K-ras in their plasma DNA, despite the absence of remarkable colonoscopy findings; 24 of these 28 patients had risk factors for colorectal cancer. Overall, 25 (39%) of 64 patients showing mutations in plasma DNA had colorectal neoplasms with K-ras mutations compared with five (3%) of 176 patients without K-ras mutations in plasma DNA. Conclusion: Plasma DNA assays for the detection of mutations in K-ras codon 12 may provide a feasible method to screen populations for somatic mutations frequently found in neoplasms. The clinical utility of using this test in screening populations requires further study.
Metabolic Bone Disease in Alcoholic Cirrhosis: A Comparison of the Effect of Vitamin D<sub>2</sub>25-Hydroxyvitamin D, or Supportive Treatment
Authors: Sohrab A. Mobarhan, Robert M. Russell, Robert R. Recker, David B. Posner, Frank L. Iber, Pamela Miller
Journal: Hepatology (1984)

In a study of 56 alcoholics with liver cirrhosis, 18 (32%) had decreased bone density and low levels of serum 25-hydroxyvitamin D (25-OH-D) (&lt;20 ng per ml). To compare the efficacy of vitamin D 2 and 25-OH-D treatment in correcting the metabolic bone disease in alcoholic cirrhosis, the 18 patients were randomized in the following manner, in groups of six patients each: Group 1, control (received no supplemental vitamin D treatment); Group 2, given vitamin D 2 (50,000 IU p.o.) two to three times weekly, and Group 3, treated with 25-OH-D (20 to 50 mg p.o.) daily as required to attain normal serum 25-OH-D levels. The study period lasted 6 to 12 months (mean, 10.7 months). Initial histomorphometric study of transiliac bone biopsy with double tetracycline labeling in nine patients in whom biopsy was feasible showed only osteoporosis without evidence of osteomalacia. By the end of the study, serum 25-OH-D levels in the control group (Group 1) raised slightly while showing marked improvement in Groups 2 and 3. Bone density results remained unchanged in control patients but demonstrated a significant increase in both treatment groups. Vitamin D 2 and 25-OH-D were equally effective in increasing bone density measurements. Posttreatment biopsies were performed in three patients of Group 2 and two patients of Group 3. While the histomorphometric results in Group 3 were not conclusive, in Group 2 improvement in static measures of bone remodeling was noted. Osteoporosis is the usual form of bone disease in alcoholic cirrhosis and a response to either vitamin D 2 or 25-OH-D treatment is suggested.
Murine Models and Cell Lines for the Investigation of Pheochromocytoma: Applications for Future Therapies?
Authors: Esther Korpershoek, Karel Pacak, Lucia Martiniova
Journal: Endocrine Pathology (2012)

Pheochromocytomas (PCCs) are slow-growing neuroendocrine tumors arising from adrenal chromaffin cells. Tumors arising from extra-adrenal chromaffin cells are called paragangliomas. Metastases can occur up to approximately 60% or even more in specific subgroups of patients. There are still no well-established and clinically accepted "metastatic" markers available to determine whether a primary tumor is or will become malignant. Surgical resection is the most common treatment for non-metastatic PCCs, but no standard treatment/regimen is available for metastatic PCC. To investigate what kind of therapies are suitable for the treatment of metastatic PCC, animal models or cell lines are very useful. Over the last two decades, various mouse and rat models have been created presenting with PCC, which include models presenting tumors that are to a certain degree biochemically and/or molecularly similar to human PCC, and develop metastases. To be able to investigate which chemotherapeutic options could be useful for the treatment of metastatic PCC, cell lines such as mouse pheochromocytoma (MPC) and mouse tumor tissue (MTT) cells have been recently introduced and they both showed metastatic behavior. It appears these MPC and MTT cells are biochemically and molecularly similar to some human PCCs, are easily visualized by different imaging techniques, and respond to different therapies. These studies also indicate that some mouse models and both mouse PCC cell lines are suitable for testing new therapies for metastatic PCC.
Sudden death in the shadows of epilepsy
Authors: E. Reynolds
Journal: BMJ (2003)

In a widely acclaimed BBC production, The Lost Prince , the short and tragic life of Prince John, son of Britain's King George V and Queen Mary, and his sudden death in the early 20th century emerged from the shadows in which he had been hidden.1 He was hidden because of his epilepsy and learning disorder, and by the medical and social ignorance of his royal parents and advisers. Prince John has shared this fate with millions of others of all social classes and cultures before and since. In the 1920s, a few years after the death of Prince John in a seizure, the young Graham Greene received a diagnosis of epilepsy from a well known neurologist from Harley Street.2 Initially his embarrassed parents concealed the diagnosis from him. When Greene learned of it he also concealed it for nearly 50 years until in his autobiography he eloquently described the impact of the diagnosis, which had led him to contemplate suicide. His greatest concerns were inheritance and marriage. These two lives from the past highlight two continuing …
CT guided biopsy: Predictors of outcome and complication rate
Authors: Rahuldeb Sarkar, Amir Baluwala, James Jamieson-Young, Andrew Wight, Elspeth Partridge, Marta Babores
Journal: European Respiratory Journal (2011)

Background: With a drive towards early diagnosis of lung cancer and aim for curative treatment, CT guided biopsy is being used increasingly. While it is a relatively safe procedure, institutions performing this should audit its practice against recommended standards.

Objective: Measuring this procedure's complication rate and positive results to ascertain if there are any predictors for these outcomes.

Method: A retrospective study was undertaken to collect data for all CT guided biopsies done in last 2 years (2009-10) in our hospital.

Result: 66 biopsies were reviewed. Mean (SD) age of patients was 69 (11) years. Conclusive histology was obtained in 38 (56%). Complication rate and the British Thoracic Society (BTS) standards are shown below.

View this table:

Table 1





The mean size and depth from chest wall of lesions in patients with and without PTX, hemorrhage and conclusive biopsies are shown in Table 2.

View this table:

Table 2





In lesions with a size of >3cm (n=43), 31 (72%) results were conclusive as opposed to 8 (35%) conclusive results in lesions  1.5 cm (n=13) was 46% while the same for lesions at depth <1.5 cm (n=53) was 61%.

Conclusion: Good pick up rate with complications well within acceptable standards were achieved in our study population. Depth of the lesion correlated well with pneumothorax and hemorrhage while size correlated with pneumothorax. Size was also a good predictors of conclusive biopsies.
The PYRIN domain–only protein POP3 inhibits ALR inflammasomes and regulates responses to infection with DNA viruses
Authors: Sonal Khare, Rojo A Ratsimandresy, Lúcia de Almeida, Carla M Cuda, Stephanie L Rellick, Alexander V Misharin, Melissa C Wallin, Anu Gangopadhyay, Eleonora Forte, Eva Gottwein, Harris Perlman, John C Reed, David R Greaves, Andrea Dorfleutner, Christian Stehlik
Journal: Nature Immunology (2014)
Why Did You Not Use Both Internal Thoracic Arteries?
Authors: John D. Puskas
Journal: Circulation (2012)

T hat is the question every cardiologist should ask if the patient he or she has referred for primary surgical coronary revascularization returns from the operating room with a single internal thoracic artery graft.][3][4] However, only 4.4% of primary isolated CABG cases in the 2011 Society of Thoracic Surgeons National Adult Cardiac Surgery Database received bilateral internal thoracic artery (BITA) grafting. 5There are several putative reasons for this failure of adoption, but referring cardiologists and patients should demand better.
Effects of the EGFR Inhibitor Erlotinib on Magnesium Handling
Authors: Henrik Dimke, Jenny van der Wijst, Todd R. Alexander, Inez M.J. Meijer, Gemma M. Mulder, Harry van Goor, Sabine Tejpar, Joost G. Hoenderop, René J. Bindels
Journal: Journal of the American Society of Nephrology (2010)

A mutation in pro-EGF causes isolated hypomagnesemia, and monoclonal antibodies targeting the extracellular domain of the EGF receptor (EGFR) affect epithelial Mg(2+) transport. The effect of the EGFR tyrosine kinase inhibitor erlotinib on Mg(2+) homeostasis, however, remains unknown. Here, we injected C57BL/6 mice with erlotinib for 23 days and observed a small but significant decrease in serum Mg(2+) concentrations at days 16 and 23, but the fractional excretion of Mg(2+) remained unchanged after 23 days. Semiquantitative immunohistochemical evaluation did not reveal detectable changes in renal expression of transient receptor potential melastatin 6 (TRPM6) protein, the channel that mediates Mg(2+) reabsorption. Patch clamp analysis in TRPM6-expressing cells demonstrated that 30 muM erlotinib inhibited EGF-induced changes in TRPM6 current density and tyrosine phosphorylation of EGFR; 0.3 muM erlotinib did not have these effects. Furthermore, 30 muM erlotinib inhibited EGF-stimulated increases in the mobile fraction of endomembrane TRPM6 channels. In summary, erlotinib can influence Mg(2+) handling but its effect on the systemic Mg(2+) concentration seems less potent than that observed with antibody-based EGFR inhibitors. These data suggest that typical human dosages of erlotinib are unlikely to severely affect serum Mg(2+) concentrations.
Cardiovascular effects of arginase inhibition in spontaneously hypertensive rats with fully developed hypertension
Authors: Teddy Bagnost, Ling Ma, Rafaela F. da Silva, Rana Rezakhaniha, Christophe Houdayer, Nikos Stergiopulos, Claire André, Yves Guillaume, Alain Berthelot, Céline Demougeot
Journal: Cardiovascular Research (2010)

Growing evidence suggests that arginase misregulation plays a key role in the pathophysiology of essential hypertension. In the present study, we investigated the potential cardiovascular therapeutic effects of a long-term treatment with an arginase inhibitor in adult spontaneously hypertensive rats (SHR) with fully developed hypertension. Treatment of 25-week-old SHR with the arginase inhibitor Nω-hydroxy-nor-l-arginine (nor-NOHA, 40 mg/day for 10 weeks) sustainably reduced systolic blood pressure (−30 mmHg, P < 0.05). The antihypertensive effect of nor-NOHA was associated with changes on mesenteric artery reactivity including the restoration of angiotensin-II-induced contraction and acetylcholine-induced vasodilation to the values of normotensive Wistar Kyoto rats. Both nitric oxide synthase and cyclooxygenase-dependent mechanisms account for the improvement of endothelial function afforded by the arginase inhibitor, which in addition blunted hypertension-induced endothelial arginase I overexpression in mesenteric arteries. Nor-NOHA also prevented the remodelling of aorta as measured by collagen content and media/lumen ratio, and improved the compliance of carotid artery in SHR. Cardiac fibrosis assessed by collagen content of left heart ventricle was reduced by nor-NOHA, with no significant effect on cardiac hypertrophy. Our results report that a long-term treatment with an arginase inhibitor reduced blood pressure, improved vascular function, and reduced cardiac fibrosis in SHR with fully developed hypertension. These data suggest that arginase represents a promising novel target for pharmacological intervention in essential hypertension.
Particle size of beclomethasone dipropionate produced by two nebulisers and two spacing devices.
Authors: C O'Callaghan
Journal: Thorax (1990)

An impactor method was used to assess the amount of beclomethasone dipropionate in particles less than 5 microns produced by two nebulisers (Pari Inhalierboy, Medix Traveller compressor with cirrhus nebuliser chamber) and two spacer devices (Volumatic and Nebuhaler). After nebulisation of 3 ml (150 micrograms) beclomethasone dipropionate the amount of drug in particles less than 5 microns was 16 micrograms (GSD 1.1) with the Pari Inhalierboy, and 27 micrograms (1.4) with the Medix Traveller with cirrhus nebuliser. This was less than the amount in particles less than 5 microns after three metered dose inhaler actuations (150 micrograms) from the Nebuhaler (58.2 (1) micrograms) or the Volumatic spacer (46.5 (1) micrograms). The greater amount of beclomethasone dipropionate in small particles with administration from a metered dose inhaler with a spacer device means that considerably more drug is likely to reach the airways than when the same dose is given by the two nebulisers studied.
VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis
Authors: Betty Y Y Tam, Kevin Wei, John S Rudge, Jana Hoffman, Joceyln Holash, Sang-ki Park, Jenny Yuan, Colleen Hefner, Cecile Chartier, Jeng-Shin Lee, Shelly Jiang, Nihar R Nayak, Frans A Kuypers, Lisa Ma, Uma Sundram, Grace Wu, Joseph A Garcia, Stanley L Schrier, Jacquelyn J Maher, Randall S Johnson, George D Yancopoulos, Richard C Mulligan, Calvin J Kuo
Journal: Nature Medicine (2006)
Mitochondria-specific transgenic overexpression of connexin-43 simulates preconditioning-induced cytoprotection of stem cells
Authors: Gang Lu, Husnain Kh Haider, Aleksey Porollo, Muhammad Ashraf
Journal: Cardiovascular Research (2010)

We previously reported that preconditioning of stem cells with insulin-like growth factor-1 (IGF-1) translocated connexin-43 (Cx-43) into mitochondria, causing cytoprotection. We posit that these preconditioning effects could be simulated by mitochondria-specific overexpression of Cx-43.During IGF-1-induced preconditioning of C57black/6 mouse bone marrow stem cell antigen-1(+) (Sca-1(+)) cells, Cx-43 was mainly translocated onto the mitochondrial inner membrane, which was abrogated by an extracellular signal-regulated kinases 1 and 2 (ERK1/2) blocker PD98059. To investigate the role of mitochondrial Cx-43, we successfully designed a vector coding for full-length mouse Cx-43 with a mitochondria-targeting sequence (mito-Cx-43) and cloned into a shuttle vector (pShuttle-IRES-hrGFP-1) for mitochondria-specific overexpression of Cx-43 (mito-Cx-43). Sca-1(+) cells with mito-Cx-43 reduced cytosolic accumulation of cytochrome c, lowered caspase-3 activity, and improved survival during index oxygen-glucose deprivation as determined by terminal deoxynucleotidyl transferase dUTP nick-end labelling and lactate dehydrogenase assays. Computational analysis revealed a B-cell lymphoma-2 (Bcl-2) homology domain-3 (BH3) motif in Cx-43 with a conserved pattern of amino acids consistent with the Bcl-2 family that regulated cytochrome c release. Moreover, computational secondary structure prediction indicated an extended α-helix in this region, a known condition for BH3-driven protein-protein interactions.Cx-43 translocation into mitochondria during preconditioning was ERK1/2-dependent. Expression of mito-Cx-43 simulated the cytoprotective effects of preconditioning in stem cells. Structural features of Cx-43 were shared with the Bcl-2 family as determined by computational analysis.
Prediction of Prostate Cancer Recurrence Using Magnetic Resonance Imaging and Molecular Profiles
Authors: Amita Shukla-Dave, Hedvig Hricak, Nicole Ishill, Chaya S. Moskowitz, Marija Drobnjak, Victor E. Reuter, Kristen L. Zakian, Peter T. Scardino, Carlos Cordon-Cardo
Journal: Clinical Cancer Research (2009)

Abstract Purpose: To evaluate whether pretreatment magnetic resonance imaging (MRI)/MR spectroscopic imaging (MRSI) findings and molecular markers in surgical specimens correlate with each other and with pretreatment clinical variables (biopsy Gleason score, clinical stage, and prostate-specific antigen level) and whether they contribute incremental value in predicting prostate cancer recurrence. Experimental Design: Eighty-eight prostate cancer patients underwent MRI/MRSI before radical prostatectomy; imaging findings were scored on a scale of 1 to 7 (no tumor seen—lymph node metastasis). Ki-67, phospho-Akt, and androgen receptor expression in surgical specimens were assessed by immunohistochemistry. To examine correlations between markers and imaging scores, Spearman's correlation was used. To test whether markers and imaging scores differed by clinical stage or Gleason score, Wilcoxon's rank sum test was used. To examine time to recurrence, the methods of Kaplan-Meier were used. Cox proportional hazards models were built and their concordance indices (C-indices) were calculated to evaluate prediction of recurrence. Results: All markers correlated moderately strongly with MRI/MRSI score (all correlation coefficients &amp;gt;0.5). Markers and MRI/MRSI score were strongly associated with clinical stage and biopsy Gleason score (P &amp;lt; 0.01 for all). At last follow-up, 27 patients had recurrence. C-indices for MRI/MRSI score and all markers were associated with time to recurrence and ranged from 0.78 to 0.89. A Cox model combining all clinical predictors had a C-index of 0.89; the C-index increased to 0.95 when MRI/MRSI score was added and to 0.97 when markers were also added. Conclusions: MRI/MRSI findings and molecular markers correlated well with each other and contributed incremental value to clinical variables in predicting prostate cancer recurrence.
Neurotrophins induce nitric oxide generation in human pulmonary artery endothelial cells
Authors: Lucas W. Meuchel, Michael A. Thompson, Steven D. Cassivi, Christina M. Pabelick, Y.S. Prakash
Journal: Cardiovascular Research (2011)

AimsMembers of the growth factor family of neurotrophins [NTs; e.g. brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3)] and their high-affinity receptors (tropomyosin-related kinase; Trk) and low-affinity receptors p75 neurotrophin receptor (p75NTR) have been localized to pulmonary artery (PA) in humans. However, their role is unclear. Based on previous findings of NTs and their receptors within the pulmonary endothelium, we tested the hypothesis that NTs induce nitric oxide (NO) production in pulmonary endothelial cells (ECs), thus contributing to vasodilation.
Rat Ileocecal Immunocytoma. An Ultrastructural Study With Special Attention to the Presence of Viral Particles&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: G. Burtonboy, A. Beckers, J. Rodhain, H. Bazin, M. E. Lamy
Journal: JNCI Journal of the National Cancer Institute (1978)

Fifteen spontaneous immunocytomas originating in the ileocecal lymph nodes of Lou/C/Wsl rats were studied by means of electron microscopy. The histology was characteristic, the tumor being formed by an accumulation of large, rounded cells with slightly eccentric ovoid nuclei, large nucleoli, and finely condensed chromatin along the nuclear walls; the cytoplasm was rich in polyribosomes. The appearance of the rough endoplasmic reticulum was apparently the same whether or not the tumor was secretory. Its development varied from one cell to another, and in only a small proportion of cells did it attain any considerable volume. In all the tumors examined, we noted the presence of intracisternal A-particles. In its morphology, the rat immunocytoma resembled the plasmacytomas induced in mice, and it also resembled certain human tumors such as Burkitt's lymphoma.
Conversion of monocytes to cells capable of anchorage-independent growth in vitro.
Authors: H S Lin, S Gordon, D M Chen, M Kurtz
Journal: The Journal of Experimental Medicine (1981)

We investigated the time-course involved in the conversion of mouse blood monocytes in vitro in cells capable of anchorage-independent growth. Two criteria were used to define when monocytes were fully converted to cells similar to mononuclear phagocytes present in inflammatory exudate, such as thioglycollate medium (TM)-elicited peritoneal exudate. They were the production of high levels of plasminogen activators and an ability to undergo anchorage-independent growth. Resident peritoneal macrophages were used as controls and for comparison. Our studies indicated that monocytes, but not resident peritoneal macrophages, could be converted to cells similar to TM-elicited mononuclear phagocytes after 2 d in culture.
Regulation of airway smooth muscle RhoA/ROCK activities by cholinergic and bronchodilator stimuli
Authors: C. Liu
Journal: European Respiratory Journal (2006)

The current study set out to compare the temporal relationships of Rho activity, Rho kinase (ROCK) activity and tone following cholinergic stimulation in the presence and absence of three different bronchodilators. Bovine trachea challenged with a half-maximally effective concentration of carbachol (CCh) was flash-frozen at different times, then assayed for Rho (rhotekin pull-down assay) and ROCK (Western blot; radiometric assay) activities. Rho was activated within 30 s, followed by ROCK (peak at 2 min); both returned to baseline by 20 min, although tone continued to rise over that period. Increasing the concentration of CCh greatly increased the magnitudes and rates of stimulation of Rho, ROCK and tone. These CCh-induced changes were next compared in tissues pre-treated with isoproterenol, salmeterol or the nitric oxide donor <i>S</i>-nitroso-<i>N</i>-acetylpenicillamine (SNAP). Neither the time course nor the magnitude of Rho-activation were reduced by the β-agonists; SNAP slowed Rho activation but it did not alter the peak magnitude. These observations were mirrored in ROCK activation and contraction. When tissues were pre-constricted with CCh and then challenged with the bronchodilators, however, all three agonists reversed cholinergically stimulated Rho, ROCK and myosin light chain kinase activities as well as tone. In conclusion, bronchodilators can suppress RhoA and Rho kinase activities, although their major effect appears to be on myosin light chain kinase activity.