tbuckley/cabot-search huggingface dataset:
Abstract LB-506: Targeted integrations of fluorescent proteins into STAT3 and STAT1 Loci via ZFN mediated homologous recombination in human cancer cell lines provides a suitable and adequate model system for cell-based testing of new candidate drugs for human tumor treatment
Authors: Andrey Samsonov, Fan Zhang, Hongyi Zhang, Nathan Zenser, John Fetter, Dmitry Malkov
Journal: Cancer Research (2012)

Abstract STAT3 which is a member of the family of signal transducers and activators of transcription is an oncogene and it is constitutively activated in numerous cancer cell lines and human cancers including breast, lung, head and neck, liver, and pancreas. Another STAT family member STAT1 possesses cancer-inhibitory properties and once activated may promote apoptosis in tumor cells. Thus STAT3 has been identified as a promising drug discovery target for many cancers. Ideally the potential inhibitors of STAT3 should be very selective and should not inactivate STAT1. To better address these cancer-research important genes, we tagged STAT3 and STAT1 loci with fluorescent protein (FP) sequences (RFP and GFP respectively) by targeted integration via Zinc-Finger Nuclease (ZFN) mediated homologous recombination in cancer derived cell lines. ZFN technology is a fast and reliable way to manipulate the genome in a targeted fashion. ZFNs are synthetic proteins engineered to bind DNA at a sequence-specific location and create a double strand break (www.compozrzfn.com). The cell's natural machinery repairs the break in one of two ways: non-homologous end joining or homologous recombination. Utilizing the homologous recombination pathway that ZFNs induce, we successfully inserted the FP transgenes into the desired target locations - at the N-terminus of the STAT3 locus and at the C-terminus of the STAT1 locus. Three cell lines were created, two with the single STAT tagged and a third with both STATs tagged. Integration resulted in endogenous expression of fluorescent STAT3 and STAT1 chimeric fusion proteins in the A549 cell lines. Functional analyses of knock-in cell lines indicated that both STAT3 and STAT1 native gene regulation is conserved resulting in normal levels of protein expression and preservation of protein function. When stimulated with IL-6 or INF-γ, A549 cells showed fast and robust nuclear translocation of RFP-STAT3 or STAT1-GFP respectively. Cell pre-incubation with a known specific STAT3 inhibitors showed that STAT1-GFP, INF-γ-induced translocation was not impaired. Thus, these cell lines provide a simple and convenient method for high-content screening and pre-clinical testing of potential STAT3 inhibitors while ensuring that the STAT1 pathway is not affected. This approach of zfn-tagging endogenous genes could be applied to other cancer targets. 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 LB-506. doi:1538-7445.AM2012-LB-506
ON THE DIET OF A PATIENT BEFORE OPERATIONS UNDER GENERAL ANAESTHESIA
Authors: R. W. Collum
Journal: BMJ (1910)

mproduce puzzling erythematous eruptions, but fail to do so in the majority of patients siuffedig from tie same form of toxaemia.The next ease illwtrates the severe-type of infection of the urinary tract.It represents a class of ease which might easiTy be, and I believe has been, mistaken for appendicitis, and be submitted to a usdless operation.CASE IV.Woman, aged 28; pregnant five and a half months; had vomiting and rigors.Temperature 1030, pulse 130, respirations 32, abdominal tenderness, especially over the rigbt iliac region and towards the right kidney; some dysuria.During the first week, sleeplessness, persistent vomiting, abdominal pain and dysuria were the most prominent features.The urine was acid, contained some pus, which increased in quantity later, and a motile bacillus in enormous numbers, which was Gram-negative, and on subsequent culture proved to be one of the colon group-that is to say, it produced acidity and dotting of litmus milk; fermented lactose; gave a luxuriant brown growth on potato, and did not liquefy gelatine.A three days' broth culture gave a deep purple colour when 1 c.cm. of a 0.02 per cent.solution sodium nitrite and 1 c.cm hydrochloric aoid were added.In this case alkalis and morphine (by the mouth) proved valueless, owing to the persistent vomiting, and at the end of the first week the case was looking very grave.It was then decided to try the effect of a vaccine made from a six-hours' subculture of the patient's own bacillus.A dose of fifty millions (approximately) was injected on the morning of the seventh day of the illness.
Comparison of Hand-Carried Ultrasound Assessment of the Inferior Vena Cava and N-Terminal Pro-Brain Natriuretic Peptide for Predicting Readmission After Hospitalization for Acute Decompensated Heart Failure
Authors: Sascha N. Goonewardena, Anthony Gemignani, Adam Ronan, Samip Vasaiwala, John Blair, J. Matthew Brennan, Dipak P. Shah, Kirk T. Spencer
Journal: JACC. Cardiovascular imaging (2008)
Abstract LB-204: Highly potent and optimized small-molecule inhibitors of MDM2 achieve complete tumor regression in animal models of solid tumors and leukemia.
Authors: Shaomeng Wang, Wei Sun, Shanghai Yu, Yu-jun Zhao, Sanjeev Kumar, Donna McEachern, Liu Liu, Denzil Bernard, Duxin Sun, Peng Zou, Xiaqin Li, Han Yi, Jeanne Stuckey, Jianting Long, Sami Malek, Dajun Yang, Snmao Kang, Ming Guo, Brian Wood, Lance Leopold, Mel Sorensen, Cedric Barriere, Isabelle Meaux, Odette Dos-Santos, Jean-christophe Carry, Pierre-yves Abecassis, Anne Charlier, Vincent Ferey, Carlos Garciaecheverria, Christophe Lengauer, Laurent Debussche
Journal: Cancer Research (2011)

Abstract Activation of p53 by blocking the interaction of MDM2-p53 using non-peptide small-molecule inhibitors is being pursued as a promising new cancer therapeutic strategy. Although genetic activation of p53 has been shown to achieve complete tumor eradication in mice, the best small-molecule inhibitors of the MDM2-p53 interaction reported to date (Nutlins including RG7112 or first generation spiro-oxindoles such as AT219) can only inhibit tumor growth but fail to achieve significant tumor regression in animal models of human cancer. In the present study, we demonstrate, for the first time, that 2 highly optimized spiro-oxindole compounds, Compound A and Compound B, are capable of achieving complete tumor regression or even permanent cure in multiple xenograft models of human cancer (sarcoma, leukemia, prostate) without causing any significant signs of toxicity to animals. They bind to human MDM2 protein with Ki values of &amp;lt;1 nM, 5000-times more potent than the wild-type p53 peptide. These potent MDM2 inhibitors are capable of activating p53 at concentrations as low as 30–100 nM and induce robust p53-dependent cell cycle arrest and apoptosis against tumor cells with wild-type p53. Both compounds display good pharmacokinetic and pharmacodynamic profiles in animals. For instance, clearance is low in mice and moderate in dog representing 4 and 15 % of hepatic blood flow respectively. Importantly, excellent oral bioavailability was shown with 25–60 % F in dogs and 75 % F in mice and both compounds trigger rapid and sustained activation of pharmacodynamic biomarkers such as p53, p21, MDM2 and PUMA. Molecular profiling using large number of primary AML leukemia samples have identified that AML cells with wild-type p53 and FLT3-ITD mutation are exquisitely sensitive to apoptosis induction by our MDM2 inhibitors, suggesting an interesting clinical trial rationale. Toxicology studies are ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-204. doi:10.1158/1538-7445.AM2011-LB-204
Subphrenic Abscess
Authors: Nicholas A. Halasz
Journal: JAMA (1970)

Missed synchronous abscesses were found to contribute greatly to therapeutic failure in the management of subphrenic abscesses. In a study of 43 patients, such failures were almost entirely limited to those patients whose abscesses were drained by various extraperitoneal approaches. Transperitoneal operation, in contrast, made adequate exploration of the several potential abscess sites possible, and permitted complete drainage of all synchronous purulent collections, with corresponding reduction in second operations and death rates. The classic recommendation for extraserous drainage is not supportable on the basis of this study.
Improvement of Impaired Counterregulatory Hormone Response and Symptom Perception by Snort-Term Avoidance of Hypoglycemia in IDDM
Authors: Thomas Lingenfelser, Ulrich Buettner, Juergen Martin, Mark Tobis, walter Renn, Rainer Kaschel, Bernhard Jakober
Journal: Diabetes Care (1995)

To test the hypothesis that impaired counterregulatory hormone response and symptom perception, induced by recurrent hypoglycemic episodes over 2 days, may be improved by short-term (2-day) avoidance of hypoglycemia. RESEARCH AND DESIGN: We examined two groups of insulin-dependent diabetes mellitus (IDDM) patients (n = 16), none of whom exhibited signs of peripheral or autonomic neuropathy. Two sequential euglycemic-hypoglycemic clamp studies were performed applying stable glycemic plateaus of 5.6, 3.3, 2.2, and 1.7 mmol/l, at which the patients' awareness of and responses to hypoglycemia were evaluated. In the intervention group (n = 11), three short-term hypoglycemic ( < 2.2 mmol/l) episodes (days 1-3) preceded the first clamp study (day 4), whereas the second clamp study (day 6) followed a 2-day interval of strict avoidance of hypoglycemia. A control group (n = 5) was introduced to detect adaptation effects caused by the study procedure per se.This short-term avoidance of hypoglycemia caused improvement of the impaired counterregulatory hormone response during insulin-induced hypoglycemia involving adrenaline (P < 0.05), adrenocorticotrophic hormone (P < 0.03), and cortisol (P < 0.05). Improvement of hypoglycemia symptom awareness encompassed overall symptom perception (multiple analysis of variance, P < 0.04) and the automatic symptoms of heart pounding (P < 0.05) and sweating (P < 0.05).The previously reported compromised neuroendocrine counterregulation and symptom awareness, occurring as a consequence of repetitive hypoglycemic episodes over 2 days, may be improved by a single 2-day interval of strict avoidance of hypoglycemia
Identification of transient and persistent segmental wall motion abnormalities in patients with unstable angina by two-dimensional echocardiography.
Authors: J V Nixon, C N Brown, T C Smitherman
Journal: Circulation (1982)

To determine the value of real-time, two-dimensional echocardiography (2-D echo) in unstable angina, regional wall motion on serial short-axis 2-D echo recordings was analyzed and summed segment scores of abnormal motion were compared and classified according to each patient's clinical status 12 weeks after hospital discharge. Nineteen male patients who fulfilled criteria for unstable angina and responded to medical therapy underwent 2-D echo study within 48 hours of admission and discharge. Of 11 patients with abnormal 2-D echo scores on admission, five patients had reduced scores and six patients had similar or increased scores at discharge. Six of eight patients who had scores of zero on admission had scores of zero at discharge. At follow-up, 11 patients had minimal or no angina pectoris (group 1), and eight patients had worsening angina or recurrent unstable angina (group 2). At discharge, 2-D echo studies showed that all group 1 patients had reduced or zero scores, while group 2 patients retained or increased their abnormal scores. This study shows that in patients with unstable angina, both transient and persistent abnormalities can be identified by 2-D echo. Abnormal segmental wall motion was transient or absent in patients with a good outcome, and worsened or remained abnormal in patients with a poor outcome.
Diagnosis of Spontaneous Perforation of the Gallbladder by Tc-99m DISIDA
Authors: HAROLD B. HAWKINS, DOROTHY C. CINTI, HEMALATHA RAO, JOHN D. RUSSELL, JAMES D. SLAVIN
Journal: Clinical Nuclear Medicine (1984)

A case of spontaneous rupture of the gallbladder correctly diagnosed preoperatively using Tc-99m DISIDA cholescintigraphy is presented.
Data in drug advertisements
Authors: E Healing
Journal: BMJ (1994)

Experience in our intensive care unit has also shown a considerable increase in the number of patients admitted after an overdose or self harm over the past three years, with the largest rise during 1993.Nine, 15, and 22 patients were admitted in 1990, 1991, and 1992, respectively.In the first 11 months of 1993, 51 patients required treatment, an increase of 566% in under three years.Using the therapeutic intervention scoring system4 and a cost of £30 per point on this score,5 we estimate that an average of £ 1638 range £150-16 620) was spent on each patient during his or her stay in the unit.The additional emergency work- load generated by such admissions has a consider- able impact on elective major surgery requiring support from the unit and often necessitates the transfer of other emergency patients to intensive care units in other districts.This worrying trend in the local rate of attempted suicide has important cost implications for purchasers and cannot be controlled by the internal market.Social and economic issues must be addressed before the government's targets can be achieved.
Effects of chronic graded ethanol consumption on the metabolism, ultrastructure, and mechanical function of the rat heart
Authors: L. D. SEGEL, S. V. RENDIG, Y. CHOQUET, K. CHACKO, E. A. AMSTERDAM, D. T. MASON
Journal: Cardiovascular Research (1975)

Three sequential sets of ethanolic rats (E) and their matched controls (C) were fed regular chow containing standard vitamins with the ethanol group in each series also receiving a progressively greater alcohol intake for 3 to 6 months: E1 5%, E2 10%, and E3 25% ethanol. Electron microscopy showed swelling of mitochondria, transverse tubules and sarcoplasmic reticulum, dehiscence of intercalated discs and disintegration of myofibrils scattered throughout the ventricular myocardium in E1 and E2 as early as 7 wk after beginning 5% ethanol; in addition, there were clumping of mitochondria and supercontraction of myofibrils in E3. Concomitant with substructural abnormalities in E3, there were slight but significant depressions of cardiac myofibrillar ATPase activity and mitochondrial function. Cardiac catecholamines, hydroxyproline, and total bound glycerol were unchanged. Alteration of isometric contraction of isolated, supported left ventricular papillary muscles occurred initially in E2 and was clearly evident in E3 by significant reduction of duration of systolic active state (time from onset to peak tension), while total tension generated and peak rate of tension rise were not yet disturbed. Extra vitamin supplementation in additional rats drinking 25% ethanol minimally lessened decline in myofibrillar ATPase activity, but otherwise provided no protection. Thus, chronic daily ingestion of graded quantities of ethanol representing 10 to 30% of total calories in well-nourished animals exerted toxic effects on microstructure, metabolism and mechanics of the ventricle. These alterations are postulated to be pertinent to early pathogenesis of clinical alcoholic cardiomyopathy.
PECAM-1 functions as a specific and potent inhibitor of mitochondrial-dependent apoptosis
Authors: Cunji Gao, Weiyong Sun, Melpo Christofidou-Solomidou, Motoshi Sawada, Debra K. Newman, Carmen Bergom, Steven M. Albelda, Shigemi Matsuyama, Peter J. Newman
Journal: Blood (2003)
Two distinct aetiologies of cardia cancer; evidence from premorbid serological markers of gastric atrophy and Helicobacter pylori status
Authors: S. Hansen, S. E. Vollset, M. H Derakhshan, V. Fyfe, K. K Melby, S. Aase, E. Jellum, K. E L McColl
Journal: Gut (2007)

Non-cardia gastric adenocarcinoma is positively associated with Helicobacter pylori infection and atrophic gastritis. The role of H pylori infection and atrophic gastritis in cardia cancer is unclear.To compare cardia versus non-cardia cancer with respect to the premorbid state of the stomach.Nested case-control study. To each of 129 non-cardia and 44 cardia cancers, three controls were matched. Serum collected a median of 11.9 years before the diagnosis of cancer was tested for anti-H pylori antibodies, pepsinogen I:II and gastrin.Non-cardia cancer was positively associated with H pylori (OR 4.75, 95% CI 2.56 to 8.81) and gastric atrophy (pepsinogen I:II <2.5; OR 4.47, 95% CI 2.71 to 7.37). The diffuse and intestinal histological subtypes of non-cardia cancer were of similar proportions and both showed a positive association with H pylori and atrophy. Cardia cancer was negatively associated with H pylori (OR 0.27, 95% CI 0.12 to 0.59), but H pylori-positive cardia cancer showed an association with gastric atrophy (OR 3.33, 95% CI 1.06 to 10.5). The predominant histological subtype of cardia cancer was intestinal and was not associated with gastric atrophy compared with the diffuse subtype ((OR 0.72, 95% CI 0.19 to 2.79) vs (OR 3.46, 95% CI 0.32 to 37.5)). Cardia cancer in patients with atrophy had an intestinal: diffuse ratio (1:1) similar to non-cardia cancer (1.9:1), whereas cardia cancers in patients without atrophy were predominantly intestinal (7:1).These findings indicate two aetiologies of cardia cancer, one associated with H pylori atrophic gastritis, resembling non-cardia cancer, and the other associated with non-atrophic gastric mucosa, resembling oesophageal adenocarcinoma. Serological markers of gastric atrophy may provide the key to determining gastric versus oesophageal origin of cardia cancer.
Consistent Principal Components from Triple Negative Breast Cancer Expression Profiles Yields Agent Specific Predictors of Chemotherapy Response.
Authors: Q. Li, A. Eklund, N. Juul, C. Desmedt, B. Haibe-Kain, B. Haibe-Kain, C. Sotiriou, W. Symmans, L. Pusztai, A. Richardson, Z. Szallasi, Z. Szallasi
Journal: Cancer Research (2009)

Abstract Genome scale expression profiling is likely to yield improved methods for optimizing therapy for individual breast cancer patients. Microarray based predictors of response to chemotherapy have been described for ER-positive tumors, but supervised methods haven't yielded highly accurate predictors of response in triple-negative breast cancer (TNBC). The problem of deriving predictive or prognostic classifiers is not trivial, and care must be taken to avoid pitfalls such as data set-specific noise and overfitting.To overcome these problems, we developed a two-stage unsupervised method to derive consistent metagenes from multiple data sets. In the first stage, we used principal component analysis to identify aspects of gene expression profiles that are consistently observed in multiple starting data sets. We then identified a subset of genes that best captured the information derived from these components. In the second stage, we factorized this subset of genes and derived metagenes applicable to any external data set. With this method, overfitting is eliminated by virtue of the unsupervised approach, and data set-specific noise is reduced by selecting only components presented in multiple data sets.We first applied our method to four TNBC data sets not obtained in a neoadjuvant setting and derived four metagenes. We then applied these metagenes to another four independent data sets annotated with response to various neoadjuvant therapies in order to assess their predictive performances. Two of the metagenes were associated with response: one predicted pathological complete response (pCR) in the two TFAC cohorts but not in the other two cohorts (Fig. a); the other was associated with pCR to TFAC, residual disease (RD) to epirubicin single agent, but not with response to FEC (Fig. b). Notably, these metagenes derived in an unsupervised manner were more strongly predictive than were classifiers derived using conventional supervised methods.As conclusion, we report and validate an unsupervised strategy as a robust and powerful alternative to supervised methods for deriving predictors for response to chemotherapy from microarray data. If confirmed in additional independent cohorts, these metagenes may lead to clinical tests to optimize therapy for individual TNBC patients.Figure 1. ROC curves indicate the association between two metagenes and agent-specific pathological complete response to neoadjuvant therapy. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3163.
The use of combinatorial topographical libraries for the screening of enhanced osteogenic expression and mineralization
Authors: Jette Lovmand, Jeannette Justesen, Morten Foss, Rune Hoff Lauridsen, Michael Lovmand, Charlotte Modin, Flemming Besenbacher, Finn Skou Pedersen, Mogens Duch
Journal: Biomaterials (2009)
Glucose Metabolism in Pregnancy at High Altitude
Authors: Elisabeth Krampl, Nikolaos A. Kametas, Peter Nowotny, Michael Roden, Kypros H. Nicolaides
Journal: Diabetes Care (2001)

OBJECTIVE—To assess insulin sensitivity and β-cell function associated with lower maternal fasting plasma glucose levels at high altitude compared with sea level. RESEARCH DESIGN AND METHODS—We studied 215 pregnant women at 8–42 weeks of gestation in Peru. The women were recruited from Cerro de Pasco, which is situated 4,370 m (14,340 feet) above sea level, and Lima, which is at sea level. We also examined 53 nonpregnant control subjects (22 in Cerro de Pasco and 31 in Lima). Fasting plasma glucose, insulin, C-peptide, and proinsulin concentrations were measured in samples obtained from the antecubital vein between 8:00 a.m. and 10:00 a.m. after an overnight period of fasting for 10–14 h. Insulin resistance and β-cell function were calculated using homeostasis model assessment. RESULTS—Fasting C-peptide levels and β-cell function were similar, fasting concentrations of insulin and proinsulin were lower, and insulin sensitivity was higher at high altitude compared with sea level. CONCLUSIONS—Maternal fasting plasma glucose that is lower at high altitude than at sea level in the presence of similar insulin secretion is associated with higher peripheral insulin sensitivity. This may partly explain the lower birth weights at high altitudes.
Hamid Kamal Khan
Authors: K Raza
Journal: BMJ (2003)

Former consultant radiologist Hillingdon (b 1942; q Gottingen, Germany, 1971; MD), died from bladder cancer on 18 May 2003.

Hamid Kamal Khan's early education was in Tanzania. At the age of 19 he joined the British army as an officer cadet before taking his medical degree in Germany in 1971. His career took him to Saudi Arabia, Pakistan, Tanzania, and the United Kingdom. He was deputy director of radiology at a hospital in Westphalia, Germany, and director of radiology in a military hospital in Saudi Arabia. In his youth he represented Tanzania at hockey in many international tournaments. He came to Hillingdon Hospital, Uxbridge, in 1999, where he worked almost continuously as locum consultant. He leaves a wife and two children.