tbuckley/cabot-search huggingface dataset:
Radiosensitization by Pan ErbB Inhibitor CI-1033 <b> <i>in Vitro</i> </b> and <b> <i>in Vivo</i> </b>
Authors: Mukesh K. Nyati, Divya Maheshwari, Sheela Hanasoge, Arun Sreekumar, Susan D. Rynkiewicz, Arul M. Chinnaiyan, Wilbur R. Leopold, Stephen P. Ethier, Theodore S. Lawrence
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Overexpression of the ErbB family of receptor tyrosine kinases has been associated with uncontrolled growth of many tumor types and, therefore, presents a promising molecular target for cancer therapy. CI-1033 is a small molecule tyrosine kinase inhibitor that differs from other 4-anilinoquinazolines by being a pan ErbB (instead of epidermal growth factor receptor-specific) irreversible (instead of reversible) inhibitor. Therefore, we investigated the antitumor effect of CI-1033 alone and in combination with ionizing radiation in vitro and in vivo. Experimental Design: We selected three human colon carcinoma cell-lines (LoVo, Caco-2, which express activated epidermal growth factor receptor and ErbB-2 family members, and SW620, which does not), and analyzed the effects of CI-1033 both in vitro and in vivo. For in vivo studies LoVo and Caco-2 cells were implanted s.c. in the flank of nude mice. After the tumor reached ∼100 mm3, treatment was initiated with 20 mg/kg of CI-1033 (orally once daily × 5 for 3 successive weeks), radiation treatment (a total of 30 Gy given in 2 Gy once daily × 5 for 3 successive weeks), or a combination of both CI-1033 and radiation treatment. Results: We found that exposure of LoVo and Caco-2, but not SW620 cells, to CI-1033 in the range of 1–3 μm could inhibit constitutive signaling by tyrosine kinases, arrest cell growth, inhibit cells in G1, stimulate expression of p53, and induce apoptosis. The inhibition of cell growth by CI-1033 seemed to produce only minimal radiosensitization in LoVo and Caco-2 cells. In contrast, the combination of CI-1033 and radiation produced significant (P &amp;lt; 0.0005 and P = 0.0002, respectively) and prolonged suppression of tumor growth in both the tumor types when compared with either treatment alone. Conclusions: These findings suggest that CI-1033 can increase the effectiveness of radiation therapy. The extent of suppression of tyrosine kinase activity by CI-1033, rather than the amount of activity in untreated cells, seemed to be more closely associated with the efficacy of combination treatment.
The Role of UGT1A1*28 Polymorphism in the Pharmacodynamics and Pharmacokinetics of Irinotecan in Patients With Metastatic Colorectal Cancer
Authors: Giuseppe Toffoli, Erika Cecchin, Giuseppe Corona, Antonio Russo, Angela Buonadonna, Mario D'Andrea, Lara Maria Pasetto, Sergio Pessa, Domenico Errante, Vincenzo De Pangher, Mauro Giusto, Michele Medici, Fernando Gaion, Paolo Sandri, Enzo Galligioni, Salvatore Bonura, Massimo Boccalon, Paola Biason, Sergio Frustaci
Journal: Journal of Clinical Oncology (2006)

Purpose UGT1A1*28 polymorphism has been associated with decreased glucuronidation of SN38, the active metabolite of irinotecan. This could increase toxicity with this agent. Patients and Methods In a prospective study, 250 metastatic colorectal cancer patients were treated with irinotecan, fluorouracil, and leucovorin as first-line treatment. UGT1A1*28 polymorphism was investigated with respect to the distribution of hematologic and nonhematologic toxicity, objective response rate, and survival. Pharmacokinetics was investigated in a subgroup of patients (71 of 250) who had been analyzed with respect to toxicity and efficacy. Results UGT1A1*28 polymorphism was associated with a higher risk of grade 3 to 4 hematologic toxicity (odds ratio [OR], 8.63; 95% CI, 1.31 to 56.55), which was only relevant for the first cycle, and was not seen throughout the whole treatment period for patients with both variant alleles TA 7 /TA 7 compared with wild-type TA 6 /TA 6 . The response rate was also higher in TA 7 /TA 7 patients (OR, 0.32; 95% CI, 0.12 to 0.86) compared with TA 6 /TA 6 . A nonsignificant survival advantage was observed for TA 7 /TA 7 when compared with TA 6 /TA 6 patients (hazard ratio, 0.81; 95% CI, 0.45 to 1.44). Higher response rates were explained by a different pharmacokinetics with higher biliary index [irinotecan area under the curve (AUC)×(SN38 AUC/SN38G AUC)] and lower glucuronidation ratio (SN38G AUC/SN38 AUC) associated with the TA 7 /TA 7 genotype and a higher response rate, indicating that the polymorphism is functionally relevant. Conclusion The results indicate that UGT1A1*28 polymorphism is of some relevance to toxicity; however, it is less important than discussed in previous smaller trials. In particular, the possibility of a dose reduction for irinotecan in patients with a UGT1A1*28 polymorphism is not supported by the result of this analysis.
Abstract 2368: Unbiased quantitative assessment of Her-2 expression of circulating tumor cells in patients with metastatic and non metastatic breast cancer
Authors: Jean-Yves Pierga, Sjoerd T. Ligthart, François-Clement Bidard, Charles Decraene, Thomas Bachelot, Suzette Delaloge, Etienne Brain, Mario Campone, Patrice Viens, Leon WMM Terstappen
Journal: Cancer Research (2012)

Abstract Circulating tumor cells (CTC) can provide the basis for a real-time liquid biopsy and may guide the use of targeted therapies. We report on unbiased quantification of Her-2 protein expression of CTC. Her-2 assessment of CTC was performed using the CellSearch® system in 103 metastatic (M1) and 88 non metastatic (M0) breast-cancer patients. Digital images of Cytokeratin-PE, DAPI, CD45-APC, and Her-2-FITC from these samples were stored. Expression of Her-2 on CTC was determined by manual review and an automated algorithm using Her-2-FITC fluorescence of leukocytes to determine the Her-2-expression threshold in each sample. Her-2 expression of CTC varied greatly within and between patients compared to Her-2 expression of leukocytes. In M1 patients, a threshold of 75% of Her-2 positive CTC in patients with &amp;gt;5 CTC showed a relatively low discrepancy rate between the primary tumor and CTC Her-2 status. Applying this threshold, 9% of M1 patients with Her-2 negative primary tumors had Her-2 positive CTC status and 29% of M1 patients with Her-2 positive primary tumors had Her-2 negative CTC status. No Her-2 discrepancy was observed between CTC and primary tumor in M0 patients. Our findings demonstrate the feasibility of real-time quantitative and reproducible assessment of treatment targets on CTC, opening a path towards personalized treatment. Her-2 expression is heterogeneous among CTC within each patient. Overall, M1 patients with Her-2 positive primary tumors exhibited Her-2 negative CTC frequently, whereas discrepancies in Her-2 status were limited in other clinical settings. 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 2368. doi:1538-7445.AM2012-2368
PTU-025 Diagnostic Yield of a Dedicated Barrett’S Surveillance List using Trimodal Imaging: Abstract PTU-025 Table 1
Authors: A K Kurup, R Mahmood, M Anderson
Journal: Gut (2013)

<h3>Introduction</h3> A dedicated endoscopy list for Barrett’s surveillance was introduced at our hospital from 2010. In this study we compared the rate of dysplasia detection and targeted biopsy of this approach with Barrett’s surveillance on a general endoscopy list. <h3>Methods</h3> In the dedicated list, all endoscopies were performed by a specific gastroenterologist who has an interest in Barrett’s oesophagus using a combination of high resolution white light magnification, auto fluorescence and narrow band imaging. This was in contrast to the practise of previous years where the endoscopies for Barrett’s surveillance were done by a physician gastroenterologist, a surgeon, or a nurse endoscopist using conventional white light endoscopy alone. In this study, we compared the detection rate of high grade dysplasia, low grade dysplasia and targeted biopsy between patients who underwent endoscopy on a dedicated list and those who underwent surveillance on a general endoscopy list. <h3>Results</h3> In group 1 were 151 endoscopies performed on a general list during the years 2008–2009, which were compared with 87 endoscopies performed on a dedicated list from 2010 to 2011. Only one targeted biopsy was taken in group 1 compared to 17 targeted biopsies in group2. The detection rate of high grade dysplasia, low grade dysplasia and all dysplasia were greater in group2 compared to group1. However we were not able to detect a statistically significant difference in rates between the two groups. On the other hand, the difference in the rates of targeted biopsies between the two groups was found to be statistically significant The difference in detection rates between the two groups [–18.88, 95% CI –26.13 – –11.62, p = &lt; 0.0001]. Three of the four high grade dysplasia were detected on a targeted biopsy and two of them had a cancer in situ. <h3>Conclusion</h3> <b>In this retrospective comparative study we were able to demonstrate that a dedicated Barrett’s surveillance</b> endoscopy list is able to generate a significantly greater number of targeted biopsies compared to surveillance endoscopy performed on varied general lists. The detection rates of high grade dysplasia, low grade dysplasia and all dysplasia were greater on the dedicated list, although this did not reach statistical significance. We would therefore recommend a dedicated Barrett’s surveillance endoscopy list <h3>Disclosure of Interest</h3> None Declared
Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia
Authors: Elaine Coustan-Smith, Jose Sancho, Frederick G. Behm, Michael L. Hancock, Bassem I. Razzouk, Raul C. Ribeiro, Gaston K. Rivera, Jeffrey E. Rubnitz, John T. Sandlund, Ching-Hon Pui, Dario Campana
Journal: Blood (2002)
Mechanism of Hydrogen Peroxide and Hydroxyl Free Radical–Induced Intracellular Acidification in Cultured Rat Cardiac Myoblasts
Authors: Mei-Lin Wu, Ke-Li Tsai, Seu-Mei Wang, Jiahn-Chun Wu, Bor-Sen Wang, Yuan-Teh Lee
Journal: Circulation Research (1996)

Abstract After a transient ischemic attack of the cardiac vascular system, reactive oxygen-derived free radicals, including the superoxide (O 2 −• ) and hydroxyl ( • OH) radicals can be easily produced during reperfusion. These free radicals have been suggested to be responsible for reperfusion-induced cardiac stunning and reperfusion-induced arrhythmia. Hydrogen peroxide (H 2 O 2 ) is often used as an experimental source of oxygen-derived free radicals. Using freshly dissociated single rat cardiac myocytes and the rat cardiac myoblast cell line, H9c2, we have shown, for the first time, that an intriguing pH i acidification (≈0.24 pH unit) is induced by the addition of 100 μmol/L H 2 O 2 and that this dose is without effect on the intracellular free Ca 2+ levels or viability of the cells. Using H9c2 as a model cardiac cell, we have shown that it is the intracellular production of • OH, and not O 2 −• or H 2 O 2 , that results in this acidification. We have excluded any involvement of (1) the three known cardiac pH i regulators (the Na + -H + exchanger, the Cl − -HCO 3 exchanger, and the Na + -HCO 3 cotransporter), (2) a rise in intracellular Ca 2+ levels, and (3) inhibition of oxidative phosphorylation. However, we have found that H 2 O 2 -induced acidosis is due to inhibition of the glycolytic pathway, with hydrolysis of intracellular ATP and the resultant intracellular acidification. In cardiac muscle and in skinned cardiac muscle fiber, it has been shown that a small intracellular acidification may severely inhibit contractility. Therefore, the sustained pH i decrease caused by hydroxyl radicals may contribute, in some part, to the well-documented impairment of cardiac mechanical function (ie, reperfusion cardiac stunning) seen during reperfusion ischemia.
Caveolin-1 Expression Is Critical for Vascular Endothelial Growth Factor–Induced Ischemic Hindlimb Collateralization and Nitric Oxide–Mediated Angiogenesis
Authors: Pierre Sonveaux, Philippe Martinive, Julie DeWever, Zuzana Batova, Géraldine Daneau, Michel Pelat, Philippe Ghisdal, Vincent Grégoire, Chantal Dessy, Jean-Luc Balligand, Olivier Feron
Journal: Circulation Research (2004)

Nitric oxide (NO) is a powerful angiogenic mediator acting downstream of vascular endothelial growth factor (VEGF). Both the endothelial NO synthase (eNOS) and the VEGFR-2 receptor colocalize in caveolae. Because the structural protein of these signaling platforms, caveolin, also represses eNOS activity, changes in its abundance are likely to influence the angiogenic process in various ways. In this study, we used mice deficient for the caveolin-1 gene (Cav −/− ) to examine the impact of caveolae suppression in a model of adaptive angiogenesis obtained after femoral artery resection. Evaluation of the ischemic tissue perfusion and histochemical analyses revealed that contrary to Cav +/+ mice, Cav −/− mice failed to recover a functional vasculature and actually lost part of the ligated limbs, thereby recapitulating the effects of the NOS inhibitor l -NAME administered to operated Cav +/+ mice. We also isolated endothelial cells (ECs) from Cav −/− aorta and showed that on VEGF stimulation, NO production and endothelial tube formation were dramatically abrogated when compared with Cav +/+ ECs. The Ser1177 eNOS phosphorylation and Thr495 dephosphorylation but also the ERK phosphorylation were similarly altered in VEGF-treated Cav −/− ECs. Interestingly, caveolin transfection in Cav −/− ECs redirected the VEGFR-2 in caveolar membranes and restored the VEGF-induced ERK and eNOS activation. However, when high levels of recombinant caveolin were reached, VEGF exposure failed to activate ERK and eNOS. These results emphasize the critical role of caveolae in ensuring the coupling between VEGFR-2 stimulation and downstream mediators of angiogenesis. This study also provides new insights to understand the paradoxical roles of caveolin (eg, repressing basal enzyme activity but facilitating activation on agonist stimulation) in cardiovascular pathophysiology.
Smad4 is critical for self-renewal of hematopoietic stem cells
Authors: Göran Karlsson, Ulrika Blank, Jennifer L. Moody, Mats Ehinger, Sofie Singbrant, Chu-Xia Deng, Stefan Karlsson
Journal: The Journal of Experimental Medicine (2007)

Members of the transforming growth factor β (TGF-β) superfamily of growth factors have been shown to regulate the in vitro proliferation and maintenance of hematopoietic stem cells (HSCs). Working at a common level of convergence for all TGF-β superfamily signals, Smad4 is key in orchestrating these effects. The role of Smad4 in HSC function has remained elusive because of the early embryonic lethality of the conventional knockout. We clarify its role by using an inducible model of Smad4 deletion coupled with transplantation experiments. Remarkably, systemic induction of Smad4 deletion through activation of MxCre was incompatible with survival 4 wk after induction because of anemia and histopathological changes in the colonic mucosa. Isolation of Smad4 deletion to the hematopoietic system via several transplantation approaches demonstrated a role for Smad4 in the maintenance of HSC self-renewal and reconstituting capacity, leaving homing potential, viability, and differentiation intact. Furthermore, the observed down-regulation of notch1 and c-myc in Smad4−/− primitive cells places Smad4 within a network of genes involved in the regulation HSC renewal.
Inclusion of latent tuberculosis infection as a separate entity into the international classification of diseases
Authors: Marc Tebruegge, Eeva Salo, Nicole Ritz, Beate Kampmann
Journal: Thorax (2012)

The 11th revision of the International Classification of Diseases (ICD-11) proposed by the WHO is currently in the consultation phase. In common with previous versions of the ICD this revised version does not contain a code for latent tuberculosis infection (LTBI), contrasting with the inclusion of a large number of codes for various manifestations of active tuberculosis (TB). Inclusion of a separate code for LTBI into ICD-11 is critically important for epidemiological, clinical and research purposes. On behalf of the Paediatric Tuberculosis Network European Trials group, we encourage colleagues worldwide who are caring for TB patients or are involved in TB research to join us in supporting the case for a long overdue ICD code for LTBI.
Exploring the Causes of Adverse Events in NHS Hospital Practice
Authors: Graham Neale, Maria Woloshynowych, Charles Vincent
Journal: Journal of the Royal Society of Medicine (2001)

In a previous paper we reported that 10.8% of patients admitted to two large hospitals in Greater London experienced one or more adverse events, of which half were deemed preventable. Here we examine the underlying causes of errors in clinical practice. Rather than identifying specific errors made by individuals, we have looked at possible faults in the organization of care. Adverse events were grouped according to stages in the care process: diagnosis, preoperative assessment and care, operative or invasive procedure (including anaesthesia), ward management, use of drugs and intravenous fluids and discharge from hospital. Less than 20% of preventable adverse events were directly related to surgical operations or invasive procedures and less than 10% to misdiagnoses. 53% of preventable adverse events occurred in general ward care (including initial assessment and the use of drugs and intravenous fluids) and 18% in care at the time of discharge. Probable contributory factors in these errors included dependence on diagnoses made by inexperienced clinicians, poor records, poor communication between professional carers, inadequate input by consultants into day-to-day care, and lack of detailed assessment of patients before discharge.
Value of Electrocardiographic Parameters and Ajmaline Test in the Diagnosis of Brugada Syndrome Caused by SCN5A Mutations
Authors: Kui Hong, Josep Brugada, Antonio Oliva, Antonio Berruezo-Sanchez, Domenico Potenza, Guido D. Pollevick, Alejandra Guerchicoff, Kiyotaka Matsuo, Elena Burashnikov, Robert Dumaine, Jeffrey A. Towbin, Vladislav Nesterenko, Pedro Brugada, Charles Antzelevitch, Ramon Brugada
Journal: Circulation (2004)

The Brugada syndrome is an arrhythmogenic disease caused in part by mutations in the cardiac sodium channel gene, SCN5A. The electrocardiographic pattern characteristic of the syndrome is dynamic and is often absent in affected individuals. Sodium channel blockers are effective in unmasking carriers of the disease. However, the value of the test remains controversial.We studied 147 individuals representing 4 large families with SCN5A mutations. Of these, 104 were determined to be at possible risk for Brugada syndrome and underwent both electrocardiographic and genetic evaluation. Twenty-four individuals displayed an ECG diagnostic of Brugada syndrome at baseline. Of the remaining, 71 received intravenous ajmaline. Of the 35 genetic carriers who received ajmaline, 28 had a positive test and 7 a negative ajmaline test. The sensitivity, specificity, and positive and negative predictive values of the drug challenge were 80% (28:35), 94.4% (34:36), 93.3% (28:30), and 82.9% (34:41), respectively. Penetrance of the disease phenotype increased from 32.7% to 78.6% with the use of sodium channel blockers. In the absence of ST-segment elevation under baseline conditions, a prolonged P-R interval, but not incomplete right bundle-branch block or early repolarization patterns, indicates a high probability of an SCN5A mutation carrier.In families with Brugada syndrome, the data suggest that ajmaline testing is valuable in the diagnosis of SCN5A carriers. In the absence of ST-segment elevation at baseline, family members with first-degree atrioventricular block should be suspected of carrying the mutation. An ajmaline test is often the key to making the proper diagnosis in these patients.
Failure of Outpatient Treatment of Drug Abuse: I. Heroin
Authors: JOHN E. O'MALLEY, WILLIAM H. ANDERSON, AARON LAZARE
Journal: American Journal of Psychiatry (1972)

Two hundred six heroin users who appeared at the Walk-In Psychiatric Clinic at Massachusetts General Hospital during an 18-month period showed no evidence of improvement although various treatment modalities including psychotropic drugs, individual and group psychotherapy, and methadone detoxification (not maintenance) were offered. The most striking finding was the small number of patients (three percent) who even followed the recommendation to return for a follow-up visit; this failure to return was independent of the type of treatment recommended.
The Emerging Role of Thrombus Aspiration in the Management of Acute Myocardial Infarction
Authors: Y.L. Gu, M.L. Fokkema, F. Zijlstra
Journal: Circulation (2008)

A n acute thrombotic event resulting in total occlusion of a coronary artery is considered the principal mechanism of ST-segment elevation myocardial infarction (STEMI).De Wood et al 1 were the first to show that total coronary occlusion was visible on the coronary angiogram in a large majority of patients presenting during the early hours of STEMI.Thrombus could be retrieved in 52 of 59 patients with angiographic, and in 5 of 20 patients without, features of thrombus, suggesting that thrombus formation plays a major role in the pathophysiology of total occlusion and subsequent infarction.Total coronary artery occlusion has also been described, though less frequently, in a range of nonthrombotic events such as intraplaque hemorrhage, vasospasm, spontaneous coronary artery dissection, coronary emboli, coronary arteritis, and compression by myocardial bridging. 2,
Echocardiographic Assessment of Ductus Arteriosus Shunt in Premature Infants
Authors: NORMAN H. SILVERMAN, ALAN B. LEWIS, MICHAEL A. HEYMANN, ABRAHAM M. RUDOLPH
Journal: Circulation (1974)

Echocardiograms were performed on premature infants with a patent ductus arteriosus (PDA) in order to assess the magnitude of the left-to-right shunt. Ten of 14 infants with a hemodynamically significant PDA required ligation because of intractable cardiac failure. Twenty infants served as controls. These consisted of seven infants without heart disease, ten infants who were examined echocardiographically after surgical ligation of a PDA, and three infants who were considered to have closed the PDA spontaneously prior to echocardiographic examination. We measured the left atrial (LA) and aortic root (Ao) diameters and an LA/Ao ratio was used to assess left atrial size. The LA/Ao ratio was 1.28 ± 0.23 ( sd ) in the group with PDA and 0.86 ± 0.10 in the control group. Infants who required surgical ligation all had an LA/Ao ratio above 1.15 (mean 1.38 ± 0.19). After ligation of the PDA the ratio returned to normal levels (0.87 ± 0.12). Sequential studies performed on seven infants demonstrated the usefulness of the LA/Ao ratio in following the changes in left-to-right ductus shunting and left ventricular failure as well as the effects of medical and surgical therapy. The LA/Ao ratio is helpful in differentiating infants with respiratory distress due to ductus shunting and left ventricular failure from intrinsic pulmonary disease.