tbuckley/cabot-search huggingface dataset:
Cytotoxicity and Mutagenicity of Frameshift-Inducing Agent ICR191 in Mismatch Repair-Deficient Colon Cancer Cells
Authors: Wei-Dong Chen, James R. Eshleman, M. Reza Aminoshariae, Ai-Hong Ma, Neil Veloso, Sanford D. Markowitz, W. David Sedwick, Martina L. Veigl
Journal: JNCI Journal of the National Cancer Institute (2000)

Deficiency of DNA mismatch repair is a common feature of cancers exhibiting instability of microsatellite DNA sequences. Cancers with microsatellite instability are recognizable by their high rate of spontaneous frameshift mutations within microsatellite sequences, their resistance to killing by cytotoxic agents, and their localization to specific tissues, e.g., the proximal colon and stomach. We hypothesized that the mismatch repair deficiency of these cancers would make them vulnerable to environmental or chemical frameshift-inducing agents. This study was undertaken to test whether exogenous frameshift-inducing agents selectively induce mutations in mismatch repair-deficient cells of mutagen-exposed tissues like the colon and whether cytotoxic doses of these agents would preferentially kill those cells.Cytotoxicity of the acridine mutagen 6-chloro-9-[3-(2-chloroethylamino)propylamino]-2-methoxy-acridine (ICR191), a DNA frameshift inducer, was determined in the mismatch repair-deficient human colon carcinoma cell line HCT116 versus the repair-reconstituted derivative HCT116+C3. Vulnerability to the mutagenic effects of ICR191 was determined by transfection of HCT116 or HCT116+C3 cells with a frameshift reporter vector, followed by treatment of the cells with ICR191. Alternatively, the reporter vector was reacted ex vivo with ICR191, and the derivatized vector was then transfected into HCT116 or HCT116+C3 cells.ICR191 proved to be fivefold to 10-fold more potent in inducing mutations in mismatch repair-deficient HCT116 cells than in mismatch repair-proficient HCT116+C3 cells. Moreover, at cytotoxic doses of ICR191, repair-deficient HCT116 cells proved to be fivefold more vulnerable to killing than did HCT116+C3 cells.Frameshift-inducing mutagens can selectively induce mutations in mismatch repair-deficient cells versus mismatch repair-proficient cells. Environmental exposures may, therefore, favor development of cancers with microsatellite instability in tissues like the gut. Frameshift-inducing agents can, however, also preferentially kill mismatch repair-deficient cancer cells and, thus, may be promising as model therapeutic compounds.
A107: Dream Doctors-Medical Clowns Increase the Effect of Nitrous Oxide Sedation in Intra-Articular Corticosteroid Injection for Juvenile Idiopathic Arthritis
Authors: Yosef Uziel, Yael Weintraub, Noa Rabinowicz, Penny Hanuka, Michal Rothschild, Shulamit Kotzki
Journal: Arthritis & Rheumatology (2014)

Background/Purpose:

Intra-articular corticosteroid injection (IASI), a common procedure in juvenile idiopathic arthritis (JIA), is usually associated with anxiety and pain.



In previous study we concluded that nitrous oxide (NO) provides effective and safe sedation for such procedures. The efficacy in reducing pain was associated with the level of the child's anxiety even before starting the procedure.



Following the introduction of “Dream Doctors” in our hospital, we added medical clown as an important integral part of the team doing IASI.



Aim:

To prospectively evaluate how a medical clown affects pain perception during IASI in JIA using NO conscious sedation.



Methods:

Patients scheduled for IASI first met and interacted with the medical clown. During the procedure, the rheumatologist and the medical clown worked in parallel to create distraction. NO was administered. The patient, parent, physician, medical clown and nurse completed a visual analog scale (VAS - (0–10) for pain. Change in heart rate (HR) ≥15% was recorded to examine physiologic response to pain and stress.



Results:

46 procedures were performed in 32 children: 23 girls, 9 boys, with a mean age of 10.87 ± 3.58 yrs. The median VAS pain score for the patients, parents, physicians, medical clown and nurses was 2, 2, 1, 1, and 1, respectively. 5 patients had increased HR, and experienced increased pain. In our previous study using only NO, the median pain score was 3.



Conclusion:

Active participation of a medical clown during IASI with NO for JIA further decreasing pain, stress, and induces a pleasant patient experience.
Evaluation of laser Doppler flowmetry for the study of benign and malignant gastric blood flow in vivo
Authors: M K Schilling, C Redaelli, H Friess, B Blum, C Signer, C A Maurer, M W Büchler
Journal: Gut (1999)

BACKGROUND Tumour vascularisation is a determinant of the development of metastases. AIMS To measure blood flow in normal stomach and gastric adenocarcinomas by laser Doppler flowmetry and correlate blood flow with vascularisation after immunohistochemical staining of resected specimens for CD31 and von Willebrand factor. PATIENTS Twenty two undergoing resection for gastric adenocarcinoma and 10 undergoing cholecystectomy. RESULTS Mean (SD) gastric blood flow was 208 (35) perfusion units (PU) in patients undergoing cholecystectomy and 190 (75) PU in the undiseased part of the stomach in patients with gastric adenocarcinoma. Gastric blood flow was higher in the border of gastric adenocarcinomas (322 (120) PU, p&lt;0.01 v normal stomach) but lower in the centre (74 (27) PU, p&lt;0.01 v normal stomach and tumour border). Blood flow was higher in tumours staged T⩾3 than in those staged T&lt;3. Blood vessel density in normal stomach was 41 (8) stained cells/field viewed and was 1.9–3.4 times higher in gastric adenocarcinomas. CONCLUSION Laser Doppler flowmetry is a valuable tool for studying the pathophysiological alterations of malignant blood flow in the human stomach in vivo.
Characterization of Complicated Carotid Plaque With Magnetic Resonance Direct Thrombus Imaging in Patients With Cerebral Ischemia
Authors: Alan R. Moody, Rachael E. Murphy, Paul S. Morgan, Anne L. Martel, G.S. Delay, Steve Allder, Shane T. MacSweeney, William G. Tennant, John Gladman, John Lowe, Beverley J. Hunt
Journal: Circulation (2003)

Background— Thromboembolic disease secondary to complicated carotid atherosclerotic plaque is a major cause of cerebral ischemia. Clinical management relies on the detection of significant (&gt;70%) carotid stenosis. A large proportion of patients suffer irreversible cerebral ischemia as a result of lesser degrees of stenosis. Diagnostic techniques that can identify nonstenotic high-risk plaque would therefore be beneficial. High-risk plaque is defined histologically if it contains hemorrhage/thrombus. Magnetic resonance direct thrombus imaging (MRDTI) is capable of detecting methemoglobin within intraplaque hemorrhage. We assessed this as a marker of complicated plaque and compared its accuracy with histological examination of surgical endarterectomy specimens. Methods and Results— Sixty-three patients underwent successful MRDTI and endarterectomy with histological examination. Of these, 44 were histologically defined as complicated (type VI plaque). MRDTI demonstrated 3 false-positive and 7 false-negative results, giving a sensitivity and specificity of 84%, negative predictive value of 70%, and positive predictive value of 93%. The interobserver (κ=0.75) and intraobserver (κ=0.9) agreement for reading MRDTI scans was good. Conclusions— MRDTI of the carotid vessels in patients with cerebral ischemia is an accurate means of identifying histologically confirmed complicated plaque. The high contrast generated by short T 1 species within the plaque allows for ease of interpretation, making this technique highly applicable in the research and clinical setting for the investigation of carotid atherosclerotic disease.
The Two Faces of Capsaicin
Authors: Ann M. Bode, Zigang Dong
Journal: Cancer Research (2011)

Abstract Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is the principal pungent component in hot peppers, including red chili peppers, jalapeños, and habaneros. Consumed worldwide, capsaicin has a long and convoluted history of controversy about whether its consumption or topical application is entirely safe. Conflicting epidemiologic data and basic research study results suggest that capsaicin can act as a carcinogen or as a cancer preventive agent. Capsaicin is unique among naturally occurring irritant compounds because the initial neuronal excitation evoked is followed by a long-lasting refractory period, during which the previously excited neurons are no longer responsive to a broad range of stimuli. This process is referred to as desensitization and has been exploited for its therapeutic potential. Capsaicin-containing creams have been in clinical use for many years to relieve a variety of painful conditions. However, their effectiveness in pain relief is also highly debated and some adverse side effects have been reported. We have found that chronic, long-term topical application of capsaicin increased skin carcinogenesis in mice treated with a tumor promoter. These results might imply that caution should be exercised when using capsaicin-containing topical applications in the presence of a tumor promoter, such as, for example, sunlight. Cancer Res; 71(8); 2809–14. ©2011 AACR.
Oesophageal reflux and gastric secretion
Authors: A. S. Ward
Journal: Gut (1970)

In the study to be described confirmation of the findings of Giles, Clark, and Buchan (1968) that the presence of acid in the lower oesophagus may stimulate gastric secretion has been sought. Also the influence of hiatal repair on the response to acid has been examined. The presence of acid in the lower oesophagus stimulates gastric secretion in man. The response to acid perfusion is greater in symptomatic hiatus hernia patients than in controls. Basal and perfusion outputs are lower in hiatus hernia patients with oesophagitis than in those without inflammatory change. Hiatal repair diminishes the gastric response in both groups; this effect is particularly marked in patients with oesophagitis.
Enhancement of t lymphocyte functions by Fc fragments of immunoglobulins. I. Augmentation of allogeneic mixed lymphocyte culture reactions requires I-A- or I-B-subregion differences between effector and stimulator cell populations
Authors: EL Morgan, ML Thoman, WO Weigle
Journal: The Journal of Experimental Medicine (1981)

Fc fragments derived from human Ig were found to be capable of enhancing T cell-mediated, antigen-induced proliferative and mixed lymphocyte culture responses. Maximum enhancement occurred when suboptimal amounts of antigen or suboptimal numbers of stimulator cells were employed. Augmentation of the allogeneic mixed lymphocyte culture reaction requires an I-A and/or I-B subregion difference between effector and stimulator cell populations. Although a significant proliferative response was observed with K- or D- region differences, Fc fragments were unable to enhance the response. The T cell population acted upon by Fc fragments in the potentiation of these responses bears the Lyt-1(+)23(-) phenotype.
Combined oral and enema treatment with Pentasa (mesalazine) is superior to oral therapy alone in patients with extensive mild/moderate active ulcerative colitis: a randomised, double blind, placebo controlled study
Authors: P Marteau, CS Probert, Stefan Lindgren, M Gassul, TG Tan, A Dignass, R Befrits, G Midhagen, J Rademaker, M Foldager
Journal: Gut (2005)

<b>Background and aims:</b> Oral aminosalicylates are well established in the treatment of active mild/moderate ulcerative colitis (UC) when the disease is extensive (that is, beyond the splenic flexure). The majority of clinical symptoms relate to disease activity in the distal part of the colon and therefore this study was designed to investigate if adding a mesalazine enema to oral mesalazine has additional benefit for patients with extensive mild/moderate active UC. <b>Methods:</b> A randomised double blind study was performed in 127 ambulatory patients. All received 4 g/day (twice daily dosing) oral mesalazine for eight weeks. During the initial four weeks, they additionally received an enema at bedtime containing 1 g of mesalazine or placebo. Disease activity was assessed using the ulcerative colitis disease activity index, with clinical and endoscopic signs at four and eight weeks. <b>Results:</b> Remission was obtained in 44% (95% confidence interval (CI) 31%, 58%) of the mesalazine enema group (Me) and in 34% (95% CI 21%, 49%) of the placebo enema group (Pl) at four weeks (p = 0.31) and in 64% (95% CI 50%, 76%) of the Me group versus 43% (95% CI 28%, 58%) of the Pl group at eight weeks (p = 0.03). Improvement was obtained in 89% (95% CI 78%, 96%) of the Me group versus 62% (95% CI 46%, 75%) of the Pl group at four weeks (p = 0.0008) and in 86% (95% CI 75%, 94%) of the Me group versus 68% (95% CI 53%, 81%) of the Pl group at eight weeks (p = 0.026). <b>Conclusion:</b> In patients with extensive mild/moderate active UC, the combination therapy is superior to oral therapy. It is safe, well accepted, and may be regarded as firstline treatment.
Life Expectancies of South African Adults Starting Antiretroviral Treatment: Collaborative Analysis of Cohort Studies
Authors: Leigh F. Johnson, Joel Mossong, Rob E. Dorrington, Michael Schomaker, Christopher J. Hoffmann, Olivia Keiser, Matthew P. Fox, Robin Wood, Hans Prozesky, Janet Giddy, Daniela Belen Garone, Morna Cornell, Matthias Egger, Andrew Boulle
Journal: PLoS Medicine (2013)

Background Few estimates exist of the life expectancy of HIV-positive adults receiving antiretroviral treatment (ART) in low- and middle-income countries. We aimed to estimate the life expectancy of patients starting ART in South Africa and compare it with that of HIV-negative adults. Methods and Findings Data were collected from six South African ART cohorts. Analysis was restricted to 37,740 HIV-positive adults starting ART for the first time. Estimates of mortality were obtained by linking patient records to the national population register. Relative survival models were used to estimate the excess mortality attributable to HIV by age, for different baseline CD4 categories and different durations. Non-HIV mortality was estimated using a South African demographic model. The average life expectancy of men starting ART varied between 27.6 y (95% CI: 25.2–30.2) at age 20 y and 10.1 y (95% CI: 9.3–10.8) at age 60 y, while estimates for women at the same ages were substantially higher, at 36.8 y (95% CI: 34.0–39.7) and 14.4 y (95% CI: 13.3–15.3), respectively. The life expectancy of a 20-y-old woman was 43.1 y (95% CI: 40.1–46.0) if her baseline CD4 count was ≥200 cells/µl, compared to 29.5 y (95% CI: 26.2–33.0) if her baseline CD4 count was <50 cells/µl. Life expectancies of patients with baseline CD4 counts ≥200 cells/µl were between 70% and 86% of those in HIV-negative adults of the same age and sex, and life expectancies were increased by 15%–20% in patients who had survived 2 y after starting ART. However, the analysis was limited by a lack of mortality data at longer durations. Conclusions South African HIV-positive adults can have a near-normal life expectancy, provided that they start ART before their CD4 count drops below 200 cells/µl. These findings demonstrate that the near-normal life expectancies of HIV-positive individuals receiving ART in high-income countries can apply to low- and middle-income countries as well. Please see later in the article for the Editors' Summary
An unusual cause of pulmonary embolism
Authors: M Bruyneel, A Peeters, P G Silance, S Alard, D Horn
Journal: Thorax (2015)

A young patient presented with acute dyspnoea. Anamnesis revealed the loss of metallic guide wire (GW) during a jugular cannulation 4 years before. Consecutive bilateral pulmonary embolism (PE) was diagnosed by thoracic angio-CT that confirmed presence of GW in the vena cava and in the …
Implementing the new oral anticoagulants into the hospital formulary
Authors: Michael Palladino, Lynda Thomson, Brian Swift,, Geno J. Merli
Journal: American Journal of Hematology (2012)

The new oral anticoagulants may prove to be one of most significant innovations in clinical practice in the past 60 years. Apixaban and rivaroxaban are direct inhibitors of Factor Xa, while dabigatran inhibits Factor IIa. The predictable pharmacological profile of these new agents allows physicians to prescribe these drugs without the need for routine coagulation monitoring, which is the mainstay of warfarin therapy. In addition, these new agents have not been shown to have any food interactions and minimal drug-drug interactions, interactions are limited to the p-glycoprotein (p-Gp) transporter or cytochrome P450 (CYP450) system, each drug is unique in its drug interaction profile, as will be discussed below. These unique pharmacokinetics profiles may usher in for clinicians a new era of managing thromboembolic disorders. In this article, the pharmacology of these new oral anticoagulants will be reviewed along with the major clinical trials evaluating the use of these agents for thromboembolic prophylaxis in patients undergoing total hip and knee arthroplastic surgery, the treatment of venous thromboembolic disorders and stroke prevention in atrial fibrillation. Am. J. Hematol., 2012. © 2012 Wiley Periodicals, Inc.
Population‐Based Incidence and Prevalence of Systemic Lupus Erythematosus: The Michigan Lupus Epidemiology and Surveillance Program
Authors: Emily C. Somers, Wendy Marder, Patricia Cagnoli, Emily E. Lewis, Peter DeGuire, Caroline Gordon, Charles G. Helmick, Lu Wang, Jeffrey J. Wing, J. Patricia Dhar, James Leisen, Diane Shaltis, W. Joseph McCune
Journal: Arthritis & Rheumatology (2013)

To estimate the incidence and prevalence of systemic lupus erythematosus (SLE) in a sociodemographically diverse southeastern Michigan source population of 2.4 million people.
A Phase I and Pharmacokinetic Study of Col-3 (Metastat), an Oral Tetracycline Derivative with Potent Matrix Metalloproteinase and Antitumor Properties
Authors: Samira Syed, Chris Takimoto, Manuel Hidalgo, Jinee Rizzo, John G. Kuhn, Lisa A. Hammond, Garry Schwartz, Anthony Tolcher, Amita Patnaik, S. Gail Eckhardt, Eric K. Rowinsky
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose of this research was to assess the feasibility of administering Col-3, an oral chemically modified tetracycline derivative with potent inhibitory effects on matrix metalloproteinase activity and production, and recommend a dose on an uninterrupted once-daily schedule. The study also sought to characterize the pharmacokinetic behavior of Col-3 and seek evidence of anticancer activity. Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of Col-3 with dose level assignment according to an accelerated titration scheme. Because photosensitivity skin reactions were being reported in concurrent trials of Col-3, patients were instructed to apply sunscreen rigorously throughout the trial. The maximum tolerated dose was defined as the highest dose at which &amp;lt;2 of the first 6 new patients experienced dose-limiting toxicity. The pharmacokinetic behavior of Col-3 was characterized, and pharmacodynamic relationships were sought. Results: Thirty-three patients were treated with 73 courses of Col-3 at four dose levels ranging from 36 to 98 mg/m2/day. Unacceptably high incidences of photosensitivity skin reactions and malaise were noted in the first 28-day courses of patients treated with Col-3 at doses exceeding 50 mg/m2/day. At 50 mg/m2/day, severe toxicity occurred in 2 of 12 new patients in first courses, and no additional dose-limiting toxicities were observed in subsequent courses. Other mild to modest adverse effects included nausea, vomiting, liver function tests abnormalities, diarrhea, mucositis, leukopenia, and thrombocytopenia. The pharmacokinetics of Col-3 were dose proportional, and mean trough concentrations at steady state were similar to biologically relevant concentrations in preclinical studies. Major responses did not occur, but durable disease stability was noted in 3 patients, one each with carcinosarcoma of the uterus, pancreas, and ovary, all of whom had experienced disease progression before Col-3 treatment. Conclusions: The recommended dose for Phase II studies of Col-3 administered once daily on an uninterrupted schedule is 50 mg/m2/day accompanied by efforts that promote adherence to the use of sunscreen and other photoprotective measures. Pharmacokinetic results indicate that plasma concentrations above biologically relevant concentrations are readily maintained at this dose, and additional disease-directed studies, particularly in patients with soft tissue sarcoma, should be considered.
FDA Approval Summary: Vemurafenib for Treatment of Unresectable or Metastatic Melanoma with the BRAFV600E Mutation
Authors: Geoffrey Kim, Amy E. McKee, Yang-Min Ning, Maitreyee Hazarika, Marc Theoret, John R. Johnson, Qiang Casey Xu, Shenghui Tang, Rajeshwari Sridhara, Xiaoping Jiang, Kun He, Donna Roscoe, W. David McGuinn, Whitney S. Helms, Anne Marie Russell, Sarah Pope Miksinski, Jeanne Fourie Zirkelbach, Justin Earp, Qi Liu, Amna Ibrahim, Robert Justice, Richard Pazdur
Journal: Clinical Cancer Research (2014)

Abstract On August 17, 2011, the U.S. Food and Drug Administration (FDA) approved vemurafenib tablets (Zelboraf, Hoffmann-LaRoche Inc.) for the treatment of patients with unresectable or metastatic melanoma with the BRAFV600E mutation as detected by an FDA-approved test. The cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems, Inc.) was approved concurrently. An international, multicenter, randomized, open-label trial in 675 previously untreated patients with BRAFV600E mutation–positive unresectable or metastatic melanoma allocated 337 patients to receive vemurafenib, 960 mg orally twice daily, and 338 patients to receive dacarbazine, 1,000 mg/m2 intravenously every 3 weeks. Overall survival was significantly improved in patients receiving vemurafenib [HR, 0.44; 95% confidence interval (CI), 0.33–0.59; P &amp;lt; 0.0001]. Progression-free survival was also significantly improved in patients receiving vemurafenib (HR, 0.26; 95% CI, 0.20–0.33; P &amp;lt; 0.0001). Overall response rates were 48.4% and 5.5% in the vemurafenib and dacarbazine arms, respectively. The most common adverse reactions (≥30%) in patients treated with vemurafenib were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, and nausea. Cutaneous squamous cell carcinomas or keratoacanthomas were detected in approximately 24% of patients treated with vemurafenib. Other adverse reactions included hypersensitivity, Stevens–Johnson syndrome, toxic epidermal necrolysis, uveitis, QT prolongation, and liver enzyme laboratory abnormalities. Clin Cancer Res; 20(19); 4994–5000. ©2014 AACR.