tbuckley/cabot-search huggingface dataset:
CSIG-11OLIG2-MEDIATED REGULATION OF GLIOMA INVASION
Authors: Shwetal Mehta, Shiv Singh, Roberto Fiorelli, Robert Kupp, Costanza Lo Cascio, Sindhu Rajan, Jonathan Yamaguchi, Jennifer Eschbacher, Michael Berens, Nader Sanai
Journal: Neuro-Oncology (2015)

Glioblastoma multiforme (GBM) is a highly aggressive, infiltrative, and lethal brain tumor. GBM patients have an overall survival of <1 year, despite major research efforts in diagnosis and treatment. Almost all GBM patients experience tumor recurrence, for which there is currently no standard of care. A major challenge with GBM is that invasive glioma cells extend beyond the surgically resected regions typically defined based on magnetic resonance imaging. These invasive cells are resistant to adjuvant therapies, lead to tumor recurrence and contribute to poor prognosis in GBM patients. It has been proposed that migrating tumor cells undergo a switch from proliferation to invasion. However, the molecular and cellular mechanism involved in the regulation of this switch from proliferation to invasion/migration in GBM is poorly understood. We have previously shown that the lineage-specific transcription factor, Olig2 plays a critical role in glioma formation. Here we examined the differential role of Olig2 in promoting the switch from proliferation to invasion. We utilized genetically relevant mouse model of as well as GBM patient-derived xenograft (PDX) models to investigate the role of Olig2 in promoting glioma invasion. We show that Olig2 expressing glioma cells are highly invasive and migratory irrespective of their TCGA molecular subtype. Knockdown of Olig2 significantly decreases the ability of GBM PDX-derived cells to invade matrigel matrix. We find that Olig2 expressing cells are present both at the proliferating tumor core as well as at the invasive rim in GBM patient tissues. Mechanistically, we find that Olig2 regulates the expression of epithelial-to-mesenchymal transition (EMT) genes such as Twist1, Snai1, Zeb1, Stat3, CD44 and Vimentin and genes involved in invasion regulation like TGFβ2 and Epha2. Our data provides evidence for a role of Olig2 in both proliferation and invasion.
Abstract 336: Cardiac Function Improvement in Infarcted Rats Treated with an Association of N-acetylcysteine and Deferoxamine
Authors: Michael Andrades, Amanda Phaelante, Virgílio Olsen, Santiago Tobar, Amanda Lopes, Nidiane Martinelli, Carolina Cohen, Felipe Dal-Pizzol, Andreia Biolo, Luis Rohde, Nadine Clausell
Journal: Circulation Research (2014)

Acute myocardial infarction (AMI) is followed by free radicals generation, which is central in cardiac remodeling. N-acetylcysteine (NAC) is an antioxidant that may have pro-oxidant activity in presence of iron ions. Thus, the association with an iron chelator might improve NAC antioxidant potential. Our aim was to test the association of NAC and an iron chelator (deferoxamine - DFX) on cardiac remodeling in a rodent model of AMI. To this end, Male Wistar rats (60 days old) were subjected to a sham surgery or subjected to myocardial infarcted by the occlusion of left ventricular descending artery. Twelve hours after, AMI was confirmed by cTnI evaluation and the animals were randomized in the following treatments: vehicle, NAC (25 mg/kg for 28 days), DFX (40 mg/kg for 7 days), or NAC plus DFX (NAC 25 mg/kg for 28 days plus DFX 40 mg/kg for 7 days). All animals were followed for 28 days. AMI induced an increase in total plasma iron levels at 7 days after the procedure and all treatments were able to decrease iron concentration. NAC/DFX was able to keep iron levels low up to 28 days. Morphofunctional assessments were made serially by echocardiography. Animals treated with NAC/DFX showed an increase in ejection fraction at 28 days when compared with vehicle group (45% ± 11% vs. 35% ± 9%,respectively; p=0.03). On histological analysis (at 28 days), NAC/DFX treated rats showed decreased oxidative stress (immunohistochemistry anti-4-hydroxynonenal, a side product of lipid peroxidation) when comparing with vehicle group (p=0.059). In conclusion, the association of NAC/DFX was able to attenuate chamber remodeling and improved left ventricle function in an animal model of AMI, whereas either NAC or DFX had no effect when given alone. The likely participation of iron and free radicals can be suggested, but further studies are necessary.
The Absorption, Excretion and Toxicity of Streptomycin in Man
Authors: Donald G. Anderson, Marjorie Jewell
Journal: New England Journal of Medicine (1945)

IN JANUARY, 1944, Schatz, Bugie and Waksman1 described the isolation of a new antibacterial substance from the culture filtrate of Actinomyces griseus. They named this substance "streptomycin" and reported that it had a marked antibacterial action in vitro against many gram-negative and gram-positive bacteria. According to its discoverers, streptomycin resembled streptothricin, another antibacterial agent isolated in 1942,2 but had a wider bacteriostatic spectrum and was quantitatively more active against certain organisms and less toxic for animals.Several studies3 4 5 6 7 8 9 have now been reported in which it has been shown that streptomycin is sufficiently effective in vivo in the treatment of experimental . . .
Routine Early Endoscopy in Upper-Gastrointestinal-Tract Bleeding
Authors: Walter L. Peterson, Cora C. Barnett, Herbert J. Smith, Michael H. Allen, Desmond B. Corbett
Journal: New England Journal of Medicine (1981)

To determine whether routine early endoscopy is beneficial to patients with upper-gastrointestinal-tract bleeding that ceases during hospitalization, we randomly assigned 206 patients to routine endoscopy (100 patients) or no routine endoscopy (106). Patients in the latter group underwent endoscopy only if recurrent bleeding occurred during hospitalization or if x-ray films disclosed gastric ulcer or suggested neoplasia. All patients were initially treated with an empiric antacid regimen. When the two groups were compared (experimental versus control), there were no significant differences in overall hospital deaths (11 versus eight), recurrence of bleeding (33 versus 32), number of transfusions required to treat recurrent bleeding (mean ±S.E.M, 7.4±1.2 versus 6.3±0.7 units), deaths after recurrent bleeding (eight versus five), or duration of hospital stay. During the 12 months after discharge, there were also no significant differences in frequency of readmission to the hospital, incidence of further gastrointestinal bleeding, number of hemorrhage-related deaths, or frequency of gastrointestinal surgery. We conclude that endoscopy should not be a routine procedure in patients with upper-gastrointestinal-tract bleeding that ceases during treatment. (N Engl J Med. 1981; 304:925–9.)
208O_PR: CRS-207 with chemotherapy (chemo) in malignant pleural mesothelioma (MPM): Results from a phase 1b trial
Authors: T. Jahan, R. Hassan, E. Alley, H. Kindler, S. Antonia, C. Whiting, L. Coussens, A.L. Murphy, A. Thomas, D.G. Brockstedt
Journal: Journal of Thoracic Oncology (2016)
Circulating Immune Complexes in Infective Endocarditis
Authors: Arnold S. Bayer, Argyrios N. Theofilopoulos, Robert Eisenberg, Frank J. Dixon, Lucien B. Guze
Journal: New England Journal of Medicine (1976)

To examine further the role of immune-complex deposition in infective endocarditis, we studied 29 patients with infective endocarditis for presence of complement-containing circulating immune complexes. Ninety-seven per cent (28 of 29) had serum levels of immune complexes greater than 12 mug per milliliter. Mean levels in these patients were significantly higher than in patients with sepsis without endocarditis or in normal controls (P less than 0.05). Circulating immune-complex levels were correlated with longer duration of illness (P less than 0.025), extravalvular manifestations of endocarditis (P less than 0.025) and hypocomplementemia (P less than 0.05). Patients with right-sided endocarditis had significantly higher circulating immune-complex levels than patients with left-sided involvement (P less than 0.025). In general, levels fell to zero with successful antimicrobial or surgical therapy. This drop was concurrent with disappearance of extravalvular signs, blood cultures becoming sterile, and rise in serum complement levels. These findings support the concept that immune complexes may be important in the pathogenesis of infective endocarditis.
Through Thick and Thin
Authors: David R. Yu, Redonda Miller, Paul F. Bray
Journal: New England Journal of Medicine (1998)

A 58-year-old woman was admitted to the hospital because of chest pain. The night before admission, the patient awoke with crushing, nonpleuritic chest pain radiating down her left arm, with associated presyncope and diaphoresis. The pain was like cardiac chest pain that she had experienced previously. She had no dyspnea, fever, chills, or cough. She had long-standing hypertension and diabetes mellitus in association with corticosteroid therapy for idiopathic thrombocytopenic purpura, as well as a family history of premature coronary artery disease. She had had two normal pregnancies and one spontaneous abortion. Five months before this admission, she had been . . .
Abstract 15813: Impact of QRS Duration on Clinical Event Reduction with Cardiac Resynchronization Therapy: A Meta-Analysis of Randomized Controlled Trials
Authors: Ilke Sipahi, Thomas P Carrigan, Douglas Y Rowland, Bruce S Stambler, James C Fang
Journal: Circulation (2010)

Context: Cardiac resynchronization therapy (CRT) is effective in reducing clinical events in patients with heart failure and prolonged QRS duration. Current guidelines recommend CRT in class III an...
Targeted and effective photodynamic therapy for cancer using functionalized nanomaterials
Authors: Eun Ji Hong, Dae Gun Choi, Min Suk Shim
Journal: Acta Pharmaceutica Sinica B (2016)

Photodynamic therapy (PDT) is an emerging, non-invasive therapeutic strategy that involves photosensitizer (PS) drugs and external light for the treatment of diseases. Despite the great progress in PS-mediated PDT, their clinical applications are still hampered by poor water solubility and tissue/cell specificity of conventional PS drugs. Therefore, great efforts have been made towards the development of nanomaterials that can tackle fundamental challenges in conventional PS drug–mediated PDT for cancer treatment. This review highlights recent advances in the development of nano-platforms, in which various functionalized organic and inorganic nanomaterials are integrated with PS drugs, for significantly enhanced efficacy and tumor-selectivity of PDT.
A Comparison of Repeated High Doses and Repeated Standard Doses of Epinephrine for Cardiac Arrest Outside the Hospital
Authors: Pierre-Yves Gueugniaud, Pierre Mols, Patrick Goldstein, Emmanuel Pham, Pierre-Yves Dubien, Carine Deweerdt, Michel Vergnion, Paul Petit, Pierre Carli
Journal: New England Journal of Medicine (1998)

Clinical trials have not shown a benefit of high doses of epinephrine in the management of cardiac arrest. We conducted a prospective, multicenter, randomized study comparing repeated high doses of epinephrine with repeated standard doses in cases of out-of-hospital cardiac arrest.Adult patients who had cardiac arrest outside the hospital were enrolled if the cardiac rhythm continued to be ventricular fibrillation despite the administration of external electrical shocks, or if they had asystole or pulseless electrical activity at the time epinephrine was administered. We randomly assigned 3327 patients to receive up to 15 high doses (5 mg each) or standard doses (1 mg each) of epinephrine according to the current protocol for advanced cardiac life support.In the high-dose group, 40.4 percent of 1677 patients had a return of spontaneous circulation, as compared with 36.4 percent of 1650 patients in the standard-dose group (P=0.02); 26.5 percent of the patients in the high-dose group and 23.6 percent of those in the standard-dose group survived to be admitted to the hospital (P=0.05); 2.3 percent of the patients in the high-dose group and 2.8 percent in the standard-dose group survived to be discharged from the hospital (P=0.34). There was no significant difference in neurologic status according to treatment among those discharged. High-dose epinephrine improved the rate of successful resuscitation in patients with asystole, but not in those with ventricular fibrillation.In our study, long-term survival after cardiac arrest outside the hospital was no better with repeated high doses of epinephrine than with repeated standard doses.
Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial
Authors: Kirsten Fischer, Jasmin Bahlo, Anna Maria Fink, Valentin Goede, Carmen Diana Herling, Paula Cramer, Petra Langerbeins, Julia von Tresckow, Anja Engelke, Christian Maurer, Gabor Kovacs, Marco Herling, Eugen Tausch, Karl-Anton Kreuzer, Barbara Eichhorst, Sebastian Böttcher, John F. Seymour, Paolo Ghia, Paula Marlton, Michael Kneba, Clemens-Martin Wendtner, Hartmut Döhner, Stephan Stilgenbauer, Michael Hallek
Journal: Blood (2015)
Phase I adjuvant trial of multi-epitope p53 vaccine for patients with squamous cell carcinoma of the head and neck (SCCHN): A preliminary report
Authors: P. Andrade, A. Deleo, C. Visus, L. Butterfield, A. Argiris, R. L. Ferris
Journal: Journal of Clinical Oncology (2009)

3012 Background: Alteration in the tumor suppressor protein, p53, is one of the most common events in human cancers. Since most mutations of p53 are associated with accumulation of p53, the nonmutated portions of protein are readily accessible to degradation into wild type (wt) sequence peptides for immune recognition by T lymphocytes. Methods: A phase I trial was conducted in stage I-IVa patients (pts) with SCCHN with no active disease using autologous dendritic cells (DC) loaded with two HLA-A*0201-restricted T cell-defined p53 peptides alone (Arm 1, 5 pts), plus either a wt p53 helper peptide (Arm 2, 5 pts) or nonspecific helper peptide (dervied from tetanus toxoid, Arm 3, 6 pts). The accrual goal is 24 patients, divided into the 3 arms. Each pt received 3 intranodal vaccinations at 2-week intervals. The primary endpoint was immunological response using ELISPOT, tetramer or delayed type hypersensitivity (DTH)reactions to p53 peptides. Results: 16 pts have been vaccinated so far. Erythema or hematoma were observed at vaccine injection sites in two pts. At 15-mo median follow-up, 11/16 pts are alive without evidence of disease, 2 developed disease recurrence, and 1 pt developed a second primary lung cancer. Two have died of unrelated causes. Immunological analyses of the SCCHN patients’ responses to immunization indicate responses to both HLA-A2 binding peptides. Tetramer frequencies for p53-specific CTL or IFN-gamma ELISPOT assays indicated a 5/16 responders. Ongoing correlative analyses include characterization of human papillomavirus (HPV) infection, HLA, antigen processing machinery, and staining with soluble T cell receptor for HLA-A2-p53 peptide complexes on tumor cells. Conclusions: Adjuvant p53 peptide-loaded DC-based vaccination is feasible and safe in pts with SCCHN. A phase II wt p53-based vaccine trial will be proposed based on the most efficacious regimen used in this trial. No significant financial relationships to disclose.
Endocrinologically Incomplete Transethmoidal Trans-Sphenoidal Hypophysectomy with Relief of Bone Pain in Breast Cancer
Authors: John T. LaRossa, M. Stuart Strong, James C. Melby
Journal: New England Journal of Medicine (1978)

To assess endocrinologic completeness of transethmoidal trans-sphenoidal hypophysectomy and the relation between postoperative pituitary hormone levels and relief of bone pain, we tested pituitary reserve by measuring base-line values of follicle-stimulating hormone and luteinizing hormone, thyrotropin-releasing-factor-stimulated thyrotropin and prolactin, and levodopa-stimulated growth hormone after hypophysectomy in 15 menopausal women with metastatic breast cancer. In all 15 bone pain diminished or disappeared within 24 hours of operation. Pituitary-function testing identified only one patient as having had an endocrinologically complete hypophysectomy. Base-line gonadotropin levels and thyrotropin-releasing-factor-stimulated prolactin were the most reliable measures of residual pituitary function. We conclude that transethmoidal trans-sphenoidal hypophysectomy may not totally ablate pituitary endocrine function; effective relief of bone pain in patients with metastatic breast cancer can follow this procedure despite residual pituitary function and the lack of objective tumor remission. (N Engl J Med 298:1332–1335, 1978)
Phase I study of irinotecan with individualized dosing based on <i>UGT1A1</i> polymorphism in Japanese patients with gastrointestinal cancer. (UGT0601)
Authors: T. Ura, T. Satoh, T. Tsujinaka, Y. Sasaki, K. Yamazaki, M. Munakata, S. Okamura, Y. Yamada, I. Hyodo, Y. Sakata
Journal: Journal of Clinical Oncology (2008)

14502 Background: UGT1A1*28 and *6 polymorphisms are reported to be associated with decreased glucuronidation of SN-38, the active metabolite of irinotecan (CPT-11). In 2005, the FDA revised the package insert of CPT-11 recommending a dose reduction in patients (pts) homozygous for the UGT1A1*28 allele, however, the level of reduction remains unclear. The purpose of this study was to determine recommended dose (RD) and incidence of dose-limiting toxicities (DLT) in UGT1A1*28 and *6 genotype pts receiving bi- weekly single-agent CPT-11. Methods: UGT1A1 polymorphisms were categorized into 3 groups: wild-type (*1/*1), heterozygous (*1/*28, *1/*6), and homozygous (*28/*28, *6/*6, *28/*6). CPT-11 was administered on Days 1 and 15. In the heterozygous and homozygous groups, starting doses were set at 100 and 75 mg/m2, and successive dose was determined by CRM from 50, 75, 100, 125 or 150 mg/m2. In the wild-type group, dosage was set at 150 mg/m2, the approved dose in Japan. DLT was defined as grade 4 hematological, or grade 3 non-hematological toxicity, occurring within 2 weeks. Pharmacokinetic evaluations were performed on day 1. Results: Seventy-four pts with advanced metastatic colorectal and gastric cancer who had failed in 1st line treatment were enrolled from June 2006 to August 2007 (wild-type, heterozygous, homozygous: 41, 20, and15, respectively). The current dose level is 150 mg/m2 in the heterozygous and homozygous groups. DLT was observed at 150 mg/m2 in one pt of the wild-type group (grade 3 anorexia and fatigue), and in two pts (*6/*6) of the homozygous group (grade 4 neutropenia and grade 3 diarrhea). The incidences of grade 3/4 neutropenia at 150 mg/m2 were 9.8% (4/41), 18.8% (3/16), and 55.6% (5/9) in the wild-type, heterozygous, and homozygous groups, respectively. Grade 3/4 neutropenia was observed in 85.7% (6/7) pts in the *6/*6 homozygous group at 150 mg/m2. Conclusions: The RD was 150 mg/m2 in patients with heterozygous group. In homozygous group, it remains to be determined. Homozygosity for UGT1A1*6/*6 as well as for *28/*28 should be considered a predictive factor in CPT-11-induced neutropenia. No significant financial relationships to disclose.
Stopping Short of Certainty
Authors: Robert A. Kreisberg
Journal: New England Journal of Medicine (1994)

A 68-year-old man was evaluated for a two-year history of hypercalcemia, constipation, generalized weakness, and slowing of intellectual function. He had a 20-year history of recurrent nephrolithiasis. He had been treated for a peptic ulcer at the age of 60 and had had no symptoms of recurrent ulcer disease thereafter. He had also had mild hypertension treated with atenolol and stable renal insufficiency (blood urea nitrogen level, 46 mg per deciliter; serum creatinine level, 3.3 mg per deciliter) since the age of 66. Hypercalcemia was first detected when the patient was 60 years old, when he passed a kidney . . .
Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction
Authors: Michelle L. O’Donoghue, Ruchira Glaser, Matthew A. Cavender, Philip E. Aylward, Marc P. Bonaca, Andrzej Budaj, Richard Y. Davies, Mikael Dellborg, Keith A. A. Fox, Jorge Antonio T. Gutierrez, Christian Hamm, Robert G. Kiss, František Kovar, Julia F. Kuder, Kyung Ah Im, John J. Lepore, Jose L. Lopez-Sendon, Ton Oude Ophuis, Alexandr Parkhomenko, Jennifer B. Shannon, Jindrich Spinar, Jean-Francois Tanguay, Mikhail Ruda, P. Gabriel Steg, Pierre Theroux, Stephen D. Wiviott, Ian Laws, Marc S. Sabatine, David A. Morrow
Journal: JAMA (2016)

p38 Mitogen-activated protein kinase (MAPK)-stimulated inflammation is implicated in atherogenesis, plaque destabilization, and maladaptive processes in myocardial infarction (MI). Pilot data in a phase 2 trial in non-ST elevation MI indicated that the p38 MAPK inhibitor losmapimod attenuates inflammation and may improve outcomes.To evaluate the efficacy and safety of losmapimod on cardiovascular outcomes in patients hospitalized with an acute myocardial infarction.LATITUDE-TIMI 60, a randomized, placebo-controlled, double-blind, parallel-group trial conducted at 322 sites in 34 countries from June 3, 2014, until December 8, 2015. Part A consisted of a leading cohort (n = 3503) to provide an initial assessment of safety and exploratory efficacy before considering progression to part B (approximately 22,000 patients). Patients were considered potentially eligible for enrollment if they had been hospitalized with an acute MI and had at least 1 additional predictor of cardiovascular risk.Patients were randomized to either twice-daily losmapimod (7.5 mg; n = 1738) or matching placebo (n = 1765) on a background of guideline-recommended therapy. Patients were treated for 12 weeks and followed up for an additional 12 weeks.The primary end point was the composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization with the principal analysis specified at week 12.In part A, among the 3503 patients randomized (median age, 66 years; 1036 [29.6%] were women), 99.1% had complete ascertainment for the primary outcome. The primary end point occurred by 12 weeks in 123 patients treated with placebo (7.0%) and 139 patients treated with losmapimod (8.1%; hazard ratio, 1.16; 95% CI, 0.91-1.47; P = .24). The on-treatment rates of serious adverse events were 16.0% with losmapimod and 14.2% with placebo.Among patients with acute MI, use of losmapimod compared with placebo did not reduce the risk of major ischemic cardiovascular events. The results of this exploratory efficacy study did not justify proceeding to a larger efficacy trial in the existing patient population.clinicaltrials.gov Identifier: NCT02145468.
Analysis of Circulating Tumor Cells in Breast Cancer
Authors: Zeynep Eroglu, Odicie Fielder, George Somlo
Journal: Journal of the National Comprehensive Cancer Network (2013)

Over the past few decades, substantial progress has been made in the diagnosis and treatment of breast cancer. Early identification of relapsed and metastatic disease has been a primary focus of ongoing research. Circulating tumor cells (CTCs) are implicated as harbingers of metastases. With advances in detection technologies, CTCs offer the option for real-time liquid biopsies. Methods to identify CTCs in the bloodstream by physical or biochemical properties, although feasible, still require improvements to promote widespread, reproducible use. Sufficient data support enumeration and assessment of changes in the number of CTCs as prognostic indicators, but controversy around their predictive utility for selecting treatments remains. As the technology to detect CTCs and characterize their heterogeneous molecular profile evolves, additional information will likely be obtained to guide targeted and individualized therapies.