tbuckley/cabot-search huggingface dataset:
Immunologic and Clinical Outcomes of Vaccination With a Multiepitope Melanoma Peptide Vaccine Plus Low-Dose Interleukin-2 Administered Either Concurrently or on a Delayed Schedule
Authors: Craig L. Slingluff, Gina R. Petroni, Galina V. Yamshchikov, Sarah Hibbitts, William W. Grosh, Kimberly A. Chianese-Bullock, Eric A. Bissonette, Donna L. Barnd, Donna H. Deacon, James W. Patterson, Jayashree Parekh, Patrice Y. Neese, Elizabeth M.H. Woodson, Catherine J. Wiernasz, Priscilla Merrill
Journal: Journal of Clinical Oncology (2004)

A phase II trial was performed to test whether systemic low-dose interleukin-2 (IL-2) augments T-cell immune responses to a multipeptide melanoma vaccine. Forty patients with resected stage IIB-IV melanoma were randomly assigned to vaccination with four gp100- and tyrosinase-derived peptides restricted by human leukocyte antigen (HLA) -A1, HLA-A2, and HLA-A3, and a tetanus helper peptide plus IL-2 administered daily either beginning day 7 (group 1), or beginning day 28 (group 2).T-cell responses were assessed by an interferon gamma ELIspot assay in peripheral blood lymphocytes (PBL) and in a lymph node draining a vaccination site (sentinel immunized node [SIN]). Patients were followed for disease-free and overall survival.T-cell responses to the melanoma peptides were observed in 37% of PBL and 38% of SINs in group 1, and in 53% of PBL and 83% of SINs in group 2. The magnitude of T-cell response was higher in group 2. The tyrosinase peptides DAEKSDICTDEY and YMDGTMSQV were more immunogenic than the gp100 peptides YLEPGPVTA and ALLAVGATK. T-cell responses were detected in the SINs more frequently, and with higher magnitude, than responses in the PBL. Disease-free survival estimates at 2 years were 39% (95% CI, 18% to 61%) for group 1, and 50% (95% CI, 28% to 72%) for group 2 (P = .32).The results of this study support the safety and immunogenicity of a vaccine composed of four peptides derived from gp100 and tyrosinase. The low-dose IL-2 regimen used for group 1 paradoxically diminishes the magnitude and frequency of cytotoxic T lymphocyte responses to these peptides.
Intermittent Preventive Treatment for Malaria in Papua New Guinean Infants Exposed to Plasmodium falciparum and P. vivax: A Randomized Controlled Trial
Authors: Nicolas Senn, Patricia Rarau, Danielle I. Stanisic, Leanne Robinson, Céline Barnadas, Doris Manong, Mary Salib, Jonah Iga, Nandao Tarongka, Serej Ley, Anna Rosanas-Urgell, John J. Aponte, Peter A. Zimmerman, James G. Beeson, Louis Schofield, Peter Siba, Stephen J. Rogerson, John C. Reeder, Ivo Mueller
Journal: PLoS Medicine (2012)

A three-arm randomized trial conducted among infants in Papua New Guinea estimates the preventive effect against malaria episodes of intermittent preventive treatment, in an area where children are exposed to both falciparum and vivax malaria.
Oxidative and electrophilic stress induces multidrug resistance-associated protein transporters via the nuclear factor-E2-related factor-2 transcriptional pathway
Authors: Jonathan M. Maher, Matthew Z. Dieter, Lauren M. Aleksunes, Angela L. Slitt, Grace Guo, Yuji Tanaka, George L. Scheffer, Jefferson Y. Chan, Jose E. Manautou, Ying Chen, Timothy P. Dalton, Masayuki Yamamoto, Curtis D. Klaassen
Journal: Hepatology (2007)

Multidrug resistance–associated proteins (Mrps) are adenosine triphosphate–dependent transporters that efflux chemicals out of cells. In the liver, Mrp2 transports bilirubin-glucuronide, glutathione (GSH), and drug conjugates into bile, whereas Mrp3 and Mrp4 efflux these entities into blood. The purpose of this study was to determine whether oxidative conditions (that is, the disruption of hepatic GSH synthesis) or the administration of nuclear factor-E2–related factor-2 (Nrf2) activators (oltipraz and butylated hydroxyanisole) can induce hepatic Mrp transporters and whether that induction is through the Nrf2 transcriptional pathway. Livers from hepatocyte-specific glutamate - cysteine ligase catalytic subunit –null mice had increased nuclear Nrf2 levels, marked gene and protein induction of the Nrf2 target gene NAD(P)H:quinone oxidoreductase 1, as well as Mrp2, Mrp3, and Mrp4 expression. The treatment of wild-type and Nrf2 -null mice with oltipraz and butylated hydroxyanisole demonstrated that the induction of Mrp2, Mrp3, and Mrp4 is Nrf2-dependent. In Hepa1c1c7 cells treated with the Nrf2 activator tert -butyl hydroquinone, chromatin immunoprecipitation with Nrf2 antibodies revealed the binding of Nrf2 to antioxidant response elements in the promoter regions of mouse Mrp2 [−185 base pairs (bp)], Mrp3 (−9919 bp), and Mrp4 (−3767 bp). Conclusion: The activation of the Nrf2 regulatory pathway stimulates the coordinated induction of hepatic Mrps.
In Vivo Monitoring of Liver Damage Using Caspase-3 Probe
Authors: Michitaka Ozaki, Sanae Haga, Takeaki Ozawa
Journal: Theranostics (2012)

Real-time monitoring of cellular and organ conditions improves our understanding of various physiopathological phenomena. Such monitoring is expected to provide important alternatives for clinical diagnosis and therapy. We have sought to show physiopathological changes of organs as well as cells. Here, we present an example of in vivo imaging of liver states using the luciferase-based caspase-3 optical probe. We examined dynamic changes of apoptosis (caspase-3 activity) of a mouse liver as well as those of liver cells, proving that the emitted signals reflected the biochemically evaluated apoptotic cell death. In live liver cell (AML 12) experiments, the optical probe for caspase-3 activity emitted signals in response to Fas-ligand, staurosporine and hypoxia/reoxygenation, demonstrating that the probe can measure cellular apoptosis quantitatively. We therefore applied this probe for mouse liver ischemia/reperfusion (I/R) and drug-toxicity to liver. By expressing the probe in a mouse liver adenovirally, we imaged liver caspase-3 activity (i.e. apoptotic damage) non-invasively and chronologically in the hepatic I/R model of mice. The duration of liver ischemia affected the post-ischemic caspase-dependent damage. Ischemia (up to 60 min) enhanced liver damage after reperfusion, but prolonged ischemia (90 min of ischemia) induced not apoptotic cell death but necrotic cell death. Direct observations of the changes of organ conditions elucidated the dynamism of organ function and damage. These technologies clearly possess clinical relevance. They are expected to provide a new diagnostic tool for various clinical settings in the future.
A simplified, single-lead unipolar transvenous cardioversion-defibrillation system.
Authors: G H Bardy, G Johnson, J E Poole, G L Dolack, P J Kudenchuk, D Kelso, R Mitchell, R Mehra, B Hofer
Journal: Circulation (1993)

BACKGROUND Transvenous implantable cardioverter-defibrillators provide significant advantages in the treatment of patients with life-threatening ventricular arrhythmias. However, present technology requires considerable electrophysiology expertise, multiple incisions, and long operative times for successful implementation. METHODS AND RESULTS In this study, we present a prototype of a new, easy-to-insert unipolar transvenous defibrillation system that has the reliability of epicardial defibrillation but the ease of pacemaker insertion. This system incorporates a single anodal right ventricular defibrillation electrode using a 65% tilt biphasic pulse delivered to a 108-cm2 surface area pulse generator titanium alloy shell as an active cathode placed in a left infraclavicular pocket. Testing of this system was performed before implantation of a standard nonthoracotomy-transvenous defibrillation system in 40 consecutive patients with a history of ventricular tachycardia or fibrillation. The simplified unipolar single-lead system resulted in a defibrillation threshold of 9.3 +/- 6.0 J with 37 of 40 patients (93%) having a defibrillation threshold of less than 20 J. Moreover, the unipolar defibrillation system was efficiently used requiring only 3.4 +/- 0.8 ventricular fibrillation inductions to measure the defibrillation threshold and 100 +/- 28 minutes to implement. CONCLUSIONS This new unipolar transvenous defibrillation system is as simple to insert as a pacemaker, requires few ventricular fibrillation inductions, demands less technical expertise, and provides defibrillation at energy levels comparable to that reported with epicardial lead systems. It should substantially reduce the morbidity, time, and cost of defibrillator implantation.
Progress Against Solid Tumors in Danger: The Metastatic Breast Cancer Example
Authors: Javier Cortés, Emiliano Calvo, Antonio González-Martín, Shaheenah Dawood, Antonio Llombart-Cussac, Leticia De Mattos-Arruda, Patricia Gómez, Orlando Silva, Edith A. Perez, Hope S. Rugo, Ana Lluch, Gabriel N. Hortobagyi
Journal: Journal of Clinical Oncology (2012)

Javier Cortes, Vall d’Hebron University Hospital; Medica Scientia Innovation Research, Academic Research Organization, Barcelona, Spain Emiliano Calvo, South Texas Accelerated Research Therapeutics—Madrid, Centro Integral Oncologico Clara Campal, Madrid, Spain Antonio Gonzalez-Martin, Centro Oncologico MD Anderson International Espana, Madrid, Spain Shaheenah Dawood, Dubai Hospital, Dubai Health Authority, Dubai, United Arab Emirates Antonio Llombart-Cussac, Arnau de Vilanova Hospital, Valencia; Medica Scientia Innovation Research, Academic Research Organization, Madrid, Spain Leticia De Mattos-Arruda and Patricia Gomez, Vall d’Hebron University Hospital, Barcelona, Spain Orlando Silva, Sylvester Comprehensive Cancer Center, Miami, FL Edith A. Perez, Mayo Clinic Cancer Center, Jacksonville, FL Hope S. Rugo, University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA Ana Lluch, Hospital Clinico, Valencia, Spain Gabriel N. Hortobagyi, The University of Texas MD Anderson Cancer Center, Houston, TX
Aging-associated inflammation promotes selection for adaptive oncogenic events in B cell progenitors
Authors: Curtis J. Henry, Matias Casás-Selves, Jihye Kim, Vadym Zaberezhnyy, Leila Aghili, Ashley E. Daniel, Linda Jimenez, Tania Azam, Eoin N. McNamee, Eric T. Clambey, Jelena Klawitter, Natalie J. Serkova, Aik Choon Tan, Charles A. Dinarello, James DeGregori
Journal: Journal of Clinical Investigation (2015)

The incidence of cancer is higher in the elderly; however, many of the underlying mechanisms for this association remain unexplored. Here, we have shown that B cell progenitors in old mice exhibit marked signaling, gene expression, and metabolic defects. Moreover, B cell progenitors that developed from hematopoietic stem cells (HSCs) transferred from young mice into aged animals exhibited similar fitness defects. We further demonstrated that ectopic expression of the oncogenes BCR-ABL, NRASV12, or Myc restored B cell progenitor fitness, leading to selection for oncogenically initiated cells and leukemogenesis specifically in the context of an aged hematopoietic system. Aging was associated with increased inflammation in the BM microenvironment, and induction of inflammation in young mice phenocopied aging-associated B lymphopoiesis. Conversely, a reduction of inflammation in aged mice via transgenic expression of α-1-antitrypsin or IL-37 preserved the function of B cell progenitors and prevented NRASV12-mediated oncogenesis. We conclude that chronic inflammatory microenvironments in old age lead to reductions in the fitness of B cell progenitor populations. This reduced progenitor pool fitness engenders selection for cells harboring oncogenic mutations, in part due to their ability to correct aging-associated functional defects. Thus, modulation of inflammation — a common feature of aging — has the potential to limit aging-associated oncogenesis.
Cyclin A1 directly interacts with B-myb and cyclin A1/cdk2 phosphorylate B-myb at functionally important serine and threonine residues: tissue-specific regulation of B-myb function
Authors: Carsten Müller-Tidow, Wenbing Wang, Gregory E. Idos, Sven Diederichs, Rong Yang, Carol Readhead, Wolfgang E. Berdel, Hubert Serve, Mark Saville, Roger Watson, H. Phillip Koeffler
Journal: Blood (2001)
Validation of the Diagnostic Value of NMP22 ® BladderChek ® Test as a Marker for Bladder Cancer by Photodynamic Diagnosis
Authors: Stefan Tritschler, Sonja Scharf, Alexander Karl, Derya Tilki, Ruth Knuechel, Arndt Hartmann, Christian G. Stief, Dirk Zaak
Journal: European Urology (2006)
Evaluation of a portable device for diagnosing the sleep apnoea/hypopnoea syndrome
Authors: K. Dingli, E.L. Coleman, M. Vennelle, S.P. Finch, P.K. Wraith, T.W. Mackay, N.J. Douglas
Journal: European Respiratory Journal (2003)

Waiting times for hospital-based monitoring of the obstructive sleep apnoea/hypopnoea syndrome (OSAHS) are rising. This study tested whether Embletta, a new portable device, may accurately diagnose OSAHS at home. A synchronous comparison to polysomnography was performed in 40 patients and a comparison of home Embletta studies with in-laboratory polysomnography was performed in 61 patients. In the synchronous study, the mean difference (polysomnography–Embletta) in apnoeas+hypopnoeas (A+H)·h −1 in bed was 2·h −1 . In comparison to the apnoea/hypopnoea index (AHI)·h −1 slept, the Embletta (A+H)·h −1 in bed differed by 8·h −1 . These data were used to construct diagnostic categories in symptomatic patients from their Embletta results: “OSAHS” (≥20 (A+H)·h −1 in bed), “possible OSAHS” (10–20 (A+H)·h −1 in bed) or “not OSAHS” (&lt;10 (A+H)·h −1 in bed). In the home study, the mean difference in (A+H)·h −1 in bed was 3·h −1 . In comparison to the polysomnographic AHI·h −1 slept, the Embletta (A+H)·h −1 in bed differed by 6±14·h −1 . Using the above classification, all nine patients categorised as not OSAHS had AHI &lt;15·h −1 slept on polysomnography and all 23 with OSAHS on Embletta had an AHI ≥15 on polysomnography, but 18 patients fell into the possible OSAHS category potentially requiring further investigation and 11 home studies failed. Most patients were satisfactorily classified by home Embletta studies but 29 out of 61 required further investigation. The study suggested a 42% saving in diagnostic costs over polysomnography if this approach were adopted.
Investigating the thyroid nodule
Authors: H M Mehanna, A Jain, R P Morton, J Watkinson, A Shaha
Journal: BMJ (2009)

#### Summary points

Thyroid nodules are common: 4-7% of the adults have a palpable nodule, and up to 50-70% will have nodules on high definition ultrasonography, which may cause considerable concern to patients. In this article, we present an evidence based guide to investigating and managing thyroid nodules and we discuss the myths about nodules. Where relevant, we also highlight the differences between the two most widely used guidelines on this topic: the recently issued second edition of the British Thyroid Association’s guidelines on thyroid cancer1 and the American Thyroid Association’s guidelines.2 These guidelines were formulated by two large committees of experts, who reviewed all the available evidence, which mainly consists of prospective and retrospective cohorts; where there was no evidence, expert consensus opinion was used.

Traditional teaching states that 20-40% of thyroid nodules are malignant.3 However, this pertains to a highly selected group of patients, with solitary cold nodules on scintigraphy.4 The risk of malignancy for a thyroid nodule identified on ultrasonography is much lower: 4-7%.5 6

Little evidence is available on referral times. Relying on expert opinion, the British Thyroid Association’s guidelines say that most thyroid nodules are benign and therefore do not require urgent referral to secondary care.1 This advice …
Angiopoietin-2 Regulates Gene Expression in TIE2-Expressing Monocytes and Augments Their Inherent Proangiogenic Functions
Authors: Seth B. Coffelt, Andrea O. Tal, Alexander Scholz, Michele De Palma, Sunil Patel, Carmen Urbich, Subhra K. Biswas, Craig Murdoch, Karl H. Plate, Yvonne Reiss, Claire E. Lewis
Journal: Cancer Research (2010)

TIE2-expressing monocytes/macrophages (TEM) are a highly proangiogenic subset of myeloid cells in tumors. Here, we show that circulating human TEMs are already preprogrammed in the circulation to be more angiogenic and express higher levels of such proangiogenic genes as matrix metalloproteinase-9 (MMP-9), VEGFA, COX-2, and WNT5A than TIE2(-) monocytes. Additionally, angiopoietin-2 (ANG-2) markedly enhanced the proangiogenic activity of TEMs and increased their expression of two proangiogenic enzymes: thymidine phosphorylase (TP) and cathepsin B (CTSB). Three "alternatively activated" (or M2-like) macrophage markers were also upregulated by ANG-2 in TEMs: interleukin-10, mannose receptor (MRC1), and CCL17. To investigate the effects of ANG-2 on the phenotype and function of TEMs in tumors, we used a double-transgenic (DT) mouse model in which ANG-2 was specifically overexpressed by endothelial cells. Syngeneic tumors grown in these ANG-2 DT mice were more vascularized and contained greater numbers of TEMs than those in wild-type (WT) mice. In both tumor types, expression of MMP-9 and MRC1 was mainly restricted to tumor TEMs rather than TIE2(-) macrophages. Furthermore, tumor TEMs expressed higher levels of MRC1, TP, and CTSB in ANG-2 DT tumors than WT tumors. Taken together, our data show that although circulating TEMs are innately proangiogenic, exposure to tumor-derived ANG-2 stimulates these cells to exhibit a broader, tumor-promoting phenotype. As such, the ANG-2-TEM axis may represent a new target for antiangiogenic cancer therapies.
A genome scale overexpression screen to reveal drug activity in human cells
Authors: Anthony Arnoldo, Saranya Kittanakom, Lawrence E Heisler, Anthony B Mak, Andrey I Shukalyuk, Dax Torti, Jason Moffat, Guri Giaever, Corey Nislow
Journal: Genome Medicine (2014)

Target identification is a critical step in the lengthy and expensive process of drug development. Here, we describe a genome-wide screening platform that uses systematic overexpression of pooled human ORFs to understand drug mode-of-action and resistance mechanisms. We first calibrated our screen with the well-characterized drug methotrexate. We then identified new genes involved in the bioactivity of diverse drugs including antineoplastic agents and biologically active molecules. Finally, we focused on the transcription factor RHOXF2 whose overexpression conferred resistance to DNA damaging agents. This approach represents an orthogonal method for functional screening and, to our knowledge, has never been reported before.
Leukocytoclastic Vasculitis Induced by Subcutaneous Injection of Human Insulin in a Patient With Type 1 Diabetes and Essential Thrombocytemia
Authors: Thomas Mandrup-Poulsen, Jens Mølvig, Julie Pildal, Åse Krogh Rasmussen, Lennart Andersen, Birgit Guldhammer Skov, Jørgen Petersen
Journal: Diabetes Care (2002)

Both local (1) and systemic immediate-type insulin allergy (2) as well as delayed-type cutaneous reactions (3) to human insulin have been reported. Histologically verified Arthus reaction to insulin has only been reported in exceptional cases in which the patient was treated with bovine/porcine insulin (4). To the best of our knowledge, no histologically verified type 3 hypersensitivity reaction has been described in a patient treated with human insulin.

We report a case of leucocytoclastic vasculitis in a 48-year-old normal-weight female patient with well-controlled (HbA1c 6.4, upper normal 6.4%) type 1 diabetes since 1984 who had always been treated with ∼0.5 units · kg−1 body wt · day−1 semisynthetic human insulin and, beginning in 1998, recombinant human insulin. The patient did not have microvascular complications (normal fundoscopy, urinary albumin, and vibration perception threshold). She presented October 1997 with monophasic tender indurations at the injection sites of both human regular and NPH insulins (Novo Nordisk) in the abdominal and femoral regions, respectively, with occurrence within 2–6 …
Prescription Opioid Duration of Action and the Risk of Unintentional Overdose Among Patients Receiving Opioid Therapy
Authors: Matthew Miller, Catherine W. Barber, Sarah Leatherman, Jennifer Fonda, John A. Hermos, Kelly Cho, David R. Gagnon
Journal: JAMA Internal Medicine (2015)

<h3>Importance</h3> The unprecedented increase in unintentional overdose events that has occurred in tandem with escalating sales of prescription opioids over the past 2 decades has raised concerns about whether the therapeutic use of opioids has contributed to increases in overdose injury. Few controlled studies have examined the extent to which ecologic measures of increases in opioid prescribing and overdose injuries reflect risk among patients prescribed opioids, let alone whether some opioid regimens are safer than others. <h3>Objective</h3> To examine whether the risk of unintentional overdose injury is associated with the duration of opioid action (ie, long-acting vs short-acting formulations). <h3>Design, Setting, and Participants</h3> A propensity score–adjusted cohort study was conducted using population-based health care utilization data from the Veterans Administration Healthcare System. The patients were veterans with chronic painful conditions who began therapy with opioid analgesics between January 1, 2000, and December 31, 2009. <h3>Main Outcomes and Measures</h3> Unintentional overdoses that are explicitly coded using<i>International Classification of Disease, Ninth Revision</i>codes as drug or medication poisonings of accidental intent (E850.x-860.x) or undetermined intent (E980.x or drug poisoning [960.x-980.x] without an accompanying external cause of injury code). <h3>Results</h3> A total of 319 unintentional overdose events were observed. Patients initiating therapy with long-acting opioids were more than twice as likely to overdose compared with persons initiating therapy with short-acting opioids. After adjustment for age, sex, opioid dose, and other clinical characteristics, patients receiving long-acting opioids had a significantly higher rate of overdose injury than did those receiving short-acting opioids (hazard ratio [HR], 2.33; 95% CI, 1.26-4.32). The risk associated with long-acting agents was particularly marked during the first 2 weeks after initiation of treatment (HR, 5.25; 1.88-14.72). <h3>Conclusions and Relevance</h3> To our knowledge, the findings of the present study provide the first evidence that the risk of unintentional overdose injury is related to the prescribed opioid's duration of action. If replicated in other cohorts, our findings suggest that clinicians weighing the benefits and risks of initiating different opioid regimens should consider not only the daily dose prescribed but also the duration of opioid action, favoring short-acting agents whenever possible, especially during the first 2 weeks of therapy.