tbuckley/cabot-search huggingface dataset:
The Interplay between the Glucocorticoid Receptor and Nuclear Factor-κB or Activator Protein-1: Molecular Mechanisms for Gene Repression
Authors: Karolien De Bosscher, Wim Vanden Berghe, Guy Haegeman
Journal: Endocrine Reviews (2003)

The inflammatory response is a highly regulated physiological process that is critically important for homeostasis. A precise physiological control of inflammation allows a timely reaction to invading pathogens or to other insults without causing overreaction liable to damage the host. The cellular signaling pathways identified as important regulators of inflammation are the signal transduction cascades mediated by the nuclear factor-κB and the activator protein-1, which can both be modulated by glucocorticoids. Their use in the clinic includes treatment of rheumatoid arthritis, asthma, allograft rejection, and allergic skin diseases. Although glucocorticoids have been widely used since the late 1940s, the molecular mechanisms responsible for their antiinflammatory activity are still under investigation. The various molecular pathways proposed so far are discussed in more detail.
Abstract 864: ANG4043: A new brain-penetrant peptide-antibody conjugate that reduces tumor growth in a HER2-positive orthotopic tumor model.
Authors: Jean E. Lachowicz, Michel Demeule, Christian Che, Sasmita Tripathy, Jean-Christophe Currie, Anthony Regina, Tran Nguyen, Simon Lord-Dufour, Jean-Paul Castaigne
Journal: Cancer Research (2013)

Abstract While monoclonal antibodies to receptor tyrosine kinases such as HER2 have been demonstrated to reduce tumor size and increase survival, these agents achieve little to no brain penetration, making them ineffective against metastatic brain tumors. The blood-brain barrier (BBB), which restricts entry of proteins such as mAbs into the brain, is comprised of capillary endothelial cells with tight junctions and efflux pumps. Brain entry of nutrients, hormones, and other required molecules is accomplished by processes such as receptor-mediated transcytosis. As low-density lipoprotein receptor-related protein 1 (LRP1) is known to perform this function in BBB endothelial cells, we have created a family of peptides (Angiopeps) designed for LRP1 recognition. These proprietary Angiopeps can be used to create novel Peptide-Drug Conjugates that successfully cross the BBB by LRP1-mediated transcytosis. Here we describe chemical conjugation of Angiopep-2 (An2) to a mAb against HER2. This Peptide-Antibody Conjugate, ANG 4043, displays HER2 binding affinity and in vitro cytotoxic potency similar to that of native anti-HER2. ANG4043 demonstrates a high rate of entry into the brain, consistent with achieving therapeutic concentrations. The plasma half-life of ANG4043 is similar to that of Anti-HER2 in mouse. Mice with intracranially implanted BT-474 cells showed reduced brain tumor size when dosed with ANG4043 compared to controls. Overall, these data demonstrate that a brain-penetrant Peptide-Antibody Conjugate is efficacious in a mouse HER2-positive tumor model. These results extend the validation of An2 conjugation beyond small molecules and peptides to include larger molecules such as therapeutic mAbs for development of new brain-penetrant antitumor therapeutics. Citation Format: Jean E. Lachowicz, Michel Demeule, Christian Che, Sasmita Tripathy, Jean-Christophe Currie, Anthony Regina, Tran Nguyen, Simon Lord-Dufour, Jean-Paul Castaigne. ANG4043: A new brain-penetrant peptide-antibody conjugate that reduces tumor growth in a HER2-positive orthotopic tumor model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 864. doi:10.1158/1538-7445.AM2013-864
TCTAP A-099 Predictors of Wound Healing in Patients with Critical Limb Ischemia with Tissue Loss Following Successful Endovascular Treatment
Authors: Norihiro Kobayashi, Toshiya Muramatsu, Reiko Tsukahara, Yoshiaki Ito, Hiroshi Ishimori, Keisuke Hirano, Masatsugu Nakano, Masahiro Yamawaki, Motoharu Araki, Tamon Kato, Yuki Inoue, Hideyuki Takimura, Yasunari Sakamoto, Shinsuke Mori, Masakazu Tsutsumi, Hiroya Takafuji, Takahiro Tokuda, Makino Kenji
Journal: Journal of the American College of Cardiology (2014)
Authors' reply to Coyle-Gilchrist and colleagues and Bocti and colleagues
Authors: S. B. d. Gage, B. Begaud, A. Pariente
Journal: BMJ (2012)

Coyle-Gilchrist and colleagues and Bocti and colleagues are directly or indirectly concerned with the possible non-causal nature of the association we found between benzodiazepines and dementia.1 2 3 We emphasise that we never concluded that this association was causal. We designed our study to go further than previously published studies by minimising possible confounding …
No Independent Association of Alanine Aminotransferase With Risk of Future Type 2 Diabetes in the Hoorn Study
Authors: Roger K. Schindhelm, Jacqueline M. Dekker, Giel Nijpels, Robert J. Heine, Michaela Diamant
Journal: Diabetes Care (2005)

We read with great interest the article by Nannipieri et al. (1), which reported no association between aspartate aminotransferase, alanine aminotransferase (ALT), or alkaline phosphatase and the 7-year incidence of impaired glucose tolerance and type 2 diabetes. Interestingly, γ-glutamyltransferase was, but ALT was not, a significant predictor of impaired glucose tolerance or type 2 diabetes. This is, as the authors stated, in contrast to previously published papers that found significant prospective associations of ALT with incident type 2 diabetes after adjustment for obesity, insulin sensitivity, or inflammation (C-reactive protein) (2–4). We studied the …
Transcription factor E3, a major regulator of mast cell–mediated allergic response
Authors: Zohar Yagil, Tal Hadad Erlich, Yifat Ofir-Birin, Sagi Tshori, Gillian Kay, Zanna Yekhtin, David E. Fisher, Chang Cheng, W. S. Fred Wong, Karin Hartmann, Ehud Razin, Hovav Nechushtan
Journal: Journal of Allergy and Clinical Immunology (2012)
Routine Temperature Monitoring During Anesthesia
Authors: Elemer K. Zsigmond
Journal: JAMA (1981)

To the Editor.—  Malignant hyperthermia, or more accurately, acute familial peranesthetic rhabdomyolysis, still causes death and disability because of its delayed recognition. In 1969 we recommended routine temperature monitoring in all patients undergoing anesthesia with triggering agents, namely, all potent inhalational anesthetics and succinylcholine. A survey that I recently conducted showed that only 60% of anesthesiologists use routine temperature monitoring in adults. Frequently the high cost of continuous temperature monitoring is quoted as an excuse for neglecting temperature monitoring. The introduction of liquid crystal thermography has brought down the cost to a negligible level, $1.50 per patient, if a temperature sensor tape is used during anesthesia. In view of the facts that (1) there is a high mortality (35%) despite the recently introduced intravenous dantrolene therapy, that (2) there is an incidence of 1:7,000 to 1:15,000 in the anesthetized population that is not negligible, and that (3) there is a
British government examines drugs white list
Authors: J Warden
Journal: BMJ (1994)

The idea of a national prescribing list for the NHS in Britain, as proposed by the Commons health committee, is to be examined by the Department of Health. The aim is to replace the blacklist of selected drugs that may not be prescribed with a “white list” covering all therapeutic categories. In this way a national formulary would gradually be built up.

Responding to the committee's report on the …
Obstetrical implications of pregnancy in primigravidae aged 16 years or less.
Authors: W. H. Utian
Journal: BMJ (1967)

JOUNAIHassan and Falls (1964) pointed out that the incidence of caesarean section for cephalo-pelvic disproportion tended to rise in the very young patients, and quoted an incidence of 7.6 % in 26 patients.Since the pelvic bones tend to fuse around the time of puberty, there can be little alteration in the pelvic measurements once the menarche has occurred.Moreover, the general standard of nutrition has improved considerably since the war years, and the average height has tended to rise.In the present series most of the patients were scattered about the mean on standard growth charts, while the younger patients were noticeably taller than average.Pre-eclampsia is a definite hazard in this group of patients, the incidence in 103 cases being 20%.Nearly all the cases were quite mild and settled well with bed rest and sedation.There was one case of eclampsia, but no stillbirths or neonatal deaths.These figures are similar to those of Claman and Bell (1964) and Marchetti and Menaker (1950), who reported the incidence of pre-eclampsia at 18 and 19.7% respectively.In the recent British series Stearn (1963) found 8 patients out of 30 in whom the blood pressure rose to 140/90 mm.Hg.Vaginal delivery presented very few difficulties, and 37%/.of patients were delivered within six hours of the onset of labour.This compares with the rate of 130% for the control group.Six of the 11 operative deliveries were by low forceps, and there were four mid-cavity rotations and extractions from posterior positions. SummaryPregnancy and labour have been considered in 103 patients under the age of 16 at the time of conception.The ages ranged from 11 years and 9 months to 15 years and 11 months.There was one multigravid patient.The incidence of pre-eclampsia was considerably increased, but the perinatal mortality rate was 1 % for the whole group.Easy spontaneous vaginal delivery was the rule.The forceps rate was 10%, and the caesarean section rate 4%.Though pregnancy in young patients presents grave socio- logical problems, pregnancy and labour usually proceed without difficulty.The greatest hazard is pre-eclampsia.We should like to thank Miss Doreen Daley and the consultant staff of St. Helier Hospital for allowing us access to case records
Bias in Observational Studies of Treatment
Authors: Dennis H. Osmond
Journal: Annals of Internal Medicine (1996)

Letters1 December 1996Bias in Observational Studies of TreatmentDennis H. Osmond, MD, Edwin Charlebois, MD, and Andrew R. Moss, MDDennis H. Osmond, MDUniversity of California, San Francisco, San Francisco, CA 94341.Search for more papers by this author, Edwin Charlebois, MDUniversity of California, San Francisco, San Francisco, CA 94341.Search for more papers by this author, and Andrew R. Moss, MDUniversity of California, San Francisco, San Francisco, CA 94341.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-125-11-199612010-00024 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:In their recent article, Glesby and Hoover [1] cite our paper on changes in survival among patients with the acquired immunodeficiency syndrome (AIDS) [2] as an analysis subject to selection bias. We agree that this is a potentially important bias, but we were surprised that they ignored our explicit concern about this effect. We noted that “because subjects with rapid CD4 lymphocyte loss were removed from the cohorts by death at a disproportionately high rate during the early years of followup … subjects dying early in follow-up or progressing rapidly had less chance to receive therapy” [2].... References1. Glesby MJ, Hoover DR. Survivor treatment selection bias in observational studies: examples from the AIDS literature. Ann Intern Med. 1996; 124:999-1005. Google Scholar2. Osmond DH, Charlebois E, Lang W, Shiboski S, Moss A. Changes in AIDS survival time in two San Francisco cohorts of homosexual men, 1983 to 1993. JAMA. 1994; 271:1083-7. Google Scholar3. Lang W, Osmond D, Page-Bodkin K, Moss A, Winkelstein W. Population-based estimates of antiretroviral therapy and anti-pneumocystis prophylaxis in San Francisco: 1991. J Acquir Immune Defic Syndr. 1993; 6:191-3. Google Scholar Author, Article, and Disclosure InformationAffiliations: University of California, San Francisco, San Francisco, CA 94341. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 December 1996Volume 125, Issue 11Page: 941KeywordsAIDSAntiretroviral therapyHIVImmunohistochemistryLymphocytesObservational studiesPneumocystis carinii pneumoniaPneumoniaProphylaxisSurvival analysis Issue Published: 1 December 1996 Copyright & PermissionsCopyright © 1996 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Engineered Enteroendocrine Cells Secrete Insulin in Response to Glucose and Reverse Hyperglycemia in Diabetic Mice
Authors: Jaeseok Han, Hyune-Hwan Lee, Hyokjoon Kwon, Seungjin Shin, Ji-Won Yoon, Hee-Sook Jun
Journal: Molecular Therapy (2007)

Type 1 diabetes is a metabolic disorder caused by loss of insulin-producing pancreatic β-cells. Expression of insulin in non-β-cells to create β-cell surrogates has been tried to treat type 1 diabetes. Enteroendocrine K cells have characteristics similar to pancreatic β-cells, such as a glucose-sensing system and insulin-processing proteases. In this study, we genetically engineered an enteroendocrine cell line (STC-1) to express insulin under the control of the glucose-dependent insulinotropic polypeptide promoter. We screened clones and chose one, Gi-INS-7, based on its high production of insulin. Gi-INS-7 cells expressed glucose transporter 2 (GLUT2) and glucokinase (GK) and secreted insulin in response to elevated glucose levels in vitro. To determine whether Gi-INS-7 cells can control blood glucose levels in diabetic mice, we transplanted these cells under the kidney capsule of streptozotocin (STZ)-induced diabetic mice and found that blood glucose levels became normal within 2 weeks of transplantation. In addition, glucose tolerance tests in mice that became normoglycemic after transplantation with Gi-INS-7 cells showed that exogenous glucose was cleared appropriately. These results suggest that engineered K cells may be promising surrogate β-cells for possible therapeutic use for the treatment of type 1 diabetes. Type 1 diabetes is a metabolic disorder caused by loss of insulin-producing pancreatic β-cells. Expression of insulin in non-β-cells to create β-cell surrogates has been tried to treat type 1 diabetes. Enteroendocrine K cells have characteristics similar to pancreatic β-cells, such as a glucose-sensing system and insulin-processing proteases. In this study, we genetically engineered an enteroendocrine cell line (STC-1) to express insulin under the control of the glucose-dependent insulinotropic polypeptide promoter. We screened clones and chose one, Gi-INS-7, based on its high production of insulin. Gi-INS-7 cells expressed glucose transporter 2 (GLUT2) and glucokinase (GK) and secreted insulin in response to elevated glucose levels in vitro. To determine whether Gi-INS-7 cells can control blood glucose levels in diabetic mice, we transplanted these cells under the kidney capsule of streptozotocin (STZ)-induced diabetic mice and found that blood glucose levels became normal within 2 weeks of transplantation. In addition, glucose tolerance tests in mice that became normoglycemic after transplantation with Gi-INS-7 cells showed that exogenous glucose was cleared appropriately. These results suggest that engineered K cells may be promising surrogate β-cells for possible therapeutic use for the treatment of type 1 diabetes.
Brodalumab, an Anti-IL17RA Monoclonal Antibody, in Psoriatic Arthritis
Authors: Philip J. Mease, Mark C. Genovese, Maria W. Greenwald, Christopher T. Ritchlin, André D. Beaulieu, Atul Deodhar, Richard Newmark, JingYuan Feng, Ngozi Erondu, Ajay Nirula
Journal: New England Journal of Medicine (2014)

We assessed the efficacy and safety of brodalumab, a human monoclonal antibody against interleukin-17 receptor A (IL17RA), in a phase 2, randomized, double-blind, placebo-controlled study involving patients with psoriatic arthritis.We randomly assigned patients with active psoriatic arthritis to receive brodalumab (140 or 280 mg subcutaneously) or placebo on day 1 and at weeks 1, 2, 4, 6, 8, and 10. At week 12, patients who had not discontinued their participation in the study were offered open-label brodalumab (280 mg) every 2 weeks. The primary end point was 20% improvement in American College of Rheumatology response criteria (ACR 20) at week 12.Of the 168 patients who underwent randomization (57 in the brodalumab 140-mg group, 56 in the brodalumab 280-mg group, and 55 in the placebo group), 159 completed the double-blind phase and 134 completed 40 weeks of the open-label extension. At week 12, the brodalumab 140-mg and 280-mg groups had higher rates of ACR 20 than the placebo group (37% [P=0.03] and 39% [P=0.02], respectively, vs. 18%); they also had higher rates of 50% improvement (ACR 50) (14% [P=0.05] and 14% [P=0.05] vs. 4%). Rates of 70% improvement were not significantly higher in the brodalumab groups. Similar degrees of improvement were noted among patients who had received previous biologic therapy and those who had not received such therapy. At week 24, ACR 20 response rates in the brodalumab 140-mg and 280-mg groups were 51% and 64%, respectively, as compared with 44% among patients who switched from placebo to open-label brodalumab; responses were sustained through week 52. At week 12, serious adverse events had occurred in 3% of patients in the brodalumab groups and in 2% of those in the placebo group.Brodalumab significantly improved response rates among patients with psoriatic arthritis. Larger studies of longer duration are necessary to assess adverse events. (Funded by Amgen; ClinicalTrials.gov number, NCT01516957 .).
Clostridial Spontaneous Peritonitis
Authors: Robert L. Brown
Journal: JAMA (1976)

THE SYNDROME of spontaneous peritonitis and bacteremia is a welldocumented complication in cirrhotic patients with ascites.<sup>1</sup><i>Escherichia coli</i>, other enteric Gram-negative rods, and<i>Streptococcus pneumoniae</i>account for most reported cases, while anaerobic bacteria are rare.<sup>1,2</sup>Clostridia bacteremia has been noted in chronic alcoholics,<sup>3</sup>but, to our knowledge, has not been previously associated with spontaneous peritonitis. <h3>Report of a Case</h3> A 54-year-old chronically alcoholic woman with biopsy-proved Laënnec cirrhosis, ascites, and esophageal varices demonstrated by prior esophagoscopy was admitted to the Rhode Island Hospital with hematemesis and melena of two days' duration. She did not have any other abdominal symptoms, fever, or chills. Significant past history included insulin-dependent diabetes mellitus. The patient was alert, in no acute distress, pale, and had a temperature of 38.8 C. The abdomen was distended with obvious ascites, but was nontender. Laboratory values included the following: hemoglobin, 6.7 gm/100 ml; leukocyte count, 13,400
AN EVALUATION OF POTASSIUM IODIDE AS A THERAPEUTIC AGENT IN THE TREATMENT OF EXPERIMENTAL HYPER-CHOLESTEREMIA AND ATHEROSCLEROSIS 1
Authors: Meyer Friedman, Richard Homer, Sanford O. Byers, Clarence Omoto, Warren Hayashi
Journal: Journal of Clinical Investigation (1956)

Absorption of CholesterolMethods A. Rats: A series of male Long-Evans rats (average weight: 235 to 251 grams) previously starved for 24 hours was given 25 mg. of cholesterol in 1.0 ml. of olive oil by stomach tube and then divided into four groups.Group I (17 rats) which served as a control received only the 25 mg. of cholesterol.Group II (9 rats) re- ceived in addition 25 mg. of KI with the cholesterol.Group III (8 rats) received 100 mg. of KI in addition to the cholesterol.Group IV (7 rats) received 200 mg. of KI plus the cholesterol.All of the animals then were
Somatostatin Receptor Scintigraphy in a Patient With Polycystic Disease and Highly Increased Tumor Markers
Authors: John T. Koutsikos, George Papathanassiou, Helen Fotinaki, Panagiota Tziannakopoulou, Alkis Katsoulis, Cherry Zerva, Anastasia Leondi
Journal: Clinical Nuclear Medicine (2007)

A 61-year-old man with end-stage renal failure resulting from polycystic disease (hepatic and renal) who was on hemodialysis was investigated because of the development of ascites. During the previous 2 months, he had extremely high levels of carbohydrate antigen (CA) 19-9 (4951.1 U/mL [normal range, 0–37 U/mL]) and CA 50 (4365.6 U/mL [normal range, 0–25 U/mL]). Ultrasound, CT, and MRI, as well as endoscopy, were negative for tumor. He was referred to our Nuclear Medicine Department to be investigated for a possible neuroendocrine pancreatic tumor by In-111 pentetreotide scintigraphy. An upward displacement of the diaphragm into the thorax was noted such that the spleen appeared in the left lower lung field and the liver at the site of the right lower lung field. These topographic changes were explained by the ascites.
Methods for and approaches to evaluating susceptibility of ecological systems to hazardous chemicals.
Authors: J Burger
Journal: Environmental Health Perspectives (1997)

Differences in genetic susceptibility to hazardous chemicals affect individuals of both human and nonhuman populations. In both cases, differences in response to chemicals or general ill health result as a function of these differences in genetic susceptibility. However, ecological systems are a compilation of hundreds or even thousands of different species, resulting in structural and functional characteristics that are themselves affected by differences in susceptibility. Although individual and population differences in susceptibility to hazardous chemicals underlie effects at the community and the ecosystem level, they do not account for all differences. I propose a two-tiered approach to evaluating susceptibility to ecological systems: a general susceptibility as a function of ecosystem type (based on structure and function of that system) and a differential in susceptibility within broad ecosystem types as a function of biotic and abiotic factors. In terrestrial ecosystems, the two factors that most affect overall susceptibility are species diversity and hydrology; evaluation of the effects of hazardous chemicals involves measuring species diversity and water movement. This same methodological approach can be applied to aquatic ecosystems and to highly altered ecosystems such as agriculture, forestry, fisheries, and urbanization.
Genomic and Functional Analysis of the E3 Ligase PARK2 in Glioma
Authors: De-Chen Lin, Liang Xu, Ye Chen, Haiyan Yan, Masaharu Hazawa, Ngan Doan, Jonathan W. Said, Ling-Wen Ding, Li-Zhen Liu, Henry Yang, Shizhu Yu, Michael Kahn, Dong Yin, H. Phillip Koeffler
Journal: Cancer Research (2015)

PARK2 (PARKIN) is an E3 ubiquitin ligase whose dysfunction has been associated with the progression of Parkinsonism and human malignancies, and its role in cancer remains to be explored. In this study, we report that PARK2 is frequently deleted and underexpressed in human glioma, and low PARK2 expression is associated with poor survival. Restoration of PARK2 significantly inhibited glioma cell growth both in vitro and in vivo, whereas depletion of PARK2 promoted cell proliferation. PARK2 attenuated both Wnt- and EGF-stimulated pathways through downregulating the intracellular level of β-catenin and EGFR. Notably, PARK2 physically interacted with both β-catenin and EGFR. We further found that PARK2 promoted the ubiquitination of these two proteins in an E3 ligase activity-dependent manner. Finally, inspired by these newly identified tumor-suppressive functions of PARK2, we tested and proved that combination of small-molecule inhibitors targeting both Wnt-β-catenin and EGFR-AKT pathways synergistically impaired glioma cell viability. Together, our findings uncover novel cancer-associated functions of PARK2 and provide a potential therapeutic approach to treat glioma.