tbuckley/cabot-search huggingface dataset:
Protein Kinase C ε Is an Endogenous Photosensitizer That Enhances Ultraviolet Radiation-Induced Cutaneous Damage and Development of Squamous Cell Carcinomas1
Authors: Deric L. Wheeler, Kaitlin E. Martin, Kristin J. Ness, Yafan Li, Nancy E. Dreckschmidt, Marybeth Wartman, Honnavara N. Ananthaswamy, David L. Mitchell, Ajit K. Verma
Journal: Cancer Research (2004)

Abstract Chronic exposure to UV radiation (UVR), especially in the UVA (315–400 nm) and UVB (280–315 nm) spectrum of sunlight, is the major risk factor for the development of nonmelanoma skin cancer. UVR is a complete carcinogen, which both initiates and promotes carcinogenesis. We found that protein kinase C ε (PKCε), a member of the phospholipid-dependent threonine/serine kinase family, is an endogenous photosensitizer, the overexpression of which in the epidermis increases the susceptibility of mice to UVR-induced cutaneous damage and development of squamous cell carcinoma. The PKCε transgenic mouse (FVB/N) lines 224 and 215 overexpressed 8- and 18-fold PKCε protein, respectively, over endogenous levels in basal epidermal cells. UVR exposure (1 kJ/m2 three times weekly) induced irreparable skin damage in high PKCε-overexpressing mouse line 215. However, the PKCε transgenic mouse line 224, when exposed to UVR (2 kJ/m2 three times weekly), exhibited minimum cutaneous damage but increased squamous cell carcinoma multiplicity by 3-fold and decreased tumor latency by 12 weeks. UVR exposure of PKCε transgenic mice compared with wild-type littermates (1) elevated the levels of neither cyclobutane pyrimidine dimer nor pyrimidine (6-4) pyrimidone dimer, (2) reduced the appearance of sunburn cells, (3) induced extensive hyperplasia and increased the levels of mouse skin tumor promoter marker ornithine decarboxylase, and (4) elevated the levels of tumor necrosis factor α (TNFα) and other growth stimulatory cytokines, granulocyte colony–stimulating factor, and granulocyte macrophage colony–stimulating factor. The role of TNFα in UVR-induced cutaneous damage was evaluated using PKCε transgenic mice deficient in TNFα. UVR treatment three times weekly for 13 weeks at 2 kJ/m2 induced severe cutaneous damage in PKCε transgenic mice (line 215), which was partially prevented in PKCε-transgenic TNFα-knockout mice. Taken together, the results indicate that PKCε signals UVR-induced TNFα release that is linked, at least in part, to the photosensitivity of PKCε transgenic mice.
Metabolic Dependencies in <i>RAS</i>-Driven Cancers
Authors: Alec C. Kimmelman
Journal: Clinical Cancer Research (2015)

Abstract The ability to inhibit the RAS oncogene has been the holy grail of oncology because of the critical role of this gene in a multitude of tumor types. In addition, RAS-mutant tumors are among the most aggressive and refractory to treatment. Although directly targeting the RAS oncogene has proven challenging, an alternative approach for treating RAS-driven cancers is to inhibit critical downstream events that are required for tumor maintenance. Indeed, much focus has been put on inhibiting signaling cascades downstream of RAS. Recent studies have shown that oncogenic RAS promotes a metabolic reprogramming of tumor cells, shifting them toward an anabolic metabolism necessary to produce biomass to support unconstrained proliferation. These cancers also use a diverse set of fuel sources to meet their metabolic needs and have even developed a variety of mechanisms to act as metabolic scavengers to obtain necessary metabolic substrates from both extracellular and intracellular sources. Collectively, these adaptations can create “metabolic bottlenecks” whereby tumor cells rely on particular pathways or rate-limiting metabolites. In this regard, inhibiting individual or combinations of these metabolic pathways can attenuate growth in preclinical models. Because these dependencies are tumor selective and downstream of oncogenic RAS, there is the opportunity for therapeutic intervention. Although targeting tumor metabolism is still in the early days of translation to patients, our continued advances in understanding critical metabolic adaptations in RAS-driven cancers, as well as the ability to study this altered metabolism in relevant tumor models, will accelerate the development of new therapeutic approaches. Clin Cancer Res; 21(8); 1828–34. ©2015 AACR. See all articles in this CCR Focus section, “Targeting RAS-Driven Cancers.”
Multiple Pathways for the Initiation of T Helper 2 (Th2) Responses
Authors: Robert L. Coffman, Thierry Weid
Journal: The Journal of Experimental Medicine (1997)

Since the initial descriptions of CD4+ T cell subsets with distinct functions and cytokine production profiles, the question of how these cells originate during an immune response has been asked. Both Th1 and Th2 cells can develop from naive, peripheral CD4+ T cell (Thp) populations, and individual
On the origin and prevention of PAIDS (Paralyzed Academic Investigator's Disease Syndrome).
Authors: J L Goldstein
Journal: Journal of Clinical Investigation (1986)

In my Presidential address, I will depart from the traditional philosophical discourse.Instead, I will take this occasion to de- scribe a newly recognized clinical syndrome.This devastating disease afflicts our brightest and most promising physician-scientists, crippling them just when they should be maturing into major investigators.The syndrome is called PAIDS-Paralyzed Academic Investigator's Disease Syndrome.The recognition of PAIDS, with its characteristic signs and symptoms, has come about as a result of my five years of service on the Council of this Society.Members ofthe ASCI Council have two duties-one pleasant and the other not so pleasant.The pleasant duty is to attend this meeting and to hear reports of exciting research with im- plications far beyond the boundaries ofmedicine.The Council's less pleasant duty is to review each year the careers of250 clinical investigators who have been nominated for membership.Se- lecting 80 members from this pool is difficult and often unsettling-for the Council as well as for the candidate.Having one's career reviewed by the ASCI Council is like having a mid-career checkup-only the sigmoidoscopy is omitted.Each candidate is examined in intimate detail.The following questions are always asked. 1) Is the science original or derivative? 2) Is the work designed to elucidate mechanisms or is it merely descriptive? 3)How independent is the investigator? 4)Is the candidate a com- mitted scientist actively seeking new knowledge or is he or she writing papers simply to enhance an academic position?As a member of the Council for five years, I have examined the credentials ofmore than 1,000 physician-scientists who have come up for their mid-career checkups.Some of the candidates are exciting investigators of the type you've heard today.They are the "shoo-ins" for the Society.But there is another type of nominee who is much more troubling and all too common.These physicians are afflicted with PAIDS.Let me present a typical case report.Case report-J.R. J.R. is a 41-yr-old male who received his M.D. degree in 1970 with honors from a medical school in the Southwest.He was introduced to research during the summer of his first year in medical school when he worked in an immunology laboratory.J.R. was a scholastic success.He even authored several scientific
Predicting Relapse in Favorable Histology Wilms Tumor Using Gene Expression Analysis: A Report from the Renal Tumor Committee of the Children's Oncology Group
Authors: Chiang-Ching Huang, Samantha Gadd, Norman Breslow, Colleen Cutcliffe, Simone T. Sredni, Irene B. Helenowski, Jeffrey S. Dome, Paul E. Grundy, Daniel M. Green, Michael K. Fritsch, Elizabeth J. Perlman
Journal: Clinical Cancer Research (2009)

The past two decades has seen significant improvement in the overall survival of patients with favorable histology Wilms tumor (FHWT); however, this progress has reached a plateau. Further improvements may rely on the ability to better stratify patients by risk of relapse. This study determines the feasibility and potential clinical utility of classifiers of relapse based on global gene expression analysis.Two hundred fifty FHWT of all stages enriched for relapses treated on National Wilms Tumor Study-5 passed quality variables and were suitable for analysis using oligonucleotide arrays. Relapse risk stratification used support vector machine; 2- and 10-fold cross-validations were applied.The number of genes associated with relapse was less than that predicted by chance alone for 106 patients (32 relapses) with stages I and II FHWT treated with chemotherapy, and no further analyses were done. This number was greater than expected by chance for 76 local stage III patients. Cross-validation including an additional 68 local stage III patients (total 144 patients, 53 relapses) showed that classifiers for relapse composed of 50 genes were associated with a median sensitivity of 47% and specificity of 70%.This study shows the feasibility and modest accuracy of stratifying local stage III FHWT using a classifier of <50 genes. Validation using an independent patient population is needed. Analysis of genes differentially expressed in relapse patients revealed apoptosis, Wnt signaling, insulin-like growth factor pathway, and epigenetic modification to be mechanisms important in relapse. Potential therapeutic targets include FRAP/MTOR and CD40.
Simple blood tests as noninvasive markers of liver fibrosis in hemodialysis patients with chronic hepatitis C virus infection
Authors: Leonardo L. Schiavon, Janaína L. N. Schiavon, Roberto J. Carvalho Filho, Juliana P. Sampaio, Valéria P. Lanzoni, Antonio Eduardo B. Silva, Maria Lucia G. Ferraz
Journal: Hepatology (2007)

HCV infection is common among patients with end-stage renal disease (ESRD) on hemodialysis, and it has been considered an independent risk factor for mortality in this setting. Although liver biopsy in ESRD patients with HCV infection is useful before kidney transplantation, it carries a high risk of complications. We sought to assess the diagnostic value of noninvasive markers to stage liver fibrosis in 203 ESRD HCV-infected patients. Univariate and multivariate analysis were used to identify variables associated with significant fibrosis (METAVIR F2, F3, or F4 stages). Significant liver fibrosis was observed in 48 patients (24%). Logistic regression analysis identified AST and platelet count as independent predictors of significant fibrosis (P < 0.001 and P = 0.001, respectively). The area under the receiver operating characteristic curve of the AST to platelet ratio index (APRI) for predicting significant fibrosis was 0.801. An APRI < 0.40 accurately identified patients with fibrosis stage 0 or 1 in 93% of the cases (NPV = 93%), and all misclassified subjects were F2. A cutoff ≥ 0.95 to confirm significant fibrosis had a PPV of 66%. If biopsy indication was restricted to APRI scores in the intermediate range (≥0.40 and < 0.95), 52% of liver biopsies could have been correctly avoided. Conclusion: Stage of liver fibrosis can be reliably predicted in ESRD HCV-infected subjects by simple and widely available blood tests such as AST levels and platelet count. These tests might obviate the requirement for a liver biopsy in a significant proportion of those patients. (HEPATOLOGY 2007.)
Force-Frequency Relationship
Authors: PAGE A. W. ANDERSON, ANDRES MANRING, EDWARD A. JOHNSON
Journal: Circulation Research (1973)

The way that contractility varies between beats--the force-frequency relationship--was determined for rabbit papillary muscles held at different lengths. When the maximum rate of rise of tension in a contraction, F max , was used as a measure of contractility, the way contractility changed between contractions was independent of length. That is, when the values of F max obtained at one length were multiplied by an appropriate scaling factor, the force-frequency relationship determined at that length was indistinguishable from the force-frequency relationship determined at another length. If, however, the peak tension in a contraction was used as a measure of contractility, the Force-frequency relationship generally was not independent of muscle length. Therefore, it is proposed that the ratio of two values of F max obtained by perturbing the rate of stimulation at any given length should be tried as a length independent index of the inotropic state of the muscle.
N-3 Fatty Acids Inhibit Vascular Calcification Via the p38-Mitogen-Activated Protein Kinase and Peroxisome Proliferator-Activated Receptor-γ Pathways
Authors: M. Abedin, J. Lim, T.B. Tang, D. Park, L.L. Demer, Y. Tintut
Journal: Circulation Research (2006)

Fish oil supplementation is associated with lower risk of coronary artery disease in humans, and it has been shown to reduce ectopic calcification in an animal model. However, whether N-3 fatty acids, active ingredients of fish oil, have direct effects on calcification of vascular cells is not clear. In this report, we investigated the effects of eicosapentaenoic acid and docosahexaenoic acid (DHA) on osteoblastic differentiation and mineralization of calcifying vascular cells (CVCs), a subpopulation of bovine aortic medial cells that undergo osteoblastic differentiation and form calcified matrix in vitro. Results showed that N-3 fatty acids inhibited alkaline phosphatase (ALP) activity and mineralization of vascular cells, suggesting that they directly affect osteoblastic differentiation in vascular cells. By Western blot analysis, DHA activated p38-mitogen-activated protein kinase (MAPK) but not extracellular-regulated kinase (ERK) or Akt. An inhibitor of p38-MAPK partially reversed the inhibitory effects of DHA on osteoblastic differentiation and mineralization. Transient transfection experiments showed that DHA also activated peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Both p38-MAPK activator and PPAR-gamma agonists reproduced the inhibitory effects of DHA on CVC mineralization. Pretreatment with DHA also inhibited interleukin-6-induced ALP activity and mineralization. Together, these results suggest that N-3 fatty acids directly inhibit vascular calcification, and that the inhibitory effects are mediated by the p38-MAPK and PPAR-gamma pathways.
Isoniazid, Meperidine, and Hypotension
Authors: RICHARD GANNON
Journal: Annals of Internal Medicine (1983)

Letters and Corrections1 September 1983Isoniazid, Meperidine, and HypotensionRICHARD GANNON, PHARM. D., WENDY PEARSALL, R.N., RICHARD ROWLEY, M.D.RICHARD GANNON, PHARM. D.Search for more papers by this author, WENDY PEARSALL, R.N.Search for more papers by this author, RICHARD ROWLEY, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-99-3-415_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: It has been postulated that there may be an interaction between meperidine and isoniazid (1). The theoretical basis of this interaction relates to inhibition of monoamine oxidase by isoniazid (2). The interaction between traditional inhibitors of monoamine oxidase and meperidine is well described. There is an immediate effect manifest by either excitation, diaphoresis, rigidity, and hypertension, or hypotension and central nervous system depression (3). We report an interaction where concurrent isoniazid and meperidine produced these effects.A 54-year-old white man weighing 60 kg was admitted to the hospital with spiking temperatures (up to 40.5°C) and new bilateral...References1. HANSTEN P. Drug Interactions. 4th ed. Philadelphia: Lea & Febiger; 1979:148. Google Scholar2. ROBINSONLOVENBERGKEISERSJOERDSMA DWHA. Effects of drugs on human blood platelet and plasma amine oxidase activity in vitro and in vivo. Biochem Pharmacol. 1968;17:109-19. CrossrefMedlineGoogle Scholar3. EVANS-PROSSER C. The use of pethidine and morphine in the presence of monoamine oxidase inhibitors. Br J Anaesth. 1968;40:279-82. CrossrefMedlineGoogle Scholar4. HAUSERBAIER MH. Interaction of isoniazid with foods. Drug Intell Clin Pharm. 1982;16:617-8. CrossrefMedlineGoogle Scholar5. MORGAN J. Isoniazid and levodopa [Letter]. Ann Intern Med. 1980;92:434. LinkGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Yale University-New Haven Hospital New Haven, CT 06504 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited ByIsoniazid and Related HydrazinesIsoniazid and Related HydrazinesOpioids and OpiatesIsoniazidOpioids and OpiatesDRUG–DRUG INTERACTIONS IN PEDIATRIC PSYCHOPHARMACOLOGY 1 September 1983Volume 99, Issue 3Page: 415-415KeywordsCentral nervous systemHypertensionHypotensionIsoniazidTemperature Issue Published: 1 September 1983 PDF DownloadLoading ...
Premedication, Preparation, and Surveillance
Authors: G. D. Bell
Journal: Endoscopy (2002)

The vigorous debate over whom to sedate, when to sedate, and how to sedate shows no sign of running out of steam. There is a general consensus that patients should be more involved in the decision-making process for the sedation "menu". A move away from the take-it-or-leave-it attitude of all or nothing to an "à la carte" choice is to be encouraged. A new textbook and several further guidelines have appeared. The particular problems associated with sedating the elderly are briefly presented. The pros and cons of using local pharyngeal anaesthesia are discussed. Enthusiasm for the use of intravenous propofol is gathering momentum, despite continuing worries about its safety in the hands of the nonanaesthetist. For many endoscopists, the combination of a benzodiazepine plus (or minus) an opioid with which they are most familiar is still the best compromise in terms of efficacy, cost, and safety. Fatal drug-induced cardiopulmonary complications continue to occur, despite a general trend toward using smaller doses of sedation than we did 5 - 10 years ago. Monitoring techniques that are at present considered as research tools may one day become commonplace. These include: the use of an electroencephalography parameter known as bispectral analysis; transcutaneous CO2 measurement; and a modified continuous capnographic waveform trace to monitor ventilatory effort. Bispectral analysis may be of use in monitoring central nervous system depression and helping to distinguish between conscious sedation and deep sedation. If the measurement of CO2 levels, either transcutaneously or in breath samples, was as easy and inexpensive as measuring SpO2 with a pulse oximeter, then undoubtedly such technology would enhance the early detection of sedative-induced hypoventilation and apnoea. Further evidence regarding droperidol's possible role in conscious sedation is presented. Pain during colonoscopy remains a problem, and the possible role for intraluminal injection of peppermint oil, as well as the value of variable-stiffness colonoscopes, in reducing the need for intravenous sedation is discussed. Case reports of hyponatraemic encephalopathy and hypocalcaemic tetany as complications of oral bowel preparation are presented, as is the challenge associated with adequate bowel preparation in diabetic patients.
1168 BL-8030: A NOVEL, POTENT, SELECTIVE, ORALLY AVAILABLE INHIBITOR OF HEPATITIS C VIRUS NS3/4A PROTEASE
Authors: P. Halfon, J. Courcambeck, T. Whitaker, P.M. Tharnish, T.R. McBrayer, S.J. Coats, Y. Pereg, R. Tabakman, J. Schumann, M. Matto, R.F. Schinazi
Journal: Journal of Hepatology (2013)
Daclizumab in vitro inhibits the secretion of pro-asthmatic and pro-inflammatory cytokines by activated T cells
Authors: T.R. Sornasse, W. Hong, R. Schreck, Y. Zhang, J. Sheridan, J. Shi, J. Woo, T. Tsao, V. Vexler
Journal: Journal of Allergy and Clinical Immunology (2005)
miR-181d: a predictive glioblastoma biomarker that downregulates MGMT expression
Authors: W. Zhang, J. Zhang, K. Hoadley, D. Kushwaha, V. Ramakrishnan, S. Li, C. Kang, Y. You, C. Jiang, S. W. Song, T. Jiang, C. C. Chen
Journal: Neuro-Oncology (2012)

Genome-wide microRNA (miRNA) profiling of 82 glioblastomas demonstrated that miR-181d was inversely associated with patient overall survival after correcting for age, Karnofsky performance status, extent of resection, and temozolomide (TMZ) treatment. This association was validated using the Cancer Genome Atlas (TCGA) dataset (n= 424) and an independent cohort (n= 35). In these independent cohorts, an association of miR-181d with survival was evident in patients who underwent TMZ treatment but was not observed in patients without TMZ therapy. Bioinformatic analysis of potential genes regulated by miR-181d revealed methyl-guanine-methyl-transferase (MGMT) as a downstream target. Indeed, transfection of miR-181d downregulated MGMT mRNA and protein expression. Furthermore, luciferase reporter assays and coprecipitation studies showed a direct interaction between miR-181d and MGMT 3′UTR. The suppressive effect of miR-181d on MGMT expression was rescued by the introduction of an MGMT cDNA. Finally, MGMT expression inversely correlated with miR-181d expression in independent glioblastoma cohorts. Together, these results suggest that miR-181d is a predictive biomarker for TMZ response and that its role is mediated, in part, by posttranscriptional regulation of MGMT.
Smoking affects collagen synthesis and extracellular matrix turnover in human skin
Authors: A. Knuutinen, N. Kokkonen, J. Risteli, K. Vahakangas, M. Kallioinen, T. Salo, T. Sorsa, A. Oikarinen
Journal: British Journal of Dermatology (2002)

Summary Background Smoking is associated with premature facial wrinkling and aberrant wound healing, but the underlying mechanisms of skin injury are poorly understood. Objectives To compare the in vivo collagen synthesis and degradation in the skin of smokers and non‐smokers. Methods The study population consisted of 47 current smokers and 51 individuals who had never smoked from northern Finland. Suction blisters were induced in the sun‐protected upper inner arm of the study subjects, after which suction blister fluid (SBF) was collected for analyses of the levels of aminoterminal procollagen propeptides of type I and III collagens (PINP and PIIINP, respectively), matrix metalloproteinase (MMP)‐8 and tissue inhibitor of MMP (TIMP)‐1. PINP, PIIINP and TIMP‐1 were also determined from serum samples. The levels of active and pro MMP‐1 were assessed from deep‐frozen skin biopsies by Western blotting. Results The synthesis rates of type I and III collagens were lower by 18% and 22%, respectively, in the SBF of the smokers compared with the non‐smokers. The levels of MMP‐8 were higher by 100% in the SBF of the smokers. The levels of MMP‐1 in the skin biopsies did not differ significantly between the groups. The levels of TIMP‐1 in SBF were 14% lower in the smokers than in the non‐smokers, whereas the serum concentrations of TIMP‐1 did not differ between the groups. Conclusions Smoking decreases the synthesis rates of type I and III collagens in skin in vivo and alters the balance of extracellular matrix turnover in skin.