tbuckley/cabot-search huggingface dataset:
Abstract IA12: Redox pathways as platforms for drug development
Authors: Kenneth D. Tew
Journal: Clinical Cancer Research (2012)

Abstract While oxygen based metabolism is the most evolved and efficient method for producing energy, the generation of reactive oxygen electrophiles creates physiological stress. Sulfur has variable valencies, and as a consequence its nucleophilicity allows it to react with electrophilic species and exist in a variety of oxidation states. Lung cancer cells, in common with most cancers have aberrant redox homeostasis, a property that has provided a platform for drug development for both therapeutic and prevention approaches. There are &amp;gt;200,000 cysteines encoded by the human genome and the most common non-protein form of sulfur in cells is glutathione (GSH). Glutathione S-Transferase P (GSTP) is one member of the family of GST's that contribute to cellular thiol and redox balance. GSTP is characteristically expressed at high levels in some tumors (including lung) and in drug resistant cancer cells. Targeting of GSTP with small molecules has identified a specific inhibitor (Telintra) that has myeloproliferative properties and may be useful in combination drug regimens. There are also a number of preclinical and clinical (e.g. Telcyta) GSTP activated pro-drug candidates that are at various stages of testing. A recently completed Phase III trial in NSCLC used NOV-002 (a glutathione disulfide mimetic) to alter the toxicity profiles of standard anticancer drugs by modulating intra- and extracellular redox balance. Changes in cellular redox homeostasis play an essential role in numerous signaling cascades, including those associated with proliferation, inflammatory responses, apoptosis, and senescence. Moreover, GSTP has been implicated in catalyzing S-glutathionylation (a post-translational modification adding glutathione to cysteine residues) of a number of proteins that fall into functional clusters important to these signaling events. Recent studies suggest that S-glutathionylated proteins may serve as clinical biomarkers of drug response. Finally, many chemoprevention drugs are designed to stimulate the production of protective Phase II detoxification enzyme systems in target normal tissues. Many of these agents are sulfur based and most contain electrophilic centers that show selectivity for the Nrf2 transcription factor and genes that contain antioxidant response elements (ARE). Chronic, low dose exposure to these agents may have short-term prevention potential, but the down sides of long term impact of low levels of electrophilic stress remains to be answered.
Abstract 622: Estrogen plus progesterone and colorectal cancer incidence and mortality in the Women's Health Initiative
Authors: Michael S. Simon, Rowan T. Chlebowski, Jean Wactawski-Wende, Karen C. Johnson, Andrew Muskovitz, Ikuko Kato, Alicia Young, F Allan Hubbell
Journal: Cancer Research (2012)

Abstract Background: During the intervention period in the Women's Health Initiative (WHI) trial, estrogen plus progestin use was associated with lower colorectal cancer incidence but the cancers were diagnosed at substantially higher stage. To assess the long term influence of estrogen plus progestin on this disease, analyses were conducted over the entire follow-up period. Methods: The WHI study is a randomized, double-blind, placebo-controlled, clinical trial involving 16,608 postmenopausal women aged 50-79 years with an intact uterus who were randomly assigned to a once-daily tablet of 0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate (N=8,506) or matching placebo (N=8,102). We assessed incidence, tumor characteristics, and mortality rates for invasive colorectal cancers. Analyses were by intention to treat. The study is registered with clinical trials CT.gov NCT00000611. Findings: After a mean of 5.6 years (SD 1.03) of therapy and 11.6 (SD 3.1) years of total follow-up, 118 women in the combined hormone therapy group were diagnosed with colorectal cancer vs 145 in the placebo group (incidence/year 0.12% vs 0.16%; hazard ratio [HR] 0.72, 95% confidence interval (CI), 0.56-0.94; P=0.014). Bowel screening exams were comparable between groups throughout. Cancers in the combined hormone therapy group more commonly had positive lymph nodes (53.4% vs 30%, P=0.007) and were at higher stage (regional or distant, 68.8% vs 51.4%, P=0.003). Somewhat more women died from colorectal cancer in the combined hormone therapy group (37 vs 27 deaths; 0.04% vs 0.03%; HR 1.29, 95% CI 0.78-2.11, P=0.320). Interpretation: Although estrogen plus progestin use was associated with lower colorectal cancer incidence, the cancers were at more advanced stage and no trend for colorectal cancer mortality reduction emerged. These findings, suggestive of diagnostic delay, do not support a clinically meaningful benefit for combined hormone therapy on colorectal cancer risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 622. doi:1538-7445.AM2012-622
Time to abandon the "tendinitis" myth
Authors: K M Khan
Journal: BMJ (2002)

Tendinitis such as that of the Achilles, lateral elbow, and rotator cuff tendons is a common presentation to family practitioners and various medical specialists.1 Most currently practising general practitioners were taught, and many still believe, that patients who present with overuse tendinitis have a largely inflammatory condition and will benefit from anti-inflammatory medication. Unfortunately this dogma is deeply entrenched. Ten of 11 readily available sports medicine texts specifically recommend non-steroidal anti-inflammatory drugs for treating painful conditions like Achilles and patellar tendinitis despite the lack of a biological rationale or clinical evidence for this approach. 2 3

Instead of adhering to the myths above, physicians should acknowledge that painful overuse tendon conditions have a non-inflammatory pathology. Light …
Photosensitivity to Oxytetracycline
Authors: Theodore A. Tromovitch, Paul H. Jacobs
Journal: Annals of Internal Medicine (1963)

Case Studies1 March 1963Photosensitivity to OxytetracyclineTHEODORE A. TROMOVITCH, PAUL H. JACOBSTHEODORE A. TROMOVITCHSearch for more papers by this author, PAUL H. JACOBSSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-58-3-529 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptPhotosensitivity to oxytetracycline (Terramycin®) is rare. Shwachman and Schuster (1) reported that 3 per cent of 300 children treated with chlortetracycline (Aureomycin®) and oxytetracycline developed photosensitive reactions; however, they do not state how many, if any, were caused by oxytetracycline alone. We are not aware of any well-substantiated cases of oxytetracycline photosensitivity other than that of the patient discussed in this report.CASE REPORTA 20-year-old white male with an atopic diathesis was treated for "flu" with oxytetracycline, 500 mg 4 times a day. After 3 days of therapy he noted redness, swelling, and itching in skin areas exposed to...References1. SHWACHMANSCHUSTER HA: The tetracyclines. Pediat. Clin. N. Amer. 3: 295, 1956. CrossrefGoogle Scholar2. ORENTREICHHARBERTROMOVITCH NLCTA: Photosensitivity and photo-oncholysis due to demethylchlortetracycline. Arch. Derm. (Chicago) 83: 730, 1961. CrossrefMedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Requests for reprints should be addressed to Paul H. Jacobs, M.D., Dermatology Clinic, United States Air Force Hospital, Andrews Air Force Base, Washington 25, D. C. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited ByFinger and toenail onycholysisPersistent Photosensitivity Induced by Ingested DrugsA study of persistent photosensitivity as a sequel of the prior administration of the drug benoxaprofenRetinoid associated phototoxicity and photosensitivityAntimicrobial chemotherapy in the dog.DRUG PHOTOSENSITIZATIONDrug-Induced PhotosensitivityThe Identification of Phototoxic Drugs by Human Assay**From the Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.Suction Blister Device for Separation of Viable Epidermis from Dermis*Complications of tetracycline therapyNewer Antimicrobial Agents Having Current or Potential Clinical Application 1 March 1963Volume 58, Issue 3Page: 529-530KeywordsChildrenInflammationPruritus Issue Published: 1 March 1963 PDF DownloadLoading ...
Haploinsufficiency of AML1 Affects the Temporal and Spatial Generation of Hematopoietic Stem Cells in the Mouse Embryo
Authors: Zhongling Cai, Marella de Bruijn, Xiaoqian Ma, Bjorn Dortland, Tanya Luteijn, James R Downing, Elaine Dzierzak
Journal: Immunity (2000)
Cyclooxygenase-2 Rescues Rat Mesangial Cells from Apoptosis Induced by Adriamycin via Upregulation of Multidrug Resistance Protein 1 (P-Glycoprotein)
Authors: Bradley Miller, Vimal A. Patel, Andrey Sorokin
Journal: Journal of the American Society of Nephrology (2006)

Cyclooxygenase-2 (COX-2) is constitutively expressed in restricted subpopulations of kidney cells, where it presumably acts as an antiapoptotic factor. In conditions that are characterized by inflammation, COX-2 expression also has been described in glomerular mesangial cells (GMC), where COX-2 is not expressed constitutively. It was shown previously that adenovirus-mediated gene transfer of COX-2 into rat GMC led to increased expression and activity of multidrug resistance protein 1 (MDR-1), a membrane transporter that functions as an efflux pump for chemotherapeutic drugs, including Adriamycin (ADR). In ADR nephrotoxicity, a pathologic change in glomeruli could be partially explained by ADR-mediated changes in GMC. Here it is demonstrated that ADR (also known as doxorubicin; 1 microg/ml) induced apoptosis in 15.3 +/- 2.2% of GMC, whereas after adenovirus-mediated COX-2 expression, only 6.6 +/- 0.4% of ADR-treated cells underwent apoptosis. This protective effect was nullified by treatment with NS398, specific COX-2 inhibitor. ADR efflux is greater in COX-2-overexpressing cells, when compared with control, which is attributed to the increased MDR-1 expression. Addition of PSC833, the specific MDR-1 inhibitor, completely abolished the protective effect of COX-2 overexpression and increased the level of apoptosis in GMC that were exposed to ADR. These data suggest that COX-2 protects GMC from ADR-mediated apoptosis via transcriptional upregulation of MDR-1 and that induced COX-2 expression would lessen ADR nephrotoxicity.
Antitumor Alkyl Ether Lipid Edelfosine: Tissue Distribution and Pharmacokinetic Behavior in Healthy and Tumor-Bearing Immunosuppressed Mice
Authors: Ander Estella-Hermoso de Mendoza, Miguel A. Campanero, Janis de la Iglesia-Vicente, Consuelo Gajate, Faustino Mollinedo, María J. Blanco-Prieto
Journal: Clinical Cancer Research (2009)

Abstract Purpose: The present study investigates and compares the dose-dependent pharmacokinetics and oral bioavailability of edelfosine in healthy, immunodeficient, and tumor-bearing immunosuppressed mouse animal models, as well as edelfosine uptake and apoptotic activity in the Z-138 mantle cell lymphoma (MCL) cell line. Experimental design: Biodistribution study of edelfosine was done in both BALB/c and severe combined immune deficiency (SCID) mice, and then the in vivo behavior of the drug after i.v. and oral administration was monitored. Results: We found that edelfosine is incorporated and induces apoptosis in the Z-138 human mantle cell lymphoma cell line, whereas normal resting peripheral blood human lymphocytes were not affected. In vivo biodistribution studies revealed that accumulation of edelfosine in the tumor of a MCL-bearing mouse animal model was considerably higher (P &amp;lt; 0.01) than in the other organs analyzed. Besides, no statistical differences were observed between the pharmacokinetic parameters of BALB/c and SCID mice. Edelfosine presented slow elimination and high distribution to tissues. Bioavailability for a single oral dose of edelfosine was &amp;lt;10%, but a multiple-dose oral administration increased this value up to 64%. Conclusion: Our results show that edelfosine is widely scattered across different organs, but it is preferentially internalized by the tumor both in vitro and in vivo. Our data, together with the apoptotic action of the drug on cancer cells, support a rather selective action of edelfosine in cancer treatment, and that multiple oral administration is required to increase oral bioavailability.
Research on Cystic Fibrosis
Authors: John W. Littlefield
Journal: New England Journal of Medicine (1981)

Geneticists call cystic fibrosis the most common lethal inherited disease of whites. Pediatricians are pleased that affected persons live twice as long as they did a decade ago, and internists now encounter it as a "new" disease. An increasing number of investigators from all backgrounds are fascinated by cystic fibrosis, reporting tantalizing clues about its pathogenesis and diagnosis. Pediatric house officers, however, still find it easier to remain uninvolved in the psychological and social problems that accompany such a chronic, relentless disease. For patients and their parents, cystic fibrosis remains a grim sentence, usually prolonged through an unhappy adolescence to . . .
UK hospitals ordered to cut risk of drugs going wrongly into spinal fluid
Authors: J. Feinmann
Journal: BMJ (2009)

<b>Objective:</b> To determine the efficacy and safety of risdiplam, a centrally and peripherally distributed oral <i>SMN2</i> pre-mRNA splicing modifier, in infants with Type 1 spinal muscular atrophy (SMA) treated for 12 months during the confirmatory Part 2 of the FIREFISH study (NCT02913482). <b>Design/Methods:</b> FIREFISH is an ongoing, multicenter, open-label study of risdiplam in infants aged 1–7 months at enrollment with Type 1 SMA and two copies of the <i>SMN2</i> gene. Part 1 (n=21) assesses the safety, tolerability, pharmacokinetics and pharmacodynamics of different risdiplam dose levels (plus exploratory efficacy outcomes). The primary objective of confirmatory Part 2 (n=41) is to investigate the efficacy of risdiplam at the dose selected in Part 1. The primary efficacy endpoint is the proportion of infants sitting without support for 5 seconds after 12 months on treatment, as assessed by Item 22 of the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development, 3rd edition. Secondary outcomes include the achievement of motor milestones and respiratory endpoints such as time to permanent ventilation and percentage of infants who achieve a reduction of ≥30° in phase angle from baseline at Month 12 (as measured by respiratory plethysmography). <b>Results:</b> The primary endpoint of FIREFISH Part 2 at 12 months was met (data-cut: 14th November 2019). We will report efficacy and safety data, including respiratory outcomes, from the confirmatory Part 2 of the FIREFISH study in participants who have received risdiplam treatment for a minimum of 12 months. <b>Conclusions:</b> FIREFISH Part 2 will provide important data on the efficacy and safety of risdiplam in infants with Type 1 SMA.
Labouring in water:Authors' reply
Authors: Elizabeth R Cluett, Kathryn Getliffe, Ruth M Pickering, Nigel James St George Saunders
Journal: BMJ (2004)

EDITOR—We defined active labour as regular painful contractions associated with full cervical effacement and a dilation of at least 3 cm. This excluded women in latent phase, who are more appropriately managed conservatively. We agree that inclusion of a conservative arm to the trial would have been desirable and …
Roentgen Diagnosis, Vol 1: General Principles and Methods
Authors: Martin W. Donner
Journal: JAMA (1968)

For many years this multivolume textbook has served radiologists all over the world as the most authoritative work on roentgen diagnosis. The sixth edition of "The Schinz" —as many admirers of the late senior editor call his magnificent contribution to radiology—has recently been published and the first volume of the American edition has just become available. Edited by Rigler, the translation into English has been skillfully accomplished, with great care exercised to maintain the authors' original meaning. Completely revised but largely rewritten by some of the most authoritative radiologists in Switzerland, Germany, and Sweden, the new edition conveys the unparalleled development of roentgen diagnosis during the past decade. The present volume comprises chapters discussing the physics of roentgen diagnosis, the application of radiology to other disciplines (eg, crystallography), the methodology of roentgen diagnosis, and its application to various systems. It also includes chapters on the use of contrast media, basic
Targeting of the β2-adrenoceptor increases nonviral gene delivery to pulmonary epithelial cells in vitro and lungs in vivo
Authors: Markus Elfinger, Johannes Geiger, Günther Hasenpusch, Senta Üzgün, Nathalie Sieverling, Manish K. Aneja, Christof Maucksch, Carsten Rudolph
Journal: Journal of Controlled Release (2009)
Imatinib Mesylate Induces Quiescence in Gastrointestinal Stromal Tumor Cells through the CDH1-SKP2-p27Kip1 Signaling Axis
Authors: Ying Liu, Sophie A. Perdreau, Payel Chatterjee, Linan Wang, Shih-Fan Kuan, Anette Duensing
Journal: Cancer Research (2008)

Abstract Gastrointestinal stromal tumors (GIST) are caused by activating mutations in the KIT or platelet-derived growth factor receptor α receptor tyrosine kinase genes. Approximately 85% of GIST patients treated with imatinib mesylate achieve disease stabilization, however, often in the presence of residual tumor masses. Complete remissions are rare and a substantial proportion of patients develop resistance to imatinib. Our study was designed to determine whether imatinib-associated responses may account for these clinical findings. We report here that imatinib stimulates cellular quiescence in a proportion of GIST cells as evidenced by up-regulation of the CDK inhibitor p27Kip1, loss of cyclin A, and reduced BrdUrd incorporation. Mechanistically, these events are associated with an imatinib-induced modulation of the APC/CDH1 signaling axis. Specifically, we provide evidence that imatinib down-regulates SKP2 and that this event is associated with increased nuclear CDH1, an activator of the APC that has been shown to regulate SKP2 stability. We also show that those GIST cells that do not undergo apoptosis in response to imatinib overexpress nuclear p27Kip1, indicating that they have withdrawn from the cell cycle and are quiescent. Lastly, we provide evidence that a fraction of primary GISTs with high SKP2 expression levels may have an increased risk of disease progression. Taken together, our results support a model in which GIST cells that do not respond to imatinib by apoptosis are removed from the proliferative pool by entering quiescence through modulation of the APC/CDH1-SKP2-p27Kip1 signaling axis. These results encourage further studies to explore compounds that modulate this pathway as antitumor agents in GISTs. [Cancer Res 2008;68(21):9015–23]
PHD–2 KNOCKOUT PROMOTES PLAQUE PROGRESSION VIA HIFla AND INCREASES THE EXPRESSION OF MAC–1, PSGL–1 AND VLA–4 ON MONOCYTES AND GRANULOCYTES IN MICE
Authors: Christian Pfluecke, Marian Christoph, Karim Ibrahim, Matthias Mensch, Peggy Barthel, Kristin Franke, Ben Wielockx, Ruth H. Strasser, Carsten Wunderlich, David M. Poitz
Journal: Journal of the American College of Cardiology (2013)
Recent progress in the development of coumarin derivatives as potent anti‐HIV agents
Authors: Donglei Yu, Madoka Suzuki, Lan Xie, Susan L. Morris‐Natschke, Kuo‐Hsiung Lee
Journal: Medicinal Research Reviews (2003)

Abstract Numerous plant‐derived compounds have been evaluated for inhibitory effects against HIV replication, and some coumarins have been found to inhibit different stages in the HIV replication cycle. This review article describes recent progress in the discovery, structure modification, and structure–activity relationship studies of potent anti‐HIV coumarin derivatives. A dicamphanoyl‐khellactone (DCK) analog, which was discovered and developed in our laboratory, and calanolide A are currently in preclinical studies and clinical trials, respectively. © 2003 Wiley Periodicals, Inc. Med Res Rev, 23, No. 3, 322‐345, 2003
Detection of myocardial infarct extension by CK-B radioimmunoassay.
Authors: M Rothkopf, J Boerner, M J Stone, T C Smitherman, L M Buja, R W Parkey, J T Willerson
Journal: Circulation (1979)

Myocardial infarct extension after the acute event was defined as a second reise in the myocardial isoenzyme of serum creatine kinase (CK-B) after the initial return of CK-B to normal values. In 43 patients with acute myocardial infarcts, CK-B was measured by radioimmunoassay every 12 hours for 14 days. Nineteen patients had anterior transmural myocardial infarcts AMI, 14 had inferior transmural myocardial infarcts (IMI) and 10 had subendocardial myocardial infarcts (SEMI). Infarct extension as detectd by a second rise in serum CK-B occurred in six patients (32%) with AMI, two (14%) with IMI and two (20%) with SEMI; these differences are not statistically significant. Infarct extension for all patients combined was 23%. Four patients with AMI also had infarct extension as determined by recurrent chest pain. ECG alterations and other enzyme changes. In the other six, the infarct extension was undetected clinically. Four patients with AMI and infarct extension died within 3 weeks after hospitalization. We did not note any additional morbidity or mortality in patients with infarct extension who had IMI or SEMI. There was no significant difference in the frequency of previous myocardial infarction, history of hypertension, diabetes mellitus or smoking history in patients with and without infarct extension shown by serum CK-B isoenzyme elevations. The measurement of serum CK-B values with a quantitative and sensitive assay suggests that myocardial infarct extension occurs more commonly than clinically recognized, but the frequency of extension may be less than that reported in patients in whom precordial mapping and total serum CK values were measured to identify this phenomenon.
When I use a word: Meta-
Authors: J. Aronson
Journal: BMJ (2002)

Mr John Gleave, a neurosurgeon, has written to ask me the origin of the meta- in meta-analysis. The answer comes from Aristotle. The Greek preposition μ![Graphic][1]</img>![Graphic][2]</img>![Graphic][3]</img>(meta) had several meanings, depending on whether it governed the accusative, genitive, or dative case. With the accusative it could mean coming into or among, in pursuit of, or coming after in place or time; with the genitive it could mean in the midst of, between, or in common with; and with the dative it could mean in the company of or over and above. It was also used as a prefix to express such notions as sharing, being in the midst of, succession, pursuit, reversal, and (most commonly) change. Examples of the last include metabolism, metamorphosis, and metaplasia. In scientific … [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gif
Department of Defense, Health Affairs: An Overview of Its Programs
Authors: John H. Moxley
Journal: New England Journal of Medicine (1980)

Military medicine has traditionally been somewhat remote from the civilian professional community. One of my resolves in accepting the position of Assistant Secretary of Defense for Health Affairs was to involve more civilians in military medicine. My purpose here is to open a dialogue with the readership of the Journal by touching briefly on a series of issues that we in the Department of Defense are facing. I believe that military medicine will benefit from open discussion of these issues.The prime purpose of the Defense Department's medical effort is to provide medical support to combat troops (our "readiness mission"). . . .