tbuckley/cabot-search huggingface dataset:
A Phase 1 Study To Assess the Safety, Tolerability and Pharmacokinetics of ARRY-380 – An Oral Inhibitor of HER2.
Authors: S. Chia, T. Baetz, S. D'Aloisio, G. Fernetich, B. Freeman, E. Barrett, C. Kass, J. Kang, B. Sajan, S. Moulder, J. Garrus
Journal: Cancer Research (2009)

Abstract Background: ARRY-380 is a potent, orally active small molecule that selectively inhibits HER2 signaling in vitro and in vivo and significantly inhibits tumor growth in a variety of HER2-dependent tumor xenograft models. Based on its preclinical activity, tolerability and pharmacokinetic (PK) profile, a Phase 1 study was initiated to evaluate the safety, tolerability and PK profile of ARRY-380 as a single agent in patients with solid tumors and to establish the maximum tolerated dose (MTD).Methods: Patients with HER2 positive breast cancer or other tumor types for which published evidence of HER2 expression exists were treated with ARRY-380 as a single oral dose on Cycle 1 Day 1, followed by continuous twice-daily (BID) oral dosing starting on Cycle 1 Day 3. ARRY-380 was escalated in cohorts of 3 to 4 patients, using standard dose-limiting toxicity (DLT) criteria during Cycle 1 to determine dose escalation. Serial PK assessments were made during Cycle 1 on Days 1, 2, 3 and at steady-state on Day 15.Preliminary Results: As of June 1, 2009, 15 patients have been treated in 5 dosing cohorts at doses of 25 to 300 mg BID. Patients had a median age of 61 years (range, 37-77 years) and ECOG PS of 0 to 2. Cancer types included HER2+ breast cancer (8), colorectal (6) and salivary gland (1). No DLTs have been observed and drug-related adverse events have included Grade 1 nausea, rash and fatigue and Grade 2 fatigue in 2 patients at the 200 mg BID dose level. Preliminary PK analyses indicate a trend for increasing Cmax and AUC with increasing dose, a median Tmax of 2 hours and a mean t1/2 of 4.6 hours across all cohorts. Two patients with HER2+ breast cancer have had stable disease for ≥ 4 months with no significant toxicity. One of these two patients had a notable reduction in liver metastases (28%) after 2 cycles of ARRY-380 and is currently on study.Conclusions: ARRY-380 has demonstrated an acceptable safety and PK profile and preliminary signs of clinical benefit. Dose escalation continues to determine the MTD. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5111.
Junctional sequences of fetal T cell receptor beta chains have few N regions.
Authors: A J Feeney
Journal: The Journal of Experimental Medicine (1991)

T cell receptors (TCRs) and immunoglobulins (Igs) derive a large fraction of their repertoire from diversity generated at the junctions of the V, D, and J coding segments. This diversity is derived both from the random deletion of nucleotides from the ends of coding regions and from the subsequent addition of nontemplated N region nucleotides. While the vast majority of TCRs and Igs from adult mice have N regions, less than 5% of both TCR-gamma/delta and Ig from fetal and neonatal mice have N regions. This study analyzed the ontogeny of junctional diversity of TCR-alpha/beta. Genomic DNA or C beta-primed cDNA was prepared from thymocytes of mice at varying stages in ontogeny, and the rearranged V beta 8 or V beta 5 sequences were amplified by polymerase chain reactions. Sequencing of the V beta-D beta-J beta junctions showed few N regions early in ontogeny, although the fraction of sequences with N regions exceeded that previously reported for Ig and for TCR-gamma/delta. N regions were found in 13% of V beta junctional sequences from day 18-19 fetal thymocytes, 33% of sequences from newborn thymocytes, 76% of sequences from day 4 postnatal thymocytes, and 88% of sequences from 5-wk-old thymocytes. In addition, nonrandom usage of the D beta and J beta segments was observed in both fetal and adult TCR sequences. While the usage of each of the six J beta 2 segments was different, the same pattern of usage was seen regardless of whether D beta 1 or D beta 2 was used, suggesting that a factor controlling the rate of usage of each J segment is intrinsic to the J gene itself. Since TCRs derive so much of their diversity from N regions, the relative paucity of N regions in fetal alpha/beta T cells would create a fetal TCR-alpha/beta repertoire that would be quite different from, and smaller than, the adult repertoire. The lack of N regions might be predicted to limit the range of affinities of TCR-MHC + peptide interactions, which may have important consequences for positive and negative selection of fetal and newborn T cells.
A patient who changed my practice: Always check the respiratory rate
Authors: P Burdett-Smith
Journal: BMJ (1997)

The young lad had been injured riding a motorbike “off road.” He was complaining of lower chest pain and had tenderness suggestive of blunt injury but with no obviously fractured ribs. His pulse and blood pressure were normal but he was breathing at 40 per minute. A drip was put up and he was sent to have an x ray examination. While being transferred to the trolley his blood pressure dropped and he became unconscious. He was rushed back to the resuscitation room and what had seemed to be a controlled …
Cardiovascular Effects of Secondhand Smoke
Authors: Joaquin Barnoya, Stanton A. Glantz
Journal: Circulation (2005)

Background— Secondhand smoke increases the risk of coronary heart disease by ≈30%. This effect is larger than one would expect on the basis of the risks associated with active smoking and the relative doses of tobacco smoke delivered to smokers and nonsmokers. Methods and Results— We conducted a literature review of the research describing the mechanistic effects of secondhand smoke on the cardiovascular system, emphasizing research published since 1995, and compared the effects of secondhand smoke with the effects of active smoking. Evidence is rapidly accumulating that the cardiovascular system—platelet and endothelial function, arterial stiffness, atherosclerosis, oxidative stress, inflammation, heart rate variability, energy metabolism, and increased infarct size—is exquisitely sensitive to the toxins in secondhand smoke. The effects of even brief (minutes to hours) passive smoking are often nearly as large (averaging 80% to 90%) as chronic active smoking. Conclusions— The effects of secondhand smoke are substantial and rapid, explaining the relatively large risks that have been reported in epidemiological studies.
Starting Insulin Therapy in Outpatients
Authors: Willie Carpentier
Journal: JAMA (1987)

<h3>To the Editor.—</h3> We read with interest the article by Wilson et al entitled "Starting Insulin Treatment as an Outpatient"1 in the Aug 15 issue of<i>JAMA</i>. Our institution has a diabetes education center serving approximately 1000 patients every year; insulin therapy is started routinely in 3% to 5% on an outpatient basis at the option of the referring physician if the patients meet certain standard criteria. All of our patients are assessed by a nurse-clinician and encouraged to attend a daily diabetes education class for the first five days of their insulin use. They are followed up by a nurse-clinician instructor and the medical director of the center or the patient's referring physician on a daily basis during this period. This program has proved to be safe and cost-effective and none of our patients have required hospitalization during institution of insulin therapy. We feel that your readers might be
Teaching Medicine in the Community: A Guide for Undergraduate Education
Authors: Robert E. Gwyther
Journal: Annals of Internal Medicine (1997)

Medical Writings15 October 1997Teaching Medicine in the Community: A Guide for Undergraduate EducationRobert E. Gwyther, MD, MBARobert E. Gwyther, MD, MBAUniversity of North Carolina at Chapel Hill, Chapel Hill, North CarolinaSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-127-8_Part_1-199710150-00038 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Whitehouse C, Roland M, Campion P; eds. 229 pages.New York: Oxford Univ Pr; 1997. $69.50. ISBN0192626531. Order phone 800-451-7556.Field of medicine: Medical education.Format: Softcover book.Audience: Physicians who teach medical students in community settings.Purpose: To give practicing physicians, who are usually not trained as educators, a blueprint from which to build learning experiences. The book was prompted by the increasingly common practice of sending medical students out of university hospitals and into the community for important parts of their education. It may be useful to show skeptical medical school faculty that community learning experiences are ... Author, Article, and Disclosure InformationAffiliations: University of North Carolina at Chapel Hill, Chapel Hill, North Carolina PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 15 October 1997Volume 127, Issue 8_Part_1Page: 659 ePublished: 15 August 2000 Issue Published: 15 October 1997 Copyright & PermissionsCopyright © 1997 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Method of Breech Management Incorporating Use of Fetal Blood Sampling
Authors: B. W. Eliot, J. G. Hill
Journal: BMJ (1972)

We have developed a method of breech management based on the use of fetal blood sampling. Twenty-five cases were studied throughout labour, and fetal blood samples taken throughout the first and second stages. These showed that the Apgar score at one minute correlated closely with the fetal pH just before delivery. We believe that cord compression is an important variable factor which can be assessed only by fetal blood sampling. If this shows that fetal anoxia is becoming severe then immediate delivery is mandatory.
Hepatocellular carcinoma: Sorafenib before liver transplantation?
Authors: Alain Braillon
Journal: Hepatology (2009)

The conclusion of the article by Vitale et al. that a Markov decision analysis suggests that sorafenib neoadjuvant therapy is cost-effective and supports the need for clinical trials deserves several comments and must be challenged.1 Markov decision processes model problems of sequential decision-making. However, here, the tested hypotheses are characterized by lack of evidence or uncertainty: The modest effectiveness of sorafenib is only documented for treating patients with advanced hepatocellular carcinoma (HCC) for whom surgical or locoregional therapies had failed or were not suitable. These indications significantly differ from the 2005 American Association for the Study of Liver Diseases (AASLD) statement "Liver transplantation is an effective option for patients with HCC corresponding to the Milan criteria". This AASLD statement is only "Grade II". The effectiveness of transplantation versus resection or percutaneous ablation still needs randomized controlled trials (RCTs). This need is not futile: (1) From the French national database, survival after transplantation for patients with HCC is lower than for other indications (less than 70% versus more than 80% at 2 years, respectively) and at 5 years, survival after transplantation for HCC is 65%, a very serious issue considering the shortage of organs.2 (2) Resection for small solitary HCC in compensated cirrhosis yields an overall survival rate comparable to upfront transplantation.3 Surgery substantially contributes to improve health, but needs high-quality outcome data. Complex mathematical models cannot be used to bypass the complexities of the surgical research framework. To limit complexity, we must begin at the beginning, namely, RCTs investigating the effectiveness of transplantation versus ablation and/or resection, or at least, the full publication of national series which are more relevant than short series of selected cases from a few leading centers. Hepatocellular carcinoma is a major health care issue which deserves both evidence-based medicine and evidence-based surgery.4 Alain Braillon*, * Public Health, University Hospital, Amiens, France.
Does nucleolin bind the NF kappa B DNA binding motif?
Authors: Lori R. Bernstein
Journal: Hepatology (2006)

Regarding a recent article by Embree-Ku and Gruppuso, which appeared in the August 2005 issue of HEPATOLOGY,1 I am concerned the data presented in the paper do not justify the conclusion that the molecule nucleolin binds to the NFκB DNA binding motif. The authors determined in Fig. 2 that nucleolin binds to this motif. They did this by excising an NFκB oligo gel shift band from a native PAGE gel shift gel and identifying the protein by MALDI analyses. They sought to confirm their conclusion in Fig. 3 by showing that immunodepletion of nucleolin decreases the intensity of the gel shift signal. These data do not justify the conclusions because nuclear extract proteins often run in native PAGE gels with mobilities that are unaffected or minimally affected by the added DNA, even when bound to the DNA. Even if the authors were to have run their gel shift gel with nuclear extract and added NO DNA, nucleolin is likely to have had the same mobility. It is likely that the identification of nucleolin is a function of its mobility in the gel, not of its binding to DNA. The authors could have attempted a Western on the band they excised from the EMSA gel to confirm the identity of nucleolin, although this would not have proven that nucleolin binds to the DNA, for the reasons cited in the previous paragraph. But it would have directly shown that nucleolin was in the band analyzed by MALDI, a necessary exercise since MALDI is a matching method with many false positives, especially for very crude samples such as nuclear extracts. In Fig. 3, the authors did attempt to confirm the identity of nucleolin by comparing the intensities of the gel shift bands for anti nucleolin depleted samples to samples mock-depleted with non-immune IgG. However, nucleolin is such an abundant protein that it is hard to deplete; successful depletion should have been verified by immunoblotting of the supernatant with anti nucleolin to show that the amount of nucleolin was significantly reduced. Another reason this experiment is not conclusive is that the same result would have been obtained if nucleolin sequesters NFκB protein by complexing with it. In this scenario the reduced signal intensity in the gel shift would be attributable to reduced presence of NFκB, which of course binds to the NFκB motif. Nucleolin binds to a number of proteins including several other transcription factors and DNA binding proteins, so this is quite plausible.2-4 Taken together, the data presented do not justify the conclusion that nucleolin binds to the NFκB DNA motif. Nucleolin may bind to this motif, but additional data are needed before this conclusion is warranted. Lori R. Bernstein Ph.D.*, * Department of Pathology and Laboratory Medicine, Texas A & M University System Health Science Center, College Station, TX.
ONLY A BABY TOOTH.
Authors: W. H. HALL
Journal: JAMA (1899)

Reference is not here made to any particular baby tooth, nor to any particular baby's tooth, but only to the deciduous or temporary teeth as a class. Interest in the subject which furnishes the topic of this treatise antedates, considerably, the discovery of the<i>first</i>baby's<i>first</i>tooth by the proud new parents. Its importance does not begin nor end here, nor is it confined within the limits of baby's and childhood's tender years, as we expect to prove. An extended theoretic discussion of the proper treatment and best material for filling roots and crown of a devitalized molar would come as far short of interesting our medical brethren as would a learned paper on typhoid fever and its treatment the dental Section of this assembly, therefore, this homely topic shall be given a plain, practical but limited consideration. ''Only a baby tooth'' is expressive of insignificance, but not in
BCG Vaccination for Hodgkin Disease
Authors: S. K. McIlvanie
Journal: JAMA (1974)

<h3>To the Editor.—</h3> The statement attributed to me that "we have been killing people with chemotherapy for so many years" is partially out of context (228:28, 1974). There are very few hematologists today who have only practiced for the last decade who have actually seen a patient die of Hodgkin disease. However, Hodgkin disease patients do die, and usually of complications of therapy. Admittedly, this is a lesser number, thanks to current treatment schedules. Even so, this smaller number must receive our continued efforts, and to this end my paper was directed. The paper clearly outlines that I undertook to improve active cell-mediated immunity (CMI) by combining the specific and nonspecific effects of BCG vaccine along with transfer factor in a specific group of patients, namely those in whom the combined regimen of mechlorethamine hydrochloride, vincristine sulfate (Oncovin), procarbazine hydrochloride, and prednisone (MOPP) had failed. While some viable T cells might
FIBROSIS OF THE LARYNX AND TRACHEA.
Authors: RALPH W. SEISS
Journal: JAMA (1903)

A fairly extensive search through modern literature has given the writer the impression that the sclerotic type of chronic laryngo-trachitis has received very meager attention, and that most text-book sections on the subject are decidedly hazy in tone. It may be simply said that the condition has long been known to laryngologists under various names, but has been much confused with wholly separate pathologic states, and has but rarely been definitely described. A review of the literature of the subject does not therefore seem specially desirable. <h3>ETIOLOGY.</h3> Laryngo-tracheal fibrosis may be regarded as the final stage of every case of progressive chronic inflammation of this region—but the element of progression is fortunately absent in the great majority of examples. We know practically nothing of the etiology of sclerosis in this, or indeed in any other region of the body. While the causes of ordinary chronic inflammation may be
POLLUTION OF THE UPPER OHIO, AND THE WATER-SUPPLY OF THE CITIES AND CHIEF TOWNS WITHIN THE FIRST HUNDRED MILES OF ITS COURSE.
Authors: JAMES E. REEVES
Journal: JAMA (1884)

Read before the American Public Health Association, at the meeting in St. Louis, October 16th, 1884. The condition of health and probable duration of life of a people may be correctly measured by the quality and quantity of their water-supply. Indeed, good health can as little be supported without pure water as without pure air; therefore, of all the diversified and complex relations which man bears to surrounding influences, none are more important than that which relates to the water-supply of the locality in which fortune has placed him. Considered either in his physical, social, moral, industrial, or political relation, the subject is of transcendent importance, for it involves the main questions of success in life. If he take up his abode in the midst of unsanitary surroundings, the inevitable sequence will be a correspondingly unfavorable influence upon his destiny—a check upon his prosperity, and a blight, more or less
Intensely Hypermetabolic Lipomatous Hypertrophy of the Interatrial Septum on 18-FDG PET With MRI and CT Correlation
Authors: Michelle A. Klein, Luke R. Scalcione, Trisha Youn, Rakesh A. Shah, Douglas S. Katz, Wei-Wen Sung, Elizabeth Y. Yung
Journal: Clinical Nuclear Medicine (2010)

We present a 69-year-old female patient with a history of emphysema, rosacea, and breast cancer. The patient was in remission for 4 years until a 15-pound weight loss prompted further evaluation with a computed tomography of the chest, abdomen, and pelvis, cardiac magnetic resonance imaging, as well as an 18-FDG-PET scan to evaluate for metastatic disease and potential cardiac abnormalities. There was an intensely hypermetabolic bilobed focus within the region of the interatrial septum, correlating with the patient's lipomatous hypertrophy of the interatrial septum (LHIS), which was identified on computed tomography and magnetic resonance imaging. LHIS is a relatively uncommon cardiac finding characterized by excessive deposition of adipocytes with varying quantities of brown fat. Brown fat in LHIS may be hypermetabolic on 18-FDG-PET examinations, and familiarity with the prevalence and features of LHIS will avoid misdiagnosis of metastatic disease.
Abstract 3610: GW182 associates with circulating microvesicles and microRNA in human plasma
Authors: Kirk Brown, Meredith Millis, Shannon E. Smith, Kim Yeatts, Jason Zhong, Adam Stark, Yuka Kojima, Julie Garcia, David B. Spetzler
Journal: Cancer Research (2012)

Abstract To date, microRNAs (miR) in human plasma have been discovered within circulating microvesicles (cMV), bound to Argonaute 2 and associated with HDL and LDL microvesicles. The protein GW182 shares an association with both multivesicular bodies and the Argonaute family of proteins. GW182 has the capacity to bind all human Argonaute proteins (1-4) and their associated miRs. In the cell, GW182 is associated with the membrane of multivesicular bodies and has the ability to congregate Argonaute-loaded RISC complexes. In addition, GW182 has been observed on the surface of purified exosomes. Here we investigated the relationship of GW182 with Argonaute and cMV in human plasma. A monoclonal antibody directed toward GW182 was used to capture the protein. This isolate also contained Argonaute proteins as determined by Western analysis. The co-precipitation of GW182 and Argonaute suggests that these two proteins retain their functional relationship in plasma. RNA was then isolated from precipitates for miR detection and analysis. The GW182-associated miR profile from human plasma contained individual miRs whose abundance either equaled or surpassed that of their matched Argonaute 2 immuno-precipitated miRs. This implies that GW182 maintains an association with the family of Argonaute proteins and a subset of cMV in human plasma. Phenotypic analysis of GW182-associated human plasma microparticles was performed using flow cytometry with a Beckman Coulter MoFlo XDP. A subpopulation of plasma-derived cMV was observed that co-expressed tetraspanins, GW182 and Argonaute 2. Since tetraspanins are transmembrane proteins highly associated with cMV, these results suggest that both GW182 and Argonaute can associate with cMV in human plasma. Thus, precipitation of GW182 enables the isolation and purification of miRs from human plasma including those bound to Argonaute 1-4 and a subset of cMV. 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 3610. doi:1538-7445.AM2012-3610
Politicians, patients, and practitioners
Authors: W. Russell
Journal: BMJ (1981)

The rush of blood to the head by the Labour Party conference in Brighton over what it will do to the NHS gave Dr Gerard Vaughan, the Health Minister, plenty of ammunition to use at his own party's conference last week in Blackpool.Dr Vaughan-whose private secretary observed at the recent reshuffle, "You seem to be a rock in a changing world, minister" -quoted with some relish at a meeting of the Conservative Medical Society the claims that private practice was a cancer in the Health Service, that it must be abolished, and that this was no time to be mealymouthed and carry on talking with the medical profession.