tbuckley/cabot-search huggingface dataset:
Reply to J. Richter et al
Authors: Philippe Rousselot, Aude Charbonnier, Pascale Cony-Makhoul, Philippe Agape, Franck E. Nicolini, Bruno Varet, Martine Gardembas, Gabriel Etienne, Delphine Réa, Lydia Roy, Martine Escoffre-Barbe, Agnès Guerci-Bresler, Michel Tulliez, Stéphane Prost, Marc Spentchian, Jean Michel Cayuela, Josy Reiffers, Jean Claude Chomel, Ali Turhan, Joëlle Guilhot, François Guilhot, François-Xavier Mahon
Journal: Journal of Clinical Oncology (2014)

We appreciate the correspondence from Richter et al reporting for the first time a so-called tyrosine kinase inhibitor withdrawal syndrome consisting of musculoskeletal pain after imatinib discontinuation in patients with chronic myelogenous leukemia (CML). All patients (15 of 50; 30%) were graded as 1 to 2 on the Common Terminology Criteria for Adverse Events scale (version 4.0), and 11 patients (22%) did not experience any musculoskeletal pain before discontinuation. Richter et al ask whether such events were observed in the According to Stop Imatinib (A-STIM) study. The A-STIM study was not designed to collect data on low-grade events, either before discontinuation or after discontinuation. We thus tried to retrospectively collect this information and asked the A-STIM investigators to check their patients’ files. As a result, we estimated that four of 80 patients presented similar symptoms after discontinuation. Because of the retrospective collection of the data, we believe that this proportion may be underestimated. French investigators have pioneered the field of tyrosine kinase discontinuation from the first pilot study in 2007 to the multicentric Stop Imatinib 1 (STIM1) study. In none of these studies was the collection of data on low-grade adverse events planned. We are currently conducting the Stop Imatinib 2 (STIM2) study for patients treated only with imatinib and are prospectively recording events of all grades at the time of discontinuation and after discontinuation. We calculated that 400 patients were enrolled in discontinuation studies in France from 2007 to 2013. Few grade 3 or grade 4 events were reported as being possibly related to the discontinuation of tyrosine kinase inhibitors. Such events were mainly related to exacerbation of preexisting inflammatory diseases such as Crohn’s disease or rheumatoid arthritis, as reported. In a recently published study, thermal pain thresholds were significantly increased in 39 patients with CML who were treated with imatinib or nilotinib as compared with ageand sex-matched healthy controls. The authors suggested that c-Kit inhibition may modulate nociceptive sensitivity in humans, as reported in mice. Sudden discontinuation of imatinib may reverse this phenomenon. Prolonged inhibition of c-Kit signaling by imatinib may also suppress mast cell function and activation over the long term, as suggested by the observation that imatinib may improve asthma in asthmatic patients with CML. Taken together, these observations favor the hypothesis that c-Kit signaling may contribute to the symptoms that were observed by Richter et al after imatinib discontinuation.
Mortality and Length of Stay in Teaching vs Nonteaching Hospitals
Authors: Norman A. Desbiens
Journal: JAMA (1997)

<h3>To the Editor.</h3> —Dr Rosenthal and colleagues<sup>1</sup>should be congratulated for undertaking a scientific study of an important real-life issue—quality of care at teaching hospitals. Although, as an educator, I would be thrilled if their conclusion that "hospital performance may be higher in major teaching hospitals" is correct, as a researcher, I have serious concerns about their methods. My major concern is with the trichotomization of hospitals into nonteaching, major teaching, and minor teaching based on membership in the Council of Teaching Hospitals (COTH). It seems that this is not a valid measure of the role of teaching in an institution, since it depends on paid membership. The cost for a hospital to join COTH for the 1997-1998 academic year is $12 500. Hospitals, especially in these tight economic times, may decide not to join COTH because of this expense. Although it is true that the 400 COTH member institutions (of the
Conducting pulmonary arteries: structural adaptation to extrauterine life in the pig
Authors: S. M HALL, S. G HAWORTH
Journal: Cardiovascular Research (1987)

A quantitative light microscopical and ultrastructural study of the elastic and large muscular pulmonary arteries of 30 Large White pigs aged from birth to 6 months yielded light microscopical measurements on 120 arteries and 62,560 ultrastructural assessments, which composed a computerised database. After birth mean arterial medial thickness and mean smooth muscle cell diameter decreased during the first 4 days (p less than 0.01). Mean interlamellar distance decreased, reaching its nadir at 1-3 weeks (p less than 0.01). All these features increased between 3 weeks and adulthood (p less than 0.01). In the smooth muscle cells synthetic rather than contractile organelles were dominant during the first 3 weeks. Between 3 weeks and adulthood, however, smooth muscle cell myofilament volume density increased (p less than 0.0001). At all ages the smooth muscle cells of the outer lamellar units of elastic arteries had a greater myofilament volume density than those of adluminal units (p less than 0.0001). The amount of connective tissue increased between 3 weeks and adulthood, collagen and basement membrane increasing preferentially (p less than 0.0001, p less than 0.05, respectively). Thus the conducting pulmonary arteries, like the peripheral resistance arteries, adapt structurally to extrauterine life. Remodelling occurred rapidly after birth, and then gradually during growth, as connective tissue was deposited and smooth muscle cells matured.
Head of healthcare watchdog resigns after series of damming reports
Authors: N. Hawkes
Journal: BMJ (2012)

Cynthia Bower, the chief executive of the Care Quality Commission, has resigned after the publication of a critical report by the Department of Health.

She has been under severe pressure in recent months with damning reports on the performance of the commission emerging from the National Audit Office ( BMJ 2011;343:d7873, doi:10.1136/bmj.d7873) and the health select committee ( BMJ 2011;343 doi:10.1136/bmj.d5882). The final blow was the department’s Performance and Capability Review, the first of its kind, published on 23 February, which repeated many of the same criticisms.

The commission failed to register health providers quickly enough, and was forced to divert staff from inspections to make up the backlog. Along with the department, it underestimated the scale of the task it faced, but should have done more to manage …
Advance Directives: Do They Provide Direction?
Authors: Joel M. Zinberg
Journal: JAMA (1990)

<h3>To the Editor.—</h3> The study by Davidson et al<sup>1</sup>purports to be "the first attempt to evaluate physicians' attitudes and experiences with advance directives." I published such an empirical study in the<i>Vermont Law Review</i>more than 6 months ago<sup>2</sup>; my results were substantially different. Determining physicians' experiences and attitudes is important. Physicians substantially control the implementation of directives. However, a mailed questionnaire is not the optimal way to elicit information about whether or how directives have changed the care patients received. A questionnaire lends itself to wide distribution and creates the illusion of statistical precision. However, it often suggests rather than elicits answers and misses the nuances of the responses. (Notice, for example, the three aberrant responses discussed on pages 2418 and 2419 in the article by Davidson et al.) Davidson et al mailed questionnaires to 1293 physicians. Eighty-two physicians were excluded and 790 responded (65.2%).
Evaluation of efficacy and safety of the anti-VWF Nanobody ALX-0681 in a preclinical baboon model of acquired thrombotic thrombocytopenic purpura
Authors: Filip Callewaert, Jan Roodt, Hans Ulrichts, Thomas Stohr, Walter Janse van Rensburg, Seb Lamprecht, Stefaan Rossenu, Sofie Priem, Wouter Willems, Josefin-Beate Holz
Journal: Blood (2012)
The Modern Treatment of Asthma with Special Reference to Gold Therapy
Authors: Leon Unger
Journal: JAMA (1961)

This is the second edition of a small book first published in 1949. Since then newer knowledge, especially that concerning the use of corticosteroids in asthma, has prompted rewriting. The work contains a good deal of valuable information. Concerning the use of corticosteroids in asthma, the author correctly urges thorough physical examinations and fluoroscopic observations. He devotes a large section of the book to a discussion of the injection of gold-containing products, with excellent results in 54% of 203 asthmatic patients, and good results in another 9%. Gold therapy is rarely used in this country. Strictly from the standpoint of allergy, there are serious omissions and controversial statements. The skin tests are done intradermally only, and only in groups. This technique is dangerous because of possible extreme sensitivity of a patient (scratch tests should be done before intradermal tests are attempted). Group testing is also wrong because positive reactions may
Disparate effects of insulin on isolated rabbit afferent and efferent arterioles.
Authors: L A Juncos, S Ito
Journal: Journal of Clinical Investigation (1993)

Despite evidence that insulin per se may be an important regulator of glomerular hemodynamics, little is known about its direct action on the glomerular afferent arterioles (Af-Art) and efferent arterioles (Ef-Art), the crucial vascular segments that control glomerular hemodynamics. In the present study, we examined the direct effect of physiological concentrations of insulin on isolated microperfused rabbit Af- and Ef-Arts. After cannulation, vessels were equilibrated in insulin-free medium for 30 min. To determine whether insulin causes vasodilation or constriction, increasing doses (5, 20, and 200 microU/ml) were added to the bath and lumen of arterioles that were either preconstricted to 50% of control diameter with norepinephrine or left nonpreconstricted. Insulin caused no vasoconstriction in either Af- or Ef-Arts, but it reversed norepinephrine-induced constriction in Ef-Arts but not Af-Arts (suggesting a vasodilator action selective to the Ef-Art): at 200 microU/ml, insulin increased Ef-Art luminal diameter by 75.8 +/- 7.0% from the preconstricted level (n = 6; P < 0.008). The vasorelaxant effect of insulin on Ef-Arts was not affected by blockade of either endothelium-derived relaxing factor/nitric oxide or prostaglandin synthesis. Despite the lack of effect of insulin on Af-Art when added after the equilibration period, when Af-Arts were equilibrated in the presence of either 20 or 200 microU/ml insulin, their basal diameter was significantly reduced (11.7 +/- 0.9 microns; P < 0.025, n = 6, and 12.0 +/- 0.9 microns; P < 0.025, n = 7, respectively) compared with nontreated Af-Arts (16.2 +/- 1.3 microns; n = 7). In conclusion, this study demonstrates that at physiological concentrations, insulin dilates NE-constricted Ef-Arts, while insulin pretreatment enhances Af-Art tone. The disparate actions of insulin on the Af- vs the Ef-Art may contribute to its beneficial effect on glomerular hypertension.
P1-154: Antitumor effect of Telomerase-Selective Oncolytic Adenoviral Agent OBP-301 (Telomelysin) in pleural dissemination of human malignant mesothelioma
Authors: Shunsuke Kagawa, Yuichi Watanabe, Yuuri Hashimoto, Toru Kojima, Futoshi Uno, Shinji Kuroda, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara
Journal: Journal of Thoracic Oncology (2007)
ACCIDENTAL INOCULATION WITH THE VIRUS OF PLAGUE.
Authors: PAUL C. FREER
Journal: JAMA (1907)

Last fall, as the unfortunate result of the accidental contamination of the cholera vaccine with a culture of plague bacilli, a number of natives were inoculated with plague and several died. The occurrence makes of interest the following account of the work with the cholera vaccine. For the last three years Dr. Richard P. Strong of this bureau has been working on a cholera vaccine which consisted of an extract of the killed, digested and filtered organisms, later modified to a mixture of such an extract with one obtained by shaking on a shaking machine the living organisms in distilled water and then filtering. Obviously this product is always carefully tested and is absolutely sterile and the health department has used it on about seven thousand persons in the Philippines. One-half of the prisoners in the government prison at Bilibid were vaccinated with this vaccine and one-half unvaccinated. The same
Screening methods for covert bacteriuria in schoolgirls.
Authors: B Edwards, R H White, H Maxted, I Deverill, P A White
Journal: BMJ (1975)

Screening tests for bacteriuria based on two different principles were evaluated in1582 schoolgirls aged 5-11 years, and in 26 girls aged 3-16 years attending hospitalwith symptomatic urinary tract infection. Tests for hypoglucosuria, performed by a semi-automated fluorometric method and with Uriglox strips on early-morning urine samples voided after overnight fasting, gave unacceptably high false-negative rates (16.7% and 20.8% respectively). Oxoid and Uricult dipslides were immersed in fresh midstreamspecimens of urine obtained at school and read overnight incubation at 37 degrees C.Both gave comparable results, with low false-positive rates and no false-negative responses. The higher cost of screening by dipslides was halved by using the "dipstream" technique, which also gave no false-negative results. Its false-positive rate of 13.5% could be reduced to 1.8% by disregarding colony counts of 10-8 non-faecal organisms and over per litre, which appear unimportant in schoolchildren. Bacteriuria was found in 2.3% of the schoolgirls; 39% of them had symptons, compared with 7.2% of the healthy girls, and 25% showed vesicoureteric reflux, which in 17% was associated with renalscarring. Since the natural history of covert bacteriuria and its relationship withreflux and scarring remain undetermined further research is required. The dipstreamtechnique offers a simple, reliable, and comparatively cheap screening method which could also be applied in general practice.
Medical ethics, the Israeli Medical Association, and the state of the World Medical Association: Author's response to allegation and to BMA
Authors: D. Summerfield
Journal: BMJ (2003)

EDITOR–I do not misrepresent Blachar: he was uncompromising in his rejection of a Lancet editorial last year documenting widespread violations against civilians, including health personnel on duty during the Israeli army invasion of the West Bank.1 Physicians for Human Rights (PHR) Israel describes an “appalling deterioration” in the attitude of the Israel military towards Palestinian health and rescue services and Blachar dismisses them as “political.” When he says that civilian deaths are “unintentional” and arise because “terrorists take cover in civilian areas” he is recycling the mantra of the political and military establishment. When a rocket is fired at an apartment block to assassinate someone living there, are the inevitable …
A Phase I Study of CUDC-101, a Multitarget Inhibitor of HDACs, EGFR, and HER2, in Combination with Chemoradiation in Patients with Head and Neck Squamous Cell Carcinoma
Authors: Thomas J. Galloway, Lori J. Wirth, Alexander D. Colevas, Jill Gilbert, Julie E. Bauman, Nabil F. Saba, David Raben, Ranee Mehra, Anna W. Ma, Ruzanna Atoyan, Jing Wang, Barbara Burtness, Antonio Jimeno
Journal: Clinical Cancer Research (2015)

CUDC-101 is a small molecule that simultaneously inhibits the epidermal growth factor receptor (EGFR), human growth factor receptor 2 (HER2), and histone deacetylase (HDAC) with preclinical activity in head and neck squamous cell cancer (HNSCC). The primary objective of this investigation is to determine the maximum tolerated dose (MTD) of CUDC-101 with cisplatin-radiotherapy in the treatment of HNSCC.CUDC-101 monotherapy was administered intravenously three times weekly (Monday, Wednesday, Friday) for a one-week run-in, then continued with concurrent cisplatin (100 mg/m(2) every 3 weeks) and external beam radiation (70 Gy to gross disease) over 7 weeks.Twelve patients with intermediate or high-risk HNSCC enrolled. Eleven were p16INKa (p16)-negative. The MTD of CUDC-101-based combination therapy was established at 275 mg/m(2)/dose. Five patients discontinued CUDC-101 due to an adverse event (AE); only one was considered a dose-limiting toxicity (DLT), at the MTD. Pharmacokinetic evaluation suggested low accumulation with this dosing regimen. HDAC inhibition was demonstrated by pharmacodynamic analyses in peripheral blood mononuclear cells (PBMC), tumor biopsies, and paired skin biopsies. Paired tumor biopsies demonstrated a trend of EGFR inhibition. At 1.5 years of median follow-up, there has been one recurrence and two patient deaths (neither attributed to CUDC-101). The remaining nine patients are free of progression.CUDC-101, cisplatin, and radiation were feasible in intermediate-/high-risk patients with HNSCC, with no unexpected patterns of AE. Although the MTD was identified, a high rate of DLT-independent discontinuation of CUDC-101 suggests a need for alternate schedules or routes of administration.
Galectin-9 exhibits anti-myeloma activity through JNK and p38 MAP kinase pathways
Authors: T Kobayashi, J Kuroda, E Ashihara, S Oomizu, Y Terui, A Taniyama, S Adachi, T Takagi, M Yamamoto, N Sasaki, S Horiike, K Hatake, A Yamauchi, M Hirashima, M Taniwaki
Journal: Leukemia (2010)
When Will Resistance Be Futile?
Authors: Katherine L.B. Borden
Journal: Cancer Research (2014)

Cancer cells rapidly evolve a multitude of defense mechanisms to evade the effects of the oncologist's drug arsenal. Unfortunately, clinical strategies to overcome these lag far behind. This mismatch likely underlies our inability to implement new durable treatment strategies. Here, a new form of multidrug resistance, inducible drug glucuronidation, is discussed. This form was discovered while developing means to target a specific oncogene, the eukaryotic translation initiation factor 4E (eIF4E), with its inhibitor ribavirin. In two clinical studies, ribavirin treatment led to substantial clinical responses, but all responding patients eventually relapsed. In most cases, this was due to the overexpression of the sonic hedgehog transcription factor Gli1, which elevated the UDP glucuronsyltransferase UGT1A enzymes. UGT1As add glucuronic acid to many drugs. Indeed, these cells are resistant to not only ribavirin, but also Ara-C, and likely other drugs. Inhibition of Gli1 reduced UGT1As, eliminated drug glucuronides, and renewed sensitivity to ribavirin and Ara-C. These studies highlight that cancer cells and their resistant counterparts metabolize drugs differently from each other as well as from normal cells. Likely, these inducible modifications go beyond glucuronidation. Understanding the extent of inducible drug modifications and the pathways that drive expression of the corresponding enzymatic machinery will better position us to finally make resistance futile.
Chemoreceptor Hypersensitivity, Sympathetic Excitation, and Overexpression of ASIC and TASK Channels Before the Onset of Hypertension in SHR
Authors: Zhi-Yong Tan, Yongjun Lu, Carol A. Whiteis, Annabel E. Simms, Julian F.R. Paton, Mark W. Chapleau, François M. Abboud
Journal: Circulation Research (2009)

Rationale : Increased sympathetic nerve activity has been linked to the pathogenesis of hypertension in humans and animal models. Enhanced peripheral chemoreceptor sensitivity which increases sympathetic nerve activity has been observed in established hypertension but has not been identified as a possible mechanism for initiating an increase in sympathetic nerve activity before the onset of hypertension. Objective : We tested this hypothesis by measuring the pH sensitivity of isolated carotid body glomus cells from young spontaneously hypertensive rats (SHR) before the onset of hypertension and their control normotensive Wistar–Kyoto (WKY) rats. Methods and Results : We found a significant increase in the depolarizing effect of low pH in SHR versus WKY glomus cells which was caused by overexpression of 2 acid-sensing non–voltage-gated channels. One is the amiloride-sensitive acid-sensing sodium channel (ASIC3), which is activated by low pH and the other is the 2-pore domain acid-sensing K + channel (TASK1), which is inhibited by low pH and blocked by quinidine. Moreover, we found that the increase in sympathetic nerve activity in response to stimulation of chemoreceptors with sodium cyanide was markedly enhanced in the still normotensive young SHR compared to control WKY rats. Conclusions : Our results establish a novel molecular basis for increased chemotransduction that contributes to excessive sympathetic activity before the onset of hypertension.
The Review of Dr. Babcock's Book on Diseases of the Lungs.
Authors: Arthur R. Elliott
Journal: JAMA (1907)

Chicago, May 5, 1907. <h3>To the Editor:</h3> —InThe Journal, April 27, page 1453, there appears a review of Dr. Robert H. Babcock's recent work on "Diseases of the Lungs." In common justice to this excellent treatise and in fairness to the author himself, I beg leave to reply to this review. In the first place, the reviewer of Dr. Babcock's book fails to take into account the fact that it is not a system that the author offers us, but a monographic treatise on a special topic, and that in consequence of this he has been subject to certain restrictions of space and scope which prevent him from exhausting in full the diseases under consideration. He has apparently neglected, as well, to read the author's preface, in which is distinctly outlined the limitations of the book. Instead of finding fault, as does this reviewer, with the fact that certain
Inhibition of Lymphotoxin-β Receptor–Mediated Cell Death by Survivin-ΔEx3
Authors: Ren-In You, Mei-Chieh Chen, Hsei-Wei Wang, Yang-Chieh Chou, Chi-Hung Lin, Shie-Liang Hsieh
Journal: Cancer Research (2006)

Abstract TNFSF14/LIGHT is a member of the tumor necrosis factor superfamily that binds to lymphotoxin-β receptor (LTβR) to induce cell death via caspase-dependent and caspase-independent pathways. It has been shown that cellular inhibitor of apoptosis protein-1 inhibits cell death by binding to LTβR-TRAF2/TRAF3 complexes and caspases. In this study, we found that both Kaposi's sarcoma–associated herpesvirus K7 (KSHV-K7), a viral inhibitor of apoptosis protein, and the structurally related protein survivin-ΔEx3 could inhibit LTβR-mediated caspase-3 activation. However, only survivin-ΔEx3 could protect cells from LTβR-mediated cell death. The differential protective effects of survivin-ΔEx3 and KSHV-K7 can be attributed to the fact that survivin-ΔEx3, but not KSHV-K7, is able to maintain mitochondrial membrane potential and inhibit second mitochondria-derived activator of caspase/DIABLO release. Moreover, survivin-ΔEx3 is able to inhibit production of reactive oxygen species and can translocate from nucleus to cytosol to associate with apoptosis signal-regulating kinase 1 after activation of LTβR. Furthermore, survivin-ΔEx3 protects LTβR-mediated cell death in caspase-3-deficient MCF-7 cells. Thus, survivin-ΔEx3 is able to regulate both caspase-dependent and caspase-independent pathways, whereas inhibition of caspase-independent pathway is both sufficient and necessary for its protective effect on LTβR-mediated cell death. (Cancer Res 2006; 66(6): 3051-61)