tbuckley/cabot-search huggingface dataset:
Sorafenib in clinical practice: Evidence-based use or abuse?
Authors: Michele Basso, Maria Basso, Carlo Barone
Journal: Hepatology (2011)

In their study, Iavarone et al.1 found a prolonged time to progression (TTP) in comparison with the Sorafenib HCC Assessment Randomized Protocol study, and they speculated that it was probably related to the utilization of the modified Response Evaluation Criteria in Solid Tumors.2 Moreover, they hypothesized that down-dosing sorafenib allowed a high percentage of the patients to retain the benefits of the drug and achieve improved survival. If TTP was so remarkably improved only because of the accuracy of the modified Response Evaluation Criteria in Solid Tumors (published in the year of the study's start), it seems strange that the median overall survival was comparable to that of phase 3 trials.2 The most unusual observation was the very short postprogression survival (1 month versus 5 months in the Sorafenib HCC Assessment Randomized Protocol study). As a rule, a median TTP approaching the median overall survival occurs because of undiagnosed progression. In our opinion, this means that the interval between computed tomography scans was longer than 2 months in actual daily practice. Another issue was the high rate of liver function deterioration, which the authors attributed to drug-related adverse events.1 It is not clear how they distinguished this from clinical tumor progression. The analysis suggesting longer survival for patients receiving half-dose sorafenib was not preplanned, and this means that the patients were not stratified according to prognostic factors and that the sample size was not calculated in advance for the hypothesis that the authors intended to demonstrate. For this reason, the aforementioned analysis was methodologically inappropriate for an observational study; it was also inconclusive because the patients' survival might simply have depended on the selection of a good-prognosis cohort. Finally, two other aspects deserve careful consideration. First, the study lacked formal approval by an ethics committee, which implies the generation of a European Union Drug Regulating Authorities Clinical Trials number according to Italian rules. Second, a cohort of Child B patients was treated, but sorafenib approval in Italy is restricted to Child A patients. Taken together, our observations suggest the following: (1) the design of this prospective study had potentially serious limitations, (2) sorafenib was used in field practice outside the approved indication, (3) computed tomography scans were not scheduled on a bimonthly basis, and (4) TTP was largely overestimated. In addition, this article subliminally conveys a somewhat hazardous and not adequately supported message about both the arbitrary acceptance of the physician's judgment in deciding the likelihood of benefits without radiological confirmation and the continuation of sorafenib beyond progression almost until death. Michele Basso M.D.*, Maria Basso M.D. , Carlo Barone M.D.*, * Medical Oncology, Catholic University of Sacred Heart, Rome, Italy, Internal Medicine, Catholic University of Sacred Heart, Rome, Italy.
Multi-professional lung cancer disclosure to change anxiety and depression: an exploratory study
Authors: F Cousson-Gelie, J-M Vernejoux, H Bazex-Chanteloube, C Raherison, A Ozier, P-O Girodet, A Taytard
Journal: Thorax (2008)

The article by Jennings and colleagues1 described interesting findings regarding the common nature of mixed viral/bacterial aetiology in patients with community acquired pneumonia (CAP) and the association between mixed rhinovirus/pneumococcal infection and severe disease. We have also examined the role of respiratory picornaviruses as causative agents of CAP in adults and their contribution to disease severity. As part of a larger prospective clinical study2 of the aetiology of CAP, the occurrence of rhinoviruses and enteroviruses was analysed in 231 patients. Detailed information on the study design …
Lack of Germline Transmission of Vector Sequences Following Systemic Administration of Recombinant AAV-2 Vector in Males
Authors: Valder R. Arruda, Paul A. Fields, Ross Milner, Luanne Wainwright, Maria P. De Miguel, Peter J. Donovan, Roland W. Herzog, Timothy C. Nichols, Jaclyn A. Biegel, Mahmood Razavi, Mike Dake, Dale Huff, Alan W. Flake, Linda Couto, Mark A. Kay, Katherine A. High
Journal: Molecular Therapy (2001)

A potential consequence of systemic administration of viral vectors is the inadvertent introduction of foreign DNA into recipient germ cells. To evaluate the safety of in vivo recombinant adeno-associated virus (rAAV) mediated gene transfer approaches for hemophilia B, we explored the risk of germline transmission of vector sequences following intramuscular (IM) injection of rAAV in four species of male animals (mouse, rat, rabbit and dog). In vector biodistribution studies in mice and rats, there is a dose-dependent increase in the likelihood that vector sequences can be detected in gonadal DNA using a sensitive PCR technique. However, in dogs DNA extracted from semen is negative for vector sequences. To address this discrepancy, studies were done in rabbits, and both semen and testicular DNAs were analyzed for the presence of vector sequences. These studies showed that no AAV vector sequences were detected in DNA extracted from rabbit semen samples collected at time points ranging from 7 to 90 days following IM injection of 1×1013 vector genomes rAAV (vg) per kg. In contrast, DNA extracted from gonadal tissue was positive for vector sequences, but the positive signals diminished in number and strength with time. By FISH analysis, AAV signals were localized to the testis basement membrane and the interstitial space; no intracellular signal was observed. We observed similar findings following hepatic artery administration of rAAV in rats and dogs, suggesting that our findings are independent of the route of administration of vector. Attempts to transduce isolated murine spermatogonia directly with AAV-lacZ were unsuccessful. In clinical studies human subjects injected IM with an AAV vector at doses up to 2×1012 vg/kg have shown no evidence of vector sequences in semen. Together, these studies suggest that rAAV introduced into skeletal muscle or the hepatic artery does not transduce male germ cells efficiently. We conclude that the risk of inadvertent germline transmission of vector sequences following IM or hepatic artery injection of AAV-2 vectors is extremely low.
Genetic dissection of lupus pathogenesis: a recipe for nephrophilic autoantibodies
Authors: Chandra Mohan, Laurence Morel, Ping Yang, Hiroshi Watanabe, Byron Croker, Gary Gilkeson, Edward K. Wakeland
Journal: Journal of Clinical Investigation (1999)

Sle1 and Sle3 are 2 loci that confer susceptibility to lupus nephritis in the NZM2410 strain of mice. Our previous work has shown that B6.NZMc1 mice, congenic for Sle1, exhibit loss of tolerance to chromatin but do not develop any pathogenic autoantibodies or disease. B6.NZMc7 mice, congenic for Sle3, exhibit low-grade polyclonal B- and T-cell activation, elevated CD4/CD8 ratios, and mildly penetrant glomerulonephritis. In contrast to these monocongenics, the present study reveals that B6.NZMc1|c7 mice, bicongenic for Sle1 and Sle3, exhibit splenomegaly, significantly expanded populations of activated B and CD4+ T cells, and a robust, variegated IgG autoantibody response targeting multiple components of chromatin (including double-stranded DNA), intact glomeruli, and basement membrane matrix antigens. As one might predict, these mice, particularly the females, exhibit highly penetrant glomerulonephritis.
Effect of Noncarcinogenic and Carcinogenic Hydrocarbons on Antibody-Forming Cells Measured at the Cellular Level &lt;italic&gt;In Vitro&lt;/italic&gt;&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: J Stjernswärd
Journal: JNCI Journal of the National Cancer Institute (1966)

The number of antibody-forming cells in adult CBA male mice was determined in vitro by an agar plaque technique 5, 11, and 36 days after exposure of the host to carcinogenic or noncarcinogenic hydrocarbons. The number of plaque-forming spleen cells (PFC) was depressed, both totally per spleen and specifically within the spleen cell population, after the host had been exposed to the carcinogenic hydrocarbons benzo[a]pyrene (BaP), 7,12-dimethylbenz[a]anthracene (DMBA), or 3-methylcholanthrene (MCA). The noncarcinogenic hydrocarbons anthracene (Ae) and benzo[e]pyrene (BeP) had no such immunodepressive effect. 7-Methyldibenzanthracene (MDBA) had a slightly depressive effect on the number of PFC. BaP, DMBA, and MCA are all potent carcinogens, inducing antigenic neoplastic cells. The lack of effect on the number of PFC observed for noncarcinogenic BeP and Ae suggests a possible correlation between carcinogenic power and inhibition of the host's immune response. This agrees with earlier results showing that MCA depresses the number of PFC for a long period, corresponding to the latency period before appearance of MCA-induced sarcomas. It is suggested that the immunodepressive effect of the carcinogens observed may favor the development of antigenic tumor cells, induced either by virus or the carcinogens themselves, or those resulting from spontaneous cellular variation.
Trastuzumab decreases the incidence of clinical relapses in patients with early breast cancer presenting chemotherapy-resistant CK-19mRNA-positive circulating tumor cells: results of a randomized phase II study
Authors: V. Georgoulias, V. Bozionelou, S. Agelaki, M. Perraki, S. Apostolaki, G. Kallergi, K. Kalbakis, A. Xyrafas, D. Mavroudis
Journal: Annals of Oncology (2012)
Nifedipine enhances the bronchodilator effect of salbutamol.
Authors: A M Lever, P A Corris, G J Gibson
Journal: Thorax (1984)

Ten male asthmatic volunteers each inhaled two puffs (200 micrograms) of salbutamol on two separate days 30 minutes after double blind oral administration of either 20 mg nifedipine or identical placebo. FEV1 was recorded before and at intervals for four hours after inhalation of salbutamol. Overall the FEV1 was significantly greater during the four hour period after premedication with nifedipine (p less than 0.025) and the difference between the effects of placebo and nifedipine was greatest four hours after salbutamol (p less than 0.005). These results suggest that nifedipine prolongs the bronchodilator action of salbutamol in vivo.
Changes in Tumor Density in Patients with Advanced Hepatocellular Carcinoma Treated with Sunitinib
Authors: Sandrine Faivre, Magaly Zappa, Valérie Vilgrain, Eveline Boucher, Jean-Yves Douillard, Ho Y. Lim, Jun S. Kim, Seock-Ah Im, Yoon-Koo Kang, Mohamed Bouattour, Safi Dokmak, Chantal Dreyer, Marie-Paule Sablin, Camille Serrate, Ann-Lii Cheng, Silvana Lanzalone, Xun Lin, Maria J. Lechuga, Eric Raymond
Journal: Clinical Cancer Research (2011)

Response Evaluation Criteria in Solid Tumors (RECIST) may underestimate the efficacy of targeted therapies. In hepatocellular carcinoma (HCC) studies with sunitinib, RECIST-defined response rates are low, although hypodensity on computed tomography (CT) scans occurs more frequently. This exploratory analysis investigated tumor density as a surrogate endpoint of sunitinib activity in a phase II HCC study.Patients received sunitinib 50 mg/d (4 weeks on/2 weeks off). Tumor size and density were assessed on CT scans by using RECIST and Choi criteria, the latter of which classify a partial response as a 15% or more reduction in tumor density or a 10% or more reduction in tumor size. The overall percentage volume of tumor necrosis was calculated with volumetric reconstruction. Tumor perfusion parameters were assessed by using perfusion CT scans with specific acquisition.Among the 26 evaluable patients, 1 achieved a partial response and 22 had tumor stabilization by RECIST. In analysis of tumor density, 17 of 26 patients (65.4%) were responders by Choi criteria. Volumetric assessment showed major tumor necrosis (≥30% of tumor volume) in 10 of 21 patients (47.6%). Among four patients evaluated, tumor blood flow was reduced by 58.8% and blood volume by 68.4% after 4 weeks of treatment. The median time to progression (TTP) was 6.4 months. Patients with responses by Choi criteria had a significantly longer TTP (7.5 months) compared with nonresponders (4.8 months; HR = 0.33, two-sided P = 0.0182).Tumor density assessment suggested that radiologic endpoints in addition to RECIST may be considered to capture sunitinib activity in HCC.
Structure, Function, and Drug Interactions of Neurotransmitter Transporters in the Postgenomic Era
Authors: Hiroshi Omote, Takaaki Miyaji, Miki Hiasa, Narinobu Juge, Yoshinori Moriyama
Journal: The Annual Review of Pharmacology and Toxicology (2015)

Vesicular neurotransmitter transporters are responsible for the accumulation of neurotransmitters in secretory vesicles and play essential roles in chemical transmission. The SLC17 family contributes to sequestration of anionic neurotransmitters such as glutamate, aspartate, and nucleotides. Identification and subsequent cellular and molecular biological studies of SLC17 transporters unveiled the principles underlying the actions of these transporters. Recent progress in reconstitution methods in combination with postgenomic approaches has advanced studies on neurotransmitter transporters. This review summarizes the molecular properties of SLC17-type transporters and recent findings regarding the novel SLC18 transporter.
Function of RasGRP3 in the formation and progression of human breast cancer
Authors: Zsuzsanna Nagy, Ilona Kovács, Miklós Török, Dezső Tóth, György Vereb, Krisztina Buzás, István Juhász, Peter M Blumberg, Tamás Bíró, Gabriella Czifra
Journal: Molecular Cancer (2014)

Ras guanine nucleotide exchange factors (RasGEFs) mediate the activation of the Ras signaling pathway that is over activated in many human cancers. The RasGRP3, an activator of H-Ras and R-Ras protein exerts oncogenic effects and the overexpression of the protein is observed in numerous malignant cancer types. Here, we investigated the putative alteration of expression and potential function of RasGRP3 in the formation and progression of human breast cancer. The RasGRP3 and phosphoRasGRP3 expressions were examined in human invasive ductal adenocarcinoma derived samples and cell lines (BT-474, JIMT-1, MCF7, SK-BR-3, MDA-MB-453, T-47D) both in mRNA (Q-PCR) and protein (Western blot; immunohistochemistry) levels. To explore the biological function of the protein, RasGRP3 knockdown cultures were established. To assess the role of RasGRP3 in the viability of cells, annexin-V/PI staining and MitoProbe™ DilC1 (5) assay were performed. To clarify the function of the protein in cell proliferation and in the development of chemotherapeutic resistance, CyQuant assay was performed. To observe the RasGRP3 function in tumor formation, the Severe combined immunodeficiency (SCID) mouse model was used. To investigate the role of the protein in Ras-related signaling Q-PCR and Western blot experiments were performed. RasGRP3 expression was elevated in human breast tumor tissue samples as well as in multiple human breast cancer cell lines. Down-regulation of RasGRP3 expression in breast cancer cells decreased cell proliferation, induced apoptosis in MCF7 cells, and sensitized T-47D cells to the action of drugs Tamoxifen and trastuzumab (Herceptin). Gene silencing of RasGRP3 reduced tumor formation in mouse xenografts as well. Inhibition of RasGRP3 expression also reduced Akt, ERK1/2 and estrogen receptor alpha phosphorylation downstream from IGF-I insulin like growth factor-I (IGF-I) or epidermal growth factor (EGF) stimulation confirming the functional role of RasGRP3 in the altered behavior of these cells. Taken together, our results suggest that the Ras activator RasGRP3 may have a role in the pathological behavior of breast cancer cells and may constitute a therapeutic target for human breast cancer.
Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against Bcr-Abl–expressing human leukemia cells
Authors: Warren Fiskus, Michael Pranpat, Purva Bali, Maria Balasis, Sandhya Kumaraswamy, Sandhya Boyapalle, Kathy Rocha, Jie Wu, Francis Giles, Paul W. Manley, Peter Atadja, Kapil Bhalla
Journal: Blood (2006)
Finding New Sea Legs for Urine Proteomics
Authors: Eric G. Neilson
Journal: Journal of the American Society of Nephrology (2009)

We draw attention to a commentary published in this issue of JASN by Knepper1 regarding studies undertaken in search of new biomarkers using urinary proteomics. Many of us who review or read these studies want important information to grace our journal pages. Proteomic technology today, even as it rapidly evolves, is capable of clever measurement and presentation, but harnessing this technology to better understand clinical or experimental disease is where true progress lies. By and large, we are not there yet. Reasonable people acknowledge this concern is more of an observation than a complaint about a discipline in its adolescence. Identification of protein/fragment signatures in urine needs context and credible evidence of improving on what is already known. A useful experimental design should test protein signatures for relevance to pathophysiology and specificity for certain diseases. We cannot get to this level without everyone making an effort to raise the bar. As editors of your journal, like any well-regarded journal, we are always torn between publishing new preliminary data of potential interest versus a more penetrating story that truly advances the ball. We hope Knepper's insightful discussion now, and what will come from new work by our community of investigators, forges greater expectations for future studies: Expectations for replication in parallel populations accompanying the initial identification of a signature, disease specificity controls where appropriate, and additional biochemical or immunologic confirmation where available. When contemplating a more advanced validation study, the design should develop along the lines of a comparative clinical trial against other markers, other diseases, or various treatments with appropriate attention to sensitivity and specificity of the results. JASN editors going forward will expect future manuscripts using urinary proteomics to contain the above enhancements. If we all promote a rigorous scientific body of work, then we can be optimistic that urinary proteomics will provide a powerful tool by which we can identify new markers, understand their use, and better care for our patients. DISCLOSURES None.
How necessary is the unconscious as a predictive, explanatory, or prescriptive construct?
Authors: Claudia González-Vallejo, Thomas R. Stewart, G. Daniel Lassiter, Justin M. Weindhardt
Journal: Behavioral and Brain Sciences (2014)

Abstract We elucidate the epistemological futility of using concepts such as unconscious thinking in research. Focusing on Newell &amp; Shanks' (N&amp;S's) use of the lens model as a framework, we clarify issues with regard to unconscious-thought theory (UTT) and self-insight studies. We examine these key points: Brunswikian psychology is absent in UTT; research on self-insight did not emerge to explore the unconscious; the accuracy of judgments does not necessitate the unconscious; and the prescriptive claim of UTT is unfounded.
An Antidepressant Decreases CSF Aβ Production in Healthy Individuals and in Transgenic AD Mice
Authors: Yvette I. Sheline, Tim West, Kevin Yarasheski, Robert Swarm, Mateusz S. Jasielec, Jonathan R. Fisher, Whitney D. Ficker, Ping Yan, Chengjie Xiong, Christine Frederiksen, Monica V. Grzelak, Robert Chott, Randall J. Bateman, John C. Morris, Mark A. Mintun, Jin-Moo Lee, John R. Cirrito
Journal: Science Translational Medicine (2014)

The antidepressant drug citalopram decreased CSF amyloid-β in healthy humans, and in an aged transgenic mouse model of Alzheimer’s disease, it decreased ISF amyloid-β in a dose-dependent manner.
ICI 74,917: A NEW ANTI‐ALLERGIC DRUG ADMINISTERED BY PRESSURISED AEROSOL
Authors: NIELS MYGIND, JENS THOMSEN
Journal: Allergy (1975)

Ten patients with allergic rhinitis were challenged intranasally with allergen before, and half an hour, 2 hours and 4 hours after intranasal administration of placebo, disodium cromoglycate powder and an aerosol containing ICI 74,917, a new compound with anti-allergic action. ICI 74,917 had a maximum protective effect after half an hour, but was significantly better than placebo 2 hours after nasal use. The effect was significantly better than that of disodium cromoglycate powder. The results will encourage studies of ICI 74,917 in the treatment of allergic rhinitis.
Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial
Authors: Rolf A Stahel, Oliver Riesterer, Alexandros Xyrafas, Isabelle Opitz, Michael Beyeler, Adrian Ochsenbein, Martin Früh, Richard Cathomas, Kristiaan Nackaerts, Solange Peters, Christoph Mamot, Alfred Zippelius, Carlo Mordasini, Clemens B Caspar, Katrin Eckhardt, Ralph A Schmid, Daniel M Aebersold, Oliver Gautschi, Wolfgang Nagel, Michael Töpfer, Jerome Krayenbuehl, Karin Ribi, llja F Ciernik, Walter Weder
Journal: The Lancet Oncology (2015)
The demise of nursing
Authors: B. Kilvington
Journal: Journal of the Royal Society of Medicine (2007)

It is clear the authors are ignorant of the role, training and history of my profession; otherwise they would have known better than to use the surgical role as their example.To appreciate the folly of this example, one must understand that for many years the theatre nursing hierarchy sought to deny ODPs the opportunity to practice in the surgical role-claiming this 'a purely nursing function'.My profession was then predominantly associated with providing care as part of the anaesthetic team, where patients are initially conscious, often fearful and requiring both psychological and physiological support.As far back as the 1970s our syllabus incorporated patient care (e.g.'Respect the dignity and rights of the patient; Principles of ethics and etiquette; Psychological reaction of patients to surgery and the theatre environment').These were introduced early and developed throughout the course.Today's qualification has developed these themes into the modern era, with emphasis on the assessment, planning and evaluation of care.Caring is not genetically implanted into nurses, but taught to all professions with caring responsibilities.The notion that ODPs are 'expropriating nurses' knowledge and skills' is laughable.We had the first nationally organized course in operating department practice in 1951.In 1989 Bevan 2 noted 'only 13.8% of nurses working in theatre had received post-registration training in operating department and/or anaesthetic nursing.'Throughout the 1990s the NVQ in Operating Department Practice, the ODP's primary qualification, was taken by many perioperative nurses as their preferred postgraduate qualification.