tbuckley/cabot-search huggingface dataset:
Genetic Patterns in Head and Neck Cancers That Contain or Lack Transcriptionally Active Human Papillomavirus
Authors: Boudewijn J M Braakhuis, Peter J F Snijders, Willem-Jan H Keune, Chris J L M Meijer, Henrique J Ruijter-Schippers, C René Leemans, Ruud H Brakenhoff
Journal: JNCI Journal of the National Cancer Institute (2004)

Background: Transcriptionally active high-risk human papilloma viruses (HPVs), particularly HPV type 16 (HPV16), are found in a subset of head and neck squamous-cell carcinomas (HNSCCs). HPV16-associated carcinogenesis is mediated by expression of the viral E6 and E7 oncoproteins, which cause deregulation of the cell cycle by inactivating p53 and pRb, respectively. We tested the hypothesis that HPV-associated HNSCCs display a pattern of genetic alterations different from those of HNSCCs without HPV DNA. Methods: Polymerase chain reaction–based assays were used to examine 143 consecutive HNSCCs (106 of the oral cavity and 37 of the oropharynx) for the presence of HPV DNA and for viral E6 and/or E7 messenger RNA (mRNA) expression. The HPV DNA–and E6 and E7 mRNA–positive HNSCCs and an equal number of HPV DNA–negative HNSCCs were further analyzed for mutations in TP53, the gene encoding p53, and for allelic loss of 28 microsatellite markers at chromosome arms 3p, 6q, 8p, 9p, 13q, 17p, and 18q, including markers located in regions of chromosome arms 9p and 17p that harbor genes involved the p53 and pRb pathways. All statistical tests were two-sided. Results: Twenty-four (16.7%) of the 143 HNSCCs were positive for HPV16 DNA, and 12 of these HNSCCs (8.4% of total number) expressed E6 and E7 mRNAs. None of the HPV DNA–and E6/E7 mRNA–positive tumors had TP53 gene mutations, whereas nine (75%) of the 12 HPV DNA–negative tumors had such mutations ( P <.001). Compared with the HPV DNA–negative HNSCCs, the E6/E7 mRNA–positive HNSCCs had statistically significantly lower levels of allelic loss for 13 of the 15 markers on 3p, 9p, and 17p. Conclusions: HNSCCs with transcriptionally active HPV16 DNA are characterized by occasional chromosomal loss, whereas HNSCCs lacking HPV DNA are characterized by gross deletions that involve whole or large parts of chromosomal arms and that already occur early in HNSCC development. These distinct patterns of genetic alterations suggest that HPV16 infection is an early event in HNSCC development.
Revalidation: the purpose needs to be clear
Authors: Tim van Zwanenberg
Journal: BMJ (2004)

every UK doctor will need a licence to practise.Most doctors will be able to secure revalidation of their licence by annual appraisal and by showing that they are compliant with local clinical governance requirements and free of any serious unresolved concerns about their fitness to practise In May 2001, the General Medical Council confirmed that all doctors would have to show regularly that they remained up to date and fit to practise in their chosen field.This process was termed revalidation, and its introduction was said to be a landmark in the history of self regulation of the medical profession.The decision was made against a background of high profile cases of medical malpractice and coincided with the first term of a new government which had a mandate to modernise the health service.Indeed the years since the 1997 election have been characterised by a range of policy developments affecting the regulation of doctors in the NHS (see table A on bmj.com).These have included the contractual need to participate in annual appraisal and the professional obligation to undergo revalidation.Recent guidance indicates that revalidation may be achieved through participating in annual appraisal. 1What then is the purpose of revalidation?
TISSUE DISTRIBUTION OF C14 AFTER THE INTRAVENOUS INJECTION OF LABELED FREE FATTY ACIDS AND CHYLOMICRONS IN NEPHROTIC RATS*
Authors: Claude L. Malmendier
Journal: Journal of Clinical Investigation (1962)

The etiology of the hyperlipemia observed in the nephrotic syndrome has been the subject of many papers in recent years.The results of these stud- ies, although not mutually exclusive, have been interpreted in a variety of ways.The authors attribute this lipemia to an increase in the syn- thesis of lipids by the liver (1-4) joined to an in- creased hepatic protein synthesis (5), a deficiency of serum albumin (6), or the appearance of an antagonist to clearing factor in the circulating blood (7).A recent study by Saffran and Kalant (8) explained the hyperlipemia on the basis of "an increased hepatic synthesis and discharge of lipid" and "a decreased ability to remove chylomicron lipid from circulation."The distribution of C'4, after intravenous in- jection into normal rats of sodium palmitate-1-C14 or of chylomicrons biosynthesized from palmitic acid-l-C14, was studied by Bragdon and Gordon (9).The modifications in composition of plasma lipids and in liver function in nephrosis suggested a comparison of the distribution of C14-palmitate and C14-chylomicrons in nephrotic rats in order to see whether a difference of distribution of C14 could yield information that might help to explain the hyperlipemia of the syndrome.METHODS Preparation of rats.The experimental animals were male Osborne-Mendel rats weighing between 160 and 300 g.Nephrosis was induced by a single injection of a pool of rabbit antirat kidney serum prepared by the
Intermittent Neuroleptic Treatment and Risk for Tardive Dyskinesia: Curaçao Extrapyramidal Syndromes Study III
Authors: P N van Harten, H W Hoek, G E Matroos, M Koeter, R S Kahn
Journal: American Journal of Psychiatry (1998)

OBJECTIVE: The authors examined the association between three lifetime medication variables (cumulative amount of neuroleptics, number of interruptions in neuroleptic treatment, cumulative amount of anticholinergics) and the occurrence and severity of tardive dyskinesia. METHOD: The study was conducted in the only psychiatric hospital of a well-defined catchment area (the Netherlands Antilles). For all patients who had a history of taking neuroleptics for at least 3 months and were currently using neuroleptics (N=133, mean age=51.5 years), the presence and severity of tardive dyskinesia were measured with the Abnormal Involuntary Movement Scale. RESULTS: Of the three lifetime medication variables, only the number of neuroleptic interruptions was significantly related to tardive dyskinesia. The risk of tardive dyskinesia was three times as great for patients with more than two neuroleptic interruptions as for patients with two or fewer interruptions. CONCLUSIONS: This finding supports the schizophrenia protocol of long-term neuroleptic treatment rather than targeted or intermittent neuroleptic treatment.
Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial
Authors: Yi-Long Wu, Caicun Zhou, Cheng-Ping Hu, Jifeng Feng, Shun Lu, Yunchao Huang, Wei Li, Mei Hou, Jian Hua Shi, Kye Young Lee, Chong-Rui Xu, Dan Massey, Miyoung Kim, Yang Shi, Sarayut L Geater
Journal: The Lancet Oncology (2014)
<i>EGFR</i>-Driven Behavior and Intrapatient T790M Mutation Heterogeneity of Non–Small-Cell Carcinoma With Squamous Histology
Authors: Paolo Graziano, Filippo de Marinis, Bruno Gori, Rita Gasbarra, Rita Migliorino, Stefano De Santis, Giuseppe Pelosi, Alvaro Leone
Journal: Journal of Clinical Oncology (2014)

Case Report 1In October 2011, a lesion measuring 8 ϫ 5 cm was found in the right upper lung lobe of a 48-year-old woman with no history of smoking.Computed tomography (CT) scanning, bone scintigraphy, and magnetic resonance imaging highlighted pleura, hilar, mediastinal, and bilateral axillary lymph node involvement along with a right femur lesion.Bronchoscopy revealed obstruction of the right upper lobe, and multiple biopsies positive for p63, p40, and cytokeratin 5/6 and negative for cytokeratin 7 and thyroid transcription factor 1 favored a diagnosis of poorly differentiated squamous cell carcinoma (SqCC) of the lung.Considering the patient's sex and never-smoker status, EGFR assessment was requested, and an exon 19 microdeletion (L747-P753ϾS; 2240-2257del18) was identified.First-line treatment with gefitinib (250 mg per day) with zoledronic acid (4 mg per month) and palliative radiation therapy was preferred over conventional histotype-guided therapy.The patient had no remarkable adverse
Influence of Robotic-Assisted Surgery on Readmission Burden
Authors: Glen J. Weiss
Journal: Journal of Clinical Oncology (2015)

TO THE EDITOR: Stitzenberg et al are to be commended on their work and conclude that “the burden of readmissions after major cancer surgery is high, resulting in substantially poorer patient outcomes and higher costs.” During the time period in which these extirpative surgeries were conducted, it is likely that the uptake of robotic surgery increased. More recently, others have reported higher rates of intraoperative bleeding and cost with robotic-assisted thoracic surgeries compared with thoracoscopic lobectomy. For extirpative surgeries of pancreas, bladder, and esophagus cancers, the jury is still out on whether clinical outcomes have been improved, although higher costs are certainly a concern. Surveying their data for robotic-assistance codes from the International Classification of Diseases (9th revision, clinical modification), for example, codes 17.4, 17.41-17.45, or 17.49, can the authors confirm whether there was an increase in robotic-assisted surgery during the time frame of their analysis? Did robotic-assisted surgery influence the length of stay, readmission rate, and cost? These variables may help further elucidate factors that contribute to the burden of readmissions in patients who underwent major cancer surgery. Glen J. Weiss Cancer Treatment Centers of America, Goodyear, AZ
The First Death From Nitrogen Dioxide Fumes
Authors: José Ramírez-R
Journal: JAMA (1974)

THE importance of nitrous fumes as a cause of pulmonary tissue damage gained universal recognition with the demonstration that these were the mysterious toxic gases evolved in silos during the first week after ensilage.<sup>1,2</sup> Two types of pulmonary chemical injuries have been described: (1) pulmonary edema may occur within 24 hours of a prolonged or concentrated exposure; (2) a more subtle bronchiolar injury may cause life-threatening bronchiolar obstruction during the repair phase, one to four weeks after a brief encounter with the toxic gases.<sup>3</sup> There are simple and accurate descriptions of man's experience with the fumes of nitric acid, but there is none more vivid than the first recording 175 years ago. To give this classical description wider reading and its due historical prominence, an edited translation of the story of a man and his dog is presented here.<sup>4</sup>The clinical events are discussed in terms of
Cancer susceptibility and embryonic lethality in Mob1a/1b double-mutant mice
Authors: Miki Nishio, Koichi Hamada, Kohichi Kawahara, Masato Sasaki, Fumihito Noguchi, Shuhei Chiba, Kensaku Mizuno, Satoshi O. Suzuki, Youyi Dong, Masaaki Tokuda, Takumi Morikawa, Hiroki Hikasa, Jonathan Eggenschwiler, Norikazu Yabuta, Hiroshi Nojima, Kentaro Nakagawa, Yutaka Hata, Hiroshi Nishina, Koshi Mimori, Masaki Mori, Takehiko Sasaki, Tak W. Mak, Toru Nakano, Satoshi Itami, Akira Suzuki
Journal: Journal of Clinical Investigation (2012)

Mps one binder 1a (MOB1A) and MOB1B are key components of the Hippo signaling pathway and are mutated or inactivated in many human cancers. Here we show that intact Mob1a or Mob1b is essential for murine embryogenesis and that loss of the remaining WT Mob1 allele in Mob1aΔ/Δ1btr/+ or Mob1aΔ/+1btr/tr mice results in tumor development. Because most of these cancers resembled trichilemmal carcinomas, we generated double-mutant mice bearing tamoxifen-inducible, keratinocyte-specific homozygous-null mutations of Mob1a and Mob1b (kDKO mice). kDKO mice showed hyperplastic keratinocyte progenitors and defective keratinocyte terminal differentiation and soon died of malnutrition. kDKO keratinocytes exhibited hyperproliferation, apoptotic resistance, impaired contact inhibition, enhanced progenitor self renewal, and increased centrosomes. Examination of Hippo pathway signaling in kDKO keratinocytes revealed that loss of Mob1a/b altered the activities of the downstream Hippo mediators LATS and YAP1. Similarly, YAP1 was activated in some human trichilemmal carcinomas, and some of these also exhibited MOB1A/1B inactivation. Our results clearly demonstrate that MOB1A and MOB1B have overlapping functions in skin homeostasis, and exert their roles as tumor suppressors by regulating downstream elements of the Hippo pathway.
Phase II Trial of Vorinostat in Recurrent Glioblastoma Multiforme: A North Central Cancer Treatment Group Study
Authors: Evanthia Galanis, Kurt A. Jaeckle, Matthew J. Maurer, Joel M. Reid, Matthew M. Ames, James S. Hardwick, John F. Reilly, Andrey Loboda, Michael Nebozhyn, Valeria R. Fantin, Victoria M. Richon, Bernd Scheithauer, Caterina Giannini, Patrick J. Flynn, Dennis F. Moore, James Zwiebel, Jan C. Buckner
Journal: Journal of Clinical Oncology (2009)

Purpose Vorinostat, a histone deacetylase inhibitor, represents a rational therapeutic target in glioblastoma multiforme (GBM). Patients and Methods Patients with recurrent GBM who had received one or fewer chemotherapy regimens for progressive disease were eligible. Vorinostat was administered at a dose of 200 mg orally twice a day for 14 days, followed by a 7-day rest period. Results A total of 66 patients were treated. Grade 3 or worse nonhematologic toxicity occurred in 26% of patients and consisted mainly of fatigue (17%), dehydration (6%), and hypernatremia (5%); grade 3 or worse hematologic toxicity occurred in 26% of patients and consisted mainly of thrombocytopenia (22%). Pharmacokinetic analysis showed lower vorinostat maximum concentration and area under the curve (0 to 24 hours) values in patients treated with enzyme-inducing anticonvulsants, although this did not reach statistical significance. The trial met the prospectively defined primary efficacy end point, with nine of the first 52 patients being progression-free at 6 months. Median overall survival from study entry was 5.7 months (range, 0.7 to 28+ months). Immunohistochemical analysis performed in paired baseline and post-vorinostat treatment samples in a separate surgical subgroup of five patients with recurrent GBM showed post treatment increase in acetylation of histones H2B and H4 (four of five patients) and of histone H3 (three of five patients). Microarray RNA analysis in the same samples showed changes in genes regulated by vorinostat, such as upregulation of E-cadherin (P = .02). Conclusion Vorinostat monotherapy is well tolerated in patients with recurrent GBM and has modest single-agent activity. Histone acetylation analysis and RNA expression profiling indicate that vorinostat in this dose and schedule affects target pathways in GBM. Additional testing of vorinostat in combination regimens is warranted.
MB-30 * ONCOLYTIC PICORNAVIRUS SVV-001 PROLONGS ANIMAL SURVIVAL IN A PATIENT TUMOR-DERIVED ORTHOTOPIC XENOGRAFT MOUSE MODEL OF GROUP 3 SUPRATENTORIAL PRIMITIVE NEUROECTODERMAL TUMOR
Authors: Z. Liu, L. Qi, X. M. Zhao, Y. Huang, M. Kogiso, Y. Du, H. Lindsay, P. Baxter, J. Su, A. Adesina, M. Chintagumpala, X.-N. Li
Journal: Neuro-Oncology (2015)

BACKGROUND: Supratentorial primitive neuroectodermal tumors (sPNET) that express mesenchymal markers (Group 3) often exhibit metastasis at diagnosis and are particularly difficult to treat.Here, we examined the anti-tumor effects of SVV-00, an oncolytic virus that can pass through the blood brain barrier, using our newly established patient tumor-derived orthotopic xenograft mouse model of group 3 sPNET.METHODS: Permissiveness toward SVV-001 was examined in cultured neurospheres and in flow sorted xenograft cells that expressed CD133 and/or CD15, the putative cancer stem cell markers of sPNET.Therapeutic efficacy was determined by systemic treatment of xenograft tumors.Effects of SVV-001 on sPNET metastasis and the mechanism of action were examined through time-course analysis of tumor cell infection, apoptosis and autophagy in vivo.Tumor responsiveness was correlated with the expression of NEUROD1 and ASCL1 mRNA.RESULTS: The cultured sPNET neurospheres as well as the dual-and the mono-positive CD133 + and CD15 + cells were effectively infected by SVV-GFP and killed by SVV-001 (MOI ¼0.5-25).A single tail vein injection of SVV-001 (9 x 10 12 viral particle/kg) significantly prolonged the survival of tumor-bearing mice.In addition to tumor mass, sPNET xenograft cells in CSF spread and local invasion were also effectively killed 72 hr post virus injection.Mechanistically, we found that SVV-001 activated apoptosis and autophagy in vivo.Increased NEUROD1/ASCL1 ratio was found in IC-2664PNT, but no positive correlations were confirmed in medulloblastoma and pediatric high grade gliomas.CONCLUSION: We have identified SVV-001 as a novel agent that can effectively target, at least some of, group 3 sPNET tumor cells, including different subpopulations of cancer stem cells.Overall survival
Plasma Viral Load and CD4+ Lymphocytes as Prognostic Markers of HIV-1 Infection
Authors: John W. Mellors
Journal: Annals of Internal Medicine (1997)

The rate of disease progression among persons infected with human immunodeficiency virus type 1 (HIV-1) varies widely, and the relative prognostic value of markers of disease activity has not been defined.To compare clinical, serologic, cellular, and virologic markers for their ability to predict progression to the acquired immunodeficiency syndrome (AIDS) and death during a 10-year period.Prospective, multicenter cohort study.Four university-based clinical centers participating in the Multicenter AIDS Cohort Study.1604 men infected with HIV-1.The markers compared were oral candidiasis (thrush) or fever; serum neopterin levels; serum beta 2-microglobulin levels; number and percentage of CD3+, CD4+, and CD8+ lymphocytes; and plasma viral load, which was measured as the concentration of HIV-1 RNA found using a sensitive branched-DNA signal-amplification assay.Plasma viral load was the single best predictor of progression to AIDS and death, followed (in order of predictive strength) by CD4+ lymphocyte count and serum neopterin levels, serum beta 2-microglobulin levels, and thrush or fever. Plasma viral load discriminated risk at all levels of CD4+ lymphocyte counts and predicted their subsequent rate of decline. Five risk categories were defined by plasma HIV-1 RNA concentrations: 500 copies/mL or less, 501 to 3000 copies/mL, 3001 to 10000 copies/mL, 10001 to 30000 copies/mL, and more than 30000 copies/mL. Highly significant (P < 0.001) differences in the percentages of participants who progressed to AIDS within 6 years were seen in the five risk categories: 5.4%, 16.6%, 31.7%, 55.2%, and 80.0%, respectively. Highly significant (P < 0.001) differences in the percentages of participants who died of AIDS within 6 years were also seen in the five risk categories: 0.9%, 6.3%, 18.1%, 34.9%, and 69.5%, respectively. A regression tree incorporating both HIV-1 RNA measurements and CD4+ lymphocyte counts provided better discrimination of outcome than did either marker alone; use of both variables defined categories of risk for AIDS within 6 years that ranged from less than 2% to 98%.Plasma viral load strongly predicts the rate of decrease in CD4+ lymphocyte count and progression to AIDS and death, but the prognosis of HIV-infected persons is more accurately defined by combined measurement of plasma HIV-1 RNA and CD4+ lymphocytes.
Accurate Model Selection of Relaxed Molecular Clocks in Bayesian Phylogenetics
Authors: Guy Baele, Wai Lok Sibon Li, Alexei J. Drummond, Marc A. Suchard, Philippe Lemey
Journal: Molecular Biology and Evolution (2012)

Recent implementations of path sampling (PS) and stepping-stone sampling (SS) have been shown to outperform the harmonic mean estimator (HME) and a posterior simulation-based analog of Akaike’s information criterion through Markov chain Monte Carlo (AICM), in Bayesian model selection of demographic and molecular clock models. Almost simultaneously, a Bayesian model averaging approach was developed that avoids conditioning on a single model but averages over a set of relaxed clock models. This approach returns estimates of the posterior probability of each clock model through which one can estimate the Bayes factor in favor of the maximum a posteriori (MAP) clock model; however, this Bayes factor estimate may suffer when the posterior probability of the MAP model approaches 1. Here, we compare these two recent developments with the HME, stabilized/smoothed HME (sHME), and AICM, using both synthetic and empirical data. Our comparison shows reassuringly that MAP identification and its Bayes factor provide similar performance to PS and SS and that these approaches considerably outperform HME, sHME, and AICM in selecting the correct underlying clock model. We also illustrate the importance of using proper priors on a large set of empirical data sets.
Epinastine (WAL 801CL) inhibits the electrical field stimulation-induced cholinergic contraction in guinea pig and human airways in vitro
Authors: LJ Dupont, JL Pype, CJ Meade, P DeLeyn, G Deneffe, MG Demedts, GM Verleden
Journal: European Respiratory Journal (1999)

Epinastine is an antihistamine drug with binding affinities at 5-hydroxytryptamine (5-HT) receptors. The current study was performed to investigate whether epinastine could modulate the cholinergic contraction in guinea pig and human airways in vitro. Isolated guinea pig and human airway preparations were suspended in organ baths containing modified Krebs-Henseleit solution. Electrical field stimulation was applied to elicit cholinergic contractions. Epinastine produced a concentration-dependent inhibition of the cholinergic contraction in guinea pig airways and pretreatment with methysergide (5-HT1/2/7 antagonist) significantly attenuated these inhibitory effects of epinastine. Pretreatment with tropisetron (5-HT3/4 antagonist), ketanserin (5-HT2 antagonist), SDZ216-525 (5-HT1A antagonist) or phentolamine (alpha-adrenergic antagonist) had no effect. Epinastine did not displace the concentration-response curve to acetylcholine. These results suggest that epinastine inhibits the cholinergic contraction in guinea pig airways through stimulation of prejunctional 5-hydroxytryptamine receptors, located to postganglionic cholinergic nerves. Inhibitory effects of epinastine on the cholinergic contraction in human airways in vitro were also demonstrated, which suggests that a similar mechanism might be present in human airways. The pharmacological profile of epinastine, which shows binding affinity at the 5-hydroxytryptamine7 receptor but not at the 5-hydroxytryptamine1 receptor subtypes corroborates the hypothesis that the inhibitory prejunctional 5-hydroxytryptamine receptor on cholinergic nerves is of the 5-hydroxytryptamine7 subtype.