tbuckley/cabot-search huggingface dataset:
Loss of the Oncogene From Human H-ras-1-Transfected NIH/3T3 Cells Grown in the Presence of Excess Methionine2
Authors: Jana Hillova, Miroslav Hill, Jean Belehradek, Régine Mariage-Samson, Zbynek Brada
Journal: JNCI Journal of the National Cancer Institute (1986)

Mouse NIH/3T3 cells, transfected with T24 genomic DNA (J10 cells), carry the human H-ras-1 (hu-H-ras-1) oncogene stably integrated in the chromosomal DNA and display the transformed phenotype with a "criss-cross" morphology and capacity for anchorage-independent growth. When these cells were cultured in the presence of 25 mM DL-methionine, they lost their transformed phenotype; the characters of the normal phenotype (before transfection) reappeared, even though cell viability, as measured by the cloning potential on a solid support, was fully conserved. Southern blot analysis showed that cells continuously propagated in methionine-supplemented medium (J10met), unlike cells grown in normal medium, progressively segregated the hu-H-ras-1 gene. The progressively fewer cells still retaining the oncogene could be selected by inoculation of J10met cells into nude (nu/nu) mice of Swiss background. After prolonged methionine treatment, however, no such oncogene-positive cells could be detected, even when the excess methionine was withdrawn from the culture medium after 105 days. Conclusive evidence for the loss of the hu-H-ras-1 oncogene sequence was provided by subcloning the J10met cells. The oncogene sequence could no longer be found, and a fraction of subclones was no longer tumorigenic when assayed in nude mice. Other subclones generated late tumors negative for the hu-H-ras-1 transforming sequence, and a small fraction of subclones gave rise to rapidly growing early tumors that were also negative for the transforming sequence. The question of how methionine can induce the phenotypic and genetic change from malignancy to normality is discussed.
Nitrogen washout slope in poorly controlled asthma
Authors: A. Bourdin, F. Paganin, C. Préfaut, D. Kieseler, P. Godard, P. Chanez
Journal: Allergy (2005)

Short‐term control of asthma is often lacking even though forced expiratory volume in 1 s (FEV 1 ) remains above normal value. Small airways are a potential key site of persistent inflammation and structural modification. Noninvasive assessment of small airways was found to be difficult, but the computerized single breath nitrogen washout test (SBNT) has been recently successfully reintroduced with this aim. Twenty‐four asthmatics (13 females) of various severity but with normal FEV 1 were compared with 24 healthy volunteers (13 females) and studied at steady‐state after bronchodilatation (400 μ g salbutamol). Spirometric values, plethysmographic data, phase III (slope of phase III of the SBNT, dN2) and IV [closing volume (CV), with closing capacity (CC) = CV + residual volume (RV)] of the SBNT were checked. Asthma severity, recent control, exacerbation rate, and therapy requirements were assessed on the basis of validated questionnaires (ACQ) and international guidelines. Patients were prospectively pooled into two equal groups according to their exacerbation rate. The reproducibility of the measurements obtained on 2 following days was assessed. All plethysmographic values, except total lung capacity (TLC), differentiated asthmatic patients from controls. The CC/TLC [124 (117–148) vs 117 (112–123), P = 0.04] and dN2 [110 (99–190) vs 94 (75–111), P = 0.02] were increased in asthma. The dN2 was significantly increased in patients with frequent exacerbations [100 (83–105) vs 195 (141–212), P = 0.0005]. A correlation was obtained between dN2 and recent asthma control ( ρ : 0.62; P = 0.003), number of exacerbations ( ρ : 0.71, P = 0.0008), and RV/TLC ( ρ : 0.49, P = 0.026). This study demonstrated that ventilation inequalities assessed by dN2 represent an important indicator of poor asthma control and high exacerbation rate in high symptom perceivers. New therapies focused on small airways should now be developed.
Abstract 2730: RNAi knockdown or chemical inhibition of anaphase-promoting complex components is synthetic lethal with HSP90 inhibition
Authors: Jennifer Howes, Bing-Feng Lu, Marissa Powers, Costas Mitsopoulos, Bissan Al-Lazikani, Spiros Linardopoulos, Paul Clarke, Paul Workman
Journal: Cancer Research (2014)

Abstract The molecular chaperone heat shock protein 90 (HSP90) maintains the conformation, stability and function of oncogenic client proteins, many of which are mutated or overexpressed. Therefore, HSP90 is an important cancer therapeutic target. To further increase the efficacy of HSP90 inhibitors, combinatorial therapeutic strategies may be beneficial. Here we report an unbiased global screening approach to identify genes that encode potentially druggable proteins that modulate cellular responses to HSP90 inhibition. From the 7,593 genes that were tested, three components of the anaphase-promoting complex (APC/C) were among the genes which when silenced caused significant HSP90 inhibitor sensitisation. siRNA knockdown of ANAPC1, -8 or -4 produced up to three-fold sensitisation to HSP90 inhibitors 17-AAG and AUY922 in human colon cancer cells. Intriguingly, we show that combinatorial siRNA-mediated ANAPC1 knockdown and HSP90 inhibition induced an accumulation of mitotic cells exhibiting a tri-polar spindle formation. A marked increase in cyclin B1 and aurora A protein levels was observed in response to combinatorial ANAPC1 knockdown and HSP90 inhibition. These effects may have been responsible for the observed formation of aberrations in the mitotic spindle architecture. Furthermore, after a period of prolonged mitotic arrest, cancer cells treated with combinational ANAPC1 knockdown and HSP90 inhibition were committed to apoptosis. Mimicking siRNA knockdown, treatment with the APC/C inhibitor proTAME synergistically sensitised human colon carcinoma cells to HSP90 inhibition. These exciting results provide a mechanistic explanation underlying the HSP90 inhibitor sensitisation phenotype, and suggest that the APC/C may represent an interesting therapeutic target to exploit in combination with HSP90 inhibitors. Furthermore, therapeutic approaches may be developed which exploit the vulnerability of mitotic cancer cells in the context of HSP90 inhibition. Citation Format: Jennifer Howes, Bing-Feng Lu, Marissa Powers, Costas Mitsopoulos, Bissan Al-Lazikani, Spiros Linardopoulos, Paul Clarke, Paul Workman. RNAi knockdown or chemical inhibition of anaphase-promoting complex components is synthetic lethal with HSP90 inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2730. doi:10.1158/1538-7445.AM2014-2730
Randomized double-blind placebo-controlled trial of homoeopathic ‘proving' for Belladonna C30
Authors: Kathryn Goodyear, George Lewith, J Lorraine Low
Journal: Journal of the Royal Society of Medicine (1998)

Homoeopathic drug pictures are developed by recording the symptomatic effects of homoeopathic remedies given to healthy volunteers (a ‘proving’). In a double-blind randomized controlled trial we tested the hypothesis that individuals using an infinitesimal dilution of Belladonna (thirtieth potency, C30) would record more true symptoms, on a questionnaire that contained both true and false Belladonna proving symptoms, than those receiving placebo.60 volunteers entered the study and 47 completed data collection. We were unable to distinguish between Belladonna C30 and placebo using our primary outcome measure. For the secondary outcome measure we analysed the number of individuals who proved to the remedy according to our predefined criteria: 4 out of 19 proved in the Belladonna C30 group and 1 out of 27 in the placebo group (difference not statistically significant).This pilot study does not demonstrate a clear proving reaction for Belladonna C30 versus placebo, but indicates how the question might be further investigated.
Patient and health care providers (HCP) perception of benefits and future use of acute non-invasive ventilation (NIV)
Authors: April Thompson, Swapna Mandal, Nicholas Hart, Craig Davidson
Journal: European Respiratory Journal (2013)

Introduction :Published data indicate that poor tolerance of acute NIV adversely affects adherence resulting in treatment failure. However, data reporting patient perception of benefits and future use are limited.   Methods :Patients requiring acute NIV admitted to high dependency unit were included. Visual analogue scores for patient and HCP perceptions of NIV comfort, tolerance and benefit were recorded. At 6 weeks, patient recollections of their experience were obtained.   Results :42 patients participated, 57% female (age 68.8±12.9 years); mean duration use 6.6±16.5 days, exacerbation of COPD constituting 75%. 6-week data were obtained in 73.8% (31/42) of patients, 22% (7/31) were unable to recall their experience of NIV, whereas 29% (9/31) recall panic, 22% (7/31) fear and 29% (9/31) poor mask satisfaction. 74% (23/31) agreed to use NIV in the future. There was a significant improvement in patient-reported comfort between initiation and cessation of NIV, and a significant discrepancy between patient and HCP reported comfort and tolerance (Figure 1).   Conclusion :Approximately half of patients recollected panic and fear and almost a third mask discomfort. Despite this, almost three-quarters would use NIV again. A wide variability between patient and HCP perceptions of comfort and tolerability was observed. Better techniques are required to measure patient comfort to enhance tolerability of acute NIV.
Selection of Carcinogens and Related Compounds Tested for Mutagenic Activity
Authors: L A Poirier, E K Weisburger
Journal: JNCI Journal of the National Cancer Institute (1979)

A list of 102 chemical was prepared for subsequent mutagenesis assay in National Cancer Institute program to determine the extent of correllation between carcinogenesis and mutegenesis in standardized assays. The chemical were divided into five major categories: 37 aromatic amines, 11 polycyclic aromatic hydrocarbons, 8 nitrosamines and nitrosamides, 16 alkylating agents, and a miscellaneous category consisting of 11 heterocyclic compounds, 7 amides, ureas and acylating agents, 5 antimetabolites, 4 inorganic chemicals, and 3 promoters. The chemicals were further described as procarcinogens (requiring metabolic activation to exert their biologic activities), ultimate carcinogens (direct-acting chemicals not requiring metabolic activation), and noncarcinogens (compound shown to be Inactive in one or more adequate carcinogenicity tests). An extensive bibliography documents the selection and categorization of the compounds.
Are general internal medical (GIM) trainees confident in the thrombolysis of acute pulmonary embolism
Authors: Rebecca Dickinson, Sega Pathmanathan
Journal: European Respiratory Journal (2014)

Background:   The decision to thrombolyse may be a difficult one with guidance for high risk (with haemodynamic instability) and intermediate risk PEs (those with evidence of cardiac dysfunction but stable) being different between international societies.   Methods:   We designed a 10 question survey using a web-based survey programme (surveymonkey.com) with a computer generated link for easy access. A Likert scale (1-5) was used for confidence assessment. The link was sent to all GIM trainees (ST3 and above) within the East and West regions of the Yorkshire Deanery. The data was analysed using Microsoft excel.   Results:   Two hundred and fifty trainees dual training in GIM and a specialty were contacted with 61 fully completing the survey (24.4%) and two partial responses.  The replies were spread amongst all training grades and specialities with ST3 (23.8%) and Care of the Elderly (27%) being most common respectively. 62% of trainees had thrombolysed a PE with the majority (88.9%) expected to initiate treatment. However only 22.2% had had formal teaching in thrombolysing PEs and 41.9% of trainees felt unconfident in deciding the need for thrombolysis.  Senior support was available to trainees mainly from the oncall respiratory or general medical consultant.   Conclusion:   Those expected to initiate and manage patients with massive PEs should be appropriately trained to deal with this situation. However there does appear to be a gap in the formal training process.  We recognise the difficulties in choosing patients who may benefit from thrombolysis and therefore it was reassuring that trainees knew who they could contact for support.
Persistence of Mitotic Circadian Rhythm of a Transplantable Mammary Carcinoma After 35 Generations: Its Bearing on the Success of Treatment With Endoxan&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Amado F. Badran, Julian M. Llanos Echave
Journal: JNCI Journal of the National Cancer Institute (1965)

The persistence of a circadian rhythm is reported in the mitotic activity of a mammary carcinoma of a C3H/Mza female mouse after 35 transplant generations carried out over a 3-year period. The possible causes of the different results found in the literature on mitotic rhythms in malignant tumors are analyzed. The antitumor effect of Endoxan administered at different times during a 24-hour period is also reported. This drug is more effective if administered when the mitotic activity of the tumor is high (4 am, 8 am, noon, and 4 pm) than when the mitotic activity is low (8 pm and midnight). The practical importance of this fact is emphasized.
Conflicts, Accidents, Catastrophes and Chaos: Road Transport in the Twenty-First Century
Authors: Christopher Wright
Journal: Journal of the Royal Society of Medicine (1994)

The author looks at trends in transportation, focusing on future traffic congestion problems, social and physical environments, and traffic accidents and their causes. The author concludes that while safety will continue to improve (but not radically), congestion will get worse. Communities will become increasingly stratified. There will be an accelerated quest for peace in the unspoiled countryside, and less unspoiled countryside available. The more efficient and reliable we try to make our road system, the more people will be attracted to use cars. It may be better to tackle the problem by reducing the level of demand either through road pricing, or through some form of rationing.
Does tolerance of neuro-muscular electrical stimulation (NMES) relate to gender in patients with an acute exacerbation (AE) of chronic obstructive pulmonary disease (COPD)?
Authors: Emma Chaplin, Linzy Houchen, Neil Greening, Theresa Harvey-Dunstan, Michael Steiner, Sally Singh
Journal: European Respiratory Journal (2012)

INTRODUCTION: The maximum intensity tolerated using NMES is relatively unknown in patients with an AECOPD. Previous data suggest that healthy males are able to tolerate higher intensities than females. The aim of this study was to compare the tolerance of NMES in patients admitted with an AECOPD between males and females.

METHODS: 188 patients hospitalised with an AECOPD were recruited [85 male, MRC 4 (IQR 4-5), mean (SD) age 70.7 (±9.3) years, FEV1 1.38L ±0.71, BMI 26.7 ±7.0]. NMES was applied daily to both quadriceps muscles (30 mins, frequency 50Hz, pulse duration 300usec) for the duration of hospital stay.

RESULTS: 175 patients completed the NMES intervention. A statistically significant difference between genders was seen in the intensity tolerated at both baseline and at discharge (p ≤ 0.01) as well as change in intensity. This change remained significantly different when correcting for baseline intensity (p=0.001) There was no significant difference in the number of sessions completed during hospitalisation between genders.

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CONCLUSION: The intensity of NMES is tolerated at significantly higher levels in males. This may have clinical implications for NMES prescription and relate to outcome measures (eg. strength).
Medullary-Type Poorly Differentiated Adenocarcinoma of the Large Bowel: A Distinct Clinicopathologic Entity Characterized by Microsatellite Instability and Improved Survival
Authors: Giovanni Lanza, Roberta Gafà, Maurizio Matteuzzi, Alessandra Santini
Journal: Journal of Clinical Oncology (1999)

Recent studies suggest the existence of a distinct class of poorly differentiated large bowel adenocarcinomas, usually termed medullary-type adenocarcinomas (MTAs). The aim of the present study was to accurately define the clinical, histopathologic, biologic, and genetic features of this tumor type.Among 1,265 surgically resected sporadic colorectal carcinomas, 45 MTAs were identified on the basis of the following criteria: predominantly solid growth pattern (at least 70% of the tumor area) and lack of marked nuclear pleomorphism. The clinicopathologic, biologic, and genetic characteristics of MTAs were compared with those of a series of 457 common glandular colorectal adenocarcinomas.The significantly different clinicopathologic features of MTAs were proximal location, large size, invasion into adjacent organs, expanding pattern of growth, low incidence of distant metastases, more frequent conspicuous peritumoral lymphocytic infiltration, and Crohn's-like lymphoid reaction. Furthermore, young patients with MTAs often demonstrated a family history highly suggestive of a hereditary background. Unlike glandular adenocarcinomas, the large majority of MTAs were DNA diploid by flow cytometric analysis (21 of 25, 84%) and p53 negative by immunohistochemistry (36 of 41, 87.8%). In addition, 18 of the 20 MTAs examined by DNA microsatellite analysis demonstrated widespread microsatellite instability (90% of cases). Patients with MTAs showed a better clinical outcome with respect to patients with common poorly differentiated adenocarcinomas (PDAs) (P <.0001) and well- or moderately differentiated adenocarcinomas (WMDAs) (P =.133). In particular, none of the 33 patients with completely resectable stage II and III MTAs developed tumor recurrence during the observation period. Conversely, 24.7% of patients with stage II and III WMDAs and 48.9% of patients with stage II and III PDAs, who had undergone curative surgical resection, died of recurrent disease (P =.01 and P <.0001, respectively).All these data strongly indicate that MTAs represent a distinct pathologic entity, with specific histologic appearance and peculiar clinical and genetic features. These tumors need to be classified separately from other poorly differentiated colorectal carcinomas.
Sophisticated misguidance
Authors: Amarasinghe A W Amarasinghe
Journal: BMJ (2008)

Silybin, a major pharmacologically active compound in silymarin, has been widely used in combination with other prescriptions in the clinic to treat hepatitis and a host of other diseases. Previous studies suggested that silybin is a potential inhibitor of multiple drug-metabolizing enzymes (DMEs); however, the in vitro to in vivo translation and the mechanisms involved remain established. The aim of this study was to provide a mechanistic understanding of the regulatory effects of silybin on principal DMEs. Silybin (50 or 150 mg/kg/d) was administered to mice for a consecutive 14 days. The plasma and hepatic exposure of silybin were detected; the mRNA, protein levels, and enzyme activities of principal DMEs were determined. The results demonstrated that the enzyme activities of CYP1A2, CYP2C, CYP3A11, and UGT1A1 were significantly repressed, whereas little alteration of the mRNA and protein levels was observed. Silybin inhibits these DMEs in a mechanism-based and/or substrate-competitive manner. More importantly, silybin was found to be a weak agonist of peroxisome proliferator-activated receptor (PPAR)<i>α</i>, as evidenced from the molecular docking, reporter gene assay, and the targeting gene expression analysis. However, silybin could significantly compromise the activation of PPAR<i>α</i> by fenofibrate, characterized with significantly repressed expression of PPAR<i>α</i> targeting genes, including L-FABP, ACOX1, and UGT1A6. This study suggests that silybin, despite its low bioavailability, may inhibit enzyme activities of multiple DMEs in a mechanism-based mode, and more importantly, may confer significant drug-drug interaction with PPAR<i>α</i> agonists via the repression of PPAR<i>α</i> activation in a competitive mode.
Serum 25-hydroxyvitamin D serum levels in a large German cohort of patients with melanoma
Authors: T. Gambichler, M. Bindsteiner, S. Höxtermann, A. Kreuter
Journal: British Journal of Dermatology (2012)

Observational studies have suggested that 25-hydroxyvitamin D [25(OH)D] is associated with better outcomes in patients with malignant melanoma (MM).To study the relationship between serum 25(OH)D levels and clinical parameters in a large German cohort of patients with MM.We prospectively investigated the 25(OH)D serum levels of 764 patients with MM using the direct competitive chemiluminescence LIAISON immunoassay. Patients with MM who were taking 25(OH)D supplements were not included.Median serum 25(OH)D baseline levels were 12·3 ng mL (lower quartile: 7·3 ng mL , upper quartile: 20·2 ng mL ). Of the 764 patients, 564 (73·8%) had 25(OH)D deficiency [25(OH)D < 20 ng mL ], 145 (18·8%) had 25(OH)D insufficiency [25(OH)D ≥ 20, < 30 ng mL ] and only 55 (7·2%) had serum 25(OH)D levels within the normal range (≥ 30 ng mL ). Using a multiple regression model, lower 25(OH)D levels were significantly associated with higher Breslow tumour thickness (class: < 1 mm; 1-4 mm; > 4 mm, regression coefficient -1·45, P = 0·028) and higher American Joint Committee on Cancer 2002 melanoma stage (regression coefficient: -0·79, P = 0·036).In patients with MM, decreased 25(OH)D serum levels are associated with increased tumour thickness and advanced tumour stage. Hence, evidence is accumulating that patients with MM might benefit from 25(OH)D supplements.
Abstract 3577: Reproducible copy number variation patterns among single circulating tumor cells of lung cancer patients
Authors: Xiaohui Ni, Minglei Zhuo, Zhe Su, Jiachun Duan, Yan Gao, Zhijie Wang, Chenghang Zong, Fan Bai, Jie Wang, X. Sunney Xie
Journal: Cancer Research (2014)

Abstract Circulating tumor cells (CTCs) enter peripheral blood from primary tumors and seed metastases. The genome sequencing of CTCs could offer noninvasive prognosis or even diagnosis, but has been hampered by the low single-cell genome coverage of scarce CTCs. Here, we report the use of the recently developed multiple annealing and looping-based amplification cycles for whole genome amplification of single CTCs from lung cancer patients. We observed characteristic cancer-associated single-nucleotide variations and insertions/deletions in exomes of CTCs. These mutations provided information needed for individualized therapy, such as drug resistance and phenotypic transition, but were heterogeneous from cell to cell. In contrast, every CTC from an individual patient, regardless of the cancer subtypes, exhibited reproducible copy number variation (CNV) patterns, similar to those of the metastatic tumor of the same patient. Interestingly, different patients with the same lung cancer adenocarcinoma (ADC) shared similar CNV patterns in their CTCs. Even more interestingly, patients of small-cell lung cancer have CNV patterns distinctly different from those of ADC patients. Our finding suggests that CNVs at certain genomic loci are selected for the metastasis of cancer. The reproducibility of cancer-specific CNVs offers potential for CTC-based cancer diagnostics. Citation Format: Xiaohui Ni, Minglei Zhuo, Zhe Su, Jiachun Duan, Yan Gao, Zhijie Wang, Chenghang Zong, Fan Bai, Jie Wang, X. Sunney Xie. Reproducible copy number variation patterns among single circulating tumor cells of lung cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3577. doi:10.1158/1538-7445.AM2014-3577