tbuckley/cabot-search huggingface dataset:
A comparison of β2-adrenoceptor desensitisation induced by olodaterol and formoterol in human lung mast cells and airway smooth muscle cells
Authors: Rebecca Lewis, Latifa Chachi, Yassine Amrani, Peter Bradding
Journal: European Respiratory Journal (2013)

Background:  The novel ultra-long-acting β 2 -adrenoceptor agonist olodaterol has been developed for the management of asthma and COPD.   Aims and Objectives:  To compare the effects of olodaterol with formoterol and salbutamol on FceRI-dependent human lung mast cell (HLMC) histamine release, and on β 2 -adrenoceptor (β 2 -AR) desensitisation in HLMCs, the HMC-1 human mast cell line and human airway smooth muscle (ASM) cells.   Experimental Approach:  FceRI-dependent histamine release was measured using a radioenzymatic assay. β 2 -AR desensitisation was measured by vasodilator-stimulated phosphoprotein (VASP) phosphorylation (HMC-1 and ASM) and histamine release (HLMCs).   Key Results:  Olodaterol and formoterol inhibited FceRI-dependent HLMC histamine release (IC 50 : 6.7 x 10 -11  M and 6.9 x 10 -11  M, respectively). Olodaterol was more potent than formoterol at inducing VASP phosphorylation in HMC-1 cells (EC 50 : 8.1 x 10 -11  M and 4.2 x 10 -10  M, respectively) (p 50 : 8.3 x 10 -10  M and 1.6 x 10 -8  M, respectively) (p 2 -agonists induced mast cell β 2 -AR desensitisation. At their EC 50  concentrations, formoterol induced ASM β 2 -AR desensitisation (p   Conclusions and Implications:  Olodaterol is a potent, effective inhibitor of FceRI-dependent HLMC mediator release, with a less pronounced desensitisation in ASM cells compared to formoterol at moderate doses.
Genetic Analyses of Differences in Incidence of Mammary Tumors and Reticulum Cell Neoplasms With the Use of Recombinant Inbred Lines of Mice&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: A Dux, O Mühlbock, D W Bailey
Journal: JNCI Journal of the National Cancer Institute (1978)

Journal Article Genetic Analyses of Differences in Incidence of Mammary Tumors and Reticulum Cell Neoplasms With the Use of Recombinant Inbred Lines of Mice Get access Anna Dux, Anna Dux Search for other works by this author on: Oxford Academic PubMed Google Scholar Otto Mühlbock, Otto Mühlbock Search for other works by this author on: Oxford Academic PubMed Google Scholar Donald W. Bailey Donald W. Bailey Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 61, Issue 4, October 1978, Pages 1125–1129, https://doi.org/10.1093/jnci/61.4.1125 Published: 01 October 1978 Article history Received: 14 December 1977 Accepted: 27 April 1978 Published: 01 October 1978
Sarcoidosis; the great mimicker: A CT study
Authors: Sheida Rostamzadeh, Shahram Kahkoueei, Shirin Dianati
Journal: European Respiratory Journal (2012)

Purpose: assessing manifestations of sarcoidosis in chest CT to make clinicians and radiologists consider this disease in daily practice.  Material and methods: CT and HRCT scans of 59 patients with biopsy-proven sarcoidosis were reviewed.  Results: Many of the classical findings including bilateral hilar and paratracheal adenopathy and parenchymal involvement like bronchovascular bundle thickening, nodularity, fibrobronchiectatic and fibrocavitary changes affecting upper and middle zones as well as pleural thickening were noted as previously mentioned by others.  But what highlights our study, is the interesting uncovering of 30.5% unilateral and 45.8% bilateral asymmetric parenchymal involvement, also scattered parenchymal metastasis-like nodules (20.3%), Patchy ground glass opacities mimicking BOOP (33.9%), the galaxy nodular pattern (11.9%) and enlargement of main pulmonary artery (23.7%).  parenchymal manifestations have been shown in Fig-1.  In addition to the usual widely known mediastinal lymphadenopathy stations, we found a considerable amount of involvement in subcarinal (55.9%), paraesophageal (22%), and 6.8% intraparenchymal lymph nodes and the least common pulmonary ligament lymph nodes (1.7%).  Conclusion: sarcoidosis can present with unusual findings in uncommon sites so whenever looking at a pulmonary CT we should ask: “Am I dealing with sarcoidosis?
High-dose therapy with iodine-131-labeled monoclonal antibody CC49 in patients with gastrointestinal cancers: a phase I trial.
Authors: M Tempero, P Leichner, G Dalrymple, K Harrison, S Augustine, J Schlam, J Anderson, J Wisecarver, D Colcher
Journal: Journal of Clinical Oncology (1997)

PURPOSE A phase I trial that evaluated for extrahematopoietic toxicity was conducted with iodine-131 (131I) labeled monoclonal antibody (MAb) CC49. Correlative studies included pharmacokinetic and biodistribution analyses, estimates of absorbed radiation dose, and measurement of human antimonoclonal antibodies (HAMA). PATIENTS AND METHODS After collection and cryopreservation of hematopoietic stem cells, 15 patients with gastrointestinal cancers were administered a tracer dose of 131I-MAb CC49. Within 5 to 6 days, 14 patients (two to three per activity level) underwent a single treatment with 131I-MAb CC49 (50, 100, 150, 200, 250, and 300 mCi/m2). Biodistribution was determined using planar and single photon emission computer tomographic (SPECT) imaging. Pharmacokinetic studies were performed by measuring radioactivity in serial blood samples. In some patients, biopsies of metastases and related normal tissues were obtained for radioactivity measurements. Radiation dosimetry estimates were calculated using available biodistribution, pharmacokinetic, and tissue biopsy data. Toxicity was evaluated using the National Cancer Institute (NCI) Common Toxicity Criteria. RESULTS No dose-limiting extrahematopoietic toxicity was identified. Twelve patients experienced grade IV myelosuppression and met criteria for infusion of hematopoietic stem cells. Radioimmunolocalization was excellent. The T1/2 for 131I-MAb CC49 after diagnostic and therapeutic administration was 39.7 +/- 10.4 and 46.1 +/- 10.6 hours, respectively. The percent injected dose per killigram of tumor ranged from 0.2 to 2.1. Absorbed radiation dose in metastatic tumor sites ranged from 630 to 3300 cGy. CONCLUSION Although extrahematopoietic dose-limiting toxicity was neither observed or predicted, suboptimal absorbed dose estimates suggested that further escalation of 131I-MAb CC49 would not be useful. Future studies should focus on the use of radionuclides with high energy beta emissions, such as yttrium 90, and on strategies to optimize access of antibody to target antigens.
Protective Role of Faecal pH in Experimental Colon Carcinogenesis
Authors: Scott L Samelson, Richard L Nelson, Lloyd M Nyhus
Journal: Journal of the Royal Society of Medicine (1985)

There is epidemiological evidence that populations with alkaline stool pH are at greater risk for colon cancer than populations with acid stool pH. This association was investigated in the laboratory using the rat-dimethylhydrazine colon carcinogenesis model. Rats with acid stool pH, produced by consumption of lactulose or sodium sulphate or both, had significantly fewer colon tumours after injections of dimethylhydrazine (DMH) than rats treated with DMH alone. The results confirm the hypothesis that acidification of the stool can protect against the induction of colon cancer.
Effect of bevacizumab (BV) and chemotherapy (CT) on serum levels of vascular endothelial growth factor receptor-2 (sVEGFR-2) in patients with inflammatory and locally advanced breast cancer
Authors: J. M. Walshe, N. Denduluri, A. W. Berman, D. Nguyen, S. Y. Yang, D. J. Liewehr, S. M. Steinberg, F. De Sauvage, H. Chen, S. M. Swain
Journal: Journal of Clinical Oncology (2006)

13003 Background: VEGFR-2 is a principal mediator of angiogenesis. The effects on sVEGFR-2 after anti-angiogenesis therapy are unknown. Methods: Twenty-one patients (pts) with breast cancer underwent neoadjuvant treatment with BV for 1 cycle (C1) followed by 6 cycles of BV, CT and filgrastim. Blood was collected at baseline (BL), post-cycles 1, 4 and 7. Objectives were to correlate sVEGFR-2 changes after treatment with response, assess wound healing complications, and evaluate for tumor VEGFR-2 mutations. sVEGFR-2 levels were measured by ELISA. Exons 17–26 were sequenced on tissue samples from 20 pts at BL and post C1 to evaluate for VEGFR-2 mutations. Statistical testing is non-parametric. All p-values are two-tailed, with a p &lt; 0.01 interpreted as a statistically significant difference. Results: Thirteen pts had a partial response (PR), 1 unconfirmed PR, 5 stable disease (SD), and 2 progressive disease (PD). Median sVEGFR-2 levels increased by 16% from BL to post C1 (p = 0.0003) and decreased by 19% post C1 to post C4 (p = 0.048). sVEGFR-2 levels were not associated with clinical response. sVEGFR-2 levels at BL did not correlate with other BL parameters: Ki67, microvessel density, VEGF-A, pVEGFR-2, VEGFR-2 or TUNEL (apoptosis). A moderate-weak correlation was seen between post C1 levels of sVEGFR-2 and pVEGFR-2 (r = 0.43). A moderate inverse correlation was seen in the relative difference of sVEGFR-2 and TUNEL from BL to post C1 (r = −0.59). Comparing pts with (n = 5) and without (n = 16) wound healing problems, median sVEGFR-2 levels were 11322 ng/ml and 7524 ng/ml at BL (p = 0.019), 13928 ng/ml and 10148 ng/ml post C1 (p = 0.029), and 10965 ng/ml and 7932 ng/ml post C4 (p = 0.042). In 40 samples where tumor VEGFR-2 sequencing was obtained, no mutations were seen compared to the reference sequence. Conclusion: sVEGFR-2 levels rose significantly following BV alone but were not associated with response. There is a suggestion that sVEGFR-2 may correlate with activated VEGFR2 and a decrease in apoptosis. sVEGFR-2 levels were higher in pts with wound healing problems and may predict pts at higher risk of this complication. There were no mutations of VEGFR2. [Table: see text]
NK cells of mice phagocytose hMSCs
Authors: Jin-Zhong Dong, Li-Ping Wang, Chun-Wei Shi, Sai-Nan Zhang, Ming-Qin Lu
Journal: Hepatology (2013)

In a recent issue of Hepatology, Herrera et al.1 reported that human bone-marrow derived mesenchymal stem cells (hMSCs) provided protection from death from fulminant liver failure (FLF) induced by intraperitoneal injection of D-galactosamine/lipopolysaccharide (GalN/LPS) in severe combined immune deficiency (SCID) mice. SCID mice lack functional T and B cells and have been used extensively in xenotransplantation. However, the mice still possess normal natural killer (NK) cells. Successful xenotransplantation in SCID mice is dependent on reduction of NK cells activity by conventional total body irradiation2 or treatment with anti-NK cell antibodies.3 No information was provided in this study1 on suppression of NK cell activity suppression prior to hMSCs injection. Activated NK cells can lyse hMSCs.4, 5 The possible mechanisms are as follows (Fig. 1). In normal cells, the expression of human leukocyte antigen (HLA) class I molecules (a classic MHC class 1 molecule) could interact with these inhibitory receptors (KIR) on NK cells and prevent NK cells from being activated. However, hMSCs have low-level expression of HLA class I molecules, and this would lessen inhibitory interactions, leading to NK-cell activation and then hMSC lysis. The hMSCs express the activating NK cell-receptor (KAR) ligands (PVR, Nectin-2, and ULBP3), which can be recognized by DNAM-1 and NKG2D of NK cells, contributing to NK cell-mediated lysis. Hence, suppression of the activation of NK cells in SCID mice is necessary before hMSCs injection. Jin-Zhong Dong, M.D. Li-Ping Wang, M.D. Chun-Wei Shi, M.D. Sai-Nan Zhang, M.D. Ming-Qin Lu, M.D. Department of Infection and Liver Diseases, Liver Research Center, First Affiliated Hospital of Wenzhou Medical College, Wenzhou, P.R. China
Metabolic tumor volume as an independent prognostic factor in lymphoma
Authors: A. Grow, A. Quon, E. E. Graves, B. W. Loo
Journal: Journal of Clinical Oncology (2005)

6594 Background: In Hodgkin’s disease (HD) and aggressive non-Hodgkin’s lymphomas (NHL), well-established clinical and laboratory parameters–the international prognostic factors (IPF) for HD and international prognostic index (IPI) for NHL–have been shown to have important prognostic value. While unidimensional measures of tumor size have not been independently predictive in these analyses, tumor burden is of recognized clinical importance. Our aim was to determine whether total body metabolic tumor volume (MTV) on FDG-PET independently predicts the likelihood of relapse for HD and aggressive NHL. Methods: We retrospectively analyzed 98 patients treated over the past two years at our institution for classical HD (n=46) and aggressive NHL (n=52) who had initial staging PET-CT scans. Average post-treatment follow-up time was 12.3 months, with disease relapse as the endpoint (17/46 for HD, 21/52 for NHL). No patients were lost to follow-up. Potential predictor variables including age, gender, stage, and IPI or IPF were identified for each patient. We also measured pre-treatment total MTV in milliliters using our own semi-automated image analysis software. Continuous variables (age, MTV) were compared using the Student’s t test, and categoric variables (gender, stage, IPI and IPF) were compared using Fisher’s exact test. IPI was categorized as low (0–1), intermediate (2–3) and high (4–5) risk, and IPF as favorable (less than 3) or unfavorable (3 or more). A univariate logistic regression was performed for each potential predictive variable, yielding odds ratios for relapse vs. non-relapse. A stepwise multivariate logistic regression was then performed to identify true independent predictors of relapse. Results: In the univariate analysis, stage (OR=1.06, 95% CI = 1.00–1.10, p=0.045), IPI (OR=1.13, 95% CI = 1.07–1.18, p=0.032), IPF (OR=1.08, 95% CI = 1.02–1.12, p=0.040) and MTV (OR=1.09, 95% CI = 1.04–1.15, p=0.021) proved to be significant predictors of relapse, but not age or gender. In the multivariate analysis, only MTV, IPI and IPF were independently predictive of relapse. Conclusions: MTV appears to have prognostic significance for early relapse in both classical HD and aggressive NHL independent of the standard prognostic indices. No significant financial relationships to disclose.
It doesn't "come with the job": violence against doctors at work must stop
Authors: S. S. Dubb
Journal: BMJ (2015)

Sukhpreet Singh Dubb reflects on the ubiquity of aggression towards healthcare workers after he was attacked by a patient in the emergency department

A drunken patient had fallen over and lost consciousness from head trauma. As he awoke I was met with indignation and racial slurs. Investigation indicated no injury to treat, and the man agreed to a few hours’ observation. But I returned later to find him verbally abusing the nursing staff, and he made physical threats on seeing me.

Despite our best intentions this man felt let down by the system, and the standard of our care fell short of his expectations. Demanding a form to discharge himself, he stormed out of the department. When I went into the waiting room to call the next patient the same man physically assaulted me, throwing me to the floor and punching me.

Patients in the emergency department who are in pain may behave uncharacteristically badly, and health workers have particular difficulty deciding which incidents of abuse to report, if any.

A good definition of workplace violence in …
An unusual development in a girl with recurrent croup - Case report
Authors: Diana Reppucci, Juerg Hammer, Daniel Trachsel
Journal: European Respiratory Journal (2012)

Background: Recurrent croup is common in childhood. Rare congenital and acquired pathologies may mimic viral croup.  Case: A girl with previously suspected laryngomalacia was admitted with a first episode of croup at 8 months of age, only partially responding to inhaled adrenalin. Laryngoscopically, the dorsal tracheal mucosa bulged into the subglottic area causing a 50% narrowing of the airway, and a CT showed a soft tissue mass between trachea and esophagus that was not suggestive of a hemangioma. In view of the inconspicuous appearance, the rapid recovery from the croup, the young age, and the location it was decided not to biopsy the lesion. After an uneventful observational period with decreasing symptoms the girl presented again at 4 years of age with a typical OSAS. With respect to the personal history, a bronchoscopy was made that confirmed significant adenotonsillar hypertrophy, but also revealed marked growth of the subglottic mass. A transtracheal biopsy was performed, and a plexiform neurofibroma was found. Due to the infiltrative growth of the neurofibroma, extensive surgery including partial tracheal resection became necessary. Eventually, the diagnosis of neurofibromatosis (NF) type 1 was made.  Conclusion: Neurofibroma in NF1 may occur in the laryngeal area, presenting early in infancy mimicking common croup.
Effect of Phospholipids on Maintenance of the Cytotoxicity of 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea in Aqueous Suspension 2
Authors: Howard S. Maker, Hasan H. Syed, Gerard M. Lehrer
Journal: JNCI Journal of the National Cancer Institute (1978)

Although the chemotherapeutic agent 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) is highly unstable in aqueous suspension, polar glycerophospholipids, notably phosphatidyl choline, had a protective action on the drug's cytotoxicity in aqueous suspension. The cytotoxicity of CCNU against C-S glioma cells in monolayer culture was maintained longer when the drug was preincubated in the presence of phosphatidyl choline (0.5 mg/ml) than when it was preincubated in medium alone or with serum or when other phosphollplds were added. Preservation of drug action may have been due to the formation of common micelles between CCNU and the phospholipid. The importance of the lipid interaction to the effectiveness of the nitrosoureas in vivo is unknown, but such interaction could be a factor in the duration of drug action, its access to the central nervous system, and its attachment to cell membranes.
Production of Interferon-Like Substances by Human Bone Marrow Tissues <italic>In Vitro</italic><xref ref-type="fn" rid="FN1">2</xref>
Authors: R L Northrop, F Deinhardt
Journal: JNCI Journal of the National Cancer Institute (1967)

Three hundred and fifty-six bone marrow tissues obtained from patients of a general hospital were tested for spontaneous production after cultivation in vitro of interferon-like substances (ILS). Seventeen percent of the tissues produced ILS that protected human, but not chick, embryo cell cultures against the cytopathic effects of challenge virus infection. The incidence of ILS did not correlate with leukemia or other neoplastic diseases, or with any non-neoplastic disease.
Studies on fibronectin in the skin.
Authors: OLE FYRAND
Journal: British Journal of Dermatology (1980)

Fibronectin is an important constituent of normal human skin, mediating cell/cell and cell/fibre interactions. In affected skin in discoid and systemic LE, changes in the distribution of fibronectin in the dermo-epidermal junction and in the papillary dermis are observed with homogenization and degenerative changes, IF negative gaps and slit formation in the dermo-epidermal region, together with IF positive globular bodies and transport of fibronectin into the epidermis. Unaffected skin in LE demonstrates the pattern of fibronectin as found in normal human skin.
Function of Depressed Immunologic Reactivity During Carcinogenesis&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: Richmond T. Prehn
Journal: JNCI Journal of the National Cancer Institute (1963)

Three series of tests were performed to challenge the hypothesis that interference with the immune response is a facet of the action of the carcinogen 3-methylcholanthrene. The first series showed that the carcinogen, in the dosages ordinarily used for sarcoma production, could interfere with a weak immune reaction. The second series demonstrated that the same carcinogen could facilitate the growth of first-transplant-generation tumors in isologous mice. Evidence was also obtained that the degree of the effect was related to the specific immunizing capacities of the tumors involved, which was in turn apparently related to the latent period of formation of the primary tumors. Since X-ray treatment of the recipients also improves the growth of first-transplant-generation tumors, the activity probably was exerted, at least in part, via interference with the immune mechanism. The last series provided evidence in favor of an indirect mechanism as a facet of carcinogenic action. The production of sarcomas at the sites of carcinogen-containing pellets was much increased by the remote application of further carcinogen. The evidence, while consistent with an indirect mechanism, was not conclusive. These experiments, augmented by further data from the literature, support the theory that the immune mechanism may normally function to inhibit the development of certain neoplasms. The theory cannot be established, however, unless and until more direct and decisive evidence is obtained.
The safety, PK and PD profile of ADC3680, a potent and selective CRTh2 antagonist, in healthy volunteers and partly controlled atopic asthmatic subjects
Authors: Mary Fitzgerald, Sue Snape, Salvatore Febbraro, David Singh, Caroline Patwell, Bharat Ruparelia, Noel Snell
Journal: European Respiratory Journal (2013)

ADC3680 is a potent and selective CRTh2 antagonist whose efficacy is currently being evaluated in subjects with uncontrolled asthma on ICS.  In Phase I, 88 healthy volunteers were exposed to ≥1 dose of ADC3680 (1 – 200 mg as single doses; 10, 30 and 90 mg once daily for 7 days; and 10 mg daily for 14 days). 24 further subjects with partly controlled atopic asthma on ICS, received a 22.73 mg ADC3680 once daily for 28 days.  ADC3680 is relatively rapidly absorbed (t max  2.5 hrs) and suitable for once-daily oral dosing (t 1/2  11–15 hrs). Total plasma clearance of ADC3680 is low with little evidence of accumulation on repeat dosing.  ADC3680 was safe and well-tolerated at single doses up to 200 mg, at doses up to 90 mg administered once daily for 7 days and in post-menopausal female volunteers at a single dose of 25 mg. ADC3680 was also well-tolerated in atopic asthmatics (22.73 mg once daily for 28 days). Most adverse events reported were mild or moderate and were considered to be unrelated to treatment and there were no clinically significant changes in laboratory safety parameters.  ADC3680 blocked PGD 2  mediated eosinophil shape change response (ESC)  ex-vivo  in blood from healthy and asthmatic subjects. >90% inhibition of ESC was observed with ADC3680 at single (1 to 200 mg) and multiple ADC3680 doses (10, 30, and 90 mg once daily for 7 days). In asthmatic subjects, ADC3680 (22.73 mg daily) blocked ESC by >95% 24 hours post-dose on Day 1, and at 24 and 48 hours post-dose after 28 days9 treatment.  The overall PK, safety and PD profile of ADC3680 support its further development as a low dose (