tbuckley/cabot-search huggingface dataset:
Pathogenesis of Lesions Induced in Rat Lung by Chronic Tobacco Smoke Inhalation23
Authors: Carol A. Heckman, Walden E. Dalbey
Journal: JNCI Journal of the National Cancer Institute (1982)

Lesions were induced in the lungs of specific-pathogen-free F344 rats by chronic tobacco smoke exposure. Animals exposed to 7 cigarettes/day were killed after 1, 1.5, or 2 years of exposure. Parallel lifetime exposures induced pulmonary tumors in 9% of the animals. In serially killed animals, four types of lesions were found: 1) perivascular or peribronchiolar accumulation of lymphoreticular cells. 2) fibrotic and cellular enlargement of peribronchiolar septa, 3) type II cell hyperplasia with septal fibrosis, and 4) air-space enlargement (emphysema). However, emphysema occurred only in animals exposed to a higher (10 cigarettes) dose of tobacco smoke. Ultrastructural studies showed all of the focal lesions to be infiltrated by cells typical of the inflammatory response. The type II hyperplastic and peribronchiolar alveolar lesions involved larger portions of the parenchyma in fibrotic changes but differed in structure, location, and frequency. The incidence of the peribronchiolar alveolar lesions was temporally related to tumor incidence.
Authors’ reply to Lewis and Bray
Authors: Stewart W Mercer, Rupert A Payne, Barbara I Nicholl, Jill Morrison
Journal: BMJ (2015)

We were interested to read the rapid responses to our editorial about Shin and colleagues’ paper.1 2 We stand by our statement about the difficulty of making evidence based decisions in patients with multiple comorbidities in general practice, for whom high quality scientific evidence is almost always lacking. And, although we agree with Lewis that computer …
Reporting of MABp1 for the Treatment of Psoriasis—Reply
Authors: Kyle M. Coleman, Johann E. Gudjonsson, Michael Stecher
Journal: JAMA Dermatology (2015)

In Reply Thank you for allowing us the opportunity to respond to the commentators’ criticism and clarify the results from our recent report using MABp1 (Xilonix) in patients with moderate to severe plaque psoriasis.
Nitrosamide Formation &lt;italic&gt;In Vivo&lt;/italic&gt;: Induction of Lung Adenomas in Swiss Mice by Concurrent Feeding of Nitrite and Methylurea or Ethylurea&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: S. S. Mirvish, M. Greenblatt, V. R. Choudari Kommineni
Journal: JNCI Journal of the National Cancer Institute (1972)

Swiss mice were treated for 6 months with methylurea (5.36 g/kg food) or ethylurea (6.36 g/kg food) together with sodium nitrite (1.0 g/liter drinking water). In both groups, more than 4 lung adenomas/mouse were induced. The alkylurea-plus-nitrite groups also had a small increase in malignant lymphomas. Similar treatment with methylurea or ethylurea alone had no effect. The results indicate that the lung adenomas were induced by methylnitrosourea and ethylnitrosourea, formed by in vivo nitrosation of the corresponding alkylureas. The possible public health implications of ureide nitrosation in vivo are discussed.
Placebo-controlled randomized trial of infusional fluorouracil during standard radiotherapy in locally advanced head and neck cancer.
Authors: G P Browman, C Cripps, D I Hodson, L Eapen, J Sathya, M N Levine
Journal: Journal of Clinical Oncology (1994)

PURPOSE To determine whether the addition of infusional fluorouracil (I-FU) to standard radiotherapy improves survival at acceptable toxicity in patients with locally advanced squamous cell head and neck cancer (SCHNC). PATIENTS AND METHODS Consenting patients with an Eastern Cooperative Oncology Group (ECOG) performance status &lt; or = 2; with stage III or IV SCHNC of the oral cavity, oropharynx, hypopharynx, or larynx; and who were recommended for radiotherapy with curative intent received 66 Gy of radiation therapy delivered in 2-Gy fractions once daily 5 days per week for 6 1/2 weeks. Those in the experimental arm received I-FU 1.2 g/m2/d, as a 72-hour infusion in the first and third weeks of radiation. Saline infusions were used in the placebo arm. RESULTS One hundred seventy-five patients were randomized (88 to I-FU and 87 to placebo), and the treatment arms were well balanced. The complete response rate was 68% for I-FU and 56% for placebo (P = .04). The overall median survival duration was 33 months for I-FU and 25 months for placebo (P = .08). Progression-free survival also favored I-FU (P = .06). Toxicity was greater in I-FU patients, but did not interfere with the scheduled delivery or completion of radiation. CONCLUSION The addition of I-FU to standard radiation in SCHNC improved the complete response rate and was associated with beneficial trends in progression-free and overall survival compared with radiation alone. I-FU patients also experienced greater morbidity, but this did not compromise delivery of radiotherapy.
Alternative p38 MAPKs Are Essential for Collagen‐Induced Arthritis
Authors: Gabriel Criado, Ana Risco, Dayanira Alsina‐Beauchamp, María J. Pérez‐Lorenzo, Alejandra Escós, Ana Cuenda
Journal: Arthritis & Rheumatology (2013)

The role of most p38 MAPK isoforms in inflammatory arthritis is not known. This study was undertaken to evaluate p38γ and p38δ deficiency in the collagen-induced arthritis (CIA) model.Wild-type, p38γ(-/-) , p38δ(-/-) , and p38γ/δ(-/-) mice were immunized with chicken type II collagen, and disease activity was evaluated by semiquantitative scoring and histologic assessment. Serum cytokine levels and in vitro T cell cytokine responses were quantified by flow cytometry and multiplex analysis, and serum anticollagen antibody levels by enzyme-linked immunosorbent assay. Cytokine and p38 MAPK isoform expression in joints were determined by quantitative polymerase chain reaction.Compound p38γ and p38δ deficiency markedly reduced arthritis severity compared with that in wild-type mice, whereas lack of either p38γ or p38δ had an intermediate effect. Joint damage was minimal in arthritic p38γ/δ(-/-) mice compared with wild-type mice. The p38γ/δ(-/-) mice had lower levels of pathogenic anticollagen antibodies and interleukin-1β (IL-1β) and tumor necrosis factor α than controls. In vitro T cell assays showed reduced proliferation, interferon-γ (IFNγ) production, and IL-17 production by lymph node cells from p38γ/δ(-/-) mice. IL-17 and IFNγ messenger RNA expression in joints was significantly inhibited in p38γ/δ(-/-) mice. Wild-type chimeric mice with p38γ/δ(-/-) bone marrow did not show decreased CIA.Reduced disease severity in p38γ/δ(-/-) mice was associated with lower cytokine production and anticollagen antibody responses than in controls, indicating that p38γ and p38δ are crucial regulators of inflammatory joint destruction in CIA. Our findings indicate that p38γ and p38δ are potential therapeutic targets in complex diseases, such as rheumatoid arthritis, that involve innate and adaptive immune responses.
Patterns of Glucose Metabolism in Normal and Virus-Transformed Chick Cells in Tissue Culture&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Mina J. Bissell, Carroll Hatié, Harry Rubin
Journal: JNCI Journal of the National Cancer Institute (1972)

The rate of glucose uptake and the formation of lactic acid and CO2 were studied in normal and Rous sarcoma virus-transformed chick-embryo fibroblasts cultured at low and high cell densities. In normal cells the ratio of lactic acid produced to CO2 evolved increased with increasing cell density. These changes were not due to variations in the pool sizes or breakdown of glycogen but indicated high cell-density cultures preferred use of the glycolytic pathway over aerobic pathways. The phosphogluconate pathway also became more prominent as cells became relatively dense. However, population density per se and not the growth rate appeared responsible for the changes in paHern of carbon flow. Transformed cultures were similarly affected by population density. Moreover, under comparable conditions of growth rate and population density, the rate of lactic acid production and the ratio of lactate/CO2 were higher in transformed than in normal cultures. These observations indicated that viral transformation of chick-embryo fibroblasts in culture causes alterations in glucose metabolism in addition to those ascribable to increasing cell density. Cells infected with a nontransforming Rous-associated virus had metabolic paHerns similar to normal cultures.
Contextual analysis of determinants of late diagnosis of hepatitis C virus infection in Medicare patients
Authors: Viktor V. Chirikov, Fadia T. Shaya, Charles D. Howell
Journal: Hepatology (2015)

Patient‐ and county‐level characteristics associated with advanced liver disease (ALD) at hepatitis C virus (HCV) diagnosis were examined in three Medicare cohorts: (1) elderly born before 1945; (2) disabled born 1945‐1965; and (3) disabled born after 1965. We used Medicare claims (2006‐2009) linked to the Area Health Resource Files. ALD was measured over the period of 6 months before to 3 months after diagnosis. Using weighted multivariate modified Poisson regression to address generalizability of findings to all Medicare patients, we modeled the association between contextual characteristics and presence of ALD at HCV diagnosis. We identified 1,746, 3,351, and 592 patients with ALD prevalence of 28.0%, 23.0%, and 15.0% for birth cohorts 1, 2, and 3. Prevalence of drug abuse increased among younger birth cohorts (4.2%, 22.6%, and 35.6%, respectively). Human immunodeficiency virus coinfection (prevalence ratio [PR] = 0.63; 95% confidence interval [CI]: 0.50‐0.80; P = 0.001), dual Medicare/Medicaid eligibility (PR = 0.89; 95% CI: 0.80‐0.98; P = 0.017), residence in counties with higher median household income (PR = 0.82; 95% CI: 0.71‐0.95; P = 0.008), higher density of primary care providers (PR = 0.84; 95% CI: 0.73‐0.98; P = 0.022), and more rural health clinics (PR = 0.90; 0.81‐1.01; P = 0.081) were associated with lower ALD risk. End‐stage renal disease (PR = 1.41; 95% CI: 1.21‐1.63; P = 0.001), alcohol abuse (PR = 2.57; 95% CI: 2.33‐2.84; P = 0.001), hepatitis B virus (PR = 1.32; 95% CI: 1.09‐1.59; P = 0.004), and Midwest residence (PR = 1.22; 95% CI: 1.05‐1.41; P = 0.010) were associated with higher ALD risk. Living in rural counties with high screening capacity was protective in the elderly, but associated with higher ALD risk among the disabled born 1945‐1965. Conclusions : ALD prevalence patterns were complex and were modified by race, elderly/disability status, and the extent of health care access and screening capacity in the county of residence. These study results help inform treatment strategies for HCV in the context of coordinated models of care. (H epatology 2015;62:68‐78)
Phase I-Phase II Trial of &lt;italic&gt;N&lt;/italic&gt;-Phosphonacetyl-&lt;sc&gt;l&lt;/sc&gt;-Aspartic Acid Given by Intravenous Infusion and 5-Fluorouracil Given by Bolus Injection&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Charles Erlichman, Ross C. Donehower, James L. Speyer, Ray Klecker, Bruce A. Chabner
Journal: JNCI Journal of the National Cancer Institute (1982)

A phase I clinical trial of N-phosphonacetyl-L-aspartic acid (PALA) and 5-fluorouracil (FUra) was performed on 30 patients. PALA was given as a 15-minute iv infusion once daily for 5 days, and FUra was given as a bolus injection on days 2, 3, 4, and 5. Cycles of treatment were repeated every 3 weeks. Dose-limiting toxicity was manifested by stomatitis and diarrhea. Skin rash was observed also but was not dose limiting. No consistent hematopoietic or renal toxicity was observed. Seventeen patients with disseminated metastatic melanoma and measurable disease were evaluated for response. One partial response was seen; however, the response was associated with significant toxicity, and the treatment could not be repeated. Stable disease was observed in 3 patients with melanoma, 1 patient with colon carcinoma, and 1 patient with ovarian carcinoma. Our findings suggest that the clinical activity of PALA and FUra given according to the above schedule for melanoma is less than 25% (P less than 0.05). Pharmacokinetic studies of FUra revealed no consistent effect of PALA pretreatment on FUra disappearance in plasma. The mean FUra elimination half-line in plasma was 7.11 +/- 0.84 minutes (SEM), which is no different from that reported for FUra alone. The recommended doses on this schedule for phase II studies are 1,000 mg PALA/m2/day iv daily for 5 days and 200 mg FUra/m2/day iv on days 2, 3, 4, and 5.
Expression and functionality of P-glycoprotein in human bronchial epithelial cells in vitro
Authors: Victoria Hutter, Constanze Hilgendorf, Anne Cooper, Vanessa Zann, David Pritchard, Cynthia Bosquillon
Journal: European Respiratory Journal (2011)

P-glycoprotein (P-gp) is expressed in normal tissues with barrier functions where it participates in cell defence mechanisms (Huls, M.  et al.  J Pharm Exp Ther 2009; 328:3-9). Its presence in the bronchial epithelium and role in lung protection against inhaled toxicants has yet to be elucidated.  The human bronchial epithelial cell line Calu-3 and normal human bronchial epithelial (NHBE) cells were cultured at an air-liquid interface on Transwell® inserts for 21 days. P-gp expression was evaluated by quantitative polymerase chain reaction and its functionality was assessed by permeability measurements using the established substrate  3 H-digoxin either alone or in the presence of chemical or biomolecular inhibitors.  P-gp was absent in NHBE cells and moderately expressed in Calu-3 cells. Net secretory transport of  3 H-digoxin was observed in both models. This was reduced at 4°C and in the presence of the selective but non specific P-gp inhibitor PSC833 and the multidrug resistance protein (MRP) inhibitor MK571. The P-gp specific antibody inhibitor UIC2 and the metabolic inhibitors sodium azide and sodium dichloroacetate had no effect on  3 H-digoxin transport in Calu-3 cells.  The presence of active transport mechanisms in cultures of human bronchial epithelial cells was demonstrated, although they differed between the models tested. P-gp was not detected in NHBE cells, in line with observed low gene expression in human lung tissue (Bleasby, K.  et al.  Xenobiotica 2006; 36:963-988). The involvement of P-gp could not be confirmed and the transporter(s) responsible for  3 H-digoxin asymmetric broncho-epithelial permeability remain(s) to be identified.
Constitutive activation of c-Abl/protein kinase C-δ/Fli1 pathway in dermal fibroblasts derived from patients with localized scleroderma
Authors: S. Noda, Y. Asano, K. Akamata, N. Aozasa, T. Taniguchi, T. Takahashi, Y. Ichimura, T. Toyama, H. Sumida, K. Yanaba, Y. Tada, M. Sugaya, T. Kadono, S. Sato
Journal: British Journal of Dermatology (2012)

Background A noncanonical pathway of transforming growth factor-β signalling, the c-Abl/protein kinase C-δ (PKC-δ)/Friend leukemia virus integration 1 (Fli1) axis, is a powerful regulator of collagen synthesis in dermal fibroblasts. Objectives To investigate the significance of the c-Abl/PKC-δ/Fli1 pathway for the establishment of the profibrotic phenotype in lesional dermal fibroblasts from patients with localized scleroderma (LSc). Methods The activation status of the c-Abl/PKC-δ/Fli1 pathway was evaluated by immunoblotting and chromatin immunoprecipitation using cultured dermal fibroblasts from patients with LSc and closely matched healthy controls and by immunostaining on skin sections. The effects of a platelet-derived growth factor receptor inhibitor AG1296 and gene silencing of c-Abl on the expression levels of type I collagen were evaluated by immunoblotting. Results The phosphorylation levels of Fli1 at threonine 312 were increased, while the total Fli1 levels and the binding of Fli1 to the COL1A2 promoter were decreased, in cultured LSc fibroblasts compared with cultured normal fibroblasts. Furthermore, in cultured LSc fibroblasts, the expression levels of c-Abl were elevated compared with cultured normal fibroblasts and PKC-δ was preferentially localized in the nucleus. These findings were also confirmed in vivo by immunohistochemistry using skin sections. Moreover, gene silencing of c-Abl, but not AG1296, significantly suppressed the expression of type I collagen in cultured LSc fibroblasts. Conclusions Constitutive activation of the c-Abl/PKC-δ/Fli1 pathway at least partially contributes to the establishment of the profibrotic phenotype in LSc dermal fibroblasts, which provides a novel molecular basis to explain the efficacy of imatinib against skin sclerosis in a certain subset of LSc.
Pulmonary hypertension: The experience of a large UK district general hospital
Authors: Sarah Clarke, Gemma Swarbrick, Sally Baddeley, Julie Chadwick, Tarek Saba
Journal: European Respiratory Journal (2012)

Introduction 

Recent advances in therapy make early identification of patients with Pulmonary Hypertension (PH) important. The 2008 consensus statement reported an average UK treatment rate of 24.9 per million.(1)

Aim 

Our institution is a District General Hospital serving a population of 330,000. Our aim was to compare our treatment rate to the national average since the appointment of a physician with an interest in PH.

Method 

Retrospective casenote review of patients attending our monthly PH clinic since 2006.

Results 

We identified 102 Outpatient and 35 Inpatient referrals. 28 went on to receive specialist treatment for PH; mean age 66 (range 36-85); 24 female 4 male. Diagnoses: Chronic thromboembolic 10, Idiopathic 8, Collagen vascular disease 5, Congenital left to right shunt 2, COPD 2 and Portal hypertension 1. Haemodynamics (mean): Cardiac catheter: mean Pulmonary Artery Pressure (PAP) 48mmHg (n=22, range 22-78), cardiac output 4.8 (n=21, range 2.5-7.7), cardiac index 2.83 (n=22, range 1.47-5.14) and pulmonary vascular resistance 760 (n=22, range 123-1600). Echocardiography: systolic PAP 66mmHg (n = 23, range 13.8-107). Treatment: Oral Monotherapy 11, Prostanoid Monotherapy 1, Combination therapy 10, Intolerant of therapy 1, Pulmonary Endarterectomy 6, Transplant referral 4, Shunt repair 1. Outcome: 18 out of 28 patients survive on medical and surgical therapies. This is equivalent to 54 patients treated per million, considerably higher than the national average.(1)

Conclusion 

Diagnosis and treatment rates for PH in the UK can be substantially improved in many areas by developing local services with the support of the regional Specialist centre.

(1) Thorax 2008;63(Suppl II):ii1-ii41.
The Vancouver Consensus: antiretroviral medicines, medical evidence, and political will
Authors: Chris Beyrer, Deborah L Birx, Linda-Gail Bekker, Françoise Barré-Sinoussi, Pedro Cahn, Mark R Dybul, Serge P Eholié, Matthew M Kavanagh, Elly T Katabira, Jens D Lundgren, Lilian Mworeko, Marama Pala, Thanyawee Puttanakit, Owen Ryan, Michel Sidibé, Julio S G Montaner
Journal: The Lancet (2015)
Prognostic biomarkers in severe community-acquired pneumonia (SCAP) patients, requiring intensive care unit (ICU) admission
Authors: Oksana Omelyanenko, Alexander Makarevich, Paulina Jagus, Joanna Chorostowska-Wynimko, Tatyana Rybina, Elena Amelchenko
Journal: European Respiratory Journal (2012)

Background: Measurement of prohormones representing different pathophysiological pathways could enhance risk stratification in SCAP pts. The aim of the study was to investigate procalcitonin(PCT),adrenomedullin(AMD),copeptin (CP),B-type natriuretic peptide (BNP-32) levels in ICU SCAP pts and their relationship with in-hospital outcomes (in-hospital mortality(IHM),length of in-hospital stay(LOS),duration of ICU stay),disease specific complications,need for invasive mechanical ventilation(IMV) and vasopressor support(VS) Methods: 20 ICU pts with proven SCAP CURB-65 class 3,4 were enrolled to the study.Serum PCT,AMD, CP,BNP-32 values were measured within the 24 hours after admission. Results: Increasing CAP severity was associated with increased PCT values(r=0,74;p=0,05).PCT in CURB-65 3 and 4 class pts was [median]0,73 vs 5,94 ng/ml,respectively(p=0,03).CP levels on admission appeared to be higher in CURB-65 4th class pts vs the 3rd class pts -74,8 vs 47,6 pg/ml,respectively(p=0,03).PCT values demonstrated statistically significant correlation with IHM (r=0,74;p=0,005),were higher in non-survivors than those in survivors[5,94 vs 0,73 ng/ml,p=0,01].PCT and CP values correlated with need for VS (r=0,74;p=0,0005 and r=0,54;p=0,02) and showed higher concentrations in pts requiring VS compared with those with stable haemodynamics [102 vs 0,73 ng/ml, p=0,01] and [74,8 vs 47,6 pg/ml, p=0,03].AMD levels on ICU admission were associated with need for IMV (r=0,47; p=0,04).BNP-32 values correlated with LOS (r=0,56; p=0,02),PCT - with duration of ICU stay(r=0,81; p=0,001). Conclusion: PCT and CP appeared to be the most reliable prognostic biomarkers in ICU pts with SCAP.
Multicongenic fate mapping quantification of dynamics of thymus colonization
Authors: Natalia Ziętara, Marcin Łyszkiewicz, Jacek Puchałka, Katrin Witzlau, Annika Reinhardt, Reinhold Förster, Oliver Pabst, Immo Prinz, Andreas Krueger
Journal: The Journal of Experimental Medicine (2015)

Postnatal T cell development depends on continuous colonization of the thymus by BM-derived T lineage progenitors. Both quantitative parameters and the mechanisms of thymus seeding remain poorly understood. Here, we determined the number of dedicated thymus-seeding progenitor niches (TSPNs) capable of supporting productive T cell development, turnover rates of niche occupancy, and feedback mechanisms. To this end, we established multicongenic fate mapping combined with mathematical modeling to quantitate individual events of thymus colonization. We applied this method to study thymus colonization in CCR7−/−CCR9−/− (DKO) mice, whose TSPNs are largely unoccupied. We showed that ∼160–200 TSPNs are present in the adult thymus and, on average, 10 of these TSPNs were open for recolonization at steady state. Preconditioning of wild-type mice revealed a similar number of TSPNs, indicating that preconditioning can generate space efficiently for transplanted T cell progenitors. To identify potential cellular feedback loops restricting thymus colonization, we performed serial transfer experiments. These experiments indicated that thymus seeding was directly restricted by the duration of niche occupancy rather than long-range effects, thus challenging current paradigms of thymus colonization.
Dual Inhibition of <i>RET</i> and <i>FGFR4</i> Restrains Medullary Thyroid Cancer Cell Growth
Authors: Shereen Ezzat, Ping Huang, Alan Dackiw, Sylvia L. Asa
Journal: Clinical Cancer Research (2005)

Abstract Medullary thyroid cancer is frequently an aggressive form of carcinoma for which there are currently no effective forms of systemic therapy. These carcinomas arise as a result of activating mutations in the RET proto-oncogene transmembrane tyrosine kinase receptor. We, therefore, examined the potential efficacy of the tyrosine kinase inhibitor STI571 on the growth of human TT medullary cancer cells in vitro and in xenografted severe combined immunodeficiency mice. Treatment with STI571 resulted in inhibition of RET phosphorylation, cell proliferation, tumor growth and invasiveness. Based on the profile of expression of fibroblast growth factor receptors (FGFR), we examined the effects of FGFR tyrosine kinase inhibition using the small molecule FGFR inhibitor PD173074. This inhibitor resulted in abrogation of fibroblast growth factor-1-mediated FGFR4 phosphorylation in TT cells, an effect that was accompanied by significant arrest of cell proliferation and tumor growth in vivo. Moreover, the combination of STI571 and PD173074 resulted in greater suppression of cell proliferation in vitro and tumor control in vivo than that achieved with either agent alone. These data highlight RET and FGFR4 as therapeutic targets and suggest a potential role for the combined use of tyrosine kinase inhibitors in the management of inoperable medullary thyroid cancers.