tbuckley/cabot-search huggingface dataset:
αB-crystallin is involved in the process of pulmonary fibrosis
Authors: Pierre-Simon Bellaye, Guillaume Wettstein, Carmen Garrido, Jack Gauldie, Martin Kolb, Philippe Camus, Philippe Bonniaud
Journal: European Respiratory Journal (2011)

Introduction:  Idiopathic Pulmonary Fibrosis (IPF) is a devastating disease with currently no treatment. In the presence of TGF-β, epithelial cells differentiate into myofibroblats, key pro-fibrotic cells in a proccess called epithelial-to-mesemchymal transition (EMT).  αB-crystallin belongs to the small heat shock protein family and is constitutively expressed in many tissues including lungs. αB-crystallin is inducible by stress and has a major role in cell cytoskeleton architecture homeostasis by interacting with intermediate filament elements. The role of αB-crystallin in fibrogenesis is unknown.   Methods:  In vitro we induced EMT on A549 cells after rTGF-β treatment. In vivo, Sprague Dawley rats received intra-tracheal administration of AdTGF-β or AdDL control. SV129 mice wild type (WT) or knock out (KO) for αB-crystallin received intra-tracheal bleomycin (0.07U/mouse).   Results:  In vitro during TGF-β1-induced EMT: 1. αB-crystallin is early overexpressed, 12 hours before α-SMA overexpression; 2. αB-crystallin colocalize with α-SMA; 3. αB-crystallin interacts with HSP27; 4. The modulation of αB-crystallin plays a role on TGF/SMAD pathway.  In vivo: 1. αB-crystallin is overexpressed in fibrotic areas induced by TGF-β overexpression in rats or bleomycin administration in mice; 2. By day 21, collagen accumulation in the lung was significantly higher in WT mice (3 fold increase, p   Conclusion:  These results provide evidence that αB-crystallin is involved in pulmonary fibrosis maybe through a role in EMT.  This work is supported by the EU, 7th FP, HEALTH-F2-2007-202224 eurIPFnet
Progression-free survival (PFS) of patients with HER2-negative, estrogen-receptor (ER)-low metastatic breast cancer (MBC) with the addition of lapatinib to letrozole: Biomarker results of EGF30008
Authors: R. S. Finn, M. Press, J. Dering, A. Florance, G. Platek, M. Arbushites, M. Koehler, S. Johnston
Journal: Journal of Clinical Oncology (2009)

1018 Background: Lapatinib (Lap), an oral, dual inhibitor of EGFR/HER-2, is approved with capecitabine for treatment of HER-2+ MBC for recurrence after taxane, anthracycline, and trastuzumab-based therapy. Letrozole (Let) has activity in hormone-receptor positive (HR+) BC. It has been hypothesized that peptide growth factor signaling and hormone signaling pathways interact and dual targeting of these pathways results in therapeutic synergy. We report a blinded analysis of HER-2, ER, and progesterone receptor (PR) expression for patients (pts) with HR+ MBC at first diagnosis or post-adjuvant relapse and response to Lap + Let versus Let. Methods: 1286 pts were randomized 1:1 to 2.5 mg Let daily plus either 1500 mg Lap daily or placebo. The primary endpoint was PFS in HR+, HER-2+ MBC pts; secondary endpoints included PFS in the intent-to-treat population. Blinded, centralized commerical laboratory analysis of archived tumor tissue for HER-2 (IHC and/or FISH) and academic laboratory semi-quantitative analysis of ER/PR (IHC, H-score) was performed and correlated with clinical outcome. Results: In 219/1286 (17%) HER-2+ (FISH+ or IHC3+) pts, a significant improvement in median PFS was observed for Lap + Let versus Let (8.2 v 3.0 mos, HR = 0.71, 95% CI 0.53, 0.96, p = 0.019). No significant difference in median PFS was seen in 952 (74%) HER-2-negative pts (13.4 v 13.7 mos, HR = 0.90, 95% CI 0.77, 1.05, p = 0.188). 821/952 (86%) HER-2-negative pts had tissue available for quantitative ER and PR analysis. Analysis of ER and PR by quartile identified a subgroup of HER-2-negative pts that benefitted from adding Lap to Let. Pts with the lowest quartile of ER expression (H-score &lt;160, n = 207) had a significant improvement in median PFS (13.6 mos v 6.6 mos, HR = 0.65, 95% CI 0.47, 0.9, p &lt; 0.005). Pts with higher levels of ER did not significantly benefit from adding Lap to Let. Analysis of PR expression did not identfiy a subgroup that benefited from Lap. Conclusions: Pts with HER-2-negative, ER+ MBC and low ER expression may benefit from the addition of lap to let. Additional analyses of EGFR, other biomarkers, and prior hormone therapy will be presented. [Table: see text]
Abstract B21: Identifying mechanisms of resistance to BET bromodomain inhibition.
Authors: Richard C. Centore, Charlie Hatton, Barbara Bryant, Robert J. Sims
Journal: Clinical Cancer Research (2015)

Abstract BET (bromodomain and extra terminal domain) family members are key transcriptional regulators that play an important role driving oncogene expression in hematologic malignancies. Several BET inhibitors (BETi) have recently entered clinical trials, including the optimized BET inhibitor CPI-0610. Understanding mechanisms of resistance to BET inhibition represents an important challenge and will likely provide insight into mechanisms of BET sensitivity. Here, we have developed a model of BETi resistance in AML using the BET inhibitor, CPI-203. Resistant cells demonstrate half-maximal growth inhibition at a concentration of CPI-203 that is greater than 10-fold that of parental cells. When challenged with CPI-203, parental cells undergo apoptosis, a phenomenon that correlates with strong suppression of MYC and the anti-apoptotic gene, BCL2. In resistant cells, transcription of MYC and BCL2 is maintained in the presence of BETi, and the apoptotic effect is severely blunted. Interestingly, withdrawal of BETi from the resistant cells triggers apoptosis, suggesting an acquired dependency on BET inhibition in these cells. To further understand the molecular mechanisms responsible for maintenance of MYC expression in resistant cells, we performed gene expression profiling and functionally interrogated transcriptional co-regulators that may facilitate BET-escape. Despite inhibition of BET proteins, MYC transcription in resistant cells remained dependent on acetyl-lysine signaling and non-BET chromatin adaptors. In summary, our work models resistance to a novel therapy and sheds light on additional targets that may allow cancer cells to bypass BETi-induced cell death. Citation Format: Richard C. Centore, Charlie Hatton, Barbara Bryant, Robert J. Sims, III. Identifying mechanisms of resistance to BET bromodomain inhibition. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B21.
Randomised placebo controlled trial of effect on mood of lowering cholesterol concentration
Authors: J Wardle, J Armitage, R Collins, K Wallendszus, A Keech, A Lawson
Journal: BMJ (1996)

Objective: To evaluate the effects on mood of a substantial and prolonged reduction in total cholesterol concentration. Design: Randomised placebo controlled comparison of patients who had been allocated to receive simvastatin 20 mg or 40 mg daily versus those allocated matching placebo in a ratio of 2:1. Follow up at an average of 152 weeks after randomisation. Subjects: Men and women aged between 40 and 75 years at entry with blood total cholesterol of 3.5 mmol/l or greater, who were considered to be at higher than average risk of coronary heart disease based on medical history. Main outcome measures: The shortened profile of mood states questionnaire, reported use of psychotropic medication, and symptoms possibly related to mood. Results: Simvastatin reduced total cholesterol by 1.9 mmol/l (26.7%) at the time of follow up. Among all 621 patients randomised to simvastatin (414 patients) or placebo (207 patients) there were no significant differences in the use of psychotropic medication or in reports of symptoms possibly related to mood. Of these patients, 491 (334 simvastatin, 157 placebo) completed the mood questionnaire, and there were no significant differences between the treatment groups in total or subscale scores, even when patients with low baseline cholesterol concentrations or elderly subjects were considered separately. Conclusion: These results do not support the hypothesis that treatment to lower cholesterol concentration causes mood disturbance. #### Key messages
Vitamin D represses rhinovirus replication in cystic fibrosis cells by inducing LL-37
Authors: Aline Schögler, Ricardo J. Muster, Elisabeth Kieninger, Carmen Casaulta, Caroline Tapparel, Andreas Jung, Alexander Moeller, Thomas Geiser, Nicolas Regamey, Marco P. Alves
Journal: European Respiratory Journal (2015)

Vitamin D has immunomodulatory properties in the defence against pathogens. Its insufficiency is a widespread feature of cystic fibrosis (CF) patients, which are repeatedly suffering from rhinovirus (RV)-induced pulmonary exacerbations.To investigate whether vitamin D has antiviral activity, primary bronchial epithelial cells from CF children were pre-treated with vitamin D and infected with RV16. Antiviral and anti-inflammatory activity of vitamin D was assessed. RV and LL-37 levels were measured in bronchoalveolar lavage (BAL) of CF children infected with RV.Vitamin D reduced RV16 load in a dose-dependent manner in CF cells (10(-7 )M, p<0.01). The antiviral response mediated by interferons remained unchanged by vitamin D in CF cells. Vitamin D did not exert anti-inflammatory properties in RV-infected CF cells. Vitamin D increased the expression of the antimicrobial peptide LL-37 up to 17.4-fold (p<0.05). Addition of exogenous LL-37 decreased viral replication by 4.4-fold in CF cells (p<0.05). An inverse correlation between viral load and LL-37 levels in CF BAL (r=-0.48, p<0.05) was observed.RV replication in primary CF bronchial cells was reduced by vitamin D through the induction of LL-37. Clinical studies are needed to determine the importance of an adequate control of vitamin D for prevention of virus-induced pulmonary CF exacerbations.
&lt;italic&gt;In Vitro&lt;/italic&gt; Viral Transformation off Chemically Transformed Cells
Authors: Joseph A. DiPaolo, Alan S. Rabson, Richard A. Malmgren
Journal: JNCI Journal of the National Cancer Institute (1968)

Hamster embryonic cells grown in a suspension of 3-methyl-cholanthrene underwent neoplastic transformation. These cells, when injected into homologous hosts, could produce tumors, but morphologic change in vitro was not significant. When these transformed cells were exposed to simian virus 40 or the LLE 46 strain of adenovirus 7 (the SV40-adenovirus 7 “hybrid”), they were further transformed with altered morphologic and growth characteristics in vitro, chromosomal changes, appearance of intranuclear SV40 T antigen, and changes in the morphology of tumors produced by injection of cells into homologous hosts.
THE INTERNIST AND LIFE INSURANCE
Authors: H E UNGERLEIDER
Journal: Annals of Internal Medicine (1954)

Article1 July 1954THE INTERNIST AND LIFE INSURANCEHARRY E. UNGERLEIDERHARRY E. UNGERLEIDERSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-41-1-124 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptLife insurance and the practice of medicine, particularly internal medicine, are interconnected in almost numberless ways. From its very beginning life insurance has drawn heavily on medical knowledge, and in recent years it has begun to repay this debt, in ways I hope to indicate. It has been said that almost the entire history of modern life insurance can be woven around the British predecessor of the Equitable Life Assurance Society, namely, the Equitable Assurance Company of London. This organization, founded in 1762 and the first to employ a physician, made use of the Breslau and Halley table in its... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: New York, N. Y.*Presented at the Thirty-fifth Annual Session of the American College of Physicians, Chicago, Illinois, April 7, 1954. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byCrystal-associated arthropathiesHyperuricemia and GoutChanging trends of mortality in GoutThe radiology of goutGoutRHEUMATISM AND ARTHRITIS: REVIEW OF AMERICAN AND ENGLISH LITERATURE OF RECENT YEARS (TWELFTH RHEUMATISM REVIEW)* Part IICHARLEY J. SMYTH, M.D., F.A.C.P., JOSEPH J. BUNIM, M.D., F.A.C.P., WILLIAM S. CLARK, M.D., F.A.C.P., DARRELL C. CRAIN, M.D., F.A.C.P., FELIX E. DEMARTINI, M.D., IVAN F. DUFF, M.D., F.A.C.P., EPHRAIM P. ENGLEMAN, M.D., F.A.C.P., DONALD C. GRAHAM, M.D., F.R.C.P. (C), MAX M. MONTGOMERY, M.D., F.A.C.P., BERNARD M. NORCROSS, M.D., F.A.C.P., HOWARD F. POLLEY, MARIAN W. ROPES, M.D., F.A.C.P., EDWARD F. ROSENBERG, M.D., F.A.C.P.Störungen des PurinstoffwechselsSome observations on 520 gouty patientsGOUT BECOMES OF AGEJOHN H. TALBOTT 1 July 1954Volume 41, Issue 1Page: 124-130 ePublished: 1 December 2008 Issue Published: 1 July 1954 PDF downloadLoading ...
High Intratumoral Stromal Content Defines Reactive Breast Cancer as a Low-risk Breast Cancer Subtype
Authors: Jennifer B. Dennison, Maria Shahmoradgoli, Wenbin Liu, Zhenlin Ju, Funda Meric-Bernstam, Charles M. Perou, Aysegul A. Sahin, Alana Welm, Steffi Oesterreich, Matthew J. Sikora, Robert E. Brown, Gordon B. Mills
Journal: Clinical Cancer Research (2016)

The current study evaluated associative effects of breast cancer cells with the tumor microenvironment and its influence on tumor behavior.Formalin-fixed, paraffin-embedded tissue and matched protein lysates were evaluated from two independent breast cancer patient datasets (TCGA and MD Anderson). Reverse-phase protein arrays (RPPA) were utilized to create a proteomics signature to define breast tumor subtypes. Expression patterns of cell lines and normal breast tissues were utilized to determine markers that were differentially expressed in stroma and cancer cells. Protein localization and stromal contents were evaluated for matched cases by imaging.A subtype of breast cancers designated "Reactive," previously identified by RPPA that was not predicted by mRNA profiling, was extensively characterized. These tumors were primarily estrogen receptor (ER)-positive/human EGF receptor (HER)2-negative, low-risk cancers as determined by enrichment of low-grade nuclei, lobular or tubular histopathology, and the luminal A subtype by PAM50. Reactive breast cancers contained high numbers of stromal cells and the highest extracellular matrix content typically without infiltration of immune cells. For ER-positive/HER2-negative cancers, the Reactive classification predicted favorable clinical outcomes in the TCGA cohort (HR, 0.36; P < 0.05).A protein stromal signature in breast cancers is associated with a highly differentiated phenotype. The stromal compartment content and proteins are an extended phenotype not predicted by mRNA expression that could be utilized to subclassify ER-positive/HER2-negative breast cancers. Clin Cancer Res; 22(20); 5068-78. ©2016 AACR.
Drivers' visual acuity
Authors: Douglas Carnall
Journal: BMJ (2000)

Adequate vision is plainly a prerequisite for driving a motor vehicle, but this week a paper in the BMJ shows that measuring adequacy is far from straightforward. Snellen charts are used to assess visual acuity in the clinic, but the actual standard required—reading a car licence plate at 20.5 metres—does not correlate perfectly with acuity …
Ischemic Predictors of Outcomes in Women With Signs and Symptoms of Ischemia and Nonobstructive Coronary Artery Disease
Authors: Tara L. Sedlak, Meijiao Guan, May Lee, Karin H. Humphries, B. Delia Johnson, Carl J. Pepine, C. Noel Bairey Merz
Journal: JAMA Cardiology (2016)

Studies suggest that the prognosis of women with signs and symptoms of ischemia and nonobstructive coronary artery disease (CAD) is not benign. [1]2][3] The Women's Ischemia Syndrome Evaluation (WISE) 4 demonstrated that the WISE CAD severity score, a measure of coronary atherosclerotic burden, is a useful predictor of mortality in women with nonobstructive CAD.However, the prognostic value of ischemia variables is less well described.We evaluated the associaton of ischemia and prior infarct with outcomes using the WISE database, which consisted of women with signs and symptoms of ischemia and nonobstructive CAD enrolled from 1996 to 2000 and followed up for up to 8.5 years.
In Infants With Necrotizing Enterocolitis, Gut Dysbiosis Precedes Disease
Authors: Julie A. Jacob
Journal: JAMA (2016)

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Concurrent radiotherapy combined with carboplatin and etoposide in limited stage small cell lung cancer
Authors: T. Qiao, D. Zhou
Journal: Journal of Clinical Oncology (2004)

7220 Background: To observe the effects of concurrent radiotherapy combined with carboplatin and etoposide in limited stage small cell lung cancer. Methods: Ninty patients with limited stage small cell lung cancer were randomized into two groups, concurrent treatment group(group C) and alternating treatment group(group A). All patients in two groups received radiotherapy (60Gy in 30 fractions) and six courses of chemotherapy (carboplatin and etoposide). Radiotherapy was started in the first course of chemotherapy in group C. Patients of group A were treated by radiation between the fourth and the fifth course of chemotherapy. Results: The median survival time was 26 months in group C and 19 months in group A.The 5-year survival rate was 27% in group C and 16% in group A. The major toxic reactions were grade IIIĨV myelosuppression. The differences of two groups were significal(P<0.05). Conclusions: Concurrent radiotherapy combined with carboplatin and etoposide can significantly improve median survival time and 5-year survival rate of patients with limited stage small cell lung cancer. No significant financial relationships to disclose.
Another Choice for Prevention of COPD Exacerbations
Authors: James F. Donohue
Journal: New England Journal of Medicine (2016)

Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines1 recommend either a long-acting beta-agonist (LABA) plus an inhaled glucocorticoid or a long-acting muscarinic antagonist (LAMA) as first-line therapy for patients with chronic obstructive pulmonary disease (COPD) who have a risk of exacerbation. The precise role of a combination of a LABA plus a LAMA in fixed doses in the prevention of COPD exacerbations is unclear. Previous studies have shown a LABA–LAMA regimen to be a preferred approach for symptomatic nonexacerbating COPD, especially among patients in GOLD group B (i.e., those who have low risk and a high symptom burden), but . . .
Phase I trial of ARQ 501, an Activated Checkpoint Therapy (ACT) agent, in patients with advanced solid tumors
Authors: G. I. Shapiro, J. G. Supko, D. P. Ryan, L. Appelman, A. Berkenblit, A. R. Craig, S. Jones, D. Yagovane, C. Li, J. Eder
Journal: Journal of Clinical Oncology (2005)

3042 Background: ARQ 501 (β-Lapachone) is a novel anticancer agent that exhibits selective antitumor activity in a broad range of in vitro and in vivo preclinical models. It induces apoptosis in cancer cells by modulating the expression of E2F-1, which in turn activates the G1/S-phase checkpoint. This novel mechanism of action stimulated interest in the clinical development of ARQ 501 as an antitumor agent. Methods: A phase I clinical trial was initiated to define the maximum tolerated dose (MTD) and characterize the pharmacokinetic behavior of ARQ 501 administered as a weekly 1-hour intravenous infusion. A modified Simon accelerated titration scheme was used for dose escalation. Results: Eighteen patients have received a total of 41 monthly courses of ARQ 501 at doses ranging from 10–550 mg/m2. Patient characteristics: 11M/7F; median age 58.5 years (range 33–73). Tumor types include: lung (2), sarcoma (5), colorectal (3), pancreatic (2), and others (6). All patients had received prior chemotherapy. Up to the 390 mg/m2 dose, ARQ 501 exhibited apparent linear pharmacokinetics, characterized by a mean (±SD) total body clearance that was of 114 ± 29 l/h/m2 (∼2-times > hepatic blood flow) and a steady-state volume of distribution of 490 ± 304 l/m2 (>10-times total body weight). There was no evidence of drug accumulation or change in disposition upon repeated weekly dosing. At the 390 mg/m2 dose level, the plasma concentration of ARQ 501 was 2434 ± 346 ng/ml at the end of the 1 h infusion and 6.9 ± 1.1 ng/ml at 24 h. A partial response has been observed in a patient with uterine leiomyosarcoma who remains on study after 56 weeks of therapy. Two patients achieved stable disease (16 and 32 weeks). Adverse events have been mild, including anemia and fatigue. Conclusions: Initial dose escalation of ARQ 501 has been achieved without evidence of dose limiting toxicity. Early signs of clinical activity have been demonstrated by partial response and stable disease cases. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ArQule ArQule ArQule