tbuckley/cabot-search huggingface dataset:
Direct α-synuclein promoter transactivation by the tumor suppressor p53
Authors: Eric Duplan, Cécile Giordano, Frédéric Checler, Cristine Alves da Costa
Journal: Molecular Neurodegeneration (2016)

Parkinson's disease (PD) is a motor disease associated with the degeneration of dopaminergic neurons of the substantia nigra pars compacta. p53 is a major neuronal pro-apoptotic factor that is at the center of gravity of multiple physiological and pathological cascades, some of which implying several key PD-linked proteins. Since p53 is up-regulated in PD-affected brain, we have examined its ability to regulate the transcription of α-synuclein, a key protein that accumulates in PD-related Lewy bodies.We show that pharmacological and genetic up-regulation of p53 expression lead to a strong increase of α-synuclein protein, promoter activity and mRNA levels. Several lines of evidence indicate that this transcriptional control is due to the DNA-binding properties of p53. Firstly, p53 DNA-binding dead mutations abolish p53 regulation of α-synuclein. Secondly, the deletion of p53 responsive element from α-synuclein promoter abrogates p53-mediated α-synuclein regulation. Thirdly, gel shift and chromatin immunoprecipitation studies indicate that p53 interacts physically with α-synuclein promoter both in vitro and in a physiological context. Furthermore, we show that the depletion of endogenous p53 in cells as well as in knockout mice down-regulates α-synuclein transcription.Overall, we have identified α-synuclein as a new transcriptional target of p53 and delineated a cellular mechanism feeding the accumulation of toxic aggregated α-synuclein in PD. This original α-syn regulatory mechanism may be central to PD-related cell death and may lead to novel opportunities to design alternative neuroprotective strategies in PD.
Association between Functional Small Airway Disease and FEV<sub>1</sub> Decline in Chronic Obstructive Pulmonary Disease
Authors: Surya P. Bhatt, Xavier Soler, Xin Wang, Susan Murray, Antonio R. Anzueto, Terri H. Beaty, Aladin M. Boriek, Richard Casaburi, Gerard J. Criner, Alejandro A. Diaz, Mark T. Dransfield, Douglas Curran-Everett, Craig J. Galbán, Eric A. Hoffman, James C. Hogg, Ella A. Kazerooni, Victor Kim, Gregory L. Kinney, Amir Lagstein, David A. Lynch, Barry J. Make, Fernando J. Martinez, Joe W. Ramsdell, Rishindra Reddy, Brian D. Ross, Harry B. Rossiter, Robert M. Steiner, Matthew J. Strand, Edwin J. R. van Beek, Emily S. Wan, George R. Washko, J. Michael Wells, Chris H. Wendt, Robert A. Wise, Edwin K. Silverman, James D. Crapo, Russell P. Bowler, MeiLan K. Han
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Rationale: The small conducting airways are the major site of airflow obstruction in chronic obstructive pulmonary disease and may precede emphysema development.Objectives: We hypothesized a novel computed tomography (CT) biomarker of small airway disease predicts FEV1 decline.Methods: We analyzed 1,508 current and former smokers from COPDGene with linear regression to assess predictors of change in FEV1 (ml/yr) over 5 years. Separate models for subjects without and with airflow obstruction were generated using baseline clinical and physiologic predictors in addition to two novel CT metrics created by parametric response mapping (PRM), a technique pairing inspiratory and expiratory CT images to define emphysema (PRMemph) and functional small airways disease (PRMfSAD), a measure of nonemphysematous air trapping.Measurements and Main Results: Mean (SD) rate of FEV1 decline in ml/yr for GOLD (Global Initiative for Chronic Obstructive Lung Disease) 0–4 was as follows: 41.8 (47.7), 53.8 (57.1), 45.6 (61.1), 31.6 (43.6), and 5.1 (35.8), respectively (trend test for grades 1–4; P < 0.001). In multivariable linear regression, for participants without airflow obstruction, PRMfSAD but not PRMemph was associated with FEV1 decline (P < 0.001). In GOLD 1–4 participants, both PRMfSAD and PRMemph were associated with FEV1 decline (P < 0.001 and P = 0.001, respectively). Based on the model, the proportional contribution of the two CT metrics to FEV1 decline, relative to each other, was 87% versus 13% and 68% versus 32% for PRMfSAD and PRMemph in GOLD 1/2 and 3/4, respectively.Conclusions: CT-assessed functional small airway disease and emphysema are associated with FEV1 decline, but the association with functional small airway disease has greatest importance in mild-to-moderate stage chronic obstructive pulmonary disease where the rate of FEV1 decline is the greatest.Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).
Phase 1B Trial of Anti-Notch 2/3 Antibody Omp-59R5 in Combination with Etoposide and Cisplatin (Ep) in Patients (Pts) with Untreated Extensive-Stage Small-Cell Lung Cancer (Ed-Sclc): the Pinnacle Study
Authors: M.C. Pietanza, A. Spira, R. Jotte, S. Gadgeel, A. Mita, S. Liu, W.L. Gluck, G.P. Kalemkerian, A. Chiang, L. Hart, A. Kapoun, L. Xu, D. Hill, L. Zhou, J. Dupont, D.R. Spigel
Journal: Annals of Oncology (2014)
Evaluation of thoracic HRCT findings in sarcoidosis
Authors: Balakrishnan Menon, Vikas Dogra, Gaki Nima, Ankit Mittal, Upasana Mittal
Journal: European Respiratory Journal (2014)

Background  Sarcoidosis involves the mediastinum and pulmonary parenchyma. The differentiation of Sarcoidosis and Tuberculosis may pose diagnostic challenge specially in areas endemic for TB. High resolution CT (HRCT) is useful in the diagnosis of sarcoidosis. Many radiological patterns are seen on HRCT. Though none are individually diagnostic of Sarcoidosis, a combination of signs may be helpful.  Methods  Fifty five subjects of histopathologically proven Sarcoidosis were recruited. They were staged as per Scadding9s staging. Thoracic HRCT scans were evaluated for parenchymal, interstitial and mediastinal involvement.  Results  Of the 55 subjects, 9.09% were in Stage 0, 23.63% in Stage 1, 40% in Stage 2, 25.45% in Stage 3 and 18.18% in Stage 4. 81.81% subjects were symptomatic with cough, breathlessness and sputum production being the commonest symptoms. Mantoux test was positive in 16.36%. The mean Angiotensin Converting Enzyme values was 70.26+19.82U/L.  On HRCT, parenchymal opacities were seen in 70.9% subjects. Interstitial thickening was seen in 32.72%, Nodular opacities in 25.45%, Consolidation in 25.45%, Ground Glass Opacities in 20%, Air cysts in 14.54% and Bronchiectasis in 5.45% subjects.  Mediastinal lymphnode enlargement was present in 90.9% cases. Paratracheal involvement was seen in 56.56% cases, Right hilar in 40%, Left hilar in 34.54%, Subcarinal in 21.81%. Para-aortic, Azygoesophageal and Subaortic nodes were involved in 9.09% subjects each. All regions were involved in 10.9%.  Conclusion  Interstitial thickening and nodular opacities were the commonest parenchymal opacities while paratracheal and hilar lymphnode enlargement were the commonest mediastinal opacity on HRCT in Sarcoidosis. No pleural opacities were observed.
Comparative Roles of the Renal Apical Sodium Transport Systems in Blood Pressure Control
Authors: PIERRE MENETON
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Human genetic studies suggest that the genes encoding renal apical Na+ transport proteins play an essential role in the control of extracellular fluid volume and BP. Mice with mutations in each of these genes provide the unique opportunity to directly assess their respective involvement in fluid homeostasis and BP control in vivo. Inactivation of either the epithelial Na+ channel (ENaC) or the Na+-Cl- cotransporter decreases BP to the same extent in mice fed a low-salt diet, despite a more pronounced perturbation of fluid homeostasis in ENaC-deficient mice. In contrast, inactivation of Na+/H+ exchanger 3 (NHE3) or the Na+-K+-2Cl- contransporter reduces BP with a normal-salt diet and renders mice unable to survive with a low-salt diet. Therefore, the general conception that ENaC in the collecting duct is the main renal controller of Na+ balance and extracellular fluid volume should be tempered. For example, NHE3 in the proximal convoluted tubule seems to play a more substantial role in the control of fluid homeostasis. The overall effect of NHE3 inacthvation on BP may also involve absorptive defects in the intestine and colon, where the exchanger normally reabsorbs significant amounts of Na+ and water.
Abstract 17905: Sudden Neurological Death: A Substantial Contributor to Causes of WHO Sudden Cardiac Deaths
Authors: Anthony S Kim, Benjamin Colburn, Lauren McGuire, Philip C Ursell, Jeffrey Olgin, Ellen Moffat, Zian H Tseng
Journal: Circulation (2013)

Background: Sudden deaths, particularly deaths that meet the World Health Organization (WHO) criteria for sudden cardiac death (SCD), are often ascribed to a cardiac cause, but low prevailing autop...
Viral Studies of SV40 Tumorigenesis in Hamsters
Authors: Paul H. Black, Wallace P. Rowe
Journal: JNCI Journal of the National Cancer Institute (1964)

After subcutaneous inoculation into newborn hamsters, SV40 virus rapidly declined in titer and could not be detected between the 10th postinoculation day and the time of tumor development, 4 months later. Frequency of virus recovery from tumor extracts appeared to be related to tumor size; 4 (31%) of 13 small tumors, 16 (62%) of 26 medium tumors, and 5 (25%) of 20 large tumors yielded virus, with titers highest in the medium-sized tumors. Neutralizing antibody developed proportionally to tumor size, even in several animals which had serial tumor biopsies consistently negative for virus; this antibody was probably largely responsible for lack of virus isolation from large tumors. The failure to recover virus during the latent period may be a manifestation of the highly integrated cell-virus relationship found in SV40 tumor cells.
Compliance with oral antiestrogens utilizing a bubble pack.
Authors: Elizabeth Carloss Riley, Anthony E. Dragun, Kelly McMasters, Charles Raben Scoggins, Amy R. Quillo, Shesh Rai, Xiaoyong Wu, Dharamvir Jain
Journal: Journal of Clinical Oncology (2014)

132 Background: Adherence to endocrine therapy in breast cancer has been a long recognized problem despite efficacy to these drugs. Most of our knowledge of noncompliance has been largely observational and retrospective. Although multifactorial, extremes of age and race are risk factors for noncompliance. This report is an interim analysis of a well-designed study prospectively measuring compliance rates of “bubble” packaging of oral anti-estrogens Methods: A total of 88 patients were enrolled between August 2012 and April 2014. Out of 88 patients, 1 declined participation and 1 was deemed ineligible based on metastatic disease. Of the remaining 86, 53 continued participation and were included in this analysis. Demographic and clinical data were collected prospectively including age, race, insurance, duration of therapy, stage, and comorbidities. Duration of therapy was divided into 3 cohorts: early (less than 12 months), middle ( 12-36 months,) or late (37-60 months.) Comorbidities were defined as none, moderate (1-3) or significant (&gt;3.) All patients received anti-estrogens in a “bubble”pack. All used bubble packs and missed dose diaries were returned at follow up appointments for review. Results: The majority of patients were white (77%)) and stage I/II (74%.) The overall compliance rate was 97%; however only 61% of enrolled patients were continued in the analysis. None of the variables examined race, age, insurance status and/ or stage had an impact on compliance. Only duration of therapy had a marginal effect on compliance (p value = 0.06.) The late cohort was least likely to be compliant at 89.53%, although only represented 9% of the included patients. Conclusions: The compliance rate of bubble packaging is higher than expected however should be interpreted with caution given the 39% withdrawal. Interestingly there was no difference in compliance rate among race, insurance status or age which contradicts our current knowledge on high risk groups. However duration of therapy did have a negative impact on compliance and may become increasingly important as duration of anti-estrogen therapy extends. However given the small number of patient in this cohort this will need to be confirmed at final analysis with larger involvement within this group. Clinical trial information: NCT01694225.
New Clinical Indications for 18 F/ 11 C-choline, New Tracers for Positron Emission Tomography and a Promising Hybrid Device for Prostate Cancer Staging: A Systematic Review of the Literature
Authors: Laura Evangelista, Alberto Briganti, Stefano Fanti, Stephen Joniau, Sven Reske, Riccardo Schiavina, Christian Stief, George N. Thalmann, Maria Picchio
Journal: European Urology (2016)
Longitudinal quality of life (QoL) study in a randomized phase II trial (FFCD 9803) assessing LV5FU2, LV5FU2-cisplatin or LV5FU2-irinotecan in patients (pts) with metastatic gastric adenocarcinoma (MGA)
Authors: F. Bonnetain, O. Bouche, J.-L. Raoul, M. Giovannini, P.-L. Etienne, L. Bedenne, J.-F. Seitz, G. Lledo, T. Conroy, P. Arveux
Journal: Journal of Clinical Oncology (2004)

4150 Background: The results of a randomized phase II trial in pts with MGA showed that LV5FU2-irinotecan (CPT arm) combination as first-line therapy had a better efficacy and toxicity profile than LV5FU2 (5FU arm) alone or LV5FU2-cisplatin (CIS arm) (Bouché et al. Proc ASCO 2003; 22: 258). QoL was assessed using the EORTC QLQ-C30 to investigate the risk-benefit ratio and to test the infrastructure for future data collection before a phase III study. Methods: QLQ-C30 was self-administered at baseline and every 8 weeks in the 134 eligible pts: 5FU arm (45 pts), CIS (44 pts) and CPT (45 pts). Scores were compared to baseline with an analysis of variance (ANOVA). During a 6-month follow-up: - QLQ C30 scores and compliance were analyzed with mean (SD) and percent of missing scores; - a mixed ANOVA model for repeated measurements was applied to summarize the better longitudinal QoL profile. The same analyses were performed with the extreme poorest QLQ-C30 allocation for non-ignorable missing scores. Results: Compliance decreased with time: missing scores for global QoL increased from 18% (5FU arm), 25% (CIS arm), 16% (CPT arm) at baseline to 59%, 62% and 52% at 6 months respectively. At inclusion, 5FU arm pts reported more constipation than in CIS arm or CPT (p<0.01) and more sleep disorders than in CPT arm (p< 0.05). During the 6-month follow-up: 1 - Global QoL improved whatever the treatment, but 14/15 scores were better in CPT arm than in 5FU arm or CIS (including 5 scales with a mean difference (MD) > 5 points); 2 - the poorest allocation analysis showed a QoL deterioration whatever the treatment, however 14 QLQ-C30 scores were better in CPT arm than in 5FU arm (4 scales with MD > 5 points) and 15 scores were better in the CPT arm than CIS arm (14 scales with MD > 5 points). Conclusion: Although QoL variability at inclusion and missing data represent a limitation, this study shows a favourable impact of LV5FU2-irinotecan on QoL during the 6-month study period and confirms its better risk-benefit ratio in 1st line MGA. Supported by Aventis, Baxter and the ARC No significant financial relationships to disclose.
In-hospital mortality risk assessment in patients with community acquired pneumonia
Authors: Vanya Kostadinova, Darina Miteva, Yordan Radkov, Iskra Mircheva
Journal: European Respiratory Journal (2014)

Background: Community-acquired pneumonia (CAP) has a high mortality rate despite of contemporary antibacterial treatment.   Aim: To determine predictive factors for in-hospital death in patients with CAP.   Methods :Population of 1278 hospitalized patients with CAP has been studied retrospectively for the period of 3 years.Mean age is 60,3±16,9 years, men are 57,4%.Receiver operating characteristics (ROC) curve,t-test analyses,nonparametric correlation and logistic regression were used.   Results :CURB65 and CRB65 have greater predictive value than IDSA/ATS severity criteria for total in-hospital death(AUC 0,887;0,879 and 0,804,respectively)(p   Conclusion :CURB65 and CRB65 are accurate mortality predictors followed by IDSA/ATS severity criteria, age and CRP levels.Respiratory failure, comorbidities and multilobar infiltrates raise mortality too.
Abstract 13202: Relationship Between Risk for Coronary Heart Disease and Serum Levels of Low-Density Lipoprotein Particles
Authors: Peter P Toth, Michael Grabner, Rajeshwari S Punekar, Ralph A Quimbo, Mark J Cziraky, Deborah A Winegar, Terry A Jacobson
Journal: Circulation (2013)

Introduction: We investigated the real-world risk of coronary heart disease (CHD) associated with LDL particle number (LDL-P) among patients with established CHD or CHD risk equivalents from a large commercially insured US population. Hypothesis: Risk for CHD events increases as serum levels of LDL-P increase, even after adjusting for LDL cholesterol (LDL-C). Methods: Adult patients with ≥1 LDL-P result were selected from the HealthCore Integrated Research DatabaseSM. Index date was the date of the most recent LDL-P (for patients with no CHD events) or of the closest LDL-P preceding the most recent CHD event between 1/1/2006 and 9/30/2012. Patients without LDL-C results were excluded. Secondary prevention patients included those with CHD, diabetes mellitus (DM), or prescription fills for clopidogrel, at any point pre-index. Baseline characteristics were assessed over 6 months pre-index and patients were followed until occurrence of a CHD event (MI, angina, or revascularization identified from ICD-9-CM and...
Does the assessment of quality of life (QoL) correlate with clinical response? Results of a prospective study in 374 patients with advanced gynecological malignancies
Authors: I. Katsares, J. Sehouli, D. Stengel, H. Sommer, E. Keil, M. Kroener, B. Lisboa, P. Klare, W. Lichtenegger
Journal: Journal of Clinical Oncology (2004)

5146 Background: In palliative care of patients (pts) with advanced gynaecological malignancies every therapeutic intervention should be evaluated by its impact on QoL. Different treatment modalities (e.g. chemotherapy) are indicated to improve symptoms. In general the response of palliative therapy will be assessed by radiological methods (e.g. CT, MRI). The purpose of this prospective study was to investigate whether QoL assessment can be used as an additional instrument to evaluate the clinical response on palliative treatment. Methods: First, we performed a phase I/II trial in 50 pts to calculate the number of required pts to answer the question: “Is there a significant difference in QoL between pts with partial response (PR) and stable disease (SD)?”. Eligibility criteria: Pts with advanced gynaecological malignancies who underwent palliative treatment. Response evaluation by radiological or serological or clinical measurements within the last 4 weeks. QoL was examined using EORTC QoL Questionnaire C30 (QLQ-C30). Results: Overall, 374 pts (median age 59 years) were recruited (11/02–11/03): 62 pts showed complete response (CR), 143 PR, 105 stable disease (SD) and 64 progressive disease (PD), respectively. Breast and ovarian cancer were the most frequent diagnosis. Best results in global health scores and symptom scales were achieved in pts with PR. Especially in fatigue, physical- and role functioning scales the differences between patients with PR and SD were significant. Conclusions: We conclude that for patients with PR and SD the assessment of QoL seems to reflect clinical response of the treatment. The results indicate that QoL assessment is an important additional instrument to asses clinical response in the palliative setting. Supported by ESSEX Pharma. No significant financial relationships to disclose.
Isolated limb perfusion (ILP) in advanced soft tissue sarcomas (STS): What is the best timing of surgery?
Authors: D. Vanel, H. Debbabi, C. Le Péchoux, P. Terrier, G. Missenard, J. Dômont, F. Rimareix, N. Lassau, A. Le Cesne, S. Bonvalot
Journal: Journal of Clinical Oncology (2008)

10590 Background: ILP with TNF-α and melphalan allows an overall response rate of 78% (complete response 31%, partial response 47%, no change 9%, and progression 13%) on locally advanced STS of the extremities (Bonvalot, ASCO 2007). Surgery is usually performed 2 months after the perfusion. We have studied prospectively all patients (pts) with a dynamic MR examination at one and two months after the perfusion in order to evaluate the best surgical timing between ILP and planned excision. Methods: Eighty-four pts with a STS (23 poorly differentiated, 18 liposarcomas, 11 leiomyosarcomas, 9 synoviosarcomas, 8 MPNSTs, 5 MFHs, 5 angiosarcomas, 5 fibrosarcomas) had an MR examination one and two months after the perfusion. MR examinations included a dynamic sequence after injection of contrast medium, allowing a precise mapping of the early uptake. Size (RECIST criteria), new lesions and early uptake were analysed and compared on both exams. A new lesion, increase in size or larger surface of early uptake were considered indicators of tumour progression, whereas decrease of either the early vascularised part of the tumour or size were indicators of an improvement. Results: In 62 (73%) cases no changes were observed between the two MR. Eight pts (9.5%) progressed: both in size and vascularisation increased (2 pts), on vascularisation only (4 pts), on size only (1 pt) and finally a new lesion appeared (1 pt). Fourteen (17.5%) pts had an radiological improvement between one and two months. Conclusions: The best timing of surgery seems 2 months after ILP. It is adequate in the majority of cases (90.5%). In the rare cases where surgery is possible and easy to perform one month after ILP, it should be considered, as 9.5% of the pts may progress between one and two months. No significant financial relationships to disclose.
Rapamycin inhibits IL-33-induced airway inflammation
Authors: Ananda Mirchandani, Robert Salmond, Foo Liew
Journal: European Respiratory Journal (2011)

Introduction: IL-33, a member of the IL-1 cytokine family, mediates a range of pathologies including asthma and arthritis (Liew F.Y. et al. Nature Reviews Immunology, 2010; 10: 103-110). The mechanism by which IL-33 induces airway inflammation and the associated signalling pathways are incompletely understood. Rapamycin was initially described as a macrolide antibiotic that selectively blocks the mammalian target of rapamycin (mTOR), a serine/threonine kinase involved in numerous signaling pathways.

Aim: To identify the role of mTOR and rapamycin in IL-33-mediated airway inflammation.

Method: BALB/c mice were treated intranasally with 1 μg IL-33 daily with or without 1mg/kg rapamycin for 5 days. Airway inflammation was assessed on day 6 by bronchoalveolar lavage (BAL) cellularity and cytokine analysis.

Results: Intranasal IL-33 induced profound airway inflammation with increased cellular recruitment on BAL consisting mainly of macrophages and eosinophils. Treatment with rapamycin significantly reduced IL-33-mediated cellular recruitment (Figure 1A) and reduced both eosinophil (Figure 1B) and macrophage (Fig. 1C) influx into the airway.

![Figure][1] 



Rapamycin also significantly reduced IL-33-mediated IL-5 and IL-13 production in BAL fluid.

Conclusions: Intranasal IL-33 induces airway inflammation that is partially blocked by treatment with intranasal rapamycin suggesting an important role for mTOR in the signaling pathway of IL-33 in vivo.

 [1]: pending:yes