tbuckley/cabot-search huggingface dataset:
Targeting filamin A reduces K-RAS–induced lung adenocarcinomas and endothelial response to tumor growth in mice
Authors: Rajesh K Nallapalli, Mohamed X Ibrahim, Alex X Zhou, Sashidar Bandaru, Sai Naresh Sunkara, Björn Redfors, David Pazooki, Yin Zhang, Jan Borén, Yihai Cao, Martin O Bergo, Levent M Akyürek
Journal: Molecular Cancer (2012)

Abstract Background Many human cancer cells express filamin A (FLNA), an actin-binding structural protein that interacts with a diverse set of cell signaling proteins, but little is known about the biological importance of FLNA in tumor development. FLNA is also expressed in endothelial cells, which may be important for tumor angiogenesis. In this study, we defined the impact of targeting Flna in cancer and endothelial cells on the development of tumors in vivo and on the proliferation of fibroblasts in vitro . Methods First, we used a Cre -adenovirus to simultaneously activate the expression of oncogenic K-RAS and inactivate the expression of Flna in the lung and in fibroblasts. Second, we subcutaneously injected mouse fibrosarcoma cells into mice lacking Flna in endothelial cells. Results Knockout of Flna significantly reduced K-RAS–induced lung tumor formation and the proliferation of oncogenic K-RAS–expressing fibroblasts, and attenuated the activation of the downstream signaling molecules ERK and AKT. Genetic deletion of endothelial FLNA in mice did not impact cardiovascular development; however, knockout of Flna in endothelial cells reduced subcutaneous fibrosarcoma growth and vascularity within tumors. Conclusions We conclude that FLNA is important for lung tumor growth and that endothelial Flna impacts local tumor growth. The data shed new light on the biological importance of FLNA and suggest that targeting this protein might be useful in cancer therapeutics.
Prospective Study of the Association of Serum γ-Glutamyltransferase with Cervical Intraepithelial Neoplasia III and Invasive Cervical Cancer
Authors: Alexander M. Strasak, Georg Goebel, Hans Concin, Ruth M. Pfeiffer, Larry J. Brant, Gabriele Nagel, Willi Oberaigner, Nicole Concin, Günter Diem, Elfriede Ruttmann, Ulrike Gruber-Moesenbacher, Felix Offner, Alfonso Pompella, Karl P. Pfeiffer, Hanno Ulmer
Journal: Cancer Research (2010)

Epidemiologic studies indicate that elevated levels of gamma-glutamyltransferase (GGT), a key enzyme of glutathione metabolism, might be associated with increased cancer risk. Furthermore, preclinical studies support a role for GGT in tumor invasion and progression. However, the relationship between GGT and risks of cervical intraepithelial neoplasia III (CIN-III) and invasive cervical cancer (ICC) have not been evaluated. We investigated the association of enzymatically determined GGT in blood serum with subsequent incidence of CIN-III and ICC in a prospective population-based cohort of 92,843 women ages 18 to 95, of whom 79% had at least one gynecologic examination including Pap smear testing during follow-up. Cox regression was used to compute adjusted hazard ratios (HR) with 95% confidence intervals for the association of GGT with CIN-III and ICC. During median follow-up of 13.8 years, 702 CIN-III and 117 ICC diagnoses were observed. Compared with normal low GGT (<17.99 units/L), risk of ICC was significantly elevated for all other baseline GGT categories, with adjusted HRs of 2.31 (1.49-3.59) for normal high GGT (18.00-35.99 units/L), 2.76 (1.52-5.02) for elevated GGT (36.00-71.99 units/L), and 3.38 (1.63-7.00) for highly elevated GGT [>72.00 units/L; P trend < 0.0001, HR log unit increase 3.45 (1.92-6.19)]. In contrast, associations between GGT serum levels and CIN-III risk were not statistically significant in the main analysis. Exclusion of the first 2 or 5 years of follow-up did not change the results. Effects did not differ by age, body mass index, or socioeconomic status. Our findings implicate GGT in the progression of premalignant cervical lesions to invasive cancer.
Exploratory biomarker results from early investigation of PEGPH20 in combination with gemcitabine (Gem) in patients with pancreatic cancer (PDA).
Authors: Sunil R. Hingorani, William Proctor Harris, Joseph Thaddeus Beck, Boris A. Berdov, Stephanie Ann Wagner, Eduard M. Pshevlotsky, Sergei Tjulandin, Oleg Gladkov, Randall F. Holcombe, Ping Jiang, Daniel C. Maneval, Ronald I Korn, Harold Michael Shepard, Craig E. Devoe
Journal: Journal of Clinical Oncology (2015)

300 Background: PEGPH20 (PEG), a PEGylated recombinant human hyaluronidase, has anti-tumor activity as a single agent and in combination with chemotherapy in preclinical models. A Phase 1b study of PEG + Gem (P+G) in patients (pts) with advanced PDA showed good anti-tumor activity, particularly in pts with HA high tumors (ECCO 2013). In this study, we investigated pharmacodynamic (PD) markers including plasma(soluble) HA (sHA), dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and 18 Fluorodeoxyglucose positron emission tomography (PET/CT) to explore additional correlates for PEG activity. Methods: 28 pts with stage IV PDA were treated with PEG at 1, 1.6, or 3µg/kg IV twice weekly for Wks 1-4 and Wks 5-7, followed by 1 wk rest, plus Gem at 1000 mg/m2 IV once weekly for Wks 1-7, then 1 wk rest. Thereafter, P+G was given once weekly for 3 wks in 4-wk cycles. Serial plasma samples were collected and analyzed in a quantitative assay for PEG and sHA. Exploratory imaging by DCE-MRI was performed on selection pts at baseline, 8hr, 24hr and end of cycle 1, PET/CT was performed at baseline and at the end of each cycle. Results: PEG pharmacokinetics was well-characterized by a 2-compartment PK model, peak plasma concentration increased in a dose-proportional manner after a single or repeat administration of PEG. Dose- and time-dependent increases in sHA were observed within 2-3 days after 1.0, 1.6, or 3.0 µg/kg of PEG administration. The median peak concentrations were 3,736; 48,150; and 74,950ng/mL, respectively, and increased with increasing doses. sHA reached steady state approximately 1 wk after repeated PEG administration, consistent with the expected hyaluronidase activity of PEG. Exploratory analysis with DCE-MRI from 6 pts showed an early increase (24hrs) in tumor perfusion (Ktrans) in target lesions. PET/CT from 5 pts showed an average reduction in the maximum standardized uptake value (SUVmax) of 37% at EOC1, and partial metabolic responses using EORTC criteria were achieved in 4 of 5 pts. These results suggest that P+G has measurable biological activity in metastatic PDA Conclusions: Plasma sHA concentration, DCE-MRI and PET/CT are PD markers for evaluation of P+G activity.
Pulmonary Microvascular Blood Flow in Mild Chronic Obstructive Pulmonary Disease and Emphysema. The MESA COPD Study
Authors: Katja Hueper, Jens Vogel-Claussen, Megha A. Parikh, John H. M. Austin, David A. Bluemke, James Carr, Jiwoong Choi, Thomas A. Goldstein, Antoinette S. Gomes, Eric A. Hoffman, Steven M. Kawut, Joao Lima, Erin D. Michos, Wendy S. Post, Ming Jack Po, Martin R. Prince, Kiang Liu, Dan Rabinowitz, Jan Skrok, Ben M. Smith, Karol Watson, Youbing Yin, Alan M. Zambeli-Ljepovic, R. Graham Barr
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Smoking-related microvascular loss causes end-organ damage in the kidneys, heart, and brain. Basic research suggests a similar process in the lungs, but no large studies have assessed pulmonary microvascular blood flow (PMBF) in early chronic lung disease.To investigate whether PMBF is reduced in mild as well as more severe chronic obstructive pulmonary disease (COPD) and emphysema.PMBF was measured using gadolinium-enhanced magnetic resonance imaging (MRI) among smokers with COPD and control subjects age 50 to 79 years without clinical cardiovascular disease. COPD severity was defined by standard criteria. Emphysema on computed tomography (CT) was defined by the percentage of lung regions below -950 Hounsfield units (-950 HU) and by radiologists using a standard protocol. We adjusted for potential confounders, including smoking, oxygenation, and left ventricular cardiac output.Among 144 participants, PMBF was reduced by 30% in mild COPD, by 29% in moderate COPD, and by 52% in severe COPD (all P < 0.01 vs. control subjects). PMBF was reduced with greater percentage emphysema-950HU and radiologist-defined emphysema, particularly panlobular and centrilobular emphysema (all P ≤ 0.01). Registration of MRI and CT images revealed that PMBF was reduced in mild COPD in both nonemphysematous and emphysematous lung regions. Associations for PMBF were independent of measures of small airways disease on CT and gas trapping largely because emphysema and small airways disease occurred in different smokers.PMBF was reduced in mild COPD, including in regions of lung without frank emphysema, and may represent a distinct pathological process from small airways disease. PMBF may provide an imaging biomarker for therapeutic strategies targeting the pulmonary microvasculature.
Human papillomavirus infection in Netherton's syndrome
Authors: F. Weber, P.G. Fuchs, H.J. Pfister, H. Hintner, P. Fritsch, R. Hoepfl
Journal: British Journal of Dermatology (2001)

Journal Article Human papillomavirus infection in Netherton's syndrome Get access F. Weber, F. Weber Department of Dermatology and Venereology, University of Innsbruck, Anichstraße 35, A‐6020 Innsbruck, Austria *Institute of Virology, University of Cologne, Germany †Department of Dermatology, General Hospital Salzburg, Austria Florian Weber. E‐mail: florian.weber@uibk.ac.at Search for other works by this author on: Oxford Academic Google Scholar P.G. Fuchs, P.G. Fuchs Department of Dermatology and Venereology, University of Innsbruck, Anichstraße 35, A‐6020 Innsbruck, Austria *Institute of Virology, University of Cologne, Germany †Department of Dermatology, General Hospital Salzburg, Austria Search for other works by this author on: Oxford Academic Google Scholar H.J. Pfister, H.J. Pfister Department of Dermatology and Venereology, University of Innsbruck, Anichstraße 35, A‐6020 Innsbruck, Austria *Institute of Virology, University of Cologne, Germany †Department of Dermatology, General Hospital Salzburg, Austria Search for other works by this author on: Oxford Academic Google Scholar H. Hintner, H. Hintner Department of Dermatology and Venereology, University of Innsbruck, Anichstraße 35, A‐6020 Innsbruck, Austria *Institute of Virology, University of Cologne, Germany †Department of Dermatology, General Hospital Salzburg, Austria Search for other works by this author on: Oxford Academic Google Scholar P. Fritsch, P. Fritsch Department of Dermatology and Venereology, University of Innsbruck, Anichstraße 35, A‐6020 Innsbruck, Austria *Institute of Virology, University of Cologne, Germany †Department of Dermatology, General Hospital Salzburg, Austria Search for other works by this author on: Oxford Academic Google Scholar R. Hoepfl R. Hoepfl Department of Dermatology and Venereology, University of Innsbruck, Anichstraße 35, A‐6020 Innsbruck, Austria *Institute of Virology, University of Cologne, Germany †Department of Dermatology, General Hospital Salzburg, Austria Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 144, Issue 5, 1 May 2001, Pages 1044–1049, https://doi.org/10.1046/j.1365-2133.2001.04196.x Published: 01 May 2001
Validation of a Rule for Termination of Resuscitation in Out-of-Hospital Cardiac Arrest
Authors: Laurie J. Morrison, Laura M. Visentin, Alex Kiss, Rob Theriault, Don Eby, Marian Vermeulen, Jonathan Sherbino, P. Richard Verbeek
Journal: New England Journal of Medicine (2006)

We prospectively evaluated a clinical prediction rule to be used by emergency medical technicians (EMTs) trained in the use of an automated external defibrillator for the termination of basic life support resuscitative efforts during out-of-hospital cardiac arrest. The rule recommends termination when there is no return of spontaneous circulation, no shocks are administered, and the arrest is not witnessed by emergency medical-services personnel. Otherwise, the rule recommends transportation to the hospital, in accordance with routine practice.
Location, location, location: studying anatomically comparable airways is highly relevant to understanding COPD
Authors: Benjamin M Smith, Eric A Hoffman, Stephen Rennard, R Graham Barr
Journal: Thorax (2014)

We have read with interest Nakano and colleague's thoughtful comments1 on Smith et al 2 and are pleased to offer the following observations.

We believe that a key strength of our paper is that it defines a rigorous sampling strategy to compare airways from matched hierarchical positions within the tracheobronchial tree with control for the known hierarchical gradient in airway dimensions.3 Nakano et al are correct to point out that hierarchical sampling by generation number results in grouping of airways from multiple anatomic locations (eg, segmental and lobar airways); conversely, hierarchical sampling by anatomic location results in grouping of airways from multiple generations.4 It is for this reason that we reported both sampling approaches (tables 2 …
Renoprotective Effects of Adding Angiotensin II Receptor Blocker to Maximal Recommended Doses of ACE Inhibitor in Diabetic Nephropathy
Authors: Kasper Rossing, Peter Jacobsen, Lotte Pietraszek, Hans-Henrik Parving
Journal: Diabetes Care (2003)

OBJECTIVE—We evaluated the renoprotective effects as reflected by short-term changes in albuminuria of dual blockade of the renin-angiotensin system (RAS) by adding an angiotensin II receptor blocker (ARB) to treatment with maximal recommended doses of an ACE inhibitor (ACEI) in patients with type 2 diabetes and nephropathy. RESEARCH DESIGN AND METHODS—A total of 20 patients (17 men and 3 women) with type 2 diabetes along with hypertension and nephropathy were enrolled in this double-blind, randomized, two-period, crossover trial of 8 weeks of treatment with the ARB candesartan 16 mg daily and placebo added in random order to existing treatment with lisinopril/enalapril 40 mg daily or captopril 150 mg daily. At the end of each treatment period, we evaluated albuminuria in three 24-h urinary collections by turbidimetry, 24-h ambulatory blood pressure (ABP) using the Takeda-TM2420, and glomerular filtration rate (GFR) by the 51Cr-EDTA plasma-clearance technique. RESULTS—During monoblockade of the RAS by ACEI treatment, albuminuria was 706 (349−1,219) mg/24 h [geometric mean (IQR)]; 24-h ABP was 138 ± 3/72 ± 2 mmHg (mean ± SE); and GFR was 77 ± 6 ml · min−1 · 1.73 m−2 (mean ± SE). During dual blockade of the RAS by addition of candesartan 16 mg daily, there was a mean (95% CI) reduction in albuminuria of 28 (17−38) compared with ACEI alone (P &amp;lt; 0.001). There was a modest reduction in systolic/diastolic 24-h ABP of 3/2 mmHg (−2 to 8 systolic, −2 to 5 diastolic; NS). Changes in albuminuria did not correlate to changes in ABP. Addition of candesartan 16 mg daily induced a small, insignificant decrease in GFR of 4 (−1 to 9) ml · min−1 · 1.73 m−2. CONCLUSIONS—Dual blockade of the RAS provides superior short-term renoprotection independent of systemic blood pressure changes in comparison with maximally recommended doses of ACEI in patients with type 2 diabetes as well as nephropathy.
S87 Relationship between bronchial reticular basement membrane thickness (RBM) and smooth muscle mass in childhood severe asthma (SA)
Authors: C. J. Bossley, N. Regamey, L. Fleming, T. Oates, C. Lloyd, A. Bush, S. Saglani
Journal: Thorax (2010)

CD4<sup>+</sup> Foxp3<sup>+</sup> regulatory T (Treg) cells are key players in immune tolerance and tissue homeostasis. Their impact on tissue homeostasis has been further reinforced by recent studies showing that Tregs in tissue control non-immunological processes. However, how Treg cell differentiation and function are influenced by tissue-derived signals remain poorly understood. We here show that a specific subset of tissue-resident macrophages can promote the differentiation and stability of Tregs. This subset of tissue-resident macrophages distinctively express complement receptor of the immunoglobulin superfamily (CRIg). The phenotype of these macrophages are F4/80<sup>hi</sup> CRIg<sup>+</sup>. Our previous studies have found that CRIg acts a coinhibitory molecule to suppress T cell proliferation. We find that in addition to dampening effector T cell proliferation, CRIg promotes the conversion of induced Treg cells (iTreg), by synergizing with TGFβ. CRIg also stabilizes Foxp3 expression in induced Tregs. In vivo CRIg-Ig fusion protein treatment increases Treg proportion, particularly in tissue (islets) of NOD mice, a commonly used animal model for autoimmune diabetes. Together, these data reveal a novel mechanism of shaping Treg pool and function by tissue-resident macrophages. CRIg may represent a novel means to generate ‘stable’ iTregs, which remains unmet need in Treg-based therapy.
Detailed Analysis of Bone Marrow From Patients With Ischemic Heart Disease and Left Ventricular Dysfunction
Authors: Christopher R. Cogle, Elizabeth Wise, Amy M. Meacham, Claudia Zierold, Jay H. Traverse, Timothy D. Henry, Emerson C. Perin, James T. Willerson, Stephen G. Ellis, Marjorie Carlson, David X.M. Zhao, Roberto Bolli, John P. Cooke, Saif Anwaruddin, Aruni Bhatnagar, Maria da Graca Cabreira-Hansen, Maria B. Grant, Dejian Lai, Lem Moyé, Ray F. Ebert, Rachel E. Olson, Shelly L. Sayre, Ivonne H. Schulman, Raphael C. Bosse, Edward W. Scott, Robert D. Simari, Carl J. Pepine, Doris A. Taylor
Journal: Circulation Research (2014)

Bone marrow (BM) cell therapy for ischemic heart disease (IHD) has shown mixed results. Before the full potency of BM cell therapy can be realized, it is essential to understand the BM niche after acute myocardial infarction (AMI).To study the BM composition in patients with IHD and severe left ventricular (LV) dysfunction.BM from 280 patients with IHD and LV dysfunction were analyzed for cell subsets by flow cytometry and colony assays. BM CD34(+) cell percentage was decreased 7 days after AMI (mean of 1.9% versus 2.3%-2.7% in other cohorts; P<0.05). BM-derived endothelial colonies were significantly decreased (P<0.05). Increased BM CD11b(+) cells associated with worse LV ejection fraction (LVEF) after AMI (P<0.05). Increased BM CD34(+) percentage associated with greater improvement in LVEF (+9.9% versus +2.3%; P=0.03, for patients with AMI and +6.6% versus -0.02%; P=0.021 for patients with chronic IHD). In addition, decreased BM CD34(+) percentage in patients with chronic IHD correlated with decrement in LVEF (-2.9% versus +0.7%; P=0.0355).In this study, we show a heterogeneous mixture of BM cell subsets, decreased endothelial colony capacity, a CD34+ cell nadir 7 days after AMI, a negative correlation between CD11b percentage and postinfarct LVEF, and positive correlation of CD34 percentage with change in LVEF after cell therapy. These results serve as a possible basis for the small clinical improvement seen in autologous BM cell therapy trials and support selection of potent cell subsets and reversal of comorbid BM impairment.http://www.clinicaltrials.gov. Unique identifiers: NCT00684021, NCT00684060, and NCT00824005.
Role of Endothelin-1 in Exposure to High Altitude
Authors: Pietro Amedeo Modesti, Simone Vanni, Marco Morabito, Alessandra Modesti, Matilde Marchetta, Tania Gamberi, Francesco Sofi, Giulio Savia, Giuseppe Mancia, Gian Franco Gensini, Gianfranco Parati
Journal: Circulation (2006)

Background— The degree of pulmonary hypertension in healthy subjects exposed to acute hypobaric hypoxia at high altitude was found to be related to increased plasma endothelin (ET)-1. The aim of the present study was to investigate the effects of ET-1 antagonism on pulmonary hypertension, renal water, and sodium balance under acute and prolonged exposure to high-altitude–associated hypoxia. Methods and Results— In a double-blind fashion, healthy volunteers were randomly assigned to receive bosentan (62.5 mg for 1 day and 125 mg for the following 2 days; n=10) or placebo (n=10) at sea level and after rapid ascent to high altitude (4559 m). At sea level, bosentan did not induce any significant changes in hemodynamic or renal parameters. At altitude, bosentan induced a significant reduction of systolic pulmonary artery pressure (21±7 versus 31±7 mm Hg, P &lt;0.03) and a mild increase in arterial oxygen saturation versus placebo after just 1 day of treatment. However, both urinary volume and free water clearance (H 2 OCl/glomerular filtration rate) were significantly reduced versus placebo after 2 days of ET-1 antagonism (1100±200 versus 1610±590 mL; −6.7±3.5 versus −1.8±4.8 mL/min, P &lt;0.05 versus placebo for both). Sodium clearance and segmental tubular function were not significantly affected by bosentan administration. Conclusions— The present results indicate that the early beneficial effect of ET-1 antagonism on pulmonary blood pressure is followed by an impairment in volume adaptation. These findings must be considered for the prevention and treatment of acute mountain sickness.
Up-Regulation of TWIST in Prostate Cancer and Its Implication as a Therapeutic Target
Authors: Wai Kei Kwok, Ming-Tat Ling, Tak-Wing Lee, Tracy C.M. Lau, Chun Zhou, Xiaomeng Zhang, Chee Wai Chua, Kwok W. Chan, Franky L. Chan, Carlotta Glackin, Yong-Chuan Wong, Xianghong Wang
Journal: Cancer Research (2005)

Androgen-independent metastatic prostate cancer is the main obstacle in the treatment of this cancer. Unlike a majority of solid cancers, prostate cancer usually shows poor response to chemotherapeutic drugs. In this study, we have shown a potential novel target, TWIST, a highly conserved bHLH transcription factor, in the treatment of prostate cancer. Using malignant and nonmalignant prostate tissues, we found that TWIST expression was highly expressed in the majority (90%) of prostate cancer tissues but only in a small percentage (6.7%) of benign prostate hyperplasia. In addition, the TWIST expression levels were positively correlated with Gleason grading and metastasis, indicating its role in the development and progression of prostate cancer. Furthermore, down-regulation of TWIST through small interfering RNA in androgen-independent prostate cancer cell lines, DU145 and PC3, resulted in increased sensitivity to the anticancer drug taxol-induced cell death which was associated with decreased Bcl/Bax ratio, leading to activation of the apoptosis pathway. More importantly, inactivation of TWIST suppressed migration and invasion abilities of androgen-independent prostate cancer cells, which was correlated with induction of E-cadherin expression as well as morphologic and molecular changes associated with mesenchymal to epithelial transition. These results were further confirmed on the androgen-dependent LNCaP cells ectopically expressing the TWIST protein. Our results have identified TWIST as a critical regulator of prostate cancer cell growth and suggest a potential therapeutic approach to inhibit the growth and metastasis of androgen-independent prostate cancer through inactivation of the TWIST gene.