tbuckley/cabot-search huggingface dataset:
Abstract 20609: Abnormalities of Mitochondrial Number and Function in Pediatric Idiopathic Dilated Cardiomyopathy
Authors: Kathryn C Chatfield, Marisa W Friederich, Shelley D Miyamoto, Carmen C Sucharov, Johan L Van Hove, Brian L Stauffer
Journal: Circulation (2014)

Introduction: Impaired mitochondrial energy production and substrate utilization have been implicated in the development of heart failure (HF) in adults. Little literature exists describing mitochondrial energetics in pediatric HF. We have previously shown that content of Cardiolipin (CL), a major mitochondrial membrane phospholipid, is depleted in both adult and pediatric idiopathic dilated cardiomyopathy (IDC), with preserved expression of mitochondrial-encodes genes. Similar CL changes occur in a rat model of HF with associated mitochondrial dysfunction that precedes myocardial dysfunction, which can be reversed by dietary interventions. Hypothesis: We hypothesize that mitochondrial dysfunction occurs in pediatric IDC. Methods: As a part of an on-going study a cross-sectional analysis of mitochondrial content and function was performed in left ventricle tissue from the University of Colorado Pediatric Heart Tissue Bank. Current contents: age 13-18: 11 IDC (64% male) and 13 NF (62% male). All NF are donor hearts with normal LVEF; all IDC specimens had LVEF &lt;30%. Results: We show lower mitochondrial copy number in pediatric IDC compared with NF controls (IDC: 44 vs NF: 24, P&lt;0.05), with paradoxical up-regulation of transcriptional co-activators, PGC1α and NRF1 (P&lt;0.01). This is in contrast to what has been shown in adult HF where PGC1α and NRF1 expression are unchanged. Electron transport chain (ETC) complex enzymatic activities were quantified in a sub-group of pediatric IDC samples, expressed as Z-scores relative to normative values in 18 NFs. Significantly decreased activities of complexes I, IV, and citrate synthase were found (Z-scores -2.2, -3.3 and -1.7 respectively), with a significant increase in complex III activity (Z-score 0.7, all P&lt;0.05). Conclusions: These results suggest impaired mitochondrial biogenesis occurs in pediatric HF by a unique mechanism from that seen in adults. Additionally, we show a very specific pattern of ETC dysfunction in pediatric IDC. Future studies will identify the how decreased mitochondrial copy number occurs in the context of PGC1α and NRF1 up-regulation and determine whether abnormalities in CL contribute to abnormalities in ETC activities.
Safety and efficacy of omalizumab in children with allergic asthma
Authors: Judy Pitts, Shahid Sheikh, Karen McCoy
Journal: European Respiratory Journal (2011)

Background: Omalizumab (Xolair) is a humanized monoclonal antibody used in the treatment of adults and children over 12 years with moderate to severe allergic asthma. Pediatric studies are few.

Objective: A retrospective chart review of pediatric patients who received omalizumab in the past 10 years for asthma at Nationwide Children's Hospital, Columbus, Ohio.

Results: We had 13 patients, M:F 7:6, median age 13 years (range 9-17), median duration of therapy 36 months (range 1 to 59 months), 9 African American and 4 Caucasian, duration of asthma 15 years (8 to 16). Eight are still on therapy. All patients had severe persistent asthma. Twelve patients were receiving combination therapy (ICS and LABA). Only 4 patients claimed compliance with their asthma controller therapy. Five had family history of asthma, 6 had smoking exposure. Median IgE before starting omalizumab was 249 (range 78 to 2600). Mean BMI was 25.7 and 46% of the patients were above the 100 percentile for BMI. Comparing between one year before and during omalizumab, mean hospital admission/patient/year decreased from 1.7±2.4 to 0.58±1.4 (p<0.05). There was also a trend towards improvement in ED visits from 2.3±3.2 to 1.7±3. Mean FEV1 during one year before omalizumab therapy, at initiation of therapy and during therapy was 91±18, 94±17, and 93±11 and was not statistically different.

Two of 13 patients were taken off omalizumab because of serious side effects, one with anaphylaxis and second with dilated cardiomyopathy. Anaphylaxis was noted on first dose and cardiomyopathy was diagnosed in 5th year on therapy.

Conclusion: Omalizumab is add-on therapy for some patients with allergic asthma. Adverse reactions in children are limiting factor.
Elevated Hematocrit Concentration and the Risk of Mortality and Vascular Events in Patients Undergoing Major Surgery.
Authors: Khaled M Musallam, John B Porter, Assaad Soweid, Jamal J Hoballah, Pierre M Sfeir, Mohamed Khalife, Salah Zeineldine, Hani M Tamim, Toby Richards, Luca Andrea Lotta, Flora Peyvandi, Faek R Jamali
Journal: Blood (2012)
MI patients should be sent to hospitals providing angioplasty
Authors: Deborah Josefson
Journal: BMJ (2002)

Primary coronary artery angioplasty, which is known to be superior to thrombolytic therapy in restoring blood flow to an ischaemic heart, can be safely implemented in hospitals that lack pre-existing angioplasty programmes and on-site cardiac surgery departments, a new study has found.

The report further suggests that treatment of acute myocardial infarction should be re-organised according to a trauma care model so that patients who have had a heart attack are preferentially directed to a facility where angioplasty is available (JAMA 2002;287:1943-51).

Two thirds of patients who have heart attacks in the United States are sent to hospitals that do not perform coronary angioplasty. Most community hospitals in the United States do not offer angioplasty despite the availability of trained interventional cardiologists and cardiac catheterisation facilities on-site, because in 1993 both the Ameri-can College of Cardiology and the American Heart Association advised against the performance of angioplasties if cardiac surgery was not also available on-site.

A total of 451 patients with acute myocardial infarction recruited from 11 community hospitals in Massachusetts and Maryland over three years were randomised into either a primary angioplasty arm or a thrombolytic arm with tissue plasminogen activator (tPA).

The researchers found that at six months, participants in the angioplasty arm experienced fewer complications and lower death rates than those in the thrombolytic arm. Mortality was 6.2% in the angioplasty cohort and 7.1% in the thrombolytic arm.
Influence of adaptive servoventilation therapy on autonomic function and baroreceptor reflex sensitivity in heart failure patients with Cheyne-Stokes respiration compared to healthy volunteers
Authors: Jens Spießhöfer, Henrik Fox, Thomas Bitter, Jessica Heinrich, Roman Lehmann, Dieter Horstkotte, Olaf Oldenburg
Journal: European Respiratory Journal (2014)

Adaptive servoventiation therapy (ASV) is designed to treat hypocapnic central sleep apnoea (Cheyne-Stokes respiration) in heart failure (HF) . It remains unclear whether this therapy increases stroke volume (SV) and if, this is mediated by a decrease in cardiac afterload due to increased parasympathetic nervous activity (PNA) or by a change in baroreceptor reflex sensitivity.  12 patients with HF (12 male; 70 ± 9 years; NYHA ≥ II; EF ≤ 45% and Cheyne- Stokes respiration) and 14 healthy volunteers (13 male, 24 ± 4 years, EF ≥ 60%, AHI   Changes in SV on ASV were significantly different between both groups (+5 ± 8% in HF patients vs. -4 ± 9% in volunteers, p=0.01). HF demonstrated a significant increase in markers of PNA (HFnuRRI) during ASV (56 ± 21 % vs. 68 ± 20 % on ASV; p=0.02), whereas volunteers showed a shift towards an increase in markers of sympathetic nervous activity (SNA, LFnudBP) during ASV (44 ± 12 % vs. 48 ± 8 % on ASV; p=0.04). Noteworthy those changes in autonomic function did not translate into a change in the mean total slope of the baroreceptor reflex neither in patients nor in volunteers.  ASV treatment in HF patients with Cheyne-Stokes respirations leads to an increase in SV likely mediated by a decrease in cardiac afterload due to an increased vagal activity. Baroreceptor reflex sensitivity remains largely unaffected.
Roflumilast added to triple therapy in severe COPD patients with frequent exacerbations: Efficacy and tolerability
Authors: Mariana Muñoz-Esquerre, Marta Diez-Ferrer, Concepción Montón, Xavier Pomares, Marta López-Sánchez, Daniel Huertas, Frederic Manresa, Jordi Dorca, Salud Santos
Journal: European Respiratory Journal (2014)

Background: Limited information is available on the impact of roflumilast in a “real-life” population of severe COPD patients that may be receiving combination therapies. This study aimed to evaluate the efficacy and safety of roflumilast in COPD patients already receiving long-acting β-agonist/inhaled corticosteroids and long-acting muscarinic antagonist.  Methods: Prospective registry that included severe COPD patients with frequent exacerbations who were prescribed roflumilast on top of triple therapy. The primary endpoint was the yearly rate of all COPD exacerbations before and after roflumilast treatment. Efficacy comparisons between patients that completed 1 year of therapy and those with early withdrawal in   Results: Among 55 patients prescribed roflumilast, 1 year of follow-up was achieved in 51: 54.9% (n=28) completed 1 year of therapy (roflumilast group) and 21.6% (n=11) had early withdrawal. A reduction of all exacerbations with roflumilast was observed (2.75±0.29 vs. 3.57±0.26; P=0.022), with a particular benefit in patients with ≥4 exacerbations prior to initiating therapy (3.55±0.51 vs. 5.00±0.30; P=0.034). A numerical reduction in exacerbations was observed when comparing to early withdrawal group (2.75±0.29 vs. 3.55±0.46; P=0.182). Side effects (mainly gastrointestinal) and treatment discontinuation occurred in 54.5% and 43.6% of the overall population, respectively.  Conclusions: Roflumilast, when added to triple therapy, reduces exacerbations in severe COPD patients. However, side effects are more common and lead more frequently to discontinuation of therapy than has been reported in trials.
Long Noncoding RNA CUDR Regulates HULC and β-Catenin to Govern Human Liver Stem Cell Malignant Differentiation
Authors: Xin Gui, Haiyan Li, Tianming Li, Hu Pu, Dongdong Lu
Journal: Molecular Therapy (2015)

Long noncoding RNA cancer upregulated drug resistant (CUDR) is overexpressed in many tumors and promotes tumorigenesis. Herein, we demonstrate CUDR could enhance the human embryonic stem cells (ESC) differentiation into hepatocyte-like cells by reducing trimethylation on histone H3 twenty-seventh lysine (H3K27me3). On the other hand, excessive CUDR triggers hepatocyte-like cells malignant transformation. Mechanistically, we identify CUDR causes highly upregulated in liver cancer (HULC) and β-catenin abnormal expression by inhibiting HULC promoter methylation and promoting β-catenin promoter-enhancer chromatin looping formation mediated by CUDR-ccctc-binding factor (CTCF) complex, which recruits more RNA polII and P300. Strikingly, HULC and β-catenin activity are crucial for CUDR oncogenic function. These findings provide the first demonstration that CUDR plays a positive potential role in liver cancer stem cell through the cascade of CUDR-HULC/CUDR-β-catenin signaling, and offer insights into a novel link between long noncoding RNA (lncRNA) and the epigenetic modification in cancer stem cells.
Asymmetric Action of STAT Transcription Factors Drives Transcriptional Outputs and Cytokine Specificity
Authors: Kiyoshi Hirahara, Atsushi Onodera, Alejandro V. Villarino, Michael Bonelli, Giuseppe Sciumè, Arian Laurence, Hong-Wei Sun, Stephen R. Brooks, Golnaz Vahedi, Han-Yu Shih, Gustavo Gutierrez-Cruz, Shigeru Iwata, Ryo Suzuki, Yohei Mikami, Yoshitaka Okamoto, Toshinori Nakayama, Steven M. Holland, Christopher A. Hunter, Yuka Kanno, John J. O’Shea
Journal: Immunity (2015)
6MWT is comparable to CPET for detecting exercise related desaturation
Authors: Roman Kalinov, Vladimir Hodzhev, Blagoi Marinov, Stephan Kostianev
Journal: European Respiratory Journal (2014)

Exercise related desaturation in patients with COPD can further impair their performance and is regarded as a predictor for all cause mortality.   Aim : To compare 6MWT and CPET as method for detection of desaturating patients with COPD.   Patients and methods : Forty patients performed 6 minutes walking test (6MWT) and cardiopulmonary exercise test (CPET) (Medical Graphics UltimaPFX, St Paul, MN) and comprehensive lung function (MasterScreen Diffusion/Body, E. Jaeger, Wurzburg) and blood gas assessment. Oxygen saturation was monitored with a pulseoxymeter (PalmSat 2500+ (NoninMedical, Plymouth, MN, USA). Desaturation was considered when SpO2 dropped ≥4% for at least 3 min.   Results : Forty moderate to severe COPD patients (FEV1% = 44.8%±14.6%; PO2 = 64.3±9.3mm Hg; CAT=21.7 ± 7.9), aged 67.2±8.4 were assessed with respect to exercise related desaturation. The distance [m] covered in the 6MWT was 498±82 vs 510±81; p>0.05 for the patients with and without desaturation, respectively. Oxygen uptake [mL.min -1 .kg -1 ] achieved by the patients in the two groups differed significantly (16.2±4.5 vs 19.9±4.7 respectively; p=0.016). During the CPET 21 patients revealed exercise related desaturation of whom 19 desaturated and during the 6MWT. In the whole group the achieved desaturation during CPET is 6.6±4.9%, while during the 6MWT it is 6.0±4.9% (p>0.05). Exercise related desaturation during 6MWT correlates strongly with that during CPET (r=0.75, p   Conclusion : In patients with moderate to severe COPD exercise related desaturations can be easily and reliably detected with 6MWT.
Local Adoptive Transfer of the Antitumor Cellular Immune Response in Syngeneic and Allogeneic Mice Studied With a Rapid Radioisotopic Footpad Assay2
Authors: Noritoshi Takeichi, Charles W. Boone
Journal: JNCI Journal of the National Cancer Institute (1975)

The immunologic nature of the cellular immune response against tumor cells inoculated in the footpad of mice was studied with a rapid, quantitative, and specific assay. The results indicate: a) The antitumor cellular immune response could be transferred adoptively in syngeneic and allogeneic mice with specific immune thymus (T) lymphocytes isolated on nylon columns; b) T-independent cells of host origin were necessary for the manifestation of the antitumor footpad reaction; and c) there was a close correlation between immune responses detected by the footpad assay and those detected by transplantation techniques. The footpad reaction consisted of several nonspecific and specific components. Nonspecific factors disturbing the specific footpad reaction in syngeneic and allogeneic recipients were discussed
Abstract 2764: The depletion of LRP5, unlike that of LRP6, promotes apoptosis in triple-negative breast cancer cells, making it an interesting therapeutic target
Authors: Sylvie Maubant, Virginie Maire, Bruno Tesson, Fariba Némati, David Gentien, Bérengère Marty-Prouvost, Stéphane Depil, Francisco Cruzalegui, Gordon Tucker, Sergio Roman-Roman, Thierry Dubois
Journal: Cancer Research (2014)

Abstract Treatment of patients with triple-negative breast cancers (TNBCs) remains a major challenge for oncologists and alternative treatments to conventional chemotherapies are needed to improve their survival. The Wnt/beta-catenin signaling, recently reported to be activated in TNBCs, may represent an interesting pathway to target. We report that both LRP5 and LRP6 Wnt coreceptors are more strongly expressed in TNBCs than in other breast tumor subtypes. As very few studies have explored potential differences between LRP5 and LRP6, we investigated the effects of modulating specifically LRP5 or LRP6 expression on Wnt signaling, cell viability and tumorigenesis in HCC38 and MDA-MB-468 TNBC cells. We found that these two cell lines are more similar to TNBC biopsy specimens in terms of Wnt pathway gene expression profiles than any other tested cell line. Unlike LRP5, LRP6 was involved in activating the canonical Wnt pathway in response to Wnt3a. LRP5 knockdown induced caspase-dependent apoptosis, whereas LRP6 knockdown had no such effect. Importantly, LRP5-depleted cells were more sensitive to conventional chemotherapy than cells depleted of LRP6. The knockdown of LRP5 or LRP6 decreased tumorigenesis both in vitro and in vivo. Overall, these data suggest that the LRP5 and LRP6 coreceptors have different functions in TNBCs, with LRP5 playing a preponderant role in survival control. Our data suggest that both LRP5 and LRP6 are potential treatment targets in TNBCs, but that LRP5 may be the most useful target, given the impact of its depletion on cell survival as well as on the response to anti-cancer drugs. Citation Format: Sylvie Maubant, Virginie Maire, Bruno Tesson, Fariba Némati, David Gentien, Bérengère Marty-Prouvost, Stéphane Depil, Francisco Cruzalegui, Gordon Tucker, Sergio Roman-Roman, Thierry Dubois. The depletion of LRP5, unlike that of LRP6, promotes apoptosis in triple-negative breast cancer cells, making it an interesting therapeutic target. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2764. doi:10.1158/1538-7445.AM2014-2764
Diabetic Retinopathy Severity and Peripheral Lesions Are Associated with Nonperfusion on Ultrawide Field Angiography
Authors: Paolo S. Silva, Amanda J. Dela Cruz, Migil G. Ledesma, Jano van Hemert, Ajlan Radwan, Jerry D. Cavallerano, Lloyd M. Aiello, Jennifer K. Sun, Lloyd Paul Aiello
Journal: Ophthalmology (2015)
Pulmonary Deposition and Retention of Inhaled Aerosols.
Authors: Anne L. Davis
Journal: Annals of Internal Medicine (1964)

This chapter discusses adhesives for specific adherend types. Proper combinations of adhesives with adherends can results in superior durability and resistance to environments. In aluminum and alloys, adhesives recommended include modified epoxies, modified phenolics, epoxy-phenolics, neoprene-phenolics, second-generation acrylics, cyanoacrylates, silicone rubbers, and vinyl plastisols. Copper and copper alloys can use adhesives such as epoxies, polyurethane, silicone, nylon-epoxy, nitrile-phenolic, neoprene-phenolic, acrylic, cyanoacrylate, anaerobics, and partially hydrogenated polybutadiene. A wide variety of adhesives such as epoxy phenolics, polyurethanes, silicones, cyanoacrylates, polyvinyl acetate, can be used for bonding magnesium as long as proper corrosion protection is maintained in keeping with joint design and end-use requirements. Adhesives used to bond acetal homopolymer to itself and to other materials such as aluminum, steel, natural rubber, neoprene rubber, and Buna rubber, include polyester with isocyanate curing agent, rubber-based adhesives, phenolics, epoxies, modified epoxies, and vinyls. Bonding of vulcanized elastomers to themselves and to other materials is generally accomplished using a pressure-sensitive adhesive derived from an elastomer similar to the one being bonded. Adhesives used includes several rubber-based materials , namely, natural, chlorinated, reclaim, butyl, nitrile, butadiene-styrene, polyurethane, polysulfide, and neoprene rubber, as well as acrylics.
TRAIL sensitization of PC3 prostate cancer cells by doxorubicin can be blocked by the anti-oxidant N-acetyl-cysteine or by the iron chelator deferoxamine
Authors: Shai White, Laura Kasman, Laura Spruill, Paul McDermott, Christina Voelkel-Johnson
Journal: Clinical Cancer Research (2006)

B59   The purpose of this study was to investigate the mechanism whereby doxorubicin sensitizes cancer cells to TNF-Related Apoptosis Inducing Ligand (TRAIL). We used PC3 prostate cancer cells which are partially resistant to TRAIL but can be more fully sensitized with doxorubicin treatment. Doxorubicin downregulates the short form of the anti-apoptotic protein Flice-Like Inhibitory Protein (FLIPs), which correlates with sensitization to TRAIL. The mechanism of FLIPs downregulation is not transcriptional or mediated by ubiquitination. Rather, doxorubicin globally inhibits translation suggesting that short half-life proteins such as FLIPs would disappear quickly. Polysome and Western blot analysis indicate that translation initiation is not inhibited. Elongation factor 2 (EF2), which mediates translocation in peptide chain elongation, is inactivated by phosphorylation. We found that doxorubicin treatment results in strong EF2 phosphorylation and therefore translational elongation became the focus of our mechanism study. EF2 is normally phosphorylated by EF2 kinase. However, EF2k is not the likely cause of doxorubicin-mediated phosphorylation because, as a short half life protein, it is also quickly downregulated by doxorubicin. As an alternative, we explored whether EF2 phosphorylation is the result of oxidative stress. When doxorubicin is administered, it binds to cellular iron, generating free radicals through Fenton chemistry. We demonstrate with hydrogen peroxide treatments that free radicals can both phosphorylate EF2 and downregulate FLIPs. Further, these effects of doxorubicin can be abrogated through the pretreatment of cells with an anti-oxidant to scavenge free radicals, N-Acetyl-Cysteine (NAC), or an iron chelator to preclude the doxorubicin/iron complex, deferoxamine (DFO). Upon pretreatment with NAC or DFO, doxorubicin treatment fails to downregulate FLIPs, phosphorylate EF2, or sensitize cells to TRAIL as shown by Western blot. However, NAC and DFO do not abrogate the G2 cell-cycle arrest that results from doxorubicin treatment. This result indicates that the arrest is likely due to the DNA damaging aspect of doxorubicin activity rather than the iron-chelation aspect. This observation may help explain why patients have a wide range of responses to doxorubicin treatment. Anti-oxidants may inadvertently protect tumors from the effectiveness of doxorubicin while a patient would still suffer the side effects of cell cycle arrest such as anemia, hair loss, and immune suppression. This potential clinical outcome merits further study. Tumors may require initial protein profiling before treatment decisions are made in order to best tailor treatment and adjunct therapy to oncogenes specific to the tumor.
Abstract 20119: Impact of Microvascular Resistance Index on Left Ventricular Remodeling after Primary Coronary Intervention for ST-elevation Acute Myocardial Infarction
Authors: Hironori Kitabata, Kohei Ishibashi, Kenichi Komukai, Takashi Tanimoto, Yasushi Ino, Keizo Kimura, Kumiko Hirata, Masato Mizukoshi, Toshio Imanishi, Takashi Akasaka
Journal: Circulation (2010)

Background:  Previous studies have shown that microvascular dysfunction in recanalized infarct-related coronary arteries may predict progressive LV dilatation. A dual-sensor (pressure and Doppler velocity) guidewire has an ability to evaluate microvascular dysfunction quantitatively. The aim of this study was to investigate the relationship between microvascular dysfunction assessed by a dual-sensor guidewire and LV remodeling after primary percutaneous coronary intervention (PCI) in AMI patients.   Methods and results:  Twenty-two patients who underwent primary PCI for a first anterior AMI were enrolled in the study. Immediately after primary PCI, using a dual-sensor guidewire, microvascular resistance index (MVRI) was calculated as the ratio of mean distal pressure to average peak flow velocity during maximal hyperemia. The degree of microvascular dysfunction was evaluated on the basis of MVRI. According to MVRI, patients were divided into two groups (MVRI  −1 •s, the incidence of MVO (64% vs. 18%, p=0.08) and transmural necrosis (64% vs. 27%, p=0.20) tended to be higher. LV volume profiles at 8-month follow-up were significantly greater in the group with a MVRI ≥ 3.03 mmHg•cm −1 •s compared with  −1 •s (Table).   Conclusion:  MVRI immediately after primary PCI predicts LV remodeling in patients with anterior AMI.