tbuckley/cabot-search huggingface dataset:
In vivo reversal of the multidrug resistance (MDR) phenotype in a multidrug resistant cancer model by jet-injection of anti-MDR1 short hairpin RNA-encoding plasmid DNA
Authors: Ulrike Stein, Wolfgang Walther, Alexandra Stege, Iduna Fichtner, Hermann Lage
Journal: Cancer Research (2007)

2279  Triggering the RNA interference (RNAi) pathway through the expression of small hairpin RNA (shRNA) molecules has become a promising tool for efficient silencing of a given gene in gene therapeutic applications. In this study, shRNA was used to reverse the classical MDR1/P-glycoprotein (MDR1/Pgp)-mediated multidrug resistance (MDR) phenotype in vivo. For delivery of naked shRNA-vector constructs, for the first time the nonviral jet-injection technology was applied for direct intratumoral in vivo transfer. For this, highly efficient anti-MDR1 shRNA expression vectors were applied twice in a human MDR1/Pgp overexpressing cancer xenograft and the corresponding drug-sensitive parental tumor xenograft bearing mice. The expression level of the MDR1 mRNA was decreased to about 90% and the corresponding MDR1/Pgp protein was no longer detectable in the tumors two days after anti-MDR1 shRNA vector injection. In order to analyze on whether downregulation of MDR1/Pgp leads to chemosensitization towards MDR-related drugs, two jet-injections of anti-MDR1 shRNA vectors into the tumors were combined with two intravenous administrations of doxorubicin. The data show, that jet-injection delivery of shRNA expressing vectors is effective and sufficient for reversing MDR1/Pgp-mediated MDR in vivo. Therefore, this therapeutic approach is a promising strategy to reverse tumors with a MDR1/Pgp-dependent MDR phenotype back to a drug-sensitive one.
Abstract 10262: Cranial Irradiation: A Novel Risk Factor For Anthracycline Cardiotoxicity in Childhood Cancer Survivors
Authors: David C Landy, Tracie L Miller, Gabriela Lopez-Mitnik, Stuart R Lipsitz, Andrea S Hinkle, Louis S Constine, Carol A French, Amy M Rovitelli, M J Adams, Steven E Lipshultz
Journal: Circulation (2010)

Introduction: Anthracycline-treated childhood cancer survivors (AT-Survivors) have reduced left ventricular (LV) mass and elevated LV afterload which can lead to LV dysfunction. These changes may be exacerbated by factors impairing LV hypertrophy such as growth hormone (GH) insufficiency, which can Results from cranial irradiation (Cr-Irr). We hypothesized Cr-Irr exposed AT-Survivors would have worsened LV abnormalities and that IGF-1, a marker of GH, would be more strongly correlated with these changes in those exposed. Methods: AT-Survivors from a NCI cohort study in Rochester, NY had echocardiograms recorded as age, sex, and body-surface area-adjusted z scores and IGF-1 recorded as the difference from the normal age-expected value. AT-Survivors were grouped by Cr-Irr exposure. Group means of LV measures were compared by t-tests and mean differences adjusted by regression. Group-specific correlation coefficients for LV measures with IGF-1 were compared. Results: Of 132 AT-Survivors, 61 had Cr-Irr exposu...
Abstract 14853: The Potential Role of Fibroblast Kv Channels in Atrial Fibrotic Profibrillatory Remodeling
Authors: Hai Huang, XiaoYan Qi, Chia-Tung Wu, Patrice Naud, Dobromir Dobrev, Stanley Nattel
Journal: Circulation (2013)

Background: Cardiac fibroblasts (FBs) maintain normal cardiac structure but also govern structural remodeling. CHF, a common cause of AF, causes major structural changes that contribute to the AF s...
Abstract 5646: Endothelial Intrinsic NF-{kappa}B Signaling Regulates iNOS And eNOS Expression in vivo in Endotoxemic Mice
Authors: Xiaobing Ye, Dongmei Song, Shu Fang Liu
Journal: Circulation (2009)

We have previously demonstrated that endothelial NF-κB blockade mitigates septic shock and septic vascular dysfunction (Circulation 118: S570, 2008). Since endothelial and inducible nitric oxide sy...
Abstract 2811: Time-dependent Impact of Distal Embolization on Myocardial and Microvascular Damage During Primary-Percutaneous Coronary Intervention: a Prospective Magnetic Resonance Study
Authors: Massimo Napodano, Diletta Peluso, Giuseppe Tarantini, Silvia Compagno, Chiara Fraccaro, Martina Perazzolo Marra, Luisa Cacciavillani, Angelo Ramondo, Sabino Iliceto
Journal: Circulation (2008)
Abstract 9911: Circulating miR-499-5p and -21 are Sensitive and Specific Biomarkers of NSTEMI in Geriatric Patients with Borderline cTnT Elevation
Authors: Yuri D Alessandra, Fabiola Olivieri, Roberto Antonicelli, Maria Lorenzi, Liana Spazzafumo, Rosamaria Lisa, Lucia La Sala, Roberta Galeazzi, Rina Recchioni, Roberto Testa, Giulio Pompilio, Maurizio C Capogrossi, Antonio Domenico Procopio
Journal: Circulation (2011)

Background: Geriatric patients with NSTEMI often present atypical symptoms, uninterpretable electrocardiogram and borderline cTnT elevation; therefore, these patients can be misdiagnosed and inappropriately treated. Some circulating miRNAs have emerged as novel biomarkers of MI. Our objective was to establish whether selected circulating microRNAs (miRNAs) are biomarkers of non-ST elevation myocardial infarction (NSTEMI) in geriatric patients and, eventually, whether miRNAs exhibit higher sensitivity and specificity than cardiac troponin T (cTnT) in patients with borderline cTnT elevation. Methods and Results: Elderly individuals (81.4 ± 7.1 years old) were enrolled; 61 patients presented with acute NSTEMI complicated by congestive heart failure (CHF) in 85 % of cases; 47 patients presented with acute CHF without MI. Blood samples were collected 4-9 hours after the onset of symptoms. A third group comprised 46 age-matched healthy control subjects (CTR). Plasma levels of miR-1, -21, -133a, -146a, -208, -423-5p and -499-5p were analysed. NSTEMI was associated with a ∼80-fold and ∼6-fold increase in miR-499-5p and -21, respectively, whereas CHF caused a ∼20-fold increase in miR-423-5p vs CTR. Moreover, miR-499-5p and -21 exhibited the highest sensitivity and specificity in differentiating between NSTEMI and CHF. Interestingly, among subjects with borderline cTnT elevation (0.03-0.10 ng/ml), NSTEMI (n=27) and CHF (n=21) patients were differentiated by miR-499-5p (AUC=0.90), miR-21 (AUC=0.89) and their combination (AUC=0.92), more effectively than by cTnT (AUC =0.61). Conclusions: Circulating miR-499-5p and -21 are sensitive and specific biomarkers of NSTEMI in the geriatric population; in patients with borderline increase in cTnT, these miRNAs are more accurate that cTnT in discriminating NSTEMI vs. CHF patients.
Volume of procedures and outcome of treatment
Authors: G. Parry
Journal: BMJ (2003)

Editor—For procedures relying primarily on individual doctors or surgeons, evidence shows that patients have better outcomes treated by providers with high versus low volumes.1 Where care is shared over a group, evidence of a relation between volume and outcome is less strong. Current theories for such relations are “practice makes perfect” and “selective referral.” Halm criticises these theories as lacking robust empirical support and providing little explanation of how high volume may relate to better outcomes.2 One explanation of the relation may be the greater uptake of effective interventions in high compared with low volume hospitals.3 It is important to examine how the timing of the introduction of new therapies impacts on relations between volume and outcome. Often trials of new interventions are conducted in specialist hospitals with high volumes. If effective, patients receiving the intervention will have benefited, and those high volume hospitals will seem to have better outcomes. Eventually, the new intervention will become adopted in all hospitals, removing that differential in the relation between volume and outcome.

For example, in neonatal intensive care in the United Kingdom in 1988-90 a volume-outcome relation seemed to exist.4 Concurrently the positive effects of treatment with surfactants and maternal steroids were both being realised with greater uptake in high versus low volume hospitals.5 By 1998-9 both treatments were routinely administered in all hospitals and the relation between volume and outcome had disappeared.4 If a major factor impacting on the volume-outcome relation is the uptake of effective treatments, there is little surprise that a relation between volume and outcome existed in 1988-90 but not in 1998-9.

In developing policies to improve NHS performance it is important to consider the effect different uptakes of new therapies have on relations between volume and outcome.

All factors affecting the relations between volume and outcome must be identified and quantified to more fully inform policymakers considering issues of access to local (smaller) hospitals and more distant (larger) hospitals in a centralised service.
关于“非侵入性心脏病学新进展”一文的来信：文章并未论及超声心动图
Authors: John, Chambers, Kevin, Fox, Alan, Fraser, 杨靓（译）, 刘靖（校）
Journal: BMJ (2005)

近期Prasad等人关于无创心脏病学进展的综述并未探讨超声心动图，仅仅在电子附录中有所提及。一个十分显著的遗漏就是三维超声心动图，在评价左室容量、同步性以及先天性心脏和瓣膜疾病方面相比二维超声有着许多优势。机器的小型化令我们可以在任何地方进行研究，因而超声心动图正越来越多地被非心脏病学家应用。
Abstract 1019: Injection of Apolipoprotein A-V Reverses the Hypertriglyceridemic Phenotype of apoa5 Knockout Mice
Authors: Xiao Shu, Lisa Nelbach, Jennifer Beckstead, Robert O Ryan, Trudy M Forte
Journal: Circulation (2009)

Elevated plasma triglyceride (TG) is a major and independent risk factor for cardiovascular disease. It is generally recognized that apolipoprotein (apo) A-V, a low abundance protein secreted solel...
Abstract 12848: Increased Fractalkine Levels Are Associated With Impaired Clopidogrel Responsiveness in Patients With Coronary Artery Disease by Activating a Signal Transduction Pathway Similar to P2y12
Authors: Ulrike Flierl, Johann Bauersachs, Andreas Schafer
Journal: Circulation (2010)

Background: Fractalkine contributes to platelet activation and plays a pivotal role in atherogenesis. Fractalkine activates an intraplatelet signaling pathway similar to the one activated by ADP vi...
Targeting p53-mdm2 interaction using a potent mdm2 inhibitor to overcome cisplatin resistance in head and neck squamous cell carcinoma
Authors: Bhavna Kumar, Joshua Bauer, Joseph Taylor, Ke Ding, Thomas Carey, Shaomeng Wang, Carol Bradford
Journal: Cancer Research (2007)

3202  p53 is a transcription factor known to be implicated in more than half of all humancancers. p53 induces G1 cell cycle arrest and/or apoptosis. Murine double-minute protein (mdm2) is one of the most critical regulators of p53. mdm2 directly binds to p53and blocks its transcriptional activity as wellas acts as an E3 ubiquitin ligase promoting proteasomal degradation. As mdm2 inhibition could increase the magnitude of wild type p53 activation following DNA damage, the use of mdm2 antagonists could be a promising strategy for anti-cancer drug design. Resistance to chemotherapy is a problem encountered in the treatment of head and neck squamous cell carcinoma (HNSCC). We found previously that overexpression of Bcl-xL in combination with wild type p53 in HNSCC cell lines is associated with resistance to cisplatin. The purpose of this study was to look at the effectiveness of a recently developed non-peptide small molecule inhibitor of mdm2 along with cisplatin to see if these agents could be combined for more effective treatment of HNSCC tumors. To study this, we used two HNSCC cell lines: a parental, cisplatin sensitive cell line UM-SCC-74B (low Bcl-xL) and a stably transfected cisplatin resistant cell line UM-SCC-74BxL (very high Bcl-xL). Both cell lines have wild-type p53. Cell lines were treated with cisplatin alone, mdm2 inhibitor alone (MI-63), inactive control alone (MI-61), or in combination (sequentially). For combination treatments, cells were treated with cisplatin first for 4 hours, washed and 24 hours later treated with MI-63 or MI-61. The inhibition of cell growth following treatment was assessed by MTT assay. In the cisplatin sensitive UM-SCC-74B cell line, 49%, 50%, 26% viable cells as compared to control were seen in the cisplatin alone, mdm2 inhibitor alone or the combination treatment arm respectively. Similarly and more importantly, in the cisplatin resistant cell line UM-SCC-74BxL, the combination of cisplatin and mdm2 inhibitor was most effective in inhibiting cell growth (27% viable cells) as compared to treatment with cisplatin alone (70%) or mdm-2 inhibitor alone (50%). The inactive control, MI-61, had no effect on the growth of cells as compared to untreated cells. Similar results were obtained using the clonogenic survival assay. Significantly fewer clones were observed in the combination group in both cell lines as compared to the individual drug treated groups. Cell cycle analysis by propidium iodine staining showed that treating with mdm2 inhibitor alone caused cells to undergo G1 arrest. Cells seemed to arrested at G2/M in the combination treatment group, and this G2/M arrest was higher than the G2/M arrest observed in the cisplatin treated group alone. These results indicate that this mdm2 inhibitor in combination with cisplatin might have a great therapeutic potential in the treatment of chemotherapy resistant tumors with wild type p53.
Interleukin-22 downregulates double-stranded RNA-induced expression of B7-H1/PD-L1 on airway epithelial cells
Authors: Nanae Seki, Koichiro Matsumoto, Satoru Fukuyama, Saaka Hamano, Ken Tonai, Keiko Kan-o, Takako Nakano, Yoichi Nakanishi
Journal: European Respiratory Journal (2014)

Background and Aim: Airway viral infectionis a cause of exacerbations of COPD. B7-H1/PD-L1is a coinhibitory molecule implicated in an escape mechanism of viruses from the host immune systems. Molecules suppressing expression of B7-H1/PD-L1 may be preventive for virus-induced exacerbation. Interleukin-22 (IL-22) is a member of the IL-10 family that is produced from a variety of immune cells and has protective properties on tissue-structural cells including epithelial cells. We investigated the effect of IL-22 on the expression of B7-H1/PD-L1.  Methods: Airway epithelial cell lines were treated with or without an analog of viral double-stranded RNA, polyinosinic-polycytidylic acid (poly I:C) in the presence or absence of human IL-22. The expression of B7-H1/PD-L1 was assessed by flow cytometry.  Results: The expression of B7-H1/PD-L1 was upregulated by poly I:C in a dose-dependent manner. The magnitude of B7-H1/PD-L1 expression remained constant from 24h to 48h after the stimulation of poly I:C. Without poly I:C, the expression of B7-H1/PD-L1 was not affected by treatment with IL-22. Poly I:C-induced upregultaion of B7-H1/PD-L1 was significantly attenuated by treatment with IL-22.  Conclusion: IL-22 downregluates double-stranded RNA-induced expression of B7-H1/PD-L1 on airway epithelial cells, suggesting a beneficial role of IL-22 in virus-associated pathogenesis of COPD. The examinations for  in vivo  effect of IL-22 is underway using a murine model of poly I:C-induced inflammation.
Body Mass Index and Mortality in Acutely Decompensated Heart Failure Across the World
Authors: Ravi Shah, Etienne Gayat, James L. Januzzi, Naoki Sato, Alain Cohen-Solal, Salvatore diSomma, Enrique Fairman, Veli-Pekka Harjola, Shiro Ishihara, Johan Lassus, Aldo Maggioni, Marco Metra, Christian Mueller, Thomas Mueller, Jiri Parenica, Domingo Pascual-Figal, William Frank Peacock, Jindrich Spinar, Roland van Kimmenade, Alexandre Mebazaa
Journal: Journal of the American College of Cardiology (2013)
Abstract 2669: The Use of Granulocyte-Colony Stimulating Factor in Angina Patients to Stimulate Neovascularization: the GAIN I study
Authors: Jason C Kovacic, Peter Macdonald, Michael P Feneley, David W Muller, David Ma, Helen Tao, Judith Freund, Sam Milliken, Anthony Dodds, John Moore, Silviu Itescu, Robert M Graham
Journal: Circulation (2007)

Background G-CSF is a novel therapy for ischemic heart disease (IHD), but its safety and efficacy in acute or ‘no option’ refractory IHD (R-IHD) remains unclear. Also, the few completed studies generally did not adapt G-CSF to IHD patients but merely administered G-CSF according to usual hematological practice. To address these issues we evaluated the safety and efficacy of G-CSF therapy in 20 patients (18 males, 2 females, mean age 62.4) with R-IHD. Three approaches were incorporated to enhance the efficacy of G-CSF in R-IHD: Repeated, controlled myocardial ischemia was induced during G-CSF therapy to activate myocardial chemokine expression as a homing signal for mobilized angioblasts; Two cycles of G-CSF were administered to enhance the likelihood of clinically meaningful angiogenesis; During the second cycle of G-CSF an intracoronary infusion of CD133+ cells was performed. Methods After baseline cardiac assessment (CA) (angina questionnaire, exercise stress test (EST), nuclear Sestamibi (MIBI) and dobutamine stress echocardiographic (DSE) imaging), patients received open-label G-CSF commencing at 10μg/kg s/c for 5 days, with an EST on days 4 and 6 (to facilitate angioblast trafficking). After 3 months CA and the same regimen of G-CSF +ESTs were repeated but in addition, leukapheresis and a randomized double blinded intracoronary infusion of CD133+ or unselected cells were performed. Final CA was 3 months thereafter. Results Eight events fulfilled pre-specified adverse event (AE) criteria, but despite the poor outlook and co-morbidities of R-IHD patients there were no deaths or AEs resulting in long-term sequelae. Administration of 2 cycles of G-CSF resulted in step-wise improvements in angina frequency, quality of life, EST performance and Duke treadmill score (all p &lt; 0.005). Pre-specified MIBI and DSE results trended towards improvement (p &gt; 0.1), while a composite post hoc computation indicated improved ischemia/perfusion compared to baseline (p = 0.025). Intracoronary infusion of CD133+ or unselected cells was safe but neither enhanced the response to G-CSF. Conclusions Administering G-CSF to R-IHD patients may be performed safely and shows promise as a therapy for debilitating angina. A phase II/III study of this therapy is warranted.
Abstract #5567: Phase I dose-escalation, safety, and pharmacokinetic study of weekly oral AEZS-112, a small molecule anti-cancer agent in patients with advanced cancer and lymphoma
Authors: Donald Northfelt, Pamela Griffin, Heidi Block, Herbert Sindermann, Michael Teifel, Daniel Von Hoff, David Mendelson
Journal: Cancer Research (2009)

Background: AEZS-112 is a novel orally available low molecular weight tubulin inhibitor which also inhibits topoisomerase II, arrests cancer cells in G2/M phase at nanomolar concentrations and induces apoptosis. It showed activity in cell lines that were resistant to cisplatin, vincristine and doxorubicin. This Phase I study was designed to evaluate the safety, tolerability and pharmacokinetics of ascending doses of AEZS-112 in patients with advanced solid tumors or lymphoma. Methods: AEZS-112 was administered once weekly for 3 consecutive weeks followed by 1 week without treatment. Capsules of 13 mg and 40 mg were administered with light food. Starting dose was 13 mg/week; at least 3 patients were to be treated per dose group. Due to the large number of capsules needed to be taken at a time and evidence of decreasing bioavailability at higher single doses in part I of the study, part II evaluates a modified split-dose scheme in which the weekly dose is divided into 3 administrations 8 hours apart. The starting dose of part II was 120 (= 40 x3) mg/week. Blood samples for pharmacokinetics (PK) of AEZS-112 and metabolites were collected to characterize peak plasma concentration and accumulation of trough levels through subsequent cycles. Results: In part I, 22 patients (12M/10F) were studied on 7 dose levels ranging from 13 to 800 mg/week. In all, 62 treatment cycles were administered (mean: 2.8 / patient); 2 patients were treated for 7 cycles (prostate CA, melanoma), 3 patients for 5 cycles (adenocarcinoma, colon CA 2x). In part II, 4 additional dose levels ranging from 120 to 480 (=160 x3) mg/week have been studied in a total of 13 patients (8M/5F). Similar to part I, prolonged courses of stable disease were noted, with lead patients ongoing after 5 (pancreas CA) and 6 (tracheal CA) treatment cycles. No clinically relevant drug-related adverse events or changes in laboratory parameters were observed. AEZS-112 was shown to be metabolically stable in human plasma. As predicted by PK modelling based on data from part I of the study (tmax \#8773; 4-6 hrs; t1/2 \#8773; 3-4 days), the split-dose scheme leads to a higher Cmax and trough values after administration of comparable doses. Conclusions: At all doses tested, AEZS-112 was well tolerated over repeated treatment courses. Dose escalation is ongoing in the absence of dose-limiting drug-related adverse events. Prolonged courses of stable disease in both parts of the study are an encouraging observation in this ongoing Phase I study.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5567.
Abstract 2307: Seattle Heart Failure Model Overestimates Time to Mortality in Patients Referred for Heart Transplantation
Authors: Grigorios Giamouzis, Vasiliki Georgiopoulou, Andreas Kalogeropoulos, Andrew Smith, Javed Butler
Journal: Circulation (2007)

Background : Accurate determination of time to death in advanced heart failure (HF) patients is critical for appropriate transplant candidate selection. Recently, Seattle Heart Failure Model (SHFM) was introduced to assess HF prognosis, however it was developed from a general HF population and its accuracy in advanced HF patients has not been reported. Methods : We collected data on 51 advanced HF patients referred for transplant evaluation who died during follow-up (mean age 57.4±17.5 years, 70.1% male, and 56.9% white). Time to death prediction by the SHFM was assessed by plotting actuarial survival time vs. model error (=predicted-actual). Gender and race based stratified analysis were also performed. Results : Median ejection fraction was 0.15 (25%–75%: 0.10 – 0.25), heart rate was 87±19 bpm, and systolic blood pressure was 117±22 mmHg. Overall 90.2% patients were on ACE inhibitor or angiotensin receptor blockers, 82.4% on beta-blockers, and 74.6% had a defibrillator implanted. Median expected survival by the SHFM was 6.4 (3.8 –9.7) years. Median actual survival was 2.0 (1.1–3.9) years. Residual analysis showed that the SHFM overestimated survival by 3.8 (1.5– 6.5) years, p&lt;0.001, Fig 1 . Overall 86.3% patients lived shorter than projected survival. The SHFM overestimated survival more in black vs. white patients (4.5 years, 25%–75%: 2.3–7.9 years in blacks vs. 2.8 years, 25%–75%: 0.7– 6.0 years in whites, p=0.07). No significant gender differences were noted. Conclusion : The SHFM significantly overestimates survival in advanced HF patients referred for transplantation, especially in blacks. Further studies are needed to modify and validate the SHFM in these patients.