tbuckley/cabot-search huggingface dataset:
Pilot study of capecitabine combined with celecoxib (CapCel) as second-line treatment for advanced pancreatic (P) and biliary tree (BT) cancer
Authors: A. Gelibter, M. Milella, P. Malaguti, S. De Marco, E. Ruggeri, P. Carlini, M. Pino, C. Nuzzo, C. N. Sternberg, F. Cognetti
Journal: Journal of Clinical Oncology (2006)

14055 Background: COX-2 is overexpressed during cancer progression in several solid tumors, including P and BT, and constitutes an attractive therapeutic target. Selective COX-2 inhibitors, such as celecoxib, have been successfully combined with fluoropyrimidine-based regimens, resulting in a lower-than-expected hematologic, GI, and skin toxicity rate. Methods: Advanced P or BT patients (pts), progressing after first-line treatment, were eligible for the study. Capecitabine was administered at 1000 mg/m 2 b.i.d. on days 1–14 q3 weeks; celecoxib was administered at 200 mg b.i.d. continuously starting on day 1. PFS was the primary endpoint. ORR, toxicity, OS, clinical benefit (CB), and QoL were secondary endpoints. Assuming that a rate of PFS &gt;15% at 3 mos would be considered of interest in this pt population, an accrual of 28 pts was planned according to the exact single-stage phase II design described by A’Herne. Results: To date, 25 pts have been accrued (M/F: 11/14; median age: 64 yrs, range 39–75; P/BT: 18/7; PS 0–1/2–3: 19/6). All pts completed at least 1 treatment cycle (median: 3, range 1–9). Twenty-three pts are currently evaluable for response: 1 PR and 1 MR (duration: 33 and 27+ wks) were observed, both in pts with P; 5 additional pts showed SD (duration: 10+, 21, 22+, 27, and 42 wks); the remaining 16 pts had PD. All pts and 83 cycles are evaluable for toxicity. Hematological toxicity was negligible; only 4 pts experienced G3 non-hematological toxicities: diarrhea (2 pts, 2 cycles), skin toxicity (1 pt, resolved with treatment delay), asthenia (1 pt, 2 cycles), and GI bleeding (1 pt, requiring treatment interruption after cycle 1). To date, 19 pts have progressed and 15 pts have died: median PFS is 11 wks (range 3–42) and median OS is 16 wks (range 4–54). Nineteen pts had elevated CA19.9 serum levels at baseline, which decreased of &gt; 25% during treatment in 7 pts, remained stable in 3 pts, and increased in 9 pts. The evaluation of CB and QoL is ongoing. Conclusions: CapCel is a feasible and well-tolerated, fully oral, treatment regimen for advanced P and BT patients, which shows activity, albeit modest, even in a second-line setting. Further evaluation of this therapeutic strategy is warranted. No significant financial relationships to disclose.
Myelodysplastic/Myeloproliferative Neoplasms, Unclassifiable (MDS/MPN, U): Natural History and Clinical Outcome By Therapeutic Approach
Authors: Courtney D. DiNardo, Naval G. Daver, Nitin Jain, Naveen Pemmaraju, Carlos E. Bueso-Ramos, Cheng Yin, Sherry R. Pierce, Elias Jabbour, Alfonso Quintás-Cardama, Jorge E. Cortes, Hagop M. Kantarjian, Guillermo Garcia-Manero, Srdan Verstovsek
Journal: Blood (2013)
Molecular stool screening for colorectal cancer
Authors: D. A Ahlquist
Journal: BMJ (2000)

Colorectal cancer is the most common fatal malignancy among non-smokers in North America and Europe. Better tools are needed to improve the accuracy, compliance rates, safety, and affordability of screening. Stool testing has several important advantages over structural screening methods and warrants more investigation. Stool testing is non-invasive, avoids unpleasant cathartic preparation, can be performed on transported specimens without people having to visit their physicians, and, unlike sigmoidoscopy, reflects the state of the full length of the colorectum. Screening for stool markers that are more accurate than occult blood could substantially improve screening outcomes, and there is a strong biological rationale for targeting the DNA alterations that are exfoliated from neoplasms.

Faecal occult blood testing, used to screen for colorectal cancer for nearly three decades, continues to be the most widely used tool. Although controlled trials have shown that is of significant benefit, deaths from colorectal cancer have only been reduced by 15-33% after 10–14 years, and it has had no real impact on reducing the cumulative incidence of cancer.1–3 These outcomes are …
Abstract 4171: Olive Oil Phenolic Antioxidants Reduce Metalloproteinase (MMP)-9 Expression and Release in Human Monocytoid Cells: Possible Contribution to Plaque Stability
Authors: Maria Annunziata Carluccio, Marika Massaro, Egeria Scoditti, Carlo Storelli, Alessandro Distante, Francesco Visioli, Raffaele De Caterina
Journal: Circulation (2006)

Background: Mediterranean diets, of which olive oil is an important component, are associated with low prevalence of cardiovascular diseases, but active dietary components and their mechanisms of action are incompletely understood. The local production of active matrix metalloproteinases (MMPs) by macrophages likely contributes to plaque matrix degradation and plaque instability leading to acute coronary events. Aim: To examine the effect of the olive oil phenolic antioxidants, hydroxytyrosol (HT)and oleuropein (OE), on MMP-9 expression and activity in monocytoid cells and to explore mechanisms of action. Methods: U937 human monocytoid cells were pre-treated with HT or OE (0–100 μmol/L) for 30 min before stimulation with 50 nmol/L phorbol myristate acetate (PMA) in a serum-free medium for 24 h. Cell supernatants were then tested for the release of MMP-9 and tissue inhibitor of metallopro-teinases (TIMP)-1 antigens (ELISA) and for gelatinase activity by zymography. MMP-9 mRNA expression was investigated by RT-PCR and the activation of transcription factors Nuclear Factor(NF)-κB and Activator Protein(AP)-1 by EMSA. Results: MMP-9 antigen and activity in U937 cells increased by about 50 fold after stimulation with PMA for 24 h (from 0.5 ± 0.3 to 24 ± 1.5, p&lt;0.01). HT and OE (1–100 μmol/L) reduced PMA-induced MMP-9 activity, at zymography analysis, in a concentration dependent manner with inhibitory concentration producing 50% of the effect (IC50) at 10 μmol/L (p&lt;0.01) and 25 μmol/L (p&lt;0.01) respectively. In addition HT and OE reduced MMP-9 protein release and MMP-9 mRNA levels by about 65% and 45% respectively at 25 mmol/L (p&lt;0.01), without significantly TIMP-1 release. HT and OE at micromolar concentrations also significantly (p&lt;0.05) inhibited PMA-induced activation of NF-κB and AP-1, suggesting a plausible mechanism for the downregulation of MMP-9 expression. Conclusions: The olive oil phenolic antioxidants inhibit MMP-9 expression and release in monocytoid cells, associated with reduced activation of NF-κB and AP-1. This may contribute to plaque stabilization explaining at least in part the cardiovascular protection by specific components of Mediterranean diets.
Abstract 19071: A Novel Role of E2f1 in the Regulation of Bone Marrow Progenitor Cell Oxidative Metabolism and Ischemic Cardiac Repair
Authors: Shiyue Xu, Jun Tao, Gangjian Qin
Journal: Circulation (2013)

Background: We have previously shown that knockout of E2F1 in mice enhances angiogenesis following induction of hind limb ischemia. Recent studies suggest that E2F1 can act as a switch between glycolysis and oxidative phosphorylation, and suppression of E2F1 enhances oxidative phosphorylation in a variety of cell types. Since an increase in oxidative phosphorylation in stem/progenitor cells is often associated with cell differentiation, we hypothesize that E2F1 regulates bone marrow (BM) progenitor cell differentiation thereby impacts on ischemic cardiac repair by switching metabolism status of the cells from glycolysis to oxidative phosphorylation. Methods and Results: We cultured bone marrow (BM) Lin - progenitor cells under hypoxic and normxic conditions for 24 h, then measured the expression of metabolism related genesand evaluated cell proliferation and differentiation. We also performed adoptive BM transplantation to reconstitute BM of WT mice with E2F1 -/- or WT BM, followed by surgical induction of myocardial infarction (MI), to compare the role of BM E2F1 in the cardiac repair in vivo . We found that the expression level of genes in the mitochondria respiration chain in the E2F1 -/- BM Lin - progenitor cells is in average about 2 holds higher than those in WT cells ( P &lt;0.05, n=3). After culture in the EPC differentiation medium for 7 days, the expression levels of EPC markers, CD31 and KDR , were significantly higher in E2F1 -/- cells than in WT control cells ( P &lt;0.05, n=3). Although there was no significant difference in the proliferating rate between WT and E2F1 -/- BM Lin - progenitor cells cultured in normoxia, when cultured under hypoxic condition the proliferating rate of E2F1 -/- cells were markedly greater than that of WT cells ( P &lt;0.05, n=3). Consistently, the infarcted size in mice transplanted with E2F1 -/- eGFP Tg BM was significantly smaller than in mice transplanted with WTeGFP Tg BM ( P &lt;0.01, n=5). Conclusions: Genetic deletion of E2F1 in the BM progenitor cells enhances oxidative metabolism that may result in enhanced differentiation towards endothelial lineage and increased proliferation in the ischemic/hypoxic tissue environment. Therefore, inhibition of E2F1 in BM progenitor cells may improve the recovery from cardiac ischemic injury.
Abstract 18297: Peri-stent Contrast Staining After Drug-eluting Balloon Angioplasty for Treatment of Coronary In-stent Restenosis
Authors: Hideaki Otsuji, Kazushige Kadota, Tsuyoshi Goto, Harumi Kato, Hiroyuki Yamamoto, Naoki Oka, Yasushi Fuku, Hiroyuki Tanaka, Tsuyoshi Tada, Seiji Habara, Yoshikazu Shigemoto, Daiji Hasegawa, Suguru Ootsuru, Naoki Saito, Yuki Hayakawa, Kohshi Miyake, Hyodo Yusuke, Masatomo Ozaki, Shunsuke Kubo, Tahei Ichinohe, Kazuaki Mitsudo
Journal: Circulation (2012)

Background: Peri-stent contrast staining (PSS) induced by sirolimus-eluting stent (SES) implantation has been reported and the PSS rate was about 2%. It is said that PSS is an abnormal vessel reaction and is related to stent thrombosis. However, it remains unknown whether PSS arises after drug-eluting balloon (DEB) angioplasty. We report on PSS which arose after DEB angioplasty in the in-stent restenosis (ISR) lesion in relation to previously deployed stents. Methods: From September 2008 to October 2011, 378 consecutive patients with 453 lesions (42 de novo and 411 ISR) underwent DEB angioplasty in our hospital. The 411 ISR lesions were classified according to the previously deployed stent: SES, 182; paclitaxel-eluting stent (PES), 61; zotarolimus-eluting stent (ZES), 54; everolimus-eluting stent (EES), 34; biolimus-eluting stent (BES), 16; bare metal stent (BMS), 64. All patients underwent midterm follow-up coronary angiography (f/u CAG) at 6 months after DEB angioplasty, and those without restenosis underwent late f/u CAG at 12 months after midterm f/u. Results: The PSS rates were as follows: overall 3.3% (15/153); de novo, 0% (0/42); SES, 4.40% (8/182); PES, 6.56% (4/61); ZES, 1.85% (1/54); EES, 0% (0/34); BES, 0% (0/16); BMS, 3.13% (2/64). There were no significant differences between each PSS lesion, between first (SES and PES) and second (ZES, EES, and BES) generation drug-eluting stents, and between de novo lesions and each generation group of drug-eluting stent. Stent thrombosis has not occurred. Conclusion: PSS can arise after DEB angioplasty for ISR. Compared with the previous report on PSS after SES implantation, PSS occurred more frequently after DEB angioplasty than after SES implantation. With respect to stent thrombosis, long-term follow-up of patients with PSS after DEB angioplasty is necessary.
Glucosylceramide Synthetase Inhibitors Sensitise B-CLL Cells to Cytotoxic Agents without Reversing P-gp Functional Activity.
Authors: Gareth Gerrard, Terry D. Butters, Atul B. Mehta, A. Victor Hoffbrand, Derryln Hughes, Michael Burgess, Kanagasabai Ganeshaguru
Journal: Blood (2004)
Abstract 3786: AMPK Mediates the Cardioprotective Effects of Urocortin during Myocardial Ischemia
Authors: Ji Li, Agnes S Kim, Haiying Cheng, Jennifer Hu, Edward J Miller, Xiaohong Wu, Lei Xiao, Lawrence H Young
Journal: Circulation (2008)

Urocortin (Ucn), a peptide of the corticotropin-releasing factor (CRF) family, binds with high affinity to type 2 CRF receptors (CRFR2) expressed on the surface of cardiomyocytes and confers protec...
Abstract 189: Characterizing Continuous Capnography at the Onset of Return of Spontaneous Circulation
Authors: David C Bluhm, Trevor C Yuen, Dana P Edelson
Journal: Circulation (2012)

BACKGROUND: Manual pulse checks are often unreliable and result in prolonged pauses in chest compressions, which may be deleterious to patient outcomes. Capnography has the potential to minimize these pauses, but the threshold for determining a pulse is not known. METHODS: We conducted a prospective study of consecutive, adult, in-hospital cardiac arrests with documented return of spontaneous circulation (ROSC) at a single academic center between April 2006 and March 2012. CPR parameters and capnography were recorded using a CPR-sensing defibrillator equipped with sidestream capnography (HeartStart MRX with QCPR, Philips Healthcare; MicroStream, Oridion). All cases with continuous capnography and compression data for at least 2 minutes preceding ROSC were included in the analysis. End-tidal carbon dioxide (ETCO2) values were extracted electronically using custom software and the nadir and peak surrounding the last chest compression were manually identified. RESULTS: A total of 69 cases met inclusion criteria. The median ETCO2 nadir was 14 mmHg (range 2 - 23), which rose to a median peak of 43 mmHg (range 21 - 98), yielding a median relative rise of 215% (range 44-1944). The figure displays the changes in ETCO2 before and after the peak. The median time from nadir to peak ETCO2 was 108 s (range 24 - 501), and the median rise was 0.25 mmHg/s (range 0.05 - 0.92). The peak occurred a median of -4.4 s relative to the last chest compression. At the end of chest compressions, the median ETCO2 was 29 mmHg (range 13 - 58), without a significant drop-off when compressions were held. At the end of chest compressions, the median ventilation and heart rate were 14/min (range 6 - 34) and 126/min (range 36 - 225), respectively. CONCLUSION: In this sample, we found that ROSC was accompanied by an abrupt increase in ETCO2. This rise has the potential to be used as a pulse detector. Future work should assess whether the failure of this rise obviates the need for a pulse check.
Outcome of neonatal hypoglycaemia
Authors: M. Cornblath, R. Schwartz, A. Lucas, R. Morley
Journal: BMJ (1999)

Laparoscopic versus open mesh repair of inguinal hernia For most patients hernias provoke minimal symptomsEditor-In Wellwood et al's trial of laparoscopic hernia repair versus open mesh repair only patients fit for general anaesthesia were preselected. 1 We do not know if the rejected patients were suitable for local anaesthesia, which is usually ideal for frail and elderly patients and those with high American Society of Anesthesiologists grades.The type of anaesthesia used greatly affects morbidity associated with elective hernia repair. 2 As the authors report, after laparoscopic repair with general anaesthesia, patients may have postoperative nausea, vomiting, and retention of urine.Disorientation and cognitive dysfunction may occur with elderly patients after general anaesthesia but are rare after local anaesthesia.In Wellwood et al's trial postoperative discomfort after laparoscopic repair was reduced slightly, but does it matter?Assessment of postoperative pain is difficult, but elderly patients commonly experience less pain and require less analgesia than young adults after open hernia repair.This might be attributed to the loss of neurones with ageing 3 combined with the decrease in muscle bulk.Although laparoscopic repair is more expensive, many people have suggested that there are economic benefits of early return to work.In reality this is not so: patients over 60 are unlikely to be engaged in the labour market, so there is minimal benefit.For elderly patients, who represent half of most series, whether laparoscopic repair offers any benefits at all remains to be proved.Even with rapid recovery most employees expect a traditional amount of time off, whereas self employed patients tend to return to work as soon as possible despite any slight discomfort.The ability and desire to return to work are subjective and greatly influenced by personal circumstances.Laparoscopic repair is a more complex invasive procedure, and catastrophic complications may occur 4 ; these are unheard of with open repair.In a statistical sense the non-occurrence of an adverse event in a surgical series, as reported in this trial, does not mean that it cannot happen.Major complications from the pneumoperitoneum, bowel and vascular perforation, and acute and delayed intestinal obstruction do occur.For most patients a hernia is a benign lump that provokes minimal symptoms.Why expose patients to the major risks of a laparoscopic approach when there are marginal differences in outcome compared with open mesh repair under local anaesthesia, especially when open mesh repair is technically simple, is easily learnt, has consistent results, and is safer and cost effective?
Abstract 11838: Real-Time Flourescence Imaging of Cardiac Tissue Slices Provides Novel Insight into Mechanisms of Myocardial Protection
Authors: Gabriel Loor, Kondapalli Jyothisri, Paul Schumacker
Journal: Circulation (2011)

OBJECTIVE: There are limited models available for the assessment of myocardial protection. Here we provide the first report of the use of mammalian cardiac tissue slices for the real time analysis ...
Inhibition of B16 melanoma growth and metastatic activity by combined administration of pterostilbene and quercetin.
Authors: Angel Ortega, Paula Ferrer, Ramón Segarra, María Benlloch, Teresa Varea, Gregorio Asensio, Miguel Asensi, Jose M. Estrela
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

3826 

Inhibition of cancer growth by resveratrol ( trans -3,5,4′-trihydroxystilbene, R), a phytoalexin present in many plant species, is limited by its low bioavailability (Asensi, M. et al. Free Radic. Biol. Med. 33: 387–398, 2002). Thus structural modifications of the R molecule to increase its bioavailability while preserving its biological activity are necessary. The 4′-OH and stereoisomery in its trans -conformation are absolutely required for inhibition of cell proliferation (Stivala, L.A. et al. J. Biol. Chem. 276: 22586–22594, 2001). Pterostilbene (3,5-dimethoxy-4′-hydroxystilobene, P), a naturally ocurring analogue of R also shows similar anticarcinogenic properties (Rimando, A.M. J. Agric. Food Chem. 50: 3453–3457, 2002). Besides, flavonoids are among the most potent antioxidants because they show one or more of the following structural elements: an o -diphenolic group, a 2–3 double bond conjugated with the 4-oxo function, OH groups in position 3 and 5. Quercetin (3,3′,4′,5,6-pentahydroxyflavone, Q) combines all these 3 properties. Both, P or Q (10 μM) decreased (70% inhibition) in vitro growth of highly metastatic B16-F10 melanoma cells (B16M-F10). However B16M-F10 growth was inhibited up to 95% when both P+Q were present. Higher concentrations (20 μM) of these polyphenols caused massive apoptotic B16M-F10 cell death in vitro . Oral administration of P+Q (10 mg each/kg body weight) decreased hepatic metastatic growth (76% inhibition) of B16M-F10 cells inoculated intrasplenically into mice. The antimetastic mechanism involved a P (2 μM)-induced inhibition of vascular adhesion molecule 1 (VCAM-1) expression in the hepatic sinusoidal endothelium, which consequently decreased in vitro B16M-F10 cell adhesion to the endothelium via very late activation antigen 4 (VLA-4). Pharmacokinetics studies showed that P and Q have much longer half-lifes than R. P bioavailability can be further improved by phosphorylating the OH group at the 4′ position. We propose P and Q as a bioavailable combination with potent anticancer effects.
Abstract 21116: Adenosine Kinase Regulation of Cardiomyocyte Hypertrophy
Authors: John T Fassett, Xinli Hu, Xin Xu, Yingjie Chen, Robert J Bache
Journal: Circulation (2010)

A deficiency in adenosine production(CD73 KO mice) exacerabates cardiac hypertrophy and heart failure in response to systolic overload(transverse aortic constriction; TAC), but genetic disruption of A1 or A3 receptors does not, suggesting additional non-receptor dependent mechanisms by which adenosine attenuates hypertrophy. Here we investigated the role of adenosine receptors and adenosine metabolism in attenuation of cardiomyocyte hypertrophy at the cellular level. In neonatal cardiomyocytes, 5 μM 2-chloroadenosine(CADO; adenosine deaminase resistant adenosine analogue) or 10 μM Adenosine attenuated phenylephrine induced increases in cell surface area, protein synthesis, and ANF expression. Antagonism of adenosine receptors partially blocked the reduction of ANF expression by CADO, but did not restore cell size or protein synthesis. We hypothesized that adenosine uptake/metabolism may contribute to attenuation of hypertrophy. In support of a role for intracellular adenosine metabolism in regulating hypertrophy, Adenosine Kinase(AK) inhibitors Iodotubercidin(ITU) and ABT-702 completely reversed attenuation of cell size, protein synthesis and expression of ANF by CADO or ADO. RNAi depletion of AK in cardiomyocytes also promoted hypertrophy, ANF expression, and insensitivity to CADO. Examination of phenylephrine induced phospho-signaling pathways revealed that CADO had little effect on AKT Ser473  phosphorylation, but did reduce sustained phosphorylation of Raf Ser338 , mTOR Ser2448 , and p70S6k Thr389  (sites associated with activation). Inhibition of AK completely reversed inhibition of these pathways by CADO. Using dominant negative Raf adenovirus, we found that Raf is necessary for phenylephrine to activate mTOR/p70S6k and hypertrophy. In the presence of constitutively active Raf however, CADO still inhibited mTOR/p70S6k and hypertrophy without reducing phosphorylation of ERK Thr204/Tyr202  or AKT Ser473 . Again, reduction of mTOR/p70S6k signaling by CADO was dependent upon adenosine kinase. Together, these results identify adenosine kinase as an important mediator of adenosine attenuation of cardiomyocyte hypertrophy which acts, in part, through inhibition of RAF signaling to mTOR/p70S6k(mTORC1).
Abstract 14993: Phosphodiesterase 3 Mediates OxLDL-induced P66shc Activation: Implications For Atherogenesis
Authors: Yi Shi, Dominique Wurth, Felix Tanner, Thomas Luescher, Giovanni Camici
Journal: Circulation (2011)

Background. p66Shc is an adaptor protein mediating oxidative stress and considered a promising therapeutic target against reactive oxygen species (ROS)-related vascular dysfunction. High fat diet, ...