bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery of the Novel mTOR Inhibitor and Its Antitumor Activities In Vitro and In Vivo
Authors: Xie Hua , Lee Mee-Hyun , Zhu Feng , Reddy Kanamata , Huang Zunnan , Kim Dong Joon , Li Yan , Peng Cong , Lim Do Young , Kang Soouk , Jung Sung Keun , Li Xiang , Li Haitao , Ma Weiya , Lubet Ronald A. , Ding Jian , Bode Ann M. , Dong Zigang 
Published: March 2013

Abstract
The phosphoinositide 3-kinase (PI3-K)/Akt and mTOR signaling pathway plays a critical role in cell survival and proliferation and is often aberrantly activated in many types of cancer. The mTOR kinase protein, one of the key molecules in this pathway, has been shown to be an important target for cancer therapy. In the present study, a ligand docking method was used to screen for novel scaffold mTOR inhibitors. Sixty thousand compounds in the Natural Product Database were screened against the mTOR homologous structure, and 13 commercially available compounds listed in the top-ranked 100 compounds were selected for further examination. Compound [(E)-3-(4-(benzo[d][1,3]dioxol-5-yl)-2-oxobut-3-en-1-yl)- 3-hydroxyindolin-2-one; designated herein as 3HOI-BA-01] was then selected for further study of its antitumor activity. An in vitro study has shown that 3HOI-BA-01 inhibited mTOR kinase activity in a dose-dependent manner by directly binding with mTOR. In a panel of non–small cell lung cancer cells, the compound also attenuated mTOR downstream signaling, including the phosphorylation of p70S6K, S6, and Akt, resulting in G1 cell-cycle arrest and growth inhibition. Results of an in vivo study have shown that intraperitoneal injection of 3HOI-BA-01 in A549 lung tumor–bearing mice effectively suppressed cancer growth without affecting the body weight of the mice. The expression of downstream signaling molecules in the mTOR pathway in tumor tissues was also reduced after 3HOI-BA-01 treatment. Taken together, we identified 3HOI-BA-01 as a novel and effective mTOR inhibitor. Mol Cancer Ther; 12(6); 950–8. ©2013 AACR.
Activation of the FGF2-FGFR1 Autocrine Pathway: A Novel Mechanism of Acquired Resistance to Gefitinib in NSCLC
Authors: Terai Hideki , Soejima Kenzo , Yasuda Hiroyuki , Nakayama Sohei , Hamamoto Junko , Arai Daisuke , Ishioka Kota , Ohgino Keiko , Ikemura Shinnosuke , Sato Takashi , Yoda Satoshi , Satomi Ryosuke , Naoki Katsuhiko , Betsuyaku Tomoko 
Published: March 2013

Abstract
Patients with non-small cell lung cancer (NSCLC) that harbors epidermal growth factor receptor (EGFR) mutations initially respond to EGFR-tyrosine kinase inhibitors (TKI) but eventually experience relapse. Acquired resistance to EGFR-TKIs is strongly associated with patient mortality. Thus, elucidation of the mechanism of acquired resistance to EGFR-TKIs is of great importance. In this study, gefitinib-resistant cell line models were established by long-term exposure to gefitinib using the gefitinib-sensitive lung cancer cell lines, PC9 and HCC827. Expression analyses indicated that both FGFR1 and FGF2 were increased in PC9 gefitinib-resistant (PC9 GR) cells as compared with PC9 naïve (PC9 na) cells. Importantly, proliferation of gefitinib-resistant cells was dependent on the FGF2 -FGFR1 pathway. Mechanistically, inhibition of either FGF2 or FGFR1 by siRNA or FGFR inhibitor (PD173074) restored gefitinib sensitivity in PC9 GR cells. These data suggest that FGF2 -FGFR1 activation through an autocrine loop is a novel mechanism of acquired resistance to EGFR-TKIs. Mol Cancer Res; 11(7); 759–67. ©2013 AACR.
Parenteral anticoagulants in heart disease: Current status and perspectives (Section II)
Authors: Husted Steen , Wallentin Lars , Andreotti Felicita , Arnesen Harald , Bachmann Fedor , Baigent Colin , Huber Kurt , Jespersen Jørgen , Kristensen Steen , Lip Gregory Y. H. , Morais João , Rasmussen Lars , Siegbahn Agneta , Verheugt Freek W. A. , Weitz Jeffrey I. , De Caterina Raffaele 
Published: March 2013

SummaryAnticoagulants are a mainstay of cardiovascular therapy, and parenteral anticoagulants have widespread use in cardiology, especially in acute situations. Parenteral anticoagulants include unfractionated heparin, low-molecular-weight heparins, the synthetic pentasaccharides fondaparinux, idraparinux and idrabiotaparinux, and parenteral direct thrombin inhibitors. The several shortcomings of unfractionated heparin and of low-molecular-weight heparins have prompted the development of the other newer agents. Here we review the mechanisms of action, pharmacological properties and side effects of parenteral anticoagulants used in the management of coronary heart disease treated with or without percutaneous coronary interventions, cardioversion for atrial fibrillation, and prosthetic heart valves and valve repair. Using an evidence-based approach, we describe the results of completed clinical trials, highlight ongoing research with currently available agents, and recommend therapeutic options for specific heart diseases.
The physiological and pathophysiological roles of platelet CLEC-2
Authors: Langan Stacey A. , Nash Gerard B. , Watson Steve P. , Navarro-Núñez Leyre 
Published: March 2013

SummaryCLEC-2 is a C-type lectin receptor which is highly expressed on platelets but also found at low levels on different immune cells. CLEC-2 elicits powerful platelet activation upon engagement by its endogenous ligand, the mucin-type glycoprotein podoplanin. Podoplanin is expressed in a variety of tissues, including lymphatic endothelial cells, kidney podocytes, type I lung epithelial cells, lymph node stromal cells and the choroid plexus epithelium. Animal models have shown that the correct separation of the lymphatic and blood vasculatures during embryonic development is dependent on CLEC-2-mediated platelet activation. Additionally, podoplanin-deficient mice show abnormalities in heart, lungs, and lymphoid tissues, whereas absence of CLEC-2 affects brain development. This review summarises the current understanding of the molecular pathways regulating CLEC-2 and podoplanin function and suggests other physiological and pathological processes where this molecular interaction might exert crucial roles.
Prognostic Value of Cardiac Time Intervals by Tissue Doppler Imaging M-Mode in Patients With Acute ST-Segment–Elevation Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention
Authors: Biering-Sørensen Tor , Mogelvang Rasmus , Søgaard Peter , Pedersen Sune H. , Galatius Søren , Jørgensen Peter Godsk , Jensen Jan Skov 
Published: March 2013

Background—
Color tissue Doppler imaging M-mode through the mitral leaflet is an easy and precise method to estimate all cardiac time intervals from 1 cardiac cycle and thereby obtain the myocardial performance index (MPI). However, the prognostic value of the cardiac time intervals and the MPI assessed by color tissue Doppler imaging M-mode through the mitral leaflet in patients with ST-segment–elevation myocardial infarction (MI) is unknown.

Methods and Results—

In total, 391 patients were admitted with an ST-segment–elevation MI, treated with primary percutaneous coronary intervention, and examined by echocardiography a median of 2 days after the ST-segment–elevation MI. Outcome was assessed according to death (n=33), hospitalization with heart failure (n=53), or new MI (n=25). Follow-up time was a median of 25 months. The population was stratified according to tertiles of the MPI. The risk of new MI, being admitted with congestive heart failure or death, increased with increasing tertile of MPI, being ≈3 times as high for the third tertile compared with the first tertile (hazard ratio, 2.8; 95% confidence interval, 1.7–4.7;
P
<0.001). MPI provided independent prognostic information in a multivariable Cox regression model adjusted for age, sex, previous MI, peak troponin, and systolic and diastolic echocardiographic parameters, with a hazard ratio of 1.24 (
P
=0.005) for the combined end point per each 0.1 increase in MPI.

Conclusions—
MPI assessed by tissue Doppler imaging M-mode is a simple and reproducible measure that provides independent prognostic information, regardless of rhythm, incremental to conventional and novel echocardiographic parameters of systolic and diastolic function in patients with ST-segment–elevation MI treated with primary percutaneous coronary intervention.
Type 5 Adenylyl Cyclase Increases Oxidative Stress by Transcriptional Regulation of Manganese Superoxide Dismutase via the SIRT1/FoxO3a Pathway
Authors: Lai Lo , Yan Lin , Gao Shumin , Hu Che-Lin , Ge Hui , Davidow Amy , Park Misun , Bravo Claudio , Iwatsubo Kousaku , Ishikawa Yoshihiro , Auwerx Johan , Sinclair David A. , Vatner Stephen F. , Vatner Dorothy E. 
Published: March 2013

Background—
For reasons that remain unclear, whether type 5 adenylyl cyclase (AC5), 1 of 2 major AC isoforms in heart, is protective or deleterious in response to cardiac stress is controversial. To reconcile this controversy we examined the cardiomyopathy induced by chronic isoproterenol in AC5 transgenic (Tg) mice and the signaling mechanisms involved.

Methods and Results—

Chronic isoproterenol increased oxidative stress and induced more severe cardiomyopathy in AC5 Tg, as left ventricular ejection fraction fell 1.9-fold more than wild type, along with greater left ventricular dilation and increased fibrosis, apoptosis, and hypertrophy. Oxidative stress induced by chronic isoproterenol, detected by 8-OhDG was 15% greater,
P
=0.007, in AC5 Tg hearts, whereas protein expression of manganese superoxide dismutase (MnSOD) was reduced by 38%, indicating that the susceptibility of AC5 Tg to cardiomyopathy may be attributable to decreased MnSOD expression. Consistent with this, susceptibility of the AC5 Tg to cardiomyopathy was suppressed by overexpression of MnSOD, whereas protection afforded by the AC5 knockout (KO) was lost in AC5 KO×MnSOD heterozyous KO mice. Elevation of MnSOD was eliminated by both sirtuin and MEK inhibitors, suggesting both the SIRT1/FoxO3a and MEK/ERK pathway are involved in MnSOD regulation by AC5.

Conclusions—
Overexpression of AC5 exacerbates the cardiomyopathy induced by chronic catecholamine stress by altering regulation of SIRT1/FoxO3a, MEK/ERK, and MnSOD, resulting in oxidative stress intolerance, thereby shedding light on new approaches for treatment of heart failure.
Influence of oily vehicles on fetal testis and lipid profile of rats exposed to di-butyl phthalate
Authors: Lourenço ACS , Gomes C , Boareto AC , Mueller RP , Nihi F , Andrade LF , Trindade ES , Coelho I , Naliwaiko K , Morais RN , Martino-Andrade AJ 
Published: March 2013

It has been hypothesized that oils containing high levels of omega-3 polyunsaturated fatty acids, such as canola and fish oil, could counteract some of the adverse effects induced by phthalates. In the present study, the influence of different oily vehicles on di-butyl phthalate (DBP)-induced testicular toxicity and lipid profile was investigated. Pregnant Wistar rats were treated by oral gavage from gestation days 13 to 20 with DBP (500 mg/kg/day) diluted in three different vehicles: corn, canola or fish oil. Male fetuses were analyzed on gestation day 20. DBP exposure lowered intratesticular testosterone levels and anogenital distance, regardless of the vehicle used. The percentage of seminiferous cords containing multinucleated gonocytes and cord diameter was increased in DBP-exposed groups, compared with vehicle controls, with no difference between the three DBP-exposed groups. Clustering of Leydig cells was seen in all DBP groups. Lipid profile indicated that administration of canola and fish oil can increase the content of omega-3 fatty acids in rat testis. However, content of omega-3 was diminished in DBP-treated groups. Overall, our results indicate that different oily vehicles did not alter fetal rat testicular toxicity induced by a high DBP dose.
A new antiallergic agent that binds to dimerized translationally controlled tumor protein and inhibits allergic symptoms is nontoxic
Authors: Kim M , Jin YB , Lee K , Lee YS 
Published: March 2013

Dimerized translationally controlled tumor protein (dTCTP) plays a role in allergic diseases. A 7-mer peptide, dimerized translationally binding protein 2 (dTBP2), binds to dTCTP and inhibits dTCTP, suggesting that the 7-mer peptide may have therapeutic potential. We assessed the safety of dTBP2 by examining its cytotoxicity to both human bronchial epithelial cells and mice. dTBP2 did not cause cytotoxicity to the epithelial cells in concentrations up to 100 μg/ml. Also, dTBP2 caused no adverse effects upon repeated administration of 50 mg/kg over 24 h to mice. Hence, we conclude that dTBP2 is a safe candidate drug for use in the therapy of allergic diseases.
Differential effects of organic and inorganic selenium compounds on adenosine deaminase activity and scavenger capacity in cerebral cortex slices of young rats
Authors: Bitencourt PER , Bellé LP , Bonfanti G , Cargnelutti LO , Bona KS de , Silva PS , Abdalla FH , Zanette RA , Guerra RB , Funchal C , Moretto MB 
Published: March 2013

Selenium (Se) has anti-inflammatory and antioxidant properties and is necessary for the development and normal function of the central nervous system. This study was aimed to compare the in vitro effects of 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one (C21H2HOSe; organoselenium) and sodium selenate (inorganic Se) on adenosine deaminase (ADA) activity, cell viability, lipid peroxidation, scavenger of nitric oxide (NO) and nonprotein thiols (NP-SH) content in the cerebral cortex slices of the young rats. A decrease in ADA activity was observed when the slices were exposed to organoselenium at the concentrations of 1, 10 and 30 µM. The same compound showed higher scavenger capacity of NO than the inorganic compound. Inorganic Se was able to protect against sodium nitroprusside-induced oxidative damage and increased the NP-SH content. Both the compounds displayed distinctive antioxidant capacities and were not cytotoxic for the cerebral cortex slices in the conditions tested. These findings are likely to be related to immunomodulatory and antioxidant properties of this compound.
The protective effects of taurine on experimental acute pancreatitis in a rat model
Authors: Akay C , Yaman H , Oztosun M , Cakir E , Yildirim AO , Eyi YE , Agilli M , Akgul EO , Aydin I , Kaldirim U , Tuncer SK , Eken A , Oztas E , Poyrazoglu Y , Yasar M , Ozkan Y 
Published: March 2013

The aim of this study was to investigate the protective effects of taurine (Tau) on experimental acute pancreatitis (AP) in a rat model by measuring cytokines and oxidant stress markers. Forty rats were randomly divided into four groups: sham, AP, Tau and AP + Tau. AP was induced with sodium taurocholate. No treatment was given to the AP. All rats were killed 5 days later. Pancreatic tissues of rats and blood samples were obtained. Tau treatment significantly decreased serum amylase activity ( p < 0.001), total injury score ( p < 0.001), malondialdehyde levels ( p < 0.001) and myeloperoxidase (MPO) activity ( p < 0.001). There was no significant difference between the Tau and AP + Tau groups in serum and pancreatic tumor necrosis factor-α, interleukin (IL)-1β and IL-6 levels ( p = 1.000). Histopathologic scores in the AP + Tau and Tau groups were significantly lower compared with the AP group (both p < 0.001). These results showed that Tau reduces lipid peroxidation, amylase and MPO activities and the concentrations of proinflammatory cytokines secondary to AP and also increases superoxide dismutase and glutathione peroxidase activities in rats with sodium taurocholate-induced AP. It also has a marked ameliorative effect at histopathologic lesions. With these effects, Tau protects the cells from oxidative damage, reduces inflammation and promotes regression of pancreatic damage.
Learning and memory-related brain activity dynamics are altered in systemic lupus erythematosus: a functional magnetic resonance imaging study
Authors: Shapira-Lichter Irit , Vakil Eli , Litinsky Ira , Oren Noga , Glikmann-Johnston Yifat , Caspi Dan , Hendler Talma , Paran Daphna 
Published: March 2013

Background Memory impairment is prevalent in systemic lupus erythematosus (SLE); however, the pathogenesis is unknown. Methods We studied 12 patients with SLE without clinically overt neuropsychiatric manifestations and 11 matched healthy controls, aiming to characterize neural correlates of memory impairment, using structural and functional magnetic resonance imaging (MRI). The paradigm consisted of three encoding and free-recall cycles, allowing characterization of dynamics along consecutive retrieval attempts. Results During learning, patients with SLE and healthy controls showed brain activity changes in two principal networks, the default mode network (DMN) and the task-positive network (TPN). Patients with SLE demonstrated significantly less deactivation in the DMN and greater activation in the TPN, reflecting greater recruitment of both networks. The anterior medial prefrontal cortex (amPFC) of the DMN emerged as the only region where brain activity dynamics were altered both over the learning process ( p < 0.006), and within free-recall period attempts ( p < 0.034). Patients showed significant positive correlations between learning efficiency and hippocampal activity, and greater hippocampal functional connectivity, with pronounced connectivity to DMN structures. Conclusions Increased brain activation in patients with SLE during learning may reflect compensatory mechanisms to overcome memory impairment. Our findings localize this impairment to the amPFC, consistent with the behavioral pattern seen in SLE. Altered networking of the hippocampal subsystem of the DMN is consistent with hippocampal neuronal damage seen in SLE, and may reflect compensatory cortical reorganization to cope with dysfunction in these regions pivotal to mnemonic functions.
Estradiol differentially regulates calreticulin: a potential link with abnormal T cell function in systemic lupus erythematosus?
Authors: Ward JM , Rider V , Abdou NI , Kimler B 
Published: March 2013

Objective Systemic lupus erythematosus (SLE) is an autoimmune disease that affects women nine times more often than men. The present study investigates estradiol-dependent control of the calcium-buffering protein, calreticulin, to gain further insight into the molecular basis of abnormal T cell signaling in SLE T cells. Methods T cells were purified from blood samples obtained from healthy females and SLE patients. Calreticulin expression was quantified by real-time polymerase chain amplification. Calreticulin and estrogen receptor-α were co-precipitated and analyzed by Western blotting to determine if the proteins associate in T cells. Results Calreticulin expression increased ( p = 0.034) in activated control T cells, while estradiol decreased ( p = 0.044) calreticulin in resting T cells. Calreticulin expression decreased in activated SLE T cell samples and increased in approximately 50% of resting T cell samples. Plasma estradiol was similar ( p > 0.05) among SLE patients and control volunteers. Estrogen receptor-α and calreticulin co-precipitated from nuclear and cytoplasmic T cell compartments. Conclusions The results indicate that estradiol tightly regulates calreticulin expression in normal human T cells, and the dynamics are different between activated and resting T cells. The absence of this tight regulation in SLE T cells could contribute to abnormal T cell function.
Impact of electrocardiographic findings for diagnosis of left ventricular hypertrophy in patients with primary aldosteronism
Authors: Kurisu Satoshi , Iwasaki Toshitaka , Mitsuba Naoya , Ishibashi Ken , Dohi Yoshihiro , Kihara Yasuki 
Published: March 2013

Background: Compared to patients with similar levels of hypertension, patients with primary aldosteronism have a greater left ventricular hypertrophy (LVH). The presence of LVH should be detected as early as possible to prevent cardiovascular complications associated with the condition. We evaluated comparative diagnostic value of electrocardiographic (ECG) indexes for LVH in patients with primary aldosteronism. Methods: ECG and echocardiographic data were obtained in 88 patients with primary aldosteronism. We analyzed the four most commonly used ECG indexes, including Sokolow-Lyon index, Cornell voltage index, Cornell product index, and Gubner index. Results: Echocardiographic LVH was found in 35 patients (40%). Sensitivity ranged from 0% for Gubner index to 49% for Cornell product index. Specificity ranged from 81% for Sokolow-Lyon index to 100% for Gubner index. Sokolow-Lyon index ( r=0.43, p<0.001), Cornell voltage index ( r=0.55, p<0.001) and Cornell product index ( r=0.52, p<0.001) correlated significantly with left ventricular mass (LVM) index. No significant correlation was found between Gubner index and LVM index. Conclusions: ECG indexes had a reasonably high specificity, but a low sensitivity for LVH in patients with primary aldosteronism. Cornell voltage index and Cornell product index had a better diagnostic value of LVH, and had a better correlation with LVM index in these patients.
The use and reporting of patient-reported outcomes in phase III breast cancer trials
Authors: Brim Remy L , Pearson Steven D 
Published: March 2013

Background Public and government attention to patient-centered research outcomes has been increasing, evidenced by the recent formation of the Patient Centered Outcomes Research Institute. Drug development clinical trials can be made more patient-centered by collecting patient-reported outcome measures that can inform decision making by patients and their health-care providers. Patient-reported outcomes are important to collect in trials of breast cancer therapeutics, which encompass a wide range of treatment regimens and side effects. Purpose We sought to determine recent trends in the use of patient-reported outcomes in drug trials for the treatment of breast cancer and evaluate the reporting of these data in study publications. Methods We searched ClinicalTrials.gov for phase III breast cancer drug trials, recording information on start date, primary completion date, primary outcome measure, primary sponsor, stage of cancer, and patient-reported outcome use. To assess the reporting of patient-reported outcome data, Google.com and PubMed.gov were searched for all publications resulting from included trials. Results We found 236 eligible trials, starting between May 1989 and December 2011. Of these trials, 83 (35%) stipulated patient-reported outcome use. The rate of patient-reported outcome use in recent years has shown no increase over earlier time periods: 37% (1989–2000) versus 36% (2004–2007) versus 30% (2008–2011) ( p = 0.8). Trials with sponsorship led by the pharmaceutical industry and trials including patients with locally advanced or metastatic disease had the highest rates of patient-reported outcome use (40/87 (46%) and 44/102 (43%), respectively). Among the 83 trials that collected patient-reported outcome measures, 36 were completed a minimum of 2 years before our analysis; of these 36 studies, 19 (53%) had published patient-reported outcome data. Limitations Data were limited to self-reported descriptions of trials listed on the ClinicalTrial.gov database, which is the best compendium of trial information available, but it is neither a complete nor a fully accurate record of all trials. Conclusions Patient-reported outcome use and reporting in breast cancer drug trials has remained relatively low despite calls for more patient-centered research. Increasing the collection and availability of patient-reported outcome data to guide clinical decisions will require aligned support from trial sponsors, researchers, journal editors, regulators and patient advocacy groups, who can all play important roles in implementing change.