tbuckley/cabot-search huggingface dataset:
Abstract 3365: <i>MAP3K10</i> mutation as a biomarker for predicting response to chemotherapy in gastric cancer patients
Authors: Chae Hwa Kwon, Sun Jin Lee, Yuri Choi, Do Youn Park
Journal: Cancer Research (2018)

Abstract Gastric cancer is one of most common malignant tumors. Although chemotherapy can improve the survival of gastric cancer, the benefit is limited because most cancer cells eventually become irresponsive to chemotherapeutic drugs. To investigate mechanism of resistance to chemotherapy, we performed whole-exome sequencing (WES) on resistant tumor and paired normal samples from 14 patients received adjuvant chemotherapy. We found that 3 patients had novel somatic mutations in mitogen-activated protein kinase kinase kinase 10 (MAP3K10), an upstream kinase of mitogen activated protein kinase (MAPK). MAP3K10R304C, MAP3K10H211R, or MAP3K10A30E were detected each patient, respectively. The survival rate was higher and apoptosis rate was smaller in the cells expressing each MAP3K10 mutations compared with parental controls and cells expressing wild-type MAP3K10, when treated with cisplatin or 5-FU. Moreover, cells expressing each MAP3K10 mutations exhibited higher levels of phosphorylated MEK1/2 and p38MAPK at baseline and when treated with cisplatin or 5-FU than wild-type AGS or MKN45 cells or those expressing wild-type MAP3K10. In summary, MAP3K10R304C, MAP3K10H211R, and MAP3K10A30E MAP3K10 confer resistance to cisplatin or 5-FU via activation of MAPK pathway in gastric cancer cells. Thus, somatic MAP3K10 mutations could be a potential biomarker for predicting resistance to chemotherapy for gastric cancer patients Citation Format: Chae Hwa Kwon, Sun Jin Lee, Yuri Choi, Do Youn Park. MAP3K10 mutation as a biomarker for predicting response to chemotherapy in gastric cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3365.
Improved Long-Term Survival After Abdominal Aortic Aneurysm Repair
Authors: KevinMani, MartinBjörck, JonasLundkvist, AndersWanhainen
Journal: Circulation (2009)

Background— Treatment of abdominal aortic aneurysm (AAA) has changed significantly over the past 2 decades. In this perspective, time trends in long-term survival were studied. Methods and Results— We identified 8663 primary intact and 4171 ruptured AAA repairs in the Swedish Vascular Registry from 1987 to 2005. Mortality was obtained from the national population registry. Crude survival was analyzed, including all mortality. To analyze the long-term outcome among those surviving the AAA repair, relative survival, which denotes the survival rate of patients compared with that of the general population adjusted for age, sex, and calendar year, was calculated, excluding 90-day mortality. In a comparison of AAA repairs from 1987 to 1999 and 2000 to 2005, age (71.4 versus 72.5 years; P<0.001), patients with comorbidities (65.0% versus 68.5%; P<0.001), and endovascular repair (1.6% versus 17.0%; P<0.001) increased. After intact AAA repair, crude 5-year survival was 69.0% (99% confidence interval [CI], 67.7 to ...
Abstract 2547: A potential new autologous mast cell cancer immunotherapy
Authors: Jesse D. Plotkin, Michael G. Elias, Tracy R. Daniels-Wells, Anthony Dellinger, Manuel L. Penichet, Christopher L. Kepley
Journal: Cancer Research (2018)

Abstract Mast cells (MC) are important immune cells that reside in tissue and are most widely recognized for their role as mediators of Type I hypersensitivity reactions (allergies). In certain cancers, such as breast cancer, the presence of MC in the tumor microenvironment has been associated with favorable prognosis, which may be due to their ability to release, through activation of the high affinity IgE receptor FcεRI, anti-tumor mediators such as tumor necrosis factor alpha (TNF-α) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Thus, developing approaches to target autologous MC to tumor antigens is a potential new form of cancer immunotherapy. However, this concept has not been realized given that MC reside in tissue; thus, efficient removal, expansion ex vivo, and targeting to tumor sites has not yet been feasible. Previous attempts to generate MC from human progenitor cells have yielded cells that are often immature and not optimally functional. We report here, for the first time, the generation of functional human MC from adipose tissue in numbers sufficient for clinical applications. The adipose derived MC (ADMC) are phenotypically similar to connective tissue MC as evidenced through their expression of tryptase, chymase, c-kit, and FcεRI. The ADMC release several anti-tumor mediators through FcεRI activation. The ADMC, sensitized with an anti-HER2/neu IgE with human constant regions, bound to and were activated by HER2/neu-positive human breast cancer cells (SK-BR-3). ADMC sensitized in this way were observed to induce apoptosis in breast cancer cells when co-cultured. Importantly, breast cancer cell apoptosis was also observed after addition of media containing mediators released from activated ADMC. In conclusion, we present a novel method for the production of functional human MC from adipose tissue and demonstrate that these cells can be directed to target and eliminate breast cancer cells. It may now be possible to use them in conjunction with IgE antibodies targeting cancer cells for autologous mast cell cancer immunotherapy (AMCIT) as a new way to treat solid tumors such as those overexpressing HER2/neu for which new therapies are urgently need. Citation Format: Jesse D. Plotkin, Michael G. Elias, Tracy R. Daniels-Wells, Anthony Dellinger, Manuel L. Penichet, Christopher L. Kepley. A potential new autologous mast cell cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2547.
Abstract 15903: An Improvement of Score Models in the Prediction of Deep Vein Thrombosis of Upper and Lower Limbs in Hospitalized Patients
Authors: Antonella Maria Cardella, Antonio D'Assoro, Giuseppe Puccia
Journal: Circulation (2015)

Introduction:Deep Vein Thrombosis (DVT) of both lower and upper limbs is increasingly being recognized as a clinical entity in patients with chronic diseases hospitalized for several comorbidities. The occurrence of DVT in sites other than lower limbs is an emerging clinical presentation in a setting of a Department of Medicine. The relationship between score models, based on risk factors, symptoms and clinical signs of lower limbs DVT, and circulating biomarkers is not well studied. Hypothesis:We hypothesized to give an additional value to score models using circulating biomarkers in the prediction of DVT in patients hospitalized in Internal Medicine Department. Methods:We prospectively recruited 178 consecutive patients who presented a D-dimer value &gt;500 ng/ml. In each patient Wells modified score for DVT, Hamilton score, Kahn score and St. André Hospital score were applied. We measured serum levels of albumin (%) and protein S (%). Diagnosis of DVT was made by Extended Compression Ultra-Sonography (ECUS) standardized procedure. All patients underwent also an angiographic-CT-scan Results:In 85 (48%) patients the diagnosis of DVT was confirmed. Sites of DVT were as follows: Lower limbs venous thrombosis n=71 (84%); Upper limb venous thrombosis n=8 (9%); portal vein thrombosis n=6 (7%). Patients with DVT had significantly lower albumin levels as compared with controls (mean ± SD 47.6 ± 7.9 vs 55.4 ± 4.6 %, respectively, P&lt;0.001) and lower Protein S (60.7 ± 26.3 vs. 87.6 ± 11.9 %, P&lt;0.001). In this setting, the use of clinical risk scores based on symptoms and clinical signs showed low accuracy (AUC 0.690). We gave an additional value to these scores by testing in combination biomarkers and two of the best items of all clinical score models used to predict DVT: we evaluated a ROC curve analysis including value of Albumin (%), Protein S (%), previous DVT and cancer obtaining a higher accuracy (AUC 0.901, Positive Likelihood Ratio (LR+) 12.97 and Negative Likelihood Ratio (LR-) 0.17). Conclusions:This study demonstrates that biomarkers improve the prediction of clinical scores in the diagnosis of DVT of all sites in hospitalized patients.
Endoplasmic Reticulum Stress As a Therapeutic Target in Cardiovascular Disease
Authors: TetsuoMinamino, IsseiKomuro, MasafumiKitakaze
Journal: Circulation Research (2010)

Cardiovascular disease constitutes a major and increasing health burden in developed countries. Although treatments have progressed, the development of novel treatments for patients with cardiovascular diseases remains a major research goal. The endoplasmic reticulum (ER) is the cellular organelle in which protein folding, calcium homeostasis, and lipid biosynthesis occur. Stimuli such as oxidative stress, ischemic insult, disturbances in calcium homeostasis, and enhanced expression of normal and/or folding-defective proteins lead to the accumulation of unfolded proteins, a condition referred to as ER stress. ER stress triggers the unfolded protein response (UPR) to maintain ER homeostasis. The UPR involves a group of signal transduction pathways that ameliorate the accumulation of unfolded protein by increasing ER-resident chaperones, inhibiting protein translation and accelerating the degradation of unfolded proteins. The UPR is initially an adaptive response but, if unresolved, can lead to apoptotic ce...
Abstract 637: Quantitative screening of serum protein biomarkers with reverse phase protein arrays
Authors: Zhizhou Kuang, Ruochun Huang, Zhiqiang Lv, Jingqiao Lv, Jian Wu, Ruo-Pan Huang
Journal: Cancer Research (2018)

Abstract Screening biomarkers in serum samples for different diseases has always been of great interest because it presents an early, reliable, and, most importantly, noninvasive means of diagnosis and prognosis. Reverse phase protein arrays (RPPAs) are a high-throughput platform that can measure single or limited sets of proteins from thousands of patients' samples in parallel. They have been widely used for detection of signaling molecules involved in diseases, especially cancers, and related regulation pathways in cell lysates. However, this approach has been difficult to adapt to serum samples. Previously, we developed a sensitive method called the enhanced protein array to quantitatively measure serum protein levels from large numbers of patient samples. Here, we further refine the technology on several fronts: 1. simplifying the experimental procedure; 2. optimizing multiple parameters to make the assay more robust, including the support matrix, signal reporting method, background control, and antibody validation; and 3. establishing a method for more accurate quantification. Using this technology, we quantitatively measured the expression levels of 6 proteins: AFP, GP73, GDF15, IGFBP2, B2M and OPN from serum samples of 132 hepatocellular carcinoma (HCC) patients and 78 healthy volunteers. We found that all 6 protein expression levels are significantly increased in HCC patients. Statistical and bioinformatical analysis has revealed decent accuracy rates of individual proteins, ranging from 0.617 (B2M) to 0.908 (AFP) as diagnostic biomarkers to distinguish HCC from healthy controls. The combination of these 6 proteins as a specific HCC signature yielded a higher accuracy of 0.923 using LR, LDA, RF and SVM predictive model analyses. Our work reveals promise for using reverse phase protein arrays for biomarker discovery and validation in serum samples. Citation Format: Zhizhou Kuang, Ruochun Huang, Zhiqiang Lv, Jingqiao Lv, Jian Wu, Ruo-Pan Huang. Quantitative screening of serum protein biomarkers with reverse phase protein arrays [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 637.
Evolution of Left Ventricular Ejection Fraction After Acute Myocardial Infarction
Authors: JohannaSjöblom, JosephineMuhrbeck, NilsWitt, MahbubulAlam, VivekaFrykman-Kull
Journal: Circulation (2014)

Background—Implantable cardioverter-defibrillator therapy improves survival in patients with reduced left ventricular ejection fraction (LVEF) after acute myocardial infarction (AMI). Although the risk of sudden cardiac death is highest in the first month after AMI, there is no survival benefit of early implantable cardioverter-defibrillator implantation, and the optimal time frame has yet to be established. Thus, the aim of this study was to investigate what proportion of post-AMI patients had improved LV function to such an extent that the indication for implantable cardioverter-defibrillator was no longer present. Methods and Results—Patients admitted for AMI with reduced LVEF (≤40%) were eligible for inclusion. Repeat echocardiographic examinations were performed 5 days, 1 month, and 3 months after the AMI. We prospectively included 100 patients with LVEF of 31±5.8% after AMI. At the 1-month follow-up, 55% had an LVEF >35%. The main improvement in LVEF had occurred by 1 month. The mean difference in L...
Vascular Smooth Muscle Cells Undergo Telomere-Based Senescence in Human Atherosclerosis
Authors: CharlesMatthews, IsabelleGorenne, StephenScott, NicolaFigg, PeterKirkpatrick, AndrewRitchie, MartinGoddard, MartinBennett
Journal: Circulation Research (2006)

Although human atherosclerosis is associated with aging, direct evidence of cellular senescence and the mechanism of senescence in vascular smooth muscle cells (VSMCs) in atherosclerotic plaques is lacking. We examined normal vessels and plaques by histochemistry, Southern blotting, and fluorescence in situ hybridization for telomere signals. VSMCs in fibrous caps expressed markers of senescence (senescence-associated β-galactosidase [SAβG] and the cyclin-dependent kinase inhibitors [cdkis] p16 and p21) not seen in normal vessels. In matched samples from the same individual, plaques demonstrated markedly shorter telomeres than normal vessels. Fibrous cap VSMCs exhibited markedly shorter telomeres compared with normal medial VSMCs. Telomere shortening was closely associated with increasing severity of atherosclerosis. In vitro, plaque VSMCs demonstrated morphological features of senescence, increased SAβG expression, reduced proliferation, and premature senescence. VSMC senescence was mediated by changes i...
Abstract 122: Cardiac mTOR Preserves Cardiac Function Following Ex Vivo Ischemia-Reperfusion in Diet-Induced Obese Mice
Authors: Toshinori Aoyagi, Takashi Matsui
Journal: Circulation Research (2012)

The risk of heart failure following myocardial infarction is higher in diabetic patients than nondiabetic patients. The mammalian target of rapamycin (mTOR), a key downstream molecule of insulin-phosphoinositide 3-kinase (PI3K)-Akt signaling pathway, plays an important role in cardioprotection. However, the role of cardiac mTOR in ischemic injury in metabolic syndrome has not been well defined. To address this question, we studied the effect of overexpressing cardiac mTOR on cardiac function following ischemia/reperfusion (I/R) in mice with high-fat diet (HFD)-induced obesity. In this study, we used transgenic mice with cardiac-specific overexpression of mTOR (mTOR-Tg) as reported previously. mTOR-Tg and WT mice at 6 weeks old were fed HFD (60% fat by calories) ad libitum for 14 weeks. Control mTOR-Tg and WT mice were fed a normal chow diet (NCD). At 14 weeks after HFD, glucose and insulin tolerance tests demonstrated that HFD generated glucose intolerance and insulin resistance in both mTOR-Tg (n=20) and WT (n=24) mice. Body weight (BW) and heart weight (HW) were significantly higher in HFD mice than SCD mice (p&lt;0.001 for BW in both strains; p&lt;0.001 and p&lt;0.01 for HW/tibia length, WT and mTOR-Tg, respectively) but there was no difference in BW or HW between HFD-mTOR-Tg and HFD-WT mice. Hearts from all four groups were subjected to global I/R (20 min ischemia, 40 min reperfusion) in the ex vivo Langendorff perfusion model. Baseline left ventricular developed pressure (LVDP) was higher in HFD mice than NCD mice in both strains [185.8 ± 10.7 vs. 143.6 ± 5.0 mmHg, HFD-WT (n=11) vs. NCD-WT (n=10) mice, p&lt;0.01; 178.6 ± 10.1 vs. 135.0 ± 6.3, HFD-mTOR-Tg (n=8) vs. NCD-mTOR-Tg (n=11) mice, p&lt;0.01]. Functional recovery after I/R was significantly lower in HFD-WT mice than NCD-WT mice (percent recovery of LVDP, 15.3 ± 5.4 vs. 44.6 ± 6.3 %, HFD-WT vs. NCD-WT mice, p&lt;0.01). Intriguingly, there was no significant difference in LVDP recovery between HFD-mTOR-Tg and NCD-mTOR-Tg mice (36.5±10.8 vs. 58.8±6.0 %, HFD-mTOR-Tg vs. NCD-mTOR-Tg mice, n.s.). These findings suggest that cardiac mTOR is sufficient to substantially limit the metabolic syndrome-induced cardiac dysfunction following I/R in a mouse model of obesity with glucose intolerance and insulin resistance.
Abstract 19432: Neuronal Isoform of Nitric Oxide Synthase is Upregulated in Cardiac Intrinsic, and Extrinsic Sympathetic Afferent and Efferent Ganglia Following Myocardial Infarction
Authors: Keijiro Nakamura, Olujimi A Ajijola, Tadanobu Irie, Kentaro Yamakawa, Jeffrey Ardell, Kalyanam Shivkumar
Journal: Circulation (2015)

Objective: The impact of myocardial infarction (MI) on neuronal nitric oxide synthase (nNOS), an important mediator of cardiac neurotransmission is not well understood. Methods: Yorkshire pigs (n=10) underwent anterior MI by LAD occlusion. After 6-8 weeks, bilateral stellate ganglia (SG), T1 dorsal root ganglia (DRG), right atrial (RAGP) and ventral inter-ventricular ganglionated plexi (VIVGP)were extracted, formalin-fixed, paraffin-embedded, and sectioned. Immno-staining for nNOS was performed on representative slides through the middle of the ganglia, and for calcitonin-gene related peptide (CGRP), a marker of sensory afferent neurons. The percentage of immunoreactive (IR) neurons was quantified. Results: An average of 63.1±40.7, 169.7±55.5, and 448.1±204.5 neurons were counted in the GPs, DRG, and SG respectively. There was no significant difference in the number of neurons counted in controls vs MIs. In the GPs, nNOS was differentially altered by MI, with significant upregulation in VIVGP but not RAGP of MI (13.8±2.8% vs 46.6±5.3%, p&lt;0.001; and 12.1±3.6% vs 12.5±2.9%, p=NS, respectively) compared to control animals. In the DRG, IR of both CGRP and nNOS was increased (36.3±6.2% vs 65.3±4.8%, p&lt;0,001 for nNOS; and 64.1±6.2% vs 85.2±5.6%, p&lt;0.001 for CGRP), with increased co-expression of both CGRP and nNOS in approximately 20% of DRG neurons. In the SG, the number of neurons demonstrating strong IR for nNOS was approximately 0.4% in control animals. After MI, this increased 8-fold to 3.12% (P&lt;0.01). Conclusions: nNOS expression is upregulated differentially following MI in the GPs, with increased expression in the ventricular GP innervating the region of MI, but not in the RAGP. Both cardiac sympathetic afferent (DRG) neurons, and efferent (SG) neurons increase expression of nNOS following MI. The impact of nNOS in these different sites warrants further investigation.
A facile route to heterotelechelic polymer prodrug nanoparticles for imaging, drug delivery and combination therapy
Authors: Daniele Vinciguerra, Stéphanie Denis, Julie Mougin, Merel Jacobs, Yohann Guillaneuf, Simona Mura, Patrick Couvreur, Julien Nicolas
Journal: Journal of Controlled Release (2018)

A facile and general synthetic methodology has been developed to prepare high drug loading heterotelechelic polymer prodrug nanoparticles; that are nanoparticles obtained by formulation of linear polymers bearing two different molecules at both extremities (at least one of them being a drug). The method relied on the combination of the "drug-initiated" method to obtain α-functional polymer prodrugs by nitroxide-mediated polymerization, followed by the nitroxide exchange reaction from a functional nitroxide to install another molecule of interest at the ω chain-end. To validate the proof of concept, two different combinations have been synthesized using polyisoprene (PI) as the polymer building block: one based on gemcitabine and rhodamine (Gem-PI-Rho) for drug delivery and imaging purposes, and one with aminoglutethimide and doxorubicin (Agm-PI-Dox) for combination therapy purposes. Fluorescent polymer prodrug nanoparticles (Dz = 161 nm) were easily obtained by co-nanoprecipitation of Gem-PI and 5 wt% of Gem-PI-Rho. They were observed by confocal microscopy and they also induced significant cytotoxicity on the human breast cancer cell line MCF-7. As for combination therapy purposes, Agm-PI-Dox nanoparticles (Dz = 63–122 nm) led to enhanced cytotoxicity against MCF-7 cells compared to both monofunctional polymer prodrug nanoparticles (ca. 50% decrease in IC50 vs. Agm-PI and 65% decrease in IC50 vs. PI-Dox) or their equimolar co-nanoprecipitation. This simple and general methodology may pave the way to the design of a broad range of different heterotelechelic polymer prodrug nanoparticles.
Abstract 10635: Changes in Cardiac Fibroblast Ion Channel Expression and Atrial Remodelling
Authors: Xiao Yan Qi, Chia-Tung Wu, Hai Huang, Masahide Harada, Stanley Nattel
Journal: Circulation (2011)

Background: Cardiac fibroblasts are pivotal in remodeling and arrhythmogenesis, by secreting excess ECM proteins (fibrosis) and coupling to/altering cardiomyocyte electrophysiology. This study characterized atrial fibroblast ionic remodeling in 2 canine AF models: atrial tachycardia remodeling (ATR) and CHF, with fibrosis potentially occurring in both but particularly CHF. Methods: Freshly isolated LA fibroblasts were obtained from control (CTL), ATR (1 wk atrial tachypacing 400 bpm) and CHF (2 wk ventricular tachypacing 240 bpm) dogs. Whole cell patch clamp was used to record K+ currents. Results: Fibroblasts had membrane capacitances of 16.7±0.1 (n=75), 18.4±1.4 (n=25), 28.5±1.9 (n=41, P<0.001 vs CTL) pF in CTL, ATR and CHF, respectively. Resting potential averaged -31±2 mV in CTL (n=16), -33±3 mV in ATR (n=10), and -41±1.9 mV in CHF (n=33, P<0.05 vs CTL) fibroblasts. Clear Ba2+ sensitive (300 μ M) inwardly rectifying K+ (Kir) current was recorded (Figure A). At -120 mV, Kir current averaged -2.4±1.6 in...