tbuckley/cabot-search huggingface dataset:
Abstract 5036: Visualization of cancer-derived exosome-mediated angiogenesis in a layered 3D stromal tissue model
Authors: Shiro Kitano, Kei Tsukamoto, Rii Morimura, Shinji Irie, Eiji Shinozaki, Kensei Yamaguchi
Journal: Cancer Research (2018)

Abstract Background: Exosomes are small vesicles of sizes ranging from 30 to 150 nm that originate from the endosomal luminal membrane and are constantly released by fusion with cell membranes. Several studies have revealed that exosomes play an important role in mediating local and systemic cellular communication through the transmission of nucleic acid materials and information in the form of proteins. Here, we demonstrated a unique layered 3D stromal tissue model of visualization of promoting angiogenesis by exosomes in colorectal cancer (CRC) patients. Method: The CRC specimens of exosome were obtained from 7 patients in stage IV. Isolation of total exosome was performed according to standard procedure by ultracentrifuge. Layered 3D stromal tissue model was constructed with human umbilical vein endothelial cells (HUVEC) and normal human dermal fibroblasts. Cells were aggregated by heparin and collagen to suspension under cationic condition. The cell suspension was seeded to transwell inserts membrane at a density of 2×106. Media were changed after 24h, and serum, exosome or supernatant after ultracentrifuge of serum (SAUS) was added to the 3D stromal tissue after 6 days. The isolated exosomes were diluted with an equal volume of PBS buffer to the serum sample. After cultivation, the tube formation of HUVEC was stained with Immunofluorescence, and the degree of hypervascularity was compared with healthy volunteers. Result: Except for one serum specimen, hypervascularization was observed in the 3D stromal tissue model in an additive-dependent manner. Especially when exosome was added, hypervascularization was observed in the layered 3D stromal tissue model more efficiently than serum in all specimens (see Table). Interestingly, the frequency of hypervascularization was drastically reduced in the SAUS. Conclusion: Our data encourage that this layered 3D stromal tissue model may be applicable to cancer diagnosis using exosomes from CRC patients. Table. Frequency of hypervascularization by exosomes derived from CRC5μl10μl50μlExosome5/7 (71.4%)7/7 (100.0%)7/7 (100.0%)Serum4/7 (57.1%)6/7 (85.7%)6/7 (85.7%)SAUS1/7 (14.3%)0/7 (0.0%)0/7 (0.0%) Citation Format: Shiro Kitano, Kei Tsukamoto, Rii Morimura, Shinji Irie, Eiji Shinozaki, Kensei Yamaguchi. Visualization of cancer-derived exosome-mediated angiogenesis in a layered 3D stromal tissue model [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 5036.
Local Ca2+ Entry Through L-Type Ca2+ Channels Activates Ca2+-Dependent K+ Channels in Rabbit Coronary Myocytes
Authors: AntonioGuia, XiaodongWan, MarcCourtemanche, NormandLeblanc
Journal: Circulation Research (1999)

Abstract—Large-conductance Ca2+-dependent K+ channels (KCa), which are abundant on the sarcolemma of vascular myocytes, provide negative feedback via membrane hyperpolarization that limits Ca2+ entry through L-type Ca2+ channels (ICaL). We hypothesize that local accumulation of subsarcolemmal Ca2+ during ICaL openings amplifies this feedback. Our goal was to demonstrate that Ca2+ entry through voltage-gated ICaL channels can stimulate adjacent KCa channels by a localized interaction in enzymatically isolated rabbit coronary arterial myocytes voltage clamped in whole-cell or in cell-attached patch clamp mode. During slow-voltage-ramp protocols, we identified an outward KCa current that is activated by a subsarcolemmal Ca2+ pool dissociated from bulk cytosolic Ca2+ pool (measured with indo 1) and is dependent on L-type Ca2+ channel activity. Transient activation of unitary KCa channels in cell-attached patches could be detected during long step depolarizations to +40 mV (holding potential, −40 mV; 219 pS in...
Ionic Remodeling of Cardiac Purkinje Cells by Congestive Heart Failure
Authors: WeiHan, DenisChartier, DanshiLi, StanleyNattel
Journal: Circulation (2001)

Background Cardiac Purkinje cells (PCs) are important for the generation of triggered arrhythmias, particularly in association with abnormal repolarization. The effects of congestive heart failure (CHF) on the ionic properties of PCs are unknown. Methods and Results PCs were isolated from false tendons of control dogs and dogs with ventricular tachypacing-induced CHF. CHF PCs were hypertrophied (capacitance, mean±SEM, 149±4 pF, n=130; versus 128±3 pF, n=150, control; P<0.001). Transient outward current density was reduced in CHF PCs without change in voltage dependence or kinetics. CHF also reduced inward-rectifier current density, with no change in form of the current-voltage relationship. Densities of L- and T-type calcium, rapid and slow delayed rectifier, and Na+-Ca2+ exchange currents were unaltered by CHF, but L-type calcium current inactivation was slowed at positive potentials. Purkinje fiber action potentials from CHF dogs showed decreased phase 1 amplitudes and elevated plateau voltages and demo...
Abstract CT103: Rationale for flat dosing of AZD9150 by population pharmacokinetic analysis
Authors: Xiao Tong, Ganesh Mugundu, Martin Scott, Carl Cook, Paul Lyne, Nidal Al-Huniti, Hongmei Xu
Journal: Cancer Research (2018)

Abstract Objective: AZD9150 (ISIS 481464) is a 16-nucleotide oligonucleotide antisense molecule designed to reduce expression of human STAT3 protein by targeted down-regulation of STAT3 messenger RNA and is currently in clinical development in advanced solid tumors. The recommended Phase 2 dose (RP2D) for AZD9150 is 3 mg/kg, dosed based on ideal body weight (IBW) with three loading doses on day 1, 3 and 5 in week 1 followed by weekly dosing thereafter. The objective of the current analysis was to assess the effect of body size on AZD9150 pharmacokinetics (PK) to determine the appropriate dosing approach using population PK modeling. Methods: PK and demographics data from 3 phase I/II studies (481464-CS1 [NCT01563302], D5660C00001 [NCT01839604], D5660C00004 [NCT02499328]) in total of 126 patients with diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma (HCC) and squamous-cell carcinoma in head and neck (SCCHN), receiving doses ranging from 1 to 4 mg/kg as monotherapy or in combination with durvalumab, were used in the population PK analysis. Both 2-compartment and 3-compartment structure PK models were tested in the analysis. Patient characteristics including age, ideal body weight (IBW), race and sex were explored as covariates on relevant AZD9150 PK parameters in an automated forward inclusion followed by backward elimination procedure through use of the stepwise covariate modelling. Once a final model was identified, simulations (n=1000, body weight distribution 30 to 100 kg) were conducted to compare AZD9150 exposures at the RP2D of 3 mg/kg versus a flat dose of 200 mg. Results: A 2-compartment model with linear elimination well described the data. None of the covariates (inc. IBW) were found to significantly impact AZD9150 PK. The final PK model parameter estimate for clearance (CL), central volume of distribution (V1) and peripheral volume of distribution (V2) are 3.11 L/h, 5.56 L and 87.3 L, respectively. Model based simulations demonstrate that systemic exposure of AZD9150 was similar between 3 mg/kg versus 200 mg dose with slightly less overall between-patients variability with the flat dosing regimen. Conclusion: Population PK modeling supports the potential switch of dosing approach from 3 mg/kg dose to a flat dose of 200 mg. The AZD9150 flat dosing rationale and schedule has been granted approval by FDA (for IND 137525) and also by MHRA (for BISCAY trial) as the first protocol / IMPD to be approved in the EU. Flat dose of 200 mg is currently being evaluated in ongoing clinical studies. Citation Format: Xiao Tong, Ganesh Mugundu, Martin Scott, Carl Cook, Paul Lyne, Nidal Al-Huniti, Hongmei Xu. Rationale for flat dosing of AZD9150 by population pharmacokinetic analysis [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 CT103.
Measurement of cytokines and chemokines and association with clinical severity of dermatomyositis and clinically amyopathic dermatomyositis
Authors: M. Chen, C. Quan, L. Diao, F. Xue, K. Xue, B. Wang, X. Li, X. Zhu, J. Zheng, H. Cao
Journal: British Journal of Dermatology (2018)

Dermatomyositis (DM) is an autoimmune disease affecting primarily the skin, muscle and lung. Dysregulations of cytokines and chemokines are commonly found in inflammatory disorders.To investigate the association between serum cytokines and chemokines and clinical severity, especially cutaneous lesions and interstitial lung disease (ILD) in patients with DM and clinically amyopathic DM (CADM).Clinical features, laboratory findings and serum of 40 patients with DM or CADM were collected and analysed. Serum cytokines and chemokines were measured by enzyme-linked immunosorbent assay or cytometric bead array. A multiple unpaired t-test was performed to compare cytokines and chemokines in patients with DM and healthy controls. Correlations of serum cytokines and chemokines with disease severity were evaluated by Spearman's rank correlation test.Serum interferon (IFN)-β [rs = 0·37, 95% confidence interval (CI) 0·078-0·62; P = 0·019] and CXCL10 (rs = 0·32, 95% CI to -0·004 to 0·57; P = 0·045) were significantly correlated with the Cutaneous Dermatomyositis Disease Area and Severity Index activity score in the subset of patients with DM or CADM. Serum levels of interleukin (IL)-6, IL-10, IL-18 and IFN-β were significantly higher in the patients with acute/subacute interstitial pneumonia (A/SIP) than in the subset without A/SIP (P < 0·05). IL-6 (rs = 0·54, 95% CI 0·27-0·72; P < 0·001) and IL-18 (rs = 0·46, 95% CI 0·21-0·65; P = 0·003) were significantly correlated with the serum level of anti-melanoma differentiation-associated protein 5 antibody.Serum levels of IFN-β and CXCL10 may be useful biomarkers for assessing cutaneous disease activity in patients with DM and CADM. In addition, serum IL-6, IL-10, IL-18 and IFN-β were highly correlated with the occurrence of A/SIP. These cytokines may play a role in the pathogenesis of DM and CADM.
Abstract 3979: Active components of <i>Alpinia katsumadai-</i>induced cell apoptosis and autophagy in human pancreatic cancer cells
Authors: Weixiao An, Honglin Lai, Yangyyang Zhang, Xiukun Lin, Shousong Cao
Journal: Cancer Research (2018)

Abstract Alpinia katsumadai, as a traditional Chinese medicine, exhibited potent anti-oxidative and anticancer effects. Studies have shown that the effect of the active components of Alpinia katsumadai (ACAK) on anticancer is via apoptosis or autophagy in colorectal and glioblastoma cancer cells. However, the effects of ACAK on anticancer effect and inducation of apoptosis and autophagy in pancreatic cancer cells are still unknown. Therefore, we investigated the effects of ACAK on cytotocixity, apoptosis and autophagy as well as associated mechanisms in pancreatic cancers Panc-1 and Panc-28 cells. We found that ACAK showed greater inhibitory effects on the proliferation of Panc-1 and Panc-28 cells in a dose- and time-dependent manners (IC50 0.1692 and 0.1554mg/ml, respectively) compared to a variety of other cancer cells including breast cancer MDA-MB-468 cells, melamoma A875 cells, lung cancer A549 cells, colon cancer HCT-116 cells, and glioblastoma cancer U87 cells (IC50 0.2302, 0.2586, 0.2642, 0.3006, and 0.4298, respectively) by CCK-8 assay. Furthermore, ACAK induced cell apoptosis in pancreatic cancer Panc-1 and Panc-28 cells in a dose- dependent manner by Hochest 33342-PI and AnnexinV-PI dual staining analysis. Moreover, the expression levels of apoptosis related proteins casepase 3, casepase 9, and PARP were significantly up-regulated by Western blotting analysis. The study of cell autophagy was dectected by mRFP -GFP-LC3 adenovirus and western-blotting. and the results showed that the expression levels of autophagy-related protein beclin-1 and LC3-II were significanlt up-regulated by mRFP-GFP-LC3 adenovirus and western-blotting analysis. Our findings demonstrated that ACAK had greater cytotoxicity than a variety of other cancer cells by inducing apoptosis and autophagy in pancreatic cancer Panc-1 and Panc-28 cells. Therefore, ACAK may be developed as a novel anticancer agent for the treatment of pancreatic cancer clinically. Citation Format: Weixiao An, Honglin Lai, Yangyyang Zhang, Xiukun Lin, Shousong Cao. Active components of Alpinia katsumadai-induced cell apoptosis and autophagy in human pancreatic cancer cells [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 3979.
Abstract 30: Nub1l Suppresses Neddylation And Enhances Misfolded Protein Clearance In Cardiomyocytes
Authors: HuaboSu, JieLi, WenxiaMa, NingHou, FaqianLi
Journal: Circulation Research (2014)

Protein modification by ubiquitin (Ub) or Ub-like proteins such as NEDD8 (neddylation) constitutes a fundamental regulatory mechanism of protein function. In contrast to well-recognized role of Ub in protein degradation, little is known about the role of NEDD8 in protein quality control. We have previously revealed that CM-restricted inactivation of deneddylation, a process that removes NEDD8 from modified proteins, accumulates neddylated proteins and impairs proteasomal and autophagic proteolysis. Here we report that proteasome inhibitors, simulated ischemia/reperfusion and H2O2 significantly increase NEDD8 conjugates in cardiomyocytes (CMs). Immunoprecipitation analysis reveals mixed modification of these proteins by Ub and NEDD8. Expression of NEDD8 but not the conjugation-deficient mutant increases neddylated proteins and accumulates a proteasome surrogate substrate GFPu in a dose-dependent manner, suggesting that excessive neddylation disrupts proteasomal proteolysis. We further targets to NUB1L, a U...
Abstract 2904: Awakening metastatic breast cancer cells to chemotherapy
Authors: Ana Rita Lourenco, Jay Lopez, Michael Crowley, Vivek Mittal, Dingcheng Gao
Journal: Cancer Research (2018)

Abstract Breast cancer is the most common cancer in women with more than 316,000 new cases and expected 40,610 deaths in the US in 2017. Despite vast improvement in cancer management and treatment in the past years, not all subtypes of breast cancer have benefited equally. This includes the most aggressive form of invasive breast cancer, triple negative breast cancer (TNBC) subtype (ER-, PR- and HER2-), which accounts for about 20-25% of all breast cancer cases and presents a higher breast cancer-related mortality compared to other breast cancer subtypes. The poor survival rates attributed to TNBC is due to the lack of available biological targets and high rates of metastatic recurrence. Therefore, chemotherapy is the only therapeutic option for patients with metastatic TNBC. However, development of chemotherapy resistance is observed in the great majority of the cases and patients relapse within 5 years of a diagnosis. Given the unmet clinical needs, the discovery of novel therapeutic options that overcome chemoresistance of metastatic breast cancer is required. We have identified a group of genes which expression was enriched in chemotherapy resistant tumors cells, suggesting that these are potential therapeutic candidates to overcome chemotherapy resistance. Of these, CDKN1A (p21) was included. Furthermore, Immunostaining of metastatic lung tissue confirmed that surviving tumor cells under CTX treatment highly express p21. The enrichment of p21 in surviving tumor cells under chemotherapy, together with its well documented functions in cell-cycle arrest and regulation of apoptosis, provides a rationale to explore the underlying mechanisms that govern p21-induced chemoresistance and whether targeting p21 will re-sensitize the chemoresistant tumor cells in vivo. Citation Format: Ana Rita Lourenco, Jay Lopez, Michael Crowley, Vivek Mittal, Dingcheng Gao. Awakening metastatic breast cancer cells to chemotherapy [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 2904.
Abstract 18804: A Comparison Between Left Appendage Morphologies on Left Appendage Flow Velocity in Patients with Atrial Fibrillation
Authors: KeikoFukushima, KenKato, KoichiroEjima, KenjiFukushima, KeikoHayashi, ChihiroSaito, KentaroYoshida, KotaroArai, TetsuyukiManaka, KyomiAshihara, MorioShoda, NobuhisaHagiwara
Journal: Circulation (2014)

Background: Reduction of left atrial appendage (LAA) flow velocity (FV) is a well-established prognostic factor for thrombus formation and increases the risk for stroke in patients with atrial fibrillation (AF). Recently, it has been reported that patients with chicken wing type of LAA morphology had less embolic events than other types. The aim of this study was to assess and compare the FV by variation of LAA morphologies in patients with AF. Methods and result: We enrolled 96 consecutive patients referred to radio-frequency catheter ablation for paroxysmal AF (age 59.0 ± 10.2, 75% were male). All patients underwent contrast enhanced computed tomography (CT), and transthoracic and transesophageal echocardiography during sinus rhythm. The LAA morphology was classified into four types (chicken wing, cactus, windsock, and cauliflower) by CT images. The distribution of each LAA morphology was chicken wing (n = 12, 12.5%), cactus (n = 37, 38.5%), windsock (n = 31, 32.3%), and cauliflower (n = 16, 16.7 %), re...
NBCn1 (slc4a7) Mediates the Na+-Dependent Bicarbonate Transport Important for Regulation of Intracellular pH in Mouse Vascular Smooth Muscle Cells
Authors: EbbeBoedtkjer, JeppePraetorius, ChristianAalkjaer
Journal: Circulation Research (2006)

The contribution of sodium-dependent bicarbonate transport to intracellular pH (pHi) regulation in vascular smooth muscle cells is controversial, partly because the molecular identity of the transporter(s) responsible has not been identified. Here, using the pH-sensitive fluorophore 2′,7′-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF), we show that smooth muscle cells of intact mouse mesenteric, coronary, and cerebral small arteries all display a sodium- and bicarbonate-dependent pHi recovery after an NH4+-prepulse. The sodium-dependent bicarbonate flux was largely 4,4′-diisothiocyanatostilbene-2,2′-disulphonic acid (DIDS) sensitive (56% to 91%) and of a magnitude similar to the amiloride-sensitive flux. Additionally, steady-state pHi was lower (0.2 to 0.4 pH units magnitude) in all 3 vascular beds when CO2/bicarbonate was omitted. RT-PCR analyses showed that NBCn1 (slc4a7) is the only Na+-dependent bicarbonate transporter of the slc4 family detectable at the mRNA level in all 3 vascular beds i...
Abstract 5497: Effective combination therapy for breast cancer targeting BACH1 and mitochondrial metabolism
Authors: Jiyoung Lee, Ali Yesilkanal, Casey Frankenberger, Mohamad Elbaz, Daniel Rabe, Jielin Yan, Felicia Rustandy, Peter Hart, Christie Kang, Elizabeth Grossman, Jason Locasale, Daniel Nomura, Marcelo Bonini, Marsha Rosner
Journal: Cancer Research (2018)

Abstract Oxidative phosphorylation is an attractive target for cancer therapy. Reprogramming metabolic pathways by promoting oxidative phosphorylation could improve the ability of metabolic inhibitors to suppress cancers with limited treatment options like triple negative breast cancer (TNBC). Here we show that BACH1, a heme-binding transcription factor whose expression is enriched in patients with TNBC, inhibits oxidative phosphorylation through direct transcriptional regulation of electron transport chain (ETC) gene expression. Treatment of cells with hemin, which induces BACH1 degradation, mimics BACH1 depletion with shRNA. Pretreatment of TNBC tumors with BACH1 shRNA or hemin overcame resistance to metformin, an anti-diabetic drug, and abolished the growth of both cell line and patient-derived tumor xenografts. BACH1 gene expression inversely correlated with ETC gene expression in breast cancer patients as well as other tumor types, highlighting the clinical relevance. This study demonstrates that oxidative phosphorylation represents an Achilles heel that can be exploited through targeting BACH1 to sensitize breast cancer and potentially other tumor tissues to mitochondrial inhibitors. Citation Format: Jiyoung Lee, Ali Yesilkanal, Casey Frankenberger, Mohamad Elbaz, Daniel Rabe, Jielin Yan, Felicia Rustandy, Peter Hart, Christie Kang, Elizabeth Grossman, Jason Locasale, Daniel Nomura, Marcelo Bonini, Marsha Rosner. Effective combination therapy for breast cancer targeting BACH1 and mitochondrial metabolism [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 5497.
Regular Physical Activity and Coronary Risk Factors in Japanese Men
Authors: Shiun DongHsieh, HideyoYoshinaga, TakashiMuto, YutakaSakurai
Journal: Circulation (1998)

Background—Physical activity decreases the risk of coronary heart disease (CHD), but its effects on risk factors require further exploration. Methods and Results—The study included 3331 adult Japanese men in whom health benefits, especially CHD risk factors, were compared among those who were sedentary and those who were engaged in continuous physical activity of 30 minutes or more per day for 1, 2 and ≥3 days per week. Significantly higher HDL cholesterol values; lower triceps, scapula, and iliac subcutaneous fat thickness; and lower smoking rates were noted in all physically active groups compared with the sedentary group, whereas body mass index did not differ significantly. Waist-to-height ratios and the prevalence of fatty liver were significantly lower in the groups who exercised 2 or ≥3 days per week than in the sedentary group. The lowest triglyceride values were noted in the group who exercised ≥3 days per week. Multiple regression analysis revealed both the frequency of physical activity and smo...