tbuckley/cabot-search huggingface dataset:
Abundance and Location of the Small Heat Shock Proteins HSP25 and αB-Crystallin in Rat and Human Heart
Authors: GudrunLutsch, RolandVetter, UlrikeOffhauss, MartinWieske, Hermann-JosefGröne, RomanKlemenz, IngolfSchimke, JoachimStahl, RainerBenndorf
Journal: Circulation (1997)

Background In the heart, there are high constitutive levels of the two related small heat shock proteins, HSP25 and αB-crystallin. To gain insight into their functional role, we have analyzed abundance and location of both proteins in rat and human hearts at different stages of development and in diseased state. Methods and Results Immunoblotting analysis of rat ventricular tissue at fetal, neonatal, and adult stages reveals the level of HSP25 to decline strongly during development, whereas the level of αB-crystallin remains nearly constant. In parallel, the portion of phosphorylated isoforms of HSP25 decreases as shown by two-dimensional polyacrylamide gel electrophoresis. HSP25 is detected in cardiomyocytes and endothelial and vascular smooth muscle cells, whereas αB-crystallin is detected in cardiomyocytes only by immunofluorescence and immunoelectron microscopy. Both proteins colocalize in the I-band and M-line region of myofibrils in cardiomyocytes. In diseased and transplanted adult human hearts, HS...
Differential Roles of GSK-3β During Myocardial Ischemia and Ischemia/Reperfusion
Authors: PeiyongZhai, SebastianoSciarretta, JonathanGaleotti, MassimoVolpe, JunichiSadoshima
Journal: Circulation Research (2011)

Rationale:Inhibition of glycogen synthase kinase-3 (GSK-3) protects the heart during ischemia/reperfusion (I/R), yet the underlying mechanisms of cardioprotection afforded by beta isoform-specific inhibition GSK-3 remain to be elucidated. Objective:We studied the molecular mechanism mediating the effect of GSK-3β activation/inhibition upon myocardial injury during prolonged ischemia and I/R. Methods and Results:Beta isoform–specific inhibition of GSK-3 by dominant negative GSK-3β in transgenic mice (Tg-DnGSK-3β) or in heterozygous GSK-3β knock-out mice (GSK-3β+/−) significantly increased, whereas activation of GSK-3β in constitutively active GSK-3β knock-in mice (βKI) significantly decreased, myocardial ischemic injury after prolonged ischemia. In contrast, inhibition of GSK-3β in Tg-DnGSK-3β or GSK-3β+/− significantly reduced, while activation of GSK-3β in βKI significantly enhanced, myocardial I/R injury. Inhibition of GSK-3β stimulated mTOR signaling and inhibited autophagy through a rapamycin-sensitiv...
Automated deep-neural-network surveillance of cranial images for acute neurologic events
Authors: Joseph J. Titano, Marcus Badgeley, Javin Schefflein, Margaret Pain, Andres Su, Michael Cai, Nathaniel Swinburne, John Zech, Jun Kim, Joshua Bederson, J. Mocco, Burton Drayer, Joseph Lehar, Samuel Cho, Anthony Costa, Eric K. Oermann
Journal: Nature Medicine (2018)
Integrated Genomic Analysis of Hürthle Cell Cancer Reveals Oncogenic Drivers, Recurrent Mitochondrial Mutations, and Unique Chromosomal Landscapes
Authors: Ian Ganly, Vladimir Makarov, Shyamprasad Deraje, YiYu Dong, Ed Reznik, Venkatraman Seshan, Gouri Nanjangud, Stephanie Eng, Promita Bose, Fengshen Kuo, Luc G.T. Morris, Inigo Landa, Pedro Blecua Carrillo Albornoz, Nadeem Riaz, Yuri E. Nikiforov, Kepal Patel, Christopher Umbricht, Martha Zeiger, Electron Kebebew, Eric Sherman, Ronald Ghossein, James A. Fagin, Timothy A. Chan
Journal: Cancer Cell (2018)
Abstract 2123: Myeloma derived macrophage inhibitory factor regulates BMSC IL6/8 via cMYC
Authors: Rachel E. Piddock, Christopher R. Marlein, Amina Abdul-Aziz, Martin J. Auger, Kristian M. Bowles, Stuart A. Rushworth
Journal: Cancer Research (2018)

Abstract Background Multiple Myeloma (MM) is a plasma cell malignancy dependent on the bone marrow microenvironment. Macrophage inhibitory factor (MIF) acts directly on malignant plasma cells affecting homing and chemotherapy resistance, however the adaptive effect that MM derived MIF has on the tumor microenvironment is not yet defined. Here we investigate the function of MM derived MIF in the MM microenvironment by examining its effects on bone marrow mesenchymal stromal cells (BMSC). Methods Primary MM and BMSC were obtained from patient bone marrow. Proteome Profiler Human XL Cytokine Array was used. Inhibitors including JQ1 were purchased from Merck. In-vivo experiments were performed using 8-10 week old NSG mice. Results First we injected 1 x 106 MM.1S MIF-knock down (KD) cells or MM.1S control-KD cells (containing the pCDH-luciferase-T2A-mCherry construct) into the tail vein of 6-8 week old NSG mice. MIF-KD in MM cells resulted in animals with significantly reduced tumor burden and improved overall survival. To further investigate the role of MIF in regulating the BM microenvironment we stimulated primary human BMSC with biologically appropriate doses of recombinant MIF and then used Human XL Cytokine Array and cytokine specific ELISA to assay the supernatant from these MIF stimulated BMSC. Results show that MIF induces IL-6 and IL-8 protein secretion from primary BMSC. To examine the mechanism of action of these observations we used a panel of inhibitors to screen for potential pathways responsible for MIF induced BMSC derived IL-6 and IL-8 expression. The c-Myc inhibitor JQ1 inhibited MIF induced IL-6 and IL-8 expression. Next, we looked at whether c-Myc regulates BMSC pro-tumoral interleukin production in-vivo. We injected NSG mice via the tail vein with human myeloma cell line U266 and then randomized animals to two groups; treating with either JQ1 (50mg/kg, IP) or alternatively vehicle control for 5 days, after which bloods were taken to assess murine IL-6 levels (IL-8 is deleted from the mouse genome). Results show that murine IL-6 was significantly reduced in the JQ1 treated animals (carrying human MM) compared to vehicle control treated animals. Summary MM derived MIF is pro-tumoral through induction of c-Myc and downstream IL-6 and IL-8 in the BMSC of the tumor micro-environment. Identification of this novel pro-tumoral crosstalk mechanism which exists between MM and the bone marrow stroma provides scientific rationale for the clinical evaluation of new therapeutic targets in MM. Citation Format: Rachel E. Piddock, Christopher R. Marlein, Amina Abdul-Aziz, Martin J. Auger, Kristian M. Bowles, Stuart A. Rushworth. Myeloma derived macrophage inhibitory factor regulates BMSC IL6/8 via cMYC [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 2123.
The Health Care System Flies in the Face of Airline Security Concepts—Reply
Authors: Yonathan Freund, Ben Bloom, Anne-Laure Philippon
Journal: JAMA Internal Medicine (2018)

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Identification of Target Domains of the Cardiac Ryanodine Receptor to Correct Channel Disorder in Failing Hearts
Authors: TakeshiYamamoto, MasafumiYano, XiaoJuanXu, HitoshiUchinoumi, HirokiTateishi, MamoruMochizuki, TetsuroOda, ShigekiKobayashi, NoriakiIkemoto, MasunoriMatsuzaki
Journal: Circulation (2008)

Background— We previously demonstrated that defective interdomain interaction between N-terminal (0 to 600) and central regions (2000 to 2500) of ryanodine receptor 2 (RyR2) induces Ca2+ leak in failing hearts and that K201 (JTV519) inhibits the Ca2+ leak by correcting the defective interdomain interaction. In the present report, we identified the K201-binding domain and characterized the role of this novel domain in the regulation of the RyR2 channel. Methods and Results— An assay using a quartz-crystal microbalance technique (a very sensitive mass-measuring technique) revealed that K201 specifically bound to recombinant RyR2 fragments 1741 to 2270 and 1981 to 2520 but not to other RyR2 fragments from the 1 to 2750 region (1 to 610, 494 to 1000, 741 to 1260, 985 to 1503, 1245 to 1768, 2234 to 2750). By further analysis of the fragment1741–2270, K201 was found to specifically bind to its subfragment2114–2149. With the use of the peptide matching this subfragment (DP2114–2149) as a carrier, the RyR2 was fl...
Insight into the preformed albumin corona on in vitro and in vivo performances of albumin-selective nanoparticles
Authors: Zhenbao Li, Dan Li, Wenjuan Zhang, Peng Zhang, Qiming Kan, Jin Sun
Journal: Asian Journal of Pharmaceutical Sciences (2018)

Preformed albumin corona of albumin-nonselective nanoparticles (NPs) is widely exploited to inhibit the unavoidable protein adsorption upon intravenous administration. However, very few studies have concerned the preformed albumin corona of albumin-selective NPs. Herein, we report a novel type of albumin-selective NPs by decorating 6-maleimidocaproyl polyethylene glycol stearate (SA) onto PLGA NPs (SP NPs) surface, taking albumin-nonselective PLGA NPs as control. PLGA NPs and SP NPs were prepared by emulsion-solvent evaporation method and the resultant NPs were in spherical shape with an average diameter around 180 nm. The corresponding albumin-coating PLGA NPs (PLGA@BSA NPs) and albumin-coating SP NPs (SP@BSA NPs) were formulated by incubating SP NPs or PLGA NPs with bovine serum albumin solution, respectively. The impact of albumin corona on particle characteristics, stability, photothermal effect, cytotoxicity, cell uptake, spheroid penetration and pharmacokinetics was investigated. In line with previous findings of preformed albumin coating, PLGA@BSA NPs exhibited higher stability, cytotoxicity, cell internalization and spheroid penetration performances in vitro, and longer blood circulation time in vivo than those of albumin-nonselective PLGA NPs, but albumin-selective SP NPs is capable of achieving a comparable in vitro and in vivo performances with both SP@BSA NPs and PLGA@BSA NPs. Our results demonstrate that SA decorated albumin-selective NPs pave a versatile avenue for optimizing nanoparticulate delivery without preformed albumin corona.
Silent Information Regulator 1 Protects the Heart From Ischemia/Reperfusion
Authors: Chiao-PoHsu, PeiyongZhai, TakanobuYamamoto, YasuhiroMaejima, ShoujiMatsushima, NirmalaHariharan, DanShao, HiromitsuTakagi, ShinichiOka, JunichiSadoshima
Journal: Circulation (2010)

Background—Silent information regulator 1 (Sirt1), a class III histone deacetylase, retards aging and protects the heart from oxidative stress. We here examined whether Sirt1 is protective against myocardial ischemia/reperfusion (I/R). Methods and Results—Protein and mRNA expression of Sirt1 is significantly reduced by I/R. Cardiac-specific Sirt1−/− mice exhibited a significant increase (44±5% versus 15±5%; P=0.01) in the size of myocardial infarction/area at risk. In transgenic mice with cardiac-specific overexpression of Sirt1, both myocardial infarction/area at risk (15±4% versus 36±8%; P=0.004) and terminal deoxynucleotidyl transferase dUTP nick end labeling–positive nuclei (4±3% versus 10±1%; P<0.003) were significantly reduced compared with nontransgenic mice. In Langendorff-perfused hearts, the functional recovery during reperfusion was significantly greater in transgenic mice with cardiac-specific overexpression of Sirt1 than in nontransgenic mice. Sirt1 positively regulates expression of prosurvi...
Dual-Tracer Assessment of Coupling Between Cardiac Sympathetic Neuronal Function and Downregulation of β-Receptors During Development of Hypertensive Heart Failure of Rats
Authors: TakashiNozawa, AkihikoIgawa, NaohiroYoshida, MasatoshiMaeda, MinoruInoue, YoshitakaYamamura, HidetsuguAsanoi, HiroshiInoue
Journal: Circulation (1998)

Background—Heart failure is associated with activation of the sympathetic nervous system and downregulation of β-receptors. However, the coupling between cardiac sympathetic neuronal function and the β-receptor during the development of hypertensive heart failure is not clear. Methods and Results—We determined cardiac neuronal function and β-receptors with a dual-tracer method of [131I]metaiodobenzylguanidine (MIBG) and 125I-cyanopindolol (ICYP) in Dahl salt-sensitive (DS) and salt-resistant (DR) rats. The rats were fed an 8% NaCl diet after the age of 6 weeks. Blood pressure was raised to >200 mm Hg at 12 weeks in DS rats and remained elevated until 18 weeks, but only slightly in DR rats. Left ventricular (LV) function of DS rats was preserved at 12 weeks but deteriorated at 18 weeks. Despite a 56% reduction of cardiac norepinephrine (NE) content at 12 weeks in DS rats, neither MIBG nor ICYP uptake in DS rats was different from that of DR rats. At 18 weeks, both MIBG and ICYP uptakes decreased, by 52% an...
Shed Membrane Microparticles With Procoagulant Potential in Human Atherosclerotic Plaques
Authors: ZiadMallat, BénédicteHugel, JeannyOhan, GuyLesèche, Jean-MarieFreyssinet, AlainTedgui
Journal: Circulation (1999)

Background—The specific role of apoptosis in human atherosclerosis remains unknown. During apoptotic cell death, phosphatidylserine exposure on the cell surface confers a high tissue-factor (TF)–dependent procoagulant activity. Methods and Results—In this study, we examined the role of apoptotic cell death in the promotion of plaque thrombogenicity. TF expression and its relation to apoptosis was analyzed in 16 human atherosclerotic plaques by the use of immunohistochemical techniques. The presence of shed membrane apoptotic microparticles was analyzed in extracts from 6 human atherosclerotic plaques and 3 underlying arterial walls. The microparticles were captured by annexin V and their amounts estimated with respect to their phospholipid content by use of a prothrombinase assay. The prothrombogenic potential of the microparticles was further assessed by the measurement of total and microparticle-dependent TF activity in the extracts. The cell origin of the microparticles was determined after capture by ...
Abstract 2390: When MLK3 meets PAK1: Its implication in breast cancer tumorigenesis
Authors: Subhasis Das, Rakesh Sathish Nair, Rajakishore Mishra, Tanmoy Bhowmik, Basabi Rana, Ajay Rana
Journal: Cancer Research (2018)

Abstract Mixed Lineage Kinase-3, also known as MAP3K11 is a member of a larger family of MAP3Ks, called MLKs. MLK3 has been reported to play an important role in pro-apoptotic signaling, however its role in tumorigenesis is still not fully elucidated. Previously, we reported that MLK3 is down regulated by estrogen and HER2 amplification and this down regulation provided a survival advantage to ER+ and HER2+ breast cancer cells. To further understand the role of MLK3 signaling in breast cancer pathogenesis, we aimed to identify the upstream kinase(s) that might regulate MLK3 activity and perhaps tumorigenesis. Based on available information from yeast, where Ste20 members are upstream of Ste11 (i.e. MAP3K), we hypothesized that mammalian homologue of Ste20, PAK1 could be upstream of MLK3. PAK1 kinase has been reported to be a major oncogene in many cancers, including breast cancer. Our results were however, counterintuitive to our hypothesis. We observed that instead, MLK3 was able to associate, and activate PAK1 Kinase activity. These results suggested that perhaps MLK3 is either upstream or parallel to PAK1 in the mammalian signaling network. We also observed that PAK1 was phosphorylated by MLK3 on Ser133 and Ser204 sites. Interestingly, Alanine substitution of S133 site constitutively activated PAK1 kinase activity, whereas Alanine substitution of the S204 site completely blocked MLK3-induced PAK1 activation. Constitutive active MLK3 was not able to phosphorylate and activate double mutant PAK1 S133A, S204A in vitro or in HEK293 cells, clearly indicated that PAK1 S204 site is important for MLK3-induced PAK1 activation. Since PAK1 is an oncogene in breast cancer, we determined the biological effect of S204 phosphorylation on breast cancer progression. Stable breast cancer cell line, MDA-MB-468, expressing PAK1 S204A, inhibited migration, invasion and showed significantly smaller tumors, compared to WT PAK1-expressing cells. Taken together, our results suggest that MLK3-induced modulation of PAK1 activity plays a major role in breast cancer tumorigenesis. First two authors are equally contributed Citation Format: Subhasis Das, Rakesh Sathish Nair, Rajakishore Mishra, Tanmoy Bhowmik, Basabi Rana, Ajay Rana. When MLK3 meets PAK1: Its implication in breast cancer tumorigenesis [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 2390.
Laminar Shear Stress Inhibits Vascular Endothelial Cell Proliferation by Inducing Cyclin-Dependent Kinase Inhibitor p21Sdi1/Cip1/Waf1
Authors: ShigeoAkimoto, MasakoMitsumata, ToshiyukiSasaguri, YojiYoshida
Journal: Circulation Research (2000)

Abstract—Alterations in the functions of vascular endothelial cells (ECs) induced by fluid shear stress may play a pivotal role in both the development and prevention of vascular diseases. We found that DNA synthesis of bovine aortic and human umbilical vein ECs, determined by [3H]thymidine incorporation, was inhibited by steady laminar shear stress (5 and 30 dyne/cm2). This growth inhibition due to shear stress was associated with suppression of cell transition from the G1 to S phase of the cell cycle. Therefore, we studied G1-phase events to find the molecules responsible for this cell cycle arrest. Shear stress inhibited the phosphorylation of a retinoblastoma protein (pRb) and the activity of cyclin-dependent kinase (cdk) 2 and cdk4, which phosphorylate pRb. The level of cdk inhibitor p21Sdi1/Cip1/Waf1 protein, but not that of p27Kip1, increased as a result of shear stress, and the amount of p21 protein associated with cdk2 also increased, although the protein level of cdk2 was unchanged. Shear stress...
An improved mouse model of hand-foot syndrome and interventional effects of herbal medicine extraction LC09 local administration.
Authors: Liqun Jia, Bo Deng, Yanni Lou
Journal: Journal of Clinical Oncology (2015)

e13560 Background: Hand-foot syndrome (HFS) is a common adverse reaction in clinical oncotherapy. HFS is mostly recorded in clinical observations or case reports, animal experiments are limited. Pharmacological intervention in HFS is lack of evaluation in animal model. Methods: Referring to Tamer’s method and with improvement approaches, a mouse model of HFS was established by doxorubicin liposome through caudal vein injection. HFS grading scale, pain behavior and pathological changes were observed. Interventional effects of LC09 (Herba Epimedii compound extraction) local administration were evaluated. Results: In model group, HFS-like lesions (erythema, desiccation, scaling and abopecia) were obvious, especially in hind claws. HFS scoring was significantly increased, with mechanical allodynia. Pathological tests showed hyperkeratosis, follicle atrophy and inflammation. In LC09 group, HFS scoring was decreased significantly, mechanical allodynia and pathological histology changes were alleviated. Conclusions: This mouse model of HFS induced by doxorubicin liposome supplied an available tool for research on pathogenesis of HFS and evaluation of drug intervention. LC09 for external use could obviously alleviate HFS scoring and pain behavior in a mouse model of HFS.
Preoperative Glutamine Administration Induces Heat-Shock Protein 70 Expression and Attenuates Cardiopulmonary Bypass–Induced Inflammatory Response by Regulating Nitric Oxide Synthase Activity
Authors: YoshitakaHayashi, YoshikiSawa, NaotoFukuyama, HiroeNakazawa, HikaruMatsuda
Journal: Circulation (2002)

Background— Heat-shock protein 70 (HSP70) plays a major role in the pathophysiology of inflammation, and the induction of HSP70 before the onset of inflammation can reduce organ damage through a self-protective system. Glutamine is known to be an inducer of HSP70, and its preoperative administration seems useful in attenuating cardiopulmonary bypass (CPB)–induced inflammatory response. Methods and Results— Adult male Sprague-Dawley rats (group G, received 100 mg/kg of glutamine via the right jugular vein 3 times per day for 1 week and just before the initiation of CPB; group C served as control) underwent CPB (60 minutes, 100 mL/kg per minute, 34°C) and were killed 3 hours after the termination of CPB. Group G showed significantly lower plasma concentrations of interleukin-6 and interleukin-8 after CPB termination. Myocardial and respiratory damages were significantly attenuated in group G, as evidenced by Langendorff perfusion, respiratory index, and neutrophil adherence. HSP70 expressions in the heart, ...
CF102 for the treatment of hepatocellular carcinoma: A phase I/II, open-label, dose-escalation study.
Authors: Salomon M. Stemmer, Ofer Benjaminov, Gal Medalia, Noa Ciuraru, Michael H. Silverman, Sara Bar Yehuda, Sari Fishman, Zivit Harpaz, Motti Farbstein, Shira Cohen, Renana Petoka, Barak Singer, William D Kerns, Pnina Fishman
Journal: Journal of Clinical Oncology (2012)

e14731 Background: The A 3 adenosine receptor (A 3 AR) is over-expressed in hepatocellular carcinoma (HCC) cells as well as in the peripheral blood mononuclear cells (PBMCs) of patients with HCC. The orally active drug candidate CF102, an A 3 AR agonist, induces in vivo apoptosis of HCC cells via de-regulation of the Wnt signaling pathway. In this open label phase I/II trial, the safety and clinical effects of CF102 were assessed in patients with advanced unresectable HCC. Methods: The primary objectives of this trial were to examine the safety and pharmacokinetic (PK) behavior of CF102 given orally twice daily in continuous cycles of 28 days each. Evaluation of anti-tumor effects and the utilization of A 3 AR as a biological predictive marker of response to CF102 were the secondary objectives. Results: 18 patients received CF102, six at each dose level (1 mg, 5 mg and 25 mg BID). No serious drug-related adverse events or dose-limiting toxicity were observed. Most adverse events were of grade 1-2 severity. CF102 demonstrated good oral bioavailability and linear PK behavior. Median overall survival in the study population, 67% of whom were sorafenib failures, was 7.8 months (range, 3·5-27·3 months) and for Child-Pugh B patients (28%) was 8.1 months. Stable disease (SD) by RECIST was observed in four patients for at least 4 months. CF102 had no adverse effect on routine measures of liver function over a 6 months period in 12 patients. A direct correlation between A 3 AR expression levels at baseline and patients’ response to CF102 was found. Conclusions: CF102 is safe and well-tolerated and shows favorable PK characteristics and hepatoprotective effects in patients with HCC. CF102 has shown preliminary evidence of clinical activity in Child-Pugh A and B HCC patients, justifying further clinical development.