tbuckley/cabot-search huggingface dataset:
Activating Transcription Factor 3 Constitutes a Negative Feedback Mechanism That Attenuates Saturated Fatty Acid/Toll-Like Receptor 4 Signaling and Macrophage Activation in Obese Adipose Tissue
Authors: TakayoshiSuganami, XunmeiYuan, YuriShimoda, KozueUchio-Yamada, NobutakaNakagawa, IbukiShirakawa, TakakoUsami, TakamitsuTsukahara, KeizoNakayama, YoshihiroMiyamoto, KazukiYasuda, JunichiroMatsuda, YasutomiKamei, ShigetakaKitajima, YoshihiroOgawa
Journal: Circulation Research (2009)

Obese adipose tissue is markedly infiltrated by macrophages, suggesting that they may participate in the inflammatory pathways that are activated in obese adipose tissue. Evidence has suggested that saturated fatty acids released via adipocyte lipolysis serve as a naturally occurring ligand that stimulates Toll-like receptor (TLR)4 signaling, thereby inducing the inflammatory responses in macrophages in obese adipose tissue. Through a combination of cDNA microarray analyses of saturated fatty acid-stimulated macrophages in vitro and obese adipose tissue in vivo, here we identified activating transcription factor (ATF)3, a member of the ATF/cAMP response element-binding protein family of basic leucine zipper-type transcription factors, as a target gene of saturated fatty acids/TLR4 signaling in macrophages in obese adipose tissue. Importantly, ATF3, when induced by saturated fatty acids, can transcriptionally repress tumor necrosis factor-α production in macrophages in vitro. Chromatin immunoprecipitation ...
SPAG5 interacts with CEP55 and exerts oncogenic activities via PI3K/AKT pathway in hepatocellular carcinoma
Authors: Yu-Feng Yang, Mei-Fang Zhang, Qiu-Hong Tian, Jia Fu, Xia Yang, Chris Zhiyi Zhang, Hong Yang
Journal: Molecular Cancer (2018)

Deregulation of microtubules and centrosome integrity is response for the initiation and progression of human cancers. Sperm-associated antigen 5 (SPAG5) is essential for the spindle apparatus organization and chromosome segregation, but its role in hepatocellular carcinoma (HCC) remains undefined.The expression of SPAG5 in HCC were examined in a large cohort of patients by RT-PCR, western blot and IHC. The clinical significance of SPAG5 was next determined by statistical analyses. The biological function of SPAG5 in HCC and the underlying mechanisms were investigated, using in vitro and in vivo models.Here, we demonstrated that SPAG5 exhibited pro-HCC activities via the activation of PI3K/AKT signaling pathway. SPAG5 expression was increased in HCC and correlated with poor outcomes in two independent cohorts containing 670 patients. High SPAG5 expression was associated with poor tumor differentiation, larger tumor size, advanced TNM stage, tumor vascular invasion and lymph node metastasis. In vitro and in vivo data showed that SPAG5 overexpression promoted tumor growth and metastasis, whereas SPAG5 knockdown led to the opposite phenotypes. SPAG5 interacted with centrosomal protein CEP55 to trigger the phosphorylation of AKT at Ser473. Inhibition of PI3K/AKT signaling markedly attenuated SPAG5-mediated cell growth. Furthermore, SPAG5 expression was suppressed by miR-363-3p which inhibited the activity of SPAG5 mRNA 3'UTR. Ectopic expression of SPAG5 partly abolished the miR-363-3p-caused cell cycle arrest and suppression of cell proliferation and migration.Collectively, these findings indicate that SPAG5 serves a promising prognostic factor in HCC and functions as an oncogene via CEP55-mediated PI3K/AKT pathway. The newly identified miR-363-3p/SPAG5/CEP55 axis may represent a potential therapeutic target for the clinical intervention of HCC.
Abstract 15077: Bilateral Inflammation in Carotid Arteries in Patients With Coronary Artery Disease is Associated With Increased Rate of Cardiovascular Events
Authors: GeorgiosBenetos, KonstantinosToutouzas, MariaDrakopoulou, FotiniMitropoulou, AngelosPapanikoloau, AndreasSynetos, HaralamposGrassos, DimitriosTousoulis, EliasSiores, ChristodoulosStefanadis
Journal: Circulation (2014)

Background: The prognostic role of both local and systemic inflammation in coronary artery disease (CAD) remains controversial. Microwave radiometry (MWR) is a new noninvasive method, which allows the in vivo measurement of the internal temperature of tissues reflecting local inflammation. The aim of the present study was to evaluate in patients with documented CAD the prognostic value of carotid atherosclerotic plaque inflammation, as assessed by MWR, in cardiovascular events. Methods: Consecutive patients with significant CAD (≥50% stenosis in at least one major epicardial vessel) were prospectively evaluated by 1) carotid ultrasound and 2) microwave radiometry (MWR). Maximum carotid plaque thickness was evaluated in all carotids during the ultrasound study. Temperature difference (ΔT) by MWR was assigned as maximal temperature along the carotid artery minus minimum. ΔT ≥0.90°C was assigned as high ΔT. Major cardiovascular event (MACE) was defined as death, stroke, myocardial infarction or revasculariza...
Abstract 4817: EP-100 sensitizes BRCA wild-type ovarian cancer cells to PARP inhibitor
Authors: Shaolin Ma, Sunila Pradeep, Sherry Wu, Mark Seungwook Kim, Wei Hu, Selanere Mangala, Robert L. Coleman, Anil K. Sood
Journal: Cancer Research (2018)

Abstract EP-100 is a synthetic lytic peptide specific for targeting LHRH receptors on cancer cells that is being clinically tested for treatment of ovarian cancer. In this study, we aimed to identify combination approaches with EP-100 in ovarian cancer models. We carried out a series of in vitro (MTT assay, immunoblot analysis, Q-PCR, reverse phase protein array (RPPA), comet assay and immunofluorescence staining) and in vivo (orthotopic mouse model) experiments in ovarian cancer models to determine the biological effects of EP-100 alone and in combination with standard of care drugs. We first examined the cytotoxic effects of EP-100 alone on 8 ovarian cancer cell lines with variable expression level of LHRH receptors and the IC50 values ranged from 0.5 to 2.0 µM. We then tested the effect of combining EP-100 with standard drugs (e.g., cisplatin, paclitaxel, doxorubicin, topotecan, and olaparib) on ovarian cancer cells. Of those drugs, we found that combination of EP-100 and olaparib was highly synergistic in drug sensitive and multi-drug resistant ovarian cancer cell lines (HeyA8, HeyA8-MDR, A2780, and A2780CP20). The combination indices (CI) were &amp;lt; 0.9 at the ED50 level. Furthermore, the nuclear foci of γH2AX were significantly increased in combination group of EP100 and olaparib after 24 h incubation compared with control, EP-100 alone, or olaparib alone groups (p &amp;lt; 0.0001, ANOVA). In addition, there was increased DNA accumulation in tails using comet assay after treating cells with EP-100 and olaparib for 24 h (p &amp;lt; 0.001, ANOVA). RPPA results identified that PI3K/AKT pathway can be blocked significantly by the combination treatment. The study in HeyA8 xenograft mouse models showed that mice treated with EP-100 and olaparib had the lowest tumor weight (0.06 ± 0.05 g) compared with those treated with vehicle (1.19 ± 0.39 g, p &amp;lt; 0.008), EP-100 alone (0.62 ± 0.28 g, p &amp;lt; 0.008), and olaparib alone (0.50 ± 0.22 g, p &amp;lt; 0.01). EP-100 has efficacy in preclinical models of ovarian cancer, especially in combination with olaparib. Our findings suggested that combining EP-100 with olaparib could be a promising therapeutic strategy for ovarian cancer. Citation Format: Shaolin Ma, Sunila Pradeep, Sherry Wu, Mark Seungwook Kim, Wei Hu, Selanere Mangala, Robert L. Coleman, Anil K. Sood. EP-100 sensitizes BRCA wild-type ovarian cancer cells to PARP inhibitor [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 4817.
His Bundle Recordings in Patients with Bundle Branch Block and Transient Neurologic Symptoms
Authors: Melvinscheinman, Alanweiss, Frederickkunkel
Journal: Circulation (1973)

His bundle electrograms were recorded in 19 patients with bundle branch block (BBB) and transient neurologic symptoms allowing for determination of intra-atrial (P-A), atrioventricular (A-V), nodal (A-H) as well as infranodal conduction (H-Q) times. The patients were initially monitored in a coronary care unit and have been followed for a mean period of 8 ± 4 months. In six patients (Group I) neurologic symptoms were observed in the absence of electrocardiographic evidence of A-V block. In six patients (Group II) the cause of symptoms was uncertain; two of these patients had relief of symptoms after permanent cardiac pacemaker insertion and were presumed to have episodic high grade A-V block. In seven subjects (Group III) complete A-V block was documented as the cause of the symptoms; these patients were studied when 1:1 antegrade A-V conduction returned. There was no significant difference between mean P-A, A-H, and QRS durations among the patients in the three groups. Mean H-Q (89 ± 20 msec) for Group I...
Bidirectional Role of Tumor Necrosis Factor-α in Coronary Microembolization
Authors: AndreasSkyschally, PetraGres, SimoneHoffmann, MichaelHaude, RaimundErbel, RainerSchulz, GerdHeusch
Journal: Circulation Research (2007)

In patients with unstable angina, plaque rupture and coronary microembolization (ME) can precede complete coronary artery occlusion and impending infarction. ME-induced microinfarcts initiate an inflammatory reaction with increased tumor necrosis factor-α (TNF-α) expression, resulting in progressive contractile dysfunction. However, TNF-α is not only a negative inotrope but can also protect the myocardium against infarction. In anesthetized pigs, we studied whether ME protects against infarction when TNF-α expression is increased. ME (group1; n=7) was induced by intracoronary infusion of microspheres (42 μm; 3000 per mL/min inflow). Controls (group 2; n=8) received saline. Groups 3 and 4 (n=4 each) were pretreated with ovine TNF-α antibodies (25 mg/kg body weight) 30 minutes before ME or placebo, respectively. Ischemia (90 minutes) was induced 6 hours after ME when TNF-α was increased (66±21 pg/g wet weight; mean±SEM) or after placebo (TNF-α, 21±10 pg/g; P<0.05). Infarct size (percentage area at risk) was...
Abstract 2388: IC50 profiling against 320 protein kinases: Improving the accuracy of kinase inhibitor selectivity testing
Authors: Daniel Mueller, Frank Totzke, Thomas Weber, Marcel Pathe, Christoph Schaechtele, Michael H. Kubbutat
Journal: Cancer Research (2018)

Abstract Protein kinases belong to one of the largest families of evolutionary related proteins. More than 500 distinct kinases are encoded by approximately 2% of all human genes. Over the past decades, numerous protein kinases have been described of which deregulation contributes to many human diseases. Today, more than 30 protein kinase inhibitors have been approved for the treatment of cancer emphasizing the significance of kinases as one of the most versatile drug targets. Due to the structural similarity especially within the ATP-binding site, many kinase inhibitors show limited selectivity. Still, sufficient selectivity within the human kinases is of critical importance e.g. to reduce the risk of adverse side effects during treatment. Therefore, measuring and improving selectivity of a compound within the kinome is of pivotal importance during drug discovery and optimization phase in the development of therapeutically relevant kinase inhibitors. Broad profiling of kinase inhibitors in biochemical activity assays of several hundred kinases is nowadays well established. Commonly, kinase profiling is done using one or two concentrations of a test compound and measurement of the relative inhibition of the kinase activity compared to a high and low control. However, due to the limited dynamic range of this approach, and the challenge to select the most appropriate compound concentration, this profiling approach gives often limited information with respect to the differences in the potency of compounds against On-target- and Off-target kinases. We set up an IC50 kinase profiling approach that consists of measuring the effect of a compound on the activity of 320 human protein kinases at six different concentrations. We will present data showing the effect of compound concentration on the selectivity score in traditional profiling setting. IC50 kinase profiles of different approved and clinical stage kinase inhibitors will be presented demonstrating that an IC50 based profiling allows the accurate determination of selectivity of a compound based on the comparison of the IC50 values against the On-target- in relation to the IC50 values of the Off-target kinases providing significantly improved guidance in the further optimization of the test compound. Citation Format: Daniel Mueller, Frank Totzke, Thomas Weber, Marcel Pathe, Christoph Schaechtele, Michael H. Kubbutat. IC50 profiling against 320 protein kinases: Improving the accuracy of kinase inhibitor selectivity testing [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 2388.
Abstract 20478: Circulating Inflammatory Potential Measured by an Endothelial Biosensor Assay in Coronary Artery Disease Patients
Authors: HeidiCung, JoeAnderson, JamesNawarskas, MatthewCampen
Journal: Circulation (2014)

Introduction: Vascular disease is driven by systemic inflammation that can arise from sites distal to the affected coronary or cerebral vessels. The objective of this study is to characterize the inflammatory potential of serum from patients with coronary artery disease (CAD) using cultured endothelial cells as a biosensor of the circulating milieu. Methods: Serum samples from CAD patients (N=48) and healthy control subjects (N=50) were incubated with primary human coronary artery endothelial cells at a 1:10 dilution for 4h, following by isolation of the cellular RNA. Alteration of inflammation-responsive elements (adhesion molecules and cytokines) was assessed on a gene expression level. Specific indicators included intercellular adhesion molecule-1 (ICAM), vascular cell adhesion molecule-1 (VCAM), and interleukin-8 (IL-8). Additionally, the serum samples from the CAD patients and healthy individuals were quantitatively analyzed for IL-1β, IL-6, IL-8, and TNF-α using an electrochemical luminescence platf...
Abstract 511: HPV mediates HNSCC carcinogenesis by exosomal exclusion of tumor suppressive miRNAs
Authors: Madhu Khullar, Varinder Singh, Nilambra Dogra, Malay Sannigrahi, Naresh Panda
Journal: Cancer Research (2018)

Abstract Background: Exosomes are small vesicles between 40-150 nm in diameter that are secreted by various cell types, including tumor cells. Exosomes of cancer cells are known to be involved in tumor pathology and have altered expression of microRNAs (miRNAs). However, the effect of HPV-16 (Human Papilloma Virus-16) infection on miRNA content of exosomes released by infected HNSCC cells has not yet been explored. Materials &amp; Methods: Exosomes were isolated from media of cultured HPV positive 93VU-147T and HPV negative UPCI:SCC 116 HNSCC cells and were characterized by Transmission Electron Microscopy. Presence of exosomal marker CD63 was confirmed using western blotting. Small RNA seq of exoRNA of HPV positive and HPV negative cells was carried out. For validation of identified miRNAs, HPV16 E6E7 was cloned into pcDNA3.1(-ve) vector and was transfected into SCC116 cells and stable cells were selected using G418. Differentially expressed miRNAs were validated in cells and exosomes using Real Time PCR. Results: Seven miRNAs 6724-5p, 6087, 4497, 4792, 4508, 199a-3p and 199b-3p were found to be significantly upregulated in HPV positive HNSCC exosomes as compared to HPV negative HNSCC exosomes from NGS data. Upregulation of these miRNAs was further confirmed in exosomes derived from HPV positive 93VU-147T cells and SCC116 E6E7 cells as compared to HPV negative cells (SCC 116 (3.1-ve) (vector only transfected SCC 116) cells. Expression of these miRNAs was significantly downregulated in 93VU14T and SCC116 E6E7 (HPV +ve) cells as compared to HPV negative cells. Three of these miRNAS (4792, 199a-3p and 199b-3p) are known tumor suppressor miRNAs. miRNA 6724-5p, a novel miRNA was found to be down regulated the most in HPV +ve cells. We identified CBX6, PDK2 and FOXK1 which are known to be involved in carcinogenesis, as its target genes through Targetscan. Expression of these genes was found to be significantly upregulated in HPV positive 93VU-147T cells and SCC116 E6E7 cells as compared to HPV negative cells indicating tumor suppressive role of miRNA 6724-5p in carcinogenesis. Conclusion: Our results suggest that HPV may mediate HNSCC carcinogenesis by exosomal exclusion of tumor suppressive miRNAs. Citation Format: Madhu Khullar, Varinder Singh, Nilambra Dogra, Malay Sannigrahi, Naresh Panda. HPV mediates HNSCC carcinogenesis by exosomal exclusion of tumor suppressive miRNAs [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 511.
Abstract 1869: Role of Nef secretion modification region (SMR) peptides and the chaperone mortalin in breast cancer and leukemia cells
Authors: Ming B. Huang, Vinvent C. Bond
Journal: Cancer Research (2018)

Abstract BACKGROUND: Mortalin/GRP-75(mt-hsp70, HSPA9) is a mitochondrial chaperone protein, also found in the cytoplasm, endoplasmic reticulum and cytoplasmic vesicles. It functions in many cellular processes such as mitochondrial biogenesis, intracellular trafficking, cell proliferation, signaling, immortalization and tumorigenesis, Thus, inhibition of mortalin is a promising avenue for cancer therapy. Previous studies in our lab have suggested that mortalin contributes to breast cancer development and progression. We showed tumor exosome secretion was decreased by knockdown of mortalin expression using HIV-1 Nef peptides. Specifically, these peptides can block exosome secretion and also mediate cell cycle arrest in MDA-MB-231 and MCF-7 breast cancer cells. AIMS: This study aims to investigate further the function and mechanism of interaction of PEG- SMR-CLU peptide and SMR-CPP peptide, and chaperone mortalin and to explore the effect of SMR-derived peptides and mortalin on human breast cancer and leukemia cell lines. RESULTS: Our results demonstrate that the modified SMRwt peptides not only affect breast cancer cell proliferation and arrest breast cancer cell growth, but they also inhibit migration of breast cancer cells. SMRwt peptides also block exosome-mediated release of complement, and allow the cells to die via complement induced cell death, and reduced mortalin protein expression. We further determined that expression levels of the mesenchymal markers vimentin (VIM) was decreased in presence of SMRwt peptides and MKT-077. CONCLUSIONS: Mortalin may promote cell proliferation and invasion via induction of epithelial mesenchymal transition (EMT) of cancer cells, which has a potential therapeutic target in cancer immunotherapy. SMRwt peptides block tumor exosome release and reduce the expression of mortalin. This may be a means to decreases breast cancer cell invasion and metastasis, which may have important clinical applications for late stage breast cancer chemotherapy. Furthermore, SMRwt peptides and inhibition of mortalin suppressed the migration and invasive capacity of cancer cells and is associated with a diminished EMT. These findings support a role for SMR peptide and mortalin in the induction of EMT, prompting a further investigation into their therapeutic value in cancer metastasis. Citation Format: Ming B. Huang, Vinvent C. Bond. Role of Nef secretion modification region (SMR) peptides and the chaperone mortalin in breast cancer and leukemia 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 1869.
Zika virus infects human testicular tissue and germ cells
Authors: Giulia Matusali, Laurent Houzet, Anne-Pascale Satie, Dominique Mahé, Florence Aubry, Thérèse Couderc, Julie Frouard, Salomé Bourgeau, Karim Bensalah, Sylvain Lavoué, Guillaume Joguet, Louis Bujan, André Cabié, Gleide Avelar, Marc Lecuit, Anna Le Tortorec, Nathalie Dejucq-Rainsford
Journal: Journal of Clinical Investigation (2018)

Zika virus (ZIKV) is a teratogenic mosquito-borne flavivirus that can be sexually transmitted from man to woman. The finding of high viral loads and prolonged viral shedding in semen suggests that ZIKV replicates within the human male genital tract, but its target organs are unknown. Using ex vivo infection of organotypic cultures, we demonstrated here that ZIKV replicates in human testicular tissue and infects a broad range of cell types, including germ cells, which we also identified as infected in semen from ZIKV-infected donors. ZIKV had no major deleterious effect on the morphology and hormonal production of the human testis explants. Infection induced a broad antiviral response but no IFN upregulation and minimal proinflammatory response in testis explants, with no cytopathic effect. Finally, we studied ZIKV infection in mouse testis and compared it to human infection. This study provides key insights into how ZIKV may persist in semen and alter semen parameters, as well as a valuable tool for testing antiviral agents.