tbuckley/cabot-search huggingface dataset:
Efficiency of In Vivo Gene Transfection Into Transplanted Rat Heart by Coronary Infusion of HVJ Liposome
Authors: YoshikiSawa, KenSuzuki, Hong-ZhiBai, RyotaShirakura, RyuichiMorishita, YasufumiKaneda, HikaruMatsuda
Journal: Circulation (1995)

Background Current methods of in vivo gene transfer into myocardium are limited by low efficiency. To improve in vivo gene transfer, a gene transfer method using hemagglutinating virus of Japan (HVJ) as a viral vector can be an alternative. Methods and Results In vivo gene transfection of FITC-labeled oligonucleotide (F-ODN) and cDNA of β-galactosidase (β-gal) was examined with use of the HVJ liposome (H group) or without it (C group). In the H group, F-ODN or cDNA of β-gal were complexed with liposomes, DNA binding nuclear protein (HMG1), and the viral protein coat of HVJ. After the harvest of donor rat hearts arrested by cardioplegia, the coronary artery was infused with the liposome gene complex. The hearts were transplanted into the abdomens of recipient rats and harvested 3 days after transplantation. Regarding F-ODN, the H group clearly showed FITC staining in the nuclei of the myocytes and endothelial cells in almost all layers of the myocardium as compared with the C group. Regarding the expressio...
Important Role of Local Angiotensin II Activity Mediated via Type 1 Receptor in the Pathogenesis of Cardiovascular Inflammatory Changes Induced by Chronic Blockade of Nitric Oxide Synthesis in Rats
Authors: MakotoUsui, KensukeEgashira, HideharuTomita, MasamichiKoyanagi, MakotoKatoh, HiroakiShimokawa, MotohiroTakeya, TeizoYoshimura, KoujiMatsushima, AkiraTakeshita
Journal: Circulation (2000)

Background—The chronic inhibition of NO synthesis by Nω-nitro-l-arginine methyl ester (L-NAME) upregulates the cardiovascular tissue angiotensin II (Ang II)–generating system and induces cardiovascular inflammatory changes in rats. Methods and Results—We used a rat model to investigate the role of local Ang II activity in the pathogenesis of such inflammatory changes. Marked increases in monocyte infiltration into coronary vessels and myocardial interstitial areas, monocyte chemoattractant protein-1 (MCP-1) expression, and nuclear factor-κB (NF-κB, an important redox-sensitive transcriptional factor that induces MCP-1) activity were observed on day 3 of L-NAME administration. Along with these changes, vascular superoxide anion production was also increased. Treatment with an Ang II type 1 receptor antagonist or with a thiol-containing antioxidant, N-acetylcysteine, prevented all of these changes. Conclusions—Increased Ang II activity mediated via the type 1 receptor may thus be important in the pathogenes...
Androgens activate protein kinase A in prostate cells
Authors: JuanJuan Wu, John French, Jae Kim, Yehia Daaka
Journal: Cancer Research (2008)

3030   Androgens manifest their effects on target cells by binding the androgen receptor (AR), which plays a critical role in normal development of the prostate gland as well as the initiation and progression of prostate cancer. The AR is a ligand-activated transcription factor that mediates the biological effects of male sex steroids in the target cells by activating transcription of androgen-regulated genes. Upon ligand binding, the AR translocates into the nucleus, binds to androgen response elements and associates with members of the transcription initiation complex to initiate transcription. This is the classical view of AR signaling, or the “genomic pathway.” This mode of androgen action requires hours to manifest fully and can be inhibited by agents that block gene transcription or protein translation. Emerging evidence indicates that stimulation with androgens can also initiate rapid (manifested in minutes), non-genomic signaling events such as increased intracellular Ca +2  and activation of ERK and PI3K pathways. The signaling steps involved in the non-genomic actions of androgen are not understood completely; however, they are likely mediated through multiple, cell type-specific mechanisms. Significantly, the non-genomic action of androgen may or may not involve nuclear AR. For instance, the androgen-mediated activation of ERK in androgen-dependent LNCaP prostate cancer cells appears to require nuclear AR, whereas the release of intracellular Ca +2  in skeletal muscle cells or IC21 macrophages occurs through nuclear AR-independent mechanisms. It is possible that these non-genomic actions of androgen contribute to and/or complement the genomic responses mediated through the classical pathway. Androgen-mediated activation of nuclear AR (through the genomic pathway) is dependent upon activity of the cAMP-dependent protein kinase (PKA). However, it is not known whether the existing pool of activated PKA inside the cell is used for this purpose, or if androgen stimulation  per se  provokes PKA activation. We have data to show that androgen causes the rapid and cAMP-dependent activation of PKA in prostate cells. The androgen-induced PKA activation is not inhibited by nuclear AR antagonist bicalutamide, and can be observed in cells that do not express nuclear AR gene. Reduction of Gαs expression with siRNA attenuates the androgen-mediated activation of PKA, which is required for the androgen-induced prostate cell proliferation. We conclude that androgen actively evokes a non-genomic signaling pathway to activate PKA that is needed for the genomic functioning of nuclear AR. The inhibition of PKA activation, together with standard AR-targeted therapies, may be more efficacious for treatment of patients with prostate cancer.
Abstract 15740: Aortic versus Carotid Arterial Stiffness in Systemic Lupus Erythematosus: Are They Simultaneously or Divergently Associated With Cerebrovascular Disease?
Authors: Paola C Roldan, Luis P Roldan, Ernest R Greene, Clifford R Qualls, Wilmer L Sibbitt, Carlos A Roldan
Journal: Circulation (2015)

Purpose: Aortic and carotid stiffness and cerebrovascular disease (CVD) are common in systemic lupus erythematosus (SLE). However, it is unknown whether aortic and carotid stiffness are associated with CVD in a parallel or divergent fashion. Methods: 43 SLE patients (41 women, age 36±11 years) and 17 age-and-sex matched healthy volunteers (14 women, age 34±12 years) prospectively underwent :1) transesophageal echocardiography and carotid ultrasonography for assessment of aortic and carotid stiffness, respectively, using the Pressure-Strain Elastic Modulus (PSEM) expressed in Pascal units; 2) assessment of CVD defined as acute stroke, neurocognitive dysfunction, or focal brain injury on MRI; and 3) follow-up for 45 months for assessment of incident stroke, cognitive disability, or death. Results: Aortic, but not carotid PSEM, was higher in SLE patients than in controls (7.96±4.16 versus 5.77±2.32 units, p=0.01 and 6.39±2.70 versus 5.55±2.68 units, p=0.29, respectively). Only aortic PSEM was positively associated with increased risk for prevalent CVD (OR=3.87, p=0.02) and incident CVD or mortality (OR=2.72, p=0.02) after simultaneously adjusting for atherogenic risk factors and antiphospholipid antibodies (Table 1). Conclusion: In young adult SLE patients, aortic stiffness in comparison to carotid stiffness is associated with a higher risk for prevalent CVD and incident CVD or mortality.
Abstract 5212: The inhibitory effect of iron control on breast cancer cells in tumor microenvironment
Authors: Wataru Goto, Shinichiro Kashiwagi, Koji Takada, Yuka Asano, Tsutomu Takashima, Satoru Noda, Naoyoshi Onoda, Kosei Hirakawa, Masaichi Ohira
Journal: Cancer Research (2018)

Abstract Background: Iron is an essential element for both normal and cancer cells, and it is well known that iron depletion leads to G1-S arrest and apoptosis. Iron depletion is also known to reduce serum hemoglobin and oxygen supply to the tissue, which may induce angiogenesis. On the other hand, it is reported that hypoxia mediates epithelial-mesenchymal transition (EMT) and cancer cell metastasis with angiogenesis. In addition, it is thought that antitumor autoimmune response relates to suppression of EMT, and we investigated previously it with clinical samples. In this study, we examined the mechanism of iron control therapy in breast cancer based on hypoxia, EMT and immune microenvironment. Material and Methods: Human breast cancer cell lines MDA-MB-231 (triple-negative breast cancer), MCF-7 (luminal type) and OCUB-1 (HER2-enriched type), and iron chelator Deferoxamine (DFO) were used in the present study. The effect of proliferation and migration of breast cancer cells by DFO was determined using MTT assay and wound healing assay. We also examined the influence of cell cycle by DFO using flow cytometry. Furthermore, we investigated the relationship between iron depletion of breast cancer cells and hypoxia, EMT and immune microenvironment using RT-PCR. We produced subcutaneous xenografts of mice, and examined the change in tumor sizes by administration of DFO. Results: The iron-depleted condition suppressed breast cancer cell proliferation and migration. In cell cycle analysis, DFO increased the population of the G0-G1 phase. In addition, iron depletion induced hypoxia and angiogenesis. Also, N-cadherin and PD-L1 expression of breast cancer cells were increased by iron-depleted condition. Subcutaneous tumors in the DFO administration group were suppressed tumor growth in vivo. Conclusion: Iron control by DFO showed the effect of tumor suppression, and suggested the possibility of novel treatment for patients with breast cancer. In addition, this mechanism related to hypoxia, EMT and immune microenvironment. Citation Format: Wataru Goto, Shinichiro Kashiwagi, Koji Takada, Yuka Asano, Tsutomu Takashima, Satoru Noda, Naoyoshi Onoda, Kosei Hirakawa, Masaichi Ohira. The inhibitory effect of iron control on breast cancer cells in tumor microenvironment [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 5212.
Phase II Trial of Alisertib in Combination with Irinotecan and Temozolomide for Patients with Relapsed or Refractory Neuroblastoma
Authors: Steven G. DuBois, Yael P. Mosse, Elizabeth Fox, Rachel A. Kudgus, Joel M. Reid, Renee McGovern, Susan Groshen, Rochelle Bagatell, John M. Maris, Clare J. Twist, Kelly Goldsmith, M. Meaghan Granger, Brian Weiss, Julie R. Park, Margaret E. Macy, Susan L. Cohn, Greg Yanik, Lars M. Wagner, Randall Hawkins, Jesse Courtier, Hollie Lai, Fariba Goodarzian, Hiroyuki Shimada, Najee Boucher, Scarlett Czarnecki, Chunqiao Luo, Denice Tsao-Wei, Katherine K. Matthay, Araz Marachelian
Journal: Clinical Cancer Research (2018)

In phase I testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; evaluate an alisertib oral solution; and evaluate biomarkers of clinical outcomes.
Abstract 107: Interaction of BIR domain of XIAP with Sp1/E2F1 activates MMP2 and bladder cancer cell invasion by inhibiting src protein translation
Authors: Xiaohui Hua, Jiheng Xu, Honglei Jin, Chuanshu Huang
Journal: Cancer Research (2018)

Abstract X-linked inhibitor of apoptosis protein (XIAP) is important in the regulation of cancer cell biological behaviors. However, little is known about the molecular mechanism by which the XIAP domains promote aggressive tumor behavior in human bladder cancer (BC). Herein, we discovered that ectopic expression of the BIR domains of XIAP rescued the MMP2 activation and human BC invasion in human BC cells with XIAP deletion. Interestingly, Src expression was upregulated in XIAP/BIR domain-deficient cells, whereas restoration of BIR domain in XIAP-deletion cells recused Src expression. Moreover, knockdown of Src reversed the defects of MMP2 activation and BC invasion in XIAP-deficient BC cells, revealing that Src acts as a XIAP downstream negative regulator for MMP2 activation and BC invasion. Mechanistic studies revealed that the regulatory effect of the BIR domains of XIAP on Src expression was due to directly inhibition of its protein translation by upregulation of miR-203 resulting from activation of the transcription factors Sp1 and E2F1, while the BIR domains of XIAP was found to interact with both Sp1 and E2F1 to activate these transcription factors. Overall, our studies demonstrate that BIR domain of XIAP is able to bind to Sp1 and E2F1 leading to their transcriptional activation, resulting their targeted miR-203 transcription, consequently directly targets the 3'-UTR of src mRNA and therefore attenuating SRC protein translation, and activating MMP2 and BC invasion. Citation Format: Xiaohui Hua, Jiheng Xu, Honglei Jin, Chuanshu Huang. Interaction of BIR domain of XIAP with Sp1/E2F1 activates MMP2 and bladder cancer cell invasion by inhibiting src protein translation [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 107.
Peptide–Gold Nanoparticle Hybrids as Promising Anti‐Inflammatory Nanotherapeutics for Acute Lung Injury: In Vivo Efficacy, Biodistribution, and Clearance
Authors: Ye Xiong, Wei Gao, Fan Xia, Yi Sun, Liya Sun, Ling Wang, Suqin Ben, Stuart E. Turvey, Hong Yang, Qiang Li
Journal: Advanced Healthcare Materials (2018)

Abstract Gold nanoparticles (GNPs) have shown great promises in various biomedical applications. Although GNPs exhibit excellent therapeutic efficacy in in vitro and in vivo in numerous studies, there still exists significant biosafety concerns, mainly for their nonbiodegradability and tendency to be trapped in the liver and spleen. To tackle this problem, hexapeptides are utilized to modify the GNP surface to not only impart them with potent anti‐inflammatory activity, but also facilitate their rapid clearance in vivo. Previously, a unique class of peptide‐GNP hybrids that potently inhibit multiple TLR signaling pathways in macrophages was identified; in this work, it is further demonstrated that these hybrids, after intratracheal instillation, are capable of effectively reducing lung inflammation and injury by decreasing neutrophil infiltration and increasing the number of regulatory T cells in the lung in a lipopolysaccharide‐induced acute lung injury (ALI) mouse model. More importantly, these hybrids can be effectively excreted 26 h post‐administration with only 8.49 ± 0.70% of them remaining in the body, primarily in the lung and intestine and less than 0.03% accumulated in the liver and spleen. This work provides strong evidences that properly designed peptide‐GNP hybrids can serve as the next generation of effective and safe anti‐inflammatory nanotherapeutics to treat ALI.
Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study
Authors: Alexander F A D Schauwvlieghe, Bart J A Rijnders, Nele Philips, Rosanne Verwijs, Lore Vanderbeke, Carla Van Tienen, Katrien Lagrou, Paul E Verweij, Frank L Van de Veerdonk, Diederik Gommers, Peter Spronk, Dennis C J J Bergmans, Astrid Hoedemaekers, Eleni-Rosalina Andrinopoulou, Charlotte H S B van den Berg, Nicole P Juffermans, Casper J Hodiamont, Alieke G Vonk, Pieter Depuydt, Jerina Boelens, Joost Wauters
Journal: The Lancet Respiratory Medicine (2018)
Abstract 892: Doxorubicin-induced cardiotoxicity in iPSC-cardiomyocytes: Altered mitochondrial gene expression and function
Authors: Monica E. Reyes, Rashida Callender, Jianzhong Ma, Megan L. Grove, Alanna C. Morrison, Michelle A. Hildebrandt
Journal: Cancer Research (2018)

Abstract Introduction: Cardiomyocytes are highly vulnerable to anthracycline-induced toxicity, which may lead to heart failure. This includes doxorubicin, which is a commonly used chemotherapeutic agent. Although mitochondrial function has been implicated as a mechanism of anthracycline-induced toxicity in rodent heart cells, the precise genes that regulate this response in humans remain to be elucidated. We hypothesized that doxorubicin significantly alters expression of mitochondrial genes in human cardiomyocytes, which impairs mitochondrial function. Methods: Human inducible pluripotent stem cell (iPSC)-derived cardiomyocytes were treated with doxorubicin or left untreated for control to assess changes in gene expression using RNAseq. A total of 169 genes involved in mitochondrial function, as defined by Ingenuity Pathway Analysis and KEGG, were analyzed for significant differences between untreated and treated conditions using DESeq2 and GenePattern 2.0. Mitochondrial respiration was measured in control and doxorubicin-treated cells using the Seahorse Bioscience XFe96 Cell Mito Stress Test kit. We used a Spearman's partial correlation coefficient analysis to correlate gene expression levels with mitochondrial basal respiration, ATP production, maximal respiration, and spare respiratory capacity for untreated and doxorubicin-treated iPSC-cardiomyocytes. Results: Of the 169 mitochondrial genes analyzed, we identified 25 genes that were significant in our global differential expression analysis across all conditions (P&amp;lt;0.05). Seven of these genes (ATP5D, COX5A, CYC1, HSD17B10, NDUFB10, NDUFS8, UQCRC1) remained significant in pairwise analyses between control and doxorubicin treated cells. We observed a decrease in mitochondrial respiration following treatment with doxorubicin. Maximal respiration (r=-0.929; P=0.022) and spare respiratory capacity (r=-0.98;P=0.0025) negatively correlated with NDUFS8 expression in doxorubicin-treated iPSC-cardiomyocytes. Conclusion: Our findings underscore a role for mitochondrial function in the development of doxorubicin-induced cardiotoxicity and implicate specific genes in this process. Doxorubicin-altered gene expression in cardiomyocytes may provide insight into how impaired mitochondrial function leads to heart failure in cancer survivors. Citation Format: Monica E. Reyes, Rashida Callender, Jianzhong Ma, Megan L. Grove, Alanna C. Morrison, Michelle A. Hildebrandt. Doxorubicin-induced cardiotoxicity in iPSC-cardiomyocytes: Altered mitochondrial gene expression and function [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 892.
Abstract 1247: Hereditary paraganglioma-pheochromocytoma syndrome: Patterns of presentation in a Brazilian oncogenetics clinic
Authors: Diogo C. Soares, Ana Milena G. Camacho, Maria Isabel Achatz, Maria Nirvana C. Formiga
Journal: Cancer Research (2018)

Abstract Introductory Sentence: More than 35% of pheochromocytomas and paragangliomas (PPGL) are thought to occur due to an underlying genetic predisposition, which explain approximately 30% of familial cases. Methods: We analyzed data of four families with clinical and molecular diagnosis of PPGL followed at Oncogenetics Department of A.C. Camargo Cancer Center, from 2010 to 2017. Results: The proband of Family 1 is a 40-year-old woman with glomus jugulare paraganglioma and confirmed SDHB mutation. Her two children have the same mutation in SDHB gene and her son had the diagnosis of retroperitoneal paraganglioma at the age 13. The brother of the index case had a pheochromocytoma and her nephew had an abdominal paraganglioma at the age of 8. In the Family 2 the index case is a 33-year-old woman with paraganglioma of the carotid body bilateral and had a molecular diagnosis with SDHB mutation. There are no other paraganglioma cases in the members of this family. Family 3 initiated counseling in our clinics with a woman with paraganglioma of the carotid body bilateral at 25-year-old with recurrence at 35-year-old and it was found in genetic test a SDHD mutation. She had two cousins with bilateral cervical paraganglioma, but without genetic testing. Our fourth family: Man with pheochromocytoma at 28-year-old and mutation in the SDHD gene. A son with metastatic phaeochromocytoma in the retroperitoneum, mediastinum and lung at 11-year-old and bilateral carotid paraganglioma at 12-year-old. Sister of the index case with glomus jugulare paraganglioma at the age of 38. Conclusions: Although PPGL are rare tumors, it is estimated that up to 30-40% of cases are hereditary, based on this it is relevant to raise the PPGL syndrome suspicion and refer a paraganglioma or pheochromocytoma patient to a cancer genetic counseling. There are clear follow-up guidelines for the early detection of these tumors in carriers and the genotype-phenotype correlation can direct the diagnosis and in some cases the management of these patients. Citation Format: Diogo C. Soares, Ana Milena G. Camacho, Maria Isabel Achatz, Maria Nirvana C. Formiga. Hereditary paraganglioma-pheochromocytoma syndrome: Patterns of presentation in a Brazilian oncogenetics clinic [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 1247.
Increased Bleeding Tendency and Decreased Susceptibility to Thromboembolism in Mice Lacking the Prostaglandin E Receptor Subtype EP3
Authors: HongMa, AkiyoshiHara, Chun YangXiao, YujiOkada, OsamuTakahata, KazuhiroNakaya, YukihikoSugimoto, AtsushiIchikawa, ShuhNarumiya, FumitakaUshikubi
Journal: Circulation (2001)

Background— Among the prostanoids, thromboxane (TX) A2 is a potent stimulator of platelets, whereas prostaglandin (PG) I2 inhibits their activation. The roles of PGE2 in the regulation of platelet function have not been established, however, and the contribution of PGE2 in hemostasis and thromboembolism is poorly understood. The present study was intended to clarify these roles of PGE2 by using mice lacking the PGE2 receptor subtype 3 (EP3−/− mice). Methods and Results— Expression of mRNAs for EP3 in murine platelets was confirmed by quantitative reverse transcription-polymerase chain reaction. PGE2 and AE-248, a selective EP3 agonist, showed concentration-dependent potentiation of platelet aggregation induced by U46619, a TXA2 receptor agonist, although PGE2 alone could not induce aggregation. PGE2 and AE-248 increased cytosolic calcium ion concentration ([Ca2+]i), and AE-248 inhibited the forskolin-induced increase in cytosolic cAMP concentration ([cAMP]i), suggesting Gi coupling of EP3. The potentiatin...
Increased Expression of P-Selectin on Platelets Is a Risk Factor for Silent Cerebral Infarction in Patients With Atrial Fibrillation
Authors: TetsuoMinamino, MasafumiKitakaze, ShojiSanada, HiroshiAsanuama, ToshiyaKurotobi, YukihiroKoretsune, MasatakeFukunami, TsunehikoKuzuya, NoritakeHoki, MasatsuguHori
Journal: Circulation (1998)

Background—Platelet activation and decreased levels of nitrite and nitrate (NOx), stable end products of nitric oxide (NO), are reported in patients with atrial fibrillation (AF). We examined the time-course changes in plasma NOx levels and the expression of P-selectin on platelets after the onset of AF in a canine model and determined whether these parameters could be risk factors for silent cerebral infarction in patients with AF. Methods and Results—AF was induced by rapid atrial pacing in the canine model of AF. Plasma NOx levels were significantly decreased and the levels of P-selectin on platelets and of neutrophil/platelet conjugates were significantly increased after the onset of AF in this model. The in vitro experiments demonstrated that the inhibition of NO synthesis increased the expression of P-selectin on platelets. Plasma NOx levels (19.7±2.4 versus 27.5±2.8 μmol/L) were significantly lower in 25 patients with AF compared with age- (±2 years) and sex-matched control subjects. Conversely, th...