tbuckley/cabot-search huggingface dataset:
Downregulation of Protein Kinase C Inhibits Activation of Mitochondrial KATP Channels by Diazoxide
Authors: YigangWang, EnTakashi, MeifengXu, AhmarAyub, MuhammadAshraf
Journal: Circulation (2001)

Background—The mitochondrial KATP (mitoKATP) channel has been shown to confer short- and long-term cardioprotection against prolonged ischemia via protein kinase C (PKC) signaling pathways. However, the exact association between PKC or its isoforms and mitoKATP channels has not yet been clarified. The present study tested the hypothesis that the activity and translocation of PKC to the mitochondria are important for cardiac protection elicited by mitoKATP channels. Methods and Results—PKC was downregulated by prolonged (24-hour) treatment with phorbol 12-myristate 13-acetate (4 μg/kg body weight) before subsequent experiments in rats. Langendorff-perfused rat hearts were subjected to 40 minutes of ischemia followed by 30 minutes of reperfusion. Effects of PKC downregulation on the activation of mitoKATP channels and other interventions on hemodynamic, biochemical, and pathological changes were assessed. Subcellular localization of PKC isoforms by Western blot analysis and immunocytochemistry demonstrated ...
Cigarette Smoking Potentiates Endothelial Dysfunction of Forearm Resistance Vessels in Patients With Hypercholesterolemia
Authors: ThomasHeitzer, SeppoYlä-Herttuala, JukkaLuoma, SabineKurz, ThomasMünzel, HanjörgJust, ManfredOlschewski, HelmutDrexler
Journal: Circulation (1996)

Background Risk factors for atherosclerosis such as hypercholesterolemia and hypertension are associated with endothelial dysfunction of conduit and resistance vessels; however, the interaction of these risk factors and underlying mechanisms affecting endothelial function remain to be determined. The present study investigated the role of long-term smoking and hypercholesterolemia and their impact on endothelial function of peripheral resistance vessels in relation to plasma levels of autoantibodies against oxidized LDL, which has been implicated in the development of endothelial dysfunction and atherosclerosis. Methods and Results The vascular responses to the endothelium-dependent agent acetylcholine (7.5, 15, 30, and 60 μg/min) and the endothelium-independent agent sodium nitroprusside (1, 3, and 10 μg/min) were studied in normal control subjects (n=10), patients with hypercholesterolemia (n=15), long-term smokers (n=15), and hypercholesterolemic patients who smoked (n=15). Drugs were infused into the ...
Platelets Activated by Collagen Through Immunoreceptor Tyrosine-Based Activation Motif Play Pivotal Role in Initiation and Generation of Neointimal Hyperplasia After Vascular Injury
Authors: HakuohKonishi, YouichiKatoh, NorihideTakaya, YujiKashiwakura, SeigoItoh, ChiseiRa, HiroyukiDaida
Journal: Circulation (2002)

Background— Platelet adhesion on components of the extracellular matrix and platelet activation by those components are crucial for the arrest of posttraumatic bleeding, but they can also harm tissue by occluding diseased vessels. Recent studies have shown that the activation of platelets by collagen is mediated through the same pathway used by immune receptors, with an immunoreceptor tyrosine-based activation motif on the Fc receptor γ chain (FcRγ) playing a pivotal role. Methods and Results— We examined the role of collagen-stimulated platelets in the development of injury-induced neointimal formation by using mice deficient in FcRγ. The left femoral arteries of 8- to 12-week-old FcRγ-deficient mice (n=16) and C57BL/6 (wild-type) mice (n=16) were injured by a straight spring wire (0.35-mm diameter). Segments of the injured and uninjured femoral arteries were excised at 7 days and 28 days after the vascular injury. Arterial segments were examined by immunohistochemistry and electron microscopy. Two hours...
Abstract 47: Brain metastatic versus non-metastatic breast cancer exosomes influence astrocyte response
Authors: Megan Sayyad, Madhavi Puchalapalli, Bin Hu, Jennifer Koblinski
Journal: Cancer Research (2018)

Abstract Brain metastasis is a devastating, late-stage event affecting 10-30% of breast cancer patients, but it is unclear how breast cancer cells can cross the blood-brain barrier (BBB) and colonize the unique brain environment. Exosomes, endosomal-derived extracellular vesicles, have been reported to support premetastatic niche formation through recruitment of tumor growth-supporting cells, creating sites conducive to cancer development. Still, it is not known how exosomes might prime the distinctive brain environment for metastasis despite the ability of circulating exosomes to readily cross the BBB. Glial cells, namely astrocytes and microglia, are important contributors to brain metastasis, and astrocytes in particular secrete exosomes that promote tumor outgrowth in the brain. We therefore investigated the effects of breast cancer exosomes on astrocytes in promoting brain premetastatic niche formation. Using ultracentrifugation, we isolated exosomes from 4T1 metastatic and 67NR nonmetastatic mouse mammary carcinoma and MDA-MB-231 human triple-negative breast cancer cell-conditioned media. Exosomes were characterized using Western immunoblot, dynamic light scatter analysis, and transmission electron microscopy, and labeled with a fluorescent lipid dye. Mouse and human astrocytes were then treated with either 4T1 or MDA-MB-231 exosomes, respectively, and vesicle internalization was assessed using confocal microscopy. Astrocytes were indeed found to internalize cancer exosomes in vitro. Using qPCR analysis, we explored gene expression changes in mouse astrocytes treated with 4T1 exosomes compared to those treated with 67NR exosome nonmetastatic controls. 4T1 exosomes were found to significantly upregulate expression of tenascin C, an astrocyte-derived brain extracellular matrix protein, suggesting the brain matrix could be remodeled prior to cancer cell arrival. Further, astrocytes treated with 4T1 exosomes exhibited significant upregulation of inflammation-associated genes, namely COX-2, IL-6, CCL4 and PDGF-alpha, genes also associated with cancer and metastasis, specifically to the brain. Alternatively, 67NR exosome treated-astrocytes exhibited significant downregulation in these genes of interest, suggesting that there is a unique response profile associated with nonmetastatic versus metastatic breast cancer-derived exosomes. Taken together, these findings suggest that breast cancer exosomes could drive transformation of the brain environment towards a prometastatic site. Citation Format: Megan Sayyad, Madhavi Puchalapalli, Bin Hu, Jennifer Koblinski. Brain metastatic versus non-metastatic breast cancer exosomes influence astrocyte response [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 47.
Abstract 328: Translating Guidelines into Practice: A Survey Study to Assess Healthcare Provider Attitudes, Preferences and Beliefs Regarding Pediatric Fluid Resuscitation Practices
Authors: Asmaa Manan, Melissa J Parker
Journal: Circulation (2012)

Introduction: Children who require fluid resuscitation for the treatment of shock present to tertiary and non-tertiary medical settings. While timely fluid therapy improves survival odds and is accepted as a key component of initial resuscitative care, guidelines are poorly translated into clinical practice. Objective: To characterize the attitudes, preferences and beliefs of health care providers regarding pediatric fluid resuscitation practices. Hypothesis: Varying attitudes and beliefs concerning pediatric fluid resuscitation performance would exist among providers who frequently resuscitate children. Methods: A single-centre survey study was conducted at McMaster Children’s Hospital from January to May, 2012. The sampling frame (n=111) included nursing staff, physician staff and subspecialty trainees working in Pediatric Emergency Medicine (PEM) or Pediatric Critical Care Medicine (PCCM). A self-administered questionnaire was developed and assessed for face validity prior to distribution. Eligible participants were invited at 0, 2, and 4 weeks to complete a web-based version of the survey. A follow-up survey administration phase utilizing a tablet-based version of the survey was conducted to improve the response rate. Results: Response rate was 75% (83/111), with 83% identifying themselves as nursing staff and 61% as PCCM providers. Resuscitation experience, frequency of shock management, and years in specialty, were similar between PCCM and PEM responders. Physicians and nurses had differing opinions regarding the most effective method to achieve rapid fluid resuscitation in young children presenting in shock (p&lt;0.001). Disagreement also existed regarding the age and size of patients in whom rapid infuser devices, such as the Level-1 Rapid Infuser, should be used (p&lt;0.001). Providers endorsed a number of potential concerns related to the use of rapid infuser devices in children, and only 14% of physicians and 55% of nursing staff felt that they had received adequate training in the use of such devices (p=0.005). Conclusions: There is a lack of consensus among health care providers regarding how pediatric fluid resuscitation guidelines should be operationalized, supporting a need for further work to define best practices.
Abstract 14: Preclinical evaluation of novel HIF-1α/P300 binding inhibitors
Authors: Jonathan D. Strope, Emily M. Harris, Shaunna L. Beedie, Cindy H. Chau, Kristina M. Cook, Christopher J. Schofield, Kirk R. Gustafson, William D. Figg
Journal: Cancer Research (2018)

Abstract A key component of tumor progression and metastasis is the hypoxic response. The hypoxic response regulates angiogenesis, tumor invasion, and metabolism. The Hypoxia Inducible Factor (HIF) is the transcriptional system responsible for the hypoxic response. The inhibition of the hypoxic response via inhibition of the HIF-1 pathway by disrupting its association with the transcriptional coactivator p300 presents a potential therapeutic target for multiple cancers where HIF is upregulated. To that end, we describe the preclinical development of previously described novel marine pyrroloiminoquinone alkaloids found using a HIF-1α/p300 assay in a high throughput screen of extracts from the National Cancer Institute's Natural Products Repository. Pyrroloiminoquinone alkaloids are a novel class of HIF-1α inhibitors, which interrupt the protein−protein interaction between HIF-1α and p300 and consequently reduce HIF-related transcription. The 2 lead candidates, discorhabdin L and H were assessed in inhibition of angiogenesis in an in vitro HUVEC assay and ex vivo rat aortic ring assay. The compounds were also evaluated for in vivo efficacy in prostate cancer cell tumor xenografts. Results show that development of these compounds for clinical use is warranted and may prevent the progression of multiple tumor types. Citation Format: Jonathan D. Strope, Emily M. Harris, Shaunna L. Beedie, Cindy H. Chau, Kristina M. Cook, Christopher J. Schofield, Kirk R. Gustafson, William D. Figg. Preclinical evaluation of novel HIF-1α/P300 binding inhibitors [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 14.
Selective Activation of Nuclear Phospholipase D-1 by G Protein–Coupled Receptor Agonists in Vascular Smooth Muscle Cells
Authors: StéphanieGayral, PaulDéléris, KarineLaulagnier, MurielLaffargue, Jean-PierreSalles, BertrandPerret, MichelRecord, MoniqueBreton-Douillon
Journal: Circulation Research (2006)

Recent studies highlight the existence of an autonomous nuclear lipid metabolism related to cellular proliferation. However, the importance of nuclear phosphatidylcholine (PC) metabolism is poorly understood. Therefore, we were interested in nuclear PCs as a source of second messengers and, particularly, nuclear phospholipase D (PLD) identification in membrane-free nuclei isolated from pig aorta vascular smooth muscle cells (VSMCs). Using immunoblot experiment, in vitro PLD assay with fluorescent substrate and confocal microscopy analysis, we demonstrated that only PLD1 is expressed in VSMC nucleus, whereas PLD1 and PLD2 are present in VSMC. Inhibition of RhoA and protein kinase Cζ (PKCζ) by C3-exoenzyme and PKCζ pseudosubstrate inhibitor, respectively, conducted a decrease of phosphatidylethanol production. On the other hand, treatment of intact VSMCs, but not nuclei, with phosphoinositide 3-kinase (PI3K) inhibitors prevented partially nuclear PLD1 activity, indicating for the first time that PI3K may ha...
Antigen-specific antibody Fc glycosylation enhances humoral immunity via the recruitment of complement
Authors: Giuseppe Lofano, Matthew J. Gorman, Ashraf S. Yousif, Wen-Han Yu, Julie M. Fox, Anne-Sophie Dugast, Margaret E. Ackerman, Todd J. Suscovich, Joshua Weiner, Dan Barouch, Hendrik Streeck, Susan Little, Davey Smith, Douglas Richman, Douglas Lauffenburger, Bruce D. Walker, Michael S. Diamond, Galit Alter
Journal: Science Immunology (2018)

HIV-specific broadly neutralizing antibodies (bNAbs) confer protection after passive immunization, but the immunological mechanisms that drive their development are poorly understood. Structural features of bNAbs indicate that they originate from extensive germinal center (GC) selection, which relies on persistent GC activity. However, why a fraction of infected individuals are able to successfully drive more effective affinity maturation is unclear. Delivery of antigens in the form of antibody-immune complexes (ICs), which bind to complement receptors (CRs) or Fc receptors (FcRs) on follicular dendritic cells, represents an effective mechanism for antigen delivery to the GC. We sought to define whether IC-FcR or CR interactions differ among individuals who develop bNAb responses to HIV. Enhanced Fc effector functions and FcR/CR interactions, via altered Fc glycosylation profiles, were observed among individuals with neutralizing antibody responses to HIV compared with those without neutralizing antibody activity. Moreover, both polyclonal neutralizer ICs and monoclonal IC mimics of neutralizer antibodies induced higher antibody titers, higher-avidity antibodies, and expanded GC B cell reactions after immunization of mice via accelerated antigen deposition within B cell follicles in a complement-dependent manner. Thus, these data point to a direct role for altered Fc profile/complement interactions in shaping the maturation of the humoral immune response, providing insights into how GC activity may be enhanced to drive affinity maturation in next-generation vaccine approaches.
Improved detection of erosions in the sacroiliac joints on MRI with volumetric interpolated breath-hold examination (VIBE): results from the SIMACT study
Authors: Torsten Diekhoff, Juliane Greese, Joachim Sieper, Denis Poddubnyy, Bernd Hamm, Kay-Geert A Hermann
Journal: Annals of the Rheumatic Diseases (2018)

Objective To compare the performance of a new three-dimensional MRI sequence (volumetric interpolated breath-hold examination; MR-VIBE) with a conventional T1-weighted sequence (MR-T1) for the detection of erosions in the sacroiliac joints (SIJs) using low-dose CT (ldCT) as reference. Methods ldCT and T1-MRI and MR-VIBE of 110 prospectively included patients with low back pain and suspected axial spondyloarthritis (axSpA) were scored for erosions by two readers. The presence of erosions on the patients’ level, the erosion sum score, sensitivity and specificity of both MRI sequences using ldCT as a reference as well as agreement between the readers were assessed. Results MR-VIBE had a higher sensitivity than MR-T1 (95% vs 79%, respectively) without a decrease in specificity (93% each). MR-VIBE compared with MR-T1 identified 16% more patients with erosions (36 vs 30 of 38 patients with positive ldCT findings). The erosion sum score was also higher for MR-VIBE (8.1±9.3) than MR-T1 (6.7±8.4), p=0.003. The agreement on erosion detection was also higher for MR-VIBE (κ=0.71) compared with MRI-T1 (κ=0.56). Conclusion VIBE detected erosions in the SIJs with higher sensitivity without a loss of specificity and superior reliability compared with a standard T1-weighted sequence. Its value for the diagnosis of axSpA has still to be determined.
Abstract 3744: Multiple endocrine-resistant breast cancer cell lines retain ER and sensitivity to endocrine therapy
Authors: Lauren M. Gutgesell, Rui Xiong, Jiong Zhao, Huiping Zhao, Debra A. Tonetti, Gregory R. Thatcher
Journal: Cancer Research (2018)

Abstract Endocrine therapy is the standard of care for breast cancer expressing estrogen receptor (ER), which occurs in 70% of patients. Unfortunately, acquired or de novo resistance to endocrine therapy is observed in up to 50% of patients, leaving a significant portion of patients with insufficient treatment options. Endocrine-resistance, usually defined as resistance to tamoxifen and aromatase inhibitor (AI) therapy, can also include resistance to selective estrogen receptor degraders (SERDs), since these also target ER. Since multiple mechanisms contribute to resistance, development of multiple resistant cell lines is needed for drug discovery and to identify characteristics that may suggest susceptibility to alternative and combination therapies. We have developed 5 stable, endocrine-resistant cell lines from a parent MCF-7 cell line, which all retain ER: one of these cell lines, MCF-7:CFR is resistant to the SERD fulvestrant. Clinical metastatic breast cancers that have gained endocrine resistance are overwhelmingly ER+. In addition to ER, progesterone receptor (PR) and glucocorticoid receptor (GR) status of these lines was assessed, and correlated with the response of these cells in culture to four classes of endocrine therapeutics: SERDs, selective ER modulators (SERMs), and selective human ER partial agonists (ShERPAs). Growth of all 5 cell lines was endocrine independent, indicating resistance to AI therapy. Two of the ER+, PR- cell lines were most resistant to the spectrum of endocrine therapies, but these cell lines both showed sensitivity to ShERPAs, especially in combination with non-endocrine targeted therapies, such as the PI3K inhibitor, alpelisib. Paradoxically, all endocrine-resistant cell lines responded to at least one of the endocrine therapies tested, demonstrating that if ER is not lost in the metastatic state, it remains a vulnerability suitable for therapeutic targeting. Citation Format: Lauren M. Gutgesell, Rui Xiong, Jiong Zhao, Huiping Zhao, Debra A. Tonetti, Gregory R. Thatcher. Multiple endocrine-resistant breast cancer cell lines retain ER and sensitivity to endocrine therapy [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 3744.
Abstract 2551: Allogeneic CRISPR engineered anti CD70 CAR T cells demonstrate potent preclinical activity against both solid and hematological cancer cells
Authors: Zinkal Padalia, Ashley Porras, Mary Lee Dequeant, Jason Sagert, Thao Nguyen, Matthias John, Melanie Allen, Henia Dar, Daniel Henderson, Seshidar Police, Dakai Mu, Kelly Maeng, Elaine Huang, Sarah Spencer, Nickolaus Lorson, Paul Gonzales, Chelsea Holmquist, Gregg Hirschfeld, Jonathan A. Terrett, Demetrios Kalaitzidis
Journal: Cancer Research (2018)

Abstract Autologous CAR T therapeutics have recently been approved for use in B-cell malignancies. While responses have been impressive using CD19 directed CAR T cells there has been a lack of comparable success for CAR T cells directed at solid tumor antigens. In an effort to address the need for effective and durable off-the shelf therapies for both hematologic and solid tumors we have developed allogeneic CAR T cells targeting the CD70 antigen. CD70 is expressed in both hematologic malignancies as well as in solid cancers such as renal cell carcinoma (RCC), while its expression in normal tissues is restricted to a subset of lymphoid cell types. CAR-T cells expressing a CD70 targeting CAR were generated by CRISPR Cas9 genome editing. T cells from healthy donors were edited to express a CD70 CAR by knocking this construct into the concurrently knocked out TCR alpha constant region (TRAC). Loss of the TCR reduces the risk of graft versus host disease enabling an allogeneic therapeutic. CD70 CAR T cells displayed potent cell killing function in vitro against CD70 expressing lymphoid and renal cancer derived cell lines across a broad range of antigen expression levels. CD70 CAR T cells also secreted IFNg, released granzyme B and proliferated in a CD70 specific manner. Furthermore, the CD70 targeting CAR T cells were able to eliminate established ccRCC tumor xenografts in mice Citation Format: Zinkal Padalia, Ashley Porras, Mary Lee Dequeant, Jason Sagert, Thao Nguyen, Matthias John, Melanie Allen, Henia Dar, Daniel Henderson, Seshidar Police, Dakai Mu, Kelly Maeng, Elaine Huang, Sarah Spencer, Nickolaus Lorson, Paul Gonzales, Chelsea Holmquist, Gregg Hirschfeld, Jonathan A. Terrett, Demetrios Kalaitzidis. Allogeneic CRISPR engineered anti CD70 CAR T cells demonstrate potent preclinical activity against both solid and hematological 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 2551.
Abstract 4374: Non-canonical activation of β-catenin by PRL-3 phosphatase in acute myeloid leukemia
Authors: Phyllis SY Chong, Jianbiao Zhou, Jing Yuan Chooi, Wee Joo Chng, Jayantha Gunaratne, Qi Zeng
Journal: Cancer Research (2018)

Abstract Aberrant activation of Wnt/β-catenin signaling pathway is essential for the development of AML; however, the mechanistic basis for the dysregulation is unclear. PRL-3 is an oncogenic phosphatase implicated in the development of LSCs. Here, we identified Leo1 as a direct and specific substrate of PRL-3. Serine-dephosphorylated form of Leo1 binds directly to β-catenin, promoting the nuclear accumulation of β-catenin and transactivation of TCF/LEF downstream target genes such as cyclin D1 and c-myc. Importantly, overexpression of PRL-3 in AML cells displayed enhanced sensitivity towards β-catenin inhibition in vitro and in vivo, suggesting that these cells are addicted to β-catenin signaling. Altogether, our study revealed a novel regulatory role of PRL-3 in the sustenance of aberrant β-catenin signaling in AML. PRL-3 may serve as a biomarker to select for the subset of AML patients subset who are likely to benefit from treatment with β-catenin inhibitors. Our study presents a new avenue of cancer inhibition driven by PRL-3 overexpression or β-catenin hyperactivation. Citation Format: Phyllis SY Chong, Jianbiao Zhou, Jing Yuan Chooi, Wee Joo Chng, Jayantha Gunaratne, Qi Zeng. Non-canonical activation of β-catenin by PRL-3 phosphatase in acute myeloid leukemia [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 4374.
Rewiring of cisplatin-resistant bladder cancer cells through epigenetic regulation of genes involved in amino acid metabolism
Authors: Austin Yeon, Sungyong You, Minhyung Kim, Amit Gupta, Myung Hee Park, Daniel J Weisenberger, Gangning Liang, Jayoung Kim
Journal: Theranostics (2018)

Alterations in DNA methylation are important epigenetic markers in bladder cancer (BC). These epigenome modifications may drive the mechanisms of aggressive chemo-resistant BC. Clinicopathological biomarkers that indicate chemotherapeutic resistance are critical for better assessing treatment strategies for individual patients. Thus, in this study, we aimed to determine whether DNA methylation of certain metabolic enzymes is significantly altered in cisplatin-resistant BC cells.