tbuckley/cabot-search huggingface dataset:
Nerve-targeted probes for fluorescence-guided intraoperative imaging
Authors: Dina V Hingorani, Michael A Whitney, Beth Friedman, Joong-Keun Kwon, Jessica L Crisp, Qing Xiong, Larry Gross, Christopher J Kane, Roger Y Tsien, Quyen T Nguyen
Journal: Theranostics (2018)

A fundamental goal of many surgeries is nerve preservation, as inadvertent injury can lead to patient morbidity including numbness, pain, localized paralysis and incontinence.Nerve identification during surgery relies on multiple parameters including anatomy, texture, color and relationship to surrounding structures using white light illumination.We propose that fluorescent labeling of nerves can enhance the contrast between nerves and adjacent tissue during surgery which may lead to improved outcomes.Methods: Nerve binding peptide sequences including HNP401 were identified by phage display using selective binding to dissected nerve tissue.Peptide dye conjugates including FAM-HNP401 and structural variants were synthesized and screened for nerve binding after topical application on fresh rodent and human tissue and in-vivo after systemic IV administration into both mice and rats.Nerve to muscle contrast was quantified by measuring fluorescent intensity after topical or systemic administration of peptide dye conjugate.Results: Peptide dye conjugate FAM-HNP401 showed selective binding to human sural nerve with 10.9x fluorescence signal intensity (1374.44 ± 425.96) compared to a previously identified peptide FAM-NP41 (126.17 ± 61.03).FAM-HNP401 showed nerve-to-muscle contrast of 3.03 ± 0.57.FAM-HNP401 binds and highlight multiple human peripheral nerves including lower leg sural, upper arm medial antebrachial as well as autonomic nerves isolated from human prostate.Conclusion: Phage display has identified a novel peptide that selectively binds to ex-vivo human nerves and in-vivo using rodent models.FAM-HNP401 or an optimized variant could be translated for use in a clinical setting for intraoperative identification of human nerves to improve visualization and potentially decrease the incidence of intra-surgical nerve injury.
Abstract LB-348: Negative roles of C/EBPα in MDSC-mediated tumor angiogenesis and immune suppression
Authors: Peng Qu, Yongfen Min, Li Yang, Charles Lin
Journal: Cancer Research (2018)

Abstract Myeloid-derived suppressor cells (MDSCs) are highly increased in peripheral blood of cancer patients, as well as tumor bearing animal models. These cells have long been known to suppress the host immune response to cancer. In the present study, we found that CCAAT/enhancer binding protein alpha (C/EBPα) expression was significantly reduced in MDSCs from tumor-bearing mice compared to non-tumor-bearing hosts. Tumor-conditioned medium down-regulated C/EBPα expression, suggesting tumor secreted factors inhibiting the gene expression. Consistent with the function of C/EBPα in regulating the balance between proliferation and growth arrest in hematopoietic progenitors, the specific deletion of C/EBPα on myeloid lineage resulted in distinctly enhanced the proliferation and expansion of MDSCs, as well as an increase of myeloid progenitors and a decrease of other mature cells. In addition, the deletion of C/EBPα in MDSCs enhanced the pro-angiogenic, immune suppressive and pro-tumorigenic behavior of these cells by upregulating the production of iNOS and arginase, as well as MMP-9 and VEGF. Accordingly, tumors growing in C/EBPα conditional null mice displayed greater MDSC infiltration, increased vascularization and accelerated tumor growth. Taken together, this study reveals dual negative roles of C/EBPα in the expansion as well as pro-angiogenic and immune suppressive functions in MDSCs. Citation Format: Peng Qu, Yongfen Min, Li Yang, Charles Lin. Negative roles of C/EBPα in MDSC-mediated tumor angiogenesis and immune suppression [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 LB-348.
Abstract 2672: Phyllanthusmins induce apoptosis and reduce tumor burden in high grade serous ovarian cancer by late-stage autophagy inhibition
Authors: Alexandria N. Young, Denisse Herrera, Andrew Huntsman, Daniel D. Lantvit, Melissa A. Korkmaz, Leslie N. Aldrich, A. Douglas Kinghorn, James R. Fuchs, Joanna E. Burdette
Journal: Cancer Research (2018)

Abstract High grade serous ovarian cancer (HGSOC) is a lethal gynecological malignancy with a need for new therapeutics. Many of the most widely used chemotherapeutic drugs are derived from natural products or their semi-synthetic derivatives. We developed potent synthetic analogues of a class of compounds known as the phyllanthusmins, inspired by natural products isolated from Phyllanthus poilanei Beille. The most potent analogue, PHY34, had the highest potency in HGSOC cell lines in vitro and displayed cytotoxic activity through activation of apoptosis. PHY34 exerts its effects by initially inhibiting autophagy at a late stage in the pathway, involving the disruption of lysosomal function. The autophagy activator, rapamycin, combined with PHY34 eliminated apoptosis, suggesting that autophagy inhibition was required for apoptosis. PHY34 was readily bioavailable through intraperitoneal administration in vivo where it significantly reduced cancer cell lines grown in hollow fibers as well as ovarian tumor burden. We show that PHY34 is a new late-stage autophagy inhibitor with nanomolar potency and significant antitumor efficacy as a single-agent against HGSOC in vivo. This class of compounds holds promise as a potential, novel chemotherapeutic and demonstrates the effectiveness of targeting the autophagic pathway as a viable strategy for combating the disease. Citation Format: Alexandria N. Young, Denisse Herrera, Andrew Huntsman, Daniel D. Lantvit, Melissa A. Korkmaz, Leslie N. Aldrich, A. Douglas Kinghorn, James R. Fuchs, Joanna E. Burdette. Phyllanthusmins induce apoptosis and reduce tumor burden in high grade serous ovarian cancer by late-stage autophagy inhibition [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 2672.
Publisher Correction: Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer
Authors: Jingjing Chen, Ilaria Guccini, Diletta Di Mitri, Daniela Brina, Ajinkya Revandkar, Manuela Sarti, Emiliano Pasquini, Abdullah Alajati, Sandra Pinton, Marco Losa, Gianluca Civenni, Carlo V. Catapano, Jacopo Sgrignani, Andrea Cavalli, Rocco D’Antuono, John M. Asara, Andrea Morandi, Paola Chiarugi, Sara Crotti, Marco Agostini, Monica Montopoli, Ionica Masgras, Andrea Rasola, Ramon Garcia-Escudero, Nicolas Delaleu, Andrea Rinaldi, Francesco Bertoni, Johann de Bono, Arkaitz Carracedo, Andrea Alimonti
Journal: Nature Genetics (2018)
Abstract 299: A susceptible-quiescent model can describe biphasic cell-kill by MCL1 inhibitor AZD5991in vitro
Authors: Francis D. Gibbons, Matthew Belmonte, Paul Secrist, Alwin Schuller
Journal: Cancer Research (2018)

Abstract AZD5991 is a potent and selective inhibitor of Mcl-1, now in phase 1 clinical development. Mcl-1 is an anti-apoptotic Bcl2-family protein that is up-regulated by cancer cells in order to avoid apoptosis. Disruption of binding of Mcl-1 to pro-apoptotic BH3-only proteins such as Bax and Bak results in loss in cellular viability of several cell-line models of multiple myeloma (MM). As a function of time, many cell lines display a biphasic response, with an initial period of rapid cell kill, followed by a period of slower kill. Such biphasic kill curves are not uncommonly seen in bacteria. As a function of concentration, cell lines display a range of efficacy (extent of cell kill) and potency (concentration of half-maximal cell kill). Here we apply a model originally developed for bacterial cell-kill to parameterize the in vitro cell kill over time and across several orders of magnitude in concentration. Cells from 10 MM cell lines were grown in culture, then plated at uniform density in microtiter plates where they were incubated at concentrations of AZD5991 ranging from 0.3nM to 30µM (with DMSO control), each plate for a duration of 0.5h to 72h. After the desired incubation period, Cell-Titer Glo® was used to assess cellular viability by luminescence. Plates were run in duplicate. A model of cell survival was implemented in MATLAB, in which cells can be in one of two states: a proliferating state ‘S' in which they are susceptible to a saturable concentration-dependent drug-induced cell death, or a quiescent state ‘Q' in which they don't proliferate and have only a constitutive death rate independent of drug concentration. Transition between the two states is possible in either direction. By fitting the model to the data across time and over a wide range of concentrations, we can succinctly and precisely describe the rate of growth and drug-induced cell death, as well as transition between the susceptible and quiescent states. To our knowledge, this represents the first application of such a model to a BH3 mimetic such as AZD5991. We find that the cell lines show much greater variation in efficacy (i.e., maximum inducible cell kill rate) than in potency, suggesting that the main difference between these lines lies in their dependence on Mcl-1 for survival. Citation Format: Francis D. Gibbons, Matthew Belmonte, Paul Secrist, Alwin Schuller. A susceptible-quiescent model can describe biphasic cell-kill by MCL1 inhibitor AZD5991 in vitro [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 299.
Adenosine Modulates Cardiovascular Functions Through Activation of Extracellular Signal-Regulated Kinases 1 and 2 and Endothelial Nitric Oxide Synthase in the Nucleus Tractus Solitarii of Rats
Authors: Wen-YuHo, Pei-JungLu, MichaelHsiao, Hwong-RuHwang, Yu-ChouTseng, Mao-HsiungYen, Ching-JiunnTseng
Journal: Circulation (2008)

Background— The nucleus tractus solitarius (NTS) is the primary integrative center for baroreflex. Adenosine has been shown to play an important modulatory role in blood pressure control in the NTS. Our previous results demonstrated that adenosine decreases blood pressure, heart rate, and renal sympathetic nerve activity and modulates baroreflex responses in the NTS. We also demonstrated that a nitric oxide synthase (NOS) inhibitor may block the cardiovascular effects of adenosine in the NTS, which suggests interaction between the adenosine receptor and NOS. However, the signaling mechanisms of adenosine that induce nitric oxide release in the NTS remain uncertain. The aim of the present study was to investigate the possible signal pathways involved in the cardiovascular regulation of adenosine in the NTS. Methods and Results— Adenosine was microinjected into the NTS of urethane-anesthetized male Sprague-Dawley rats. Blood pressure and heart rate decreased significantly after microinjection. The cardiovas...
Abstract 3746: Targeting adrenal androgen to treat prostate cancer
Authors: Yue Wu, Jianmin Wang, Li Tang, Elena Pop, John J. Stocking, Kristopher M. Attwood, Gary J. Smith
Journal: Cancer Research (2018)

Abstract Background: Adrenal androgens are the most abundant androgens in humans, with dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S) being the major adrenal androgens in circulation. Significantly, adrenal androgens may serve as substrates for intratumoral (intracrine) production of testosterone (T) and/or dihydrotestosterone (DHT), the ligands for androgen receptor (AR). However, adrenal androgens also have functions that are independent of AR. The present study addressed the capability of prostate cancer tissue to use adrenal androgens for T/DHT production, delineated signaling pathways activated by adrenal androgens, and determined whether adrenal androgens sustained tumor growth after androgen-deprivation therapy (ADT). Experimental Procedures: Metabolism of adrenal androgen was evaluated ex vivo using fresh clinical prostate tissue specimens. The production of DHT or DHEA was determined using ELISA. Human prostate cancer cells lines were used for in vitro experiments. The effects of adrenal androgens on tumor growth were evaluated in vivo using xenografts of the human prostate cancer cell line VCaP in castrated or intact mice. Results: 1) Human prostate tissue was able to produce DHT using DHEA-S at a physiologic concentration (3.5 μM). The production of DHT from DHEA-S was absolutely dependent on the activity of steroid sulfatase (STS). DHEA at a physiologic concentration (10 nM) was not a suitable substrate for DHT production, but was used by prostate tissue when available at a supra-physiologic concentration (3.5 μM) to produce DHT. 2) DHEA-S was able to stimulate growth of prostate cancer cells in vitro. The growth stimulatory effect of DHEA-S was mediated by AR-dependent and AR-independent signaling pathways. A subset of the genes modulated specifically by DHEA-S were distinctive from the T-modulated genes. 3) DHEA sustained tumor growth after castration. DHEA-stimulated growth was attributed to activation of the insulin-like growth factor 1 receptor (IGF1R) signaling pathway. Conclusions: Prostate tissue can use adrenal androgens for DHT production. Adrenal androgens may stimulate prostate cancer growth using AR-dependent pathways that are mediated via intratumoral T/DHT production, or using AR-independent signaling pathways such as the IGF1R signaling pathway. Identification of targets and therapeutics to block the adrenal androgen-stimulated pathways may help develop novel strategies to treat prostate cancer. Citation Format: Yue Wu, Jianmin Wang, Li Tang, Elena Pop, John J. Stocking, Kristopher M. Attwood, Gary J. Smith. Targeting adrenal androgen to treat prostate cancer [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 3746.
Abstract 3346: PRMT5-mediated methylation of YBX1 regulates NF-kB activity in colorectal cancer
Authors: Antja-Voy Hartley, Benlian Wang, Masaru Miyagi, Rasika Mundade, James Hamilton, Tao Lu
Journal: Cancer Research (2018)

Abstract Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US with a staggeringly less than 14% survival rate for patients with metastatic disease. This poor clinical outcome for CRC patients is largely attributed to the lack of understanding of the factors that drive CRC progression, leading to a dearth of available treatment strategies for this disease. Today, treatment modalities and clinical management of colorectal cancer (CRC) are fundamentally based on the success of controlling specific tumorigenic pathways. Interestingly, aberrant activation of the transcription factor nuclear factor ĸB (NF-ĸB) is increasingly recognized as a crucial player in CRC progression. Therefore, understanding the mechanisms underlying regulation of NF-ĸB holds great promise for devising new therapeutic strategies for CRC. Recently, we identified the oncogenic protein, Y-box binding protein 1 (YBX1), as a novel activator of NF-κB. Since YBX1 overexpression has also been linked to poor patient outcome in CRC, we sought to further understand whether this YBX1/NF-ĸB axis could be a potential target for CRC treatment. In this study, we discovered that YBX1 is methylated on arginine 205 (YBX1-R205me2), an event that is critical for YBX1-mediated NF-ĸB activation and target gene expression. Additionally, co-immunoprecipitation studies revealed that the R205 to alanine (A) mutant (YBX1-R205A) also significantly diminished the interaction between YBX1 and the p65 subunit of the transcriptionally active NF-ĸB, demonstrating a novel mechanism by which methylation of YBX1 mediates protein-protein interactions. Overexpression of YBX1-R205A significantly attenuated the migration, proliferation, and anchorage-independent growth of a panel of CRC cells, suggesting that YBX1-R205me2 is essential to the oncogenic functions exerted by the YBX1/NF-ĸB axis in CRC. Furthermore, we revealed that protein arginine methyltransferase 5 (PRMT5) is responsible for the methylation of YBX1-R205. Collectively, our novel findings present a complex picture of the sophisticated regulation of NF-ĸB through PRMT5-mediated YBX1-R205 methylation and suggest that pharmacological disruption of the YBX1/NF-κB axis using PRMT5 inhibitors could serve as the basis for new therapeutics that impede YBX1/NF-κB-driven CRC progression. Citation Format: Antja-Voy Hartley, Benlian Wang, Masaru Miyagi, Rasika Mundade, James Hamilton, Tao Lu. PRMT5-mediated methylation of YBX1 regulates NF-kB activity in colorectal cancer [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 3346.
Abstract 151: Phenotypic selection screening reveals Annexin A2 as a pancreatic cancer stem cell target
Authors: Elaine M. Hurt, Matt Flynn, Paul Hynes, M. Carla Cabrera, Suneetha B. Thomas, Lilian van Vlerken-Ysla, Louise Slater, Alan Sandercock, Steven Rust, Ralph Minter, Ronald Herbst
Journal: Cancer Research (2018)

Abstract Cancer stem cells (CSCs) represent an important clinical entity given their role in tumor initiation, metastasis and patient relapse. Phenotypic selection allows for identification of novel antigens important in biological processes. Therefore, we undertook a phenotypic selection campaign using a designed ankyrin-repeat (DARPin) library to identify new cancer stem cell (CSC) targets. CSCs generated from late-stage pancreatic cancer patient-derived xenograft (PDX) models were used to pan a designed Ankyrin repeat (DARPin) library. The most prevalent target identified in this screen was Annexin A2 (ANXA2). ANXA2 is a member of the Annexin family that has diverse roles in cancer including proliferation and invasion and is widely expressed in cancer. Furthermore, expression of ANXA2 is linked to poor prognosis in pancreatic cancer. Targeting of Annexin A2 on the surface of pancreatic cancer cells using DARPins resulted in decreased frequency of CSCs both in vitro and in vivo in several pancreatic patient-derived xenografts. ANXA2 DARPins also reduced proliferation and tumor growth of HPAC cells both in vitro and in vivo. Mechanistically, we found that blocking ANXA2 resulted in decreased IL6 and IL8 secretion, two cytokines that have been linked to CSC expansion and survival. Additionally, we found that pharmacological blockade of ANXA2 resulted in decreased plasmin activation, a pathway that has been linked to dissemination of cancer cells. Together our data suggests that targeting of cell surface ANXA2 is effective at reducing CSCs and could be a novel target for the treatment of pancreatic cancer. Citation Format: Elaine M. Hurt, Matt Flynn, Paul Hynes, M. Carla Cabrera, Suneetha B. Thomas, Lilian van Vlerken-Ysla, Louise Slater, Alan Sandercock, Steven Rust, Ralph Minter, Ronald Herbst. Phenotypic selection screening reveals Annexin A2 as a pancreatic cancer stem cell target [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 151.
Abstract P349: Ambient Air Pollution Compromises Nitric Oxide Bioavailability, Leading to Accelerated Endothelial Cell Senescence
Authors: Nicole Buechner, Ulrich Sydlik, Klaus Unfried, Joachim Altschmied, Judith Haendeler
Journal: Circulation Research (2011)

Particulate matter (PM) pollution is a burden to public health. Although PM causes a health risk to the lung, the overall evidence indicates that the majority of the PM effects are upon the cardiovascular system. Several studies demonstrated that ultrafine particles can directly enter the circulation and thus may interact with endothelial cells. However, intracellular mechanisms affected by non-cytotoxic, in vivo relevant concentrations of particles have not been investigated in endothelial cells in vitro and in vivo. Therefore, this study aims for the first time to analyze the effects of ultrafine and fine particles of different materials in non-toxic concentrations on human endothelial cells (EC) and in animals. We incubated EC with ultrafine and fine Carbon Black (ufCB and fCB) particles as well as Titaniumdioxide (ufTiO2 and fTiO2) and determined the non-toxic concentrations. MTT measurements revealed that 0.1 and 1 µg/cm2 did not reduce endothelial cell viability. To test whether these concentrations influence endothelial cell function, we measured nitric oxide (NO) bioavailability, which is important for vessel function. Only ultrafine particles reduced the S-NO content of EC, whereas fine particles had no effect at the same concentrations. Interestingly, the effects observed with ufCB and ufTiO2 were more pronounced than with the known reducer of NO bioavailability, H2O2. We previously demonstrated that NO increases activation of Telomerase Reverse Transcriptase (TERT), an enzyme essential for telomere maintenance. TERT activation is required to protect EC from apoptosis and the onset of senescence and TERT is inactivated by the Src kinase under conditions of oxidative stress. Therefore, we investigated the effects of ufCB and ufTiO2 on TERT and Src activation. ufCB and ufTiO2 significantly reduced TERT and increased Src kinase activation. To investigate whether ufCB show also effects in vivo, we instilled ufCB into rats and determined eNOS and TERT expression in the aorta. ufCB reduced eNOS and TERT expression in the abdominal aorta of animals treated with ufCB. Thus, ultrafine nanoparticles, which we inhale every day, seem to reduce endothelial function and thus should be considered a risk factor for cardiovascular disease.
Present Status of Electroversion in the Management of Cardiac Dysrhythmias
Authors: Leonresnekov
Journal: Circulation (1973)

The theoretical and practical considerations of electrical reversion of cardiac dysrhythmias are reviewed and a comparison made between AC and DC defibrillation, indicating the superiority of DC under all circumstances. The indications for, immediate and late results of DC shock for atrial and ventricular dysrhythmias are presented, the complication of such treatment reviewed, and the need for anticoagulant cover, anesthesia, and drug therapy preceding and following the electrical treatment discussed. Each patient requires individual assessment, particularly those with chronic rhythm disturbances, especially atrial fibrillation, in whom electrical energy settings in excess of 300 joules are rarely indicated for the risk of complications becomes progressively higher as the energy setting is increased and the length of time sinus rhythm persists in this group of patients may be short. Patients with acute rhythm disturbances, however, with potentially serious hemodynamic consequences should be treated with m...