tbuckley/cabot-search huggingface dataset:
Expression of Human Scavenger Receptor Class B Type I in Cultured Human Monocyte-Derived Macrophages and Atherosclerotic Lesions
Authors: Ken-ichiHirano, ShizuyaYamashita, YumikoNakagawa, TakeshiOhya, FumihikoMatsuura, KosukeTsukamoto, YoshihisaOkamoto, AkifumiMatsuyama, KengoMatsumoto, Jun-ichiroMiyagawa, YujiMatsuzawa
Journal: Circulation Research (1999)

Abstract—The scavenger receptor class B type I (SR-BI) and its human homologue CLA-1 (CD36 and LIMPII Analogous-1) have recently been identified to bind HDL and mediate the selective uptake of HDL lipids. Tissue distribution of both murine and human receptors is quite similar, in that they are expressed abundantly in liver and steroidogenic tissues. However, expression and function of the human SR-BI (hSR-BI), in the periphery of reverse cholesterol transport such as macrophages, are still unclear. In the present study, we have raised two different kinds of anti–hSR-BI polypeptide antibodies (Abs): one against the extracellular domain and the other against the intracellular domain. We have investigated the expression of hSR-BI mRNA and immunoreactive mass in freshly isolated cultured human monocyte-derived macrophages (hMφ) and in atherosclerotic lesions. Contrary to the earlier report, hSR-BI mRNA was expressed in cultured hMφ and markedly upregulated with differentiation, determined by Northern blot and...
Sexual function and satisfaction in Mexican young women undergoing breast cancer treatment.
Authors: Cynthia Mayte Villarreal-Garza, Alejandra Platas, Andrea Castro-Sanchez, Melina Miaja, Alan Fonseca, Yoatzin Vega, Regina Barragan-Carrillo, Alexandra Bukowski, Judy-Anne Williams Chapman, Enrique Bargallo-Rocha, Paul E. Goss, Jessica St. Louis, Alejandro Mohar
Journal: Journal of Clinical Oncology (2017)

e21714 Background: Compared to other regions, the burden of breast cancer (BC) in Mexico is disproportionately borne by younger women. Yet, their particular needs and concerns have remained understudied, including treatment-related sexual adverse effects. We aim to assess the sexual function and satisfaction in Mexican young women with BC undergoing treatment. Methods: This is a prospective sexual assessment study in BC patients of the pilot phase of the Joven y Fuerte Mexican cohort (N=96). Sexual health was assessed using the Female Sexual Function Index (FSFI) and the Sexual Satisfaction Inventory (SSI) at two points in time: baseline (BL) and 6-months follow-up (6-FU). FSFI and SSI scores lower than 26.55 and 111, respectively, were defined as sexual morbidity. Differences between proportions of BL and 6-FU were examined with Pearson chi-square test. Matched t-tests were used to test for differences in the domains of the FSFI and in the SSI total score. Results: 70 women completed the FSFI at both time points and 69 the SSI. Our results showed a high percentage of sexual dysfunction among Mexican women at BL and 6-FU (61.4% and 74.3%, respectively, p&lt;0.001), as well as an elevated proportion of sexual low satisfaction at both time lines (40.6% and 43.5%, p=0.004). Most 6-FU FSFI domain scores were significantly worse than those at BL (Table 1). There were no significant differences in the SSI total score (102.31 [BL] vs 96.11 [6-FU], p=0.16). Conclusions: Mexican young patients with BC report significant sexual morbidity at BL, which even worsens after the first short follow-up. Reasons for the low sexual performance among Mexican women remain understudied and should be actively sought. In this prospective study, data will be annually collected for five years. This information will provide valuable information in an often-neglected matter of BC patients’ care. [Table: see text]
Abstract 17086: Alirocumab LDL-C-Lowering Efficacy in Patients With Moderate CKD
Authors: Peter P Toth, Christopher P Cannon, John J Kastelein, Helen M Colhoun, Andrew Koren, Michael J Louie, Gaëlle Asset, Daniel J Rader
Journal: Circulation (2015)

Background: Patients with chronic kidney disease (CKD) are at increased risk of premature cardiovascular disease. Many of these patients require adjuvant lipid-lowering therapy because of dosing restrictions of some statins in patients with CKD. Objective: To determine LDL-C lowering efficacy and safety of the PCSK9 inhibitor alirocumab (ALI) in patients with hypercholesterolemia and with or without moderate CKD. Methods: This analysis included data from 10 ODYSSEY Phase 3 trials. Moderate CKD was defined as glomerular filtration rate 30-59 mL/min/1.73m 2 . LONG TERM and HIGH FH (n=2448) compared ALI 150 mg every two wks (Q2W) vs placebo. The remaining 6 trials (n=2535) evaluated ALI 75 mg Q2W vs placebo/ezetimibe, with increase to ALI 150 mg Q2W at wk 12 if LDL-C was ≥70 or ≥100 mg/dL at wk 8 depending on CV risk. Patients received stable background statin ± other LLT, except in ALTERNATIVE and MONO (no statin) and COMBO II (statin but no other LLT). Results: Moderate CKD at baseline was present in 481/4983 (9.7%) of patients. Mean baseline LDL-C levels of patients with and without moderate CKD were 109.6 and 127.8 mg/dL, respectively, and 96.9% and 92.7% were receiving a statin. Overall, having moderate CKD did not impact the LDL-C lowering efficacy of ALI (Figure). The smaller LDL-C reduction (vs other studies) seen in alirocumab-treated patients with moderate CKD in the ALTERNATIVE study may be related to low patient number. Adverse events (AEs) were reported by 79.0% ALI vs 81.1% control patients with moderate CKD and 74.7% ALI vs 74.5% control patients without. AEs led to discontinuation in 10.0% ALI vs 8.2% control patients with moderate CKD and 6.0% ALI and 6.6% control patients without. Conclusions: ALI consistently lowered LDL-C levels vs control regardless of baseline moderate CKD status. There was no significant difference in % AEs between patients with and without moderate CKD and a numerically higher rate of discontinuations due to AEs in patients with moderate CKD.
Vasodilatation to Arachidonic Acid in Humans
Authors: KiranBhagat, JoeCollier, PatrickVallance
Journal: Circulation (1995)

Background Human endothelial and vascular smooth muscle cells synthesize prostanoids. Several of these have been implicated in the physiological and pathophysiological regulation of vascular tone; however, there is no direct evidence that human blood vessels synthesize sufficient prostanoid to alter vessel tone. Methods and Results We explored the effects of local infusions of arachidonic acid on the tone of preconstricted superficial hand veins in healthy volunteers. Aspirin was used to assess the contribution of prostanoids to the responses seen. Local infusion of arachidonic acid produced a dose-dependent dilatation of preconstricted veins. This was abolished by local infusion of aspirin. Oral aspirin was also effective: a high (anti-inflammatory) dose of aspirin (1 g) taken 2 hours before the experiment blocked the arachidonic acid–induced venodilatation; however, a low (cardioprotective) dose of aspirin (75 mg) did not. Unlike the responses to arachidonic acid, responses to glyceryltrinitrate and bra...
Abstract 1452: The receptor tyrosine kinase EphA2 promotes glutamine metabolism in tumors by activating the transcriptional coactivators YAP and TAZ
Authors: Deanna N. Edwards, Verra M. Ngwa, Shan Wang, Eileen Shiuan, Dana Brantley-Sieders, Laura Kim, Albert B. Reynolds, Jin Chen
Journal: Cancer Research (2018)

Abstract Malignant tumors reprogram cellular metabolism to support cancer cell proliferation and survival. Although most cancers depend on a high rate of aerobic glycolysis, many cancer cells also display addiction to glutamine. Glutamine transporters and glutaminase activity are critical for glutamine metabolism in tumor cells. We found that the receptor tyrosine kinase EphA2 activated the TEAD family transcriptional coactivators YAP and TAZ (YAP/TAZ), likely in a ligand-independent manner, to promote glutamine metabolism in cells and mouse models of HER2-positive breast cancer. Overexpression of EphA2 induced the nuclear accumulation of YAP and TAZ and increased the expression of YAP/TAZ target genes. Inhibition of the GTPase Rho or the kinase ROCK abolished EphA2-dependent YAP/TAZ nuclear localization. Silencing YAP or TAZ substantially reduced the amount of intracellular glutamate through decreased expression of SLC1A5 and GLS, respectively, genes that encode proteins that promote glutamine uptake and metabolism. The regulatory DNA elements of both SLC1A5 and GLS contain TEAD binding sites and were bound by TEAD4 in an EphA2-dependent manner. In patient breast cancer tissues, EphA2 expression positively correlated with that of YAP and TAZ, as well as that of GLS and SLC1A5. Although high expression or EphA2 predicted enhanced metastatic potential and poor patient survival, it also rendered HER2-positive breast cancer cells more sensitive to glutaminase inhibition. The findings define a previously unknown mechanism of EphA2-mediated glutaminolysis through YAP/TAZ activation in HER2-positive breast cancer and identify therapeutic targets in patients. Citation Format: Deanna N. Edwards, Verra M. Ngwa, Shan Wang, Eileen Shiuan, Dana Brantley-Sieders, Laura Kim, Albert B. Reynolds, Jin Chen. The receptor tyrosine kinase EphA2 promotes glutamine metabolism in tumors by activating the transcriptional coactivators YAP and TAZ [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 1452.
Abstract 2423: Hypoxia regulates tumor cell invasiveness through altered glycosylation
Authors: Gordon Greville, Esther Llop, Rosa Peracaula Miró, Amanda McCann, Pauline M. Rudd, Radka Saldova
Journal: Cancer Research (2018)

Abstract Glycosylation, one of the most fundamental post-translational modifications, is altered in many cancers. These alterations have been proven to impact on the progression of the tumor cell and promote survival. In literature published over the last half century, it is obvious there is a clear link between (a) chemo-resistance and hypoxia (b) hypoxia and epigenetics and more recently (c) glycosylation and epigenetics. We aim to bring these paradigms together with the remit of offering a more complete story and opening up new avenues of approach for the detection, diagnosis and treatment of breast and ovarian cancer. Ovarian and breast cancer cells were exposed to differential hypoxic conditions (0.5%, 1.0%, 2.0%) and normoxia. Firstly, we compared the methylation status of hypoxia exposed cells to the normoxic controls. A combination of hydrophilic interaction liquid chromatography (HILIC) and statistical analyses allowed comparisons of the secreted N-glycans from cells exposed to differential hypoxic conditions. Western blots assessed apoptosis, senescence, autophagy and epithelial to mesenchymal transition. The OrisTM migration assay assessed the migration of the cells pre- and post-differential hypoxic exposure. RT-qPCR was used to measure gene expression of appropriate glycosyltransferases and possible transcription factors (TFs) in these samples to determine any associations with changes seen in N-glycosylation. There were non-significant trends observed between the percentage oxygen that the cells were exposed to and resultant changes seen in branching and sialylation on secreted N-glycans from the breast and ovarian cancer cell lines. While only some of these changes could be explained by RT-qPCR data, GATA2/3 transcripts, identified in-silico as possible TFs, have been shown to significantly correlate with ST3GAL4 and MGAT5 glycosyltransferases, respectively. Hypoxia exposed cells also displayed increased migration with a greater effect seen in the 0.5% hypoxia exposed samples. The GATA2 and GATA3 transcription factors are gaining popularity in recent years, with links to cancer stage, increased invasiveness and as possible therapeutic targets. Our recent data shows a strong correlation between GATA2 and GATA3 and the levels of glycosyltransferases involved in branching and sialyation. These glycan changes are known to be strongly involved in cancer cell survival and metastases. Here for the first time we may have a possible mechanism of action linking GATA2 and 3 and invasiveness of breast and ovarian cancer cells. Citation Format: Gordon Greville, Esther Llop, Rosa Peracaula Miró, Amanda McCann, Pauline M. Rudd, Radka Saldova. Hypoxia regulates tumor cell invasiveness through altered glycosylation [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 2423.
Abstract 18304: Are Prolonged Resuscitation Efforts Worthwhile? Patient Outcomes by Time to Restoration of Spontaneous Circulation in Out-of-Hospital Cardiac Arrest Patients
Authors: Kristian Kragholm, Monique Anderson, Carolina Malta Hansen, Phillip J. Schulte, Michael C. Kurz, Emil L. Fosbol, Shahzleen Rajan, Mads Wissenberg, Ian Stiell, Graham Nichol, Eric Peterson
Journal: Circulation (2015)

Introduction: How long resuscitation attempts should be continued before termination of efforts is not clear in patients with out-of-hospital cardiac arrest (OHCA). We studied outcomes in patients with return of spontaneous circulation (ROSC) across quartiles of time from 9-1-1 call to ROSC. Hypothesis: Survival with favorable neurological outcome is seen in all time intervals from 9-1-1 call to ROSC. Methods: Using data from Resuscitation Outcomes Consortium (ROC) Prehospital Resuscitation clinical trials: IMpedance valve and an Early vs. Delayed analysis (PRIMED) available via National Institute of Health, patients with ROSC not witnessed by the emergency medical service (EMS) were identified and grouped by quartiles of time from 9-1-1 call to ROSC. We defined favorable neurological outcome as modified Rankin Scale (mRS) scores of ≤3. Results: Included were 3,431 OHCA patients with ROSC. Median time from 9-1-1 call to ROSC was 22.8 min (25%-75% 17 min–29.2 min); 953 (27.8%) survived to discharge (20.4% mRS ≤3). Significant survival and favorable neurological outcome were seen in each quartile (Figure). In patients who received bystander cardiopulmonary resuscitation (CPR), survival rates were 60.9%, 33.2%, 18.3% and 11.1% across quartiles of time to ROSC versus (vs.) 51.5%, 25.6%, 13.3% and 8.9% in patients without bystander CPR; corresponding rates of favorable neurological outcome were 50.7%, 23.8%, 12.2% and 9.1% vs. 40.1%, 16.6%, 8% and 4.8%. Correspondingly, survival rates in defibrillated patients were 70.1%, 45.9%, 25.5% and 16.4% vs. 36.3%, 9.5%, 6% and 3.4% in non-defibrillated patients; corresponding rates of favorable neurological outcome were 59.8%, 33.4%, 18.3% and 11.4% vs. 24.4%, 4.1%, 1.9% and 1.8%. Conclusions: Survival with favorable neurological outcome was seen in all quartiles of time to ROSC, even in cases without bystander CPR or shocks delivered. This suggests that EMS personnel should not terminate resuscitation efforts too early.
Abstract 2721: Selective FcγR engagement by CTLA-4 antibodies results in increased functional activity
Authors: Jeremy D. Waight, Dhan Chand, Sylvia Dietrich, Randi Gombos, Thomas Horn, Ana M. Gonzalez, Mariana Manrique, Antoine Tanne, Christopher Dupont, Lukasz Swiech, Ben A. Croker, Jennifer S. Buell, Robert Stein, Alex Duncan, David A. Savitsky, Nicholas S. Wilson
Journal: Cancer Research (2018)

Abstract Therapeutic antibodies targeting T cell co-inhibitory pathways, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1), have emerged as an important class of cancer therapies. Insights into how different IgG isotypes modulate biological activities of antibodies have opened new avenues to enhance their therapeutic effects. For example, Fc-FcγR interactions have been shown to enhance antibody-directed effector cell activities, as well as antibody-dependent forward signaling into target cells via receptor clustering. Here, we describe a novel FcγR-dependent mechanism for antibodies targeting CTLA-4. Our findings suggest that selective Fc-FcγR binding dramatically improves the quality of the immune synapse, which in turn modifies apical T cell receptor signaling events to increase effector T cell activity. Our data also suggest that subsets of antigen-presenting cells (APCs), expressing FcγRIV in mice and FcγRIIIA in humans are important mediators of this effect. Importantly, we find this mechanism to be independent of regulatory T cell (Treg) depletion. Altogether, we describe a novel mechanism of action that provides a foundation for a new class of Fc-engineered antibodies to enhance antitumor immune responses. Citation Format: Jeremy D. Waight, Dhan Chand, Sylvia Dietrich, Randi Gombos, Thomas Horn, Ana M. Gonzalez, Mariana Manrique, Antoine Tanne, Christopher Dupont, Lukasz Swiech, Ben A. Croker, Jennifer S. Buell, Robert Stein, Alex Duncan, David A. Savitsky, Nicholas S. Wilson. Selective FcγR engagement by CTLA-4 antibodies results in increased functional activity [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 2721.
CAR T-cell Integration of Multiple Input Signals Allows for Precise Targeting of Cancer
Authors: Daniela Achkova, Martin Pule
Journal: Cancer Discovery (2018)

Abstract Summary: Chimeric antigen receptor (CAR)–mediated adoptive T-cell therapy has achieved unprecedented success in the treatment of relapsed and refractory hematologic malignancies. However, this success may be more difficult to recapitulate in the treatment of metastatic solid tumors, where the lack of costimulatory signals and cytokine support as well as the strongly inhibitory microenvironment pose a substantial challenge to unleashing the antitumor potential of CAR T cells. Furthermore, nearly all described target antigens are expressed on normal tissue. In this issue of Cancer Discovery, Sukumaran and colleagues address these challenges by engineering T cells to recognize a specific expression pattern unique to the tumor site using independent chimeric molecules that cooperatively deliver a fully functional T-cell response selectively in the tumor microenvironment. Cancer Discov; 8(8); 918–20. ©2018 AACR. See related article by Sukumaran et al., p. 972.
Concordance assessment of a clinical decision support software in patients with solid tumors.
Authors: Harit Suwanrusme, Surasit Issarachai, Theera Umsawasdi, Suthida Suwanvecho, Wimolrat Decha, Irene Dankwa-Mullan, Ching-Kun Wang, Alexandra Urman, Narongsak Kiatikajornthada
Journal: Journal of Clinical Oncology (2018)

e18584 Background: IBM Watson for Oncology (WFO) is a clinical decision support software that uses natural language processing (NLP) to assist providers to make expeditious treatment decisions. This study expands on a pilot assessing the degree of concordance between treatment recommendations provided by oncologists at Bumrungrad International Hospital (BIH) and WFO at the point of care (Concordance assessment of a cognitive computing system in Thailand 2016, Suwanvecho et al). This study incorporates additional cancer types and new cancer cases from patients seen and treated in 2017. Methods: Clinical data from patients treated at BIH from January to December 2017 were entered into WFO. 264 retrospective cases were entered after a treatment plan had been determined and 326 prospective cases were entered during patients’ treatment planning sessions at the point of care. WFO treatment recommendations were provided in 3 categories: “Recommended”, “For Consideration” and “Not Recommended.” Concordance was analyzed by comparing oncologists’ decisions to WFO recommendations. Concordance was met when the oncologist’s treatment decision was in the WFO “Recommended” or “For Consideration” categories. Results: A total of 590 cases were assessed for concordance. The overall concordance rate for the retrospective cases was 81%; 78% for bladder, 70% for breast, 56% for cervical, 90% for colon, 82% for gastric, 93% for lung, 79% for ovarian, 82% for prostate and 94% for rectal. Similarly, the overall concordance rate for the prospective cases was 80%; 75% for bladder, 72% for breast, 78% for cervical, 95% for colon, 71% for gastric, 87% for lung, 63% for ovarian, 86% for prostate and 76% for rectal. Conclusions: The results are similar to those observed in the 2015-2016 pilot. Both showed a high degree of concordance between WFO treatment options and the decisions made by BIH oncologists. Discordance, in order of frequency, from highest to lowest, was attributable to BIH oncologists' preferences, including favoring non-U.S. guidelines for certain cancers, patient preferences, including toxicity, cost and logistic concerns. Other reasons for non-concordance included recommended U.S. treatment options not available in Thailand.
Abstract 5134: Desacetylvinblastine monohydrazide disrupts tumor vessels by promoting VE-cadherin internalization
Authors: Minfeng Chen, Xueping Lei, Wencai Ye, Dongmei Zhang
Journal: Cancer Research (2018)

Abstract Vinca alkaloids, the well-known tubulin-binding agents, are widely used for the clinical treatment of malignant tumors. However, little attention has been paid to their vascular disrupting effects, and the underlying mechanisms remain largely unknown. This study aims to investigate the vascular disrupting effect and the underlying mechanisms of vinca alkaloids. Methods: The capillary disruption assay and aortic ring assay were performed to evaluate the in vitro vascular disrupting effect of desacetylvinblastine monohydrazide (DAVLBH), a derivate of vinblastine, and the in vivo vascular disrupting effect was assessed on HepG2 xenograft model using magnetic resonance imaging, hematoxylin and eosin staining and immunohistochemistry. Tubulin polymerization, endothelial cell monolayer permeability, western blotting and immunofluorescence assays were performed to explore the underlying mechanisms of DAVLBH-mediated tumor vascular disruption. Results: DAVLBH has potent vascular disrupting activity both in vitro and in vivo. DAVLBH disrupts tumor vessels in a different manner than classical tubulin-targeting VDAs; it inhibits microtubule polymerization, promotes the internalization of vascular endothelial cadherin (VE-cadherin) and inhibits the recycling of internalized VE-cadherin to the cell membrane, thus increasing endothelial cell permeability and ultimately resulting in vascular disruption. DAVLBH-mediated promotion of VE-cadherin internalization and inhibition of internalized VE-cadherin recycling back to the cell membrane are partly dependent on inhibition of microtubule polymerization, and Src activation is involved in DAVLBH-induced VE-cadherin internalization. Conclusions: This study sheds light on the tumor vascular disrupting effect and underlying mechanisms of vinca alkaloids and provides new insight into the molecular mechanism of tubulin-targeting VDAs. Key words: Vascular disrupting agents; vinca alkaloids; desacetylvinblastine monohydrazide; tubulin polymerization; VE-cadherin internalization Citation Format: Minfeng Chen, Xueping Lei, Wencai Ye, Dongmei Zhang. Desacetylvinblastine monohydrazide disrupts tumor vessels by promoting VE-cadherin internalization [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 5134.
Abstract 18426: Improved Aerobic Capacity up to a Year Following an Exercise Intervention in Patients Undergoing Aortic Valve Replacement for Aortic Stenosis
Authors: Kristofer Hedman, Sabina Borg, Eva Nylander, Éva Tamás
Journal: Circulation (2016)

Introduction: In the RASP (Rehabilitation in Aortic Stenosis Patients) study, we investigate effects of supervised exercise compared to physical activity recommendations on aerobic capacity (peakVO...