tbuckley/cabot-search huggingface dataset:
Abstract 14064: Institutional Experience With Stability of a VDD Implantable Cardioverter Defibrillator Lead
Authors: Chee Yuan Ng, Guy Rozen, Theofanie Mela, David Milan
Journal: Circulation (2017)

Introduction: The VDD implantable cardioverter defibrillator (ICD) system offers diagnostic information of a dual chamber system via a floating atrial electrode mounted in a single ventricular lead...
Abstract 3297: Prediagnostic circulating concentrations of vitamin D binding protein and survival among colorectal cancer patients
Authors: Chen Yuan, Mingyang Song, Brian M. Wolpin, Jeffrey A. Meyerhardt, Shuji Ogino, Bruce W. Hollis, Andrew T. Chan, Charles S. Fuchs, Kana Wu, Molin Wang, Stephanie A. Smith-Warner, Edward L. Giovannucci, Kimmie Ng
Journal: Cancer Research (2019)

Abstract Higher total 25-hydroxyvitamin D [25(OH)D] levels are associated with an improvement in survival among colorectal cancer (CRC) patients, but the relationships between plasma vitamin D binding protein (VDBP), bioavailable or free 25(OH)D, and CRC survival remain unknown. In two prospective cohort studies, the Health Professionals Follow-Up Study and the Nurses’ Health Study, we examined the association between prediagnostic plasma levels of VDBP, bioavailable 25(OH)D, and free 25(OH)D and survival among 604 participants diagnosed with CRC between 1991 and 2011. Plasma 25(OH)D and VDBP were directly measured, while bioavailable and free 25(OH)D were calculated using a validated formula based on total 25(OH)D, VDBP, and albumin levels. Cox proportional hazards models were used to estimate hazard ratios (HRs) for overall and CRC-specific mortality, adjusted for other prognostic markers and potential confounders. During the follow-up, there were 279 deaths, 177 of which were due to CRC (63%). Higher VDBP levels were associated with a significant improvement in overall and CRC-specific survival (Ptrend=0.005 and 0.02, respectively). Compared to patients in the lowest quartile, those in the highest quartile of VDBP had a multivariable-adjusted HR of 0.61 (95% confidence interval [CI], 0.42-0.89) for overall mortality and 0.56 (95% CI, 0.35-0.92) for CRC-specific mortality. The results remained similar after further adjustment for total 25(OH)D levels. In contrast, no association with overall or CRC-specific mortality was observed for bioavailable or free 25(OH)D levels. In conclusion, higher prediagnostic plasma VDBP levels were associated with improved survival among CRC patients. The clinical utility of VDBP as a prognostic marker warrants further exploration, as well as research into underlying mechanisms of action. Citation Format: Chen Yuan, Mingyang Song, Brian M. Wolpin, Jeffrey A. Meyerhardt, Shuji Ogino, Bruce W. Hollis, Andrew T. Chan, Charles S. Fuchs, Kana Wu, Molin Wang, Stephanie A. Smith-Warner, Edward L. Giovannucci, Kimmie Ng. Prediagnostic circulating concentrations of vitamin D binding protein and survival among colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3297.
A phase I/II study of the anti-programmed cell death-1 (PD-1) antibody AK105 in patients with relapsed or refractory classic Hodgkin lymphoma (cHL).
Authors: Yuqin Song, Jun Zhu, Ningjing Lin, Chen Zhang, Xiaoping Jin, Shuping Xu, Baiyong Li, Yu Xia
Journal: Journal of Clinical Oncology (2019)

e19017 Background: AK105 is a humanized IgG1 mAb that blocks PD-1 binding to PD-L1 allowing T-cells to recognize and kill tumor cells. Key attributes of AK105 include antibody engineering to eliminate Fc mediated effector function, and a slower off-rate on antigen binding resulting in improved receptor occupancy. These features were designed to offer more robust biological effect and enhance anti-tumor activity of AK105. Methods: A multicenter, Phase I/II, single-arm study in relapsed/refractory cHL (NCT03722147) began in July, 2018, evaluating the safety and efficacy of AK105 administered IV q2w till disease progression (response assessed by Lugano 2014 criteria). Eligible pts had relapsed/refractory cHL after most recent therapy with progression after autologous hematopoietic stem cell transplantation, or at least 2 lines of prior chemotherapy. Enrollment for Phase I part of the study was completed, and Phase II at the RP2D of AK105 200 mg q2w is ongoing. Results: As of 1 Feb, 2019, in the Phase I part, 6 Chinese patients (pts) median age 26.5 years [19–38], female 33%, ECOG 0/1 ([67%/33%]), had received a median of 7 (3–12) doses of AK105 200mg q2w. No DLT and SAE were reported. No immune-related grade 2 (G2) or higher adverse reactions were reported. Treatment-related adverse events (TRAEs) occurred in 83% (5/6) of pts (G3 in 17% [1/6], no G4, none leading to treatment interruption or discontinuation). Most frequent TRAEs (≥2 pts) were hypothyroidism (33%, 2/6) and ALT increased (33%, 2/6). PK profile for Chinse pts is consistent with that in Caucasian pts. Of 5 evaluable heavily pretreated pts, ORR was 100% (5/5, 3 CR and 2 PR). All 3 pts achieved CR at the first tumor assessment (i.e., week 8) and remained in CR at the last assessment (i.e., week 24) prior to data cutoff. The other 2 pts achieved PR at week 8 and the responses are still ongoing. Conclusions: The reported safety profile and encouraging early antitumor activity of AK105 supports continued clinical development, which include: pivotal studies in relapsed/refractory cHL and metastatic nasopharyngeal carcinoma, phase 2/3 combination studies with chemotherapy in NSCLC and combination study with anlotinib, a multi-targeting tyrosine kinase inhibitor in hepatocellular carcinoma. Clinical trial information: NCT03722147.
Environmentally Persistent Free Radicals: Linking Air Pollution and Poor Respiratory Health?
Authors: Peter D. Sly, Stephania A. Cormier, Slawomir Lomnicki, Jeffrey N. Harding, Keith Grimwood
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Epidemiological relations between exposure to air pollution (both indoor and outdoor) and adverse respiratory outcomes, are examined. Although oxidative stress (OS) is presumed to be involved, a direct culprit is lacking. A proposal of a recently recognized by-product of thermal and combustion process that is capable of inducing OS as the missing link between exposure and respiratory disease, is presented. These products are called environmentally persistent free radicals (EPFRs). However, EPFRs persist in both the environment and biological systems for prolonged periods of time. An increasing number of studies are demonstrating the presence of EPFRs in a variety of environmental settings which include traffic-related air pollution (TRAP), coal dust and other combustion residues.
Strategies to Avoid the “Hemolyzed” Physical Examination—Reply
Authors: Zaven Sargsyan
Journal: JAMA Internal Medicine (2019)

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Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study
Authors: Udai Banerji, Carla M L van Herpen, Cristina Saura, Fiona Thistlethwaite, Simon Lord, Victor Moreno, Iain R Macpherson, Valentina Boni, Christian Rolfo, Elisabeth G E de Vries, Sylvie Rottey, Jill Geenen, Ferry Eskens, Marta Gil-Martin, Ellen C Mommers, Norbert P Koper, Philippe Aftimos
Journal: The Lancet Oncology (2019)
Abstract 19492: Successful Reversed Polarity Defibrillation With the Wearable Cardioverter Defibrillator
Authors: Nicole Bianco, Steven J Szymkiewicz
Journal: Circulation (2015)

Introduction: Published literature suggests that switching the direction of the external defibrillation pathway does not impact the efficacy of the shock. Consequently, the European Resuscitation Council Guidelines for Resuscitation 2010 states that it does not matter, for defibrillation success, which electrode is placed in either position. The primary objective of this study was to evaluate if these results are consistent for the asymmetrical electrodes of a wearable defibrillator, which uses two large posterior and one apical self-gelling defibrillator electrodes. Methods: Six swine were fibrillated and defibrillated at each energy level (75J, 100J, 125J, or 150J) during apex-posterior defibrillation comparing an initially positive apex electrode (standard) with an initially negative apex electrode (reversed) using a customized wearable cardioverter defibrillator (WCD, LifeVest®, ZOLL). The first three swine received the standard shocks first, while the last three swine received the reversed shocks first. If the first shock did not convert the rhythm, rescue shocks were delivered by either the WCD at 150J or an external defibrillator at 200J until conversion took place. Shock success and ECGs were recorded for all shocks. Fisher’s exact test was used to determine P-values. Results: Six swine were studied (average wt = 28.3 ± 3.0 kg, range: 24.0-31.8 kg). All energy levels (75J, 100J, 125J, and 150J) were tested at least once using both normal and reversed electrodes on all pigs. The first-shock results (excluding the rescue shocks) are shown in the figure below. No animal died from irreversible VF, asystole, or pulseless electrical activity during the study. No differences in defibrillation success were found to be significant at any energy level. Conclusions: In this animal model of VF, the polarity of the apex-posterior shocks did not influence transthoracic defibrillation success by the asymmetric electrodes of the WCD.
PKM2 expression as biomarker for resistance to oxaliplatin-based chemotherapy in colorectal cancer
Authors: M. Sfakianaki, C. Papadaki, M. Tzardi, M. Trypaki, S. Manolakou, I. Messaritakis, Z. Saridaki, D. Mavroudis, V. Georgoulias, J. Souglakos
Journal: Annals of Oncology (2019)
HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers
Authors: Bilon Khambu, Nazmul Huda, Xiaoyun Chen, Daniel J. Antoine, Yong Li, Guoli Dai, Ulrike A. Köhler, Wei-Xing Zong, Satoshi Waguri, Sabine Werner, Tim D. Oury, Zheng Dong, Xiao-Ming Yin
Journal: Journal of Clinical Investigation (2019)

Autophagy is important for liver homeostasis, and the deficiency leads to injury, inflammation, ductular reaction (DR), fibrosis, and tumorigenesis. It is not clear how these events are mechanistically linked to autophagy deficiency. Here, we reveal the role of high-mobility group box 1 (HMGB1) in two of these processes. First, HMGB1 was required for DR, which represents the expansion of hepatic progenitor cells (HPCs) implicated in liver repair and regeneration. DR caused by hepatotoxic diets (3,5-diethoxycarbonyl-1,4-dihydrocollidine [DDC] or choline-deficient, ethionine-supplemented [CDE]) also depended on HMGB1, indicating that HMGB1 may be generally required for DR in various injury scenarios. Second, HMGB1 promoted tumor progression in autophagy-deficient livers. Receptor for advanced glycation end product (RAGE), a receptor for HMGB1, was required in the same two processes and could mediate the proliferative effects of HMBG1 in isolated HPCs. HMGB1 was released from autophagy-deficient hepatocytes independently of cellular injury but depended on NRF2 and the inflammasome, which was activated by NRF2. Pharmacological or genetic activation of NRF2 alone, without disabling autophagy or causing injury, was sufficient to cause inflammasome-dependent HMGB1 release. In conclusion, HMGB1 release is a critical mechanism in hepatic pathogenesis under autophagy-deficient conditions and leads to HPC expansion as well as tumor progression.
Abstract 2835: Breast tumor microbiota populations are modulated by chemotherapy and may be indicative of outcome
Authors: Akiko Chiba, Alaa Bawaneh, Christine Velazquez, Edward Levine, Katherine L. Cook
Journal: Cancer Research (2019)

Abstract Breast tumors were identified to have their own microbiota population distinct from mammary gland tissue. Breast cancer patients that present in the clinic with larger tumors often undergo neo-adjuvant chemotherapy to reduce tumor burden before surgery. The purpose of our study was to evaluate whether chemotherapy can modulate the tumor microbiome and the potential impact of microbes in the development of distant metastases. Using snap-frozen aseptically collected breast tumor tissue from women that underwent neo-adjuvant chemotherapy or women with no prior therapy at time of surgery, we performed 16S rRNA sequencing to identify tumoral bacterial populations. We also stained breast tumor microarrays (normal breast tissue, primary breast tumor, and lymph node metastases) to confirm presence of identified microbiota. Our data indicates that chemotherapy administration significantly increased breast tumor Pseudomonas and reduced the proportional abundance of Streptococcus. Primary breast tumors from patients that developed distant metastases later on in life (regardless of therapy) displayed increased tumoral abundance of Acinetobacter, Brevundimonas, and Staphylococcus. Stratifying patients based upon BMI indicates that obesity modulates breast tumor microbiota populations and needs to be considered in analyses. Furthermore, we confirm presence of Pseudomonas in breast tumor tissue by immunohistochemical staining. Our results indicate breast tumor microbiota populations can be modified by chemotherapy and specific microbes correlate with tumor recurrence. Further studies with a larger patient cohort may provide greater insights into the role of microbiota in therapeutic outcome and for the development of novel bacterial biomarkers that could predict distant metastases. Citation Format: Akiko Chiba, Alaa Bawaneh, Christine Velazquez, Edward Levine, Katherine L. Cook. Breast tumor microbiota populations are modulated by chemotherapy and may be indicative of outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2835.
Post-transplant cyclophosphamide in matched and haploidentical transplant recipients receiving myeloablative timed sequential busulfan conditioning regimen: Results of a phase II study.
Authors: Uday R. Popat, Rohtesh S. Mehta, Roland Bassett, Amanda Leigh Olson, Amin Majid Alousi, Paolo Anderlini, Gheath Alatrash, Qaiser Bashir, Stefan O. Ciurea, Chitra Hosing, Partow Kebriaei, Issa F. Khouri, David Marin, Yago Nieto, Betul Oran, Katayoun Rezvani, Muzaffar H. Qazilbash, Elizabeth J. Shpall, Richard E. Champlin, Borje Andersson
Journal: Journal of Clinical Oncology (2019)

7007 Background: Myeloablative stem cell transplants have a lower rate of relapse than reduced intensity regimens. Timed sequential busulfan (TSB) with fludarabine (Flu) is a promising myeloablative regimen for patients undergoing matched sibling (MSD) or unrelated (MUD) donor transplantation (HCT) with low non-relapse mortality (NRM) (Popat et al Lancet Haematology 2018), but was not tested in haploidentical (haplo). Also, whether this approach can be used with post-transplant cyclophosphamide (PTCy) in MSD, MUD and haplo HCT is unknown. To address these issues, we conducted a prospective phase II study. Methods: Patients with hematological malignancies with MSD, MUD or haplo donor were eligible. They received fixed doses of Busulfan(BU) 80mg/m2 either on day -13 and -12 (n=45) or on -20 and -13 (n=10). Then, Flu 40mg/m2 was given on day -6 to -2 followed by Bu dosed to achieve target area under the curve (AUC) of 20,000 umol/min for the whole course based on pharmacokinetic studies. Thiotepa 5mg/kg was given on day -7 to haplo group. GVHD prophylaxis was PTCy 50mg/kg on day 3 and 4 and tacrolimus. Haplo and later MUD recipients also received mycophenolate mofetil. Results: 55 patients with a median age of 47 (15-65) years were enrolled. 30 patients had AML or MDS, 9 CML or MPD, 5 lymphoma, 5 myeloma and 6 ALL. About half had haplo 26 (47%); others had MUD 18 (33%) or MSD 11(20%). Disease risk index was high in 18 (32%), intermediate in 32 (58%), and low in 5 (9%) patients. Comorbidity score was ≥3 in 22 (40%) patients. With a median follow up of 17 months (5-28), 1-year OS, PFS, NRM and relapse rates were 71% (60-84%), 63% (51-77%), 20% (9-31%), and 17% (7-27%), respectively [Table]. There were no graft failures. Day 100 grade II-IV and III-IV acute GVHD rates were 38% (25-51%) and 9% (95% CI 1-17%), respectively; 1-year chronic GVHD and extensive chronic GVHD rates were 10% (2-28%) and 8% (0-15%), respectively. 1-year OS in MSD, MUD and haplo groups were 91% (75-100%), 72% (54-96%), and 62% (45-83%) respectively (P=0.11). Conclusions: Myeloablative TSB with PTCy is feasible in MSD, MUD and haplo HCT. It lowers the incidence of severe acute and chronic GVHD without apparent increase in relapse. Clinical trial information: NCT02861417. [Table: see text]
Nucleolin : Another role as a receptor of Acharan sulfate
Authors: EunJi Joo, Hui Yang, Kiyoshi Suzuki, Takeshi Ishimaru, Koji Yamamoto, YeongShik Kim
Journal: Cancer Research (2008)

4750  Acharan sulfate(AS), isolated from the giant African snail Achatina fulica, is a novel glycosaminoglycan similar to heparin or heparan sulfate. AS has a unique structure composed of α-D-N-acetylglucosaminyl (1◊4) 2-sulfoiduronic acid and has showed biologically diverse functions such as antiangiogenic, anticoagulant, antimitogenic activity and immunomodulating action. In previous study, we have reported that exogenous AS decreased tumor size in Lewis lung carcinoma(LLC)-bearing C57BL/6 mice and was located on the tumor cell surface. We have focused on the cell surface proteins among AS-binding proteins and characterized nucleolin from LLC. To identify cell surface nucleolin in various tumor cells, we prepared AS affinity column and applied the biotinylated lysates of those cells to the column. Expectedly, we confirmed cell surface nucleolin of 110 kDa and fragmented 80 kDa by anti-nucleolin antibody and horseradish peroxidase conjugated streptavidin. To investigate how AS influences on A549 human lung carcinoma and its nucleolin, we treated AS according to the concentration- and time-dependent manners in both serum free and serum containing conditions. Under the stimulation of AS, the expression of total nucleolin slightly increased. But the amount of 110 kDa-intact nucleolin decreased when treated with the AS sample preincubated with heparin and serum. Also, by immunocytochemistry using anti-nucleolin antibody, we verified that AS encouraged the translocation of nucleolin from nucleus to membrane. These results elucidate AS directly binds to cell surface nucleolin and influences on the movement of nucleolin for tumor inhibition. Our studies demonstrate that nucleolin might be a novel functional receptor for Acharan sulfate in tumor cells.
Abstract 158: A Tether Containing a UBX Domain (TUG) Mediates Glucose Transporter Translocation in the Ischemic Heart
Authors: Ji Li, Yina Ma, Jonathan Bogan
Journal: Circulation Research (2017)

Introduction: The adaptive metabolic regulation of glucose and fatty acid in the heart plays a critical role in limiting cardiac damage caused by ischemia and reperfusion (I/R). TUG (tether containing a UBX domain, for GLUT4) can be cleaved to mobilize glucose transporter GLUT4 from intracellular vesicles to the cell surface in skeletal muscle and adipose in response to insulin stimulation. The energy sensor AMP-activated protein kinase (AMPK) plays an important cardioprotective role in response to ischemic insults by modulating GLUT4 translocation. Hypothesis: TUG is one of the downstream targets of AMPK in the heart. TUG could be phosphorylated by ischemic AMPK and cleaved to dissociate with GLUT4 and increase GLUT4 translocation in the ischemic heart. Methods: In vivo regional ischemia by ligation of left anterior coronary artery and ex vivo isolated mouse heart perfusion Langendorff system were used to test the hypothesis. Results: Antithrombin (AT) is an endogenous AMPK agonist in the heart and used to define the role of TUG in regulating GLUT4 trafficking during ischemia and reperfusion in the heart. AT showed its cardioprotective function through recovering cardiac pumping function and activating AMPK. The results showed that AMPK activation by AT treatment was through LKB1 and Sesn2 complex. Furthermore, the ex vivo heart perfusion data demonstrated that AT administration significantly increase GLUT4 translocation, glucose uptake, glycolysis and glucose oxidation during ischemia and reperfusion (p&lt;0.05 vs . vehicle). Moreover, AT treatment increased abundance of a TUG cleavage product (42 KD) in response to I/R. The TUG protein was clearly phosphorylated by activated AMPK in HL-1 cardiomyocytes. The in vivo myocardial ischemia results demonstrated that ischemic AMPK activation triggers TUG cleavage and significantly increases GLUT4 translocation to the cell surface. Moreover, an augmented interaction between AMPK and TUG was observed during ischemia. Conclusions: Cardiac AMPK activation stimulates TUG cleavage and causes the dissociation between TUG and GLUT4 in the intracellular vesicles. TUG is a critical mediator that modulates cardiac GLUT4 translocation to cell surface and enhances glucose uptake by AMPK signaling pathway.
Abstract 14779: A Deletion Polymorphism in Interferon Regulatory Factor 2 Binding Protein 2 That Confers Risk for Coronary Atherosclerosis Disrupts Binding of RNA-Binding Proteins Following Innate Immune Activation
Authors: Ragnar O Vilmundarson, An Duong, Hsiao-Huei Chen, Alexandre F Stewart
Journal: Circulation (2018)

Background: Interferon Regulatory Factor 2 Binding Protein 2 (IRF2BP2) is an anti-inflammatory transcription co-factor in innate immunity. A 9 nucleotide deletion polymorphism in the 3’UTR of IRF2B...