tbuckley/cabot-search huggingface dataset:
Abstract 168: Remote Ischemic Preconditioning Rescues Cardiac Dysfunction in Atg5 Knockdown Mice
Authors: Fangfei Wang, Quan He, Andrew N Redington
Journal: Circulation Research (2019)

Objective: Remote ischemic pre-conditioning (RIPC) is highly cardioprotective in models of ischemia-reperfusion (IR) injury but has not been tested in genetically modified mice. This study was design to test whether RIPC rescues cardiomyopathy induced by knockdown of autophagy-related 5 protein (Atg5). Approach and Results: Atg5 knockdown was induced by feeding tamoxifen diet for two weeks in Atg5 flox/flox Cre +/- (KD) mice which were created by crossing Atg5 flox/flox and heterozygous cardiac-specific Cre recombinase transgenic (Cre +/- ) mice. Atg5 flox/flox Cre -/- mice served as controls (CONT). Cardiac function was evaluated by echocardiography 28 days after tamoxifen induction. Autophagy proteins were determined by Western blot analysis. RIPC was induced by four cycles of five minutes of hind limb ischemia with tourniquet followed by five minutes reperfusion. Tamoxifen feeding knocked down Atg5 to 32% (CONT 0.91 ± 0.09 vs KD 0.29 ± 0.01, p &lt; 0.01, n = 7), leading to 96% decrease of autophagy activity indicated by LC3-II/LC3-I ratio (CONT 0.96 ± 0.07 vs 0.06 ± 0.03, p &lt; 0.01, n = 7). This was associated with significant cardiac dysfunction (LV ejection fraction, CONT 59.78% ± 3.26 vs KD 47.13% ± 2.50, n = 8 and 10, p &lt; 0.01) and increased heart weight to body weight ratio (CONT 0.50 ± 0.02 vs KD 0.57 ± 0.01, n = 8 and 10, p &lt; 0.01). RIPC increased levels of Atg5 in Atg5 KD mice by 183% (Sham 1.00 ± 0.16 vs RIPC 1.83 ± 0.14, p &lt; 0.01, n = 11 and 13), leading to 148% increase of autophagy activity (Sham 0.99 ± 0.13 vs RIPC 1.47 ± 0.18, p &lt; 0.05, n = 6 and 7), and resulted in rescued cardiac function in terms of heart weight (CONT 0.50 ± 0.01 vs KD 0.53 ± 0.10, n = 11 and 13 ) and LV ejection fraction (CONT 55.64% ± 2.45 vs 52.48% ±1.61, n = 11 and 13). RIPC also suppressed mTOR phosphorylation by 62% compared with sham procedure in Atg5 KD mice (Sham 1.00 ± 0.18 vs RIPC 0.45 ± 0.08 p &lt; 0.01 n = 11 and 13) which was increased by 650% in Atg5 KD compared with CONT mice (CONT 1.23 ± 0.14 vs KD 6.35 ± 0.09, p &lt; 0.01, n = 7). Conclusion: We conclude that RIPC rescues Atg5 knockdown-induced cardiomyopathy. Our data adds to the emerging data suggesting benefits of RIPC beyond acute cardioprotection in IR injury.
Anticoagulation With an Inhibitor of Factors XIa and XIIa During Cardiopulmonary Bypass
Authors: Valérie Pireaux, Joël Tassignon, Stéphanie Demoulin, Sandrine Derochette, Nicolas Borenstein, Angélique Ente, Laurence Fiette, Jonathan Douxfils, Patrizio Lancellotti, Michel Guyaux, Edmond Godfroid
Journal: Journal of the American College of Cardiology (2019)

Exposure of blood to polyanionic artificial surfaces, for example, during cardiopulmonary bypass (CPB), induces a highly procoagulant condition requiring strong anticoagulation. Unfractionated heparin (UFH) is currently used during CPB but can lead to serious bleeding complications or development of a hypercoagulable state culminating in life-threatening thrombosis, highlighting the need for safer antithrombotics. Ixodes ricinus contact phase inhibitor (Ir-CPI) is a protein expressed by I. ricinus ticks, which specifically inhibits both factors XIIa and XIa, 2 factors contributing to thrombotic disease while playing a limited role in hemostasis. This study assessed the antithrombotic activity of Ir-CPI in animal contact phase-initiated thrombosis models, including CPB. The safety of Ir-CPI also was evaluated. The authors evaluated the antithrombotic activity of Ir-CPI by using in vitro catheter-induced clotting assays and rabbit experimental models of catheter occlusion and arteriovenous shunt. During CPB with cardiac surgery in sheep, the clinical applicability of Ir-CPI was investigated and its efficacy compared to that of UFH using an uncoated system suitable for adult therapy. Taking advantage of the similar hemostatic properties of pigs and humans, the authors performed pig liver bleeding assays to evaluate the safety of Ir-CPI. Ir-CPI prevented clotting in catheter and arteriovenous shunt rabbit models. During CPB, Ir-CPI was as efficient as UFH in preventing clot formation within the extracorporeal circuit and maintained physiological parameters during and post-surgery. Unlike UFH, Ir-CPI did not promote bleeding. Preclinical animal models used in this study showed that Ir-CPI is an effective and safe antithrombotic agent that provides a clinically relevant approach to thrombosis prevention in bypass systems, including highly thrombogenic CPB.
Treatment Intensification of Traditional BFM Therapy with 3 Chemotherapy Blocks and Double Delayed Intensification (Protocol II) Improves Outcome in Infants with High Risk (HR) Acute Lymphoblastic Leukemia (ALL): Results of Two Consecutive AIEOP Studies.
Authors: Carmelo Rizzari, Maria Grazia Valsecchi, Paola De Lorenzo, Maurizio Aricò, Giuseppe Basso, Franco Locatelli, Luca Lo Nigro, Giulio De Rossi, Giuseppe Masera, Andrea Biondi
Journal: Blood (2005)
Abstract 110: Role of Beclin1 in Regulating Parkin-mediated Mitophagy
Authors: Eileen R Moreno, Mark A Lampert, Rita H Najor, Åsa B Gustafsson
Journal: Circulation Research (2019)

Autophagy is a cellular quality control mechanism involved in the selective elimination of damaged organelles and cytotoxic protein aggregates. Beclin1 is a component of the PI3 kinase complex that initiates autophagy in cells. Here, we have investigated the role of Beclin1 in autophagosome formation and Parkin-mediated mitophagy. Using Beclin1-deficient mouse embryonic fibroblasts (MEFs), we found that autophagosomes are still formed in the absence of Beclin1 in response to various treatments known to induce autophagy (FCCP, nutrient deprivation, rapamycin). Autophagic flux is also intact in the Beclin1-/- MEFs, indicating an alternative mechanism of autophagy is induced. Next, we examined whether elimination of mitochondria via autophagy (mitophagy) was intact in Beclin1-/- MEFs. Unexpectedly, we observed that Parkin-mediated mitophagy was significantly reduced in the absence of Beclin1. We confirmed that Parkin was recruited to depolarized mitochondria in both WT and Beclin1-/- MEFs which correlated with increased ubiquitination of mitochondrial proteins. However, high resolution imaging revealed that autophagosomes failed to sequester mitochondria that had been labeled by Parkin. We observed that Parkin was degraded in Beclin1-/- MEF’s, but not WT, after mitochondrial stress. We also found that Beclin1 selectively localized as discrete puncta on Parkin-positive mitochondria suggesting a potential role for Beclin1 in linking mitochondria to autophagosomes. In contrast to our findings in MEFs, characterization of autophagy in mice with cardiac specific deletion of Beclin1 revealed that these hearts had a reduced number of autophagosomes which correlated with a reduction in autophagic flux as indicated by accumulation of cytosolic LC3I and p62. Beclin1-deficient hearts also had significantly reduced Parkin protein levels without changes in mRNA levels, suggesting an impairment in mitophagy. Overall, these findings suggest Beclin1 is required for the proper targeting of mitochondria into autophagosomes and that the adult heart is dependent on Beclin1 to induce formation of autophagosomes.
Abstract 544: microRNA181c Activates Mitochondrial Calcium Uptake by Regulating Micu1 in the Heart
Authors: Hemanth Banavath, Barbara Roman, Brian O'Rourke, Mark Kohr, Elizabeth Murphy, Charles Steenbergen, Samarjit Das
Journal: Circulation Research (2019)

Translocation of miR-181c into heart-mitochondria downregulates the mitochondrial gene, mt-COX1. miR-181c/d -/- hearts experience less oxidative stress during I/R and are protected against I/R injury. Additionally, miR-181c overexpression can increase mitochondrial matrix Ca 2+ ([Ca 2+ ] m ); the mechanism is unknown. By RNA-Seq, here we show that hearts from miR-181c/d -/- mice overexpress nuclear-encoded Ca 2+ regulatory genes, suggesting that alterations in miR-181c and mt-COX1 perturb mitochondria-to-nucleus retrograde signaling and [Ca 2+ ] m regulation. qPCR validation of transcription factors that are known to initiate retrograde signaling revealed significantly higher Sp1 expression in the miR-181c/d -/- hearts. Furthermore, an association of Sp1 with the promoter region of MICU1 was confirmed by ChIP-qPCR and higher expression of MICU1 was found in the miR-181c/d -/- hearts. Conversely, downregulation of Sp1 by siRNA decreased MICU1 expression in NMVM. Changes in PDH activity provided evidence for a change in [Ca 2+ ] m via the miR-181c/MICU1 axis. Moreover, this mechanism was implicated in the pathology of I/R injury. When MICU1 was knocked down in the miR-181c/d -/- heart by lentiviral expression of an shRNA against MICU1, cardioprotective effects against I/R injury were abrogated. Furthermore, using an in vitro I/R model in miR-181c/d -/- NMVM, we confirmed the contribution of Sp1-MICU1 in ischemic injury. In summary, miR-181c regulates mt-COX1, which in turn regulates MICU1 through the Sp1-mediated mitochondria-to-nucleus retrograde pathway. Loss of miR-181c can protect the heart from I/R injury by modulating [Ca 2+ ] m through the upregulation of MICU1.
Abstract 869: Cysteine-based Redox Regulation of Soluble Guanylyl Cyclase
Authors: Chuanlong Cui, Maryam Alapa, Ping Shu, Vlad Kholodovych, Hong Li, Annie V Beuve
Journal: Circulation Research (2019)

Soluble guanylyl cyclase (GC1) is the major receptor of nitric oxide (NO) and a key regulator for cardiovascular physiology. NO binding to the heme of GC1 catalyzes conversion of GTP to cGMP, which in turn activates protein kinase G pathway, thus leading to vasodilation. However, the mechanism by which NO signaling is propagated within the GC1 molecule for its stimulation is still poorly understood. The high frequency of solvent-exposed cysteines (Cys) of GC1 suggests a potential role of Cys posttranslational modifications (PTMs) in regulating GC1 activity. Our previous studies show that the disulfide reductase Thioredoxin 1 (Trx1) can interact with GC1 and affect its activity in cells. Together with studies showing that GC1 activity is modulated by thiol redox, we hypothesize that thiol/disulfide switch might be a mechanism that regulates the activity of GC1. Here we show that dithiol oxidant diamide can dose-dependently affect the activity of GC1. PEG-switch assay, LC/MS/MS and mutational analysis identified Cys involved in redox regulation of GC1. In addition, we show that Trx1 modulates Cys-based redox PTMs of GC1 in cells and blocking the interaction between Trx1 and GC1 affects GC1 activity in a purified system. Taken together, these results suggest that the thiol/disulfide switch of GC1 and its interaction with Trx1 could be an underlying mechanism for NO stimulation of GC1.
T Regulatory Cell Receptor Repertoire Focusing and Clonal Expansion Indicates Control of Acute GvHD after Donor Lymphocyte Infusion
Authors: Christian R Schultze-Florey, Leonie Kuhlmann, Solaiman Raha, Ivan Odak, Saleh Tavil, Melanie Drenker, Elke Dammann, Lothar Hambach, Steve Ehrlich, Michael Stadler, Michael Heuser, Felicitas Thol, Reinhold Foerster, Arnold Ganser, Immo Prinz, Christian Koenecke
Journal: Blood (2018)
Trends in the use of novel hormonal agents at the end of life in metastatic castration-resistant prostate cancer.
Authors: Jason Hu, Armen G. Aprikian, Marie Vanhuyse, Alice Dragomir
Journal: Journal of Clinical Oncology (2019)

40 Background: The approval of novel hormonal agents (NHAs), abiraterone and enzalutamide, have increased the therapeutic arsenal available in metastatic castration-resistant prostate cancer (mCRPC). However, the use of chemotherapy and other antineoplastics at the end of life has been suggested as an indicator of poor quality of care. In this study, we report the use of NHAs at the end of life in men with mCRPC in the province of Quebec, Canada. Methods: Using Quebec public healthcare administrative databases, we identified patients with prostate cancer who used an NHA (abiraterone or enzalutamide) after androgen deprivation therapy and who died between 2012 and 2016. The primary outcome was the use of an NHA in the 30 days before death. Use of an NHA in the 60 and 90 days before dying, and initiation (first prescription) of an NHA in the 30 days before death were evaluated as secondary outcomes. Multivariable analysis of the primary outcome was performed with logistic regression with results reported as odds ratios (OR) with 95% confidence intervals (95%CI). Results: The cohort consists of 1316 patients who used an NHA over the course of their disease and died at a median age of 78 years old, with 292 (22.2%), 464 (35.3%), and 575 (43.7%) having used an NHA in the 30, 60 and 90 days of life, respectively. Use of NHA 30 days before dying decreased over the study period, from 44.8% in 2012 to 17.0% in 2016 (Cochran-Armitage test p-value &lt; 0.001). On multivariable analyses, later years of death remained associated with lower odds of NHA use 30 days before death (OR 0.74, 95%CI 0.66 to 0.81, p &lt; 0.001). Fifty-eight (4.4%) patients initiated a NHA 30 days before dying. Conclusions: Rates of NHA use 30 days before dying were high initially but decreased over the study period. Further assessment of NHA use at the end of life is warranted to examine if the trend will be maintained given the recent approval of additional oral NHAs for prostate cancer.
Genetic Evidence for Involvement of Human Endogenous Retrovirus Herv-Fc1 in the Pathogenesis of MPNs
Authors: Vibe Skov, Katrine LM Schmidt, Kasper Mønsted Pedersen, Bettina Hansen, Tobias Wirenfeldt Klausen, Torben A Kruse, Mads Thomassen, Lasse Kjær, Christina Ellervik, Morten Holmstrøm, Bjørn Nexø, Hans Carl Hasselbalch, Magdalena J Laska
Journal: Blood (2018)
Connexin-43 Mediates Fcγ Receptor-Induced Calcium Signaling by Acting as an NAD/Cyclic ADP-Ribose Transporter.
Authors: Eun-Kyung Song, Young-Rae Lee, Hong-Nu Yu, So-Young Rah, Uh-Hyun Kim, Seun-Jin Lee, Jong-Suk Kim, Myung-Kwan Han
Journal: Blood (2007)
Autologous Expanded Natural Killer Cells As a New Therapeutic Option for High-Risk Myeloma
Authors: Tarun K. Garg, Junaid Khan, Susann Szmania, Amy D Greenway, Joshuah D Lingo, Amberly Moreno-Bost, Katie Stone, Antje Hoering, Emily Woods, Bijay Nair, William Bellamy, Dario Campana, Shmuel Yaccoby, Bart Barlogie, Joshua Epstein, Frits van Rhee
Journal: Blood (2011)
A novel tool to monitor adherence to oral oncolytics: A pilot study.
Authors: Wendy Sun, Rebecca Reeve, Timothy Ouellette, Martha Stutsky, Rachel De Jesus, Michael J Huffer, Sarah Schellhorn Mougalian
Journal: Journal of Clinical Oncology (2019)

286 Background: Non-adherence is an important issue in cancer care as more oral cytotoxic and targeted agents become available. Although oral therapies may be more convenient for patients, measuring and optimizing adherence is challenging. The Nomi system records real-time medication taking behavior from a "smart" prescription bottle and displays the data on a web-based interface. Nomi can also communicate with patients via text message to intervene in cases of non-adherence. We report the results of a 28-patient pilot study aiming to assess Nomi’s ability to assist patients taking capecitabine, an oral chemotherapy agent with a complex, cyclical regimen. Methods: Eligible patients were prescribed capecitabine for breast, colorectal, pancreatic, or biliary cancer. The study had a pre-intervention stage, during which patients were monitored, and an intervention stage, in which the text messaging feature was enabled. Adherence was defined as the number of correct doses (both timing and quantity) over the total number of prescribed doses. Conversions were events in which patients took a dose after receiving a text intervention (from Nomi). We defined three categories of patients by percent change in adherence: category 1 ( &gt; 8%), category 2 (-8% to 8%), and category 3 ( &lt; -8%). Results: We collected data from 28 patients (24 pre/post and 4 pre-only). On average, patients were 84% adherent (N = 28; SD = 11%). During pre-intervention, patients had a self-adherence of 89% (SD = 12%), and afterwards, they had an average adherence of 90% (SD = 6%). Most of the patients in category 1 demonstrated a substantial conversion rate ( &gt; 35%). Patients in category 1 tended to live in regions with lower average household income (Mean = $58,937) than those in category 2 (Mean = $77,482) and category 3 (Mean = $90,972). Of survey respondents, 56% indicated that they would want to continue using Nomi, while 67% indicated that they would recommend it to others. Conclusions: This innovative technology is able to monitor, measure and intervene for patients taking capecitabine in real-time. Adherence overall was high, and some patients appeared to benefit more from text message interventions. Future work should focus on patients deemed high risk for non-adherence.
Pilot study to assess a pharmacist- and medication navigator-led intervention of oral anticancer medication (OAM) adherence.
Authors: Mingqian Lin, Douglas W. Hackenyos, Susan K. Parsons, Angie Mae Rodday, Rachel Murphy-Banks, Ruth Ann Weidner, Nicole Savidge
Journal: Journal of Clinical Oncology (2019)

58 Background: While advances in OAM make treatment more convenient for patients, OAM must be taken and handled correctly. Studies show gaps in patients’ knowledge of taking/handling OAM, suboptimal adherence, and worse outcomes. A prior study at our institution showed low patient understanding of OAM taking (30%) and handling (15%). Other pharmacist (RPh)- or nurse-led interventions have included patient education, short-term follow-up, and reminder tools. No studies have examined multisession interventions co-led by an RPh and medication navigator (MN). This ongoing pilot study assesses the feasibility of such an intervention, its impact on patients’ understanding and adherence, and patient acceptability. Methods: Patients at our institution met with an RPh and MN for an education and teach-back session at OAM initiation (T1). Patients were given a Drug Information Sheet and Medication Calendar as educational tools. Patients were then invited to enroll in a multisession intervention, including an RPh-led re-education at the first refill (T3) and MN-led boosters (T2, T4). At each session, teach-back responses were recorded and participants completed study measures and evaluations. Preliminary results on T1 and T2 are presented. Results: To date, 37 (95%) patients enrolled at T1 and 33 completed the MN-led booster a week later (T2). At T1 and T2, 85% of participants demonstrated sufficient understanding of OAM taking and handling. However, despite high levels of self-reported adherence, 48% lacked knowledge about when or where to get a refill. At T1 (32%) and T2 (60%), of patients raised issues that were not previously shared with their clinical team. Patients were highly satisfied with the intervention and found the education session, booster, and educational tools useful. Conclusions: While data collection is ongoing, preliminary results suggest this intervention is feasible, enhances patient understanding and adherence to their medications, and is acceptable to patients undergoing OAM treatment. Integration of RPh and MN into oncology teams can enhance care delivery and provide timely assistance for OAM-related issues, providing insight into future models of care.
Development of Donor Cell Derived Leukemia After Allogeneic Stem Cell Transplant
Authors: Sairah Ahmed, Antonio Di Stasi, Elizabeth J. Shpall, Issa F. Khouri, Amin M. Alousi, Stefan O. Ciurea, Qaiser Bashir, Muzaffar Qazilbash, Roy B. Jones, Yago Nieto, Simrit Parmar, Partow Kebriaei, Nina Shah, Katy Rezvani, Chitra M Hosing, Betul Oran, Michael Andreeff, Paolo Anderlini, Borje S Andersson, Richard E Champlin, Uday Popat
Journal: Blood (2013)
Improving pregnancy screening prior to chemo: An institutional approach.
Authors: Brittany Kayla Rogers, Merry Jennifer Markham
Journal: Journal of Clinical Oncology (2019)

252 Background: Screening appropriate female patients of childbearing potential for pregnancy prior to cancer therapy is crucial, but who and when to screen is unclear. Prior institutional data revealed low screening rates (35% of eligible women, with medical oncology performing 7% of screening) and less than half within two weeks of treatment. A QI intervention was implemented in the outpatient infusion center by adding screening to the infusion nurses’ (IC RN) pre-chemo checklist. If a patient was deemed eligible for screening, the RN could utilize a standing order for a urine pregnancy test. Following intervention, screening rates for medical oncologists improved but remained low (30.6%). Methods: A second PDSA cycle was initiated by surveying medical oncologists and IC RNs on screening practices and perceived barriers. Results: Survey response rates were 42.8% (9/21) for IC RNs, 53.3% (8/15) for oncologists. 50% of oncologists felt the screening age should be 18-50 vs. 37.5% for 18-45 vs. 12.5% for 18-55. 50% of medical oncologists felt that screening should occur the same day of chemo. Only 12.5% of oncologists reported "always" verifying a negative test prior to chemo, with 37.5% verifying "most", 25% “half", and 25% verifying "some” of the time. 62.5% of oncologists felt menopause should be an exclusion. 100% of IC RNs felt a negative test should be obtained the same day. 87.5% of IC RNs "always" confirm a negative test before chemo. Most IC RNs felt menopause should an exclusion (75%) and this would not increase IC RNs’ workload (87.5%). The barriers for screening are reported below. Conclusions: This survey was useful to identify barriers in our pregnancy screening QI initiative. Clearly defining patients (age 18-50), time frame for screening (same day) and excluding for menopause are manageable changes to decrease nurse workload and increase rates closer to our goal of 80%. Modification of the IC RN checklist will occur based on these results. [Table: see text]