tbuckley/cabot-search huggingface dataset:
Abstract 16349: Influenza Activity is Associated With Hospitalizations for Heart Failure- Results From the Atherosclerosis Risk in Communities Study
Authors: Sonja Kytomaa, Sheila Hegde, Orly Vardeny, Brian Claggett, Jacob Udell, Scott Solomon
Journal: Circulation (2018)

Introduction: Influenza is associated with an increased risk of cardiovascular events, yet few studies have explored the temporal association between influenza activity and hospitalizations, especi...
T Cell Receptor Gene Transfer into Naive and Central Memory Lymphocytes by Lentiviral Vectors for a Safe and Effective Adoptive Immune Therapy of Leukemia
Authors: Elena Provasi, Oscar Muniz Pello, Zulma Magnani, Jurgen Kuball, Angelo Lombardo, Attilio Bondanza, Philip D. Gregory, Claudio Bordignon, Michael C. Holmes, Phil D. Greenberg, Luigi Naldini, Chiara Bonini
Journal: Blood (2008)
SNP Array Karyotyping Improves Detection Rate of Clonal Chromosomal Abnormalities in Refractory Anemia with Ringed Sideroblasts.
Authors: Theodore Ghazal, Lukasz P. Gondek, Abdo S. Haddad, Karl S. Theil, Mikkael A. Sekeres, Alan Lichtin, Jaroslaw P. Maciejewski
Journal: Blood (2007)
KLF4 inhibition promotes the expansion of keratinocyte precursors from adult human skin and of embryonic-stem-cell-derived keratinocytes
Authors: Nicolas O. Fortunel, Loubna Chadli, Julien Coutier, Gilles Lemaître, Frédéric Auvré, Sophie Domingues, Emmanuelle Bouissou-Cadio, Pierre Vaigot, Sophie Cavallero, Jean-François Deleuze, Paul-Henri Roméo, Michèle T. Martin
Journal: Nature Biomedical Engineering (2019)
Why do payers refuse to fund "effective" therapies?
Authors: Henry Jacob Conter, Parneet Kaur Cheema
Journal: Journal of Clinical Oncology (2019)

6 Background: The pan-Canadian Oncology Drug Review (pCODR) provides funding recommendations to the provinces of Canada on Health Canada approved systemic therapies. Why would they recommend against funding drugs that meet regulatory standards? Methods: 136 reviews for 70 compounds were completed by pCODR from inception to January 1, 2019 were collected and data abstracted using a standardized form. For all submissions that received a negative recommendation, the Clinical Guidance Panel (CGP), Economic Guidance Panel (EGP), and Expert Review Committee (pERC) reports were examined to determine the underlying cause for rejection. Results: 32 (24%) of submissions received a negative recommendation. In all cases, this was due to concerns regarding the clinical effectiveness of the compound. Economic considerations were never cited as rational for rejection. 10 (32%) were submitted with supporting evidence from non-comparative phase 2 clinical data, and this level of evidence was cited as the basis for the recommendation. 4 (12%) supported by randomized phase 2 evidence were rejected in support of awaiting phase 3 trials in progress. 6 phase 2-based recommendations have since been overturned on re-submission with phase 3 data. Of the 18 (56%) rejected with phase 3 data, 4 had demonstrated an overall survival advantage over standard of care (range 1.5-3.8 months) that was deemed not clinically significant. 12 were rejected due to lack of confidence in surrogate end-points employed in the trial. 1 was rejected due to diminishing clinical benefit observed over time, and 1 was rejected due to data quality. The EGP calculated the median cost-effectiveness of the proposed indications to be $188,537/QALY (range 22,326-2,120,433), with a median cost increase of $47,529 (2,536-226,752) and life-years gained of 3.8 months (0.8-11). Conclusions: Regulatory approval does not translate to clinically meaningful effectiveness. Bodies that consider opportunity cost may have a higher threshold for minimum benefit than regulators.
High Response Rates to Bortezomib-Dexamethasone Followed by Donor Lymphocyte Infusions in Patients with Multiple Myeloma Relapsing After Allogeneic Stem Cell Transplantation: Results of a Multicentric Prospective Phase II Study
Authors: Vittorio Montefusco, Francesco Spina, Francesca Patriarca, Massimo Offidani, Benedetto Bruno, Lucia Farina, Alessandra Sperotto, Mara Morelli, Anna Dodero, Luisa Giaccone, Renato Fanin, Pinuccia Valagussa, Paolo Corradini
Journal: Blood (2011)
SF3B1 Mutant Clones From Patients With Refractory Anaemia With Ringed Sideroblasts (RARS) Originate From The Early Haematopoietic Stem Cells and Maintain Their Engraftment Potential
Authors: Syed A Mian, Kevin Rouault-Pierre, Alexander E Smith, Thomas Seidl, Austin G Kulasekararaj, Azim M Mohamedali, Sneha Shinde, Dominique Bonnet, Ghulam J. Mufti
Journal: Blood (2013)
Clinical and Prognostic Features of Essential Thrombocythemia: Comparison of Who 2001 Versus Who 2008/2016 Criteria in a Large Single Center Cohort
Authors: Sofia Chiatamone Ricci, Maria Antonietta Arleo, Stefania Trasarti, Cristina Santoro, Massimo Breccia, Luisa Bizzoni, Ida Carmosino, Marco Mancini, Erminia Baldacci, Matteo Molica, Daniela De Benedittis, Giulia Ciotti, Elena Mariggiò, Sara Mohamed, Maria Lucia De Luca, Giacinta Pistilli, Annalisa Mancuso, Chiara Lisi, Daniela Diverio, Marco Vignetti, Robin Foà, Roberto Latagliata, Antonietta Ferretti
Journal: Blood (2018)
Abstract 112: Endogenous-Antigen-Specific T Cell Receptor Activation of CD4+ T Cells in the Heart is Required for Maladaptive Cardiac Remodeling Due to Pressure Overload
Authors: Njabulo Ngwenyama, Francisco Carrillo-Salinas, Mark Aronovitz, Annet Kirabo, David G Harrison, Pilar Alcaide
Journal: Circulation Research (2019)

Cardiac pressure overload is associated with an adaptive immune response that drives maladaptive cardiac remodeling. CD4+ T cells are activated and expanded specifically in the heart-draining mediastinal lymph nodes (mLNs) and infiltrate the left ventricle (LV) in response to transverse aortic constriction (TAC). However, the specific mechanisms triggering T cell activation during the progression of TAC-induced HF remain unknown. We hypothesized that T cell receptor (TCR)-dependent activation of CD4+ T cells by endogenous antigens initiates and sustains maladaptive cardiac remodeling during the progression of TAC induced HF. We evaluated TCR mediated CD4+ T cell activation in the LV of Nur77 GFP mice, which transiently express GFP exclusively upon TCR stimulation. Strikingly, we found LV-infiltrated GFP + CD4+ T cells that increased in number as maladaptive remodeling and cardiac dysfunction progressed in response to TAC. Next generation sequencing of LV-sorted GFP + CD4+ T cells after 8 weeks of TAC revealed a limited repertoire of TCR clones relative to the periphery, demonstrating a restricted CD4+ T cell response to endogenous antigens. We further assessed the requirement for endogenous antigens by immunizing OT-II transgenic mice, which exclusively express a TCR specific for exogenous chicken ovalbumin (OVA), with OVA in the onset of TAC. While OVA induced CD4+ T cell activation and infiltration into the LV, this was not sufficient to induce cardiac dysfunction, demonstrating the importance of an endogenous antigen-specific response. Reactive isolevuglandins (IsoLGs) are formed during oxidative stress, and rapidly adduct to self-proteins forming endogenous neoantigens that elicit CD4+ T cell activation. We treated mice with the IsoLG scavenger 2-hydroxybenzylamine (2-HOBA) in the onset of TAC, which significantly reduced accumulation of IsoLG-protein adducts in dendritic cells, prevented CD4+ T cell activation in the mLNs, and prevented cardiac dysfunction. Thus, our results demonstrate that CD4+ T cell recognition of endogenous antigens in the LV, including IsoLG-protein adducts, via the TCR is required for maladaptive cardiac remodeling and cardiac dysfunction in pressure overload-induced HF.
Current trends in drug metabolism and pharmacokinetics
Authors: Yuhua Li, Qiang Meng, Mengbi Yang, Dongyang Liu, Xiangyu Hou, Lan Tang, Xin Wang, Yuanfeng Lyu, Xiaoyan Chen, Kexin Liu, Ai-Ming Yu, Zhong Zuo, Huichang Bi
Journal: Acta Pharmaceutica Sinica B (2019)

Pharmacokinetics (PK) is the study of the absorption, distribution, metabolism, and excretion (ADME) processes of a drug. Understanding PK properties is essential for drug development and precision medication. In this review we provided an overview of recent research on PK with focus on the following aspects: (1) an update on drug-metabolizing enzymes and transporters in the determination of PK, as well as advances in xenobiotic receptors and noncoding RNAs (ncRNAs) in the modulation of PK, providing new understanding of the transcriptional and posttranscriptional regulatory mechanisms that result in inter-individual variations in pharmacotherapy; (2) current status and trends in assessing drug-drug interactions, especially interactions between drugs and herbs, between drugs and therapeutic biologics, and microbiota-mediated interactions; (3) advances in understanding the effects of diseases on PK, particularly changes in metabolizing enzymes and transporters with disease progression; (4) trends in mathematical modeling including physiologically-based PK modeling and novel animal models such as CRISPR/Cas9-based animal models for DMPK studies; (5) emerging non-classical xenobiotic metabolic pathways and the involvement of novel metabolic enzymes, especially non-P450s. Existing challenges and perspectives on future directions are discussed, and may stimulate the development of new research models, technologies, and strategies towards the development of better drugs and improved clinical practice.
Abstract 622: Load-Independent Systolic Dysfunction and Altered Z-Disc Protein Phosphorylation in Swine with Stretch-Induced Myocardial Stunning
Authors: Brian R Weil, Sailee Rasam, Filip Konecny, Cody Smith, Jun Qu, John M Canty
Journal: Circulation Research (2019)

Objective: We recently demonstrated that a transient rise in left ventricular (LV) preload leads to a reversible reduction in LV ejection fraction in the absence of ischemia (“stretch-induced stunning”). The present study was designed to determine whether this phenomenon is characterized by impaired load independent LV systolic function and alterations in sarcomeric protein phosphorylation. Methods: Swine (n=9) received a 1 hour infusion of phenylephrine (PE; 18 mg/hour iv) to transiently elevate LV end-diastolic pressure (EDP). Load independent systolic function was derived from LV pressure volume loops collected during inferior vena cava occlusion at baseline and 30 min after PE (Transonic SciSense). In a subset of animals (n=5), LV tissue was collected 1 hour after PE for TMT-labeled, LC-MS-based quantitative phosphoproteomics using Orbitrap. Results: PE elicited a rise in LV EDP (9±2 to 29±3 mmHg, p&lt;0.01), followed by a reduction in LV ejection fraction and LV dP/dt max 30 min later. At this time, load independent indices of LV systolic function tended to exhibit a reduced slope with a significant rightward shift of the volume-axis intercept (V 0 ), indicative of decreased contractility ( Table ). This was accompanied by altered phosphorylation of 16 sarcomeric Z disc proteins at 27 phosphosites, including increased phosphorylation of α actinin, α crystallin B chain, desmin, and myotilin. Conclusions: Stretch-induced stunning following transient preload elevation is characterized by load independent systolic dysfunction. Phosphoproteomics implicate alterations in Z disc protein phosphorylation as a mechanism underlying contractile dysfunction in this condition.
Planetary health: from concept to decisive action
Authors: Montira J Pongsiri, Sam Bickersteth, Cristina Colón, Ruth DeFries, Mandeep Dhaliwal, Lucien Georgeson, Andrew Haines, Natalia Linou, Virginia Murray, Shahid Naeem, Roy Small, Judit Ungvari
Journal: The Lancet Planetary Health (2019)
Use of remote symptom monitoring with breast cancer survivors using patient reported outcome measures through Epic Mychart.
Authors: Shelby A. Terstriep, James Wacker, Charissa Quinlan, Kiara Pochardt, Ethan M. Basch
Journal: Journal of Clinical Oncology (2019)

208 Background: Electronic patient-reported outcome (PRO) monitoring has been found to improve quality of life and overall survival in patients with metastatic cancer patients during active treatment. There has been limited data using PROs to enhance clinical outcomes in cancer survivorship. This pilot study of breast cancer survivors assessed utilization and satisfaction of proactive PRO symptom and adherence monitoring through an EHR patient portal (EPIC MyChart). Methods: Eighty breast cancer survivors who had completed surgery, chemotherapy, and/or radiation and received a survivorship care plan were randomized 1:1 either to usual care or PRO monitoring. The PRO group received questions from the NIH PROMIS toolkit through EPIC MyChart monthly between visits for 6 months. The triage nurse received an EPIC Inbasket alert if the survivor reported moderate to severe symptoms, had not taken their medication(s), or reported they would like to speak to a nurse. Participants in the control group were assessed for sadness, anxiety and satisfaction with provider communication at their usual follow visits. Results: Of 239 surveys sent out, 214 (90%) were completed. Eighty-five (36%) surveys triggered Inbasket alerts to the nurse. The most common nursing response to alerts was calling the patient for counseling/education. Compared to control, the PRO monitoring group exhibited no difference in satisfaction at 3 months, but had significantly higher scores at 6 months for satisfaction with communication (P=0.005) and monitoring (P=0.002). Anxiety scores did not differ between groups. Conclusions: Remote electronic monitoring of symptoms and adherence through the EHR bet was feasible with high completion rates, improved satisfaction, and did not increase anxiety in breast cancer survivors. Follow up work is assessing PRO monitoring to improve efficiency of following cancer survivors, and implementation of survivorship care plans.
Abstract 162: Liproxstatin-1 Treatment Protects the Myocardium Against I-R Injury By Decreasing VDAC1 Levels and Increasing GPX4 Activity
Authors: Yansheng Feng, Ngonidzashe B Madungwe, Nathalie Tombo, Li Liu, Abdulhafiz Aliagan, Jean C Bopassa
Journal: Circulation Research (2019)

Introduction: Ferroptosis is a non-apoptotic form of cell death characterized by iron-dependent accumulation of lethal lipid reactive oxygen species (ROS) and liproxstatin-1 is a potent inhibitor of ferroptosis. We investigated whether Liproxstatin-1 can protect the heart against ischemia/reperfusion (I/R) injury and determined the mechanism underlying cardioprotection. Methods: Isolated hearts from C57BL/6J mice were subjected to 35 min ischemia followed 120 min reperfusion and treated with Liproxstatin-1 (200nM). Myocardial infarct size was assessed by TTC staining at the end of reperfusion. Mitochondrial integrity was measured by analyzing cristae morphology and ROS production was assessed using Amplex red method. The calcium retention capacity (CRC) required to induce mitochondrial permeability transition pore (mPTP) opening was measured using calcium green dye. The levels of mitochondrial proteins cyclophilin D (CypD), Glutathione peroxidase 4 (GPX4), VDAC1, 2 and 3 were assessed by Western blot. And GPX4 activity was measured using a kit. Results: We found that liproxstatin-1 treatment decreased myocardial infarction size, ROS production, and VDAC1 expression as well as preserved mitochondrial structural integrity by protecting cristae from damage. These mitochondrial effects of liproxstatin-1 were associated with the increase in GPX4 levels and activity. But, we also found that liproxstatin-1 did not affect the CypD, VDAC2, and VDAC3 expression as well as mitochondrial CRC. Conclusion: Together, these results indicate that liproxstatin-1 treatment protects myocardium against I/R injury by increasing GPX4 activity resulting in the decrease in mitochondrial ROS production; preserving mitochondrial structure as well as a decrease in VDAC1 (but not VDAC 2 and 3) expression. Liproxstain-1 cardioprotective action does not involve the regulation of the mPTP opening. These results point to the cardioprotective role of this anti-ferroptosis compound after I/R.
Abstract 734: NF-kB Signaling Regulates Mitochondrial Permeability Transition Pore Opening of Cardiac Myocytes via Cyclophilin D (CypD) Modulation
Authors: Lorrie A Kirshenbaum, Rimpy Dhingra, Matthew Guberman, Victoria Margulets, Floribeth Aguilar
Journal: Circulation Research (2019)

Nuclear Factor-κB (NF-κB) is ubiquitously present transcription factor that regulates a variety of cellular functions including cell survival. Herein, we show a critical role for NF-κB signaling in regulation of mitochondrial permeability transition pore opening (mPTP) of cardiac myocytes that involves cyclophilin D (CypD). Cardiac myocytes expressing a kinase defective form of IKKβ (IKK K-M ), the principle IKK required for NF-κB activation, displayed impaired NF-κB gene activity. Defects in NF-κB signaling coincided with an increase in mPTP opening and cell death. Interestingly, mPTP opening and cell death observed in the NF-κB defective cardiomyocytes was supressed by inhibition of mPTP modulator CypD, with cyclosporin A (CSA) or by siRNA knock down (CypDsiRNA), suggesting a link between mPTP regulation and NF-κB signaling. Earlier, we reported that doxorubicin (Dox) treatment resulted in severe ultra-structural defects including disrupted mitochondrial cristae and impaired respiration, increased mitochondrial calcium overload, mPTP opening and a widespread cell death. Interestingly, we observed a dramatic reduction in NF-κB signaling in cardiac myocytes treated with doxorubicin (18 Hrs), coupled with mitochondrial dysfunction including impaired respiration. Inhibition of CyPD suppressed doxorubicin induced cell death of cardiac myocytes. Finally restoration of NF-κB signaling in cardiac myocytes treated with doxorubicin by IKKβ, active kinase, suppressed mitochondrial calcium overload, mitochondrial perturbations, respiration and cell death. The data herein, provides the first direct evidence that impaired NF-κB signaling predispose Dox treated cardiac myocytes to cell death. Hence, interventions that preserve NF-κB survival signaling pathways in the heart may prove beneficial in reducing cardiac dysfunction and heart failure in cancer patients undergoing doxorubicin chemotherapy.
Long-Term, Clonal Tracking Comparing Autologous Transplantation of G-CSF/SCF-Primed Bone Marrow CD34+ Cells with G-CSF/SCF-Mobilized Peripheral Blood CD34+ Cells in Rhesus Macaques
Authors: Sanggu Kim, Robert E. Donahue, Aylin Bonifacino, Mark Metzger, Cynthia E. Dunbar, Irvin Chen
Journal: Blood (2018)
Abstract 548: Cardiomyocyte-KLF5 Expression is Increased by FOXO1 and Accounts for Cardiomyopathy in Type-1 Diabetes
Authors: Ioannis D Kyriazis, Mathhew Hoffman, Charikleia Kalliora, Lea Gaignebet, Thomas D Bannister, Melpo Christofidou-Solomidou, Ira J Goldberg, Vincent W Yang, Agnieszka B Bialkowska, Georgios Kararigas, Konstantinos Drosatos
Journal: Circulation Research (2019)

Cardiomyopathy in type 1 diabetes (T1D) is accompanied by altered cardiac energetics, impaired mitochondrial function and oxidative stress. We showed previously increased cardiac expression of Krüppel-like factor 5 (KLF5) and Peroxisome Proliferator Activated Receptor (PPAR)α at late T1D stage in mice. We confirmed that KLF5 expression is higher in cardiomyocytes of diabetic patients than in non-diabetic individuals. Mechanistic analyses in human cardiomyocyte cells (AC16) and in mice with cardiomyocyte-specific FOXO1 deletion (αMHC- Foxo1 -/- ) revealed that FOXO1 activation accounts for the increased KLF5 expression via direct binding on Klf5 promoter. Both pharmacologic and cardiomyocyte-specific inhibition of KLF5 alleviated diabetic-related cardiac dysfunction. Accordingly, mice with doxycycline-mediated cardiomyocyte-specific KLF5 constitutive expression (αMHC-rtTA- Klf5 ) recapitulated cardiomyopathy even in the absence of T1D. We also showed that diabetic PPARα -/- mice had elevated cardiac KLF5 expression and cardiac dysfunction, suggesting that KLF5-driven diabetic cardiomyopathy is PPARα-independent. Furthermore, cardiomyocyte KLF5 upregulation was associated with oxidative stress, increased NADPH oxidase (NOX)4 expression, lower NADPH levels and impaired cellular Ca 2+ handling. Conversely, KLF5 inhibition prevented NOX4 upregulation and alleviated cardiac superoxide formation. Lipidomic analysis followed by Euclidean clustering showed strong correlation of lipidome profiles between αMHC-rtTA- Klf5 mice and diabetic C57BL/6 mice, while diabetic αMHC- Klf5 -/- mice and diabetic C57BL/6 mice that were treated with pharmacologic KLF5 inhibitor grouped with the non-diabetic C57BL/6 mice. Further analysis of individual lipid species showed increased ceramide accumulation in diabetic C57BL/6 and αMHC-rtTA- Klf5 mice that was reversed upon KLF5 inhibition. Treatment of αMHC-rtTA- Klf5 mice and diabetic C57BL/6 mice with the antioxidant LGM2605 improved partially cardiac dysfunction. In conclusion, cardiomyocyte KLF5 expression is activated by FOXO1 and drives diabetic cardiomyopathy in a non-PPARα-dependent manner, suggesting KLF5 inhibition as a therapeutic intervention in T1D cardiomyopathy.
Utilization of Patient-Reported Outcomes in Myeloproliferative Neoplasm Clinical Trials Registered at Clinicaltrials.Gov
Authors: Blake T. Langlais, Gina Mazza, Crystal S. Langlais, Heidi E. Kosiorek, Holly L. Geyer, Ruben A. Mesa, Robyn M. Scherber, Amylou C. Dueck
Journal: Blood (2018)
Time to treatment for lung cancer patients at an urban safety net institution.
Authors: Kalyani Narra, Yan Lu, Bassam Ghabach, Rohit P. Ojha
Journal: Journal of Clinical Oncology (2019)

26 Background: Lung cancers are rapidly fatal, but no guidelines currently exist in the US for the optimal time between symptomatic presentation and treatment. A recent study from multiple institutions estimated a median of 52 days from symptomatic presentation to treatment, but this estimate was based on patient self-report and the study under-represented settings that provide care to patients with socioeconomic barriers to care that could affect time to treatment. Therefore, we aimed to assess time to treatment for lung cancer patients at an urban safety-net institution. Methods: We used institutional registry data from the JPS Center for Cancer Care (Fort Worth, TX), an accredited Comprehensive Community Cancer Program. Eligible patients were aged ≥18 years and had a pathological diagnosis of lung cancer between January 1, 2018 and December 31, 2018. We estimated the median overall and stage-specific time from abnormal imaging (chest X-ray or CT scan) to initiation of treatment, which were documented in medical records. Results: Our study population comprised 75 lung cancer patients. The majority of patients who received treatment ( n=46) were aged 55–64 years (54%), female (52%), and racial/ethnic minorities (54%). The overall median time to treatment was 81 days (interquartile range [IQR]=48–111) which varied by stage: stage I=108 (IQR=92–140), stage II=123 (IQR=111–134), stage III=85 (IQR=45, 102), stage IV=59 (IQR=39–72). In particular, the median time from ordering chemotherapy to start was 22 days (IQR= 13–30). Conclusions: Time to treatment for lung cancer patients at our institution is substantially longer than reported in the literature, which may partially reflect the patient population but warrants interventions (e.g. enhanced care coordination) to reduce this interval. Nevertheless, without an optimal time to treatment that is associated with improved outcomes among lung cancer patients, we and other institutions lack a meaningful benchmark.