tbuckley/cabot-search huggingface dataset:
Abstract 449: Transplantation Alters Function and Clonality of Cytomegalovirus-Responsive T Cells
Authors: Lauren E Higdon, Steven Schaffert, Naresha Saligrama, Mark M Davis, Purvesh Khatri, Jonathan S Maltzman
Journal: Circulation Research (2019)

Background: Cytomegalovirus (CMV) infection is a major complication of organ transplantation. CMV establishes lifelong latency in infected individuals. Healthy people are protected from CMV reactivation by immune memory, but immunosuppression limits protection in transplant recipients. Despite antiviral prophylaxis strategies, long-term survival is impaired. CMV-responsive memory CD8 T cells expand during the first year after transplantation in the absence of detectable viremia. The observed expansion correlates with protection against CMV. The objective of this study was to determine whether these cells are protective, utilizing innovative single cell sequencing analyses to probe their functional characteristics. Methods: Mononuclear cells from peripheral blood of heart and kidney transplant recipients pre- and three months and one year post-transplant were stimulated with immunodominant CMV peptides. Single IFN gamma+ CMV-responsive T cells were index sorted into 96 well plates, and nested PCR, barcoding, and sequencing performed to analyze T cell receptor (TCR) and a panel of functional genes. Results: Expanded CMV-responsive T cells tend to express a limited number of dominant CMV-responsive TCR clones. Clonally expanded CMV-responsive T cells express multiple antiviral proteins. The TCR repertoire may change from pre- to post-transplant. Once established at three months, clonal dominance is maintained until at least one year. The number of antiviral proteins expressed per clonally expanded T cell increases between these time points. Conclusions: Protection from CMV post-transplant correlates with maintenance of TCR clonality and increased number of functions per cell. The stability of clonality post-transplant contrasts with the expansion of the total T cell population, and suggests that clonal expansion in the absence of disease recapitulates the pre-existing repertoire. The increased number of functions suggests that the expanded population may become more protective. The potential impact on clinical practice would be to provide further information on the relationship between the T cell response to CMV and long-term outcomes after transplantation.
Abstract 903: Rapamycin Treatment Reduces Myocardial Stiffness and Promotes Cardiomyocyte Relaxation to Restore Diastolic Function in Old Murine Hearts
Authors: Ying Ann Chiao, Kristi Kooiker, Yuanhua Cheng, Joe Powers, Maria Razumova, Henk Granzier, Michael Regnier, Peter Rabinovitch, Farid Moussavi-Harami
Journal: Circulation Research (2019)

Aging is associated with a decline in diastolic function and is a strong risk factor for heart failure with preserved ejection fraction (HFpEF), which has no effective treatment. We previously showed that late-life rapamycin treatment can reverse age-related cardiac dysfunction in mice. However, the mechanisms of the reversal of diastolic dysfunction have not been established. The objective of this study is to determine the mechanisms by which rapamycin reverses age-related diastolic dysfunction. To study the effects of rapamycin on myocardial stiffness, we assessed the passive length-tension relationship of demembranated trabecular muscle from young, old control and old rapamycin-treated mice. We observed a substantial increase in the slope of the length-tension curve with aging, indicating an age-related increase in myocardial stiffness. The age-related increase in myocardial stiffness was significantly reduced by rapamycin treatment, by a mechanism independent of titin isoform shift. We measured the force-calcium relationship of the demembranated trabeculae and revealed an age-related increase in Ca 2+ sensitivity, as indicated by a left-shift of the force-pCa curve, which was partially restored after rapamycin treatment (pCa50: 5.59±0.04 for young controls; 5.76±0.04 for old controls; and 5.65±0.04 for old rapamycin-treated group). To investigate the changes at myofibril level, we assessed kinetic properties of control and rapamycin-treated myofibrils following maximal (pCa 4.0) and submaximal (pCa 5.6) Ca 2+ activation. Myofibrils from rapamycin-treated mice displayed increased rate of the fast phase of relaxation (kREL, fast) compared to old control at both maximal and submaximal Ca 2+ levels, potentially due to reduced myofibril Ca 2+ sensitivity. Studies have detected age-related reductions in expression and activity of SERCA2, which is responsible for SR calcium reuptake during diastole. In this study, we showed that rapamycin increased SERCA2 expression, which may improve cardiomyocyte relaxation. In summary, our results suggest that rapamycin normalizes age-related increases in myocardial stiffness and Ca 2+ sensitivity and improves myofibril relaxation kinetics, therefore, improving diastolic function.
Discordance Between Peripheral Blood and Tissue CD4+ Lymphocyte Reconstitution In Rhesus Monkeys Following Autologous Hematopoietic CD34+ Cell Transplantation: An In Vivo imaging Study
Authors: Robert E. Donahue, Sharat Srinivasula, Naoya Uchida, Insook Kim, Gorka Duralde, Paula DeGrange, Marisa St. Claire, Richard C. Reba, Aylin C. Bonifacino, Allen E. Krouse, Mark E. Metzger, Chang H. Paik, H. Clifford Lane, John F. Tisdale, Michele Di Mascio
Journal: Blood (2013)
Orbital Non Hodgkin Lymphomas. Features and Evolution of 63 Patients From Two Oncological Centers in Buenos Aires, Argentina: Marie Curie Hospital and Henry Moore Institute
Authors: Marta O Dragosky, Marisa Marquez, Graciela P Luchetta, Susana Alcaraz, Isabel Annetta, Ariel Corzo, Cecilia Jozami, Eduardo Gil Deza, Marta Zerga
Journal: Blood (2011)
Juxtaposing CD20 and CD74 with Novel Bispecific Antibodies Evokes Potent Cytotoxicity in Mantle Cell Lymphoma (MCL)
Authors: Pankaj Gupta, David M. Goldenberg, Edmund A Rossi, Thomas M. Cardillo, John C. Byrd, Natarajan Muthusamy, Richard R. Furman, Chien-Hsing Chang
Journal: Blood (2011)
Abstract 15474: Acute Increase in Systemic Arterial Load Blunts Afterload Release after Transcatheter Aortic Valve Implantation. Frequency-Domain and Wave-Intensity Analyses
Authors: Raquel Yotti, Javier Bermejo, Enrique Gutiérrez, Candelas Pérez del Villar, Ana González-Mansilla, Alicia Barrio, Yolanda Benito, Pedro Luis Sánchez, Jaime ElÍzaga, Francisco Fernández-Avilés
Journal: Circulation (2012)

The interaction between ventricular, valvular and vascular components determines the hemodynamic consequences of aortic stenosis (AS). Acute valvular relief is an excellent scenario to assess the e...
Abstract 549: Cardiac Aging is Associated With Impaired Mitophagy and Formation of Megamitochondria
Authors: Wenjing Liang, Alexandra G Moyzis, Rita A Najor, Mark A Lampert, Åsa B Gustafsson
Journal: Circulation Research (2019)

Aging is associated with increased risk of developing cardiovascular disease. Currently, the molecular mechanisms contributing to the cardiac aging process and the resulting pathogenesis are unclear. Here, we have characterized changes in mitochondria and mitochondrial autophagy (mitophagy) in aging mouse hearts. To evaluate structural and functional changes that occur with cardiac aging, we compared young (4 months) and old (24 month) mice. We found that aging led to cardiac hypertrophy as characterized by increased left ventricular (LV) mass index and heart weight/body weight ratio as well as elevated myosin heavy chain 7 mRNA levels. Although echocardiography analysis showed no detectable changes in systolic function, the aged mice showed evidence of diastolic dysfunction as there was a significant decrease in the E/A ratio. We also found increased levels of fibrosis and inflammation in the aged hearts. Evaluation of autophagy in aged hearts revealed impaired autophagic flux, as indicated by accumulation of the autophagy substrate p62. Treatment of mice with the mTOR inhibitor Rapamycin, led to the expected increase in LC3II-positive autophagosomes in young hearts but not in the aged hearts. Parkin is an E3 ubiquitin ligase involved in labeling mitochondria for mitophagy by ubiquitinating proteins on the outer mitochondrial membrane. We found a significant increase in Parkin at the mitochondria in aged hearts which was accompanied with a significant increase in mitochondrial protein ubiquitination and p62 levels. However, LC3II protein levels in the mitochondrial fraction did not increase. This suggests that although mitochondria have been labeled for mitophagy, they are not eliminated due to decreased formation of autophagosomes. Finally, ultrastructural analysis of hearts showed the presence of enlarged mitochondria in aged hearts. Although we observed no changes in mitochondrial fusion proteins Mfn1/2, we found decreased activation of the mitochondrial fission protein Drp1. Overall, these data suggest that which might contribute to the development of age-related cardiac pathologies.
A Prospective, Multicenter Surveillance Study for Adverse Events Associated with Hematopoietic Stem Cell Infusion: Analysis of Pediatric and Low Body-Weight Recipients
Authors: Kazuhiko Ikeda, Hitoshi Ohto, Yoshiki Okuyama, Minami Yamada-Fujiwara, Heiwa Kanamori, Shin-ichiro Fujiwara, Kazuo Muroi, Takehiko Mori, Kinuyo Kasama, Tohru Iseki, Tokiko Nagamura-Inoue, Nobuharu Fujii, Takashi Ashida, Kazuaki Kameda, Junya Kanda, Asao Hirose, Tsutomu Takahashi, Kazuhiro Nagai, Keiji Minakawa, Ryuji Tanosaki
Journal: Blood (2018)
David Oliver: What to say when patients are “sick enough to die”
Authors: David Oliver
Journal: BMJ (2019)

One weekend, as a consultant for acute admissions, I spoke to the families of three patients and explained that their relative was critically ill and would probably die soon. Two of those patients rallied sufficiently to return home days later.

The next week on my ward I had similar chats with three other patients and their families. Death followed within hours, their symptoms well palliated. We also got two more patients home, whose admitting doctors had said to expect the worst and who had moved away from active intervention to supportive care.

I’ve practised at the acute end of geriatrics and internal medicine for 30 years. Like many colleagues I find such conversations and scenarios commonplace yet critical. Very sick people present acutely or deteriorate quickly, necessitating time critical assessments. But those few …
Serum Dickkopf-1 Is Increased and Correlates with Bone Mineral Density in Patients with Thalassemia-Induced Osteoporosis. Reduction Post Zoledronic Acid Administration
Authors: Ersi Voskaridou, Dimitrios Christoulas, Thodoris Pantelaros, Konstantinos Varvagiannis, Charoula Xirakia, Athanasios Papatheodorou, Kleio Sinopoulou, Aggeliki Mpalasopoulou, Antonios Bilalis, Evangelos Terpos
Journal: Blood (2008)
Corticosteroids Combined with Cyclosporine a Is Superior to Corticosteroids As First-Line Treatment for Autoimmune Hemolytic Anemia after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Weiran Lv, Hong Qu, Meiqing Wu, Zhiping Fan, Fen Huang, Na Xu, Li Xuan, Ren Lin, Ke Zhao, Jing Sun, Yongrong Lai, Yajing Xu, Qifa Liu
Journal: Blood (2018)
Double-Unit Cord Blood Transplantation (DCBT) for Acute Leukemia: High Disease-Free Survival in Adults and Children with Comparable Survival in European and Minority Patients
Authors: Juliet N Barker, Doris M Ponce, Anne Marie R Gonzales, Marissa N Lubin, Hugo Castro-Malaspina, Sergio Giralt, Jenna D Goldberg, Ann A Jakubowski, Guenther Koehne, Esperanza B Papadopoulos, Miguel-Angel Perales, Craig S Sauter, Marcel R.M. van den Brink, James W Young, Farid Boulad, Rachel Kobos, Richard J. O'Reilly, Susan E Prockop, Trudy N Small, Cladd E Stevens, Nancy A. Kernan, Andromachi Scaradavou
Journal: Blood (2011)
Abstract 430: Impaired Autophagic Off-rate Causes Cardiac Aging in Progeria Mouse Model
Authors: Yasuko K Bando, Takahiro Kamihara, Toyoaki Murohara
Journal: Circulation Research (2019)

Background/Introduction: Aging is known to be one of the primary causes of heart failure. Werner syndrome is one of the aging disorder due to dysfunction of DNA helicase-regulatory protein (WRN) and exhibiting progressive phenotype of natural aging. Ample evidences demonstrated progeria may promotes autophagic disorder. [PURPOSE] To elucidate whether autophagic disorder may be mechanistically responsible for cardiac aging. Methods: We employed progeria mouse model harboring amino acid (AA) substitution of WRN at position 577 (WRN-K577M, 18 week-old male). Results: WRN-K577M exhibited diffuse left-ventricular (LV) hypertrophy, enhanced fibrosis, and diastolic LV dysfunction with preserved systolic ejection fraction. DNA microarray analysis of WRN-K577M heart revealed that 253 genes were upregulated compared to age- and gender-matched wild-type counterpart. Sixteen genes were increased &gt; 4 fold higher than wild-type as follows: hypertrophy (Myh7, Klkb11), fibrosis (CTGF), inflammatorymolecules (Ap1s3, Pla2g2e, Has1, MMP9), and oxidative stress (catalase). Cardiac aging markers (PARP-1, p53 and γH2AX) increased in heart of WRN-K577M with concomitant increase in oxidative stress (DHE staining) and apoptosis (TUNEL). Notably, autophagic turnover markers (p62 and LC3-II/I) were increased in myocardium of WRN-K577M, which was refractory to fasting-induced increase in on-rate of autophagy. Consistently, one of the key regulators of autophagy is the target of rapamycin, TOR kinase, which is the major inhibitory signal that shuts off autophagy with concomitant activation of Akt signaling. Collectively, these data indicates that the on-rate step of autophagy could be pathologically augmented with disruption of downstream process, i.e. impaired off-rate pathway that modulates turnover of autophagosome and lysosome under cardiac aging observed in WRN-K577M. Changes in autophagosomal and lysosomal accumulation were monitored by specific fluorescence indicators and chloroquine (50 microg/g body weight) augmented lysosomal accumulation with reduced LC3-II/I ratio. Conclusion(s): In WRN-mutant progeria model, off-rate disorder of cardiac autophagy is, at least in part, the cause of cardiac aging.
Abstract 618: Overexpression of Rrm2B Elevates dATP and Cardiac Function
Authors: Jason Murray, Sabrina Do, Tim McMillen, Michael Regnier, Farid Moussavi-harami
Journal: Circulation Research (2019)

Cardiac myosin can use 2-deoxy-ATP (dATP) instead of ATP as energy substrate, significantly enhancing the rate and magnitude of force development and relaxation. Our group has shown repeatedly that overexpression of the enzyme ribonucleotide reductase (RNR; the rate-limiting step in de novo dNTP synthesis) in cardiomyocytes, by either transgenic or viral vector approach, enhances cardiac function by significantly elevating cytosolic concentrations of dATP. We are exploring different promotor, gene constructs and engineered mutations of RNR to be able to vary the amount of dATP maintained in cardiomyocytes. RNR activity is partially governed by levels of the small subunit, Rrm2, whose concentration oscillates with the cell cycle via degradation by the ubiquitin-proteasome system. The p53-inducible small subunit Rrm2B is naturally present in quiescent cells and does not contain the amino acid sequence that is targeted by the ubiquitin-conjugating enzyme. We hypothesized that Rrm2B overexpression may be more stable than Rrm2 through its resistance to degradation by this pathway. Transgenic mice that overexpress Rrm1 and Rrm2B have a ~60 fold increase in myocardial [dATP] as measured by liquid chromatography-mass spectrometry compared to wild-type littermates. This translates to significantly elevated left-ventricular developed pressure as well as higher rates of contraction and relaxation in perfused isolated hearts, as well as enhanced shortening and relaxation in isolated cardiomyocytes. Isolated rat cells also have an increase in [dATP] and corresponding greater fractional shortening and rates of contraction and relaxation when transduced in vitro with adenovirus encoding Rrm1 and Rrm2B when compared to cells transduced with a control vector. We are currently in the process of comparing the effectiveness of adeno-associated viruses encoding Rrm2 and Rrm2B in vivo. Our ultimate goal is to develop an improved vector to enable stable and consistent overexpression of RNR and elevation of dATP in cardiomyocytes transduced in vivo , thereby improving both systolic and diastolic function for treatment of cardiomyopathies.
High PARP-1 expression Predicts Poor Survival in Acute Myeloid Leukemia and PARP-1 Inhibitor and SAHA-Bendamustine Hybrid Inhibitor Combination Treatment Synergistically Enhances Anti-Tumor Effects
Authors: Xia Li, Chenying Li, Jingrui Jin, Jinghan Wang, Jie Jin
Journal: Blood (2018)
Abstract 295: Cysteine 202 of Cyclophilin D is a Site of Multiple Post-translational Modifications and Plays a Role in Cardioprotection
Authors: Georgios Amanakis, Junhui Sun, Matthew Brody, Tyler Bauer, Shane McGinty, Jennifer Boylston, Chengyu Liu, Jeffery Molkentin, Elizabeth Murphy
Journal: Circulation Research (2019)

Cyclophilin-D (CypD) is a well-known regulator of the mitochondrial permeability transition pore (PTP), the main effector of cardiac ischemia/reperfusion (I/R) injury characterized by oxidative stress and calcium overload. However, the binding of CypD to the PTP is poorly understood. Cysteine 202 of CypD (C202) is highly conserved across species and can undergo redox-sensitive post-translational modifications. To study the importance of C202, we developed a knock-in mouse model using CRISPR where CypD-C202 was mutated to a serine (C202S). In a Langendorff perfused heart model, infarct size is reduced by 51% in CypD-C202S hearts compared to WT (n=4, p=0.003). Isolated cardiac mitochondria from CypD-C202S mice also have a 49% higher calcium retention capacity compared to WT (n=5, p=0.011). We hypothesized that oxidation of C202 might target CypD to the PTP and that the cardioprotection in CypD-C202S mice is due to a post-translational modification on C202. Indeed, isolated cardiac mitochondria subjected to oxidative stress exhibit less binding of CypD-C202S to the proposed PTP component ATP synthase by 48% compared to WT (p=0.012, n=4). We previously found C202 to be S-nitrosylated in ischemic preconditioning. Cysteines can also undergo S-acylation (attachment of a fatty acid), and C202 matched a S-acylation motif. To assess S-acylation of CypD-C202 we employed a resin-assisted capture. Lysates were treated with N-ethylmaleimide to block free cysteines, and then with hydroxylamine to free cysteines from fatty acids. Subsequently, free cysteines were captured by a sepharose resin, followed by western-blot of the eluate. CypD-C202 is abundantly S-acylated, but CypD-C202S hearts exhibit less S-acylation than WT by 63% (n=6, p&lt;0.001). We investigated the importance of S-acylation of CypD-C202 in cell death in a mouse embryonic fibroblast (MEFs) model. CypD-C202S MEFs exhibit 20% less oxidative cell death than WT (n=5, p=0.003). Inhibition of S-acylation with 2-bromopalmitate attenuates oxidative cell death in the WT by 20% (n=5, p=0.018), while CypD-C202S MEFs are unaffected. Thus, S-acylation and oxidation of CypD-C202 possibly target CypD to the PTP, sensitizing it under oxidative stress and making them potent regulators of cardiac I/R injury.
Cysteinyl maresins regulate the prophlogistic lung actions of cysteinyl leukotrienes
Authors: Bruce D. Levy, Raja-Elie E. Abdulnour, Alexander Tavares, Thayse R. Brüggemann, Paul C. Norris, Yan Bai, Xingbin Ai, Charles N. Serhan
Journal: Journal of Allergy and Clinical Immunology (2019)
Specific Donor Human Leukocyte Antigen (HLA) Allotypes and CMV IgG Serology Status Predict the Risk of Cytomegalovirus-Related Disease in Acute Myeloid Leukemia Patients Who Received Allogeneic Hematopoietic Stem Cell Transplantation
Authors: GI June MIN, Heeje Kim, Tai-Gyu Kim, Seung-Joo Hyun, In-Cheol Baek, Seug Yun Yoon, Sung-Soo Park, Silvia Park, Seung-Ah Yahng, Young-Woo Jeon, Seung-Hwan Shin, Jae-Ho Yoon, Sung-Eun Lee, Byung Sik Cho, Ki-Seong Eom, Yoo-Jin Kim, Seok Lee, Chang-Ki Min, Seok-Goo Cho, Dong-Wook Kim, Jong-Wook Lee
Journal: Blood (2018)
Abstract 457: The Effect of Dietary Patterns on Cardiometabolic Risks in Healthy Asian Adults
Authors: Chiu-fen Yang, Tsung-Jen Lin, Chin-Hung Liu
Journal: Circulation Research (2019)

Rationale: Atherosclerosis often leads to acute myocardial infarction and stroke. Diet may be involved in innate immunity-mediated inflammation and the pathogenesis of atherosclerosis. Objective: To investigate the effects of various dietary patterns on metabolic profiles, inflammation and atherosclerosis. Methods and Results: We began by understanding the dietary pattern using questionnaire for 75 healthy adults who were enrolled in this study. To obtain the metabolic and inflammation profiles, we collected peripheral blood for analysis. The healthiness of vessels was evaluated by carotid intimal-media thickness (CIMT). We found that participants who adhere to vegetarian diet more than ten years showed lower levels of serum total cholesterol compared to omnivores. However, we did not find any beneficial effect of vegetarian diet on other parameters as C-reactive protein, interleukins and CIMT were no difference between two groups. Among “junk foods”, the amount of instant noodles and sugar drink consumption was positively associated with the levels of triglyceride and uric acid. Notably, the increment of sugar drink usage was correlated with higher expression of toll-like receptor (TLR) 2 and TLR4 on peripheral monocytes, but showed no impact on fasting serum glucose. As for the concern of “healthy foods”, participants who took more fresh fruit had significantly better fasting glucose and higher high-density lipoprotein, as well as lower monocyte TLR2 and TLR4 expression. The amount of green vegetable consumption was inversely correlated with low-density lipoprotein and CIMT. In addition to food, water was also important. Participants who drank water more than 2000 ml per day had significant lower CIMT. On the other hand, we did not find any significant effects on coffee consumption. Moreover, for factors that may promote or prevent atherosclerosis, we found that trimethylamine N-oxide and S-adenosyl-L-homocysteine was positively correlated with CIMT whereas L-Lysine and L-Carnitine showed inverse association with CIMT. Conclusions: We discovered that consumption of healthy foods and water, but not vegetarian diets per se, is positively correlated with cardiovascular health from the perspective of metabolic panel and inflammation.
Design and standardization of pcr primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations. Section 7. TCRD gene rearrangements: Vd-Dd-Jd; Dd-Dd; Vd-Dd and Dd-Jd.
Authors: F. L. Lavender, E. Hodges, K. I. Mills, H. E. White, T. Flohr, M. Nakao, A. W. Langerak, P. J. T. A. Groenen, R. Villuendas, B. A. Jennings, Benedict Jon Milner, D. Bloxham, J. Droese, E. A. Macintyre, K. Beldjord, F. Davi, J. L. Smith
Journal: Leukemia (2003)
The Proportional Association between WT1 mRNA Level in Peripheral Blood before Allogeneic Hematopoietic Cell Transplantation and Risk of Mortality in Acute Myeloid Leukemia Not in Remission
Authors: Kentaro Ido, Mika Nakamae, Hideo Koh, Hiroshi Okamura, Satoru Nanno, Mitsutaka Nishimoto, Yoshinori Hashimoto, Yasunobu Takeoka, Asao Hirose, Yasuhiro Nakashima, Takahiko Nakane, Masayuki Hino, Hirohisa Nakamae
Journal: Blood (2018)