tbuckley/cabot-search huggingface dataset:
Abstract 166: MCL-1 Facilitates the Removal of Damaged Mitochondria via the Mitophagy Receptor BNIP3
Authors: Alexandra G Moyzis, Navraj S Lally, Rita A Najor, Leonardo J Leon, Åsa B Gustafsson
Journal: Circulation Research (2019)

Myeloid Cell Leukemia-1 (MCL-1) is an anti-apoptotic BCL-2 family protein that is necessary to maintain cardiac homeostasis in the adult heart. MCL-1 localizes to two distinct mitochondrial locations in myocytes, both on the outer mitochondrial membrane (MCL-1 OM ) and in the mitochondrial matrix (MCL-1 Matrix ). Our lab previously showed that cardiac-specific ablation of MCL-1 at both of these mitochondrial locations in mice led to severe contractile dysfunction and compromised mitochondrial function. Intriguingly, these defects were accompanied by signs of necrotic, rather than apoptotic, cell death. This indicates that MCL-1 has an alternate role in maintaining mitochondrial homeostasis in cardiac myocytes. Unexpectedly, we found that MCL-1 induces mitochondrial clearance in response to treatment with the chemical uncoupler FCCP in a Parkin-independent manner. Hypoxia is also known to induce mitochondrial clearance, and overexpression of MCL-1 further enhances hypoxia-mediated mitophagy. Fluorescence imaging identified MCL-1-positive mitochondria sequestered inside autophagosomes. MCL-1-mediated clearance is abrogated in autophagy deficient Atg5-/- cells, confirming that clearance is occurring via the autophagy pathway. Mutation of MCL-1’s BH3 domain (G198E D199A) does not affect its ability to induce clearance, suggesting that this role may be independent of its anti-apoptotic function. Also, replacing MCL-1’s BH domains with those of BCL-2, does not affect its ability to induce mitophagy. Next, we investigated whether MCL-1 functions as a mitophagy receptor and promotes removal of damaged mitochondria by binding to directly to LC3 through one or more of its three putative LC3-Interacting Region (LIR) motifs. Endogenous MCL-1 and LC3 co-immunoprecipitate in response to stress induced by FCCP. However, mutating each of MCL-1’s individual LIR motifs, as well as generating combined mutations in all three, does not affect MCL-1-mediated mitophagy. Instead, we found that MCL-1 interacts with the known mitophagy receptor BNIP3 both in vitro and in vivo . Thus, our data suggest that MCL-1 promotes elimination of dysfunctional mitochondria by positively regulating the mitophagy receptor BNIP3.
Phosphatidylserine on Blood Cells and Microparticles Contributes to the Hyper-Coagulable State in Diabetic Kidney Disease
Authors: Muxin Yu, Rujuan Xie, Muhua Cao, Yan Zhang, Hui Liang, Baorong Li, Yingmiao Liu, Li Hou, Junjie Kou, Yayan Bi, Jialan Shi
Journal: Blood (2017)
Abstract 616: Glycogen Synthase Kinase 3b Localizes to and Modulates Sarcomere Function in Health and Disease
Authors: Jonathan A Kirk
Journal: Circulation Research (2019)

Ischemic damage to a region of myocardium renders it weaker than the surrounding tissue, leading to contractile heterogeneity. This heterogeneity causes abnormal stress and strain patterns, further reducing systolic function. We hypothesized glycogen synthase kinase 3β (GSK-3β) may be a therapeutic target for improving function in patients with ischemic damage, as we previously discovered its activity is reduced by abnormal mechanical stress and it can phosphorylate myofilament proteins. We measured GSK-3β levels in LV whole tissue lysate from patients with ischemic cardiomyopathy (ICM) and non-failing rejected donor hearts (NF), but detected no differences. However, we found GSK-3β present at the myofilament, and ICM patients had a ~70% reduction in this localized pool compared to NF controls. Furthermore, GSK-3β phosphorylated at Y216 (pY216), an understudied site, was highly enriched in the myofilament. We used immunofluorescence, co-immunoprecipitation, and adenoviral constructs of Y216 phospho-mimetic or -blocked, in human, mouse, or neonatal rat ventricular myocytes to confirm Y216 phosphorylation results in GSK-3β binding to the myofilament. pY residues can dock to SH2 domains. The only SH2-containing protein that associates with the myofilament is tensin-1 (discovered by us in the myofilament by mass spectrometry). Here we further found tensin-1 localizes to the cardiac z-disk. GSK-3β and tensin-1 co-IP together in myocytes and in HEK cells (in the absence of the myofilament), but this interaction is reduced if Y216 phosphorylation is blocked. To identify the functional consequences of this interaction, we utilized an inducible myocyte specific GSK-3β knock-out mouse. Skinned myocytes from GSK-3β KO mice had significantly depressed calcium sensitivity compared to WT mice. Furthermore, treating skinned myocytes isolated from ICM patients with GSK-3β significantly increased calcium sensitivity, but had no effect in NF cells. These findings identify a novel functional role for GSK-3β in the ischemic human heart. GSK-3β is a promiscuous kinase, but we have discovered a specific regulatory mechanism (Y216 phosphorylation) that could allow precise therapeutic intervention to improve contractile function in ICM patients.
Abstract 416: Approach of mRNA Delivery by Using Nanoparticles to Recover Endocardial Notch Signaling
Authors: Victoria L Messerschmidt, Aneetta Kuriakose, Kytai Nguyen, Juhyun Lee
Journal: Circulation Research (2019)

Notch signaling plays a significant role in cardiac development and morphogenesis, especially for cardiac chamber development. Failure of mechanotransduction of endocardial Notch signaling in ventricular chamber causes lack of trabeculation. Advent of nanoparticle (NP) technology offers a therapeutic approach of targeted delivery. Although delivering mRNA is an effective method, it is challenging due to stability and cell defense mechanisms. To overcome the limitations and effectively deliver mRNA to endocardium, we used Poly(lactic-co-glycolic acid) (PLGA) synthesized NPs, which have been used in various drug delivery systems due to its biocompatibility, efficient encapsulation of hydrophilic and hydrophobic materials, specific targeting effects, and lower payload concentration. We hypothesized our PLGA NPs are able to deliver NICD mRNA to target endocardium to overexpress Notch signaling in a Notch inhibited zebrafish animal model. Using double emulsion, we synthesized PLGA NPs at 55–65 kDa and performed in vitro test on HUVECs. 69.8 ± 4.3% of Rhodamine B was successfully loaded into the NPs, and after incubation with HUVECs the signal lasted for 28 days after burst release. Hemolysis and whole blood clotting assays proved that NPs did not interfere with the blood clotting process or lyse blood cells. We characterized mRNA incorporated PLGA nanoparticles and incubated with HUVECs after antibody conjugation. To test in vivo study, we injected gata1a morpholino oligomer (MO) to Tg(fli1:gfp) transgenic line to inhibit hematopoiesis, which reduces wall shear stress (WSS) of ventricular chamber leading lack of trabeculae. At 2 days post fertilization (dpf), NICD mRNA incorporated nanoparticles were injected into the circulatory system of gata1a MO injected zebrafish to rescue trabeculation. At 5 dpf, zebrafish hearts were harvested and analyzed via qRT-PCR to compare Notch related gene expression among control, gata1a MO injected, and rescue group. The NICD mRNA injected group successfully rescued the expression level of Notch components despite a lack of WSS and mechanosensitive Notch signaling via gata1a MO injection. This finding will provide an initial therapeutic approach of NICD mRNA for trabecular related congenital heart disease.
Conservative Oxygen Therapy during Mechanical Ventilation in the ICU
Authors: Diane Mackle, Rinaldo Bellomo, Michael Bailey, Richard Beasley, Adam Deane, Glenn Eastwood, Simon Finfer, Ross Freebairn, Victoria King, Natalie Linke, Edward Litton, Colin McArthur, Shay McGuinness, Rakshit Panwar, Paul Young
Journal: New England Journal of Medicine (2019)

Patients who are undergoing mechanical ventilation in the intensive care unit (ICU) often receive a high fraction of inspired oxygen (Fio2) and have a high arterial oxygen tension. The conservative use of oxygen may reduce oxygen exposure, diminish lung and systemic oxidative injury, and thereby increase the number of ventilator-free days (days alive and free from mechanical ventilation).
Topical Microbicides in HIV Prevention: State of the Promise
Authors: Jared M. Baeten, Craig W. Hendrix, Sharon L. Hillier
Journal: Annual Review of Medicine (2019)

HIV topical microbicides are products with anti-HIV activity, generally incorporating a direct-acting antiretroviral agent, that when applied to the vagina or rectum have the potential to prevent the sexual acquisition of HIV in women and men. Topical microbicides may meet the prevention needs of individuals and groups for whom oral daily forms of pre-exposure prophylaxis (PrEP) have not been acceptable. Microbicides can provide personal control over HIV prevention and offer the possibility of discreet use, qualities that may be particularly important for receptive partners in sexual relationships such as women and transgender women and men, who together account for the clear majority of new HIV infections worldwide. Although the promise of such a product emerged nearly three decades ago, proof of concept has been demonstrated only within the last decade. A robust pipeline of microbicidal gels, films, inserts, and rings has been evaluated in multiple studies among at-risk women and men, and refinement of products for ease of use, reversibility, and high safety is the priority for the field.
Identification of Gene Expression Profiles in Acute Lymphoblastic Leukemia Cells That Discriminate Intracellular Thioguanine Nucleotide Accumulation in ALL Cells after In Vivo Treatment with Mercaptopurine.
Authors: Gianluigi Zaza, Meyling Cheok, Wenjian Yang, Pei Deqing, Cheng Cheng, Ching-Hon Pui, Mary V. Relling, William E. Evans
Journal: Blood (2004)
Reply:
Authors: Yoshitaka Arase, Tatehiro Kagawa
Journal: Hepatology (2019)

We thank Dr. Sugiyama for having interest in our work on denosumab therapy for osteoporosis in patients with autoimmune liver diseases.1 Osteodystrophy is a worrisome complication in chronic liver diseases (CLDS), especially in autoimmune liver diseases such as primary biliary cholangitis and autoimmune hepatitis accompanying vitamin D malabsorption and use of corticosteroid. Given that physical activity is closely associated with bone health,2 physical inactivity in CLD is likely to worsen bone metabolism. We think that regular exercise should be recommended in patients receiving denosumab treatment. Osteoporosis is closely associated with sarcopenia. For example, Hayashi et al. reported that the appendicular skeletal muscle mass index was significantly correlated with bone mineral density of the lumbar spine and femur neck.3 Several studies demonstrated that exercise improved muscle strength and function in CLD patients. In addition, exercise ameliorated VO2 peak, anaerobic threshold, 6-mintute walk distance, and quality of life in patients with compensated and decompensated cirrhosis.4, 5 Therefore, exercise programs should be incorporated in the management of CLD. However, appropriate type, intensity, and duration of exercise are largely unknown. These factors should be arranged based upon patients' liver function (compensated or decompensated) and physical condition. The combination of exercise and a specific treatment such as denosumab will be the focus of future trials.
Non-invasive prediction of liver-related events in patients with HCV-associated compensated advanced chronic liver disease after oral antivirals
Authors: Mònica Pons, Sergio Rodríguez-Tajes, Juan Ignacio Esteban, Zoe Mariño, Víctor Vargas, Sabela Lens, Maria Buti, Salvador Augustin, Xavier Forns, Beatriz Mínguez, Joan Genescà
Journal: Journal of Hepatology (2019)
Ibrutinib, Single Agent BTK Inhibitor, for Treatment Naïve (TN) and Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia: A Real-Life Experience from Rete Ematologica Pugliese (REP)
Authors: Potito Rosario Scalzulli, Attilio Guarini, Giacomo Loseto, Giorgina Specchia, Anna Maria Giordano, Domenico Pastore, Giovanni Quintana, Patrizio Mazza, Alessandro Maggi, Nicola Di Renzo, Maria Rosaria De Paolis, Giuseppe Tarantini, Gaetano De Santis, Vincenzo Pavone, Antonino Greco, Maria Rosa Valvano, Nicola Cascavilla
Journal: Blood (2018)
The Comparison of Unmanipulated Bone Marrow Versus Peripheral Blood Haploidentical Stem Cell Transplantation in Adult Acute Leukemia: A Systematic Review and Meta-Analysis
Authors: Seren Durer, Ceren Durer, Faiza Jamil, Insija Ilyas Selene, Mustafa Nadeem Malik, Abdul Rafae, Muhammad Abu Zar, Ahmad Kamal, Awais Ijaz, Muhammad Usman, Ali Younas Khan, Jemin Aby Jose, Muhammad Junaid Tariq, Emmanuel Katsanis, Faiz Anwer
Journal: Blood (2018)
Allogeneic Bone Marrow Transplantation From HLA Mismatched Family Donors in Children with Aplastic Anemia
Authors: Hideki Muramatsu, Hiromasa Yabe, Ryoji Kobayashi, Akira Kikuchi, Kazuko Kudo, Keisei Kawa, Koji Kato, Ritsuro Suzuki, Yoshiyuki Takahashi, Jiro Inagaki, Masami Inoue, Seiji Kojima
Journal: Blood (2011)
Abstract 859: Sepsis-Induced Cardiomyopathy is Caused by Mitochondrial Dysfunction Due to Protein Kinase C (PKC) Delta Activation
Authors: John P Morrow, Leroy C Joseph, Michael V Reyes, Konstaninos Drosatos
Journal: Circulation Research (2019)

Objective: Sepsis-induced cardiomyopathy (SIC) is a frequent complication of sepsis that is associated with increased mortality. There are no effective therapies. Oxidative stress and mitochondrial dysfunction are part of the pathophysiology of SIC but the upstream molecular pathways involved are unclear. Methods: We used PKCdelta knock-out (KO) mice and WT littermates for surgically-induced polymicrobial sepsis from cecal ligation and puncture (CLP). Isolated cardiomyocytes were used to evaluate oxidative stress, mitochondrial function, contractility, and calcium transients. Results: PKCdelta is activated in cardiomyocytes in sepsis models. In vivo, PKCdelta KO mice do not have decreased systolic function after sepsis, unlike WT littermates. WT cardiomyocytes show increased mitochondrial oxidative stress, partial depolarization of the mitochondrial inner membrane, decreased contractility, and decreased calcium transient amplitude. PKCdelta KO cardiomyocytes are protected from all of these abnormalities. Further, mitotempo improves contractility and calcium transients in WT cardiomyocytes, supported the role of mitochondrial dysfunction as a mechanism of SIC. Conclusion: PKDdelta KO mice are protected from SIC. Cardiomyocyte experiments indicate that mitochondrial dysfunction promotes oxidative stress and a decrease in contractility during sepsis. Translational impact: PKCdelta inhibition could be effective treatment for SIC.
Abstract 364: Klotho Gene Deficiency Causes Heart Failure via Disruption of Phosphate Metabolism
Authors: Kai Chen, Zhongjie Sun
Journal: Circulation Research (2019)

Heart failure is the major cause of mortality for patients with chronic kidney damage (CKD). Although a decrease in plasma klotho levels has been linked to chronic kidney disease (CKD), the relationship between Klotho and heart failure is unclear. Here, using Klotho mutant homozygous (KL -/-) mice, we found that Klotho deficiency caused hyperphosphatemia and heart failure. Normalization of serum phosphorous by dietary phosphate restriction rescued Klotho deficiency-induced heart failure in male mice. However, low phosphate diet did not rescue hyperphosphatemia and heart failure in KL (-/-) female mice. Therefore, hyperphosphatemia may be an important mechanism of Klotho deficiency-induced heart failure. Dietary phosphate restriction did not prevent estrogen depletion in KL (-/-) female mice, suggesting that estrogen depletion may involve in Klotho deficiency induced hyperphosphatemia and heart failure. Normalization of serum estrogen level by 17β-estradiol prevented cardiac remodeling and heart dysfunction in KL (-/-) female mice. Moreover, treatment with 17β-estradiol normalized phosphate metabolism via regulating renal NaPi co-transporter expression. Treatment with 17β-estradiol abolished mitochondrial dysfunction and cardiac apoptosis in Klotho deficient mice. This study demonstrates for the first time that hyperphosphatemia is an important mediator of heart failure which can be prevented by dietary phosphate restriction in male KL (-/-) mice. Estrogen deficiency mediates hyperphosphatemia leading to heart failure due to klotho deficiency in female mice.
Infectious Complications after High-Dose Chemotherapy and Autologous Stem Cell Transplantation for Hematologic Malignancies in a 12-Year Period in Hospital Britanico, Uruguay
Authors: Ana Carolina Oliver, Eloisa Riva, Ricardo Fabian Mosquera, Silvia Pierri, Sebastian Galeano, Ada Caneiro, Laura Bello, Carolina Errecarte, Regis Gai, Andrew Miller, Pablo J. Muxi
Journal: Blood (2018)
Abstract 277: Neonatal Cardiomyocyte-Released Signaling Protein Reduces Adipocyte Differentiation
Authors: Kenneth S Gresham, Walter J Koch
Journal: Circulation Research (2019)

The heart continuously cycles through periods of muscle contraction and relaxation to pump blood throughout the body, which requires a constant supply of metabolic substrates to the heart to power these contractile cycles. To ensure adequate energy availability, the heart must communicate with other organ systems to maintain global metabolic energy homeostasis. In addition to the role of the sympathetic nervous system in global metabolic regulation, mounting evidence suggests cardiomyocytes can release signaling factors that alter global energy balance through communication with other organ systems, including the liver and adipose tissue. To identify potential cardiomyocyte-released circulating factors, we collected media conditioned by neonatal rat ventricular myocytes (NRVM-CM) and screened for released-factor activity using an in vitro adipocyte differentiation assay. Treatment of differentiating 3T3-L1 adipocytes reduced lipid accumulation and decreased expression of adipocyte proteins, demonstrating NRVM-released factor activity. Released factor activity was also under the control of regulators of GPCR signaling as overexpression of G-protein coupled receptor kinase 2 (GRK2) further enhanced the NRVM-released factor activity. We further determined that NRVM released-factor activity was abolished by trypsin treatment and could be segregated into &gt;30kDa CM fractions using centrifugal filter units. To identify proteins responsible for the NRVM-released factor activity, NRVM-CM retained in the 30kDA centrifugal filter units (containing all proteins &gt;30kDa) was analyzed by mass spectrometry. This revealed a number of signaling proteins with known adipocyte regulatory roles that could potentially regulate adipocyte physiology. We confirmed these results by examining NRVM cell lysate and concentrated NRVM-CM by Western blot to test for the presence of decorin, one of the proteins identified by mass spectrometry known to have adipocyte regulatory roles. These results provide a framework to identify potential in vivo cardiomyocyte-released factors that regulate global energy balance.
Health Care Costs of Patients With Biopsy-Confirmed Nonalcoholic Fatty Liver Disease Are Nearly Twice Those of Matched Controls
Authors: Hannes Hagström, Patrik Nasr, Mattias Ekstedt, Ulf Hammar, Linnea Widman, Per Stål, Rolf Hultcrantz, Stergios Kechagias, Martin Henriksson
Journal: Clinical Gastroenterology and Hepatology (2019)
Timeliness of Initial Therapy in Multiple Myeloma (MM): Trends and Factors Influencing Patient Care
Authors: Vivek Kumar, Taimur Sher, Leyla Bojanini, Prakash Vishnu, Vivek Roy, Rami Manochakian, Sri Lekha Bodepudi, Zan Tahir Shareef, Salman Ahmed, Prachi Jani, Victoria R. Alegria, Meghna Ailawadhi, Aneel Paulus, Sonikpreet Aulakh, Madiha Iqbal, Asher A. Chanan-Khan, Sikander Ailawadhi
Journal: Blood (2018)
A multimodal, interprofessional training program on chemotherapy safety for nurses and pharmacists: Development and preliminary evaluation.
Authors: Christopher Ryan Friese, Michelle L. Aebersold
Journal: Journal of Clinical Oncology (2019)

266 Background: Chemotherapy is a high-volume, high-risk clinical intervention that requires interprofessional clinical teams. With increased demand for chemotherapy, a record number of newly-approved drugs, and health system cuts to professional development, we sought to develop and deliver an evidence-based educational program for nurses and pharmacists on safe handling of hazardous drugs, management of oncology emergencies, extravasations, oral oncolytic therapy, and promoting clinical practice change. Methods: After mail and web-based recruitment activities, selected participants completed pre-workshop online modules. Live workshops included a blend of faculty-led interactive sessions and four simulations to reinforce content. Post-simulation debriefing sessions clarified concepts and identified participant action plans for clinical practice change. Attendees have access to lecture videos, handouts, resources, and a discussion board. Applying Kirkpatrick’s framework, we assessed participant confidence to meet program objectives before and after the workshop, a 27-item knowledge assessment before and after the workshop, and satisfaction with specific learning activities on a 5-point Likert scale. Results: To date, faculty have led two workshops. 266 nurses and 72 pharmacists applied and we accepted 77 (29%) and 30 (42%), respectively. Participants' change scores in confidence to meet program objectives increased from pre- to post-workshop (range 0.51-1.00). Knowledge scores increased between pre- and post- workshop (16.3 vs. 18.76, p &lt; .01). Overall satisfaction was high across all content areas (range 4.76 - 4.98). Nearly all participants (n = 104, 97.2%) reported they were extremely satisfied with the program. Conclusions: An interprofessional education program with online modules, in-person interactive sessions, and simulation activities is a promising strategy to deliver chemotherapy safety content to practicing oncology nurses and pharmacists. Future efforts include recruiting a more diverse pool of participants, and expanding the program to include advanced practice providers.
Antifibrinolytic Efficacy of Truncated L17R Mutant of Kunitz Domain 1 (KD1) of Tissue Factor Pathway Inhibitor-2 (TFPI-2): Comparison with Lysine Analogues
Authors: Madhu S Bajaj, Yogesh Kumar, Godwin I Ogueli, Kanagasabai Vadivel, Amy E Schmidt, Nalaka Rannulu, Joseph Loo, S. Paul Bajaj
Journal: Blood (2011)