tbuckley/cabot-search huggingface dataset:
Elevated Lipoprotein (a) in Cardiac Outcomes: A Review
Authors: Sahoo Alor, Strong Laura, Jensen Alexander, Flaherty Daniel, Anand Mukul, Alromheen Hassan, Singh, Sarabjeet
Journal: Clinical Cardiology and Cardiovascular Interventions (2020)

Context Elevated lipoprotein (a) [Lp(a)] levels is an often-ignored risk factor for major adverse cardiac events (MACEs) in humans. Even after accounting for established risk factors (discussed in the text), some residual risk can still be independently attributed to elevated Lp(a) levels. Current guidelines dictating normal and elevated Lp(a) levels and subsequent treatment have proven haphazard due to unstandardized studies. Many studies offer cutoff values in units mg/dL, which do not account for the heterogeneity of Lp(a). Interpretation of elevated Lp(a) necessitates consideration of ethnicity necessary for proper predictions. Numerous studies detail the effects of elevated Lp(a) in relation to myocardial infarction, aortic valve stenosis, and atherosclerosis, among other conditions. This article aims to clarify the numerous cutoffs and guidelines presented. Methods Searches were primarily conducted through Google, PubMed.gov, and cochrane.org. Results Elevated Lp(a) seems to correlate with the incidence of MACEs and should be considered when assessing risk. Specific cutoff values remain quite unclear. Conclusions We urge for further detailed investigation on the effects of elevated Lp(a) on cardiac outcomes with the use of isoform independent assays. Particular attention should be given to ethnicity when assigning risk cutoffs for cardiac conditions. Proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors can lower Lp(a) levels significantly and should be investigated.
Superior Outcomes with Fludarabine-Busulfan (Flu/Bu) Based Conditioning for Allogeneic Hematopoietic Cell Transplantation in Myelofibrosis - a Comparative Analysis By CIBMTR
Authors: Guru Subramanian Guru Murthy, Soyoung Kim, Noel Estrada-Merly, Ronald M. Sobecks, Betul Oran, Ryotaro Nakamura, Bart L. Scott, Wael Saber
Journal: Blood (2021)
CTNI-36. SAFETY OF ONC201 ADMINISTERED TWO CONSECUTIVE DAYS PER WEEK IN PEDIATRIC H3 K27M-MUTANT GLIOMA PATIENTS
Authors: Sharon Gardner, Carl Koschmann, Rohinton Tarapore, Jeffrey Allen, Wafik Zaky, Yazmin Odia, Matthew Hall, Doured Daghistani, Ziad Khatib, Dolly Aguilera, Tobey MacDonald, Peter de Blank, Susan McGovern, Sabine Mueller, Cassie Kline, Nicholas Vitanza, Joshua Allen, Soumen Khatua
Journal: Neuro-Oncology (2021)

Abstract ONC201, an anti-cancer DRD2 antagonist and ClpP agonist, is in Phase II trials for adult H3 K27M-mutant diffuse midline gliomas. The recommended phase 2 dose (RP2D) of 625mg ONC201 once a week has been established as a biologically active dose that is well tolerated in adult and pediatric populations. Radiographic regressions with single agent ONC201 have been reported in recurrent H3 K27M-mutant glioma patients. In another study, twice/week dosing was explored in adult patients and deemed to be safe (no DLTs observed). This warranted exploration of twice/week dosing in pediatric patients and will be discussed in this presentation. This multi-arm, dose-escalation and dose-expansion trial (ONC014; NCT03416530) determined the pediatric RP2D of ONC201 administered once per week and twice per week on two consecutive days. ONC201 was orally administered and scaled by body weight. Dose escalation was performed by a 3 + 3 design beginning with two 125mg capsules less than the adult RP2D equivalent. Twelve children (8 females; 4 males) with H3 K27M-mutant gliomas (pons: 8; thalamus: 2; spinal cord: 2) aged 4-19 years have been treated post-radiation: 3 at dose level -1; 3 at dose level 1; 6 as part of the dose expansion cohort on dose level 2. Median KPS was 90 (range 70-100). One treatment cycle was 21 days (6 doses), which also defined the DLT window. Patients were on-treatment for a median length of 4 cycles (range: 2-11). Twice weekly dosing of ONC201 was tolerated well, as observed with weekly dosing, with no instance of DLT. A total of 4 SAEs were reported, none of which were related to the study drug. The most common AEs (regardless of relatedness) included headache, facial nerve disorder, abducens nerve disorder, nausea, fatigue and ataxia. Additional safety data, PK, and clinical outcomes from this arm will be reported.
Polatuzumab Vedotin Use before Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in Aggressive Lymphoma: A US Single Center Experience
Authors: Arushi Khurana, Radhika Bansal, Matthew Hathcock, Adrienne Nedved, Yucai Wang, Jonas Paludo, Jose C Villasboas, N. Nora Bennani, Patrick B. Johnston, Stephen M. Ansell, Yi Lin
Journal: Blood (2021)
Real World Data on the Outcomes of Richter's Transformation of Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma in the Australian Population: An Australasian Lymphoma Alliance Study
Authors: Stephen K Walker, Sean Harrop, Pietro Di Ciaccio, Katharine Louise Lewis, Rachael Boles, Aditya Tedjaseputra, Nada Hamad, Georgina Hodges, Costas K. Yannakou, Constantine S. Tam, Stephen Opat, Chan Yoon Y. Cheah, Matthew Ku
Journal: Blood (2021)
Single-Cell Characterization of the Immune and Leukemic Cells Following Anti-TIM3 and Hypomethylating Agent Combination Therapy in Patients with AML or MDS
Authors: Jani Huuhtanen, Oscar Brück, Karita Peltonen, Anna Kreutzman, Olli Dufva, Matti Kankainen, Mette Ilander, Hanna Lähteenmäki, Tiina Kasanen, Jay Klievink, Mika Kontro, Elena J Orlando, Viviana Cremasco, Joel Wagner, Marc Pelletier, Harri Lähdesmäki, Catherine A. Sabatos-Peyton, Mikael L. Rinne, Kimmo Porkka, Satu Mustjoki
Journal: Blood (2021)
Pediatric Sickle Cell Disease and the COVID-19 Pandemic: A Year in Review at Children's National Hospital
Authors: Olufunke Y. Martin, Deepika S. Darbari, Stefanie Margulies, Robert Sheppard Nickel, Alexis Leonard, Barbara Speller-Brown, Brenda Martin, Jennifer Webb, Suvankar Majumdar, Matthew Sharron, Andrew D. Campbell
Journal: Blood (2021)
Dual roles of p62/SQSTM1 in the injury and recovery phases of acetaminophen-induced liver injury in mice
Authors: Hui Qian, Qingyun Bai, Xiao Yang, Jephte Y. Akakpo, Lili Ji, Li Yang, Thomas Rülicke, Kurt Zatloukal, Hartmut Jaeschke, Hong-Min Ni, Wen-Xing Ding
Journal: Acta Pharmaceutica Sinica B (2021)

Acetaminophen (APAP) overdose can induce liver injury and is the most frequent cause of acute liver failure in the United States. We investigated the role of p62/SQSTM1 (referred to as p62) in APAP-induced liver injury (AILI) in mice. We found that the hepatic protein levels of p62 dramatically increased at 24 h after APAP treatment, which was inversely correlated with the hepatic levels of APAP-adducts. APAP also activated mTOR at 24 h, which is associated with increased cell proliferation. In contrast, p62 knockout (KO) mice showed increased hepatic levels of APAP-adducts detected by a specific antibody using Western blot analysis but decreased mTOR activation and cell proliferation with aggravated liver injury at 24 h after APAP treatment. Surprisingly, p62 KO mice recovered from AILI whereas the wild-type mice still sustained liver injury at 48 h. We found increased number of infiltrated macrophages in p62 KO mice that were accompanied with decreased hepatic von Willebrand factor (VWF) and platelet aggregation, which are associated with increased cell proliferation and improved liver injury at 48 h after APAP treatment. Our data indicate that p62 inhibits the late injury phase of AILI by increasing autophagic selective removal of APAP-adducts and mitochondria but impairs the recovery phase of AILI likely by enhancing hepatic blood coagulation.
ERK1/2 Inhibition Overcomes Resistance in Acute Myeloid Leukemia (AML) and Alters Mitochondrial Dynamics
Authors: Priyanka Sharma, Sujan Piya, Huaxian Ma, Natalia Baran, Malgorzata Anna Zal, Christopher J. Hindley, Kim-Hien Dao, Martin Sims, Tomasz Zal, Vivian Ruvolo, Michael Andreeff, Gautam Borthakur
Journal: Blood (2021)
Extracellular Vesicles Generated Using Bioreactors and their Therapeutic Effect on the Acute Kidney Injury Model
Authors: Hyejin Kang, Yeon‐hee Bae, Yongmin Kwon, Sejoong Kim, Jaesung Park
Journal: Advanced Healthcare Materials (2021)

Extracellular vesicles (EVs) are nano-sized vesicles secreted by cells, having beneficial effects for various types of regenerative processes. Although EVs have shown promising effects as therapeutic agents, these effects are difficult to research due to the limitations of EV production. In this study, an EV production method based on a flat-plate bioreactor is introduced. The bioreactor produces approximately seven times more mesenchymal stem cell-derived EVs than static culture conditions. The mechanism underlying the increased production of EVs in a flat-plate bioreactor and its application to acute kidney injury is investigated. This study describes the mechanism of EV production by demonstrating the link between EV biogenesis and increased calcium ion concentration under flow conditions. EVs secreted by cells cultured in the bioreactor have therapeutic efficacy in terms of improving kidney damage, resulting in tissue regeneration in a cisplatin-induced acute kidney injury model. This method will help overcome the limitations of EV production, and the analysis of the application of EVs will increase their reliability as well as the understanding of the use of bioreactor-derived EVs as therapeutic agents.
Lisocabtagene Maraleucel (liso-cel), a CD19-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy, Versus Standard of Care (SOC) with Salvage Chemotherapy (CT) Followed By Autologous Stem Cell Transplantation (ASCT) As Second-Line (2L) Treatment in Patients (Pts) with Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL): Results from the Randomized Phase 3 Transform Study
Authors: Manali Kamdar, Scott R. Solomon, Jon E. Arnason, Patrick B. Johnston, Bertram Glass, Veronika Bachanova, Sami Ibrahimi, Stephan Mielke, Pim G.N.J. Mutsaers, Francisco J. Hernandez-Ilizaliturri, Koji Izutsu, Franck Morschhauser, Matthew A. Lunning, David G. Maloney, Alessandro Crotta, Sandrine Montheard, Alessandro Previtali, Lara Stepan, Ken Ogasawara, Timothy Mack, Jeremy S. Abramson
Journal: Blood (2021)
EPCO-08. ATRX DEFICIENCY INDUCES DYSFUNCTIONAL HETEROCHROMATIN ARCHITECTURE IN GLIOMAS AND ESTABLISHES DISEASE-DEFINING TRANSCRIPTIONAL NETWORKS
Authors: Prit Benny Malgulwar, Carla Danussi, Anand Singh, Kasthuri Kannan, Kunal Rai, Jason Huse
Journal: Neuro-Oncology (2021)

Abstract Loss of ATRX (Alpha Thalassemia/Mental Retardation Syndrome X, a member of SWI/SNF family chromatin regulator is altered in diffuse gliomas and defines molecular subtypes with aggressive behavior. Mechanistically, ATRX regulates incorporation of histone H3.3 into chromatin sites across the genome, maintains alternative lengthening of telomeres and establishes genomic distribution of polycomb responsive genes. We have recently reported Atrx deficiency induces glioma oncogenic features via widespread alterations in chromatin accessibility using mouse Neural Progenitor Cells (mNPCs- Tp53 -/-,Atrx -/-). Surprisingly, Atrx was found to be associated with transcription start site and enhancer regions, suggesting their strong association with epigenome architecture. In this background, we have recently performed ChIP-seq for histone marks that define active transcription, enhancers, repressors and gene bodies and Cohesion molecules on Atrx intact and deficient mNPCs. Our integrated analysis reports depletion of H3K9me3 loci’s with enrichment of H3K27me3 marks that coincidently enriched with Atrx binding sites and Lamina-Associated Domains (LADs). GSEA confirmed that the genes corresponding to “newly formed LADs” in mNPC-to-astrocyte differentiation are significantly enriched for genes down-regulated in Atrx deficient mNPCs and belongs to Gene Ontology categories such as cell cycle, chromosome organization and DNA damage. Alternatively, genes corresponding to decreased LAD association are enriched for up-regulated genes in Atrx deficient mNPCs and for regulation of differentiation, adhesion and cell death. Additionally, whole-genome bisulphite sequencing further demonstrated loss of methylation marks at H3K9me3 sites in Atrx deficient mNPCs, suggesting perturbations of heterochromatin regions leading to activation of canonical signals that define glioma phenotype and disease-state. To summarize, our data establishes tangible links between Atrx deficiency and dysregulated chromatin and heterochromatin architecture in gliomas and suggests the role of Atrx in establishing global chromatin features and transcriptional networks. Further, our data unravel novel therapeutic molecules/pathways for engineering potential.
Abstract 9548: De Novo Atypical Atrial Flutters: Locations, Mechanisms, and Long Term Outcomes Post Ablation
Authors: Alyssa Zaidi, Jared Kirzner, Christopher F Liu, Jim W Cheung, George Thomas, James E Ip, Bruce B Lerman, Steven Markowitz
Journal: Circulation (2021)

Introduction: Atypical atrial flutter (aAFL) has been described in the absence of prior atrial interventions, but prognosis for these patients after catheter ablation is poorly defined. This study was designed to define characteristics and ablation outcomes in patients with de novo aAFL. Methods: Patients with non-CTI flutter, without prior ablation or cardiac surgery, were identified from an institutional database. Clinical, mapping, ablation, and follow up data were compared to an equally sized group of randomly selected patients with typical flutter (tAFL). Results: The 35 patients with aAFL had 45 mapped non-CTI flutters. aAFL patients had similar age, gender, cardiovascular comorbidities, and LA size compared to tAFL, except aAFL patients had higher LVEF (54 ± 12 vs 46 ± 19%, p=0.04). Cycle length of aAFL was longer (268 [IQR 231, 310] vs 230 [220, 250] msec, p=0.0006). aAFL localized to the RA in 16, LA in 28, and biatrial in 1. Mechanisms were macroreentry in 23 (8 RA, 15 LA) and localized reentry in 22 (8 RA, 14 LA). Areas of scar predominated in the lateral/posterior RA (N=9), anterior LA (N=14), and posterior LA (N=6). Most common LA circuits were perimitral reentry (N=8) and roof dependent (N=8), including dual loop reentry. Localized reentry occurred most commonly in the anterior LA (N=7) or involved the pulmonary veins (N=4). Ablation was acutely successful for 41/45 aAFLs (91%) and for all tAFL. After median follow-up of 33 [6.6, 55] mo, atrial arrhythmias recurred in 23/34 aAFL patients (68%) and 24/35 tAFL patients (69%); those with aAFL had earlier recurrences (1.9 [0.43, 11] vs 19 [2.3, 36] mo, p=0.01). First recurrences after aAFL ablation were more likely to be AFL rather than AF (83% vs 17%) whereas tAFL patients were more likely to recur with AF (24% AFL vs 76% AF, p&lt;0.0001). Conclusions: Patients with de novo aAFL tend to have spontaneous scar, commonly in the lateral/posterior RA and anterior LA, consistent with an atrial myopathy. Ablation can be accomplished with high acute success, but recurrent atrial arrhythmias are common, most re-presenting with atrial tachycardias. Future studies should clarify if a substrate-based approach or adjunctive antiarrhythmic drugs would result in better long term outcomes.
Lesbian, Gay, Bisexual, and Transgender Identity and Disclosure Among Dermatologists in the US
Authors: Matthew D. Mansh, Erica Dommasch, J. Klint Peebles, Kara Sternhell-Blackwell, Howa Yeung
Journal: JAMA Dermatology (2021)

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Estimated Cost-effectiveness of Atezolizumab Plus Cobimetinib and Vemurafenib for Treatment of<i>BRAF V600</i>Variation Metastatic Melanoma
Authors: Chao Cai, Ismaeel Yunusa, Ahmad Tarhini
Journal: JAMA Network Open (2021)

<h3>Importance</h3> In the IMspire150 trial, triplet treatment with atezolizumab and vemurafenib plus cobimetinib significantly improved progression-free survival (PFS) compared with vemurafenib plus cobimetinib alone for treatment of<i>BRAF V600</i>variation metastatic melanoma. However, considering high cost of this combination, it is unclear if the incremental cost is worth the additional survival benefit. <h3>Objective</h3> To evaluate the cost-effectiveness of atezolizumab and vemurafenib plus cobimetinib vs vemurafenib plus cobimetinib alone in patients with newly diagnosed unresectable<i>BRAF V600</i>variation metastatic melanoma from the US health care perspective. <h3>Design, Setting, and Participants</h3> This economic evaluation study used a 3-state partitioned survival model to assess the cost-effectiveness of the combination of atezolizumab with vemurafenib plus cobimetinib vs vemurafenib plus cobimetinib alone. The observed Kaplan-Meier curves for overall survival and PFS were digitized from the IMspire150 trial (January 2017-April 2018) and the long-term survivals (over a lifetime horizon) beyond the end of the trial were extrapolated using 7 different survival models. The cost and health preference data were collected from a literature review. This study was performed from March 2021 through June 2021. <h3>Main Outcomes and Measures</h3> The outcomes of interest were expected life-years (LYs) gained and quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratio (ICER), expressed as cost per LYs and per QALYs saved. <h3>Results</h3> Adding atezolizumab to vemurafenib and cobimetinib provided an additional 3.267 QALYs compared with the doublet regimen of vemurafenib plus cobimetinib, at an ICER of $271 669 per QALY, which is not considered cost-effective at the willingness-to-pay threshold of $150 000 per QALY. However, the scenario analyses found that atezolizumab combined with vemurafenib plus cobimetinib could be cost-effective at 20-year (ICER, $121 432 per QALY) and 30-year ($98 092 per QALY) time horizons when both strategies were stopped after 2 years of treatments, and over a lifetime horizon ($122 220 per QALY) when only immunotherapy with atezolizumab was stopped after 2 years of treatment. <h3>Conclusions and Relevance</h3> These findings suggest that the atezolizumab and vemurafenib plus cobimetinib regimen provides significant survival benefits over vemurafenib plus cobimetinib alone, and a price reduction would be encouraged to maximize the value of its survival gain.
Treatment Selection in First-line Metastatic Renal Cell Carcinoma—The Contemporary Treatment Paradigm in the Age of Combination Therapy
Authors: Vishal Navani, Daniel Y. C. Heng
Journal: JAMA Oncology (2021)

The treatment landscape of metastatic renal cell carcinoma has evolved rapidly over the last decade. Recent combination approaches heralded by targeting immune checkpoints cytotoxic T-lymphocyte antigen 4 and programmed death-1 (PD-1) have been followed in consecutive years by protocols targeting vascular endothelial growth factor receptor, PD-1, and programmed death ligand-1. The differences in baseline patient characteristics, statistical plans, follow-up length, biomarker-derived approaches, and trial design make cross-trial comparisons difficult. Given the regulatory approval of a number of these regimens, the current available evidence is reviewed herein for combination first-line regimens with published randomized phase 3 trial data.Combination approaches have transformed outcomes for patients. Durable disease control and prolonged overall survival have been achieved by both doublet immune checkpoint blockade and vascular endothelial growth factor receptor plus PD-1 blockade. Rationale for variations in trial outcome are offered, alongside approaches to navigating patient-empowered treatment selection, focusing on predictive tools, biomarkers, and the role of real-world data.Advances in the genomic, molecular, and immunologic understanding of metastatic clear cell renal cell carcinoma have lifted the survival curves for this disease markedly in recent years. Combination approaches will remain standard of care in the first-line setting. However, thoughtful study design is needed to accurately estimate outcomes and integrate novel approaches into the treatment armamentarium.
Uptake of oxidative stress-mediated extracellular vesicles by vascular endothelial cells under low magnitude shear stress
Authors: Xian Qin, Kun Zhang, Juhui Qiu, Nan Wang, Kai Qu, Yuliang Cui, Junli Huang, Li Luo, Yuan Zhong, Tian Tian, Wei Wu, Yi Wang, Guixue Wang
Journal: Bioactive Materials (2021)

Extracellular vesicles (EVs) are increasingly used as delivery vehicles for drugs and bioactive molecules, which usually require intravascular administration. The endothelial cells covering the inner surface of blood vessels are susceptible to the shear stress of blood flow. Few studies demonstrate the interplay of red blood cell-derived EVs (RBCEVs) and endothelial cells. Thus, the phagocytosis of EVs by vascular endothelial cells during blood flow needs to be elucidated. In this study, red blood cell-derived extracellular vesicles (RBCEVs) were constructed to investigate endothelial cell phagocytosis in vitro and animal models. Results showed that low magnitude shear stress including low shear stress (LSS) and oscillatory shear stress (OSS) could promote the uptake of RBCEVs by endothelial cells in vitro. In addition, in zebrafish and mouse models, RBCEVs tend to be internalized by endothelial cells under LSS or OSS. Moreover, RBCEVs are easily engulfed by endothelial cells in atherosclerotic plaques exposed to LSS or OSS. In terms of mechanism, oxidative stress induced by LSS is part of the reason for the increased uptake of endothelial cells. Overall, this study shows that vascular endothelial cells can easily engulf EVs in areas of low magnitude shear stress, which will provide a theoretical basis for the development and utilization of EVs-based nano-drug delivery systems in vivo.
Microlyse: a thrombolytic agent that targets VWF for clearance of microvascular thrombosis
Authors: Steven de Maat, Chantal C. Clark, Arjan D. Barendrecht, Simone Smits, Nadine D. van Kleef, Hinde El Otmani, Manon Waning, Marc van Moorsel, Michael Szardenings, Nicolas Delaroque, Kristof Vercruysse, Rolf T. Urbanus, Silvie Sebastian, Peter J. Lenting, Christoph Hagemeyer, Thomas Renné, Karen Vanhoorelbeke, Claudia Tersteeg, Coen Maas
Journal: Blood (2021)
Ensuring equal access to care for all transgender people
Authors: Adam Shepherd, Benjamin Hanckel
Journal: BMJ (2021)

There have been growing efforts to make healthcare inclusive of all trans people.Inclusive care is often measured through care provider practices, often resulting in visible LGBTIQ+pamphlets, rainbow flags, posters, and pronoun badges to promote inclusivity.While such changes are important, they do not address some of the more ingrained problems with current healthcare systems, such as unhelpful categorisations of gender on medical records.These designate a patient as either "male" or "female," which presumes that people have particular anatomies and physiologies based on these categories, and does not provide trans people with the support they require.
Haploidentical Versus Cord Blood Stem Cell Transplantation As the Second Transplant for Relapsed Acute Myeloid Leukemia Patients after the First Stem Cell Transplantation
Authors: Jong Hyuk Lee, Daehun Kwag, Tong-Yoon Kim, Gi June Min, Sung-Soo Park, Silvia Park, Seung-Ah Yahng, Seung-Hwan Shin, Sung-Eun Lee, Jae-Ho Yoon, Byung Sik Cho, Yoo-Jin Kim, Ki-Seong Eom, Seok Lee, Chang-Ki Min, Seok-Goo Cho, Jong Wook Lee, Hee-Je Kim
Journal: Blood (2021)