bluuebunny/crossref_metadata_2025_split huggingface dataset:
Semiquantitative Power Doppler Ultrasound Score to Predict Acute Kidney Injury in Patients With Sepsis or Cardiac Failure: A Prospective Observational Study
Authors: Zhi Hai Jun , Zhao Jing , Nie Shen , Ma Yun Jie , Cui Xiao Ya , Zhang Meng , Li Yong 
Published: November 2019

Background: Diagnosing acute kidney injury (AKI) stage 3 in critically ill patients may help physicians in making treatment decisions. This diagnosis relies chiefly on urinary output and serum creatinine, which may be of limited value. This study aimed to explore the diagnostic performance of renal resistive index (RRI) and semiquantitative power Doppler ultrasound (PDU) scores in predicting AKI stage 3 in patients with sepsis or cardiac failure. Methods: This study is a prospective observational study that included 83 patients (40 with sepsis and 43 with cardiac failure). Renal resistive index and semiquantitative PDU scores were measured within 6 hours following admission to the intensive care unit. Acute kidney injury was defined according to the criteria set by Kidney Disease Improving Global Outcomes. Results: The predictive values of RRI (area under the curve [AUC] = 0.772, 95% confidence interval [CI] = 0.658-0.886) and PDU score (AUC = 0.780, 95% CI = 0.667-0.892) were similar in all patients. Power Doppler ultrasound score (AUC = 0.910, 95% CI = 0.815-1.000) could effectively predict AKI stage 3 in the cardiac failure subgroup, and the optimal cutoff for this parameter was ≤ 1 (sensitivity = 87.5%, specificity = 92.6%, Youden index = 0.801, accuracy in our population = 90.7%). However, PDU scores (AUC = 0.620, 95% CI = 0.425-0.814) could not predict AKI stage 3 in the sepsis subgroup. The predictive values of RRI for AKI stage 3 in the cardiac failure (AUC = 0.820, 95% CI = 0.666-0.974) and sepsis (AUC = 0.724, 95% CI = 0.538-0.910) subgroups were similar. Conclusions: Power Doppler ultrasound scores could effectively predict AKI stage 3 in patients with cardiac failure but not in patients with sepsis. Renal resistive index is a poor predictor of AKI stage 3 in patients with sepsis or cardiac failure.
Intrinsic and Extrinsic Factors Driving Hematopoietic Stem Cell Aging and Bone Marrow Failure
Authors: Trowbridge Jennifer J. 
Published: November 2019

Decline in function of the hematopoietic system and hematopoietic stem cells (HSCs) during aging increases the risk of hematological malignancies including the acquired bone marrow failure condition myelodysplastic syndrome (MDS). As median lifespan is increasing at a global level, the incidence of MDS and associated conditions is also anticipated to increase significantly. Given the poor survival rate and significant morbidities associated with MDS, there is an unmet critical need to develop prophylactic strategies for the prevention of MDS. Current barriers to achieving this goal include a lack of understanding of how to ameliorate functional hematopoietic decline during aging and whether successfully doing so will prevent or delay development of MDS. Understanding both the overlapping and distinct mechanistic alterations in HSCs causing benign physiological aging, aging-associated clonal hematopoiesis (CH) and MDS is needed. A number of HSC-intrinsic and extrinsic mechanisms have been implicated across physiological aging, CH, and MDS including cell cycle regulation, DNA damage, gene expression, chromatin modifications, altered composition and architecture of the bone marrow (BM) microenvironment, and altered chemokine and cytokine levels. Our group has recently determined that both HSC-intrinsic and extrinsic alterations accumulate by middle age and are jointly responsible for HSC aging including phenotypic expansion, impaired regenerative capacity, transcriptional and functional myeloid lineage bias, loss of polarization, and increased DNA damage. We find that diminished local production of insulin-like growth factor 1 (IGF1) by mesenchymal stromal cells (MSCs) in the BM microenvironment causes HSC aging and transient stimulation with IGF1 ligand is sufficient to restore aged HSC regenerative capacity, transcriptional and functional myeloid lineage bias, and polarization. In parallel to these studies, our group has recently generated a new mouse model of CH and its progression to MDS (Loberg et al. 2019). This model incorporates an inducible, canonical missense mutation in the DNA methyltransferase Dnmt3a (R878H) that drives not only long-term (LT)-HSC expansion but also progression to MDS with aging and/or replicative stress. Integrating the above concepts and models, we are now examining whether strategies to rescue benign physiological aging by transient stimulation with IGF1 are sufficient to prevent or delay HSC expansion observed in CH and/or progression of CH to MDS. Ultimately, the goal of this work and future studies will be to restore functional hematopoiesis during aging to prevent acquired bone marrow failure and its complications.
Loberg MA, Bell RK, Goodwin LO, et al. Sequentially inducible mouse models reveal that Npm1 mutation causes malignant transformation of Dnmt3a-mutant clonal hematopoiesis. Leukemia. 2019;33:1635-1649.

Disclosures
Trowbridge: Fate Therapeutics: Patents & Royalties: licensed patent.
The Power of ONE: Immunology in the Age of Single Cell Genomics
Authors: Amit Ido 
Published: November 2019

The immune system is a complex, dynamic and plastic network composed of various interacting cell types that are constantly sensing and responding to environmental cues. From very early on, the immunology field has invested great efforts and ingenuity to characterize the various immune cell types and elucidate their functions. However, accumulating evidence indicates that current technologies and classification schemes are limited in their ability to account for the functional heterogeneity of immune processes. Single cell genomics hold the potential to revolutionize the way we characterize complex immune cell assemblies and study their spatial organization, dynamics, clonal distribution, pathways, and crosstalk. This emerging field can greatly affect basic and translational research of the immune system. I will discuss how recent single cell genomic studies are changing our perspective of various immune related pathologies from cancer to neurodegeneration. Finally, I will consider recent and forthcoming technological and analytical advances in single cell genomics and their potential impact on the future of immunology research and immunotherapy.

Disclosures
No relevant conflicts of interest to declare.
Aptamers as Rapid Onset and Rapidly Reversible Antithrombotic Agents
Authors: Sullenger Bruce A. 
Published: November 2019

Clinical evaluation of our factor IXa RNA aptamer in two thousand patients undergoing percutaneous coronary intervention has demonstrated that aptamers can rapidly and potently inhibit their target proteins in patients and that antidote molecules can rapidly and precisely control such activity in the minute time frame. These observations suggest that aptamers represent useful molecules to tightly control biochemical processes in humans in real time. To begin to explore this potential further, we have started to evaluate the utility of antidote-mediated control of aptamers for a variety of other therapeutic and diagnostic applications. We will describe our recent progress developing a rapidly controllable factor Xa anticoagulant aptamer to effectively yet reversibly control blood coagulation during cardiopulmonary bypass surgery and a rapidly reversible VWF aptamer for improving the treatment of thrombotic stroke. We have observed that aptamers, which target exosites on coagulation factors, can complement active site inhibitors to yield potent anticoagulant regiments (Gunaratne et al., 2018) that can support circulation of blood through extracorporeal oxygenator circuits. Moreover we have observed that an aptamer targeting the A1 domain of VWF can serve as a rapid onset and rapidly reversible antithrombotic agent. This aptamer prevents platelet recruitment and can induce recanalization of occluded arteries while a matched antidote oligonucleotide can rapidly reverse such anti-platelet activity and thereby limit bleeding following vascular injury (Nimjee et al., 2019). Collectively these clinical and preclinical studies lead us to believe that rapidly controllable aptamers represent valuable therapeutic agents that will provide physicians the ability to monitor and precisely control blood coagulation, as well as other biological pathways, in real time in response to individual patients' needs.
GunaratneR, KumarS, FrederiksenJW, et al. Multimodal, antidote-controllable anticoagulation for cardiopulmonary bypass using aptamer-drug pairs. Nature Biotechnology 2018;36:606-613.
NimjeeSM, Dornbos, IIID, Pitoc GA, et al. Preclinical Development of a VWF Aptamer to Limit Thrombosis and Engender Arterial Recanalization of Occluded Vessels. Molecular Therapy. 2019;27:1228-1241.

Disclosures
Sullenger: Basking Biosciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Founder, Patents & Royalties.
Immune-Tumor Interactions in Resistance to Cancer Immunotherapy
Authors: Wucherpfennig Kai W. 
Published: November 2019

MICA and MICB (MICA/B) are expressed by many human cancers due to cellular stress and tag cells for elimination by cytotoxic lymphocytes through NKG2D receptor activation. However, tumors evade this immune recognition pathway through proteolytic shedding of MICA/B proteins. We rationally designed antibodies targeting the MICA α3 domain, the site of proteolytic shedding, and found that these antibodies prevented loss of cell surface MICA/B by human cancer cells. These antibodies inhibited tumor growth in multiple fully immunocompetent mouse models and also reduced human melanoma metastases in a humanized mouse model. Anti-tumor immunity was mediated mainly by NK cells through activation of NKG2D and CD16 Fc receptors. This novel approach prevents the loss of important immunostimulatory ligands by human cancers and reactivates antitumor immunity.

Disclosures
Wucherpfennig: BMS: Research Funding; Novartis: Research Funding; TCR2: Consultancy; Tscan: Consultancy.
Blood Cell Fate Decisions: Insights from Single-cell RNA-seq
Authors: Socolovsky Merav 
Published: November 2019

The manner by which multipotent hematopoietic progenitors commit to the erythroid lineage, and the subsequent processes that govern early erythroid progenitor development, are not well understood. Part of the challenge for investigating these was the lack of a rigorous strategy for isolating directly from tissue the early erythroid progenitors, which are functionally defined as the cell 'units' that give rise to erythroid colonies (CFU-e) or bursts (BFU-e) in culture. Indeed, the early erythroid trajectory, that starts with multi-potential progenitors and gives rise to BFU-e, CFU-e and to erythroblasts undergoing terminal differentiation, was not fully elucidated. We addressed these gaps using single cell transcriptomics, combined with functional assays that validated computational predictions 1. These showed that early hematopoietic progenitors form a continuous, hierarchical branching structure, in which the erythroid and basophil/mast cell fates are unexpectedly coupled. We delineated a novel flow-cytometric strategy that prospectively isolates CFU-e and BFU-e progenitors with high purity, and in combination with computational predictions, identified novel growth factor receptors that regulate early erythropoiesis. We further discovered that early erythroid development entails profound remodeling of both G1 and S phases of the cycle, resulting in cell cycle specializations that orchestrate the developmental process, including a gradual shortening of G1 during the CFU-e phase, followed by a sharp increase in the speed of S phase during the S-phase dependent activation of the erythroid terminal differentiation program 1-3(Figure 2).
1. Tusi BK, Wolock SL, Weinreb C, et al. Population snapshots predict early haematopoietic and erythroid hierarchies. Nature. 2018;555(7694):54-60.
2. Hwang Y, Futran M, Hidalgo D, et al. Global increase in replication fork speed during a p57KIP2-regulated erythroid cell fate switch. Science Advances. 2017;3:e1700298.
3. Pop R, Shearstone JR, Shen Q, et al. A key commitment step in erythropoiesis is synchronized with the cell cycle clock through mutual inhibition between PU.1 and S-phase progression. PLoS Biol. 2010;8(9).

Disclosures
No relevant conflicts of interest to declare.
Bio-Inspired Artificial Red Blood Cell: Design, Pre-Clinical Results and Novel Indications
Authors: Doctor Allan 
Published: November 2019

In blood, the primary role of RBCs is to transport oxygen and to regulate regional blood flow distribution, via highly regulated mechanisms. In the setting of exsanguinating haemorrhage or severe anemia, RBC loss may critically restrict tissue oxygenation and result in morbidity and mortality. In such cases, transfusion of whole blood or RBCs can significantly improve survival. However, blood products including RBCs have limited availability and portability and present additional challenges related to type matching, pathogenic contamination risks, and short shelf-life. These issues lead to substantial logistical barriers to their pre-hospital use or in austere battlefield and remote civilian conditions. To date, efforts to develop hemoglobin (Hb) based oxygen carriers (HBOCs) have failed, because of design flaws which do not preserve physiologic interactions of Hb with: O2 (they capture O2 in lungs, but do not release O2 effectively to tissue) and nitric oxide (NO) (they trap NO, causing vasoconstriction). While robust efforts are underway to resolve these issues, recent research breakthroughs have led to bio-inspired engineering of RBC surrogates, using various cross-linked, polymeric and encapsulated Hb in the form of 'bio-synthetic RBC surrogates'. These 'next-generation' Hb-based oxygen carriers (HBOCs) can potentially provide therapeutic oxygenation when whole blood or RBC are not available. This talk will comprehensively review both historical and new HBOC designs, including current state-of-the-art and novel bio-inspired artificial RBC designs in development, along with a critical discussion of successes and challenges in this field.

Disclosures
Doctor: Biogen: Membership on an entity's Board of Directors or advisory committees; Fresenius Kabi: Honoraria; KaloCyte, Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Etiometry: Membership on an entity's Board of Directors or advisory committees.
Three-D Codes in the Human Genome
Authors: Aiden Erez Lieberman 
Published: November 2019

Stretched out from end-to-end, the human genome -a sequence of 3 billion chemical letters inscribed in a molecule called DNA -is over 2 meters long. Famously, short stretches of DNA fold into a double helix, which wind around histone proteins to form the 10nm fiber. But what about longer pieces? Does the genome's fold influence function? How does the information contained in such an ultra-dense packing even remain accessible?In this talk, I describe our work developing 'Hi-C' (Lieberman-Aiden et al., Science, 2009; Aiden, Science, 2011) and more recently 'in-situHi-C' (Rao & Huntley et al., Cell, 2014), which use proximity ligation to transform pairs of physically adjacent DNA loci into chimeric DNA sequences. Sequencing a library of such chimeras makes it possible to create genome-wide maps of physical contacts between pairs of loci, revealing features ofgenome folding in 3D. Next, I will describe recent work using in situ Hi-C to construct haploid and diploid maps of nine cell types. The densest, in human lymphoblastoid cells, contains 4.9 billion contacts, achieving 1 kb resolution. We find that genomes are partitioned into contact domains (median length, 185 kb), which are associated with distinct patterns of histone marks and segregate into six subcompartments. We identify ∼10,000 loops. These loops frequently link promoters and enhancers, correlate with gene activation, and show conservation across cell types and species. Loop anchors typically occur at domain boundaries and bind the protein CTCF. The CTCF motifs at loop anchors occur predominantly (>90%) in a convergent orientation, with the asymmetric motifs "facing" one another. Next, I will discuss the biophysical mechanism that underlies chromatin looping. Specifically, our data is consistent with the formation of loops by extrusion (Sanborn & Rao et al., PNAS, 2015). In fact, in many cases, the local structure of Hi-C maps may be predicted in silicobased on patterns of CTCF binding and an extrusion-based model. Finally, I will show that by modifying CTCF motifs using CRISPR, we can reliably add, move, and delete loops and domains. Thus, it possible not only to "read" the genome's 3D architecture, but also to write it.

Disclosures
No relevant conflicts of interest to declare.
Ex Vivo Drug Sensitivity Screens Identify Personalized Treatment Options for CLL Patients
Authors: Skånland Sigrid Strand , Henrik Bendiksen , Cremaschi Andrea , Thimiri Govinda Raj Deepak Balaji , Munthe Ludvig Andre , Tjønnfjord Geir Erland , Taskén Kjetil 
Published: November 2019

In the era of targeted therapies, it remains a challenge to determine the optimal treatment for the individual cancer patient. By screening the tumor cells for drug sensitivity ex vivo it is possible to predict to which drugs and drug combinations the cancer will respond. We have developed an ex vivo culture protocol that mimics the chronic lymphocytic leukemia (CLL) tumor microenvironment and allows cell proliferation. Using our unique method, we performed drug sensitivity screens on B cells from 22 CLL patients and 5 matched healthy donors. The drug library consisted of 70 single drugs and 39 drug combinations that are clinically relevant for treatment of CLL, including venetoclax (Bcl-2 antagonist), ibrutinib (Btk inhibitor) and idelalisib (PI3K inhibitor). B cells were cultured in 384-well plates in the presence of drugs covering a concentration range of 5 log10 increments. Drug sensitivity was assessed after three days using the CellTiter-Glo luminescent cell viability assay. The Drug Sensitivity Score (DSS) was then calculated for each treatment based on area under the concentration-response curve. We observed specificity towards CLL cells for drugs including TAK-659 (SYK inhibitor), TGR-1202 and duvelisib (PI3K inhibitors), trametinib (MEK1/2 inhibitor) and venetoclax. Ten combinations with venetoclax were investigated, and all showed high drug sensitivity and specificity towards CLL cells. When ranking the drug combinations from high to low DSS, CLL selectivity and obtained synergy, combinations of venetoclax with trametinib, ibrutinib or duvelisib showed the highest potency. Of interest, similar effects were not observed for venetoclax in combination with other Btk or PI3K inhibitors. In order to understand the mechanisms underlying these differences, signaling analyses by use of phospho flow is currently ongoing. In summary, by applying drug sensitivity screens, we have identified drugs and drug combinations that kill CLL cells. These findings should be investigated further in animal models and in precision medicine clinical trials.

Disclosures
Tjønnfjord: Mundipharma: Research Funding.
Predictive and Prognostic Factors Associated with the Incidence and Mortality of Hematologic Malignancies
Authors: Deloughery Emma P. , Shatzel Joseph J 
Published: November 2019

Background:
Identifying individual and systemic risk factors are key to reducing cancer incidence and improving mortality. Unfortunately for hematologic malignancies, few clear-cut common cause-and-effect relationships exist. Multiple myeloma has been associated with Black race and obesity, and the lymphomas and leukemias differ in incidence with age. In order to identify potential risk factors, in this study we compared incidence and mortality rates among U.S. states for myeloma, all leukemias and lymphomas, and correlated these rates with the prevalence of several lifestyle and demographic characteristics.
Methods:
Data came from the following sources: cancer incidence and mortality data from 1999-2015 came from the CDC WONDER database; race and poverty prevalence from the 2015 American Community Survey; gross domestic product (GDP) data from the Bureau of Economic Analysis; median household income from the Census Bureau; and weight and physical activity data from the Behavioral Risk Factor Surveillance System survey. Spearman's rank correlation coefficient was used to compare cancer incidence/mortality and potential risk factors.
Results:
Myeloma incidence and mortality were more common in obese individuals (incidence, rho = 0.27, P = 0.05; mortality, 0.38, P = 0.006) and individuals identifying as Black (0.65, P < 0.001; 0.42, P = 0.002). Incidence was lower in physically active individuals. (-0.51, P < 0.001).
Leukemia incidence and mortality were more common in individuals identifying as white (0.45, P = 0.001; 0.36, P = 0.009). Mortality was positively associated with obesity (0.39, P = 0.005), and negatively associated with physical activity (-0.36, P = 0.009) and median household income (-0.39, P = 0.004).
Lymphoma incidence and mortality were more common in white individuals (0.38, P = 0.006; 0.40, P = 0.004). Incidence was negatively associated with state poverty percentage (-0.40, P = 0.003). Mortality was positively associated with obesity (0.35, P = 0.01), and negatively associated with a healthy weight (-0.35, P = 0.01).
Discussion:
This data suggests that weight and activity are modifiable risk factors for a variety of hematologic cancers, while race may be a non-modifiable risk factor. Individual and state wealth do not appear to play a large role in incidence or mortality. Although further study is needed, these results underscore the importance of maintaining a healthy weight and regular physical activity in cancer prevention. This data also confirms the higher incidence of myeloma in Black individuals and suggests lymphoma and leukemias may be more common among those identifying as white.

Disclosures
Shatzel: Aronora, Inc.: Consultancy.