Publications by authors named "Alfredo Lucas"

21 Publications

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Withdrawn as duplicate: Commentary: "Zooming in" on Glioblastoma: Understanding Tumor Heterogeneity and its Clinical Implications in the Era of Single-Cell Ribonucleic Acid Sequencing.

Neurosurgery 2021 Sep;89(4):E237-E238

University of Pennsylvania, Philadelphia, Pennsylvania, USA.

This article has been withdrawn due to an error that caused the article to be duplicated. The definitive version of this article is published under DOI 10.1093/neuros/nyab288.
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http://dx.doi.org/10.1093/neuros/nyab280DOI Listing
September 2021

Increased hemoglobin affinity for oxygen with GBT1118 improves hypoxia tolerance in sickle cell mice.

Am J Physiol Heart Circ Physiol 2021 08 2;321(2):H400-H411. Epub 2021 Jul 2.

Department of Bioengineering, University of California San Diego, La Jolla, California.

Therapeutic agents that increase the Hb affinity for oxygen (O) could, in theory, lead to decreased O release from Hb and impose a hypoxic risk to tissues. In this study, GBT1118, an allosteric modifier of Hb affinity for O, was used to assess the impact of increasing Hb affinity for O on brain tissue oxygenation, blood pressure, heart rate, O delivery, and tolerance to hypoxia in Townes transgenic sickle cell disease (SCD) mice. Brain oxygenation and O delivery were studied during normoxia and severe hypoxic challenges. Chronic treatment with GBT1118 increased Hb affinity for O, reducing the Po for 50% HbO saturation (P50) in SCD mice from 31 mmHg to 18 mmHg. This treatment significantly reduced anemia, increasing hematocrit by 33%, improved cardiac output (CO), and O delivery and extraction. Chronically increasing Hb affinity for O with GBT1118 preserved cortical O tension during normoxia, improved cortical O tension during hypoxia, and increased tolerance to severe hypoxia in SCD mice. Independent of hematological changes induced by chronic treatment, a single dose of GBT1118 significantly improved tolerance to hypoxia, highlighting the benefits of increasing Hb affinity for O and consequently reducing sickling of RBCs in blood during hypoxia in SCD. Chronic pharmacologically increased hemoglobin affinity for oxygen in sickle cell disease mice alleviated hematological consequences of sickle cell disease, increasing RBC half-life, hematocrit, and hemoglobin concentration, while also decreasing reticulocyte count. Additionally, chronically increased hemoglobin affinity for oxygen significantly improved survival as well as cortical tissue oxygenation in sickle cell disease mice during hypoxia, suggesting that oxygen delivery and utilization is improved by increased hemoglobin affinity for oxygen.
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http://dx.doi.org/10.1152/ajpheart.00048.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410120PMC
August 2021

Resuscitation from hemorrhagic shock after traumatic brain injury with polymerized hemoglobin.

Sci Rep 2021 01 28;11(1):2509. Epub 2021 Jan 28.

Department of Bioengineering, University of California San Diego, 9500 Gilman Dr. La Jolla, San Diego, CA, 92093-0412, USA.

Traumatic brain injury (TBI) is often accompanied by hemorrhage, and treatment of hemorrhagic shock (HS) after TBI is particularly challenging because the two therapeutic treatment strategies for TBI and HS often conflict. Ischemia/reperfusion injury from HS resuscitation can be exaggerated by TBI-induced loss of autoregulation. In HS resuscitation, the goal is to restore lost blood volume, while in the treatment of TBI the priority is focused on maintenance of adequate cerebral perfusion pressure and avoidance of secondary bleeding. In this study, we investigate the responses to resuscitation from severe HS after TBI in rats, using fresh blood, polymerized human hemoglobin (PolyhHb), and lactated Ringer's (LR). Rats were subjected to TBI by pneumatic controlled cortical impact. Shortly after TBI, HS was induced by blood withdrawal to reduce mean arterial pressure (MAP) to 35-40 mmHg for 90 min before resuscitation. Resuscitation fluids were delivered to restore MAP to ~ 65 mmHg and animals were monitored for 120 min. Increased systolic blood pressure variability (SBPV) confirmed TBI-induced loss of autoregulation. MAP after resuscitation was significantly higher in the blood and PolyhHb groups compared to the LR group. Furthermore, blood and PolyhHb restored diastolic pressure, while this remained depressed for the LR group, indicating a loss of vascular tone. Lactate increased in all groups during HS, and only returned to baseline level in the blood reperfused group. The PolyhHb group possessed lower SBPV compared to LR and blood groups. Finally, sympathetic nervous system (SNS) modulation was higher for the LR group and lower for the PolyhHb group compared to the blood group after reperfusion. In conclusion, our results suggest that PolyhHb could be an alternative to blood for resuscitation from HS after TBI when blood is not available, assuming additional testing demonstrate similar favorable results. PolyhHb restored hemodynamics and oxygen delivery, without the logistical constraints of refrigerated blood.
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http://dx.doi.org/10.1038/s41598-021-81717-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843604PMC
January 2021

The vascular landscape of human cancer.

J Clin Invest 2021 01;131(2)

Department of Medicine.

Tumors depend on a blood supply to deliver oxygen and nutrients, making tumor vasculature an attractive anticancer target. However, only a fraction of patients with cancer benefit from angiogenesis inhibitors. Whether antiangiogenic therapy would be more effective if targeted to individuals with specific tumor characteristics is unknown. To better characterize the tumor vascular environment both within and between cancer types, we developed a standardized metric - the endothelial index (EI) - to estimate vascular density in over 10,000 human tumors, corresponding to 31 solid tumor types, from transcriptome data. We then used this index to compare hyper- and hypovascular tumors, enabling the classification of human tumors into 6 vascular microenvironment signatures (VMSs) based on the expression of a panel of 24 vascular "hub" genes. The EI and VMS correlated with known tumor vascular features and were independently associated with prognosis in certain cancer types. Retrospective testing of clinical trial data identified VMS2 classification as a powerful biomarker for response to bevacizumab. Thus, we believe our studies provide an unbiased picture of human tumor vasculature that may enable more precise deployment of antiangiogenesis therapy.
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http://dx.doi.org/10.1172/JCI136655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810485PMC
January 2021

Polymerized human hemoglobin increases the effectiveness of cisplatin-based chemotherapy in non-small cell lung cancer.

Oncotarget 2020 Oct 20;11(42):3770-3781. Epub 2020 Oct 20.

Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA.

Cisplatin is a promising therapeutic for the treatment of non-small cell lung cancer (NSCLC). Unfortunately, a significant portion of NSCLC patients relapse due to cisplatin chemoresistance. This chemoresistance is thought to be primarily associated with hypoxia in the tumor microenvironment. Administration of hemoglobin (Hb)-based oxygen (O) carriers (HBOCs) is a promising strategy to alleviate hypoxia in the tumor, which may make cisplatin more effective. In this study, we administered a high O affinity, relaxed state (R-state) polymerized hemoglobin (PolyHb) to three different NSCLC cell lines cultured and implanted into healthy mice. The R-state PolyHb administered in this study is unable to deliver O unless under severe hypoxia which significantly limits its oxygenation potential. sensitivity studies indicate that the administration of PolyHb increases the effectiveness of cisplatin under hypoxic conditions. Additional animal studies revealed that co-administration of PolyHb with cisplatin attenuated tumor growth without alleviating hypoxia. Analysis of reactive O species production in the presence of hypoxic culture indicates that exogenous ROS production by oxidized PolyHb may the mechanism of chemosensitization. This ROS mechanism, coupled with oxygenation, may be a potential chemosensitizing strategy for use in NSCLC treatment.
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http://dx.doi.org/10.18632/oncotarget.27776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584239PMC
October 2020

Tumor vascular status controls oxygen delivery facilitated by infused polymerized hemoglobins with varying oxygen affinity.

PLoS Comput Biol 2020 08 20;16(8):e1008157. Epub 2020 Aug 20.

William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio, United States of America.

Oxygen (O2) delivery facilitated by hemoglobin (Hb)-based O2 carriers (HBOCs) is a promising strategy to increase the effectiveness of chemotherapeutics for treatment of solid tumors. However, the heterogeneous vascular structures present within tumors complicates evaluating the oxygenation potential of HBOCs within the tumor microenvironment. To account for spatial variations in the vasculature and tumor tissue that occur during tumor growth, we used a computational model to develop artificial tumor constructs. With these simulated tumors, we performed a polymerized human hemoglobin (hHb) (PolyhHb) enhanced oxygenation simulation accounting for differences in the physiologic characteristics of human and mouse blood. The results from this model were used to determine the potential effectiveness of different treatment options including a top load (low volume) and exchange (large volume) infusion of a tense quaternary state (T-State) PolyhHb, relaxed quaternary state (R-State) PolyhHb, and a non O2 carrying control. Principal component analysis (PCA) revealed correlations between the different regimes of effectiveness within the different simulated dosage options. In general, we found that infusion of T-State PolyhHb is more likely to decrease tissue hypoxia and modulate the metabolic rate of O2 consumption. Though the developed models are not a definitive descriptor of O2 carrier interaction in tumor capillary networks, we accounted for factors such as non-uniform vascular density and permeability that limit the applicability of O2 carriers during infusion. Finally, we have used these validated computational models to establish potential benchmarks to guide tumor treatment during translation of PolyhHb mediated therapies into clinical applications.
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http://dx.doi.org/10.1371/journal.pcbi.1008157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462268PMC
August 2020

Polymerized human hemoglobin facilitated modulation of tumor oxygenation is dependent on tumor oxygenation status and oxygen affinity of the hemoglobin-based oxygen carrier.

Sci Rep 2020 07 9;10(1):11372. Epub 2020 Jul 9.

William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, 43210, USA.

Administration of hemoglobin-based oxygen carriers (HBOCs) into the systemic circulation is a potential strategy to relieve solid tumor hypoxia in order to increase the effectiveness of chemotherapeutics. Previous computational analysis indicated that the oxygen (O) status of the tumor and HBOC O affinity may play a role in increased O delivery to the tumor. However, no study has experimentally investigated how low- and high-affinity HBOCs would perform in normoxic and hypoxic tumors. In this study, we examined how the HBOC, polymerized human hemoglobin (PolyhHb), in the relaxed (R) or tense (T) quaternary state modulates O delivery to hypoxic (FME) and normoxic (LOX) human melanoma xenografts in a murine window chamber model. We examined microcirculatory fluid flow via video shearing optical microscopy, and O distributions via phosphorescence quenching microscopy. Additionally, we examined how weekly infusion of a 20% top-load dose of PolyhHb influences growth rate, vascularization, and regional blood flow in the FME and LOX tumor xenografts. Infusion of low-affinity T-state PolyhHb led to increased tissue oxygenation, decreased blood flow, decreased tumor growth, and decreased vascularization in hypoxic tumors. However, infusion of both T-state and R-state PolyhHbs led to worse outcomes in normoxic tumors. Of particular concern was the high-affinity R-state PolyhHb, which led to no improvement in hypoxic tumors and significantly worsened outcomes in normoxic tumors. Taken together, the results of this study indicate that the tumor O status is a primary determinant of the potency and outcomes of infused PolyhHb.
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http://dx.doi.org/10.1038/s41598-020-68190-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347553PMC
July 2020

Balance between oxygen transport and blood rheology during resuscitation from hemorrhagic shock with polymerized bovine hemoglobin.

J Appl Physiol (1985) 2020 07 18;129(1):97-107. Epub 2020 Jun 18.

Department of Bioengineering, University of California, San Diego, La Jolla, California.

Alternatives to blood for use in transfusion medicine have been investigated for decades. An ideal alternative should improve oxygen (O)-carrying capacity and O delivery and support microvascular blood flow. Previous studies have shown that large-molecular diameter hemoglobin (Hb)-based oxygen carriers (HBOCs) based on polymerized bovine Hb (PolybHb) reduce the toxicity and vasoconstriction of first-generation HBOCs by increasing blood and plasma viscosity and preserving microvascular perfusion. The objective of this study was to examine the impact of PolybHb concentration and therefore O-carrying capacity and solution viscosity on resuscitation from hemorrhagic shock in rats. PolybHb was diafiltered on a 500-kDa tangential flow filtration (TFF) module to remove low-molecular weight (MW) PolybHb molecules from the final product. Rats were hemorrhaged and maintained in hypovolemic shock for 30 min before transfusion of PolybHb at 10 g/dL (PHB10), 5 g/dL (PHB5), or 2.5 g/dL (PHB2.5) concentration, to restore blood pressure to 90% of the animal's baseline blood pressure. Resuscitation restored blood pressure and cardiac function in a PolybHb concentration-dependent manner. Parameters indicative of the heart's metabolic activity indicated that the two higher PolybHb concentrations better restored coronary O delivery compared with the low concentration evaluated. Markers of organ damage and inflammation were highest for PHB10, whereas PHB5 and PHB2.5 showed similar expression of these markers. These studies indicate that a concentration of ~5 g/dL of PolybHb may be near the optimal concentration to restore cardiac function, preserve organ function, and mitigate the toxicity of PolybHb during resuscitation from hemorrhagic shock. Large-molecular diameter polymerized bovine hemoglobin avoided vasoconstriction and impairment of cardiac function during resuscitation from hemorrhagic shock that was seen with previous hemoglobin-based O carriers by increasing blood viscosity in a concentration-dependent manner. Supplementation of O-carrying capacity played a smaller role in maintaining cardiac function than increased blood and plasma viscosity.
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http://dx.doi.org/10.1152/japplphysiol.00016.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469229PMC
July 2020

A Review on Microvascular Hemodynamics: The Control of Blood Flow Distribution and Tissue Oxygenation.

Crit Care Clin 2020 Apr 10;36(2):293-305. Epub 2020 Feb 10.

Department of Bioengineering, University of California, 9500 Gilman Drive, La Jolla, CA 92093-0412, USA. Electronic address:

The microcirculation is a complex network of vessels ranging from as large as 100 μm to as small as 5 μm. This complex network is responsible for the regulation of oxygen to the surrounding tissues and ensures metabolite washout. With a more complete understanding of the microcirculation's physiologic and pathologic tendencies, engineers can create new solutions to combat blood pathologies and shock-related diseases. Over the last number of decades a grown interest in the microcirculation has resulted in the development of fundamental techniques to quantify the microvasculature flow and the release of oxygen to tissues.
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http://dx.doi.org/10.1016/j.ccc.2019.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093304PMC
April 2020

Resuscitation From Hemorrhagic Shock With Fresh and Stored Blood and Polymerized Hemoglobin.

Shock 2020 10;54(4):464-473

Department of Bioengineering, University of California San Diego, La Jolla, California.

Background: Hemoglobin (Hb)-based oxygen carriers (HBOCs) have been proposed as alternatives to blood for decades. Previous studies demonstrated that large molecular diameter HBOCs based on polymerized bovine Hb (PolybHb) attenuate Hb side-effects and toxicity. The objective of this study was to test the safety and efficacy of tense state PolybHb after long-term storage.

Methods And Results: PolybHb was subjected to diafiltration to remove low molecular weight (< 500 kDa) species and stored for 2 years. PolybHb was studied in parallel with blood, collected from rats and stored leukodepleted under blood bank conditions for 3 weeks. Rats were hemorrhaged and resuscitated to 90% of the blood pressure before the hemorrhage with fresh blood, stored blood, fresh PolybHb, or 2-year-stored PolybHb. Hemorrhagic shock impaired oxygen delivery and cardiac function. Resuscitation restored blood pressure and cardiac function, but stored blood required a significantly larger transfusion volume to recover from shock compared with fresh blood and PolybHb (fresh and stored). Stored blood transfusion elevated markers of organ damage compared with all other groups.

Conclusions: These studies indicate that large molecular diameter PolybHb is as efficacious as fresh blood in restoring cardiac function and confirm the lack of degradation of PolybHb's safety or efficacy during long-term storage.
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http://dx.doi.org/10.1097/SHK.0000000000001530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442586PMC
October 2020

Numerical Model for the Determination of Erythrocyte Mechanical Properties and Wall Shear Stress From Intravital Microscopy.

Front Physiol 2019 23;10:1562. Epub 2020 Jan 23.

Functional Cardiovascular Engineering, Department of Bioengineering, University of California, San Diego, San Diego, CA, United States.

The mechanical properties and deformability of Red Blood Cells (RBCs) are important determinants of blood rheology and microvascular hemodynamics. The objective of this study is to quantify the mechanical properties and wall shear stress experienced by the RBC membrane during capillary plug flow utilizing high speed video recording from intravital microscopy, biomechanical modeling, and computational methods. Capillaries were imaged in the rat cremaster muscle pre- and post-RBC transfusion of stored RBCs for 2-weeks. RBC membrane contours were extracted utilizing image processing and parametrized. RBC parameterizations were used to determine updated deformation gradient and Lagrangian Green strain tensors for each point along the parametrization and for each frame during plug flow. The updated Lagrangian Green strain and Displacement Gradient tensors were numerically fit to the Navier-Lame equations along the parameterized boundary to determined Lame's constants. Mechanical properties and wall shear stress were determined before and transfusion, were grouped in three populations of erythrocytes: native cells (NC) or circulating cells before transfusion, and two distinct population of cells after transfusion with stored cells (SC1 and SC2). The distinction, between the heterogeneous populations of cells present after the transfusion, SC1 and SC2, was obtained through principle component analysis (PCA) of the mechanical properties along the membrane. Cells with the first two principle components within 3 standard deviations of the mean, were labeled as SC1, and those with the first two principle components greater than 3 standard deviations from the mean were labeled as SC2. The calculated shear modulus average was 1.1±0.2, 0.90±0.15, and 12 ± 8 MPa for NC, SC1, and SC2, respectively. The calculated young's modulus average was 3.3±0.6, 2.6±0.4, and 32±20 MPa for NC, SC1, and SC2, respectively. o our knowledge, the methods presented here are the first estimation of the erythrocyte mechanical properties and shear stress during capillary plug flow. In summary, the methods introduced in this study may provide a new avenue of investigation of erythrocyte mechanics in the context of hematologic conditions that adversely affect erythrocyte mechanical properties.
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http://dx.doi.org/10.3389/fphys.2019.01562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989587PMC
January 2020

Itaconate modulates tricarboxylic acid and redox metabolism to mitigate reperfusion injury.

Mol Metab 2020 02 13;32:122-135. Epub 2019 Dec 13.

Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, 92093 La Jolla, CA, USA. Electronic address:

Objectives: Cerebral ischemia/reperfusion (IR) drives oxidative stress and injurious metabolic processes that lead to redox imbalance, inflammation, and tissue damage. However, the key mediators of reperfusion injury remain unclear, and therefore, there is considerable interest in therapeutically targeting metabolism and the cellular response to oxidative stress.

Methods: The objective of this study was to investigate the molecular, metabolic, and physiological impact of itaconate treatment to mitigate reperfusion injuries in in vitro and in vivo model systems. We conducted metabolic flux and bioenergetic studies in response to exogenous itaconate treatment in cultures of primary rat cortical neurons and astrocytes. In addition, we administered itaconate to mouse models of cerebral reperfusion injury with ischemia or traumatic brain injury followed by hemorrhagic shock resuscitation. We quantitatively characterized the metabolite levels, neurological behavior, markers of redox stress, leukocyte adhesion, arterial blood flow, and arteriolar diameter in the brains of the treated/untreated mice.

Results: We demonstrate that the "immunometabolite" itaconate slowed tricarboxylic acid (TCA) cycle metabolism and buffered redox imbalance via succinate dehydrogenase (SDH) inhibition and induction of anti-oxidative stress response in primary cultures of astrocytes and neurons. The addition of itaconate to reperfusion fluids after mouse cerebral IR injury increased glutathione levels and reduced reactive oxygen/nitrogen species (ROS/RNS) to improve neurological function. Plasma organic acids increased post-reperfusion injury, while administration of itaconate normalized these metabolites. In mouse cranial window models, itaconate significantly improved hemodynamics while reducing leukocyte adhesion. Further, itaconate supplementation increased survival in mice experiencing traumatic brain injury (TBI) and hemorrhagic shock.

Conclusions: We hypothesize that itaconate transiently inhibits SDH to gradually "awaken" mitochondrial function upon reperfusion that minimizes ROS and tissue damage. Collectively, our data indicate that itaconate acts as a mitochondrial regulator that controls redox metabolism to improve physiological outcomes associated with IR injury.
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http://dx.doi.org/10.1016/j.molmet.2019.11.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961711PMC
February 2020

Increased Hemoglobin Oxygen Affinity With 5-Hydroxymethylfurfural Supports Cardiac Function During Severe Hypoxia.

Front Physiol 2019 30;10:1350. Epub 2019 Oct 30.

Department of Bioengineering, University of California, San Diego, San Diego, CA, United States.

Acclimatization to hypoxia or high altitude involves physiological adaptation processes, to influence oxygen (O) transport and utilization. Several natural products, including aromatic aldehydes and isothiocyanates stabilize the R-state of hemoglobin (Hb), increasing Hb-O affinity and Hb-O saturation. These products are a counter intuitive therapeutic strategy to increase O delivery during hypoxia. 5-Hydroxymethylfurfural (5-HMF) is well known Amadori compound formed during the Maillard reaction (the non-enzymatic browning and caramelization of carbohydrate-containing foods after thermal treatment), with well documented effects in Hb-O affinity. This study explores the therapeutic potential of 5-HMF on left ventricular (LV) cardiac function (LVCF) during hypoxia. Anesthetized Golden Syrian hamsters received 5-HMF i.v., at 100 mg/kg and were subjected to stepwise increased hypoxia (15, 10, and 5%) every 30 min. LVCF was assessed using a closed chest method with a miniaturized conductance catheter via continuous LV pressure-volume (PV) measurements. Heart hypoxic areas were studied using pimonidazole staining. 5-HMF improved cardiac indices, including stroke volume (SV), cardiac output (CO), ejection fraction (EF), and stroke work (SW) compared to the vehicle group. At 5% O, SV, CO, EF, and SW were increased by 53, 42, 33, and 51% with 5-HMF relative to vehicle. Heart chronotropic activity was not statistically changed, suggesting that differences in LV-CF during hypoxia by 5-HMF were driven by volume dependent effects. Analysis of coronary blood flow and cardiac muscle metabolism suggest no direct pharmacological effects from 5-HMF, therefore these results can be attributed to 5-HMF-dependent increase in Hb-O affinity. These studies establish that naturally occurring aromatic aldehydes, such as 5-HMF, produce modification of hemoglobin oxygen affinity with promising therapeutic potential to increase O delivery during hypoxic hypoxia.
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http://dx.doi.org/10.3389/fphys.2019.01350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831744PMC
October 2019

Transfusion of Anaerobically or Conventionally Stored Blood After Hemorrhagic Shock.

Shock 2020 03;53(3):352-362

Department of Bioengineering, University of California San Diego, La Jolla, California.

Background: Resuscitation from hemorrhagic shock (HS) by blood transfusion restores oxygen (O2) delivery and provides hemodynamic stability. Current regulations allow red blood cells (RBCs) to be stored and used for up to 42 days. During storage, RBCs undergo many structural and functional changes. These storage lesions have been associated with adverse events and increased mortality after transfusion, increasing the need for improved RBC storage protocols. This study evaluates the efficacy of anaerobically stored RBCs to resuscitate rats from severe HS compared with conventionally stored RBCs.

Methods And Results: Rat RBCs were stored under anaerobic, anaerobic/hypercapnic, or conventional conditions for a period of 3 weeks. Hemorrhage was induced by controlled bleeding, shock was maintained for 30 min, and RBCs were transfused to restore and maintain blood pressure near the prhemorrhage level. All storage conditions met current regulatory 24-h posttransfusion recovery requirements. Transfusion of anaerobically stored RBCs required significantly less RBC volume to restore and maintain hemodynamics. Anaerobic or anaerobic/hypercapnic RBCs restored hemodynamics better than conventionally stored RBCs. Resuscitation with conventionally stored RBCs impaired indices of left ventricular cardiac function, increased hypoxic tissue staining and inflammatory markers, and affected organ function compared with anaerobically stored RBCs.

Conclusions: Resuscitation from HS via transfusion of anaerobically stored RBCs recovered cardiac function, restored hemodynamic stability, and improved outcomes.
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http://dx.doi.org/10.1097/SHK.0000000000001386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017949PMC
March 2020

Use of Accelerometry for Long Term Monitoring of Stroke Patients.

IEEE J Transl Eng Health Med 2019 4;7:2100310. Epub 2019 Feb 4.

2Department of Electrical and Computer EngineeringUniversity of CaliforniaSan DiegoCA92106USA.

Stroke patients are monitored hourly by physicians and nurses in an attempt to better understand their physical state. To quantify the patients' level of mobility, hourly movement (i.e. motor) assessment scores are performed, which can be taxing and time-consuming for nurses and physicians. In this paper, we attempt to find a correlation between patient motor scores and continuous accelerometer data recorded in subjects who are unilaterally impaired due to stroke. The accelerometers were placed on both upper and lower extremities of four severely unilaterally impaired patients and their movements were recorded continuously for 7 to 14 days. Features that incorporate movement smoothness, strength, and characteristic movement patterns were extracted from the accelerometers using time-frequency analysis. Support vector classifiers were trained with the extracted features to test the ability of the long term accelerometer recordings in predicting dependent and antigravity sides, and significantly above baseline performance was obtained in most instances ([Formula: see text]). Finally, a leave-one-subject-out approach was carried out to assess the generalizability of the proposed methodology, and above baseline performance was obtained in two out of the three tested subjects. The methodology presented in this paper provides a simple, yet effective approach to perform long term motor assessment in neurocritical care patients.
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http://dx.doi.org/10.1109/JTEHM.2019.2897306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588341PMC
February 2019

Prediction of Recovery From Severe Hemorrhagic Shock Using Logistic Regression.

IEEE J Transl Eng Health Med 2019 1;7:1900509. Epub 2019 Jul 1.

Department of BioengineeringUniversity of California at San DiegoLa JollaCA92092USA.

This paper implements logistic regression models (LRMs) and feature selection for creating a predictive model for recovery form hemorrhagic shock (HS) with resuscitation using blood in the multiple experimental rat animal protocols. A total of 61 animals were studied across multiple HS experiments, which encompassed two different HS protocols and two resuscitation protocols using blood stored for short periods using five different techniques. Twenty-seven different systemic hemodynamics, cardiac function, and blood gas parameters were measured in each experiment, of which feature selection deemed only 25% of the them as relevant. The reduced feature set was used to train a final logistic regression model. A final test set accuracy is 84% compared to 74% for a baseline classifier using only MAP and HR measurements. Receiver operating characteristics (ROC) curve analysis and Cohens kappa statistics were also used as measures of performance, with the final reduced model outperforming the model, including all parameters. Our results suggest that LRMs trained with a combination of systemic hemodynamics, cardiac function, and blood gas parameters measured at multiple timepoints during HS can successfully classify HS recovery groups. Our results show the predictive ability of traditional and novel hemodynamic and cardiac function features and their combinations, many of which had not previously been taken into consideration, for monitoring HS. Furthermore, we have devised an effective methodology for feature selection and shown ways in which the performance of such predictive models should be assessed in future studies.
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http://dx.doi.org/10.1109/JTEHM.2019.2924011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661015PMC
July 2019

Image Annotation by Eye Tracking: Accuracy and Precision of Centerlines of Obstructed Small-Bowel Segments Placed Using Eye Trackers.

J Digit Imaging 2019 10;32(5):855-864

Department of Radiology, University of California, San Diego, CA, USA.

Small-bowel obstruction (SBO) is a common and important disease, for which machine learning tools have yet to be developed. Image annotation is a critical first step for development of such tools. This study assesses whether image annotation by eye tracking is sufficiently accurate and precise to serve as a first step in the development of machine learning tools for detection of SBO on CT. Seven subjects diagnosed with SBO by CT were included in the study. For each subject, an obstructed segment of bowel was chosen. Three observers annotated the centerline of the segment by manual fiducial placement and by visual fiducial placement using a Tobii 4c eye tracker. Each annotation was repeated three times. The distance between centerlines was calculated after alignment using dynamic time warping (DTW) and statistically compared to clinical thresholds for diagnosis of SBO. Intra-observer DTW distance between manual and visual centerlines was calculated as a measure of accuracy. These distances were 1.1 ± 0.2, 1.3 ± 0.4, and 1.8 ± 0.2 cm for the three observers and were less than 1.5 cm for two of three observers (P < 0.01). Intra- and inter-observer DTW distances between centerlines placed with each method were calculated as measures of precision. These distances were 0.6 ± 0.1 and 0.8 ± 0.2 cm for manual centerlines, 1.1 ± 0.4 and 1.9 ± 0.6 cm for visual centerlines, and were less than 3.0 cm in all cases (P < 0.01). Results suggest that eye tracking-based annotation is sufficiently accurate and precise for small-bowel centerline annotation for use in machine learning-based applications.
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http://dx.doi.org/10.1007/s10278-018-0169-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737137PMC
October 2019

Doxorubicin-loaded red blood cells reduced cardiac toxicity and preserved anticancer activity.

Drug Deliv 2019 Dec;26(1):433-442

a Department of Bioengineering , University of California , San Diego , CA , USA.

Doxorubicin (DOX) is one of the most widely used anticancer agents. DOX is known for inducing cardiotoxicity, resulting in the long-term development of heart failure. Intravascular delivery of DOX may benefit from the carriage by red blood cells (RBCs), as they can limit the systemic toxicity while delivering the DOX to the tumor. This study proposes a methodology for the synthesis of electrophoretically DOX-loaded red blood cells (RBC-DOX), as well as the assessment of its antitumorigenic effects in human colon cancer cells (HT-29), and in colon cancer xenograft models. In addition, healthy mice without tumors were dosed with RBC-DOX to assess cardiotoxicity via assessment of indexes of cardiac function after multiple doses of RBC-DOX. The HT-29 IC was found to be lower for RBC-DOX compared to free DOX. Tumor volume for the RBC-DOX group was smaller than the free DOX groups in HT-29 xenografts models. Statistically higher concentrations of DOX were found in the liver, spleen, and lungs for the RBC-DOX group compared to the free DOX group. However, the heart and the skin had statistically lower DOX concentrations for the RBC-DOX group compared to the free DOX group, with no significant differences in tumor biodistribution. All hemodynamic and cardiac function parameters were closer to control parameters for the RBC-DOX treated compared to for the free DOX-treated mice. These results suggest that RBC-DOX can be an alternative to prolong treatments with DOX, with superior antitumorigenic effects, decreased myelosuppression, and limited cardiac toxicity compared to equivalent doses of free DOX.
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http://dx.doi.org/10.1080/10717544.2019.1591544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450495PMC
December 2019

Red Blood Cell Metabolic Responses to Torpor and Arousal in the Hibernator Arctic Ground Squirrel.

J Proteome Res 2019 04 28;18(4):1827-1841. Epub 2019 Feb 28.

Department of Biochemistry and Molecular Genetics , University of Colorado Denver - Anschutz Medical Campus , Aurora , Colorado 80045 , United States.

Arctic ground squirrels provide a unique model to investigate metabolic responses to hibernation in mammals. During winter months these rodents are exposed to severe hypothermia, prolonged fasting, and hypoxemia. In the light of their role in oxygen transport/off-loading and owing to the absence of nuclei and organelles (and thus de novo protein synthesis capacity), mature red blood cells have evolved metabolic programs to counteract physiological or pathological hypoxemia. However, red blood cell metabolism in hibernation has not yet been investigated. Here we employed targeted and untargeted metabolomics approaches to investigate erythrocyte metabolism during entrance to torpor to arousal, with a high resolution of the intermediate time points. We report that torpor and arousal promote metabolism through glycolysis and pentose phosphate pathway, respectively, consistent with previous models of oxygen-dependent metabolic modulation in mature erythrocytes. Erythrocytes from hibernating squirrels showed up to 100-fold lower levels of biomarkers of reperfusion injury, such as the pro-inflammatory dicarboxylate succinate. Altered tryptophan metabolism during torpor was here correlated to the accumulation of potentially neurotoxic catabolites kynurenine, quinolinate, and picolinate. Arousal was accompanied by alterations of sulfur metabolism, including sudden spikes in a metabolite putatively identified as thiorphan (level 1 confidence)-a potent inhibitor of several metalloproteases that play a crucial role in nociception and inflammatory complication to reperfusion secondary to ischemia or hemorrhage. Preliminary studies in rats showed that intravenous injection of thiorphan prior to resuscitation mitigates metabolic and cytokine markers of reperfusion injury, etiological contributors to inflammatory complications after shock.
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http://dx.doi.org/10.1021/acs.jproteome.9b00018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219541PMC
April 2019

Blood Quality Diagnostic Device Detects Storage Differences Between Donors.

IEEE Trans Biomed Circuits Syst 2017 12 5;11(6):1400-1405. Epub 2017 Oct 5.

In 2013, nearly 15 million units of banked blood were transfused in the United States of America alone. Blood shortages are expected to increase globally. Donated blood is not equal due to differences in quality and deterioration rate. There are no methods to detect time-dependent biochemical and biophysical changes of red blood cells (RBCs) or the deterioration rate of donated RBCs. Nine randomly selected RBC units collected by the San Diego Blood Bank were examined for interdonor variability over six weeks of storage. In vitro RBC quality was assessed weekly by conventional biochemical tests including free Hb, K+, ATP, P50, 2,3 DPG, lactate, and pH. Deformability was measured via cell filtration. Briefly, the RBC suspension (10% Hct), was forced through a 5.0-μm pore membrane (106 mm) at various flow rates. No interdonor variability in biochemical or mechanical parameters was observed at baseline. Interdonor variability in biochemical properties (free Hb, K+, ATP, P50, 2,3 DPG, lactate, and pH) was observed after 14 days of storage. However, significant differences from baseline in RBC mechanical properties (i.e., filterability) were observed as early as 7 days into storage at the lowest flow rates and after 28 days of storage at all flow rates. There was a net decrease in filterability over time for all donors, but the rate at which filterability decreased (i.e., deterioration rates) was different when comparing individual donors. Changes in all biochemical parameters were significant different between donors. These data suggest that filterability is more sensitive to changes in blood quality than conventional biochemical parameters.
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http://dx.doi.org/10.1109/TBCAS.2017.2749304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5779850PMC
December 2017
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