Fine-tuned long-acting interleukin-2 superkine potentiates durable immune responses in mice and non-human primate.

Background: Recombinant human interleukin-2 (rhIL-2, aldesleukin) is Food and Drug Administration approved for the treatment of metastatic melanoma and renal cell carcinoma and has achieved durable response in a subset of patients. However, its utility as an immunotherapeutic drug is limited by undesirable activation of immune suppressive regulatory T cells (Tregs) and a short half-life requiring frequent high dose administration, leading to unacceptable toxicities. We have engineered MDNA11, a long-acting IL-2 superkine, to overcome these limitations by (1) modifying receptor selectivity in favor of anti-cancer immune cells to increase therapeutic efficacy and (2) fusion to human albumin to extend the pharmacokinetic (PK) profile, circumventing the need for frequent dosing.

Thymol treatment of bacteria prior to matrix-assisted laser desorption/ionization time-of-flight mass spectrometric analysis aids in identifying certain bacteria at the subspecies level.

Rationale: The identification of bacteria based on mass spectra produced by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) has become routine since its introduction in 1996. The major drawback is that bacterial patterns produced by MALDI are dependent on sample preparation prior to analysis. This results in poor reproducibility in identifying bacterial types and between laboratories.

Partial least square and k-nearest neighbor algorithms for improved 3D quantitative spectral data-activity relationship consensus modeling of acute toxicity.

A diverse set of 154 chemicals that included US Food and Drug Administration-regulated compounds tested for their aquatic toxicity in Daphnia magna were modeled by a 3-dimensional quantitative spectral data-activity relationship (3D-QSDAR). Two distinct algorithms, partial least squares (PLS) and Tanimoto similarity-based k-nearest neighbors (KNN), were used to process bin occupancy descriptor matrices obtained after tessellation of the 3D-QSDAR space into regularly sized bins. The performance of models utilizing bins ranging in size from 2 ppm × 2 ppm × 0.

Complementary PLS and KNN algorithms for improved 3D-QSDAR consensus modeling of AhR binding.

Multiple validation techniques (Y-scrambling, complete training/test set randomization, determination of the dependence of R2test on the number of randomization cycles, etc.) aimed to improve the reliability of the modeling process were utilized and their effect on the statistical parameters of the models was evaluated. A consensus partial least squares (PLS)-similarity based k-nearest neighbors (KNN) model utilizing 3D-SDAR (three dimensional spectral data-activity relationship) fingerprint descriptors for prediction of the log(1/EC50) values of a dataset of 94 aryl hydrocarbon receptor binders was developed.

¹³C NMR-distance matrix descriptors: optimal abstract 3D space granularity for predicting estrogen binding.

An improved three-dimensional quantitative spectral data-activity relationship (3D-QSDAR) methodology was used to build and validate models relating the activity of 130 estrogen receptor binders to specific structural features. In 3D-QSDAR, each compound is represented by a unique fingerprint constructed from (13)C chemical shift pairs and associated interatomic distances. Grids of different granularity can be used to partition the abstract fingerprint space into congruent "bins" for which the optimal size was previously unexplored.

Modeling chemical interaction profiles: II. Molecular docking, spectral data-activity relationship, and structure-activity relationship models for potent and weak inhibitors of cytochrome P450 CYP3A4 isozyme.

Polypharmacy increasingly has become a topic of public health concern, particularly as the U.S. population ages.

Modeling chemical interaction profiles: I. Spectral data-activity relationship and structure-activity relationship models for inhibitors and non-inhibitors of cytochrome P450 CYP3A4 and CYP2D6 isozymes.

An interagency collaboration was established to model chemical interactions that may cause adverse health effects when an exposure to a mixture of chemicals occurs. Many of these chemicals--drugs, pesticides, and environmental pollutants--interact at the level of metabolic biotransformations mediated by cytochrome P450 (CYP) enzymes. In the present work, spectral data-activity relationship (SDAR) and structure-activity relationship (SAR) approaches were used to develop machine-learning classifiers of inhibitors and non-inhibitors of the CYP3A4 and CYP2D6 isozymes.

Improving proton MR spectroscopy of brain tissue for noninvasive diagnostics.

Purpose: To examine preprocessing methods affecting the potential use of Magnetic Resonance Spectroscopy (MRS) as a noninvasive modality for detection and characterization of brain lesions and for directing therapy progress.

Materials And Methods: Two reference point re-calibration with linear interpolation (to compensate for magnetic field nonhomogeneity), weighting of spectra (to emphasize consistent peaks and depress chemical noise), and modeling based on chemical shift locations of 97 biomarkers were investigated. Results for 139 categorized scans were assessed by comparing Leave-One-Out (LOO) cross-validation and external validation.

Human organ/tissue growth algorithms that include obese individuals and black/white population organ weight similarities from autopsy data.

Physiologically based pharmacokinetic (PBPK) models need the correct organ/tissue weights to match various total body weights in order to be applied to children and the obese individual. Baseline data from Reference Man for the growth of human organs (adrenals, brain, heart, kidneys, liver, lungs, pancreas, spleen, thymus, and thyroid) were augmented with autopsy data to extend the describing polynomials to include the morbidly obese individual (up to 250 kg). Additional literature data similarly extends the growth curves for blood volume, muscle, skin, and adipose tissue.

HBOC-201 vasoactivity in a phase III clinical trial in orthopedic surgery subjects--extrapolation of potential risk for acute trauma trials.

Background: Vasoactivity has hampered progress of hemoglobin-based oxygen carriers (HBOCs) due to concern for adverse blood pressure responses and secondary complications. A recent formulation, highly polymerized HBOC-201 (Biopure, Cambridge, MA), has been found to be less vasoactive than prior less polymerized formulations, and to improve outcome in animal models of hemorrhagic shock (HS) compared with standard resuscitation fluids. HBOCs are envisioned to have life- saving potential for severe trauma patients for whom death due to HS is common despite transport to level I trauma centers.

A model-free ensemble method for class prediction with application to biomedical decision making.

Objective: A classification algorithm that utilizes two-dimensional convex hulls of training-set samples is presented.

Methods And Material: For each pair of predictor variables, separate convex hulls of positive and negative samples in the training set are formed, and these convex hulls are used to classify test points according to a nearest-neighbor criterion. An ensemble of these two-dimensional convex-hull classifiers is formed by trimming the (m)C(2) possible classifiers derived from the m predictors to a set of classifiers comprised of only unique predictor variables.

Windows based general PBPK/PD modeling software.

A physiologically based pharmacokinetic (PBPK) model and program (called PostNatal) was developed which focuses on postnatal growth. Algorithms defining organ/tissue growth curves from birth through adulthood for male and female humans, dogs, rats, and mice are utilized to calculate the appropriate weight and blood flow for the internal organs/tissues. This Windows based program is actually four linked PBPK models with each PBPK model acting independently or totally integrated with the others through metabolism by first order or Michaelis-Menten kinetics.

Innate immune response after resuscitation with hemoglobin-based oxygen carrier and recombinant factor VIIA in uncontrolled hemorrhagic shock in a swine model.

Background: Rapid resuscitation with oxygen-carrying fluids is critically important in hemorrhagic shock (HS) combat casualties in remote areas where blood is not available. Hemoglobin-based oxygen carrier-201 (HBOC-201) has been shown to increase survival and reduce immune activation following HS in animal models. Recombinant factor VIIa (rfVIIa), a systemic hemostatic agent, is Food and Drug Administration approved for use in acute hemorrhage in hemophilic patients.

HBOC-201 as an alternative to blood transfusion: efficacy and safety evaluation in a multicenter phase III trial in elective orthopedic surgery.

Background: The ability of hemoglobin based oxygen carrier-201 (HBOC-201) to safely reduce and/or eliminate perioperative transfusion was studied in orthopedic surgery patients.

Methods: A randomized, single-blind, packed red blood cell (PRBC)-controlled, parallel-group multicenter study was conducted. Six hundred eighty-eight patients were randomized to treatment with HBOC-201 (H, n = 350) or PRBC (R, n = 338) at the first transfusion decision.

Resuscitation with the hemoglobin-based oxygen carrier, HBOC-201, in a swine model of severe uncontrolled hemorrhage and traumatic brain injury.

The purpose of this investigation was to compare the effects of initial resuscitation with HBOC-201 to that of lactated Ringer (LR) solution in the setting of uncontrolled hemorrhage and traumatic brain injury (TBI). Anesthetized immature swine underwent fluid-percussion TBI and liver laceration. During a 75-min "prehospital phase," the animals were resuscitated with HBOC-201, LR solution, or nothing (NON).

The effects of decreasing low-molecular weight hemoglobin components of hemoglobin-based oxygen carriers in swine with hemorrhagic shock.

Background: Some hemoglobin-based oxygen carriers (HBOCs) improve outcome in animal models of hemorrhagic shock (HS) in comparison with standard asanguinous resuscitation fluids. Nevertheless, concern about intrinsic vasoactivity, linked in part to low-molecular weight (MW) hemoglobin (Hb), has slowed HBOC development. We assessed the impact of decreasing the low-MW Hb component of bovine HBOC on vasoactivity in severe HS.

Immune effects of decreasing low-molecular weight hemoglobin components of hemoglobin-based oxygen carriers (HBOC) in a swine model of severe controlled hemorrhagic shock.

Hemoglobin-based oxygen carriers (HBOCs) show potential as safe, efficacious, pre-hospital resuscitation fluids. The major criticism of HBOC-201 is its vasoactive property, attributed partially to low-molecular weight (low-MW) tetrameric/dimeric (TD) hemoglobin (Hb) in HBOC solution. Here we sought to determine whether resuscitation with decreasing concentrations of low-MW Hb component of HBOC affects immune responses in hemorrhagic swine.

Innate immune responses in Swine resuscitated from severe traumatic hemorrhagic shock with hemoglobin-based oxygen carrier-201.

Hemoglobin-based oxygen carrier-201 transports oxygen and improves survival in swine with hemorrhagic shock, but has potential to be immune activating. Herein, we evaluated HBOC-201's immune effects in swine with more severe hemorrhagic shock due to soft tissue injury and 55% blood volume catheter withdrawal over 15 minutes followed by fluid resuscitation at 20 minutes with HBOC-201, Hextend, or no treatment (NON) before hospital arrival. Survival rates were similar with HBOC-201 and Hextend (p > 0.

Postnatal growth considerations for PBPK modeling.

A physiologically based pharmacokinetic (PBPK) model and Windows-based program (called PostNatal) was developed that focuses on postnatal growth, from birth through adulthood, using appropriate growth curves for each species and gender. Postnatal growth algorithms relating organs/tissues weights with total body weight for male and female humans, dogs, rats, and mice are an integral part of the software and are utilized to assign the appropriate weight and blood flow for each of 22 organs/tissues for each simulation. Upper limits of body weight were chosen that reflect the available data used to define the algorithms; above these limits a set percent body weight was assigned to all organs/tissues.

Bovine polymerized hemoglobin versus Hextend resuscitation in a swine model of severe controlled hemorrhagic shock with delay to definitive care.

To compare the efficacy of low-volume resuscitation with bovine polymerized hemoglobin (HBOC-201) versus hetastarch (HEX) in an intermediate severity combat-relevant hemorrhagic shock swine model with a simulated delay to hospital care. Twenty-four anesthetized pigs were hemorrhaged 55% estimated blood volume in conjunction with a 5-min rectus abdominus crush. At 20 min, pigs were resuscitated with 10 mL/kg of HBOC-201 or HEX or nothing (NON); resuscitated pigs received additional infusions (5 mL/kg) at 30, 60, 120, or 180 min if hypotension or tachycardia persisted.

Mode of action: yolk sac poisoning and impeded histiotrophic nutrition--HBOC-related congenital malformations.

Rodents form an early inverted yolk sac placenta (invYSP) by apposing the yolk sac to the uterine wall. The invYSP supplies nutrients via histiotrophic nutrition involving pinocytosis of materials from uterine gland secretions, lysosomal degradation, and transfer of the products to the embryo. Interference with histiotrophic trafficking through the invYSP by high-molecular-weight molecules (such as trypan blue) causes malformations and resorptions.

Immune effects of resuscitation with HBOC-201, a hemoglobin-based oxygen carrier, in swine with moderately severe hemorrhagic shock from controlled hemorrhage.

HBOC-201, a hemoglobin-based oxygen carrier, improved physiologic parameters and survival in hemorrhagic shock (HS) animal models. However, resuscitation from HS and the properties of different fluids influence immune responses. The aim of this study was to determine if HBOC-201 significantly alters immune function in traumatic HS.

A hemoglobin-based oxygen carrier, bovine polymerized hemoglobin (HBOC-201) versus hetastarch (HEX) in a moderate severity hemorrhagic shock swine model with delayed evacuation.

Objective: To evaluate the efficacy of HBOC-201 for resuscitation of hemorrhagic shock in a swine model incorporating soft tissue injury and delayed evacuation.

Methods: A muscle crush injury and 40% estimated blood volume controlled hemorrhage was completed in 24 Yucatan mini-pigs. Pigs were untreated or resuscitated with HBOC-201 or 6% hetastarch (HEX) at 20 min.

Effects of bovine polymerized hemoglobin on coagulation in controlled hemorrhagic shock in swine.

HBOC-201, a bovine polymerized hemoglobin, has been proposed as a novel oxygen-carrying resuscitative fluid for patients with hemorrhagic shock (HS). Herein, we evaluated the hemostatic effects of HBOC-201 in an animal model of HS. A 40% blood loss-controlled hemorrhage and soft tissue injury were performed in 24 invasively monitored Yucatan mini-pigs.