The Immunopeptidome from a Genomic Perspective: Establishing the Noncanonical Landscape of MHC Class I-Associated Peptides.

Tumor antigens can emerge through multiple mechanisms, including translation of noncoding genomic regions. This noncanonical category of tumor antigens has recently gained attention; however, our understanding of how they recur within and between cancer types is still in its infancy. Therefore, we developed a proteogenomic pipeline based on deep learning de novo mass spectrometry (MS) to enable the discovery of noncanonical MHC class I-associated peptides (ncMAP) from noncoding regions.

Development of a Subcutaneous Fixed-Dose Combination of Pertuzumab and Trastuzumab: Results From the Phase Ib Dose-Finding Study.

Adding pertuzumab to trastuzumab (both monoclonal antibodies targeting human epidermal growth factor receptor 2 [HER2]) has proven survival benefits when combined with chemotherapy for patients with HER2-positive breast cancer. The combination of pertuzumab and trastuzumab together in 1 vial for subcutaneous (SC) administration is being developed as a ready-to-use formulation to reduce the treatment burden on patients while improving healthcare efficiency. An open-label, 2-part, phase Ib dose-finding study (NCT02738970) was undertaken in healthy male volunteers (part 1) and female patients with HER2-postive early breast cancer who had completed standard (neo)adjuvant treatment (part 2).

S-nitroso human serum albumin attenuates pulmonary hypertension, improves right ventricular-arterial coupling, and reduces oxidative stress in a chronic right ventricle volume overload model.

Background: This study examined the acute effect of intravenous S-nitroso human serum albumin (S-NO-HSA) infusion on overall hemodynamics and oxidative stress in a chronic left-to-right shunt-induced pulmonary arterial hypertension model with right ventricle (RV) failure.

Methods: An aortocaval fistula (pulmonary-to-systemic blood flow ratio [Qp/Qs] > 2.0) was surgically created in 50 male Wistar rats.

The nitric oxide donor, S-nitroso human serum albumin, as an adjunct to HTK-N cardioplegia improves protection during cardioplegic arrest after myocardial infarction in rats.

Objectives: Currently available cardioplegic solutions provide excellent protection in patients with normal surgical risk; in high-risk patients, however, such as in emergency coronary artery bypass surgery, there is still room for improvement. As most of the cardioplegic solutions primarily protect myocytes, the addition of substances for protection of the endothelium might improve their protective potential. The nitric oxide donor, S-nitroso human serum albumin (S-NO-HSA), which has been shown to prevent endothelial nitric oxide synthase uncoupling, was added to the newly developed histidine-tryptophan-ketoglutarat (HTK-N) cardioplegia in an isolated heart perfusion system after subjecting rats to acute myocardial infarction (MI) and reperfusion.

S-nitroso albumin enhances bone formation in a rabbit calvaria model.

Nitric oxide (NO) is a mediator involved in bone regeneration. We therefore examined the effect of the novel NO donor, S-nitroso human serum albumin (S-NO-HSA) on bone formation in a rabbit calvaria augmentation model. Circular grooves (8 mm diameter, two per animal) were created by a trephine drill in the cortical bone of 40 rabbits and titanium caps were placed on the rabbit calvaria bone filled with a collagen sponge soaked with either 100 μL S-NO-HSA (5%, 20%) or human albumin (5%, 20%).

Acoustic interference and recognition space within a complex assemblage of dendrobatid frogs.

In species-rich assemblages of acoustically communicating animals, heterospecific sounds may constrain not only the evolution of signal traits but also the much less-studied signal-processing mechanisms that define the recognition space of a signal. To test the hypothesis that the recognition space is optimally designed, i.e.

Ten polymorphic microsatellite loci for Allobates femoralis, an Amazonian dendrobatoid frog.

Within the anuran amphibians, dendrobatoids (poison-arrow frogs) are renowned for their parental care, but the lack of highly variable DNA markers so far precluded precise and comprehensive measurements of their genetic mating system. Here we present 10 polymorphic microsatellites for Allobates femoralis, a widespread dendrobatoid from the Amazon basin. In 24 field-collected individuals, we found between seven and 15 alleles per locus, without deviations from Hardy-Weinberg equilibrium or linkage disequilibrium.

S-nitroso human serum albumin given after LPS challenge reduces acute lung injury and prolongs survival in a rat model of endotoxemia.

Endotoxemia leads to the induction of inducible nitric oxide synthase (NOS-2) and increased expression of numerous inflammatory mediators contributing to endotoxin-induced acute lung injury. We tested the hypothesis that supplementation of nitric oxide (NO) by the novel NO donor S-nitroso human serum albumin (S-NO-HSA) given after lipopolysaccharide (LPS) challenge may reduce NOS-2 expression, lung inflammation and acute lung injury. Rats were divided into four groups: sham-operated (no treatment), LPS, LPS+HSA (human serum albumin), and LPS+S-NO-HSA.

S-nitroso human serum albumin reduces ischaemia/reperfusion injury in the pig heart after unprotected warm ischaemia.

Aims: Uncoupled endothelial nitric oxide synthase (eNOS) is a major contributor to vascular reactive oxygen species generation in ischaemia/reperfusion (I/R) injury. Supplementation of NO by the novel NO donor S-nitroso human serum albumin (S-NO-HSA) may inhibit uncoupling of eNOS (feedback inhibition).

Methods And Results: Pigs (n = 14; 33.

S-nitroso human serum albumin attenuates ischemia/reperfusion injury after cardioplegic arrest in isolated rabbit hearts.

Background: Depletion of nitric oxide (NO) is associated with ischemia/reperfusion injury. The novel NO donor, S-nitroso human serum albumin (S-NO-HSA), could bridge NO depletion during reperfusion in cardiac transplantation and minimize ischemia/reperfusion injury.

Methods: In an isolated erythrocyte-perfused working heart model, rabbit hearts were randomly assigned after assessment of hemodynamic baseline values to receive S-NO-HSA (0.

S-nitroso human serum albumin improves oxygen metabolism during reperfusion after severe myocardial ischemia.

Nitric oxide (NO) supplementation may modify myocardial oxygen consumption and vascular function after ischemia. We investigated the effects of the NO donor, S-nitroso human serum albumin (S-NO-HSA), on cardiac oxygen metabolism during controlled reperfusion on normothermic cardiopulmonary bypass after severe myocardial ischemia. Pigs randomly received either S-NO-HSA or human serum albumin prior to and throughout global myocardial ischemia.

The attenuation of hepatic microcirculatory alterations by exogenous substitution of nitric oxide by s-nitroso-human albumin after hemorrhagic shock in the rat.

Hepatic microcirculatory disorders such as narrowing of sinusoids after hemorrhagic shock play a major role in the pathogenesis of organ failure. It is known that the balance of vasoactive mediators such as endothelin and nitric oxide (NO) regulate microvascular perfusion, including the diameter of hepatic sinusoids. The present study was designed to evaluate the role of exogenous substitution of NO by S-nitroso-albumin (S-NO-HSA) in the prevention of pathophysiological alterations of hepatic microcirculation.

Protective effect of a novel NO-donor on ischemia/reperfusion injury in a rat epigastric flap model.

An altered metabolism of endothelial cell-derived nitric oxide has been implicated in the microvascular dysfunction associated with ischemia/reperfusion. The objective of this study was to examine whether S-nitroso human serum albumin, a novel nitric oxide-donor, improves flap viability and whether it influences edema formation after prolonged ischemia when administered prior to and in the initial phase of reperfusion. Denervated epigastric island skin flaps were elevated in 30 male Sprague Dawley rats, rendered ischemic for 8 hours, subsequently reperfused and further observed for either 3 hours (acute) or 7 days (chronic).

Symptom spread to contiguous body parts as a presentation of cerebral ischemia.

Background: Ischemic stroke commonly presents with sudden onset of focal deficit that is maximal at onset. Symptom onset marked by the spread of symptoms to contiguous body parts may suggest migraine, seizure or cerebral amyloid angiopathy (CAA) that is mimicking ischemic symptoms.

Objective: To assess (1) if the spread of symptoms to contiguous body parts is an uncommon presentation of ischemic stroke and transient ischemic attack (TIA) and (2) if patients presenting with this symptom complex frequently have migraine, seizure or CAA mimicking stroke or TIA.

Quinaprilat during cardioplegic arrest in the rabbit to prevent ischemia-reperfusion injury.

Objectives: This study evaluated intracardiac angiotensin-converting enzyme inhibition as an adjuvant to cardioplegia and examined its effects on hemodynamic, metabolic, and ultrastructural postischemic outcomes.

Methods: The experiments were performed with an isolated, erythrocyte-perfused, rabbit working-heart model. The hearts excised from 29 adult New Zealand White rabbits (2950 +/- 200 g) were randomly assigned to four groups.

S-nitroso human serum albumin treatment reduces ischemia/reperfusion injury in skeletal muscle via nitric oxide release.

Background: Peroxynitrite generated from nitric oxide (NO) and superoxide (O2-) contributes to ischemia/reperfusion (I/R) injury. Feedback inhibition of endothelial NO synthase by NO may inhibit O2- production generated also by endothelial NO synthase at diminished local L-arginine concentrations accompanying I/R.

Methods And Results: During hindlimb I/R (2.

Continuous venovenous hemofiltration improves arterial oxygenation in endotoxin-induced lung injury in pigs.

Background: Hypoxemia is common in septic acute lung failure. Therapy is mainly supportive, and most trials using specific inhibitors of key inflammatory mediators (ie., tumor necrosis factor alpha, interleukin 1) have failed to prove beneficial.

Protection against endotoxemia in rats by a novel tetrahydrobiopterin analogue.

We studied the effects of a novel pterin antagonist of NO synthase, the 4-amino analogue of tetrahydrobiopterin (4-ABH4), in a rat model of endotoxic shock and compared its properties with those of N(G)-monomethyl L-arginine (L-NMMA). Treatment with a bolus dose of 4-ABH4 at 2 h after LPS challenge significantly improved the 6-day survival rate, compared with the controls treated with saline. L-NMMA treatment did not significantly influence the survival rate.

Oxidatively modified plasma phospholipids containing reactive carbonyl functions measured by HPLC: evidence for phosphatidylcholine-bound aldehydes in plasma of burn patients.

A HPLC method has been developed to measure phosphatidylcholine (PC) containing reactive carbonyl functions in the sn-acyl residue in order to study processes in which such reactive carbonyls can be formed due to e.g. oxidative fragmentation.

Exposure of the hydrophobic components of porcine lung surfactant to oxidant stress alters surface tension properties.

We have tested the hypothesis that oxidation of lung surfactant results in loss of surface tension lowering function. Porcine lung surfactant was exposed to conditions known to cause lipid peroxidation (0.2 mM FeCl2 + 0.

Free radical activity and loss of plasma antioxidants, vitamin E, and sulfhydryl groups in patients with burns: the 1993 Moyer Award.

This study examines the relationship of burn injury and plasma levels of conjugated dienes, total sulfhydryl groups, and vitamin E in patients with thermal injuries. Plasma neopterin levels were determined as an index of macrophage activity and serine elastase as an index of polymorphonuclear cell activation. Thirteen patients with burns, six survivors and seven nonsurvivors, were studied for the first 4 days, then every other day until postburn day 14.

Involvement of oxygen radicals in shock related cell injury.

Shock-related organ failure evolves from a variety of starting points--ischemia, reperfusion, non-bacterial or bacterial inflammation--several mechanisms are involved. In addition to the effects of xanthine oxidase after ischemia/reperfusion, toxic oxygen species from phagocytes that accumulate in both intra- and extravascular tissue spaces are of central importance. A critical event is the contact (adhesion) of leukocytes to endothelial cells, which consequently are the targets for leukocyte products.

Characterization of phosphatidylcholines in rabbit lung lavage fluid by positive and negative ion fast-atom bombardment mass spectrometry.

The relative distribution of intact diacylphosphatidylcholine species isolated from the lung lavage fluid of rabbits has been investigated by positive ion fast-atom bombardment (FAB) mass spectrometry. Two different isolation/purification methods were applied and evaluated prior to mass spectrometric analysis. The first method consisted of a Bligh and Dyer extraction of the lung lavage fluid followed by isocratic high-performance liquid chromatographic (HPLC) separation.

Methodological approach to the characterization of diacylphosphatidyl cholines in rabbit lung lavage fluid by fast-atom bombardment mass spectrometry.

Strong evidence exists that the distribution of phospholipids in the lung is a function of the degree of adult respiratory distress syndrome. The capabilities of positive-ion fast-atom bombardment (FAB) mass spectrometry for the determination of the relative distribution of intact diacylphosphatidylcholine species in lung lavage fluid were investigated. Two different FAB matrices and two different isolation/purification procedures--extraction/thin layer chromatography--high performance liquid chromatography (TLC-HPLC)--have been evaluated.

Normal phosphatidylcholine composition of lung surfactant 24 hours after inhalation injury.

The effects of cotton smoke injury on the phosphatidylcholine composition of pulmonary surfactant material were studied. While under halothane anesthesia, 18 ewes were intubated using a double-lumen tube. In six sheep the left lung was exposed to smoke; in another six sheep the right lung was exposed to smoke.