Plasma Protein Concentration Research Articles

Depressive symptoms, low-grade inflammation, and poor oral health prevents the success of nutritional guidance in older caregivers

The present study aimed to determine which factors prevents the success of nutritional interventions for older family caregivers (FCs), in the form of individually tailored nutritional guidance. The present study focuses on the intervention group of FCs (n=63) of a randomized controlled trial. Older FCs (≥60 years of age) receiving a care allowance for a home-living care recipient (≥65 years of age) were included in the present study, which focused on nutritional interventions via individually tailored nutritional guidance provided by a clinical nutritionist. The associations between changes in protein intake (3-day food record), Mini Nutritional Assessment (MNA) scores, and plasma albumin and prealbumin concentrations, as well as associated factors, for the 6-month intervention period were analyzed using generalized estimating equations. Intervention time, female sex, older age, higher net income, better hand grip strength, more teeth, and removable denture use were positively associated with an increase in protein intake. Fewer depressive symptoms were associated with a positive change in the MNA scores. Younger age, lower education level, lower body mass index (BMI), higher depressive symptoms, and fewer teeth were associated with an increase in plasma albumin concentration. Younger age, lower education, lower plasma concentration of high-sensitivity C-reactive protein at 6 months, lower Sense of Coherence (SOC)-13 score, fewer teeth, and absence of removable dentures were associated with an increase in plasma prealbumin concentration. Older female FCs with a higher income, better hand grip strength, lower education, and lower SOC benefited most from individually tailored nutritional guidance. Depressive symptoms, oral health, and low-grade inflammation should be considered when providing nutritional guidance to older FCs. ClinicalTrials.gov NCT04003493 (July 1, 2019).

Obesity in dogs: dimension of the problem and effects of feed

Obesity in dogs is a growing problem which affects between 30 – 60 % of the pet population world-wide. It is mainly caused by an energy consumption greater than the animal’s requirement; and needs to be detected and faced accordingly because it negatively affects their well-being and longevity. Some important observations are; although it has been reported that depends on the composition of the diet, that dogs fed 2 times a day have lower blood glucose levels, as well as insulin levels showing the same tendency as glucose. Ghrelin and GLP1 concentrations are no different feeding 1 or 2 times a day. Energy expenditure through physical activity is important as it increases the rate of energy utilization and helps to raise the metabolic rate, which contributes to a comprehensive weight reduction program. Metabolic Energy Rate (MER) in sterilized dogs is lower than for intact animals; therefore, sterilization of pets increases the risk of obesity. The level of protein in the diet is important for promoting body protein synthesis and tissue repair. High protein diets work best when feed is offered ad libitum. Omega fatty acids reduce plasma concentrations of C-reactive protein and insulin. Dietary fiber helps to significantly reduce blood cholesterol and triglycerides.

#2749 QUANTIFICATION OF URINE PROTEINS FOR DISCOVERY OF BIOMARKERS FOR KIDNEY INJURIES BY DIA-PROTEOMICS

Abstract Background and Aims Recent advances in proteomics have enabled to quantify proteins comprehensively. We aimed to establish a platform of urine quantitative proteomics for selection of the biomarkers and assessment of health conditions. Since plasma proteins of varying amounts of were present in urine especially from proteinuric patients, we subtracted the plasma protein conteents from total urine proteomes after the quantitative proteomics for discovery of biomarkers for kidney injuries. On the other hand, urine proteins excreted from plasma may be indicators of pathophysiological conditions in the body, suggesting that the urine proteome profiles figure out health conditions and early discovery of any diseases in the future. Method More than 120,000 urine samples (∼10 ml each) have been collected from ∼15,000 patients with various diseases and healthy volunteers (HV) and stored in -20C freezers. In this study, urine samples were selected from HV, diabetic patients (DM) with or without microalbuminuria and other CKD patients. Proteins were precipitated by a methanol/chloroform precipitation method from 1 ml urine. The protein fractions were digested with trypsin and the tryptic peptides were purified by C18 column chromatography. The tryptic peptides of 200 ng each were analyzed by LC-MS (tims-TOFpro, Bruker) by quantitative Data-independent acquisition (DIA) proteomics and proteins were quantified by the DIA-nn tool. Major top 30 plasma proteins were removed from the quantitative proteomics data and kidney- and other urinary tract organ-derived proteins were normalized to compare their proportions in urine. Results Approximately 2,500 proteins were quantified by the DIA analysis. In urine from HV, proportions of plasma proteins were small, however, in urine from DM patients with microalbuminuria or CKD patients, the plasma protein contents were increased, resulting in relative decreases of urine proportions of other proteins derived from the kidney or other urinary tract organs. By subtraction of the plasma proteins from total urine proteins, protein proportions were comparable to select candidates of biomarkers for kidney injuries. Comparison of total urine protein profiles between HV and DM elucidated their differences, which might indicate changes of pathophysiological conditions. Conclusion By recent quantitative proteomics urine proteins were quantified comprehensively, facilitating discovery of biomarkers for kidney injuries and also evaluation of health conditions in the body.

Neurofilament L dynamics description in the model of tauopathy

AbstractBackgroundNeurofilament proteins are important constituents of neuronal cytoskeleton along with microtubules. Increased concentration of neurofilament light protein in cerebrospinal fluid(CSF) and plasma is considered as a potential biomarker of axonal degeneration [1]. Together with tau, neurofilaments are contained in the neurofibrillary tangles (NFT), the biomarker of Alzheimer’s disease and other tauopathies [2]. The goal of this study was to develop a quantitative systems pharmacology (QSP) model to describe neurofilament dynamics during progression of tauopathies both in human patients and in transgenic P301L Tau mice.MethodThe quantitative model correctly describes the dynamics of neurofilament proteins during neurodegeneration processes, which include cytoskeletal degradation by calpain, proteasome, autophagy and caspase, formation of pathological aggregates, release of neurofilament proteins from degenerated axons to cerebrospinal fluid and plasma. These processes are dependent on pathological processes in tauopathy models, such as changes in protein degradation, axonal transport deficits, pathological hyperphosphorylated tau accumulation. To calibrate the model, the literature data on neurofilament concentration in brain, cerebrospinal fluid and plasma, phosphorylation and degradation level were used. Description of the processes is partially based on neuron homeostasis model developed earlier [3]. The model was validated on taupathy P301L transgenic mice, amyloid APP/PS1 mice and on Alzheimer’s disease patients’ data.ResultThe described model correctly predicts the increase of neurofilament light protein concentration in CSF and plasma both in P301L transgenic mice model of tauopathy and in human patients versus controls. Pathological changes of microtubule dynamics and cytoskeleton breakdown are also described. Model predicts the reduction of NfL concentration in CSF during potential tau targeting therapy in P301L transgenic mice and humans.ConclusionThe developed model can be helpful in simulating potential effects of therapeutics used in neurodegeneration diseases treatment.

Status of some biochemical markers in Sprague dawley rats following sub-chronic consumption of alum- treated water

Alum is a double salt of aluminum and potassium sulfates. The aim of this study was to investigate the status of some biochemical markers in Sprague-dawley rats following sub-chronic consumption of alum- treated water. It consisted of 21 rats of 3–4 months old weighing roughly 122 ± 0.5 g. They were divided into three groups at random with 7 rats / group. The control group received 15 ml of distilled water daily for 30 days, while experimental groups one and two received 15ml of 0.04% concentration of alumtreated water for 15 days daily and 30 days respectively. Following this, 5 ml of blood specimen was withdrawn via cardiac puncture and introduced into corresponding lithium heparin anti-coagulated bottles. These specimens were spun at 1,500 revolutions per minute for 10 minutes using an 800 D macro centrifuge to extract the plasma that were utilized for the measurement of alanine aminotransferase, aspartate aminotransferase (colorimetric method), urea (urease Berthelot method), creatinine (Jaffe reaction method) and C-reactive protein (Latex turbidimetry method). Using SPSS 23.0 to perform statistical analysis on the study's findings, it was discovered that there were no significant differences between the experimental group one and the control group for all the measured biochemical parameters (p>0.05). However, in comparison to the control group, the results of the experimental group two revealed significant elevations (p<0.05) in revealed significant elevations (p<0.05) in plasma levels of alanine aminotransferase, aspartate aminotransferase and C-reactive protein. It is concluded that the plasma concentrations of alanine aminotransferase, aspartate aminotransferase and C-reactive protein may be altered in Sprague-dawley rats following consumption of 15 ml of 0.04% concentration of alum- treated water for 30 days. Thus, it is recommended that this study in a well guided manner be carried out in humans to ascertain if the findings will be consistent.

A blood-based composite panel that screens Alzheimer’s disease

BackgroundBlood tests would be much easier to implement in the clinical diagnosis of Alzheimer’s disease (AD) as minimally invasive measurements. Multiple inspection technologies promoted AD-associated blood biomarkers’ exploration. However, there was a lack of further screening and validation for these explored blood-based biomarkers. We selected four potential biomarkers to explore their plasma levels in AD and amnestic mild cognitive impairment (aMCI) and developed a composite panel for AD and aMCI screening.MethodThe plasma concentrations of soluble low-density lipoprotein receptor-associated protein 1 (sLRP1), Gelsolin (GSN), Kallikrein 4 (KLK4) and Caspase 3 were measured in the discovery and validation cohort. The receiver operating characteristic (ROC) curve was generated to assess the classification panel with the area under the curve (AUC).ResultsA total of 233 participants (26 CN, 27 aMCI, and 26 AD in the discovery cohort, and 51 CN, 50 aMCI, and 53 AD in the validation cohort) with complete data were included in the study. The plasma concentrations of sLRP1 and Caspase 3 were significantly decreased in AD and aMCI when compared with those in the CN group. Compared with the CN group, the concentrations of KLK4 and GSN were increased in AD, but not in MCI. Interestingly, one of four proteins, sLRP1 in plasma level was higher in Apolipoprotein E (APOE) ε4 non-carriers than that in APOE ε4 carriers, especially among CN and MCI. No significant difference was found between females and males in the plasma levels of four proteins. The composite panel is based on four blood biomarkers accurately classifying AD from CN (AUC = 0.903–0.928), and MCI from CN (AUC = 0.846–0.865). Moreover, dynamic changes in the plasma levels of four proteins exhibited a significant correlation with cognitive assessment.ConclusionsAltogether, these findings indicate that the plasma levels of sLRP1, KLK4, GSN and Caspase 3 changed with the progression of AD. And their combination could be used to develop a panel for classifying AD and aMCI with high accuracy, which would provide an alternative approach for developing a blood-based test for AD and aMCI screening.

Investigation of the Changes in Concentrations of Vitamin D-Binding Protein and Lactoferin in Plasma and Peritoneal Fluid of Patients with Endometriosis.

An evaluation of the association between the concentrations of vitamin D-binding protein and lactoferrin in the plasma and peritoneal fluid may facilitate the elucidation of molecular mechanisms in endometriosis. Vitamin D-binding protein and lactoferrin concentrations were measured by ELISA in plasma and peritoneal fluid samples from 95 women with suspected endometriosis as classified by laparoscopy into groups with (n = 59) and without endometriosis (n = 36). There were no differences (p > 0.05) in the plasma and peritoneal fluid concentrations of vitamin D-binding protein and lactoferrin between women with and without endometriosis. In women with endometriosis, there was a significant correlation between plasma and peritoneal fluid vitamin D-binding protein concentrations (r = 0.821; p = 0.000), but there was no correlation between lactoferrin concentrations in those compartments (r = 0.049; p > 0.05). Furthermore, in endometriosis, lactoferrin was found to correlate poorly with vitamin D-binding protein (r= -0.236; p > 0.05) in plasma, while in the peritoneal fluid, the correlation between those proteins was significant (r = 0.399; p = 0.002). The characteristic properties of vitamin D-binding protein and lactoferrin and the associations between their plasma and peritoneal fluid concentrations found in women with endometriosis may provide a novel panel of markers to identify high-risk patients in need of further diagnostic measures.

Using Plasma NfL and GFAP to Monitor Response to Anti-CD20 Treatment in MS (P1-3.010)

<h3>Objective:</h3> To compare changes in plasma concentrations of Neurofilament light (NfL) and Glial Fibrillary Acidic Protein (GFAP) in individuals with relapsing multiple sclerosis (RMS) vs progressive multiple sclerosis (PMS), treated with anti-CD20 immunotherapy (rituximab or ocrelizumab) <h3>Background:</h3> Blood biomarkers, especially NfL, can augment clinical and radiographic data in MS treatment monitoring. Few studies have investigated longitudinal change in NfL or GFAP in PMS patients taking anti-CD20s or compared changes in these biomarkers between RMS and PMS. <h3>Design/Methods:</h3> Subjects were selected by MS diagnosis, anti-CD20 treatment for at least 6 months, and presence of multiple blood samples in our Center’s Biorepository. Demographic/clinical information was extracted by chart review. SIMOA plasma assays of NfL and GFAP were conducted at baseline and follow-up (between 3 and 12 months) on Quanterix SR-X. Biomarker concentrations were log transformed. Summary statistics and longitudinal regression analyses, correcting for age, were generated. <h3>Results:</h3> 37 subjects and 67 samples were analyzed (n=7 had no follow-up samples between 3 and 12 months). 64.9% were female. RMS (n=19) had mean(SD) age 38.7(9.2). PMS (n=18) had mean age 56.1(10.4). Age-adjusted mean concentrations of NfL and GFAP did not differ significantly between RMS and PMS at baseline. Geometric mean NfL declined between baseline (6.8, 95%CI 4.2–11.0) and follow-up (4.9, 95%CI 3.3–7.3) in RMS but stayed stable in PMS. Geometric mean GFAP increased between baseline (52.4, 95%CI 35.2–77.9) and follow-up (60.8, 95%CI 40.4–91.4) in PMS but stayed stable in RMS. The changes for both NfL and GFAP differed statistically significantly between MS types. <h3>Conclusions:</h3> With anti-CD20 treatment, plasma NfL levels decreased in RMS by 27.6% while staying stable in PMS; GFAP levels increased in PMS by 16% while remaining stable in RMS. Results correlate with clinical evidence showing greater benefit of anti-CD20 immunotherapy in RMS compared to PMS. Future studies will include more subjects, longer observation, and different immunotherapies. <b>Disclosure:</b> Dr. Gross has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for AP Expert Group. The institution of Stefan Sillau has received research support from Alzheimer’s Association. The institution of Stefan Sillau has received research support from Hewitt Family Foundation; State of Colorado. The institution of Stefan Sillau has received research support from PCORI. The institution of Stefan Sillau has received research support from NINR. The institution of Stefan Sillau has received research support from Michael J. Fox Foundation. The institution of Stefan Sillau has received research support from Department of Defense. The institution of Stefan Sillau has received research support from Colorado Department of Public Health and Environment. The institution of Stefan Sillau has received research support from Benign Essential Blepharospasm Research Foundation. Stefan Sillau has a non-compensated relationship as a Statistician with Novartis that is relevant to AAN interests or activities. Stefan Sillau has a non-compensated relationship as a Statistician with Biogen that is relevant to AAN interests or activities. Sean Selva has nothing to disclose. Mrs. Ritchie has nothing to disclose.

Plasma Proteomic Associations With Incident Ischemic Stroke in Older Adults: The Cardiovascular Health Study.

Plasma proteomics may elucidate novel insights into the pathophysiology of ischemic stroke (IS), identify biomarkers of IS risk, and guide development of nascent prevention strategies. We evaluated the relationship between the plasma proteome and IS risk in the population-based Cardiovascular Health Study (CHS). Eligible CHS participants were free of prevalent stroke and underwent quantification of 1,298 plasma proteins using the aptamer-based SOMAScan assay platform from the 1992-1993 study visit. Multivariable Cox proportional hazards regression was used to evaluate associations between a 1-SD increase in the log2-transformed estimated plasma protein concentrations and incident IS, adjusting for demographics, IS risk factors, and estimated glomerular filtration rate. For proteins independently associated with incident IS, a secondary stratified analysis evaluated associations in subgroups defined by sex and race. Exploratory analyses evaluated plasma proteomic associations with cardioembolic and noncardioembolic IS and proteins associated with IS risk in participants with left atrial dysfunction but without atrial fibrillation. Of 2,983 eligible participants, the mean age was 74.3 (±4.8) years, 61.2% were women, and 15.4% were Black. Over a median follow-up of 12.6 years, 450 participants experienced an incident IS. N-terminal probrain natriuretic peptide (NTproBNP, adjusted HR 1.37, 95% CI 1.23-1.53, p = 2.08 × 10-08) and macrophage metalloelastase (MMP12, adjusted HR 1.30, 95% CI 1.16-1.45, p = 4.55 × 10-06) were independently associated with IS risk. These 2 associations were similar in men and women and in Black and non-Black participants. In exploratory analyses, NTproBNP was independently associated with incident cardioembolic IS, E-selectin with incident noncardioembolic IS, and secreted frizzled-related protein 1 with IS risk in participants with left atrial dysfunction. In a cohort of older adults, NTproBNP and MMP12 were independently associated with IS risk. We identified plasma proteomic determinants of incident cardioembolic and noncardioembolic IS and found a novel protein associated with IS risk in those with left atrial dysfunction.

Complement-targeted therapeutics: An emerging field enabled by academic drug discovery.

Within a short few years, the number of complement inhibitors that are either approved for therapeutic application or evaluated in late-stage clinical trials has expanded remarkably. The sudden emergence of this target area in the pipelines of many biotech start-ups and even large pharmaceutical companies appears even more surprising when considering that the involvement of the complement system in various clinical conditions had long been recognized. In many aspects, however, the complement system is far from being a traditional drug target, which may explain the delayed breakthrough of this therapeutic strategy. While complement modulation is now considered an attractive "platform technology" with applications in a wide spectrum of disorders, the broad yet heterogeneous disease involvement of the complement system has long restricted its placement in traditional drug discovery programs. Concerns about the safety of complement-targeted interventions, the large number and high plasma concentrations of target proteins, and the complexity of the complement system's engagement in biological processes are among other factors that kept complement off the drug discovery radar for decades. Alongside technical advances and financial incentives, the innovation and persistence of academic and clinical researchers have been the critical driving force to navigate complement therapeutics out of the shadow into the spotlight. In this commentary, we document this remarkable development using select examples and aim to venture some predictions where this promising field may be headed to.

Quantitative determination of lurbinectedin, its unbound fraction and its metabolites in human plasma utilizing ultra-performance LC-MS/MS.

Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) methods to quantify total lurbinectedin, its plasma protein binding to derive the unbound fraction and its main metabolites 1',3'-dihydroxy-lurbinectedin (M4) and N-desmethyl-lurbinectedin (M6) in human plasma, were developed and validated. For lurbinectedin, sample extraction was performed using supported liquid extraction. For metabolites, liquid-liquid extraction with stable isotope-labeled analogue internal standards was used. Plasma protein binding was evaluated using rapid equilibrium dialysis. In vitro investigations at different plasma protein concentrations were carried out to estimate dissociation rate constants to albumin and alpha-1-acid glycoprotein (AAG). Calibration curves displayed good linearity over 0.1 to 50 ng/mL for lurbinectedin and 0.5 to 20 ng/mL for the metabolites. Methods were validated in accordance with established guidance. The inter-day precision and accuracy ranged from 5.1% to 10.7%, and from -5% to 6% (lurbinectedin in plasma); from 3.1% to 6.6%, and from 4% to 6% (lurbinectedin in plasma:PBS); from 4.5% to 12.9%, and from 4% to 9% (M4); and from 7.5% to 10.5%, and from 6% to 12% (M6). All methods displayed good linearity (r2 >0.99). Recovery was evaluated for lurbinectedin in plasma:PBS (66.4% to 86.6%), M4 (7.82% to 13.4%) and M6 (22.2% to 34.3%). The method for lurbinectedin in plasma has been applied in most clinical studies, while the plasma:PBS and metabolites methods were used to evaluate the impact of special conditions on lurbinectedin PK. Lurbinectedin plasma protein binding was 99.6% and highly affected by AAG concentration. These UPLC-MS/MS methods enable the rapid and sensitive quantification of lurbinectedin and its main metabolites in clinical samples.

Targeted plasma proteomics identifies MICA and IL1R1 proteins associated with HIV-1 reservoir size

HIV-1 reservoir shows high variability in size and activity among virally suppressed individuals. Differences in the size of the viral reservoir may relate to differences in plasma protein concentrations. We tested whether plasma protein expression levels are associated with levels of cell-associated (CA) HIV-1 DNA and RNA in 211 virally suppressed people living with HIV (PLHIV). Plasma concentrations of FOLR1, IL1R1, MICA, and FETUB showed a positive association with CA HIV-1 RNA and DNA. Moreover, SNPs in close proximity to IL1R1 and MICA genes were found to influence the levels of CA HIV-1 RNA and DNA. We found a difference in mRNA expression of the MICA gene in homozygotes carrying the rs9348866-A allele compared to the ones carrying the G allele (p<0.005). Overall, our findings pinpoint plasma proteins that could serve as potential targets for therapeutic interventions to lower or even eradicate cells containing CA HIV-1 RNA and DNA in PLHIV.

Metabolic profile of transition period in ewes and its influence on passive immunity transference in lambs.

The intensification of ewe production, focusing on increasing prolificity, results in a higher incidence of metabolic disorders, especially in the transition period, which can lead to production losses with consequences for the health of the animals. The objective of this study was to evaluate the metabolic profile in transition period Lacaune ewes according to the parity and litter size born and its influence on the transference of passive immunity. Nineteen Lacaune ewes, with initial mean body weight of 76.36 ± 10.37kg (SD), kept in a semi-extensive system and receiving the same diet, were used. Ewes were classified according to parity (primiparous and multiparous) and the litter size born at parturition (1, 2, and 3). On days - 14, - 7, and - 4 of the expected date of parturition and on days 1, 4, 7, and 14days postpartum, blood sampling, the evaluation of the body condition score (BCS), and the weighing of animals were performed. Blood samples were taken from the lambs 48h after birth. Colostrum was collected up to 6h postpartum to determine the brix percentage. Serum concentrations of total plasma proteins (TPP), albumin, aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), beta-hydroxybutyrate (BHB), non-esterified fatty acids (NEFA), paraoxonase (PON1), calcium (Ca), and magnesium (Mg) were evaluated. In lambs, the blood parameters evaluated were TPP, albumin, GGT, and PON1. Lamb plasma was used to estimate colostrum efficiency, brix percentage immunity, and total plasma protein (PPT). Productive data, pre- and postpartum metabolic variables for ewes, lambs, and those related to colostrum brix were analyzed. The BCS had a reduction (p < 0.0001) in the postpartum period, which is evidenced on days 7 and 14 (2.88 and 2.73, respectively). Serum concentration of BHB presented the highest concentrations in the prepartum period for ewes that gave birth to triplets, from day - 14, and for ewes that gave birth to twins on day - 4 (p = 0.0245). Serum concentration of NEFA demonstrated the highest value on day 14 in primiparous (1.07; p = 0.0402). Calcium had the lowest concentrations on day 1 (8.85mg/dl, p < 0.0001) and magnesium on day 3 (1.79mg/dl, p < 0.0001) postpartum. The multiparous with two lambs had higher brix percentages (30.5%), and the lowest value was observed in primiparous ewes that gave birth to a single lamb (27.06%; p = 0.0395). Triplet lambs had the lowest weight (3.73kg, p = 0.0007), and the best brix percentage in plasma was observed in twins (10.29%, p = 0.0174). Regardless of the parity, the ewes that presented the greatest metabolic challenge were those that gave birth to triplets, and these lambs presented the worst immunity and the lowest live weight. The quality of colostrum was influenced by the parity, and multiparous ewes that gave birth to triplets had the lowest brix percentage in the colostrum.

Pharmacokinetics and pharmacodynamics of imatinib for optimal drug repurposing from cancer to COVID-19

IntroductionIn the randomized double-blind placebo-controlled CounterCOVID study, oral imatinib treatment conferred a positive clinical outcome and a signal for reduced mortality in COVID-19 patients. High concentrations of alpha-1 acid glycoprotein (AAG) were observed in these patients and were associated with increased total imatinib concentrations. AimsThis post-hoc study aimed to compare the difference in exposure following oral imatinib administration in COVID-19 patients to cancer patients and assess assocations between pharmacokinetic (PK) parameters and pharmacodynamic (PD) outcomes of imatinib in COVID-19 patients. We hypothesize that a relatively higher drug exposure of imatinib in severe COVID-19 patients leads to improved pharmacodynamic outcome parameters. Methods648 total concentration plasma samples obtained from 168 COVID-19 patients were compared to 475 samples of 105 cancer patients, using an AAG-binding model. Total trough concentration at steady state (Cttrough) and total average area under the concentration-time curve (AUCtave) were associated with ratio between partial oxygen pressure and fraction of inspired oxygen (P/F), WHO ordinal scale (WHO-score) and liberation of oxygen supplementation (O2lib). Linear regression, linear mixed effects models and time-to-event analysis were adjusted for possible confounders. ResultsAUCtave and Cttrough were respectively 2.21-fold (95%CI 2.07–2.37) and 1.53-fold (95%CI 1.44–1.63) lower for cancer compared to COVID-19 patients. Cttrough, not AUCtave, associated significantly with P/F (β=-19,64; p-value=0.014) and O2lib (HR 0.78; p-value= 0.032), after adjusting for sex, age, neutrophil-lymphocyte ratio, dexamethasone concomitant treatment, AAG and baseline P/F-and WHO-score. Cttrough, but not AUCtave associated significantly with WHO-score. These results suggest an inverse relationship between PK-parameters, Cttrough and AUCtave, and PD outcomes. ConclusionCOVID-19 patients exhibit higher total imatinib exposure compared to cancer patients, attributed to differences in plasma protein concentrations. Higher imatinib exposure in COVID-19 patients did not associate with improved clinical outcomes. Cttrough and AUCtave inversely associated with some PD-outcomes, which may be biased by disease course, variability in metabolic rate and protein binding. Therefore, additional PKPD analyses into unbound imatinib and its main metabolite may better explain exposure-response.

Abstract P248: Plasma Proteins Associated With Depressive Symptoms and Perceived Global Stress Among African American Adults in the Jackson Heart Study

Introduction: Analyzing plasma proteins is a novel approach to uncover molecular mechanisms by which psychosocial stress may lead to chronic illness, including cardiometabolic disease. Proteomic analyses of cardiometabolic disease have been reported; however, proteomic studies of stress and depressive symptoms are limited. Hypothesis: We hypothesized that plasma protein concentrations are both positively and negatively associated with greater depressive symptoms and perceived global stress, respectively, in African American adults from the Jackson Heart Study (JHS). Methods: Participants from exam 1 (2000-2004) with SomaScan 1.3k platform proteomics data were utilized (n=2143, mean age=55.3). Depressive symptoms and global stress scores were measured via the 20-item Centers for Epidemiological Studies (CES-D) Scale and an 8-item global perceived stress scale adapted for the JHS, respectively. Multivariable linear models were used to test the association between depressive symptoms and global stress scores and proteins, controlling for age, sex, and proteomics batch. Bonferroni correction was used to adjust the p-value threshold for multiple testing (3.78e-5, for 1,322 tested proteins). Results: Six (6) proteins were found to be significantly associated with either depressive symptoms or perceived global stress. Angiopoietin-2 (β=0.014, SE=0.003, p =1.33e-5), growth/differentiation factor 15 or MIC-1 (β=0.014, SE=0.003, p=7.08e-8), and kynureninase (β=0.014, SE=0.003, p =1.55e-5) were positively associated with depressive symptoms. Contactin-5 (β=-0.017, SE=0.003, p =1.40e-7) and neural cell adhesion molecule 1 (120 kDa isoform) (β=-0.016, SE=0.003, p =6.74e-7) were negatively associated with depressive symptoms. Leukotriene A-4 hydrolase or LKHA4 (β=0.024, SE=0.005, p =2.72e-6) was positively associated with perceived stress. We note that several of these proteins which are associated with higher levels of stress or depression symptoms have also been associated with cardiovascular disease and related phenotypes; for example, LKHA4 was the lead association with left ventricular mass in previous JHS analyses. Conclusions: JHS proteomic profiles revealed differences in protein concentrations by psychosocial measures. We will next explore the extent to which identified proteins may mediate relationships between stress and depressive symptoms and cardiovascular endpoints. Future investigations may identify potentially targetable proteomic mechanisms by which psychosocial stressors manifest into disease.

Assessment of lipids and adrenal hormones in the Florida manatee (Trichechus manatus latirostris) from different habitats

Florida manatees (Trichechus manatus latirostris), a federally protected species, are classified as threatened due to anthropogenic stressors. Manatees inhabit sites that are impacted by human activities that can negatively affect stress physiology and metabolism. Samples collected from healthy manatees (pregnant females, non-pregnant females, and males) at Crystal River and Indian River Lagoon in Florida, were assessed for adrenal hormones, proteins, glucose, and lipid content in plasma. The objective was to determine if healthy manatees sampled between 2010–2014 from the Indian River Lagoon exhibited evidence of stress compared to healthy manatees sampled between 2012–2019 from Crystal River. Plasma cortisol concentrations were not different in male and non-pregnant female manatees between sites but were elevated in pregnant manatees. Plasma aldosterone concentrations were elevated in Indian River Lagoon manatees relative to those at Crystal River, possibly due to differences in salinity and available freshwater between the two environments. Site differences were noted for plasma protein and glucose concentrations in manatees; additionally, differences between the sexes were also observed in glucose concentrations. Fifteen lipid subclasses, including oxidized lysophosphatidylcholines, oxidized phosphatidylcholines, oxidized triacylglycerols, were elevated in manatees from the Indian River Lagoon relative to manatees from Crystal River. Evidence of a stress response in healthy Indian River Lagoon manatees was lacking compared to Crystal River manatees. Differences in metabolites related to energy (glucose, protein, and lipids) may be related to site-specific variables, such as salinity and food availability/quality. This study generates novel data on plasma lipid profiles and provides cortisol, aldosterone, glucose, and protein values from healthy Florida manatees in two disparate sites that can be referenced in future studies. These data contribute to an improved understanding of manatee physiology to better inform population management.

Alterations in the Plasma Protein Expression Pattern in Congenital Analbuminemia—A Systematic Review

Albumin is a highly abundant plasma protein with multiple functions, including the balance of fluid between body compartments and fatty acid trafficking. Humans with congenital analbuminemia (CAA) do not express albumin due to homozygosity for albumin gene mutation. Lessons about physiological control could be learned from CAA. Remarkably, these patients exhibit an apparently normal lifespan, without substantial impairments in physical functionality. There was speculation that tolerance to albumin deficiency would be characterized by significant upregulation of other plasma proteins to compensate for analbuminemia. It is unknown but possible that changes in plasma protein expression observed in CAA are required for the well-documented survival and general wellness. A systematic review of published case reports was performed to assess plasma protein pattern remodeling in CAA patients who were free of other illnesses that would confound interpretation. From a literature search in Pubmed, Scopus, and Purdue Libraries (updated October 2022), concentration of individual plasma proteins and protein classes were assessed. Total plasma protein concentration was below the reference range in the vast majority of CAA patients in the analysis, as upregulation of other proteins was not sufficient to prevent the decline of total plasma protein when albumin was absent. Nonetheless, an impressive level of evidence in the literature indicated upregulated plasma levels of multiple globulin classes and various specific proteins which may have metabolic functions in common with albumin. The potential role of this altered plasma protein expression pattern in CAA is discussed, and the findings may have implications for other populations with hypoalbuminemia.

Retrospective analysis of the use of canine-specific albumin in 125 critically ill dogs.

To describe the clinical use of canine-specific albumin (CSA) in critically ill dogs, report adverse events, and evaluate measurable clinical effects of CSA administration. Retrospective case series from 2019 to 2020. Large, urban, private-practice referral and emergency center. Consecutive sample of 125 client-owned dogs administered CSA transfusions. None. The conditions most commonly associated with the use of CSA were surgical (32/125) and nonsurgical (20/125) gastrointestinal disease. Both serum albumin and total plasma protein concentrations were significantly increased posttransfusion (P<0.001), and 16% albumin transfusions produced the greatest magnitude increase in serum albumin (P=0.0015). Concurrent crystalloid administration did not affect change in albumin. While there was no significant improvement in blood pressure seen in those patients that received albumin, a significant improvement in shock index was identified (P=0.02). Adverse events were uncommon; however, 8 critically ill dogs died during CSA administration. CSA appears to be a relatively safe alternative to synthetic colloids and complementary to crystalloids in critically ill patients. More concentrated solutions may be more effective in raising serum albumin concentration. Further investigation into the indications for and efficacy of CSA will continue to improve our knowledge of this blood product.

Feeding rumen-protected lysine altered immune and metabolic biomarkers in dairy cows during the transition period

This experiment was conducted to determine the effects of feeding rumen-protected lysine (RPL; AjiPro-L Generation 3, Ajinomoto Health and Nutrition North America Inc.) from -26 ± 4.6 d prepartum (0.54% RPL of dietary dry matter intake) to 28 d postpartum (0.39% RPL of dietary dry matter intake) on immunometabolic status and liver composition in dairy cows. Seventy-five multiparous Holstein cows, blocked by parity, previous 305-d mature-equivalent milk production, expected calving date, and body condition score during the far-off dry period were assigned to 1 of 4 dietary treatments in a randomized, complete block design with a 2 × 2 factorial arrangement of treatments. Treatments prepartum consisted of total mixed ration top dressed with RPL (PRE-L) or without RPL (PRE-C), and postpartum treatments consisted of total mixed ration top dressed PRE-L prepartum and postpartum, PRE-L prepartum and PRE-C postpartum, PRE-C prepartum and PRE-L postpartum, and PRE-C prepartum and postpartum in 300 g of molasses. Blood samples were taken on -7 ± 0.5, 0 ± 0.5, 7 ± 0.9, 14 ± 0.9, and 28 ± 0.5 d relative to calving. Whole blood samples were taken on -14 ± 0.5, -7 ± 0.5, 7 ± 0.9, and 14 ± 0.9 d relative to calving for oxidative burst and phagocytic capacity of monocytes and neutrophils. Liver samples were collected via a biopsy on -12 ± 4.95 and 13 ± 2.62 d relative to calving and analyzed for liver composition (triacylglyceride and carnitine concentrations), mRNA expression of hepatic genes, and protein abundance. Protein abundance was calculated by normalizing intensity bands for a specific protein with glyceraldehyde-3-phosphate dehydrogenase. Concentrations of haptoglobin and glutathione peroxidase activity in plasma were lower at d 0 for cows in PRE-L (102 µg/mL and 339 nmol/min per mL, respectively) compared with cows in PRE-C (165 µg/mL and 405 nmol/min per mL, respectively). Oxidative burst capacity in monocytes tended to be greater on d 7 postpartum for cows in PRE-L (65.6%) than cows in PRE-C (57.5%). Additionally, feeding RPL altered the mRNA expression in liver tissue prepartum [decreased INSR (insulin receptor), CPT1A (carnitine palmitoyltransferase 1A), and IL1B (interleukin 1 β)] and postpartum [increased IL8 (interleukin 8), EHMT2 (euchromatic histone lysine methyltransferase 2), TSPO (translocator protein), and SLC3A2 (solute carrier family 3 member 2); and decreased SLC7A1 (solute carrier family 7 member 1), SOD1 (superoxide dismutase 1), and SAA3 (serum amyloid A 3)] compared with cows not consuming RPL]. Additionally, cows in the PRE-C prepartum and PRE-L postpartum treatment tended to have greater protein abundance of mTOR postpartum compared with the PRE-C prepartum and postpartum treatment. Protein abundance of SLC7A7 (solute carrier family 7 member 7) pre- and postpartum tended to be greater and BBOX1 (gamma-butyrobetaine dioxygenase 1) tended to be less when RPL was consumed prepartum. In conclusion, cows that consumed RPL during the transition period had molecular changes related to liver composition, enhanced liver function indicated by greater total protein and albumin concentrations in plasma, and improved immune status indicated by decreased haptoglobin, glutathione peroxidase activity, and immune related mRNA expression.

Ability of L-Asparginase Produced from Locally E.coli Isolates on Negative Effect of UV Rays on Laboratory Rabbits

This study was carried out to illustrate the effective of injected L-asparginase enzyme produced from E.coli isolate at 1 and 2 ml on natural and biochemical blood characterized in laboratory rabbits induced tumor through exposure to UV rays with a wavelength 256 ƞm for 28 days. Results indicated that the exposure to UV arrays from laboratory rabbits have caused an significantly (p&lt; 0.05) reducing the total count of red blood corpuscular RBCs which became at 3.0×106/mm3 and the hemoglobin concentration at 9.1 g/dl compared with the same value at animals control group which was at 6.5x106/mm3 and 13.2 g/dl, respectively, as well as increased the total count of white blood cells WBCs and lymphocytes percentage deposited neutrophils percentage. Also, was caused significantly decline of total protein, albumin and globulin concentration in rabbits plasma and increase its liver enzymes activates for Aspartate amino transferase (AST), Alanine amino transferase (ALT), Alkaline phosphatase (ALP), which became at 52.3, 48.7 and 207 IU/ml, respectively, compared with the control group values at 32.0, 43.6, 141 IU/ml, respectively. The injection of an L-asparginase enzyme at 1 and 2 ml contains (72 IU/ml) due to inhibition of negative influence of UV rays altered in laboratory rabbits and improved the natural blood picture as red blood corpuscular, white blood cells, proteins parameters and liver enzymes activities significantly to close levels in control group animals. It can be concluded that bacterial isolates from E.coli species were as efficient in the L-asparginase enzyme production and the effectiveness of this enzyme were high in improving physiological parameters of laboratory rabbits exposed to UV rays.