Exogenous Albumin Research Articles

Preclinical Development of a Genetically Engineered Albumin‐Binding Nanoparticle of Paclitaxel

Nab‐paclitaxel (Abraxane), an albumin‐bound solvent‐free paclitaxel (PTX) formulation that takes advantage of the endogenous albumin transport pathway, is the current gold standard for treatment of solid tumors with PTX. However, nab‐paclitaxel has several limitations, including complex manufacturing, immunogenicity, slow drug‐release, and a narrow therapeutic window. Nevertheless, no other PTX formulation has gained the Food and Drug Administration approval since Abraxane's 18‐year reign. Addressing these concerns, herein, a PTX‐loaded nanoparticle of a recombinant polypeptide that—like nab‐paclitaxel—capitalizes on the long in vivo half‐life of albumin is reported. This genetically engineered nanoparticle packages PTX in the core of the nanoparticle and displays an albumin‐binding domain on the exterior of the nanoparticle. Upon in vivo administration, the drug‐loaded nanoparticle binds albumin with nanomolar affinity, and acquires an albumin‐corona, which eliminates the need to use exogenous albumin. The nanoparticles can be stored at subzero temperature as lyophilized powder without any cryoprotectants for upto a year and can be reconstituted on‐demand in aqueous buffer at high concentration, thus greatly simplifying formulation processes. These albumin‐binding nanoparticles improve the therapeutic window by at least twofold compared to nonalbumin‐binding counterpart and outperform nab‐paclitaxel in multiple murine tumor models, results that have been independently replicated by a contract research organization.

Abstract P360: MicroRNAs: Potential Biomarkers and Therapeutic Targets for Hypertensive Nephropathy

Introduction: Hypertensive nephropathy (HN) is the second most common cause of end-stage renal disease after diabetic nephropathy. miRNAs are small epigenetic modulators whose levels change in many diseases. This review summarizes the diagnostic and therapeutic potential of miRNAs in HN. Methodology: We conducted a thorough literature review on PubMed, including both retrospective and prospective studies on animal and human subjects. Additional references were sourced through cross-referencing the bibliographies of the initial articles. Results: Our literature review revealed that intra-renal levels of miR-200a, miR-141, miR-200b, miR-205, miR-429, and miR-192 were elevated in patients with HN. Conversely, intra-renal miR-204-5p levels were decreased, and further reductions in animal models using anti-miR-204-5p or miR-204 gene knockout exacerbated renal injury. Exposure of renal tissue to exogenous albumin increased intra-renal miR-184 levels, prompting further investigation into whether albumin excretion from kidney injury alters miRNA expression or if miRNA dysregulation initiates kidney injury and subsequent albumin excretion. Urinary miR-146a, miR-184, and miR-34a levels were lower in patients with albuminuria than those without, whereas urinary miR-200a levels were higher. Interestingly, urinary miR-21 levels increased before the onset of albuminuria in hypertensive mice. A positive correlation was also observed between miR-208b and miR-133a levels in blood cells and urinary albumin excretion (UAE). Notably, plasma levels of miR-let-7g-5p and miR-191-5p correlated positively with eGFR but not with UAE. Since miRNA levels varied based on the sampling source, a pivotal study identified a consistent miRNA profile in HN patients, showing that miR-208a and miR-301a were upregulated in urine yet downregulated in plasma. The therapeutic potential of miRNAs was highlighted by an animal study showing that the knockdown of miR-103a-3p can nullify albuminuria in hypertensive mice. Conclusion: The role of miRNAs in HN is increasingly evident. Studies have linked varying miRNA expression profiles in patients with HN, and specific miRNAs were detectable earlier than albuminuria. Furthermore, certain miRNAs correlate with eGFR independently of UAE. Targeting specific miRNAs, using miRNA mimics and anti-miRNAs, could underpin preventive and therapeutic strategies. These findings advocate for further research into miRNAs as potential biomarkers and therapeutic targets for HN.

#1329 Assessing eGFR performance against measured GFR stratifying for ethnicity and albumin: development of the AIM CKD UK study

Abstract Background and Aims Accurate measurement of kidney function using estimated glomerular filtration rate (eGFR) is essential for appropriate risk stratification of cardiovascular events, kidney failure and prescribing medications. The AIM CKD UK study (IRAS 320215) will assess the accuracy of current and novel creatinine-based eGFR equations compared to exogenous filtration marker derived measured GFR (mGFR) for people of different ethnicities in large national cohort. We performed a preliminary analysis from a single centre in AIM CKD UK to inform future data collection and assessed: Method All adults (≥18-years) who had paired mGFR and eGFR tests within 30 days between 2009-2022 were included. Patients with mGFR ≥150 ml/min/1.73 m2, incomplete datasets and previous amputations were excluded. Age, reported ethnicity, biological sex, referral specialty, height, weight, exogenous filtration marker, creatinine and albumin concentration were recorded. eGFR was calculated from creatinine, age and sex using five equations (Fig. 1). Each eGFR equation was compared to mGFR using median bias, precision, 30% accuracy (P30). Agreement was demonstrated with Bland-Altman plots. Results were stratified for time between eGFR-mGFR (≤7 days vs 8-30 days) and albumin concentration; low (<35 g/L) vs normal / high (≥35 g/L). Assessment of equation performance in different ethnicity was also stratified for the three largest ethnicity groups (White, Black and South Asian ethnicity). Data were analysed using software R V4.2.2. Results There were 2623 patients who met the inclusion criteria. Mean age was 54.8 ± 13.1 years, with 57.8% male (N = 1515). The majority of patients were White ethnicity (58.7%; N = 1539). Median mGFR was 77 mL/min/1.73 m2 (IQR 62–91 mL/min/1.73 m2). Median serum creatinine concentration was 74 umol/L (IQR 61–90 umol/L). The CKD-EPI 2009 equation, compared to mGFR, demonstrated a median bias of +12.8 mL/min/1.73 m2, percentage bias of 16.9% and P30 of 68.6%. The Lund-Malmo revised equation performed best with median bias of 2.1 mL/min/1.73 m2 (percentage bias 2.9%) and a P30 of 82.7%. Agreement, with ethnicity stratification is summarised in Table 1. The majority of patients (N = 2439; 93.0%) had paired mGFR-eGFR tests within 7-days. There was no significant difference between the median bias of each group (P = .749). 2610 (99.5%) patients had concurrent albumin tests performed; 183 (7.0%) of these patients had low albumin concentrations. Median bias was significantly higher in this group compared to normal/high albumin for each equation (e.g. Low vs Normal/high albumin median bias for CKD-EPI equation = 20.3 vs 12.5 mL/min/1.73 m2; P <. 001). Conclusion The LM revised and European Kidney Function Consortium equations perform best in this cohort. Limitations include selection bias and retrospective data. Future data analysis for the AIM CKD study can include paired samples within 30 days as there is no significant difference between 0-7 and 8-30 days. The impact of serum albumin on mGFR-eGFR association in a larger cohort stratified for confounding variables, such as liver disease, malignancy and body mass index is required.

Modulation of the capillary leakage by exogenous albumin in a rat model of endothelial glycocalyx damage.

Endothelial glycocalyx (EG) plays a crucial role in maintaining the plasma proteins within the intravascular space. We studied whether exogenous albumin protects the EG in an experimental model of EG enzymatic damage in rats. Rats were divided into three groups of 10 animals that received (1) Evans blue (2) Evans blue + hyaluronidase, or (3) Evans blue + hyaluronidase + 20% human albumin via the tail vein. Spectrophotometric analysis was performed 2 h later to quantify the leakage of Evans blue-labeled albumin into the heart, lungs, brain, kidneys, liver, small intestine, spleen, and skeletal muscle. Administration of hyaluronidase numerically increased the capillary leakage of Evans blue in all examined tissues. Co-administration of albumin decreased the leakage of albumin in all tissues except the heart. In the lungs, the ratio between the absorbance and dry organ weight decreased from 5.3 ± 2.4 to 1.7 ± 0.5 (mean ± SD) (P < 0.002), and in the liver, the absorbance decreased from 2.2 ± 0.7 to 1.5 ± 0.4 (P < 0.011). Exogenous albumin decreased the capillary leakage of albumin which was interpreted as a sign of maintained EG integrity.

Albumin-binding prodrugs use in treating cancer

Throughout the past few decades, the use of targeted delivery methods for cancer therapies has dramatically increased. Prodrug, a type of drug that can apply the targeting therapy, is defined as chemicals that undergo chemical transformations after enters the patients body. They will be activated and release the parent drug after reached the targeted site. Both passively and actively targeted therapies are explored. The albumin-binding prodrug, a model of prodrug applying passively targeted therapy, this paper introduces the enhanced permeability and retention (EPR) effect to target the tumor site. Besides, since the human serum albumin is an endogenous substance originated from human body, its nanoparticles is able to carry the anticancer drugs to elongate the circulatory half-lives of drugs since it will not be rejected by the immune system. However, the activated compound's systemic toxicity and the dearth of information regarding the biodistribution of prodrugs are two possible disadvantages. Moreover, some exogenous albumin formulations are prohibited from participating in clinical trials because of their very poor delivery efficiency. In conclusion, the albumin-binding prodrug is a cancer treating therapy that has great promise and great capability despite the potential risks.

Study of the f-cell ratio using plasma dilution and albumin mass kinetics

BackgroundThe f-cell ratio of 0.91 is a conversion factor between the hematocrit measured in peripheral blood and the hematocrit obtained by separate measurements of the red blood cell mass and plasma volume. The physiological background of the f-cell ratio is unclear. MethodsData were retrieved from 155 intravenous infusion experiments where 15–25 mL/kg of crystalloid fluid diluted the blood hemoglobin and plasma albumin concentrations. The hemodilution was converted to plasma dilution using the peripheral hematocrit, and the volume of distribution of exogenous albumin was calculated in 41 volunteers who received 20 % or 5 % albumin by intravenous infusion. Finally, the kinetics of plasma albumin was studied during 98 infusion experiments with 20 % albumin. ResultsPlasma dilution based on hemoglobin and albumin showed a median difference of −0.001 and a mean difference of 0.000 (N = 2184), which demonstrates that these biomarkers indicate the same expandable vascular space. In contrast, exogenous albumin occupied a volume that was 10 % larger than the plasma volume indicated by the anthropometric equations of Nadler et al. and Retzlaff et al. The kinetic analysis identified a secondary compartment that was 450 mL in size and rapidly exchanged albumin with the circulating plasma. ConclusionsThe results suggest that the f-cell ratio is due to rapid exchange of albumin between the plasma and a non-expandable compartment located outside the circulating blood (possibly the liver sinusoids). This means that the hematocrit measured in peripheral blood correctly represents the ratio between the red cell volume and the circulating plasma volume.

How Much Furosemide Should be Administered to Prevent Transfusion-Associated Circulatory Overload? Results of a Dose-Finding Study

BACKGROUND: Transfusion-associated circulatory overload (TACO) is a common but under-reported complication of transfusion therapy, and results in significant morbidity and mortality. Pre-transfusion furosemide has been proposed as a mitigating strategy but has not received widespread endorsement, in part due to uncertainty regarding safe and effective dosing. An observational study was therefore conducted with the goal of creating a reliable dose-response curve in patients at high risk of TACO, using the statistical technique of Multiple Comparisons Procedure with Modelling (MCP-MOD). METHODS: Eligible patients were identified by screening bolus intravenous (IV) furosemide orders at two large academic hospitals. Eligibility criteria were selected to mimic those of a planned randomized controlled trial (RCT) of pre-transfusion furosemide for the prevention of TACO. Inclusion criteria were inpatients 50 years of age or older. Exclusion criteria were active bleeding, hemodynamic instability, glomerular filtration rate (GFR) &amp;lt; 30mL/min or need for dialysis, diuretic therapy (other than furosemide) administered less than 24 hours, furosemide (either IV or PO) administered less than 12 hours, or exogenous albumin administered less than 8 hours prior to index furosemide therapy. The primary outcome measure was the total volume of urine output in the six hours following IV furosemide administration. MCP-MOD analysis was performed after every 50 patients and continued until a weight-adjusted dose-response curve could be established with 100 mL precision, using the following covariates: age, sex, mean arterial pressure (MAP), serum albumin, GFR and history of chronic furosemide use. RESULTS: A total of 149 participants (53 female and 96 male) were enrolled over 2 years. As too few patients received doses exceeding 0.6 mg/kg to allow for a precise dose-response curve, only 132 patients receiving weight-adjusted doses ranging from 0.1 to 0.6 mg/kg were included in the MCP-MOD analysis. The characteristics of these patients are shown in Table 1. The dose-response curve formula that was derived from these patients was: Urine Output at 6 hours (mL) = 717.21 + 191.33 ln(dose (mg)/weight (kg)) + 0.73 × Age (years) + 103.37 × Sex (M=1/F=0) + 1.63 × GFR (ml/min) + 5.45 × MAP (mmHg) - 9.56 × albumin (g/L) - 62.31 × chronic diuretic use (Y=1/N-0) The curve with accompanying 95% confidence intervals is shown in Figure 1 This formula suggests that in an 80 kg patient with a GFR of 75 mL/min, a MAP of 85 mmHg, albumin of 40 g/L and no history of chronic diuretic use, 10 mg of IV furosemide should produce a diuresis of approximately 600 mL, sufficient to prevent circulatory overload from the transfusion of 1 unit of RBCs. A dose of 20 mg would be required to achieve a similar diuresis in patients with either a MAP &amp;lt; 60 mmHg, or a combination of both a GFR &amp;lt; 45 mL/min and a history of chronic diuretic use. CONCLUSIONS: A statistically precise dose-response curve for IV furosemide is possible with the inclusion of relevant clinical covariates, and can be used to guide dosing decisions in patients at risk of transfusion-associated circulatory overload. This formula derived from this study will inform the dosing recommendations of a planned RCT: Transfusion-Associated Circulatory Overload: Best Eliminated by Lasix® (TACO-BEL).

NIR‐II cyanine@albumin fluorophore for deep tissue imaging and imaging‐guided surgery

AbstractThe near‐infrared (NIR)‐II bioimaging technique is highly important for both diagnosing and treating life‐threatening diseases due to its exceptional imaging capabilities. However, the lack of suitable NIR‐II fluorescent probes has hindered their widespread clinical application. To address this issue, the binding of albumin to cyanine dyes has emerged as a practical and efficient method for developing high‐performance NIR‐II probes. Cyanine dyes can bind with exogenous and endogenous albumin through either covalent or noncovalent interactions, serving various purposes. The resulting cyanine@albumin (or albumin@cyanine) fluorophores offer significant advantages, including strong brightness, excellent photostability, good biosafety, and a long‐term, high‐resolution imaging window. Cyanine dye in situ binding with endogenous albumin can also enhance the targeting imaging capability. This review provides a summary of the interaction mechanism, performance enhancement, tumor‐targeting feature, and in vivo imaging applications of the cyanine@albumin fluorophores. These advancements not only highlight the unique characteristics of cyanine@albumin fluorophores in preclinical research but also emphasize their potential for clinical diagnosis.

Albumin and Cardioprotection in On-Pump Cardiac Surgery—A Post Hoc Analysis of a Randomized Trial

To study the quantitative potency of plasma albumin on cardioprotection in terms of creatinine kinase-myocardial band mass (CK-MBm) in on-pump cardiac surgery. Post hoc analysis of a double-blinded randomized clinical trial. Single-center study in the Helsinki University Hospital. A total of 1,386 adult on-pump cardiac surgical patients. Administration of 4% albumin (n = 693) or Ringers acetate (n = 693) for cardiopulmonary bypass priming and volume replacement intraoperatively and postoperatively during the first 24 hours. Albumin concentration was measured preoperatively and intraoperatively (after protamine administration), and CK-MBm on the first postoperative morning. Multivariate linear regression analyses were measured in the whole cohort and the Ringer group. Plasma albumin concentration did not differ between the groups preoperatively (Ringer v albumin: 38.3 ± 5.0 g/L v 38.6 ± 4.5 g/L; p = 0.171) but differed intraoperatively (29.5 ± 5.2 g/L v 41.5 ± 6.0 g/L; p < 0.001). Creatinine kinase-myocardial band mass was higher in the Ringer (32.0 ± 34.8 μg/L) than in the albumin group (24.3 ± 33.0 μg/L) (p < 0.001). Aortic cross-clamping time associated with CK-MBm in the whole cohort (standardized β = 0.376 [95% CI 0.315-0.437], p < 0.001) and the Ringer group (β = 0.363 [0.273-0.452]; p < 0.001). Albumin administration in the whole cohort (β = -0.156 [-0.201 to -0.111]; p < 0.001) and high intraoperative albumin concentration in the Ringer group (β = -0.07 [-0.140 to -0.003]; p = 0.04) associated with reduced CK-MBm. Compared with ischemia-induced increase in CK-MBm, albumin's potency to reduce CK-MBm was 41% in the whole cohort (β-value ratio of -0.156/0.376) and 19% in the Ringer group (β-value ratio of -0.07/0.363). Both endogenous and exogenous albumin appear to be cardioprotective regarding CK-MBm release in on-pump cardiac surgery.

Effect of Exogenous Albumin Replacement on Plasma Colloid Osmotic Pressure in Severe Preeclampsia: A Case-control Study

Background: In preeclampsia, hypoalbuminemia reduces plasma colloid osmotic pressure (PCOP) and favors capillary leakage. Replacement with exogenous albumin is a therapeutic alternative.&#x0D; Objective: to determine the effect of exogenous albumin replacement on PCOP in patients with severe preeclampsia (SP).&#x0D; Methods: A case-control study was carried out in 76 pregnant patients with SP from the Intensive Care Unit (ICU). The case group (n=38) received 0.9% saline solution 1000 ml every 8 hours and 25% albumin 50 ml every 8 hours and the control group (n=38) only received 0.9% saline solution 1000 ml every 8 hours. Plasma albumin concentrations, PCOP, hemodynamic and laboratory data from admission (baseline measurement) vs discharge from the ICU (final measurement) of both groups were compared.&#x0D; Statistical Analysis: the data was analyzed with descriptive statistics, paired Student's t-test and Pearson's correlation coefficient with the statistical program SPSS® version 20. The p value &lt;0.05 was significant.&#x0D; Results: A significant decrease in plasma albumin was found (case group 2.72±0.44 vs 2.45±0.48 g/dL, p=0.0141; control group 3.06±0.33 vs 2.58±0.29 g/dL, p=0.0431). PCOP was also significantly reduced (case group 18.44±2.92 vs 16.82±2.70 mmHg, p=0.0210; control group 20.38±2.28 vs 17.46±1.96 mmHg, p=0.0763). The group of cases showed an increase in uresis (p=0.0326), but without changes in central venous pressure (p=0.3246) and serum creatinine (p=0.9515). With this evidence the recommendation is that its use in patients with preeclampsia should be reserved for the experience of the medical team.&#x0D; Conclusion: Exogenous albumin replacement therapy did not correct the PCOP values or the blood albumin concentration.

MSR6 Assessing the Impact of Early Albumin Administration in Patients Requiring Intravascular Resuscitation: Application of Machine Learning Techniques to Electronic Health Record (EHR) Data

Exogenous human albumin administration has shown improved outcomes in patients requiring intravascular resuscitation (e.g., spontaneous bacterial peritonitis, and hepatorenal syndrome). However, its acute use in other conditions and liver disease-associated complications requiring fluid resuscitation is unclear. We applied machine learning (ML) techniques to electronic health records data from patients with anemia and gastrointestinal bleeding, alcoholic liver disease, hepatic failure, acute pancreatitis, and nephrotic syndrome, to identify subpopulations that may benefit from early albumin administration.

Expert Consensus on the Use of Human Serum Albumin in Adult Cardiac Surgery.

Expert Consensus on the Use of Human Serum Albumin in Adult Cardiac Surgery.

Effects of Protein Components on the Chemical Composition and Sensory Properties of Millet Huangjiu (Chinese Millet Wine).

Millet Huangjiu is a national alcoholic beverage in China. The quality of Chinese millet Huangjiu is significantly influenced by the protein components in the raw materials of millet. Therefore, in this study, the impact of different protein components on the quality of millet Huangjiu was investigated by adding exogenous proteins glutelin and albumin either individually or in combination. The study commenced with the determination of the oenological parameters of different millet Huangjiu samples, followed by the assessment of free amino acids and organic acids. In addition, the volatile profiles of millet Huangjiu were characterized by employing HS-SPME-GC/MS. Finally, a sensory evaluation was conducted to evaluate the overall aroma profiles of millet Huangjiu. The results showed that adding glutelin significantly increased the contents of total soluble solids, amino acid nitrogen, and ethanol in millet Huangjiu by 32.2%, 41.5%, and 17.7%, respectively. Furthermore, the fortification of the fermentation substrate with glutelin protein was found to significantly enhance the umami (aspartic and glutamic acids) and sweet-tasting (alanine and proline) amino acids in the final product. Gas chromatography-quadrupole mass spectrometry coupled with multivariate statistical analysis revealed distinct impacts of protein composition on the volatile organic compound (VOC) profiles of millet Huangjiu. Excessive glutelin led to an over-accumulation of alcohol aroma, while the addition of albumin protein proved to be a viable approach for enhancing the ester and fruity fragrances. Sensory analysis suggested that the proper amount of protein fortification using a Glu + Alb combination could enhance the sensory attributes of millet Huangjiu while maintaining its unique flavor characteristics. These findings suggest that reasonable adjustment of the glutelin and albumin contents in millet could effectively regulate the chemical composition and improve the sensory quality of millet Huangjiu.

The Association of Pre-operative Serum Albumin Levels and Post-operative In-Hospital Death in Patients Undergoing Gastrointestinal Surgeries in Thailand: A Retrospective Cohort Study.

Pre-operative hypoalbuminemia is known to predict negative outcomes for patients undergoing major surgeries. However, various cut-off points for starting exogenous albumin have been recommended. This study investigated the association between pre-operative severe hypoalbuminemia, in-hospital death, and length of hospital stay in patients undergoing gastrointestinal surgery. A retrospective cohort study using a database analysis was undertaken on hospitalized patients who underwent major gastrointestinal surgery. The pre-operative serum albumin level was classified into three groups: severe hypoalbuminemia (<2.0 mg/dL) and non-severe hypoalbuminemia (≥2.0-3.4 g/dL) and normal level (3.5-5.5 g/dL). To compare between different cut-offs, a sensitivity analysis using another albumin level classification as severe hypoalbuminemia (<2.5 mg/dL) and non-severe hypoalbuminemia (≥2.5-3.4 g/dL) and normal level (3.5-5.5 g/dL) was applied. The primary outcome was post-operative in-hospital death. Propensity-score adjusted regression analyses were applied. A total of 670 patients were included. Their average age was 57.4 ± 16.3 years, and 56.1% were men. Only 59 patients (8.8%) had severe hypoalbuminemia. Overall, a total of 93 in-hospital deaths (13.9%) occurred among all included patients, but there were 24/59 (40.7%) deaths among patients with severe hypoalbuminemia, 59/302 (19.5%) deaths among patients with non-severe hypoalbuminemia, and 10/309 (3.2%) deaths among patients with normal albumin level. The adjusted odds ratio for post-operative in-hospital death comparing patients with severe hypoalbuminemia and patients with normal albumin level was 8.11 (3.31-19.87; p < 0.001), while the odds ratio for in-hospital death comparing patients with non-severe and patients with normal albumin level was 3.89 (1.87-8.10; p < 0.001). A sensitivity analysis showed similar findings, the odds ratio for in-hospital death for severe hypoalbuminemia (cut-off as <2.5 g/dL) was 7.44 (3.38-16.36; p < 0.001), while the odds ratio for in-hospital death for severe hypoalbuminemia (cut-off as 2.5-3.4 g/dL) was 3.02 (1.40-6.52; p = 0.005). Severe pre-operative hypoalbuminemia in patients undergoing gastrointestinal surgery was associated with an increased risk of in-hospital mortality. The risk of death for patients with severe hypoalbuminemia was relatively similar when using different cut-offs such as <2.0 and <2.5 g/dL.

Chemically defined cytokine-free expansion of human haematopoietic stem cells.

Haematopoietic stem cells (HSCs) are a rare cell type that reconstitute the entire blood and immune systems after transplantation and can be used as a curative cell therapy for a variety of haematological diseases1,2. However, the low number of HSCs in the body makes both biological analyses and clinical application difficult, and the limited extent to which human HSCs can be expanded ex vivo remains a substantial barrier to the wider and safer therapeutic use of HSC transplantation3. Although various reagents have been tested in attempts to stimulate the expansion of human HSCs, cytokines have long been thought to be essential for supporting HSCs ex vivo4. Here we report the establishment of a culture system that allows the long-term ex vivo expansion of human HSCs, achieved through the complete replacement of exogenous cytokines and albumin with chemical agonists and a caprolactam-based polymer. A phosphoinositide 3-kinase activator, in combination with a thrombopoietin-receptor agonist and the pyrimidoindole derivative UM171, were sufficient to stimulate the expansion of umbilical cord blood HSCs that are capable of serial engraftment in xenotransplantation assays. Ex vivo HSC expansion was further supported by split-clone transplantation assays and single-cell RNA-sequencing analysis. Our chemically defined expansion culture system will help to advance clinical HSC therapies.

Immunogenicity analysis of BPV-1 positive equine sarcoid-derived cultured fibroblasts

Sarcoids are the most common equine skin tumours Although they do not metastasize, they can be locally aggressive and cause significant clinical symptoms in affected horses. Despite being common, very little is known about the host immune response and the biological mechanisms underlying persistence and recurrence of equine sarcoids. The latter reflects the need for further research in this field. This in-vitro study used sarcoid explants from horses with naturally occurring sarcoids (n = 12) to evaluate the induction of a humoral immune response directed against equine sarcoid-derived bovine papilloma-virus (BPV)− 1 infected fibroblasts using a flow cytometric crossmatch assay. The presence of antibodies against exogenous bovine serum albumin (BSA) and fibroblast-like mesenchymal stromal cells (MSCs) was also evaluated by ELISA and flow cytometry, respectively. The viral load in the sarcoid explants, the corresponding cultured sarcoid fibroblasts, and matched peripheral blood mononuclear cells (PBMCs) from affected horses were determined by quantitative BPV-1/− 2 PCR analysis. Antibodies against autologous sarcoid cells were present in six out of twelve sarcoid-affected horses. Serum from all horses showed cross reactivity with allogeneic sarcoid cells, while only a part reacted with BSA or MSCs. Screening of host PBMCs demonstrated the absence of BPV E1 nucleic acids. Statistical analysis revealed a significantly higher mean viral load in the parental sarcoid tissue compared to the low passage fibroblasts (P < 0.001). These results support the hypothesis that sarcoid-affected horses may develop antibodies recognizing tumour-specific antigens. In contrast to sarcoid explants, equine PBMCs do not seem to contain complete BPV genomes. These results provide a basis for future investigations on the clinical relevance of these antibodies.

Albumin infusion in hospitalized patients with acute heart failure: a retrospective cohort study

BackgroundHeart failure is frequently associated with hypoalbuminaemia and poor prognosis. Acute heart failure (AHF) patients are commonly treated with intravenous albumin to improve osmotic pressure and haemodynamics. However, the effects of exogenous albumin supplementation on the fatality rate of AHF patients have not yet been demonstrated. Therefore, the present study strived to examine the impacts of albumin injections on the mortality rate of patients with AHF.MethodsThis retrospective cohort study evaluated the clinical outcomes of all consecutive hospitalized patients. Data were collected from medical records. The primary end-point was a composite of intubation, emergency renal replacement, or mortality in a time-to-event analysis. An inverse probability-weighted multivariable Cox model was used to compare outcomes between patients who were treated with albumin and those who were not based on the propensity score.ResultsAmong the 1420 consecutive patients hospitalized in our hospital with acute decompensated heart failure between 1 January 2017 and 27 February 2021, 382 were excluded, 337 (32.5%) were administered albumin (median treatment dose of 29.0 g), and 701 (67.5%) were not. The albumin exposure varied by body mass index, age group, previous diagnoses, clinical signs and symptoms, laboratory tests, and use of other drugs in the unmatched sample. The patients receiving albumin exhibited a lower serum albumin level at baseline in contrast with those who were not treated with albumin (median, 37.3 g/L vs. 31.7 g/L, respectively). Overall, primary end-point events occurred in 357 patients (34.4%) (79 died without being intubated or during an emergency renal replacement therapy, 118 were intubated and 160 had an emergency renal replacement therapy). In the inverse probability weighted multivariable analysis based on the propensity score, albumin use was not significantly associated with the composite primary end-point (hazard ratio, 1.05; 95% confidence interval, 0.75–1.47).ConclusionIn this observational study of AHF patients hospitalized in our hospital, the administration of albumin did not show a relationship with either a greatly reduced or aggregated risk of the composite end-point of intubation, emergency renal replacement therapy, or death. Therefore, randomized controlled trials of albumin administration are needed for patients with AHF.

TRPC6 Inactivation Reduces Albuminuria Induced by Protein Overload in Sprague Dawley Rats.

Canonical transient receptor potential-6 (TRPC6) channels have been implicated in familial and acquired forms of focal and segmental glomerulosclerosis (FSGS), and in renal fibrosis following ureteral obstruction in mice. TRPC6 channels also appear to play a role in driving glomerular disease in aging and in autoimmune glomerulonephritis. In the present study, we examine the role of TRPC6 in the proteinuric state caused by prolonged albumin overload (AO) in Sprague Dawley rats induced by daily injections of exogenous albumin. This was assessed in rats with a global and constitutive inactivation of TRPC6 channels (Trpc6del/del rats) and in wild-type littermates (Trpc6wt/wt rats). AO for 14 and 28 days caused increased urine albumin excretion that was significantly attenuated in Trpc6del/del rats compared to Trpc6wt/wt controls. AO overload did not induce significant glomerulosclerosis or azotemia in either genotype. AO induced mild tubulointerstitial disease characterized by fibrosis, hypercellularity and increased expression of markers of fibrosis and inflammation. Those changes were equally severe in Trpc6wt/wt and Trpc6del/del rats. Immunoblot analysis of renal cortex indicated that AO increased the abundances of TRPC3 and TRPC6, and caused a nearly complete loss of TRPC5 in Trpc6wt/wt rats. The increase in TRPC3 and the loss of TRPC5 occurred to the same extent in Trpc6del/del rats. These data also suggest that TRPC6 plays a role in the normal function of the glomerular filtration barrier. However, whether TRPC6 inactivation protects the tubulointerstitial compartments in Sprague Dawley rats depends on the disease model examined.

The Effect of Exogenous Human Albumin Administration on Acute Kidney Injury Development in Hypoalbuminemic Patients in the Intensive Care Unit

The Effect of Exogenous Human Albumin Administration on Acute Kidney Injury Development in Hypoalbuminemic Patients in the Intensive Care Unit

Emerging Albumin-Binding Anticancer Drugs for Tumor-Targeted Drug Delivery: Current Understandings and Clinical Translation.

Albumin has shown remarkable promise as a natural drug carrier by improving pharmacokinetic (PK) profiles of anticancer drugs for tumor-targeted delivery. The exogenous or endogenous albumin enhances the circulatory half-lives of anticancer drugs and passively target the tumors by the enhanced permeability and retention (EPR) effect. Thus, the albumin-based drug delivery leads to a potent antitumor efficacy in various preclinical models, and several candidates have been evaluated clinically. The most successful example is Abraxane, an exogenous human serum albumin (HSA)-bound paclitaxel formulation approved by the FDA and used to treat locally advanced or metastatic tumors. However, additional clinical translation of exogenous albumin formulations has not been approved to date because of their unexpectedly low delivery efficiency, which can increase the risk of systemic toxicity. To overcome these limitations, several prodrugs binding endogenous albumin covalently have been investigated owing to distinct advantages for a safe and more effective drug delivery. In this review, we give account of the different albumin-based drug delivery systems, from laboratory investigations to clinical applications, and their potential challenges, and the outlook for clinical translation is discussed. In addition, recent advances and progress of albumin-binding drugs to move more closely to the clinical settings are outlined.