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To elucidate the role of Tau isoforms and post-translational modification (PTM) stoichiometry in Alzheimer's disease (AD), we generated a high-resolution quantitative proteomics map of 95 PTMs on multiple isoforms of Tau isolated from postmortem human tissue from 49 AD and 42 control subjects. Although Tau PTM maps reveal heterogeneity across subjects, a subset of PTMs display high occupancy and frequency for AD, suggesting importance in disease. Unsupervised analyses indicate that PTMs occur in an ordered manner, leading to Tau aggregation. The processive addition and minimal set of PTMs associated with seeding activity was further defined by analysis of size-fractionated Tau. To summarize, features in the Tau protein critical for disease intervention at different stages of disease are identified, including enrichment of 0N and 4R isoforms, underrepresentation of the C terminus, an increase in negative charge in the proline-rich region (PRR), and a decrease in positive charge in the microtubule binding domain (MBD).

Bovine alkaline phosphatase (BALP) mediated interference is a potential issue in the Beckman Access unconjugated estriol (uE3) assay. As the uE3 assay is a component of second trimester maternal serum screening characterizing this interference is essential for delivering accurate trisomy 18 and trisomy 21 risks.

Residual serum samples (n=517) were measured by two different lots of uE3 assay. Scavenger BALP (sBALP) was added to all samples to remove potential BALP dependent interference and assessed using both lots of uE3 reagent.

BALP mediated interference was observed in similar frequency in both lots of reagent (~3%), although the patterns of positive and negative interference differed between the lots. Pretreatment with sBALP improved lot-to-lot comparison. The presence of BALP related interference was not related to the concentration of endogenous human alkaline phosphatase. The use of polyethylene glycol and sBALP treatment appeared to mitigate BALP mediated interference equally well, and resulted in concordance in measured uE3 concentrations between reagent lots. Additionally, heterophile antibody interference was observed in two samples affected with BALP interference, and the heterophile antibody interference was resolved by both PEG and heterophile antibody blocking reagent treatment, but not sBALP treatment. While the maternal screen numeric risk for affected samples changed, the risk classification changed from a negative to positive screen in two samples.

Interference in the uE3 assay has the potential to affect maternal serum risk calculations in different reagent lots, and pretreatment of samples with scavenger BALP or PEG should be considered in cases of unexplained uE3 concentrations.

Interference in the uE3 assay has the potential to affect maternal serum risk calculations in different reagent lots, and pretreatment of samples with scavenger BALP or PEG should be considered in cases of unexplained uE3 concentrations.

Leptin, adiponectin, secreted frizzled-related protein 5 (Sfrp5) and wingless-type family member 5a (Wnt5a) are novel adipokines that are involved in insulin sensitivity and atherosclerosis. The aim of the present study was to investigate the serum and periarterial adipose tissue leptin/adiponectin and Sfrp5/Wnt5a levels in patients with peripheral arterial occlusive disease (PAOD).

A total of 75 patients with PAOD and 39 control subjects were recruited. The serum concentrations of leptin, adiponectin, Sfrp5 and Wnt5a were measured by ELISAs, and the leptin, adiponectin, Sfrp5 and Wnt5a levels in the periarterial adipose tissue were observed by western blotting.

The serum Sfrp5 levels were significantly lower in the patients with PAOD than in the control subjects (p<0.001) and Wnt5a levels were higher in the patients with PAOD (p<0.001). The serum leptin levels were significantly higher in the patients with PAOD than in the control subjects (p<0.001), and adiponectin levels were significantly lcts. The leptin and Wnt5a levels in the serum and periarterial adipose tissue were significantly higher in the patients with PAOD than in the control subjects.The Ski (Sloan-Kettering Institute) is an evolutionarily conserved protein that plays a dual role as an oncoprotein and tumor suppressor gene in the development of human cancer. GC376 clinical trial The Ski oncogene was first identified as a transforming protein of the avian Sloan-Kettering retrovirus in 1986. Since its discovery, Ski has been identified as a carcinogenic regulator in a variety of malignant tumors. Later, it was reported that Ski regulates the occurrence and development of some cancers by acting as an oncogene. Ski mediates the proliferation, differentiation, metastasis, and invasion of numerous cancer cells through various mechanisms. Several studies have shown that Ski expression is correlated with the clinical characteristics of cancer patients and is a promising biomarker and therapeutic target for cancer. In this review, we summarize the mechanisms and potential clinical implications of Ski in dimorphism, cancer occurrence, and progression in various types of cancer.

The commutability of control materials used for external quality assessment (EQA) programs is of great importance. Evaluating the commutability of control materials is crucial to assess their suitability for EQA programs.

Forty-eight individual patient serum samples, commercial EQA samples, human serum pools (HSPs), commercially available sterile filtered charcoal stripped serum (CS) and swine serum were analyzed using the isotope dilution liquid chromatography-tandem mass spectrometry (ID LC-MS/MS) comparative method and six immunoassays for progesterone. The commutability was assessed according to the EP14-A2 guideline and the difference in bias approach, respectively.

According to the EP14-A2 guideline, HSPs and CS were commutable for all the tested immunoassays, while swine serum showed positive matrix effects in some assays. Based on the difference in bias approach, a large number of inconclusive and noncommutable results appeared.

The commutability of the processed materials varied depending on which evaluation approach and criterion was applied. Noncommutability of the EQA materials was observed. And HSPs and CS were possible commutable candidate control materials according to the EP14-A2 guideline.

The commutability of the processed materials varied depending on which evaluation approach and criterion was applied. Noncommutability of the EQA materials was observed. And HSPs and CS were possible commutable candidate control materials according to the EP14-A2 guideline.

Gaucher disease (GD) is caused by a deficiency of β-glucosidase (GCase), leading to accumulation of glucosylceramide (GlcC) and glucosylsphingosine (Lyso-Gb1). Lyso-Gb1 is a reliable biomarker for GD.

This study aims to develop a simple, effective and accurate method for the screening and diagnosis of GD using dried blood spot (DBS) samples.

Lyso-Gb1 in DBS was extracted by 50% acetonitrile aqueous solution containing isotope-labeled internal standard and analyzed using liquid chromatography tandem mass spectrometry (LC-MS/MS). A reference interval was established by analyzing samples from 277 healthy controls. Lyso-Gb1 was detected in the residual DBS samples from 142 high-risk patients with splenomegaly and/or thrombocytopenia. Based on GCase activity in DBS, samples were classified into four groups confirmed GD patients (n=52), GD carriers (n=5), false positive (n=36) and negative (n=49).

The optimized Lyso-Gb1 assay showed intra- and inter-assay variations ranged between 2.0%-8.2% and 3.8%-10.2%, respectively. Accuracies ranged from 93.5% to 112.6%. The lowest limit of quantification was 1ng/mL. The normal reference interval of Lyso-Gb1 in DBS ranged from 2.1 to 9.9ng/mL. Among the 142 subjects, except for one GD patient (Lyso-Gb1>2500ng/mL), the Lyso-Gb1 concentrations in 51 GD patients ranged from 190.5 to 2380.6ng/mL (the median 614.8ng/mL). Also, one negative patient was found to have an elevated Lyso-Gb1 level (684.5ng/mL), while the other patients were normal. The negative case was then confirmed to be an atypical GD patient with a c.1091A>G (p.Y364C) homozygous variant in PSAP gene by next generation sequencing.

The optimized method to determine Lyso-Gb1 in DBS was demonstrated as a useful tool for the screening and diagnosis of GD.

The optimized method to determine Lyso-Gb1 in DBS was demonstrated as a useful tool for the screening and diagnosis of GD.

Tranexamic acid is a drug used during open cardiac surgery to prevent blood loss. The blood levels of 10-100µg/mL are reported to be in the therapeutic range and higher levels are linked to increased incidence of adverse effects. The aim of this study was to optimize and validate an LC-MS/MS method for serum tranexamic acid and measure its levels in patients from the DEPOSITION Pilot trial in order to prove the concept that topical administration will yield lower serum concentration.

The method development was carried out in several steps including sample preparation, and optimization of chromatography and tandem mass spectrometry parameters. Method validation including day-to-day precision with 4 QC levels, limit of detection, sample stability, carryover, and concentration-signal linearity was carried out. Ninety patient samples were analyzed using the validated method.

Fast and efficient LC-MS/MS method for analysis of tranexamic acid in serum was developed. The run time was 7min with the total time o.6%) with no sample carryover observed. The matrix effect on the analytical sensitivity was negligible and the lower limit of detection was 0.5 µg/mL. The difference in the mean adjusted concentrations between topical (45 patients) and intravenous (45 patients) groups was statistically significant (0.1154 µg/mL/kg vs. 0.2542 µg/mL/kg, p less then 0.0001) CONCLUSIONS Rapid and simple LC-MS/MS method for analysis of tranexamic acid was optimized and validated. The laboratory has played a crucial role in proving the concept that topical administration yields significantly lower systemic levels of tranexamic acid, and thus decreases the risk of adverse outcomes in patients undergoing open cardiac surgery.Reference intervals (RI) for ferritin are the subject of some controversy, with indications that changes in lifestyle and demographics (e.g., obesity) have limited the validity of RIs established decades ago. Package insert RIs for the Roche Elecsys® immunoassay do not include expected values for pediatric (50 years) females. Established RIs were verified using specimens obtained from healthy donors.The present work aims to study the role of air pollutants in relation to the number of deaths per each Italian province affected by COVID-19. To do that, specific mortality from COVID-19 has been standardized for each Italian province and per age group (10 groups) ranging from 0 to 9 years to >90 years, based on the 2019 national population figures. The link between air pollutants and COVID-19 mortality among Italian provinces was studied implementing a linear regression model, whereas the wide set of variables were examined by means of LISA (Local Indicators of Spatial Autocorrelation), relating the spatial component of COVID-19 related data with a mix of environmental variables as explanatory variables. As results, in some provinces, namely the Western Po Valley provinces, the SMR (Standardized Mortality Ratio) is much higher than expected, and the presence of PM10 was independently associated with the case status. Furthermore, the results for LISA on SMR and PM10 demonstrate clusters of high-high values in the wide Metropolitan area of Milan and the Po Valley area respectively, with a certain level of overlap of the two distributions in the area strictly considered Milan.