Correction to: Recommendations for the Development and Validation of Neutralizing Antibody Assays in Support of Biosimilar Assessment.

In the published article, the author B. Babbitt was cited as affiliation 9, but should have been cited as affiliation 2. In addition, there are 2 errors in the affiliations. The correct affiliations are shown in this erratum.

Recommendations for the Development and Validation of Neutralizing Antibody Assays in Support of Biosimilar Assessment.

The American Association of Pharmaceutical Scientists (AAPS) biosimilar focus group on nonclinical and clinical assays has developed this manuscript to guide the industry on best practices and testing strategies when developing neutralizing antibody (NAb) assays for biosimilar programs. The immunogenicity assessment to biosimilar and originator drug products is one of the key aspects of clinical programs for biosimilars to demonstrate biosimilarity. Establishing that there are no clinically meaningful differences in immune response between a proposed product and the originator product is a key element in the demonstration of biosimilarity. It is critical to collect, evaluate, and compare the safety and immunogenicity data from the clinical pharmacology, safety, and/or efficacy studies especially when the originator drug product is known to have potential for immune-mediated toxicity. This manuscript aims to provide a comprehensive review and recommendations on assay formats, critical reagents, approaches to method development, and validation of the neutralizing antibody assays in extrapolation within the scope of biosimilar drug development programs. Even if there are multiple options on the development and validation of NAb assays for biosimilar programs, the type of drug and its MoA will help determine the assay format and technical platform for NAb assessment (e.g., cell-based or non-cell-based assay). We recommend to always perform a one-assay approach as it is better to confirm the biosimilarity using one-assay for NAb. If a one-assay approach is not feasible, then a two-assay format may be used. This manuscript will provide all the details necessary to develop NAb assays for biosimilars.

FOXP3 and FOXP3-regulated microRNAs suppress SATB1 in breast cancer cells.

The transcription factor FOXP3 has been identified as a tumour suppressor in the breast and prostate epithelia, but little is known about its specific mechanism of action. We have identified a feed-forward regulatory loop in which FOXP3 suppresses the expression of the oncogene SATB1. In particular, we demonstrate that SATB1 is not only a direct target of FOXP3 repression, but that FOXP3 also induces two miRs, miR-7 and miR-155, which specifically target the 3'-UTR of SATB1 to further regulate its expression. We conclude that FOXP3-regulated miRs form part of the mechanism by which FOXP3 prevents the transformation of the healthy breast epithelium to a cancerous phenotype. Approaches aimed at restoring FOXP3 function and the miRs it regulates could help provide new approaches to target breast cancer.

Cognitive impairment in hemodialysis patients is common.

BACKGROUND: Hemodialysis patients are at high risk for cognitive impairment due to their older age and high prevalence of stroke and cardiovascular risk factors. METHODS: Using a cross-sectional design, the authors measured cognitive function in 374 hemodialysis patients aged 55 years and older and an age-matched comparison group in Minneapolis and St. Paul, MN. Cognitive performance was measured in three domains: memory, executive function, and language. Subjects were classified as having no, mild, moderate, or severe cognitive impairment. RESULTS: Of 338 subjects who completed testing in at least two of the three cognitive domains, 13.9% (95% CI 10.4, 18.1) were classified with mild impairment, 36.1% (31.0, 41.5) with moderate impairment, 37.3% (32.1, 42.7) with severe impairment, and 12.7% (9.4, 16.8) with normal cognition. Only 2.9% had a documented history of cognitive impairment. Factors associated with severe cognitive impairment on adjusted logistic regression were stroke (adjusted OR [AOR] 1.95; 95% CI 1.08, 3.49; p < 0.03), equilibrated Kt/V > 1.2 (1.67; 1.01, 2.75; p < 0.05), and education >12 years (0.32; 0.14, 0.72; p < 0.01). The AOR for severe cognitive impairment in a random sample of 101 hemodialysis patients vs an age-matched comparison group was 3.54 (1.28, 9.78; p < 0.02). CONCLUSIONS: Moderate to severe cognitive impairment is common and undiagnosed in hemodialysis patients. Further studies are needed to determine whether dialysis exacerbates the cognitive impairment attributable to underlying disease. Cognitive testing in hemodialysis patients before dialysis initiation and periodically may be warranted.

Safety, pharmacokinetics, and immunogenicity of single-dose rFXIII administration to healthy volunteers.

BACKGROUND: Factor XIII (FXIII) is a transglutaminase that cross-links fibrin and other proteins to improve clot strength and resistance to fibrinolysis. Both congenital and acquired FXIII deficiency may result in a bleeding diathesis, and plasma-derived FXIII has been used to treat many of these clinical conditions. OBJECTIVES: A clinical study was designed and performed to evaluate the safety, pharmacokinetics, and immunogenicity of recombinant FXIII (rFXIII) administration to healthy adult volunteers. PATIENTS AND METHOD: Fifty healthy adult volunteers were enrolled in this randomized, double-blinded, placebo-controlled study. A single dose of rFXIII, ranging from 2 U kg(-1) to 50 U kg(-1), or placebo was administered. Safety was evaluated by capturing adverse events, clinical safety laboratory studies, and clinical score for deep venous thrombosis. Blood samples were taken for pharmacokinetic and immunogenicity analysis throughout the 28-day follow-up period. RESULTS: Recombinant FXIII was well tolerated, with no serious adverse events or dose-related toxicities. Following a single i.v. injection of 50 U kg(-1) rFXIII, the estimated terminal half-life was 270-320 h, the volume of distribution ranged from 40 to 75 mL kg(-1), and FXIII activity increased 1.77% per 1 U kg(-1) rFXIII administered. Increase in circulating A2B2 and decrease in free FXIII-B subunit indicate in vivo formation of FXIII heterotetramer. An immunogenic response to rFXIII or yeast, the production host, was not observed. CONCLUSIONS: Recombinant FXIII was well tolerated at doses of up to 50 U kg(-1) in healthy adult volunteers. The safety, pharmacological and immunological profile of rFXIII suggests it should be studied in patients with congenital FXIII deficiency as well as evaluated as a systemic hemostat in patients with acquired FXIII deficiency or hemorrhage.

Mechanisms of activation of NHE by cell shrinkage and by calyculin A in Ehrlich ascites tumor cells.

The Na+/H+ exchanger isoforms NHE1, NHE2, and NHE3 were all found to be expressed in Ehrlich ascites tumor cells, as evaluated by Western blotting and confocal microscopy. Under unstimulated conditions, NHE1 was found predominantly in the plasma membrane, NHE3 intracellularly, and NHE2 in both compartments. Osmotic cell shrinkage elicited a rapid intracellular alkalinization, the sensitivity of which to EIPA (IC50 0.19 microM) and HOE 642 (IC50 0.85 microM) indicated that it predominantly reflected activation of NHE1. NHE activation by osmotic shrinkage was inhibited by the protein kinase C inhibitors chelerythrine (IC50 12.5 microM), Gö 6850 (5 microM), and Gö 6976 (1 microM), and by the p38 MAPK inhibitor SB 203580 (10 microM). Furthermore, hypertonic cell shrinkage elicited a biphasic increase in p38 MAPK phosphorylation, with the first significant increase detectable 2 minutes after the hypertonic challenge. Neither myosin light chain kinase-specific concentrations of ML-7 (IC50 40 microM) nor ERK1/2 inhibition by PD 98059 (50 microM) had any effect on NHE activation. Under isotonic conditions, the serine/threonine protein phosphatase inhibitor calyculin A elicited an EIPA- and HOE 642-inhibitable intracellular alkalinization, indicating NHE1 activation. Similarly, shrinkage-induced NHE activation was potentiated by calyculin A. The calyculin A-induced alkalinization was not associated with an increase in the free, intracellular calcium concentration, but was abolished by chelerythrine. It is concluded that shrinkage-induced NHE activation is dependent on PKC and p38 MAPK, but not on MLCK or ERK1/2. NHE activity under both iso- and hypertonic conditions is increased by inhibition of serine/threonine phosphatases, and this effect appears to be PKC-dependent.

Diagnostic errors using the Short Portable Mental Status Questionnaire with a mixed clinical population.

The validity of the Short Portable Mental Status Questionnaire (SPMSQ) was evaluated using two criteria: clinical diagnosis and neuropsychological diagnosis. The 40 study participants represented a mixed clinical sample of neurologic and psychiatric patients, all of whom were or had been inpatients. Laboratory data (CT, EEG, etc.) were available for 45% of the patients. Neuropsychological diagnosis of organic impairment was based on an extensive test battery. The SPMSQ did not significantly relate to either clinical or neuropsychological diagnosis. It is recommended that a "normal" score on the SPMSQ be regarded as nonspecific regarding organic cognitive impairment rather than suggestive of normal brain functioning.

Clinical types in a normal population: concurrent and construct validity.

Examined the relationship between personality and psychopathology through the use of the Multivariate Personality Inventory (MPI) (N = 100). The concurrent validity study compared the factors of the MPI with those of the Lazare-Klerman Personality Inventory, which was developed for a pathological population. Factor analysis of these two inventories yielded three factors that correspond to the three predicted personality styles: Hysteric, Compulsive, and Character Disorder. In the second part of this study the construct validity of these scales was examined. Results showed significant differences among groups in the predicted directions, which indicates that the personality groups as defined by the MPI in a normal population perform as would be predicted from work with pathological groups that bear the same label. Construct validity measures did not support the predictions with regard to the performance of the personality types.

Personality styles and psychopathy.

Administered the Multivariate Personality Inventory (MPI) and established measures of psychopathy to students (N = 71) to determine the relationship between the Character Disorder Style subscale of the MPI and psychopathy. Results clearly showed the independence of the Character Disorder Style subscale and psychopathy. Additionally, the Manic Style subscale was shown to be independent from both psychopathy and the Character Disorder Style subscale.

Personality styles, manifest needs, and the perception of time in college women.

Reports the continued development of a multivariate theory of personality styles and a scale, the Multivariate Personality Inventory, designed to measure these styles in both pathological and normal populations. In a sample of college women, theory-generated predictions of the manifest needs of each personality style were examined with the Edwards Personal Preference Schedule. Results supported the validity of the Multivariate Personality Inventory in regard to the need profile of each personality style group. To examine the relationship between the personality styles and behavior, a series of time estimation measures also were employed.