Novel Finding of Urinary Erythropoietin as an Early Biomarker of Cisplatin-Induced Nephrotoxicity.

Cisplatin is a chemotherapeutic drug used to treat a great variety of solid tumors. Its dose is commonly limited by its nephrotoxicity, manifested as acute kidney injury (AKI). Erythropoietin (Epo) is a glycoprotein hormone that regulates the production of red blood cells. This study was performed to evaluate the presence of endogenous Epo in male Wistar rat urine and to analyse changes in urinary Epo levels in response to cisplatin- induced AKI. Dose-dependent studies and time-dependent experiments were performed to evaluate changes in urea nitrogen and creatinine in plasma as well as Epo, neutrophil gelatinase-associated lipocalin (NGAL), alkaline phosphatase (AP) activity, creatinine and total proteins in urine at 2 days post-dosing. Rats received 2, 5 or 10 mg/kg b.w., i.p. of cisplatin. At 5 mg/kg b.w., i.p. cisplatin, significant increases in urinary Epo were detected. Significant increases in urea nitrogen and creatinine in plasma, NGAL, AP, proteins, and Epo were observed in urine from rats that received 10 mg/kg b.w., i.p. of cisplatin. In the time-dependent experiments, rats were injected with a dose of 5 mg/kg b.w., i.p. of cisplatin, and sampling occurred 2, 4, and 14 days post-dosing. In these animals, there were significant increases in urea nitrogen and creatinine in plasma and total proteins, AP activity, Epo, and NGAL in urine on day 4. Urinary Epo was also detected on day 2. Taken together, these findings provide weight of evidence for urinary Epo as a promising early biomarker of cisplatin-induced AKI in male rats.

Oral exposure to DEHP may stimulate prostatic hyperplasia associated with upregulation of COX-2 and L-PGDS expressions in male adult rats.

Di-(2-ethylhexyl) phthalate (DEHP), a typical environmental endocrine disruptor (EED), can disrupt estrogen and androgen secretion and metabolism process, thus inducing dysfunctional reproduction such as impaired gonadal development and spermatogenesis disorder. Prostaglandin synthases (PGS) catalyze various prostaglandins biosynthesis, involved in inflammatory cascade and tumorigenesis. Yet, little is known about how PGS may impact prostatic hyperplasia development and progression. This study concentrates predominantly on the potential prostatic toxicity of DEHP exposure and the mediating role of PGS. In vivo study, adult male rats were administered via oral gavage 30 µg/kg/d, 90 µg/kg/d, 270 µg/kg/d, 810 µg/kg/d DEHP or vehicle for four weeks. The results elucidated that low-dose DEHP may cause the proliferation of the prostate with an increased PCNA/TUNEL ratio. Given the importance of estrogens and androgens in prostatic hyperplasia, our first objective was to evaluate the levels of sex hormones. DEHP improved the ratio of estradiol (E2)/testosterone (T) in a dose-dependent manner and upregulated estrogen receptor alpha (ERα) and androgen receptor (AR) expressions. Prostaglandin synthases, including cyclooxygenase-2 (COX-2) and lipocalin-type prostaglandin D synthase (L-PGDS), were significantly upregulated in the ventral prostate. COX-2 and L-PGDS might mediate the tendency of prostatic hyperplasia induced by low-dose DEHP through estradiol/androgen regulation and imbalance between proliferation and apoptosis in vivo. These findings provide the first evidence that prostaglandin synthases contribute to the tendency toward benign prostatic hyperplasia induced by DEHP. Further investigations will have to be performed to facilitate an improved understanding of the role of prostaglandin synthases in DEHP-induced prostatic lesions.

First-in-human phase I study of PRS-050 (Angiocal), an Anticalin targeting and antagonizing VEGF-A, in patients with advanced solid tumors.

BACKGROUND: To report the nonrandomized first-in-human phase I trial of PRS-050, a novel, rationally engineered Anticalin based on human tear lipocalin that targets and antagonizes vascular endothelial growth factor A (VEGF-A). METHODS: Patients with advanced solid tumors received PRS-050 at 0.1 mg/kg to 10 mg/kg by IV in successive dosing cohorts according to the 3+3 escalation scheme. The primary end point was safety. RESULTS: Twenty-six patients were enrolled; 25 were evaluable. Two patients experienced dose-limiting toxicity, comprising grade (G) 3 hypertension and G3 pyrexia, respectively. The maximum tolerated dose was not reached. Most commonly reported treatment-emergent adverse events (AEs) included chills (52%; G3, 4%), fatigue (52%; G3, 4%), hypertension (44%; G3, 16%), and nausea (40%, all G1/2). No anti-PRS-050 antibodies following multiple administration of the drug were detected. PRS-050 showed dose-proportional pharmacokinetics (PK), with a terminal half-life of approximately 6 days. Free VEGF-A was detectable at baseline in 9/25 patients, becoming rapidly undetectable after PRS-050 infusion for up to 3 weeks. VEGF-A/PRS-050 complex was detectable for up to 3 weeks at all dose levels, including in patients without detectable baseline-free VEGF-A. We also detected a significant reduction in circulating matrix metalloproteinase 2, suggesting this end point could be a pharmacodynamic (PD) marker of the drug's activity. CONCLUSIONS: PRS-050, a novel Anticalin with high affinity for VEGF-A, was well-tolerated when administered at the highest dose tested, 10 mg/kg. Based on target engagement and PK/PD data, the recommended phase II dose is 5 mg/kg every 2 weeks administered as a 120-minute infusion. TRIAL REGISTRATION: ClinicalTrials.gov NCT01141257 http://clinicaltrials.gov/ct2/show/NCT01141257.

Animal lipocalin allergens.

Lipocalins represent the most important group of inhalant animal allergens. For some of them, three-dimensional protein structures have been resolved, but their functions are still elusive. Lipocalins generally display a low sequence identity between family members. The characterization of new lipocalin allergens has revealed however that some of them display a high sequence identity to lipocalins from another species. They constitute a new group of potentially cross-reactive molecules which, in addition to serum albumins, may contribute to allergic cross-reactions between animal dander of different species. However, the clinical relevance of cross-reactivity needs to be assessed. Further studies are needed to understand which of these animal lipocalins are the primary allergens and which are cross-reacting molecules. The use of single, well characterized allergens for diagnosis will allow the identification of the sensitizing animal, which is a prerequisite for specific immunotherapy.

Direct and indirect exposure to horse: risk for sensitization and asthma.

Most studies on the sensitization to horse allergens in populations without professional exposure have been carried out in geographical areas where the rate of horse ownership is high and horse riding is popular. Very few studies have been carried out in populations living in large urban areas. This gap in the literature probably reflects the widespread view that prevalence of horse-related allergy is low in urban populations because the latter are not regularly exposed to horses. On the contrary, we suggest that urban areas constitute a model useful to study potential modalities of exposure and sensitization to horse allergen by other routes of exposure than horse-riding. In this article, we describe the risks related to various modalities of exposure to horse allergen, clinical aspects of airway sensitization to horse allergens in patients living in urban areas, and non-occupational exposure to horse allergen. In addition, we illuminate some aspects related to dispersion of horse allergens from sources such as stables to indoor environments.

[Value of the microarray for the study of Laboratory Animal Allergy (LAA)]. / II microarray proteico per lo studio dell'allergia da animali da laboratorio (LAA): principi e prospettive.

Since 1989, the National Institute for Occupational Safety and Health (NIOSH) considers the Laboratory Animal Allergy - LAA a risk for workers and in 1998 the LAA has been recognized as occupational risk in the USA. Rat and mouse are the most source of allergens, not so much for the higher power of allergy respect to the other animals, but because represent the more utilized species in the research. Most of the allergens are members of the lipocalin superfamily, small extracellular proteins represented by at least 50 proteins that mainly bind or carry small hydrophobic molecules. The recent and innovative molecular techniques, as the microarray, have allow the characterization of numerous allergens. The protein microarray gives the possibility to study of IgE profile for each individual, simultaneos analysis of a wide number of parameters concerning the allergy, giving new diagnostic and therapeutic opportunities for the allergies. In the study of occupational allergy--as LAA--the protein microarray could improve: the identification and characterization of new allergens; the individuation of susceptible workers; the study of immunological responses in exposed workers; the strategies of prevention and protection; the environmental and housing conditions. The participation, formation and information of the workers could improve the behavioural and occupational practices, the use of personal and collective protective devices in order to reduce the exposure to LAA in occupational context.