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We propose a model on how to promote clinical collaboration on AKI across Europe, the creation of a pan-European nephrology network of interested units is proposed, to improve clinical outcomes, increase nephrologist involvement and awareness outside nephrology, and stimulate research on AKI in Europe. Accordingly, we also propose a list of research priorities and stress the need for more European funding of AKI research.

An open-label phase 1 study was conducted to evaluate the effect of voclosporin on blood levels of mycophenolic acid (MPA, active moiety) and mycophenolic acid glucuronide (MPAG, pharmacologically inactive metabolite) following dosing with mycophenolate mofetil (MMF) in subjects with systemic lupus erythematosus (SLE) and to assess the safety and tolerability of the combination.

MMF was orally administered at a dose of 1 g BID for at least 28 days prior to the study and continued at the same dose throughout the study. Voclosporin was orally administered at a dose of 23.7 mg BID for seven consecutive days (Day 1 to Day 7), starting in the evening of Day 1 and ending with the morning dose on Day 7. Dense PK blood samplings were collected pre-dose in the morning and from 0.25 to 12 hours post-morning doses. Analyses were derived by non-compartmental methods.

In 24 patients, MPA exposure (Cmax and AUC0-12) was similar in the presence and absence of voclosporin, with treatment ratios of 0.94 and 1.09, respectively (Cmax 16.5 μg/mL [Day 1] vs.15.8 μg/mL [Day 7], AUC0-12 39.1 μg.h/mL [Day 1] vs. 40.8 μg.h/mL [Day 7]. MPAG exposure showed a small increase in the presence of voclosporin (12% for Cmax and 27% for AUC0-12). Combination therapy was well tolerated.

There is no clinically meaningful interaction between voclosporin and MMF. As changes in exposure to MPA may affect efficacy and safety, these data confirm that voclosporin and MMF can be given concomitantly without the need for dose adjustment.

There is no clinically meaningful interaction between voclosporin and MMF. As changes in exposure to MPA may affect efficacy and safety, these data confirm that voclosporin and MMF can be given concomitantly without the need for dose adjustment.Bloodfeeding is employed by many parasitic animals and requires specific innovations for efficient feeding. Some of these innovations are molecular features that are related to the inhibition of hemostasis. For example, bloodfeeding insects, bats, and leeches release proteins with anticoagulatory activity through their salivary secretions. The antistasin-like protein family, composed of serine protease inhibitors with one or more antistasin-like domains, is tightly linked to inhibition of hemostasis in leeches. However, this protein family has been recorded also in non-bloodfeeding invertebrates, such as cnidarians, mollusks, polychaetes, and oligochaetes. The present study aims to 1) root the antistasin-like gene tree and delimit the major orthologous groups, 2) identify potential independent origins of salivary proteins secreted by leeches, and 3) identify major changes in domain and/or motif structure within each orthologous group. Five clades containing leech antistasin-like proteins are distinguishable through rigorous phylogenetic analyses based on nine new transcriptomes and a diverse set of comparative data the trypsin + leukocyte elastase inhibitors clade, the antistasin clade, the therostasin clade, and two additional, unnamed clades. The antistasin-like gene tree supports multiple origins of leech antistasin-like proteins due to the presence of both leech and non-leech sequences in one of the unnamed clades, but a single origin of factor Xa and trypsin + leukocyte elastase inhibitors. This is further supported by three sequence motifs that are exclusive to antistasins, the trypsin + leukocyte elastase inhibitor clade, and the therostasin clade, respectively. We discuss the implications of our findings for the evolution of this diverse family of leech anticoagulants.

Standard glucocorticoid therapy in congenital adrenal hyperplasia (CAH) regularly fails to control androgen excess, causing glucocorticoid overexposure and poor health outcomes.

We investigated whether modified-release hydrocortisone (MR-HC), which mimics physiologic cortisol secretion, could improve disease control.

A 6-month, randomized, phase 3 study was conducted of MR-HC vs standard glucocorticoid, followed by a single-arm MR-HC extension study. Primary outcomes were change in 24-hour SD score (SDS) of androgen precursor 17-hydroxyprogesterone (17OHP) for phase 3, and efficacy, safety and tolerability of MR-HC for the extension study.

The phase 3 study recruited 122 adult CAH patients. Although the study failed its primary outcome at 6 months, there was evidence of better biochemical control on MR-HC, with lower 17OHP SDS at 4 (P = .007) and 12 (P = .019) weeks, and between 0700h to 1500h (P = .044) at 6 months. The percentage of patients with controlled 0900h serum 17OHP (< 1200 ng/dL) was 52% at baseline, at 6 months 91% for MR-HC and 71% for standard therapy (P = .002), and 80% for MR-HC at 18 months’ extension. The median daily hydrocortisone dose was 25 mg at baseline, at 6 months 31 mg for standard therapy, and 30 mg for MR-HC, and after 18 months 20 mg MR-HC. Blasticidin S research buy Three adrenal crises occurred in phase 3, none on MR-HC and 4 in the extension study. MR-HC resulted in patient-reported benefit including menses restoration in 8 patients (1 on standard therapy), and 3 patient and 4 partner pregnancies (none on standard therapy).

MR-HC improved biochemical disease control in adults with reduction in steroid dose over time and patient-reported benefit.

MR-HC improved biochemical disease control in adults with reduction in steroid dose over time and patient-reported benefit.Sexual dimorphism in cancer incidence and outcome is widespread. Understanding the underlying mechanisms is fundamental to improve cancer prevention and clinical management. Sex disparities are particularly striking in kidney cancer across diverse populations, men consistently show unexplained 2-fold increased incidence and worse prognosis. We have characterized genome-wide expression and regulatory networks of 609 renal tumors and 256 non-tumor renal tissues. Normal kidney displayed sex-specific transcriptional signatures, including higher expression of X-linked tumor suppressor genes in women. Sex-dependent genotype-phenotype associations unraveled women-specific immune regulation. Sex differences were markedly expanded in tumors, with male-biased expression of key genes implicated in metabolism, non-malignant diseases with male predominance and carcinogenesis, including markers of tumor infiltrating leukocytes. Analysis of sex-dependent RCC progression and survival uncovered prognostic markers involved in immune response and oxygen homeostasis.