Supplementary Data from Development of Immunohistochemistry Assays to Assess GALNT14 and FUT3/6 in Clinical Trials of Dulanermin and Drozitumab

Supplementary Data from Development of Immunohistochemistry Assays to Assess GALNT14 and FUT3/6 in Clinical Trials of Dulanermin and Drozituma

Chlorocyclinones A−D, Chlorinated Angucyclinones from <i>Streptomyces</i> sp. Strongly Antagonizing Rosiglitazone-Induced PPAR-γ Activation

In the course of our screening to identify novel PPAR-γ modulators for the potential treatment of type 2 diabetes, four new chlorinated angucyclinones, chlorocyclinones A−D (1−4), were isolated from the mycelium of Streptomyces sp. strain DSM 17045. Their structures were established by spectroscopic methods. Chlorocyclinones antagonize rosiglitazone-induced peroxisome proliferator-activated receptor gamma (PPAR-γ) activation with IC50ʼs 50 values between 0.60 and 7.0 µM. Chlorocyclinone C (3) exhibited the most potent activity in all assays

BI-32169, a Bicyclic 19-Peptide with Strong Glucagon Receptor Antagonist Activity from <i>Streptomyces</i> sp.

A new bicyclic 19-peptide, BI-32169 (1), has been isolated from the culture broth of Streptomyces sp. (DSM 14996). Its structure has been established by amino acid analysis, mass spectrometry, and 2D NMR analysis. BI-32169 consists exclusively of protein amino acids and is cyclized from the side chain of Asp9 to the N-terminus of Gly. One disulfide bond between Cys6 and Cys19 forms a bicyclic structure. BI-32169 and its methyl ester derivative (2) showed potent inhibitory activity against the human glucagon receptor (IC50 440 and 320 nM, respectively) in a functional cell-based assay

Distribution on both <i>FMR1</i> alleles, of CGG _n in <i>BRCA1/2</i> mutation carriers as well as U.S. controls in form of scattergrams.

<p>Horizontal and vertical parallel lines in scattergrams define the <i>norm</i> distribution area (CGG _{n = 26–34}), with areas below and above representing <i>low</i> and <i>high</i>, sub-genotypes, respectively; a represents higher and lower count allele, respectively, for individual patients. Only the lower count allele varied significantly between the two groups (Mann-Whitney U test, P<0.001). Scattergrams, as well as a, demonstrate graphically the significant shift towards <i>low FMR1</i> sub-genotypes, especially on the lower count allele of <i>BRCA1/2</i> mutation carriers. In a - - - represents mean; ______ represents median.</p

Distribution of <i>FMR1</i> genotypes and sub-genotypes in women with <i>BRCA1/2</i> mutations (black bars) and U.S. (gray) comparison group; * within each category denotes significance at P<0.05. Noteworthy are the excess of <i>het-norm/low</i> and complete absence of <i>het-norm/high</i> in <i>FMR1</i> sub-genotypes in <i>BRCA1/2</i> mutation carriers, and the very low prevalence of women with <i>norm FMR1</i> genotype.

<p>A numerical presentation of these data is presented in (a), In description of genotypes <i>norm</i> stands for normal, <i>het</i> for heterozygous and <i>hom</i> for homozygous. In description of sub-genotypes <i>high</i> stands for CGG_n>34 and <i>low</i> for CGG_n<26.</p

Sex‑, Species‑, and Tissue-Specific Metabolism of Empagliflozin in Male Mouse Kidney Forms an Unstable Hemiacetal Metabolite (M466/2) That Degrades to 4‑Hydroxycrotonaldehyde, a Reactive and Cytotoxic Species

Following oral administration of empagliflozin (1000 mg/kg/day) to male and female CD-1 mice for 2 years, renal tubular injury was identified in male mice. Renal injury was not detected in male mice (≤300 mg/kg/day), in female mice (1000 mg/kg/day), or in male or female Han Wistar rats (700 mg/kg/day). Using transfected HEK293 cells and <i>Xenopus</i> oocytes, empagliflozin was found to be a substrate of various mouse and rat organic anion transporters (oat/Oat) and organic anion transporting polypeptide (oatp/Oatp) transporters: mouse oat3, rat Oat3, mouse oatp1a1, and rat Oatp1a1. However, using isolated kidney slices from male and female mice and rats, no sex-based difference in the extent of uptake of empagliflozin occurred. Metabolism studies using hepatic and renal microsomes from male and female mice, rats, and humans revealed a hemiacetal metabolite of empagliflozin (M466/2), predominantly formed in male mouse kidney microsomes. Formation of M466/2 in male mouse kidney microsomes was 31-fold higher compared to that in female mouse kidney microsomes and was ∼29- and ∼20-fold higher compared to that in male and female mouse liver microsomes, respectively. M466/2 is unstable and degrades to form a phenol metabolite (M380/1) and 4-hydroxycrotonaldehyde (4-OH CTA). Formed 4-OH CTA was trapped by reduced GSH, and the structure of the GSH adduct was confirmed by mass spectrometry. Stoichiometric formation of M380/1 from M466/2 was observed (93–96% at 24 h); however, formation of 4-OH CTA was considerably lower (∼17.5% at 40 h), which is consistent with 4-OH CTA being a highly reactive species. These data represent a highly selective tissue-, species-, and sex-specific lesion in male CD-1 mice associated with a cytotoxic metabolite product, 4-OH CTA. In humans, glucuronidation of empagliflozin is the most prevalent metabolic pathway, and oxidation is a minor pathway. Thus, renal toxicity due to the formation of 4-OH CTA from empagliflozin is not expected in humans

Individual <i>BRCA1/2</i> mutations in study group.

<p>None of the <i>BRCA1</i>/2 mutations demonstrated significant associations with <i>FMR1</i>. The single mutation noted in 10 patients was in 9 women associated with a <i>het-norm/low FMR1</i> sub-genotype.</p

Additional file 2: of Self-confidence and knowledge of German ICU physicians in palliative care – a multicentre prospective study

Appendix 2. Questionnaire for the evaluation of the participants’ self-confidence related to palliative care medicine. (DOCX 88 kb