Impact of elexacaftor/tezacaftor/ivacaftor on lipid and fat-soluble vitamin levels and association with body mass index.

INTRODUCTION: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators improve gastrointestinal absorption of nutrients and may result in changes in body mass index (BMI), serum lipids, and fat-soluble vitamin levels. We hypothesized that serum lipids and vitamin levels would increase with CFTR modulator therapy and that greater increase in lipids and vitamin levels would be related to greater increase in BMI. METHODS: A retrospective study was performed to evaluate the impact of elexacaftor/tezacaftor/ivacaftor (ETI) on nutritional parameters, serum lipids, and fat-soluble vitamin levels. Pre-ETI values (<2 years prior) and post-ETI values (>1 month after) were compared. Linear regression was used to evaluate whether change in BMI is associated with the change in lipid and/or vitamin levels and whether modulator duration is associated with the degree of rise in lipid and/or vitamin levels. RESULTS: Adults and adolescents with CF (n = 137) were evaluated before and 31-300 days after starting ETI. Median BMI (adults 21.9 vs. 23.5 kg/m2 ; adolescents 48 vs. 63 percentile) increased after initiation of ETI. Total cholesterol (126 vs. 154 mg/dL), low-density lipoprotein cholesterol (63 vs. 78 mg/dL), non-high-density lipoprotein cholesterol (84 vs. 102 mg/dL), and high density lipoprotein cholesterol (43 vs. 49 mg/dL) increased after ETI, while triglycerides and very low density lipoprotein did not change. Median values for vitamin D (34.5 vs. 38.0 ng/mL) and vitamin A (40.1 vs. 47.9 µg/dL) increased, while vitamin E did not change significantly. There was no significant correlation between BMI change or duration of modulator therapy with vitamin levels or lipid changes. CONCLUSION: After initiation of ETI therapy, serum lipids increased in our population, but most values remained within the normal range. Vitamins A and D levels increased post-ETI and no changes were noted in vitamin E. No significant correlation between the degree of BMI change and the magnitude of increase in lipids or vitamin levels was found.

Surgical telementoring: Feasibility, applicability, and how to.

Surgical training does not end at the conclusion of residency training. Expansions in medical technology and surgical technique have created a steep learning curve for the young attending surgeon. The emergence of intraoperative telementoring has allowed experienced surgeons to guide learners through complex surgical cases remotely with the assistance of streaming video technology. Here, we describe the basics of telementoring, financial and legal considerations, and recommend hardware specifications for optimal use.

Class II Phosphoinositide 3-Kinases as Novel Drug Targets.

The phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases central to regulating a wide range of important intracellular processes. Despite the vast knowledge around class I PI3Ks, the class II PI3Ks have been neglected, seemingly only due to the chronology of their discovery. Here we focus on the cellular functions of the three class II PI3K isoforms, PI3KC2α, PI3KC2ß, and PI3KC2γ, in different cell systems and underline the emerging importance of these enzymes in different physiological and pathological contexts. We provide an overview on the current development of class II PI3 kinase inhibitors and outline the potential use for such inhibitors. The field is in its infancy as compared to their class I counterparts. Nevertheless, recent advances in understanding the roles of class II PI3 kinases in different pathological contexts is leading to an increased interest in the development of specific inhibitors that can provide potential novel pharmacological tools.

Class II but Not Second Class-Prospects for the Development of Class II PI3K Inhibitors.

The Class II PI3 kinases are emerging from the shadows of their Class I cousins. The data emerging from PIK3C2 genetic modification studies and from siRNA knockdown suggest important roles in physiology and pathology. With some well-studied Class I isoform inhibitors showing strong Class II activity and a wealth of crystallographic information available, the structural similarity of these isoforms to Class I provides both the opportunity and the challenge in design of selective pharmacological inhibitors.

Selective inhibition of human type-5 17ß-hydroxysteroid dehydrogenase (AKR1C3) by baccharin, a component of Brazilian propolis.

The human aldo-keto reductase (AKR) 1C3, also known as type-5 17ß-hydroxysteroid dehydrogenase and prostaglandin F synthase, has been suggested as a therapeutic target in the treatment of prostate and breast cancers. In this study, AKR1C3 inhibition was examined by Brazilian propolis-derived cinnamic acid derivatives that show potential antitumor activity, and it was found that baccharin (1) is a potent competitive inhibitor (K(i) 56 nM) with high selectivity, showing no significant inhibition toward other AKR1C isoforms (AKR1C1, AKR1C2, and AKR1C4). Molecular docking and site-directed mutagenesis studies suggested that the nonconserved residues Ser118, Met120, and Phe311 in AKR1C3 are important for determining the inhibitory potency and selectivity of 1. The AKR1C3-mediated metabolism of 17-ketosteroid and farnesal in cancer cells was inhibited by 1, which was effective from 0.2 µM with an IC(50) value of about 30 µM. Additionally, 1 suppressed the proliferation of PC3 prostatic cancer cells stimulated by AKR1C3 overexpression. This study is the first demonstration that 1 is a highly selective inhibitor of AKR1C3.

Structure of the His269Arg mutant of the rat aldose reductase-like protein AKR1B14 complexed with NADPH.

Rat aldose reductase-like protein (AKR1B14) is an orthologue of mouse vas deferens protein (AKR1B7) and plays roles in the detoxification of reactive aldehydes and synthesis of prostaglandin F(2α). Here, the 1.87 Å resolution crystal structure of the His269Arg mutant of AKR1B14 complexed with NADPH is described and shows that the negatively charged 2'-phosphate group of the coenzyme forms an ionic interaction with the positively charged guanidinium group of Arg269 that is also observed in the human aldose reductase (AKR1B1) structure. Previous experiments on the site-directed mutagenesis of His269 to Arg, Phe and Met revealed fourfold, sevenfold and 127-fold increases in the K(m) for NADPH, respectively, which are in agreement with the present molecular-modelling and X-ray crystallographic studies. This is the first tertiary structure of a mutant form of this AKR1B7 orthologue to be reported in order to investigate the structure-function relationship of the nonconserved His269 and its role in coenzyme binding.

Activation of aldo-keto reductase family member 1B14 (AKR1B14) by bile acids: Activation mechanism and bile acid-binding site.

Aldo-keto reductase (AKR) 1B14, a rat ortholog of mouse androgen-dependent vas deferens protein (AKR1B7), is involved in the synthesis of prostaglandin F(2α) and detoxification of 4-oxononenal formed by lipid peroxidation. The NADPH-linked reductase activity of AKR1B14 was activated by various bile acids. Although the activation was increased by decreasing pH from 9.0 to 6.0, the concentrations giving maximum stimulation (2- to 18-fold) were 0.2-6.0 µM for bile acids at pH 7.4. Kinetic analyses of the activation by glycochenodeoxycholic acid in the forward and reverse reactions, together with fluorescence changes and protection against 4-oxononenal-induced inactivation by bile acid, indicate that the bile acid binds to the enzyme and its coenzyme binary complex as a non-essential activator. The bile acid binding to AKR1B14 mainly accelerates the NADP(+) dissociation, the rate-limited step of the enzyme reaction. AKR1B7 was also activated by bile acids, but the activation was low and independent of pH. The mutagenesis of His269 and Leu267 of AKR1B14 into the corresponding residues (Arg and Pro, respectively) of AKR1B7 resulted in low and pH-independent activation by bile acids. The results, together with the docking of the bile acid in the recently determined crystal structure of AKR1B14, identify the bile acid-binding site of which His269 plays a key role in significant activation through its electrostatic interaction with the carboxyl group of bile acid, facilitating the release of NADP(+).

Structure of rat aldose reductase-like protein AKR1B14 holoenzyme: Probing the role of His269 in coenzyme binding by site-directed mutagenesis.

Rat aldose reductase-like protein (AKR1B14) is the ortholog of mouse vas deferens protein (AKR1B7) playing roles in detoxification of reactive aldehydes and synthesis of prostaglandin F(2α). The crystal structure of the binary complex (AKR1B14-NADPH) was determined at 1.86Å resolution, and showed that the adenine ring and the 2'-phosphate group of the coenzyme formed π-stacking and electrostatic interactions with the imidazole ring and ND1 atom, respectively, of His269, which is not conserved in other aldose reductase-like proteins. The interactions were supported by site-directed mutagenesis of His269 to Arg, Phe and Met, which increased the K(m) for NADPH by 4, 7 and 127-fold, respectively. This is the first report of the tertiary structure of a rodent AKR1B7 ortholog, which describes the role of a novel dual interaction for the non-conserved His269 in coenzyme binding.