Treatment of exudative age‐related macular degeneration with aflibercept combined with pranoprofen eye drops or nutraceutical support with omega‐3: A randomized trial

Purpose

To determine whether a combination of intravitreal aflibercept (IVA) and pranoprofen eyedrops or nutraceutical support provides additional benefit over IVA monotherapy for the treatment of choroidal neovascularization (CNV) in age‐related macular degeneration.

Methods

This was a prospective, randomized, pilot study in 60 patients with treatment‐naïve CNV. Patients were randomized 1:1:1 into 3 groups: aflibercept monotherapy (AM), aflibercept plus pranoprofen (AP), or aflibercept plus nutraceutical (AN) tablets containing multivitamin antioxidant and mineral supplementation plus omega‐3.

Results

At 12 months, all groups showed significant improvement in both best‐corrected visual acuity (BCVA) and central retinal thickness (CRT). The mean BCVA change from baseline to 12 months was –0.26 ± 0.06 LogMAR,–0.30 ± 0.06 LogMAR, and –0.24 ± 0.04 LogMAR in the AM, AP, and AN groups, respectively. The mean CRT change from baseline to 12 months was –76.9 ± 10.9 μm, –129 ± 19.9 μm, and –105 ± 11.6 μm in the AM, AP, and AN groups, respectively. The AN group required 1 less IVA injection than the AM group.

Conclusion and Implications

Compared with AM, both combination groups acted synergistically, although no significant benefits in BCVA were found over AM. Nutraceutical support with omega‐3 leads to a reduced need for IVA.

http://bit.ly/2WjRLRY

Targeting the hepcidin‐ferroportin pathway in anemia of chronic kidney disease

Aims

Erythropoiesis stimulating agents (ESAs) used to treat anemia in patients with chronic kidney disease (CKD) has been associated with cardiovascular adverse events. Hepcidin production, controlled by BMP6, regulates iron homeostasis via interactions with the iron transporter, ferroportin. High hepcidin levels are thought to contribute to increased iron sequestration and subsequent anemia in CKD patients. To investigate alternative therapies to ESAs for CKD patients, monoclonal antibodies, LY2928057 and LY3113593, targeting ferroportin and BMP6 respectively, were tested in CKD patients.

Methods

Preclinical in vitro/vivo data and clinical data in healthy subjects and CKD patients were used to illustrate the translation of pharmacological properties of LY2928057 and LY3113593, highlighting the novelty of targeting these nodes within the hepcidin‐ferroportin pathway.

Results

LY2928057 bound ferroportin and blocked interactions with hepcidin, allowing iron efflux, leading to increased serum iron and transferrin saturation (TSat) levels and increased hepcidin in monkeys and humans. In CKD patients, LY2928057 led to slower hemoglobin decline and reduction in ferritin (compared to placebo). Serum iron increase was (1.98 [1.46‐2.68] and 1.36 [1.22‐1.51]), mean [90%CI], fold‐relative to baseline following LY2928057 600 mg and LY311593 150 mg respectively in CKD patients). LY3113593 specifically blocked BMP6 binding to its receptor and produced increases in iron and TSat and decreases in hepcidin preclinically and clinically. In CKD patients, LY3113593 produced an increase in hemoglobin and reduction in ferritin (compared to placebo).

Conclusion

LY2928057 and LY3113593 pharmacological effects (serum iron and ferritin) were translated from preclinical‐to‐clinical development. Such interventions may lead to new CKD anemia treatments.

http://bit.ly/2RdxXf7

First‐in‐human, phase I study of PF‐06647263, an anti‐EFNA4 calicheamicin antibody–drug conjugate, in patients with advanced solid tumors

PF‐06647263, a novel antibody–drug conjugate consisting of an anti‐EFNA4 antibody linked to a calicheamicin payload, has shown potent anti‐tumor activity in human xenograft tumor models, including triple‐negative breast cancer (TNBC). In the dose‐escalation part 1 of this multicenter, open‐label, phase I study (NCT02078752), successive cohorts of patients (n, 48) with advanced solid tumors and no available standard therapy received PF‐06647263 every 3 weeks (Q3W) or every week (QW), following a modified toxicity probability interval (mTPI) method (initial dosing: 0.015 mg/kg Q3W). Primary objective in part 1 was to estimate the maximum tolerated dose (MTD) and select the recommended phase 2 dose (RP2D). In part 2 (dose‐expansion cohort), 12 patients with pretreated, metastatic TNBC received PF‐06647263 at the RP2D to further evaluate tumor response and overall safety. PF‐06647263 QW administration (n, 23) was better tolerated than the Q3W regimen (n, 25) with only 1 DLT reported (thrombocytopenia). The most common AEs with the QW regimen (fatigue, nausea, vomiting, mucosal inflammation, thrombocytopenia, and diarrhea) were mostly mild to moderate in severity. The MTD was not estimated. PF‐06647263 exposures increased in a dose‐related manner across the doses evaluated. The RP2D was determined to be 0.015 mg/kg QW. Six (10%) patients achieved a confirmed partial response and 22 (36.7%) patients had stable disease. No correlations were observed between tumor responses and EFNA4 expression levels. Study findings showed manageable safety and favorable PK for PF‐06647263 administered QW at the RP2D, with preliminary evidence of limited anti‐tumor activity in patients with TNBC and ovarian cancer.

This article is protected by copyright. All rights reserved.

http://bit.ly/2WefLpm

Sclerosing mucoepidermoid carcinoma with eosinophilia of the thyroid: Case report of a rare lesion with novel genetic mutation

Sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE) is a rare primary cancer of the thyroid. This tumor is analogous to other primary tumors of the salivary glands, breast, pancreas, and esophagus. We present a case of this rare tumor with characteristic clinical features, ultrasound images, cytopathology, histopathology, and a heretofore undocumented somatic gene mutation. Additionally, we provide a succinct review of the controversial literature for this uncommon lesion.

http://bit.ly/2DyESvR

Gonadal steroid hormone secretion during the juvenile period depends on host‐specific microbiota and contributes to the development of odor preference

Abstract

The host microbial community is thought to have an important role in the host endocrine system and behavioral phenotype. We investigated chronological changes of levels of gonadal hormones and corticosterone in the feces of 4‐ to 8‐week‐old female germ‐free (GF) mice, and conducted odor preference test at 8 weeks of age. We further evaluated the developmental impact of the microbial community by analyzing 4‐week‐old GF mice orally administered the fecal microbiota of specific pathogen‐free (SPF) mice or guinea pigs (GF‐SPF mice or GF‐Guinea pig mice). The fecal estradiol, progesterone, and corticosterone levels of GF mice were lower than those of SPF mice. Furthermore, the increased levels in GF mice were suggested to be caused by colonization of microbiota of SPF mice or guinea pigs. However, the degree of recovery of progesterone and corticosterone by microbiota of guinea pigs was lower than that by SPF mice. In odor preference tests, interestingly, female GF mice preferred female odors to male odors, although this preference was not seen in other mice. These findings suggested that the microbial community plays an important role in the development of the host endocrine system for gonadal hormones and corticosterone, and odor preference in mice.

http://bit.ly/2T8KBxS

Gramicidin increases lipid flip-flop in symmetric and asymmetric lipid vesicles

\Unlike most transmembrane proteins, phospholipids can migrate from one leaflet of the membrane to the other. Because this spontaneous lipid translocation (flip-flop) tends to be very slow, cells facilitate the process with enzymes that catalyze the transmembrane movement and thereby regulate the transbilayer lipid distribution. Non-enzymatic membrane-spanning proteins with unrelated primary functions have also been found to accelerate lipid flip-flop in a non-specific manner and by various hypothesized mechanisms.

http://bit.ly/2sJi1aN

Cooperative changes in solvent exposure identify cryptic pockets, switches, and allosteric coupling

Proteins are dynamic molecules that undergo conformational changes to a broad spectrum of different excited states. Unfortunately, the small populations of these states make it difficult to determine their structures or functional implications. Computer simulations are an increasingly powerful means to identify and characterize functionally-relevant excited states. However, this advance has uncovered a further challenge: it can be extremely difficult to identify the most salient features of large simulation datasets.

http://bit.ly/2sIPodN