A Pilot Study of Soluble Form of LOX-1 as a Novel Biomarker for Neonatal Hypoxic-Ischemic Encephalopathy

To evaluate the soluble form of lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) as a biomarker of severity staging and prognosis in neonatal hypoxic-ischemic encephalopathy (HIE).

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Clinical outcomes of oral metronomic vinorelbine in advanced non-small cell lung cancer: correlations with pharmacokinetics and MDR1 polymorphisms

Abstract

Purpose

This study investigated correlations of the clinical outcomes of oral metronomic vinorelbine (VNR) with VNR pharmacokinetics and MDR1 polymorphisms.

Methods

Eighty-two patients with metastatic non-small cell lung cancer (NSCLC) unfit for standard chemotherapy were treated with VNR at the oral doses of 20–30 mg every other day or 50 mg three times a week. They had a performance status (PS) ≤ 3, were > 70-year-old and drug-naïve or cisplatin-pretreated. MDR1 2677G > T and 3435C > T polymorphisms were analysed and blood concentrations of VNR and desacetyl-VNR (dVNR: active metabolite) assayed. Overall survival (OS), treatment duration and drug-related toxicity were the main endpoints.

Results

Median OS and treatment duration were 27 weeks (range 1.3–183) and 15 weeks (range 1.3–144), respectively. OS was directly correlated with the duration of VNR treatment and number of therapy lines after VNR treatment (multiple linear regression: adjusted r² = 0.71; p < 0.00001). Neither MDR1 genotypes nor VNR/dVNR concentrations predicted OS. VNR blood levels were positively correlated with platelet counts (r² = 0.12; p = 0.0036). Patients who had long-term benefit (treated for ≥ 6 month without toxicity) showed lower VNR concentrations than those who had not. Twelve patients stopped therapy due to grade 3–4 toxicity. Toxicity was associated with blood concentrations of VNR ≥ 1.57 ng/mL and dVNR ≥ 3.04 ng/mL, but not with MDR1 polymorphisms.

Conclusions

Neither pharmacokinetic nor pharmacogenetic monitoring seem useful to predict OS. On the other hand, high VNR and dVNR blood levels were associated with severe toxicity.

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Homocysteine-Enhanced Proteolytic and Fibrinolytic Processes in Thin Intraluminal Thrombus and Adjacent Wall of Abdominal Aortic Aneurysm: Study In Vitro

Homocysteine (Hcy) may affect the pathogenesis of abdominal aortic aneurysms (AAAs) through enhancement of proteolysis and an impaired coagulation/fibrinolysis system. Intensified haemostatic capacity may promote local proteolytic degradation of the aortic wall. This study aimed to examine the effects of Hcy on haemostatic and proteolytic processes in samples of thick and thin fragments of the ILT and underlying walls. Subjects and Methods. Thirty-six patients who underwent AAA surgery were enrolled. Aneurysm tissue sections were incubated with DL-Hcy (100 and 500 μmol/L) in a series of experiments and analyzed for concentration/activity of proteolytic and haemostatic markers by enzyme-linked immunosorbent assay. Results. Incubation of wall underlying thin ILT segments (B) with DL-Hcy resulted in an increase of active MMP-2 levels compared to control tissue (9.54 ± 5.88 versus 7.44 ± 4.48, p=0.011). DL-Hcy also induced t-PA and plasminogen concentration increases in thin thrombus sections (B1) compared to control tissue (respectively: 1.39 ± 1.65 versus 0.84 ± 0.74, p=0.024; 11.64 ± 5.05 versus 10.34 ± 5.52, p=0.018). In contrast, wall adjacent to thick thrombus segments (A) showed decreases in MMP-2 and TF activities compared to control (respectively, 5.89 ± 3.39 versus 7.26 ± 5.49, p=0.046; 67.13 ± 72.59 versus 114.46 ± 106.29, p=0.007). In thick ILT sections (A1), DL-Hcy decreased MMP-2 activity and t-PA and plasminogen concentrations compared to control tissue (respectively, 2.53 ± 2.02 versus 3.28 ± 2.65, p=0.006; 0.67 ± 0.57 versus 0.96 ± 0.91, p=0.021; 9.25 ± 4.59 versus 12.63 ± 9.56, p=0.017). In addition, analysis revealed positive correlations at all sites between activities/concentrations of MMP-2, TF, and PAI-1 measured in control tissues and after incubation with DL-Hcy. Conclusions. These data indicate the potential for excess Hcy to enhance damage of arterial wall in thinner AAA segments as a result of the increased activity of MMP-2 and fibrinolytic factors.

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Long-Term Storage of Vegetable Juices Treated by High Hydrostatic Pressure: Assurance of the Microbial Safety

Food business operators search for new, mild technologies, which extend the shelf life of product without changing the sensory and nutritional properties. High hydrostatic pressure (HHP) meets these requirements; however it also triggers sublethal injury of bacterial cells. Sublethal injuries could spoil the product during storage and potentially pose major public health concerns. This study aims to examine the changes of sublethally injured pathogens cells in two vegetable juices: carrot juice (pH 6.0-6.7) and beetroot juice (pH 4.0-4.2) that are induced by HHP (300-500 MPa). The possibilities of recovery of bacterial cells during 28 days of juices storage at two different temperatures (5°C and 25°C) were determined using plate count methods. During the entire period of storage of carrot juice at refrigerated temperature, the propagation and regeneration of L. innocua strains were observed. Storage at 25°C showed that the number of these bacteria drastically decreased between 14 and 21 days. The above phenomenon was not detected in E. coli case. There was no cells recovery during long-term refrigerated storage for all strains in beetroot juice. However, in some cases spoiling of this product intermittently occurred at 25°C storage temperature. This work demonstrates that carrot juice supports growth and regeneration of HHP-sublethally injured L. innocua, while beetroot juice can be classified as a safe product.

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Digital Anatomy to Improve Screw Insertion Techniques for Plate-Screw Fixation of the Pubic Body

Objectives. This study aims to investigate screw insertion sites on the pubic body and the safe screw insertion parameters of a plate-screw fixation system based on the premise of avoiding damage to the inguinal canal and disruption of the rectus abdominis at the pubic symphysis and pubic crest. Research Methods. Excluding cases with poor image quality, tumors, malformations, and fractures, the data of 80 healthy adults (40 males and 40 females aged from 21 to 83 years old, with an average age of 51.65 years) undergoing a computed tomography (CT) scan of the pelvis between January and June of 2017 were collected from Shandong Provincial Hospital. The CT scans were imported to Mimics® software to reconstruct three-dimensional pelvic models. A 3.5 mm pelvic reconstruction plate was placed starting at the outer edge of the pubic tubercle and along the pelvic brim. The two innermost screw insertion sites were marked. The safe range for the screw insertion sites was then determined. The screw insertion plane was selected to measure the safe screw insertion parameters. The length of the screw, the direction of insertion, and intersex differences were then explored via statistical analyses. Results. The medial inclination angles (MIAs) of the screw insertion plane for males and females were 30.42±7.95° and 32.88±10.65°, respectively, with no statistically significant differences. For the medial screw, the maximum anterior inclination angle (MAIA), the maximum screw length, and the maximum posterior inclination angle (MPIA) were 46.51±4.01°, 12.40±9.53 mm, and 11.78±10.22° on average, respectively, with no significant differences by gender (P>0.05). For the lateral screw, the MAIA was 10.35±9.46° and showed no gender differences (P>0.05), but the male group had a greater MPIA (male 11.80±11.00° vs. female 6.23±7.91°, P0.05), although the screw length in the male group was significantly longer than that in the female group. Conclusions. Insertion of two screws into the pubic body through a plate from the lateral side of the pubic tubercle is safe and can maintain the origin of the rectus abdominis and the integrity of the inguinal canal compared to traditional plate-screw fixation. Considering that the pubic body is thinner on the lateral side, we suggest a more medial inclination angle for the lateral screw.

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5-Fluorouracil rechallenge after 5-fluorouracil-induced hyperammonemic encephalopathy

For several decades, 5-Fluorouracil (5-FU) has been the backbone of many chemotherapy regimens for various tumor types. Its most common side effects are gastrointestinal disorders, mucositis, myelosuppression, hand–foot syndrome, and rarely cardiac toxicity. More rarely, 5-FU infusion can induce hyperammonemic encephalopathy. 5-FU toxicities can be worsened by complete or partial genetic and/or phenotypic dihydropyrimidine dehydrogenase deficiency. Here, we report the case of a patient who initially developed a 5-FU-induced hyperammonemic encephalopathy after receiving FOLFIRINOX (oxaliplatin, irinotecan, folinic acid, and 5-FU) chemotherapy with bevacizumab to treat a metastatic gastrointestinal cancer of unknown primary. Thereafter, the patient was rechallenged successfully by the same chemotherapy regimen (FOLFIRINOX) for more than 6 months with a protocol consisting in a free protein diet, and administration of ammonium chelators, and Krebs and urea cycle intermediates, to prevent further hyperammonemia. We also present a review of the literature on 5-FU rechallenge after 5-FU-induced hyperammonemic encephalopathy. Correspondence to Alice Boilève, MD, Medical Oncology Department, Gustave Roussy Hospital, 114 Rue Edouard Vaillant, 94800 Villejuif, France Tel: +33 014 211 4308; fax: +33 014 211 5229; e-mail: alice.boileve@gmail.com Received August 30, 2018 Accepted November 13, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Design, synthesis, and biological evaluation of tetrahydroisoquinoline-based diaryl urea derivatives for suppressing VEGFR-2 signaling

A novel structural series of tetrahydroisoquinoline-based compounds that incorporate the diaryl urea moiety was designed, synthesized, and biologically evaluated as suppressors of VEFGR-2 signaling. As a consequence, compounds 9k and 9s exhibited comparable or superior cytotoxic activity to that of gefitinib against the tested three cell lines, including A549, MCF-7, and PC-3. Importantly, both of them downregulated the expression of VEGFR-2, and inhibited VEGFR-2 phosphorylation at the concentration of 0.5 or 1.0 μmol/l. Besides, they suppressed human umbilical vein endothelial cell tube formation at the concentration of 4.0 μmol/l. Considering their capability of down-regulating VEGFR-2 expression and inhibiting VEGFR-2 phosphorylation, 9k and 9s may serve as suppressors of angiogenesis for further investigation. Correspondence to Jiaming Li, PhD, School of Pharmacy, Anhui University of Traditional Chinese Medicine, Hefei 230031, China Tel: +86 137 0569 4971; e-mail: lijiaming2017@sina.com Received May 7, 2018 Accepted October 30, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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