Binding-Induced Fluorescence of Serotonin Transporter Ligands: A Spectroscopic and Structural Study of 4-(4-(Dimethylamino)phenyl)-1-methylpyridinium (APP+) and APP+ Analogues

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Sacubitril/valsartan (LCZ696) for the treatment of heart failure

The PARADIGM-HF study, a large outcome trial in heart failure and reduced ejection fraction (HFrEF), has recently shown improved cardiovascular outcomes with sacubitril/valsartan (Entresto®, Novartis), still commonly referred to as LCZ696, compared to ACE-inhibitor therapy, possibly leading us to a new era for heart failure (HF) treatment. LCZ696 represents a first-in-class drug acting through inhibition of angiotensin receptor and neprilysin, thus modulating the renin angiotensin aldosterone system and vasoactive substances such as natriuretic peptides. Based on the PARADIGM-HF results, the FDA recently approved LCZ696 as an effective means to reduce the burden of HF with reduced ejection fraction. Furthermore, these data also provided rationale to test LCZ696 in an ongoing trial with HF and preserved ejection fraction. Despite the enthusiasm regarding this novel compound, real world data on its efficacy and safety are eagerly expected. This article summarizes all evidences regarding LCZ696 and how to implement this new drug in the current HF armamentarium.     

Cutting Efficiency of Reciproc and WaveOne Reciprocating Instruments

Introduction

The aim of the present study was to evaluate the cutting efficiency of 2 new reciprocating instruments, Reciproc and WaveOne.

Methods

Twenty-four new Reciproc R25 and 24 new WaveOne Primary files were activated by using a torque-controlled motor (Silver Reciproc) and divided into 4 groups (n = 12): group 1, Reciproc activated by Reciproc ALL program; group 2, Reciproc activated by WaveOne ALL program; group 3, WaveOne activated by Reciproc ALL program; and group 4, WaveOne activated by WaveOne ALL program. The device used for the cutting test consisted of a main frame to which a mobile plastic support for the handpiece is connected and a stainless steel block containing a Plexiglas block (inPlexiglass, Rome, Italy) against which the cutting efficiency of the instruments was tested. The length of the block cut in 1 minute was measured in a computerized program with a precision of 0.1 mm. Means and standard deviations of each group were calculated, and data were statistically analyzed with 1-way analysis of variance and Bonferroni test (P < .05).

Results

Reciproc R25 displayed greater cutting efficiency than WaveOne Primary for both the movements used (P < .05); in particular, Reciproc instruments used with their proper reciprocating motion presented a statistically significant higher cutting efficiency than WaveOne instruments used with their proper reciprocating motion (P < .05). There was no statistically significant difference between the 2 movements for both instruments (P > .05).

Conclusions

Reciproc instruments demonstrated statistically higher cutting efficiency than WaveOne instruments.     

Conservative surgical and microsurgical techniques for the management of dental implants that impinge on the inferior alveolar nerve

Loss of sensation in the lip after insertion of an implant is annoying. The aim of this paper was to describe two techniques for management of osseointegrated dental implants that impinge on the mandibular nerve, the purpose of which is to improve sensation without unscrewing the dental implant.     

光固化胶粘剂性能的初步研究

目的：制备一种光固化纳米胶粘剂,对其性能进行初步研究。方法：正交法制备出多个胶粘剂样品,讨论各个因素对材料力学性能的影响,探索合适的配方比例和工艺参数。结果：光固化胶粘剂最优配比为引发剂Darocur1173含量占1％,纳米SiO2含量占50％,基质树脂与稀释单体（Bis—GMA：TEGDMA）的比例为1：1。结论：制备的光固化胶粘剂配方的综合性能最优,可应用于临床。     

In vivo anticancer activity of rhomboidal Pt(II) metallacycles

The development of novel antitumor agents that have high efficacy in suppressing tumor growth, have low toxicity to nontumor tissues, and exhibit rapid localization in the targeted tumor sites is an ongoing avenue of research at the interface of chemistry, cancer biology, and pharmacology. Supramolecular metal-based coordination complexes (SCCs) have well-defined shapes and geometries, and upon their internalization, SCCs could affect multiple oncogenic signaling pathways in cells and tissues. We investigated the uptake, intracellular localization, and antitumor activity of two rhomboidal Pt(II)-based SCCs. Laser-scanning confocal microscopy in A549 and HeLa cells was used to determine the uptake and localization of the assemblies within cells and their effect on tumor growth was investigated in mouse s.c. tumor xenograft models. The SCCs are soluble in cell culture media within the entire range of studied concentrations (1 nM–5 µM), are nontoxic, and showed efficacy in reducing the rate of tumor growth in s.c. mouse tumor xenografts. These properties reveal the potential of Pt(II)-based SCCs for future biomedical applications as therapeutic agents.Molecular assemblies of nanoscale-size and well-defined geometries have recently emerged as an interesting new paradigm in drug design and drug delivery. To date, liposomes, the self-assembled lipid nanoparticles held together by weak interactions, are among the most widely studied and clinically successful nanoparticle-based drug carriers. Their use allows the drug to achieve sustained plasma levels while encapsulated, with the size preventing the fast clearance by the kidneys that often occurs with the free drug. However, liposomes themselves do not produce a therapeutic effect and their application as drug carriers for medical purposes has often been hindered by poor loading capacity (<5 wt %) and the inability to pass through biological barriers (1, 2). Inorganic and hybrid porous materials, such as molecular organic frameworks (MOFs), have also shown promise due to their higher loading capacities (>25 wt %) (3–5), but MOFs have poor hydrolytic stability (6, 7). Recent studies on materials from Institut Lavoisier (MIL)-100(Cr) and MIL-100(Fe), however, suggest that MOFs can persist in biologically relevant environments and can act as vehicles for some anticancer and antiviral agents (8–10). These early findings have prompted further investigations into the biomedical applications of supramolecular coordination complexes (SCCs) (11–24). SCCs preserve the attractive properties of MOFs, such as building block modularity (22, 23, 25), yet afford an increased solubility in the biological milieu and lend themselves to small-molecule characterization techniques due to their well-defined structure.Although development of SCCs for biomedical applications is in its infancy, some SCCs, such as trigonal prisms self-assembled from p-cymene and ruthenium-based metal fragments with pyridyl donors, have shown the ability to act as effective carriers of some chemotherapeutic agents (26–28). Moreover, a library of cytotoxic to cancer cells p-cymene ruthenium-based polygons and cages has also been developed (11). For biomedical applications, the information about the cellular uptake, delivery of a guest, and metabolism of the drug delivery vehicle is critical, although currently the fate of SCCs in biological environments is not well understood. In a rare report, a systematic investigation of the structural stability of a water-soluble, hexacationic ruthenium-based trigonal prism was performed; however, it was determined that the ruthenium-based trigonal prisms decompose in the presence of amino acids histidine, lysine, and arginine (29).An intriguing approach is the design of tumor-targeted modalities that combine detection and treatment through the self-assembly of emissive, metal-based coordination complexes. Such modalities can be especially valuable as they often do not require photoexcitation to elicit cytotoxicity. Recently Gray, Gross, and Medina-Kauwe and coworkers reported HerGa, a self-assembled tumor-targeted particle that bears the Ga(III)-metalated derivative of the sulfonated corrole (30, 31). The particle, which contained Ga(III)-corrole noncovalently bound to the tumor-targeting cell penetration protein HerPBK10, provided both tumor detection and elimination. Systemic injection of this protein–corrole complex resulted in tumor accumulation, which can be visualized in vivo due to the red corrole fluorescence. Cytotoxic and cytostatic properties of these targeted Ga(III) corroles were found to be cell-line dependent, with the ability to induce late M-phase arrest in several cancer cell lines (32).Despite the well-known cytotoxic properties of mono- and multinuclear platinum complexes (33–35), studies of the antitumor properties of platinum-based SCCs are rare (17, 36). Moreover, recent reports have demonstrated that platinum-based SCCs can act as effective hosts for guests and have interesting photophysical properties (37–42). In particular, highly emissive rhomboids based on aniline-containing donors and Pt-based metal acceptors have been developed that display different photophysical properties from those of their constituent subunits (40). These assemblies are interesting targets to investigate the cytotoxicity of organoplatinum SCCs, whereas their emission spectra could be used for interrogating the structural integrity in vitro. Here, for the first time to our knowledge, we report the uptake of SCCs in vitro in cell-based assays, determined by using laser-scanning confocal microscopy, and an in vivo assessment of the anticancer activity of SCCs in mouse s.c. tumor xenograft models.