5-Benzylidene, 5-benzyl, and 3-benzylthiazolidine-2,4-diones as potential inhibitors of the mitochondrial pyruvate carrier: Effects on mitochondrial functions and survival in Drosophila melanogaster.

A series of thiazolidinediones (TZDs) were synthesized and screened for their effect on the mitochondrial respiration as well as on several mitochondrial respiratory system components of Drosophila melanogaster. Substituted and non-substituted 5-benzylidene and 5-benzylthiazolidine-2,4-diones were investigated. The effect of a substitution in position 3, at the nitrogen atom, of the thiozolidine heterocycle was also investigated. The designed TZDs were compared to UK5099, the most potent mitochondrial pyruvate carrier (MPC) inhibitor, in in vitro and in vivo tests. Compared to 5-benzylthiazolidine-2,4-diones 6-7 and 3-benzylthiazolidine-2,4-dione 8, 5-benzylidenethiazolidine-2,4-diones 2-5 showed more inhibitory capacity on mitochondrial respiration. 5-(4-Hydroxybenzylidene)thiazolidine-2,4-dione (3) and 5-(3-hydroxy-4-methoxybenzylidene)thiazolidine-2,4-dione (5) were among the best compounds that compared well with UK5099. Additionally, TZDs 3 and 5, showed no effects on the non-coupled respiration and weak effects on pathways using substrates such as proline, succinate, and G3P. 5-Benzylidenethiazolidine-2,4-dione 3 showed a positive effect on survival and lifespan when added to Drosophila standard and high fat diet. Interestingly, analog 3 completely reversed the effects of high fat diet on Drosophila longevity and induced metabolic changes which suggests an in vivo inhibition of MPC at the mitochondrial level.

Reversible disruption of XPO1-mediated nuclear export inhibits respiratory syncytial virus (RSV) replication.

Respiratory syncytial virus (RSV) is the primary cause of serious lower respiratory tract disease in infants, young children, the elderly and immunocompromised individuals. Therapy for RSV infections is limited to high risk infants and there are no safe and efficacious vaccines. Matrix (M) protein is a major RSV structural protein with a key role in virus assembly. Interestingly, M is localised to the nucleus early in infection and its export into the cytoplasm by the nuclear exporter, exportin-1 (XPO1) is essential for RSV assembly. We have shown previously that chemical inhibition of XPO1 function results in reduced RSV replication. In this study, we have investigated the anti-RSV efficacy of Selective Inhibitor of Nuclear Export (SINE) compounds, KPT-335 and KPT-185. Our data shows that therapeutic administration of the SINE compounds results in reduced RSV titre in human respiratory epithelial cell culture. Within 24 h of treatment, RSV replication and XPO1 expression was reduced, M protein was partially retained in the nucleus, and cell cycle progression was delayed. Notably, the effect of SINE compounds was reversible within 24 h after their removal. Our data show that reversible inhibition of XPO1 can disrupt RSV replication by affecting downstream pathways regulated by the nuclear exporter.

Inhibition of Calpain Alleviates Apoptosis in Coxsackievirus B3-induced Acute Virus Myocarditis Through Suppressing Endoplasmic Reticulum Stress.

Virus myocarditis (VMC) is a common cardiovascular disease and a major cause of sudden death in young adults. However, there is still a lack of effective treatments. Our previous studies found that calpain activation was involved in VMC pathogenesis. This study aims to explore the underlying mechanisms further. Neonatal rat cardiomyocytes (NRCMs) and transgenic mice overexpressing calpastatin (Tg-CAST), the endogenous calpain inhibitor, were used to establish VMC model. Hematoxylin and eosin and Masson staining revealed inflammatory cell infiltration and fibrosis. An ELISA array detected myocardial injury. Cardiac function was measured using echocardiography. CVB3 replication was assessed by capsid protein VP1. Apoptosis was measured by TUNEL staining, flow cytometry, and western blot. The endoplasmic reticulum (ER) stress-related proteins were detected by western blot. Our data showed that CVB3 infection resulted in cardiac injury, as evidenced by increased inflammatory responses and fibrosis, which induced myocardial apoptosis. Inhibiting calpain, both by PD150606 and calpastatin overexpression, could attenuate these effects. Furthermore, ER stress was activated during CVB3 infection. However, calpain inhibition could downregulate some ER stress-associated protein levels such as GRP78, pancreatic ER kinase-like ER kinase (PERK), and inositol-requiring enzyme-1α (IRE-1α), and ER stress-related apoptotic factors, during CVB3 infection. In conclusion, calpain inhibition attenuated CVB3-induced myocarditis by suppressing ER stress, thereby inhibiting cardiomyocyte apoptosis.

Development of Novel Mitochondrial Pyruvate Carrier Inhibitors to Treat Hair Loss.

Herein, we report the synthesis and evaluation of novel analogues of UK-5099 both in vitro and in vivo for the development of mitochondrial pyruvate carrier (MPC) inhibitors to treat hair loss. A comprehensive understanding of the structure-activity relationship was obtained by varying four positions of the hit compound, namely, the alkyl group on the N1 position, substituents on the indole core, various aromatic and heteroaromatic core structures, and various Michael acceptors. The major discovery was that the inhibitors with a 3,5-bis(trifluoromethyl)benzyl group at the N1 position were shown to have much better activity than JXL001 (UK-5099) to increase cellular lactate production. Additionally, analogue JXL069, possessing a 7-azaindole heterocycle, was also shown to have significant MPC inhibition activity, which further increases the chemical space for drug design. Finally, more than 10 analogues were tested on shaved mice by topical treatment and promoted obvious hair growth on mice.

Design, synthesis and biological evaluation of benzoylacrylic acid shikonin ester derivatives as irreversible dual inhibitors of tubulin and EGFR.

In this study, a series of shikonin derivatives combined with benzoylacrylic had been designed and synthesized, which showed an inhibitory effect on both tubulin and the epidermal growth factor receptor (EGFR). In vitro EGFR and cell growth inhibition assay demonstrated that compound PMMB-317 exhibited the most potent anti-EGFR (IC50 = 22.7 nM) and anti-proliferation activity (IC50 = 4.37 µM) against A549 cell line, which was comparable to that of Afatinib (EGFR, IC50 = 15.4 nM; A549, IC50 = 6.32 µM). Our results on mechanism research suggested that, PMMB-317 could induce the apoptosis of A549 cells in a dose- and time-dependent manner, along with decrease in mitochondrial membrane potential (MMP), production of ROS and alterations in apoptosis-related protein levels. Also, PMMB-317 could arrest cell cycle at G2/M phase to induce cell apoptosis, and inhibit the EGFR activity through blocking the signal transduction downstream of the mitogen-activated protein MAPK pathway and the anti-apoptotic kinase AKT pathway; typically, such results were comparable to those of afatinib. In addition, PMMB-317 could suppress A549 cell migration through the Wnt/ß-catenin signaling pathway in a dose-dependent manner. Additionally, molecular docking simulation revealed that, PMMB-317 could simultaneously combine with EGFR protein (5HG8) and tubulin (1SA0) through various forces. Moreover, 3D-QSAR study was also carried out, which could optimize our compound through the structure-activity relationship analysis. Furthermore, the in vitro and in vivo results had collectively confirmed that PMMB-317 might serve as a promising lead compound to further develop the potential therapeutic anticancer agents.

Anti-chlamydial activities of cell-permeable hydrophobic dipeptide-containing derivatives.

The obligate intracellular bacteria chlamydia is major human pathogen that causes millions of trachoma, sexually transmitted infections and pneumonia worldwide. We serendipitously found that both calpain inhibitors z-Val-Phe-CHO and z-Leu-Nle-CHO showed marked inhibitory activity against chlamydial growth in human epithelial HeLa cells, whereas other calpain inhibitors not. These peptidomimetic inhibitors consist of N-benzyloxycarbonyl group and hydrophobic dipeptide derivatives. Both compounds strongly restrict the chlamydial growth even addition at the 12 h post infection. Notably, inhibitors-mediated growth inhibition of chlamydia was independent on host calpain activity. Electron microscopic analysis revealed that z-Val-Phe-CHO inhibited chlamydial growth by arresting bacterial cell division and RB-EB re-transition, but not by changing into persistent state. We searched and found that z-Leu-Leu-CHO and z-Phe-Ala-FMK also inhibited chlamydial growth. Neither biotin-hydrophobic dipeptide nor morpholinoureidyl-hydrophobic dipeptide shows inhibitory effects on chlamydial intracellular growth. Our results suggested the possibility of some chemical derivatives based on z-hydrophobic dipeptide group for future therapeutic usage to the chlamydial infectious disease.

CGK062, a small chemical molecule, inhibits cancer upregulated gene 2­induced oncogenesis through NEK2 and ß­catenin.

The mechanisms through which cancer­upregulated gene 2 (CUG2), a novel oncogene, affects Wnt/ß­catenin signaling, essential for tumorigenesis, are unclear. In this study, we aimed to elucidate some of these mechanisms in A549 lung cancer cells. Under the overexpression of CUG2, the protein levels and activity of ß­catenin were evaluated by western blot analysis and luciferase assay. To examine a biological consequence of ß­catenin under CUG2 overexpression, cell migration, invasion and sphere formation assay were performed. The upregulation of ß­catenin induced by CUG2 overexpression was also accessed by xenotransplantation in mice. We first found that CUG2 overexpression increased ß­catenin expression and activity. The suppression of ß­catenin decreased cancer stem cell (CSC)­like phenotypes, indicating that ß­catenin is involved in CUG2­mediated CSC­like phenotypes. Notably, CUG2 overexpression increased the phosphorylation of ß­catenin at Ser33/Ser37, which is known to recruit E3 ligase for ß­catenin degradation. Moreover, CUG2 interacted with and enhanced the expression and kinase activity of never in mitosis gene A­related kinase 2 (NEK2). Recombinant NEK2 phosphorylated ß­catenin at Ser33/Ser37, while NEK2 knockdown decreased the phosphorylation of ß­catenin, suggesting that NEK2 is involved in the phosphorylation of ß­catenin at Ser33/Ser37. Treatment with CGK062, a small chemical molecule, which promotes the phosphorylation of ß­catenin at Ser33/Ser37 through protein kinase C (PKC)α to induce its degradation, reduced ß­catenin levels and inhibited the CUG2­induced features of malignant tumors, including increased cell migration, invasion and sphere formation. Furthermore, CGK062 treatment suppressed CUG2­mediated tumor formation in nude mice. Taken together, the findings of this study suggest that CUG2 enhances the phosphorylation of ß­catenin at Ser33/Ser37 by activating NEK2, thus stabilizing ß­catenin. CGK062 may thus have potential for use as a therapeutic drug against CUG2­overexpressing lung cancer cells.

Modulating human mesenchymal stem cells using poly(n-butyl acrylate) networks in vitro with elasticity matching human arteries.

Non-swelling hydrophobic poly(n-butyl acrylate) network (cPnBA) is a candidate material for synthetic vascular grafts owing to its low toxicity and tailorable mechanical properties. Mesenchymal stem cells (MSCs) are an attractive cell type for accelerating endothelialization because of their superior anti-thrombosis and immune modulatory function. Further, they can differentiate into smooth muscle cells or endothelial-like cells and secret pro-angiogenic factors such as vascular endothelial growth factor (VEGF). MSCs are sensitive to the substrate mechanical properties, with the alteration of their major cellular behavior and functions as a response to substrate elasticity. Here, we cultured human adipose-derived mesenchymal stem cells (hADSCs) on cPnBAs with different mechanical properties (cPnBA250, Young's modulus (E) = 250 kPa; cPnBA1100, E = 1100 kPa) matching the elasticity of native arteries, and investigated their cellular response to the materials including cell attachment, proliferation, viability, apoptosis, senescence and secretion. The cPnBA allowed high cell attachment and showed negligible cytotoxicity. F-actin assembly of hADSCs decreased on cPnBA films compared to classical tissue culture plate. The difference of cPnBA elasticity did not show dramatic effects on cell attachment, morphology, cytoskeleton assembly, apoptosis and senescence. Cells on cPnBA250, with lower proliferation rate, had significantly higher VEGF secretion activity. These results demonstrated that tuning polymer elasticity to regulate human stem cells might be a potential strategy for constructing stem cell-based artificial blood vessels.

Poly(propylacrylic acid)-peptide nanoplexes as a platform for enhancing the immunogenicity of neoantigen cancer vaccines.

Cancer vaccines targeting patient-specific tumor neoantigens have recently emerged as a promising component of the rapidly expanding immunotherapeutic armamentarium. However, neoantigenic peptides typically elicit weak CD8+ T cell responses, and so there is a need for universally applicable vaccine delivery strategies to enhance the immunogenicity of these peptides. Ideally, such vaccines could also be rapidly fabricated using chemically synthesized peptide antigens customized to an individual patient. Here, we describe a strategy for simple and rapid packaging of peptide antigens into pH-responsive nanoparticles with endosomal escape activity. Electrostatically-stabilized polyplex nanoparticles (nanoplexes) can be assembled instantaneously by mixing decalysine-modified antigenic peptides and poly(propylacrylic acid) (pPAA), a polyanion with pH-dependent, membrane destabilizing activity. These nanoplexes increase and prolong antigen uptake and presentation on MHC-I (major histocompatibility complex class I) molecules expressed by dendritic cells, resulting in enhanced activation of CD8+ T cells. Using an intranasal immunization route, nanoplex vaccines inhibit formation of lung metastases in a murine melanoma model. Additionally, nanoplex vaccines strongly synergize with the adjuvant α-galactosylceramide (α-GalCer) in stimulating robust CD8+ T cell responses, significantly increasing survival time in mice with established melanoma tumors. Collectively, these findings demonstrate that peptide/pPAA nanoplexes offer a facile and versatile platform for enhancing CD8+ T cell responses to peptide antigens, with potential to complement ongoing advancements in the development of neoantigen-targeted cancer vaccines.

Optimizing outcomes with polymethylmethacrylate fillers.

INTRODUCTION: The ideal filler should be long-lasting, biocompatible, chemically inert, soft and easy to use, and have a long history of safety. This review focuses on the evolution and development of the PMMA-collagen gel, Bellafill, and the 10 years of postmarketing experience of Bellafill since it received premarket approval (PMA) from the FDA as Artefill in 2006. Artefill was rebranded to Bellafill in 2015. METHODS: The authors conducted a literature search on PubMed for key articles describing the steps in which Arteplast, a PMMA filler developed in 1989, led to the development of Bellafill, the only PMMA filler approved by the US FDA for the treatment of nasolabial folds and acne scar correction. The factors governing efficacy and safety were also evaluated for the major PMMA fillers available in the world. RESULTS: The process of manufacturing and purifying PMMA has played a major role in minimizing adverse events for Bellafill. Postmarketing surveillance data for the 2007-2016 period show that for more than 530 000 Bellafill syringes distributed worldwide, 11 confirmed granulomas (excluding clinical trial data) (0.002% of syringes sold) have been reported. Data on other PMMA fillers are limited and inconsistent. The authors suggest that adverse events are often attributable to lack of proficiency in treatment technique and other factors. CONCLUSION: Bellafill has demonstrated an excellent safety and effectiveness profile in multiple clinical studies, customer feedback, and 10 years of postmarketing surveillance experience. Adverse events occur with all fillers for a variety of reasons. In addition to quality of the product, injector skill and technique are critical to ensuring good clinical outcomes.

Optimization of antimalarial, and anticancer activities of (E)-methyl 2-(7-chloroquinolin-4-ylthio)-3-(4-hydroxyphenyl) acrylate.

Chemically modified versions of bioactive substances, are particularly useful in overcoming barriers associated with drug formulation, drug delivery and poor pharmacokinetic properties. In this study, a series of fourteen (E)-methyl 2-(7-chloroquinolin-4-ylthio)-3-(4-hydroxyphenyl) acrylate (2-15) were prepared by using a one step synthesis from 1 previously described by us as potential antimalarial and antitumor agent. Molecules were evaluated as inhibitors of ß-hematin formation, where most of them showed a significant inhibition value (% > 70). The best inhibitors were tested in vivo as potential antimalarials in mice infected with P. berghei ANKA, chloroquine susceptible strain. Three of them (5, 6, and 15) displayed antimalarial activity comparable to that of chloroquine. Also, molecules were evaluated for their cytotoxic activity against two human cancer cell lines (Jurkat E6.1 and HL60) and primary culture of human lymphocytes. Most of the synthesized compounds, except for analogs 2-6, 8, and 10-12, displayed cytotoxicity against cancer cell lines without affecting normal cells. The potency of the compounds was 15 ≫ 1, and 14 > 7, 9, and 13. Flow cytometry analysis demonstrated an increase in apoptotic cell death after 24 h. The compounds may affect tumor cell autophagy and consequently increase cell apoptosis.

Radiation preparation of L-arginine/acrylic acid hydrogel matrix patch for transdermal delivery of propranolol HCl in hypertensive rats.

In the present study, L-arginine/acrylic acid (Arg/AAc) batch hydrogel was successfully prepared by gamma irradiation for transdermal delivery of propranolol HCl in hypertensive rats. The resulted system has been characterized by FTIR to confirm the hydrogel formation. The swelling behavior of the prepared hydrogels was investigated as a function of time and pH. The kinetics of swelling has been investigated. In vivo pharmacokinetics evaluation, skin irritation test, and histopathological studies were investigated. Furthermore, the antihypertensive efficacy of transdermal propranolol-loaded Arg/AAc hydrogel on methyl prednisolone acetate-induced hypertensive rats was evaluated. It was found that the prepared patches exhibited a sustained release of the drug into systemic circulation over oral route which is subjected to hepatic first-pass metabolism, coupled with a short plasma half-life. Transdermal administration displayed a prolonged antihypertensive effect in spontaneously hypertensive rats. Moreover, the skin irritation test and histopathological examination indicated that the prepared patches are not irritant and can be safely applied on the skin. These results indicated that the hydrogel system composed of Arg and AAc has potential as a transdermal delivery system.

Clinical performance of a glass ionomer sealant protected with two different resin-based agents over a 2-year follow-up period.

AIM: To evaluate the effects of two different resin coating materials on the clinical performance of a conventional glass ionomer sealant. MATERIALS AND METHODS: Permanent first mandibular molars of 60 children aged 6-9 years were sealed with Fuji VII. In each child, G-Coat Plus coating agent was applied to molars on one side and Heliobond coating agent to molars on the opposite side of the mouth. Clinical evaluations were carried out at 1, 6, 12, 18 and 24 months after sealant and coating application. RESULTS: At 1, 6, 12, 18 and 24 months after sealant and coating application, total sealant retention rates were 88%, 40%, 19%, 15% and 9% for molars coated with G-Coat Plus, and 93%, 47%, 17%, 15% and 7% for those coated with Heliobond. The differences between the two coating agents were not statistically significant (p>0.05). No incidence of caries was observed in either group during the two-year evaluation period. STATISTICS: Wilcoxon signed rank test was used to compare differences in retention rates and caries incidence by coating agent. CONCLUSION: Although retention rates of Fuji VII were relatively low and similar for both resin coating agents tested, dental caries were not observed in either group during the 24-month study period. In children with a high risk of caries and partially erupted molars, the use of a glass ionomer sealant with a resin-based coating agent should be encouraged.

Development of an Acrylate Derivative Targeting the NLRP3 Inflammasome for the Treatment of Inflammatory Bowel Disease.

Pharmacological inhibition of NLRP3 inflammasome activation may offer a new option in the treatment of inflammatory bowel disease. In this work, we report the design, synthesis, and biological screening of a series of acrylate derivatives as NLRP3 inhibitors. The in vitro determination of reactivity, cytotoxicity, NLRP3 ATPase inhibition, and antipyroptotic properties allowed the selection of 11 (INF39), a nontoxic, irreversible NLRP3 inhibitor able to decrease interleukin-1ß release from macrophages. Bioluminescence resonance energy transfer experiments proved that this compound was able to directly interfere with NLRP3 activation in cells. In vivo studies confirmed the ability of the selected lead to alleviate the effects of colitis induced by 2,4-dinitrobenzenesulfonic acid in rats after oral administration.

Calpain inhibitor alleviates permanent hearing loss induced by intense noise by preventing disruption of gap junction-mediated intercellular communication in the cochlear spiral ligament.

Our previous studies demonstrated that intense noise-induced hearing loss might be at least in part due to an oxidative stress-induced decrease in the level of gap junction-composing protein connexins in the spiral ligament (SL) of the cochlear lateral wall structures in mice. Further, an in vivo exposure of mice to intense noise activates calpain in the cochlear SL. Based on these studies, we sought to determine whether a calpain inhibitor would prevent an intense noise exposure from causing hearing loss, disruption of gap junction-mediated intercellular communication (GJIC) in the SL. An exposure of mice to intense noise (8-Hz octave band noise, 110-dB sound pressure level, 1h) produced permanent hearing loss and cochlear hair cell death. The results of an ex vivo assay using gap-fluorescence recovery after photobleaching of dissected lateral wall structures revealed that the intense noise disrupted GJIC in the cochlear SL at day-7 post exposure. A prior intracochlear injection of the calpain inhibitor PD150606 significantly abolished this noise-induced hearing loss on days 5 and 7 post exposure. Similarly, PD150606 prevented noise-induced hair cell death and the GJIC disruption on day-7 post exposure. The intense noise temporarily enhanced the gene expression of calpain subtypes Capn1 and Capn2 immediately after exposure. Taken together, our data suggest that calpain inhibitor alleviated the noise-induced hearing loss, at least in part, by preventing disruption of GJIC in the cochlear SL. It possible that calpain inhibitors would be useful as a candidate of therapeutic drugs for sudden sensorineural hearing loss.

Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer.

Tetrahydroisoquinoline 40 has been identified as a potent ERα antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimization of the THIQ scaffold leading to THIQ 40 and showcase the racemization of the scaffold, pharmacokinetic studies in preclinical species, and the in vivo efficacy of THIQ 40 in a MCF-7 human breast cancer xenograft model.

Clinical Evaluation of a Skin Protectant for the Management of Incontinence-Associated Dermatitis: An Open-Label, Nonrandomized, Prospective Study.

PURPOSE: The purpose of this study was to evaluate the efficacy of an investigational skin protectant product at managing severe skin breakdown associated with incontinence. DESIGN: Open-label, nonrandomized, prospective study. SUBJECTS AND SETTING: The sample comprised 16 patients; inclusion criteria were: patients older than 18 years, cared for in the intensive care unit of a level I trauma center hospital or in long-term care facilities in the northeast region of the United States, and had incontinence-associated dermatitis (IAD). Twelve of the patients had epidermal skin loss and 4 had severe redness. METHODS: The investigational product is a formulation based on acrylate chemistry. The skin protectant application schedule was twice weekly for up to 3 weeks for a maximum of 6 applications during the study period. The skin was evaluated via a skin assessment instrument specifically designed for use in this study; this instrument has not undergone validation studies. The main outcome measure was changes in the instrument score over time. In addition, complete reepithelialization was recorded when observed, and pain scores (associated with IAD) were noted in participants who were able to report pain. RESULTS: The IAD score improved in 13 of 16 patients, remained unchanged in 1 patient, and deteriorated in 2 patients. The median percent improvement in the skin assessment instrument was 96% (P = .013). Four of the patients with epidermal skin loss had complete reepithelialization of the skin surface with 4 to 6 applications of the skin protectant, and 5 had substantial improvement. The 4 patients with severe red skin returned to healthy normal skin with 2 to 4 skin protectant applications. Substantial pain reduction was reported by all 9 patients who reported pain at enrollment. No adverse events associated with the skin protectant application were reported during data collection. CONCLUSION: Results of this study suggest that an acrylate-based product, evaluated here for the first time in patients, may be effective as a protective barrier in the presence of continued incontinence. Additional research is needed to confirm these findings.

Comparison Between Acrylic Cage and Polyetheretherketone (PEEK) Cage in Single-level Anterior Cervical Discectomy and Fusion: A Randomized Clinical Trial.

STUDY DESIGN: Prospective, single-blind randomized-controlled clinical study. OBJECTIVE: To compare polyetheretherketone (PEEK) cage with a novel Acrylic cage to find out which fusion cage yielded better clinical outcomes following single-level anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: ACDF is considered a standard neurosurgical treatment for degenerative diseases of cervical intervertebral disks. There are many options, including bone grafts, bone cement, and spacers made of titanium, carbon fiber, and synthetic materials, used to restore physiological disk height and enhance spinal fusion, but the ideal device, which would provide immediate structural support and subsequent osteointegration and stability, has not been identified yet. To overcome this, we designed a new, inexpensive Acrylic cage. MATERIALS AND METHODS: A total of 64 patients were eligible to participate and were randomly allocated to undergo ACDF either with Acrylic interbody fusion cage filled with bone substitute (n=32) or PEEK cage (n=32). Nurick's grading was used for quantifying the neurological deficit. Clinical and radiologic outcome was assessed preoperatively, immediately after surgery, and subsequently at 2, 6, and 12 months of follow-up using Odom's criteria and dynamic radiographs (flexion-extension) and computed tomography scans, respectively. RESULTS: There was a statistically significant improvement in the clinical outcomes of the Acrylic cage group compared with the PEEK cage group (mean difference: -0.438; 95% confidence interval, -0.807 to -0.068; P=0.016). There was a statistically significant difference in disk space height increase between the 2 groups at the 6- and 12-month follow-up. The Acrylic cage achieved higher fusion rate (good fusion) than the PEEK cage (96.9% vs. 93.8%). Intervertebral angle demonstrated a significant difference among the 2 treated groups throughout the follow-up period. CONCLUSION: This study suggests that the use of Acrylic cage is associated with good clinical and radiologic outcomes and it can be therefore a good substitute for bone graft and other cages in ACDF.

HCVerso3: An Open-Label, Phase IIb Study of Faldaprevir and Deleobuvir with Ribavirin in Hepatitis C Virus Genotype-1b-Infected Patients with Cirrhosis and Moderate Hepatic Impairment.

This study evaluated the interferon-free, oral combination of deleobuvir (non-nucleoside HCV NS5-RNA-polymerase inhibitor) and faldaprevir (HCV NS3/4A-protease inhibitor) with ribavirin in patients with HCV genotype-1b and moderate (Child-Pugh B [CPB], n = 17) or mild hepatic impairment (Child-Pugh A [CPA], n = 18). Patients received faldaprevir 120 mg and deleobuvir (600 mg [CPA], 400 mg [CPB]) twice-daily with weight-based ribavirin for 24 weeks. Baseline characteristics were similar between groups. Among CPA patients, 13/18 completed treatment; discontinuations were for adverse events (AEs, n = 1), lack of efficacy (n = 3) and withdrawal (n = 1). Among CPB patients, 8/17 completed treatment; discontinuations were for AEs (n = 6), withdrawal (n = 1) and 'other' (n = 2). Sustained virologic response at post-treatment Week 12 (SVR12) was achieved by 11 (61%) CPA patients (95% confidence interval: 38.6%-83.6%) and 9 (53%) CPB patients (95% confidence interval: 29.2%-76.7%), including most CPA (11/16) patients with Week 4 HCV RNA <25 IU.mL-1 (target detected or not detected) and most CPB (8/9) patients with Week 4 HCV RNA <25 IU.mL-1 (target not detected); 0/4 CPB patients with Week 4 HCV RNA <25 IU.mL-1 (target detected) achieved SVR12. The most common AEs in both groups were nausea, diarrhoea and vomiting. Serious AEs were observed in 9 (53%) CPB patients and 1 (6%) CPA patient. Plasma trough concentrations of deleobuvir and faldaprevir were not substantially different between the CPA and CPB groups. In conclusion, in this small study the safety and efficacy profiles for 24 weeks of treatment with faldaprevir+deleobuvir+ribavirin in patients with mild or moderate hepatic impairment were consistent with the safety and efficacy profile of this regimen in non-cirrhotic patients. Faldaprevir+deleobuvir+ribavirin resulted in SVR12 in 53-61% of patients: proportions achieving SVR4 but not SVR12 were higher than in non-cirrhotic patients and overall response rates were lower than rates reported with other all-oral regimens in patients with cirrhosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT01830127.