Chitosan scaffolds with BMP-6 loaded alginate microspheres for periodontal tissue engineering

The aim of this study is to develop an effective growth factor releasing scaffold-microsphere system for promoting periodontal tissue engineering. Bone morphogenetic protein-6 (BMP-6)-loaded alginate microspheres in narrow size distribution were produced by optimising electrospraying conditions. The addition of these microspheres to chitosan gels produced a novel scaffold in which not only the pore sizes and interconnectivity were preserved, but also a controlled release vehicle was generated. Loading capacity was adjusted as 50?ng or 100?ng BMP-6 for each scaffold and the controlled release behaviour of BMP-6 from chitosan scaffolds was observed during seven days. Cell culture studies were carried out with rat mesenchymal stem cells derived from bone marrow in three groups; chitosan scaffolds, chitosan scaffolds containing BMP-6-loaded alginate microspheres and chitosan scaffolds with free BMP-6 in culture medium. Results showed that controlled delivery of BMP-6 from alginate microspheres has a significant effect on osteogenic differentiation.     

护理查对方法的改进及效果观察

目的观察护理查对方法改进后的“四查八对”制度在预防临床护理差错中的效果,并论证执行“四查八对”制度的可行性。方法（1）通过分析本院2009年上报护理部的护理差错及患者参与查对能力调查结果,依据患者十大安全目标要求,建立并执行“四查八对”制度,即在原“三查七对”的基础上增加一查一对,一查是增加患者或家属参与查;一对是增加药物质量和有效期的核对。观察实施“四查八对”制度前后护理差错发生情况。（2）采用自行设计的问卷分别对2009年和2010年的363例和392例住院患者进行了参与查对相关知识和护理安全满意度调查,并进行对比分析。结果（1）执行“四查八对”制度后,护理差错发生率由0．23‰降至0．13‰,差异有极显著性（X^2=7．89,P〈0．01）。（2）患者对参与查对相关知识知晓率由25．6％升高至75．3％,患者满意度由76．9％升高达98．5％,差异均有极显著性（X^2=81．6,P〈0．01;X^2=83．8,P〈0．01）。结论“四查八对”作为护理核心制度应用于临床,保障了护理安全措施的进一步落实,促进了护理健康教育水平的提高,进而提高了患者的满意度,较“三查七对”具有优越性、可行性,值得推广应用。     

Small molecule inhibitors of anthrax toxin-induced cytotoxicity targeted against protective antigen

Two molecular scaffolds were designed using the CAVEAT molecular design package to inhibit the oligomerization of protective antigen (PA(63) ), a key protein component of anthrax toxin. The inhibitors were designed to prevent heptamerization of PA(63) by mimicking key residues of PA(63) needed for the intermolecular interactions that stabilize the heptamer. Using the scaffolds identified by CAVEAT, seven candidate inhibitors were synthesized and tested for their ability to inhibit anthrax toxin-induced cytotoxicity, with three of the agents demonstrating modest inhibition in murine J774A.1 macrophage cells.     

Statin-associated gynecomastia: evidence coming from the Italian spontaneous ADR reporting database and literature

Purpose

The aim of this study was to add to the body of evidence on statin-induced gynecomastia based on data retrieved from the Italian spontaneous adverse drug reaction (ADR) reporting database.

Methods

Spontaneous ADR reports collected in the Italian database up to 31 December 2010 were assessed on a case-by-case basis in a search for evidence of a possible causal association between statins and gynecomastia. Cases of gynecomastia or possible gynecomastia, according to the Medical Dictionary of Regulatory Activities (MedDRA) classification, associated with statin use were retrieved from the database. The findings were compared with the available literature in PubMed.

Results

The database contained 90,448 ADR reports on 21 December 2010. At least one statin was listed as the suspected drug in 2,862 reports, of which 1,334 concerned a male patient. Among these reports, we identified eight cases with the preferred term “gynecomastia” with a statin as suspected drug: four reports of rosuvastatin and four of atorvastatin. One additional report of an unspecified “breast disorder” in a male patient attributed to fluvastatin was identified and included as a possible case. Four case-reports of statin-induced gynecomastia published between 2006 and 2010 were retrieved from PubMed.

Conclusions

Our findings suggest an association between gynecomastia and statins as a drug class, and the occurrence of this ADR would appear to be more likely with active substances that show an higher potency in inhibiting HMG-CoA reductase enzyme. To date, the safety information provided on the labels of different statin-containing medicines is not standardized. Harmonization of this information would be helpful for both healthcare practitioners and patients.     

ScafBank: a public comprehensive Scaffold database to support molecular hopping

Aim:

The search for molecules whose bioactivities are similar to those of given compounds or to optimize the initial lead compounds from high throughput screening has attracted increasing interest in recent years. Our goal is to provide a publically searchable database of scaffolds out from a large collection of existing chemical molecules.

Results:

Although a number of in silico methods have emerged to facilitate this process, which has become known as ”scaffold hopping” or “molecular hopping”, there is an urgent need for a database system to provide such valuable data in the drug design field. Here we have systematically analyzed a collection of commercially available small molecule databases and a bioactive compound database to identify unique scaffolds and we have built apublically searchable database. The analysis of approximately 4 800 000 of these compounds identified 241 824 unique scaffolds, which are stored in a relational database (http://202.127.30.184:8080/db.html). Each entry in the database is associated with a molecular occurrence and includes its distribution of molecular properties, such as molecular weight, logP, hydrogen bond acceptor number, hydrogen bond donor number, rotatable bond number and ring number. More importantly, for scaffolds derived from the bioactive compounds database, it also contains the original compounds and their target information.

Conclusion:

This Web-based database system could help researchers in the fields of medicinal and organic chemistry to design novel molecules with properties similar to the original compounds, but built on novel scaffolds.     

Discovery of prolyl hydroxylase 2 inhibitors with new chemical scaffolds as in vivo active erythropoietin inducers through a combined virtual screening strategy

Hypoxia‐inducible factor (HIF) is identified to be a promising target to mediate the response to hypoxia. Its stability and activation are negatively controlled by prolyl hydroxylase 2 (PHD2). Thus, PHD2 inhibition has been perceived as a promising anti‐anemia therapy. In this study, we carried out a structure‐based virtual screening followed by in vitro and in vivo biological validation, with the goal to identify novel PHD2 inhibitors. As a result, a set of hits with new chemical scaffolds were revealed to be active in vitro for PHD2 inhibition. Compounds 2 and 3 were revealed to be capable of stabilizing HIF‐α and stimulating erythropoietin (EPO) expression in cell‐based assays. Notably, further in vivo assays revealed that 2 was capable of elevating the EPO plasma levels in C57BL/6 mice model. These findings provide new chemical scaffolds for further development of PHD2 inhibitors.     

46例成人肾病综合征临床与病理分析

目的探讨成人肾病综合征临床与病理分型特点,以及肾穿刺活检术在成人肾病综合征诊断中的意义。方法在B超或彩超引导下,应用半自动肾活检针单人操作行经皮肾穿刺活检术46例次,标本送福州总医院病理科行光镜、免疫组化及电镜等病理检查。结果46例肾病综合征按临床表现分单纯型15例、非单纯型31例,后者可再细分为血尿型12例,高血压型4例,肾炎综合征型7例和肾功能衰竭型8例。病理类型有：微小病变1例,系膜增生性肾小球肾炎11例,膜性肾病3例,局灶性节段性肾小球硬化3例,IgA肾病7例,增生硬化性肾小球肾炎1例,新月体肾炎1例,狼疮肾炎8例,乙肝相关性肾小球肾炎8例,糖尿病肾病1例,肾淀粉样变性1例,过敏性紫癜肾小球肾炎1例。结论肾病综合征临床表现差异性提示其病因、病理类型及严重程度不同,其治疗及预后也不同。肾穿刺活检对于成人肾病综合征的诊断、治疗和预后判断有重要的临床意义,如无禁忌证应积极开展此项检查以明确诊断。     

A pilot study to build a database on seven anti-hypertensive drugs

PURPOSE: In Japan, all patients are able to see freely any clinics or hospitals. So clinical data of all patients have been stored at clinics, hospitals and medical institutes respectively. These patients' clinical course data stocks have not been combined with one another. There is no large-scale database, which has been available and has played its role in complementing spontaneous adverse drug reaction (ADR) reporting system. We tried to build an original database using anti-hypertensive drugs' data from Drug Use Investigation conducted for the Japanese Drug Re-examination application by every pharmaceutical manufacturer in conformity with Japanese Pharmaceutical Affairs Law and Related Regulation. METHODS: The 43 565 case data of seven anti-hypertensive drugs (one Ca-antagonist, one alpha-blocker, two beta-blockers, three ACE inhibitors) were kindly offered from seven manufacturers who were members of RAD-AR Council, Japan. After examining the data items and categories, they were standardized into common codes based on Japanese Drug Category Classification (JDCC), International Classification of Diseases 9 (ICD-9) and Japanese Adverse Drug Reaction Terminology (J-ART). As each manufacturer had a different coding method in accordance to manufacturer's own practice of data management, the original forms were divided into several datasets. The data processing and statistical analysis were conducted using Statistical Analysis System (SAS). RESULTS: (1) Technology and know-how to combine data coded by different methods were established for building a database that had never been tried in Japan. (2) The following are the by-products of the study: a) Onset of ADR concentrated in the early stage but onset of some disorders prevailed equally throughout the investigation period. b) Although the number of collected cases of anti-hypertensive drugs was 43 565, total number of administrated anti-hypertensive drugs reached to 70 714 because additional anti-hypertensive drugs were often used with subject drugs. CONCLUSION: There is no large-scale database of patients' clinical course in Japan. However, since the Japanese Drug Re-examination System started in 1979, almost eight million cases of Drug Use Investigation on about 700 drugs have been collected with enormous human power and huge expenditure for Japanese Drug Re-examination application by pharmaceutical manufacturers. New and more appropriate information will be detected by the database, built using Drug Use Investigation data that were collected only for the Japanese Drug Re-examination application.     

Virtual screening of human 5-aminoimidazole-4-carboxamide ribonucleotide transformylase against the NCI diversity set by use of AutoDock to identify novel nonfolate inhibitors

AICAR transformylase (5-aminoimidazole-4-carboxamide ribonucleotide transformylase) is a folate-dependent activity of the bifunctional protein ATIC (AICAR transformylase and IMP cyclohydrolase) and is responsible for catalyzing the penultimate step of the de novo purine biosynthetic pathway. As such, AICAR transformylase has been proposed as a potential target for antineoplastic drug design. Virtual screening of the human AICAR transformylase active site by use of AutoDock against the NCI diversity set, a library of compounds with nonredundant pharmacophore profiles, has revealed 44 potential inhibitor candidates. In vitro inhibition assay of 16 soluble compounds from this list revealed that eight compounds with novel scaffolds, relative to the general folate template, had micromolar inhibition. Subsequent extension of docking trials on compounds with similar scaffolds from the entire NCI-3D database has unveiled 11 additional inhibitors that were confirmed by the in vitro inhibition assay. In particular, one compound, NSC30171, had nanomolar inhibition (K(i) = 154 nM, IC(50) = 600 nM) against AICAR transformylase. These 19 inhibitors serve as novel templates/scaffolds for development of more potent and specific non-folate-based AICAR transformylase inhibitors.     

板蓝根化学成分研究（Ⅱ）

目的：提取分离板蓝根化学成分。方法：板蓝根用95％乙醇渗漉,用不同极性溶剂分级萃取,再分别用硅胶和大孔树脂做柱层析分离,测定纯化合物的理化常数和波谱数据,鉴定化学结构。结果：从板蓝根中分离得到31种化合物。结论：13种为已知化合物,18种为新发现,其中6种为新化合物,3种为首次从自然界中已分得的。其中的两种新化合物分别命名为isaindigotone,hydroxyindirubin。     

Fragment-based drug design and drug repositioning using multiple ligand simultaneous docking (MLSD): identifying celecoxib and template compounds as novel inhibitors of signal transducer and activator of transcription 3 (STAT3)

We describe a novel method of drug discovery using MLSD and drug repositioning, with cancer target STAT3 being used as a test case. Multiple drug scaffolds were simultaneously docked into hot spots of STAT3 by MLSD, followed by tethering to generate virtual template compounds. Similarity search of virtual hits on drug database identified celecoxib as a novel inhibitor of STAT3. Furthermore, we designed two novel lead inhibitors based on one of the lead templates and celecoxib.     

Combining Computational Methods for Hit to Lead Optimization in Mycobacterium Tuberculosis Drug Discovery

Purpose

Tuberculosis treatments need to be shorter and overcome drug resistance. Our previous large scale phenotypic high-throughput screening against Mycobacterium tuberculosis (Mtb) has identified 737 active compounds and thousands that are inactive. We have used this data for building computational models as an approach to minimize the number of compounds tested.

Methods

A cheminformatics clustering approach followed by Bayesian machine learning models (based on publicly available Mtb screening data) was used to illustrate that application of these models for screening set selections can enrich the hit rate.

Results

In order to explore chemical diversity around active cluster scaffolds of the dose–response hits obtained from our previous Mtb screens a set of 1924 commercially available molecules have been selected and evaluated for antitubercular activity and cytotoxicity using Vero, THP-1 and HepG2 cell lines with 4.3%, 4.2% and 2.7% hit rates, respectively. We demonstrate that models incorporating antitubercular and cytotoxicity data in Vero cells can significantly enrich the selection of non-toxic actives compared to random selection. Across all cell lines, the Molecular Libraries Small Molecule Repository (MLSMR) and cytotoxicity model identified ~10% of the hits in the top 1% screened (>10 fold enrichment). We also showed that seven out of nine Mtb active compounds from different academic published studies and eight out of eleven Mtb active compounds from a pharmaceutical screen (GSK) would have been identified by these Bayesian models.

Conclusion

Combining clustering and Bayesian models represents a useful strategy for compound prioritization and hit-to lead optimization of antitubercular agents.     

Proteomic changes in response to acute cadmium toxicity in gill tissue of Paralichthys olivaceus

In the present study, we developed a two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) technique for examining the response of the proteome from gill tissue of Paralichthys olivaceus (POGT) to acute cadmium (AC) toxicity. Approximately 700 protein spots were detected from the gill sample when applying a 600μg protein 2D-PAGE gel in the pH range 5.0-8.0, and approximately 400 of these were identified by peptide mass fingerprinting (PMF) and database search. Compared to a control sample, significant changes were visualized in 18 protein spots exposed to seawater cadmium acute toxicity at 10.0ppm for 24h. Among these spots, two were up-regulated, one was down-regulated, seven showed low expression, and eight showed high expression. The collected spots were further identified by PMF and database search. Ten of the 18 proteins identified on the 2D-PAGE gel, including heat shock protein 70 and calcium-binding protein, demonstrated a synchronous response to AC, and we suggest that the variable levels and trends of these spots on the gel might be utilized as biomarker profiles to investigate cadmium contamination levels in seawater and to evaluate the degree of risk of human fatalities. The experimental results emphasize that the application of multiple biomarkers has an advantage over single biomarkers for monitoring levels of heavy metal contamination in seawater.     

High-grade dysplasia in Barrett's oesophagus: natural history and review of clinical practice

BACKGROUND: Management of high-grade dysplasia in Barrett's oesophagus is controversial: surgery carries an appreciable morbidity/mortality, high-grade dysplasia may not progress to cancer and endoscopic ablation is an emerging option. AIM: To review Barrett's oesophagus-related high-grade dysplasia management and outcome over a 10-year period. METHODS: This was a retrospective case note review of 36 patients identified from a pathology database. RESULTS: There were 31 men of mean age 67 years. Endoscopic surveillance identified nine. Median follow-up was 21 months. Seven patients had no further intervention because of age/comorbidity. The other 29 had repeat endoscopic biopsies, nine showing cancer (six oesophagectomized). Of the 20 remaining patients with persisting high-grade dysplasia, eight had surgery (histology showed cancer in six), seven continued endoscopic surveillance (high-grade dysplasia regressed in four) and five had 'curative' argon ablation. An intensive biopsy protocol was not followed in 55% of endoscopies. Prevalent cancers occurred in 44% with an annual incidence of 5% over 5 years. All cause mortality was 39% (14 of 36, eight of 14 from cancer). CONCLUSIONS: Management of high-grade dysplasia was not uniform. Unsuspected cancer was common in high-grade dysplasia patients undergoing surgery but 13% regressed under surveillance. High-grade dysplasia patients have a high mortality but 43% did not die from cancer.     

An early evaluation of bleeding-related hospital readmissions among hospitalized patients with nonvalvular atrial fibrillation treated with direct oral anticoagulants

Objective:

Clinical trials have demonstrated that direct oral anticoagulants (DOACs) are efficacious in reducing stroke risk among patients with nonvalvular atrial fibrillation (NVAF) with differences in the reduction of bleeding risks vs. warfarin. The objective of this study was to assess bleeding-related hospital readmissions among hospitalized NVAF patients treated with dabigatran, rivaroxaban, and apixaban in the US.

Research design and methods:

Patients (≥18 years) with a discharge diagnosis of NVAF who received apixaban, dabigatran, or rivaroxaban during hospitalization were identified from the Premier Hospital database (1 January 2012–31 March 2014) and the Cerner Health Facts hospital database (1 January 2012–31 August 2014). Patients identified from each database were analyzed separately and grouped into three cohorts depending on which DOAC was received. Patient characteristics, hospital resource use and costs, and frequency of readmissions within 1 month were evaluated.

Results:

Among study populations identified from the Premier database (N?=?74,730) and the Cerner database (N?=?14,201), patients who received apixaban were older, had greater comorbidity, and had higher stroke and bleeding risks. After controlling for patient characteristics, including comorbidity and stroke and bleeding risks, compared with patients who received apixaban during their index hospitalizations, the odds of bleeding-related hospital readmissions were significantly greater by 1.4-fold (p?<?0.01) for patients who received rivaroxaban and 1.2-fold (p?=?0.16) numerically greater for patients who received dabigatran among patients identified from the Premier Hospital database. Among patients in the Cerner Health Facts hospital database, bleeding-related hospital readmissions were significantly greater by 1.6-fold (p?=?0.04) for patients who received rivaroxaban and 1.3-fold (p?=?0.30) numerically greater for patients who received dabigatran compared to patients who received apixaban.

Limitations:

No causal relationship between treatment and outcomes can be concluded.

Conclusions:

NVAF patients using different DOACs had different characteristics, including stroke and bleeding risks. Use of rivaroxaban, compared to apixaban was associated with significantly greater risk of bleeding-related readmissions across two database claims analyses.     

Tyrosinase inhibitors: a patent review (2011-2015)

Introduction: Tyrosinase is responsible for melanin production. The overproduction of melanin causes many skin disorders. The inhibition of tyrosinase activity would appear to be the most rational and explicit way of overcoming these issues.

Areas covered: Thirty eight patents on synthetic tyrosinase inhibitors issued since 2011 were reviewed. Inhibitors were categorized by chemical structure and assigned to eight classes. Information on potent inhibitors in each class is provided.

Expert opinion: Many tyrosinase inhibitors of natural or synthetic origin have been identified, but very few are qualified for clinical use. Thus medicinal scientists have to work more on the identification of potent and safe tyrosinase inhibitors. Various chemical scaffolds have been explored. Among them, the scaffolds such as resorcinol, biaryl, imidazolethione, β-phenyl-α,β-unsaturated carbonyl, and some double strand oligonucleotides have shown high tyrosinase inhibition, low toxicities, and great potencies. Detail structure activity relationship studies of these potential scaffolds could provide directions for a new and potent tyrosinase inhbitors. Furthermore new trends, such as the use of synergistic phenomena, salt formation, drug repositioning and designing of multi-targeted tyrosinase inhibitors could expand search areas for much improved tyrosinase inhibitors.     

Privileged structures - dream or reality: preferential organization of azanaphthalene scaffold

The concept of privileged structures/substructures (PS) is the idea that certain structural features produce biological effects more often than others. The PS method can be seen as an offspring of fragonomics, which is based on recent experimental measurements of protein-ligand interactions. If PS prove to be true, then chemical motives that enrich biological activity can be used when designing new drugs. However, PS remain controversial because we cannot be sure whether the excess of active structures does not result from an abundance in chemical libraries. In this review, we will focus, in particular, on the preferential organization of azanaphthalene scaffolds (AN) in drugs and natural products (NP), which are preferred by Nature in evolution. We will show that knowledge discovery in molecular databases can reveal interesting time-trends profiles for important classes of potentially privileged scaffolds. The chemical library of AN is dominated by monoaza-compounds, among which quinoline appears to be the most frequently investigated scaffold; however; more sophisticated database mining seems to indicate different PS patterns within the AN scaffold family.     

Identification of specific markers for amphetamines synthesized from glycidic acid pre‐precursors and retrospective search in German profiling database

The pre‐precursor market and the clandestine production of amphetamine‐type stimulants (ATS) has become more diverse in recent years. Besides α‐phenylacetoacetonitrile (APAAN) and α‐phenylacetoacetamide (APAA), glycidic acid derivatives and methyl α‐phenylacetoacetate (MAPA) are gaining importance. This conclusion is based on seizure data of police and customs. However, analytical data are needed to confirm and quantify the actual prevalence of new pre‐precursors by elucidating the percentage of seized ATS that have been produced from them. A recent study showed that APAAN use is currently declining, which supports the view that new pre‐precursors are being used. In this study, several conversion procedures using different batches of glycidic acid derivatives and a complete Leuckart reaction to produce amphetamine were carried out. The resulting organic phases were analyzed using gas chromatography ? mass spectrometry to identify possible marker compounds. Three marker compounds were discovered and characterized using mass spectra and nuclear magnetic resonance spectroscopy. They were identified as phenyl‐1‐propanone, N‐(1‐phenylpropyl)formamide and 1‐phenylpropan‐1‐amine. Their prevalence was investigated by searching the markers in an amphetamine impurity profiling database to determine to what extent they occurred in amphetamine samples from recent years. Data from the central German amphetamine profiling database of more than 250 cases were used for this purpose. The yearly occurrence of the three glycidate marker compounds was determined going back as far as 2009, revealing an increasing trend from 2016 on. This article presents experimental proof that APAAN is currently being replaced by other pre‐precursors, such as glycidic acid derivatives.