Fimepinostat Impairs NF-κB and PI3K/AKT Signaling and Enhances Gemcitabine Efficacy in H3.3K27M-Diffuse Intrinsic Pontine Glioma.

Diffuse intrinsic pontine glioma (DIPG) is the most aggressive pediatric brain tumor, and the oncohistone H3.3K27M mutation is associated with significantly worse clinical outcomes. Despite extensive research efforts, effective approaches for treating DIPG are lacking. Through drug screening, we identified the combination of gemcitabine and fimepinostat as a potent therapeutic intervention for H3.3K27M DIPG. H3.3K27M facilitated gemcitabine-induced apoptosis in DIPG, and gemcitabine stabilized and activated p53, including increasing chromatin accessibility for p53 at apoptosis-related loci. Gemcitabine simultaneously induced a prosurvival program in DIPG through activation of RELB-mediated NF-κB signaling. Specifically, gemcitabine induced the transcription of long terminal repeat elements, activated cGAS-STING signaling, and stimulated noncanonical NF-κB signaling. A drug screen in gemcitabine-treated DIPG cells revealed that fimepinostat, a dual inhibitor of HDAC and PI3K, effectively suppressed the gemcitabine-induced NF-κB signaling in addition to blocking PI3K/AKT activation. Combination therapy comprising gemcitabine and fimepinostat elicited synergistic antitumor effects in vitro and in orthotopic H3.3K27M DIPG xenograft models. Collectively, p53 activation using gemcitabine and suppression of RELB-mediated NF-κB activation and PI3K/AKT signaling using fimepinostat is a potential therapeutic strategy for treating H3.3K27M DIPG. SIGNIFICANCE: Gemcitabine activates p53 and induces apoptosis to elicit antitumor effects in H3.3K27M DIPG, which can be enhanced by blocking NF-κB and PI3K/AKT signaling with fimepinostat, providing a synergistic combination therapy for DIPG.

Effects of NCSTN Mutation on Hair Follicle Components in Mice.

BACKGROUND AND OBJECTIVES: Hidradenitis suppurativa (HS)/acne inversa is an intractable skin disease that is characterized by destructive lesions - primarily on the flexural areas. Although its etiology is unknown, genetics is considered to be a factor of its pathology - mutations in γ-secretase genes have been identified in certain familial HS patients, and follicular occlusion is widely accepted as the primary cause of HS. But, no relationship between these mutations and the components of hair follicles has been reported. Thus, we examined changes in these components in mice with a mutation in NCSTN (a γ-secretase gene). METHODS: We generated C57BL/6 mice with an NCSTN mutation and examined their expression of hair cortex cytokeratin and trichohyalin by Western blot and immunohistochemistry, in addition to nicastrin, the product of NCSTN, and NICD compared with wild-type mice. The structure of hair follicles was analyzed by hematoxylin-eosin staining and transmission electron microscopy. RESULTS: In mice with an NCSTN mutation, HS-like skin lesions appeared after age 6 months, the pathological manifestations of which were consistent with the features of human HS. The structure of hair follicles was abnormal in mice with an NCSTN mutation versus wild-type mice, and hair cortex cytokeratin, trichohyalin, nicastrin, and NICD were downregulated in these mice. CONCLUSIONS: This NCSTN mutant mouse model could be an improved model to study early lesion development aspects of human HS pathogenesis and could perhaps be a better alternative for evaluating early-acting and preventive therapeutics for HS experimentally before clinical trials in HS patients. NCSTN mutations disrupt the development of hair follicles, leading to abnormal hair follicle structures, perhaps resulting in the onset of HS.

Correction: Blood compatibility of a new zwitterionic bare metal stent with hyperbranched polymer brushes.

Correction for 'Blood compatibility of a new zwitterionic bare metal stent with hyperbranched polymer brushes' by Xiaobo Wang et al., J. Mater. Chem. B, 2013, 1, 5036-5044, DOI: 10.1039/C3TB20855A.

Quality of Health Economic Evaluations in Mainland China: A Comparison of Peer-Reviewed Articles in Chinese and in English.

OBJECTIVE: Our objective was to assess the incidence and quality of reporting of published health economic evaluations in mainland China and compare the quality of peer-reviewed articles in Chinese and English. METHODS: A comprehensive search was conducted for economic evaluations pertaining to China published from 2006 to 2015 using the PubMed, CBM, CMCC, CNKI, VIP, and Wanfang databases. All studies in English that met the inclusion criteria were included. For studies in Chinese, 200 sampled studies were included according to the random seeds method, and the same number of the most-cited studies in Chinese as those in English were included according to the number of citations and journal grades. Researchers independently assessed the quality of the studies using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. RESULTS: After literature search and screening, a total of 310 studies were identified. The majority of these studies were cost-effectiveness studies (82.26%). Scores among different CHEERS items varied greatly. There was a gap between the average quality scores of the studies published in Chinese and those published in English (49.78 ± 9.31 vs. 82.48 ± 17.69) and between the average quality scores of the included most-cited studies in Chinese and English, which was slightly smaller (54.08 ± 10.27 vs. 82.48 ± 17.69). The methods, results, and discussion sections of studies published in Chinese were of low quality. CONCLUSION: The quality of reporting of health economic evaluations in mainland China has developed slowly. Most of the included studies were incomplete in the presentation of content, making the results less reliable. It is important to standardize and improve the quality of Chinese health economic research.

Tapered multicore fiber interferometer for refractive index sensing with graphene enhancement.

An in-line, highly sensitive refractive index (RI) sensor based on a tapered multicore fiber (MCF) structure sandwiched between two single-mode fibers is proposed and demonstrated. The fiber tapering technique was employed to fabricate in-line interferometers based on the multicore fiber. The waist diameter is one of the dominant factors of the intercore coupling. The tapered MCF interferometer is highly sensitive to the surrounding refractive index with a maximum sensitivity of 9194.6 nm/RIU in the RI range of 1.4264 to 1.4278 when the waist diameter is 9 µm. The enhancement of the evanescent field by graphene coating is proved to be able to improve the RI sensitivity further. A graphene-coated MCF interferometer with waist diameter of 9 µm offers the maximum sensitivity of 12617.6 nm/RIU in the RI range of 1.4144 to 1.4159. The experimental data have good agreement with the simulated results.

Unsupervised Person Re-Identification by Deep Asymmetric Metric Embedding.

Person re-identification (Re-ID) aims to match identities across non-overlapping camera views. Researchers have proposed many supervised Re-ID models which require quantities of cross-view pairwise labelled data. This limits their scalabilities to many applications where a large amount of data from multiple disjoint camera views is available but unlabelled. Although some unsupervised Re-ID models have been proposed to address the scalability problem, they often suffer from the view-specific bias problem which is caused by dramatic variances across different camera views, e.g., different illumination, viewpoints and occlusion. The dramatic variances induce specific feature distortions in different camera views, which can be very disturbing in finding cross-view discriminative information for Re-ID in the unsupervised scenarios, since no label information is available to help alleviate the bias. We propose to explicitly address this problem by learning an unsupervised asymmetric distance metric based on cross-view clustering. The asymmetric distance metric allows specific feature transformations for each camera view to tackle the specific feature distortions. We then design a novel unsupervised loss function to embed the asymmetric metric into a deep neural network, and therefore develop a novel unsupervised deep framework named the DEep Clustering-based Asymmetric MEtric Learning (DECAMEL). In such a way, DECAMEL jointly learns the feature representation and the unsupervised asymmetric metric. DECAMEL learns a compact cross-view cluster structure of Re-ID data, and thus help alleviate the view-specific bias and facilitate mining the potential cross-view discriminative information for unsupervised Re-ID. Extensive experiments on seven benchmark datasets whose sizes span several orders show the effectiveness of our framework.

Educational attainment and mortality: results from the Sixth Population Census in China.

BACKGROUND: Health and education are two closely related factors that affect human development. A limited number of studies have been conducted in China, most of which have been based on small sample sizes and with inconsistent results. The study investigates the association between mortality rate and educational level in China based on the sixth national population census in 2010. METHODS: This is large-scale population study based on the nationally administrated data sets of population census in 2010, 2000 and 1990. The 2010 census covered a total population of 1 332 810,869 in China. RESULTS: In general, standardized mortality rate decreased as educational level increased. The standardized mortality rate is higher among males than among females with equivalent educational levels. The standardized mortality rate in all the educational groups declined to varying degrees from 1990. 2000 to 2010. The standardised mortality rate declined with increasing educational levels from no education to university undergraduate groups in 1990, 2000 and 2010. The standardized mortality rate declined as the degree of education increased in cities, towns, and villages, but gradually increased at the same educational level from cities, towns, to villages in general. The difference in each region is considerable and the population quality of the developed area is generally high. The percentage of the uneducated population to the total population aged 15 years and over (%) was positively correlated with the standardized mortality rate. By contrast, the percentage of the population with a high school education to the total population aged 6 years and over (%) was negatively correlated with the standardized mortality rate. CONCLUSIONS: We found that educational level was negatively correlated with the mortality rate. The crude and standardized death rate is lower among individuals with higher educational level. Together with previous research findings, this study indicates that improving total population education attainment remains an important challenge that requires imperative action, while reducing educational inequities remains crucial for the government.

Why were doctors unable to accomplish their rural-aid mission in China? A qualitative study.

BACKGROUND: To alleviate the difficulties of rural residents in receiving timely healthcare, the Chinese government launched a medical rural-aid program that solicited urban medical professionals to go to rural hospitals for a 1-year tenure. However, many of urban doctors did not accomplish this task. In this study, we attempted to investigate the reasons behind the failure to fulfill this program and to explore a more feasible solution. METHODS: Eleven doctors and nurses participated in the focus group discussions. Twenty-five interviewees, including health administrative officials, doctors and managers from both urban tertiary hospitals and county-level hospitals, participated in semi-structured in-depth telephone interviews. The interview data were summarized and analyzed using the grounded theory. RESULTS: The failure of this program was attributed to multiple causes, such as problems with the recipient hospitals, the support hospitals and the participating doctors, and overall defects in the program strategy itself. One major reason is the competition between the recipient hospitals and the support hospitals, which distorted the original purpose of this rural-aid program. CONCLUSION: The rural-aid program strategy should be adjusted. The recipient hospitals should be township-level health centers rather than county-level hospitals. In addition, the relevant policies should be amended and improved accordingly. Copyright © 2015 John Wiley & Sons, Ltd.

How to overcome violence against Healthcare professionals, reduce medical disputes and ensure patient safety.

BACKGROUND & OBJECTIVE: In recent years there have been many cases of violence against healthcare professionals (HCPs) in China leading to the death of some doctors as well as nurses by patient's relatives. Our objective was to identify the causative factors for these violent acts and address these isssues which is vital to ensure patient safety. METHODS: A multidisciplinary research task force was formed to do a root cause analysis of the violent acts against the healthcare professionals. A flowchart was developed to identify the steps in the process and discover the potential links. RESULTS: There are complex reasons behind the violence against HCPs. However, the main reasons were found to be poor quality of medical services and increased awareness of patients' rights and their willingness to knock at the doors of courts to seek justice. The feasible counter measures includes stimulating hospital directors to improve patient safety, aligning incentives with quality of service provided in healthcare facilities, monitoring educational quality of HCPs, making necessary changes in medical education programmes besides setting up a reasonable academic promotion mechanism for health professionals based on merit and competence. CONCLUSION: Poor quality of medical services, increased awareness among patients about their rights has resulted in increase in medical disputes and at times violence against healthcare professionals. A number of effective measures can be undertaken by the government, hospitals, and medical schools ensuring patient safety. However, it is essential to sensitize the hospital directors to elevate their quality of medical services.

A randomized controlled trial of combination treatment with ketoconazole 2% cream and adapalene 0.1% gel in pityriasis versicolor.

BACKGROUND: Ketoconazole cream and adapalene gel are effective drugs against pityriasis versicolor. However, there are no reports on combination treatment with both compounds in pityriasis versicolor. OBJECTIVE: To evaluate the efficacy and safety of combination therapy with adapalene 0.1% gel and ketoconazole 2% cream against pityriasis versicolor. METHODS: Participants with pityriasis versicolor were randomly assigned to two groups: the combination group was treated with adapalene 0.1% gel and ketoconazole 2% cream once daily, and the monotherapy group received ketoconazole 2% cream twice daily. The treatment lasted 2 weeks in both groups. Outcomes were assessed at baseline and 1, 2 and 4 weeks after the initiation of treatment. RESULTS: We noted clinically significant differences in total improvement rates between groups Weeks 1 and 2. A statistically significant difference was obtained Week 4. The treatment was well tolerated by all participants. CONCLUSIONS: The combination of adapalene 0.1% gel and ketoconazole 2% cream is effective and safe in the treatment of pityriasis versicolor. This therapeutic regimen was rapid, providing a valuable option for patients with pityriasis versicolor.

Combination treatment of oral terbinafine with topical terbinafine and 10% urea ointment in hyperkeratotic type tinea pedis.

Hyperkeratotic-type tinea pedis is chronic and recalcitrant to topical antifungal agents. Some topical antifungal agents are effective; however, long duration of therapy is required, which often reduce the treatment compliance of patients. To seek for short period therapy of hyperkeratotic type tinea pedis, in this study, we observed the efficacy and safety of treatment of topical terbinafine and 10% urea ointment combined oral terbinafine. Participants with hyperkeratotic type tinea pedis were randomly assigned to two groups. Patients in group I were treated with oral terbinafine for 2 weeks and topical terbinafine and 10% urea ointment for 4 weeks, whereas in group II, only the above topical agents were applied for 12 weeks. Clinical improvement rates and fungal eradication rates were compared between the two groups at 24 weeks after the initiation of treatment. The group I had stopped the topical therapy 8 weeks earlier than group II. There were no significant differences in mycological eradication rates and clinical improvement rates between the two groups, besides, no major side effects were noted in both groups. The short combination therapy with oral terbinafine was effective and safe; it should be a valuable option for patients with hyperkeratotic type tinea pedis.

Blood compatibility of a new zwitterionic bare metal stent with hyperbranched polymer brushes.

Different approaches have been used in developing new coronary stents to protect against thrombosis and minimize restenosis. Here we describe a new zwitterionic bare metal stent (BMS) surface based on 2-((bromobutyryl)oxy)ethyl acrylate (BBEA) hyperbranched polymer. The new BMS produced was studied for its blood compatibility. The hemocompatibility studied including platelet adhesion tests, hemolysis assay, morphological changes of red blood cells (RBCs), coagulation time tests, plasma recalcification time (PRT) assay, complement activation, and platelet activation at the molecular level. Moreover the cytotoxicity of BMS before and after modification was also characterized by MTT assays. Most assays had remarkable differences in the presence of the new zwitterionic BMS, indicating the importance of the zwitterion.

Roles of adapalene in the treatment of pityriasis versicolor.

BACKGROUND: Ketoconazole is a typical treatment available for pityriasis versicolor; tretinoin cream is effective, too. Adapalene gel is a tretinoin derivative and has a lower incidence of irritation compared with other topical retinoid products. However, there are no reports on adapalene gel for the treatment of pityriasis versicolor. OBJECTIVE: To study the effect of adapalene gel comparing the treatment with adapalene gel and 2% ketoconazole cream in pityriasis versicolor. METHODS: Eighty patients suffering from pityriasis versicolor were randomly divided into two groups; one group were treated with 2% ketoconazole cream topically twice daily for 2 weeks, adapalene gel was used for the other group in a similar fashion. RESULTS: There were no significant differences in efficacy between the two groups. No major side effects were noted in any of the groups either. CONCLUSION: Adapalene was the favorable option in the treatment of pityriasis versicolor. The probable therapeutic mechanism of adapalene is also discussed.