Novel brd4 inhibitors with a unique scaffold exhibit antitumor effects

Since bromodomain containing 4 (brd4) has been considered as a prominent cancer target, numerous attempts have been made to develop potent brd4 bromodomain inhibitors. The present study provided a novel chemical scaffold which inhibited brd4 activity. Mid-throughput screening against brd4 bromodomain was performed using alpha-screen and homogeneous time-resolved fluorescence assays. Furthermore, cell cytotoxicity and xenograft assays were performed to examine if the compound was effective both in vitro and in vivo. As a result, it was revealed that compounds having naphthalene-1,4-dione scaffold inhibited the binding of bromodomain to acetylated histone. The compounds with naphthalene-1,4-dione had cytotoxic effects against the Ty82 cell line, a NUT midline carcinoma cell line, whose proliferation is dependent on brd4 activity. A10, one of the compounds with naphthalene-1,4-dione scaffold, also exhibited tumor growth inhibition effects in the xenograft assay. In addition, the compounds exhibited cytotoxic effects against gastric cancer cell lines which were resistant to I-BET-762, a BET bromodomain inhibitor. In conclusion, the novel scaffold to suppress brd4 activity was effective against cancer cells both in vitro and in vivo.     

Personalized designs of adjuvant radiotherapy for pancreatic cancer based on molecular profiles

This study aims to identify postoperative recurrence patterns of pancreatic cancer with different molecular profiles, which provides evidence for personalized target volumes of adjuvant radiotherapy. Patients with pathologically confirmed resectable pancreatic ductal adenocarcinoma were included. Recurrences were treated with stereotactic body radiation therapy. Immunohistochemical staining of Ki‐67, P53, and programmed cell death‐ligand 1 (PD‐L1) was carried out. Both of the intensities of Ki‐67 and P53 were classified as 10% or less, 11%‐49%, and 50% or more. Eighty‐nine patients had PD‐L1 tested, stratified as TC0 and IC0, and TC1/2 or IC1/2. Distances with significant differences among different levels or beyond 10 mm were of interest. With the increasing intensity of Ki‐67, the distance from the superior and posterior border of 80% recurrences to the celiac axis (CA) ranged from 10.1 to 13.8 mm and 9.2 to 11.0 mm. The distance from the inferior and posterior border of 80% recurrences to the superior mesenteric artery (SMA) ranged from 9.4 to 9.9 mm and 9.4 to 11.0 mm. Similarly, with the increasing intensity of P53, the distance from the superior and posterior border of 80% recurrences to the CA ranged from 9.7 to 13.2 mm and 10.1 to 10.6 mm. The distance from the inferior and anterior border of 80% recurrences to the SMA ranged from 9.5 to 9.9 mm and 8.6 to 9.4 mm. Regarding the increasing level of PD‐L1, the distance from the superior border of 80% recurrences to the CA ranged from 10.9 to 13.5 mm. A biologically effective dose of more than 65 Gy to local recurrences was predictive of favorable outcomes in all levels of Ki‐67, P53, and PD‐L1. Nonuniform expansions of regions of interest based on different levels of molecular profiles to form target volumes could cover most recurrences, which might be feasible for adjuvant radiotherapy.     

Possible ways of reducing dental erosive potential of acidic beverages

Frequent consumption of acidic beverages is related to excessive tooth wear, namely dental erosion. Preventive measures may involve reduction or elimination of acidic drink consumption. However, the success of this approach is difficult to achieve as it is highly dependent on patient compliance. Therefore, a practical way of minimizing the erosive potential of popular acidic drinks may be their chemical modification. The aim of this article was to review the different methods of modification and their shortcomings. The available literature demonstrates that the erosive potential of most acidic beverages could be reduced. To date, the effectiveness of soluble calcium salts supplementation is the best established. However, modification can reduce the sensorial quality of the drink and shorten its shelf‐life. There is also a need to evaluate the lowest effective and safe dose of the additive.     

α-氰基丙烯酸酯类医用黏合剂的研究进展

α-氰基丙烯酸酯类化合物可作为快速黏合剂,广泛应用于医疗领域,用于止血、伤口黏合、骨骼黏接、医疗栓塞、无痛绝育等。α-氰基丙烯酸酯化合物的合成路线各有优缺点,应结合结构特点进行选择。通过结构修饰可期望改善性能,扩大应用。本文综述了α-氰基丙烯酸酯类化合物的合成方法,结构修饰以及在医疗领域的研究进展,并展望在军事医学方面的应用前景。     

The occupational profile and associated training needs of the nurse prescriber: an empirical study of family planning nurses

RATIONALE, AIMS AND OBJECTIVES: The issue of nurse prescribing is highly topical, with various United Kingdom Government directives recommending this extension to the nursing role. However, despite an imperative to provide 23 000 nurse prescribers by March 2001 and to expand this function to half the nursing workforce by 2004, there is as yet no agreement as to the occupational profile of the nurse prescriber, nor the level and content of any pre-requisite educational programme. This study was an attempt to address these unresolved aspects with family planning nurses. METHOD: A psychometrically valid and reliable training needs analysis instrument was distributed to 1142 family planning nurses, of which 388 were returned. This instrument required the respondents to assess 40 core clinical tasks according to three criteria: how critical each task was both to their current role as family planning nurses and to the role of the family planning nurse prescriber, and how well each was performed. Comparisons of the ratings provided an indicative profile of the role of the family planning nurse prescriber and a prioritized list of training needs to achieve this status. RESULTS: Generally, and unsurprisingly, the nurse prescribing role was defined primarily in terms of prescribing functions, although advanced professional issues, communication, teamwork and business/administration were also deemed to be salient. Research was not identified as being important. However, with regard to the top 15 training needs, seven research tasks were recorded, with the remainder including advanced clinical activities, applied pharmacology, administration and technical activities. CONCLUSION: This study offers a role definition of the nurse prescriber in family planning, and an indicative curriculum for cognate educational programmes.     

In vivo multicolor molecular MR imaging using diamagnetic chemical exchange saturation transfer liposomes

A variety of (super)paramagnetic contrast agents are available for enhanced MR visualization of specific tissues, cells, or molecules. To develop alternative contrast agents without the presence of metal ions, liposomes were developed containing simple bioorganic and biodegradable compounds that produce diamagnetic chemical exchange saturation transfer MR contrast. This diamagnetic chemical exchange saturation transfer contrast is frequency-dependent, allowing the unique generation of "multicolor" images. The contrast can be turned on and off at will, and standard images do not show the presence of these agents. As an example, glycogen, L-arginine, and poly-L-lysine were encapsulated inside liposomes and injected intradermally into mice to image the lymphatic uptake of these liposomes. Using a frequency-dependent acquisition scheme, it is demonstrated that multicolor MRI can differentiate between different contrast particles in vivo following their homing to draining lymph nodes. Being nonmetallic and bioorganic, these diamagnetic chemical exchange saturation transfer liposomes form an attractive novel platform for multicolor imaging in vivo.     

Effectiveness of a lifestyle modification programme in weight maintenance in obese subjects after cessation of treatment with Orlistat

OBJECTIVE: To examine the efficacy of a lifestyle modification programme in weight maintenance for obese subjects after cessation of treatment with Orlistat. METHODS: Fifty-five subjects with and without diabetes mellitus were randomized to a lifestyle modification programme or to usual care at the end of 6 months' treatment with Orlistat. The intervention programme was nutritionist led, consisting of components of dietary management, physical activity, peer group support and discussion using techniques of self-monitoring, stimulus control and cognitive restructuring. Anthropometric indices, body composition, basal metabolic rate, blood pressure, fasting glucose, glycosylated haemoglobin, lipid profile, 24-hour urinary albumin excretion, dietary intake, physical activity level, and quality of life were assessed before and after the intervention period. Results Subjects in the intervention group maintained their weight loss and favourable anthropometric, metabolic, dietary intake, physical activity and quality of life profiles, while most parameters deteriorated in the usual care group, being more marked in subjects with diabetes. The magnitude of weight gain was comparable to that lost during Orlistat treatment. CONCLUSION: A specially designed nutritionist-led lifestyle modification programme for obese subjects is effective in weight maintenance after treatment with Orlistat, in the absence of which the benefits of drug treatment were lost. The magnitude of the effect of lifestyle modification is comparable to that observed with Orlistat.