Dual-target inhibitors of bromodomain-containing protein 4 (BRD4) in cancer therapy: Current situation and future directions

Bromodomain-containing protein 4 (BRD4) is emerging as a therapeutic target that acts synergistically with other targets of small-molecule drugs in cancer. Therefore, the discovery of potential new dual-target inhibitors of BRD4 may be a promising strategy for cancer therapy. In this review, we highlight a series of strategies to design therapeutic dual-target inhibitors of BRD4 that focus on the synergistic functions of this protein. Drug combinations that exploit synthetic lethality, protein–protein interactions, functional complementarity, and blocking of resistance mechanisms could ultimately overcome the barriers inherent to the development of BRD4 inhibitors as future cancer drugs.     

The effect of massage therapy on pain after surgery: A comprehensive meta-analysis

BackgroundFindings on the usefulness of massage therapy (MT) in postoperative pain management are often inconsistent among studies.ObjectivesThis study’s aim is to conduct a meta-analysis of randomized controlled trials (RCT) to clarify the effects of massage therapy in the treatment of postoperative pain.MethodsThree databases (PubMed, Embase, and Cochrane Central Register of Controlled Trials) were searched for RCTs published from database inception through January 26, 2021. The primary outcome was pain relief. The quality of RCTs was appraised with the Cochrane Collaboration risk of bias tool. The random-effect model was used to calculate the effect sizes and standardized mean difference (SMD) with 95 % confidential intervals (CIs) as a summary effect. The heterogeneity test was conducted through I². Subgroup and sensitivity analyses were used to explore the source of heterogeneity. Possible publication bias was assessed using visual inspection of funnel plot asymmetry.ResultsThe analysis included 33 RCTs and showed that MT is effective in reducing postoperative pain (SMD, −1.32; 95 % CI, −2.01 to −0.63; p = 0.0002; I² = 98.67 %). A similar significant effect was found for both short (immediate assessment) and long terms (assessment performed 4–6 weeks after the MT). Remarkably, we found neither the duration per session nor the dose had an impact on the effect of MT and there seemed to be no difference in the effects of different MT types. In addition, MT seemed to be more effective for adults. Furthermore, MT had better analgesic effects on cesarean section and heart surgery than orthopedic surgery.LimitationsPublication bias is possible due to the inclusion of studies in English only. Additionally, the included studies were extremely heterogeneous. Double-blind research on MT is difficult to implement, and none of the included studies is double-blind. There was some heterogeneity and publication bias in the included studies. In addition, there is no uniform evaluation standard for the operation level of massage practitioners, which may lead to research implementation bias.ConclusionsMT is effective in reducing postoperative pain in both short and long terms.     

俄罗斯学术期刊的发展现状与思考

【目的】 分析俄罗斯学术期刊的发展状况,归纳中俄学术期刊交流合作中存在的障碍,提出进一步推动两国学术期刊合作的措施和建议,为我国期刊界和相关管理部门提供借鉴。【方法】 采用文献调研法与网络调查法,从出版情况、传播体系、作者群体、相关法律、国际化进程等方面对俄罗斯学术期刊的发展状况进行调查,在此基础上分析中俄学术期刊交流合作存在的障碍。【结果】 中俄学术期刊交流存在着政策障碍、语言障碍、获取性障碍、写作障碍和投稿障碍。【结论】 两国相关部门有必要组织制定学术共同体统一评价体系,打造品牌化学术期刊交流平台。我国期刊应组建专业化编委团队,探索多元化交流方式。     

Ground reaction forces during stair ascending and descending in congenitally blind and sighted individuals

BackgroundStair ascending and descending are common in daily life activities which are challenging for blind individuals. Visual information plays an important role in controlling an individual's movements. However, the relationship between visual information and stair ascending and descending is poorly understood.ObjectiveThe aim of this study was to investigate how blindness alters the ground reaction force (GRF) components during ascending and descending the stairs.MethodsTen individuals with congenital blindness and 10 able-bodied sighted individuals were served as experimental (EG) and control groups (CG), respectively. The GRFs were recorded during stair ascending and descending tasks using a portable 40 × 40 cm Kistler force plate which was placed on a firm stair. CG repeated the ascending/descending tasks in both open and closed-eyes conditions. For within and between groups comparisons the repeated measure ANOVA and MANOVA tests were used, respectively. The significance level was set at p < 0.05 for all comparisons.ResultsIn ascending task, there was not any significant between group differences on GRF components. However, closing the eyes in CG resulted in a significant decrease in some GRF components in the stair descending (p < 0.05). The GRF components of the stair descending in CG with open and closed-eyes were significantly different from those in the blind group; however, the differences were less in closed-eyes.SignificanceThe GRF in the stair descent was similar in both blind and sighted individuals with closed-eyes condition, that it can increase the risk of falling in blind people. As a result, the provision of tools and equipment for the blind in descent conditions is essential.     

Asymptomatic or mildly symptomatic COVID-19 patients with craniomaxillofacial injuries have an increased risk of surgical site infection

The aim of this paper was to evaluate the association between ‘asymptomatic or mildly symptomatic’ severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (AS/MS-COVID) and surgical site infection (SSI) after repair of craniomaxillofacial injury (CMFI). Using a case-control study design with a match ratio of 1:4, we enrolled a cohort of AS/MS-COVID cases with immediately treated CMFI during a one-year period. The main predictor variable was SARS-CoV-2 infection (yes/no), and the outcome of interest was SSI (yes/no). The other variables were demographic, clinical, and operative. Appropriate statistics were computed, and p<0.05 was considered statistically significant. The study group comprised 257 cases (28.8% female; 13.2% aged ≥ 60 years; 10.5% with fractures; 39.7% with involvement of nasal/oral/orbital tissue [viral reservoir organs, VROs]; 81.3% with blunt trauma; 19.1% developed an SSI [vs 6.8% in the control group]) with a mean (SD) age of 39.8 (16.6) years (range 19–87). There was a significant relation between SARS-CoV-2 infection and SSI events (p<0.0001; odds ratio 3.22; 95% confidence interval 2.17 to 4.78). On subgroup analysis, SSIs significantly increased with age ≥ 60 years, presence and treatment of fracture, contact with VROs, and prolonged antibiotic use (PAU). However, multivariate logistic regression analysis confirmed a positive effect only from old age, contact with VROs, and PAU (relative risk = 1.56, 2.52, and 2.03, respectively; r = 0.49; p = 0.0001). There was a significant 2.8-fold increase in SSIs among AS/MS-COVID cases, especially in those aged ≥ 60 years, or those with injuries to VROs, or both, who therefore required PAU.     

High-flow via a tracheostomy tube and speaking valve during weaning from mechanical ventilation and tracheostomy

Background

Weaning from mechanical ventilation and tracheostomy after prolonged intensive care consume enormous resources with optimal management not currently well described. Restoration of respiratory flow via the upper airway is essential and early cuff-deflation using a one-way valve (OWV) is recommended. However, extended OWV use may cause dry airways and thickened secretions which challenge the weaning process. High-flow therapy via the tracheostomy tube (HFT-T) humidifies inspired air and may be connected via an in-line OWV (HFT-T-OWV) alleviating these problems. We aim to provide clinical and experimental data on the safety of HFT-T-OWV along with a practical guide to facilitate clinical use during weaning from mechanical ventilation and tracheostomy.

Methods

Data on adverse events of HFT-T-OWV were retrieved from a quality register for patients treated at an intensive care rehabilitation center between 2019 and 2022. Benchtop experiments were performed to measure maximum pressures and pressure support generated by HFT-T-OWV at 25–60 L/min flow using two different HFT-T adapters (interfaces). In simulated airway obstruction using a standard OWV (not in-line) maximum pressures were measured with oxygen delivered via the side port at 1–3 L/min.

Results

Of 128 tracheostomized patients who underwent weaning attempts, 124 were treated with HFT-T-OWV. The therapy was well tolerated, and no adverse events related to the practice were detected. The main reason for not using HFT-T-OWV was partial upper airway obstruction using a OWV. Benchtop experiments demonstrated HFT-T-OWV maximum pressures <4 cmH₂O and pressure support 0–0.6 cmH₂O. In contrast, 1–3 L/min supplemental oxygen via a standard OWV caused pressures between 84 and 148 cmH₂O during simulated airway obstruction.

Conclusions

Current study clinical data and benchtop experiments indicate that HFT-T-OWV was well tolerated and appeared safe. Pressure support was low, but humidification may enable extended use of a OWV without dry airway mucosa and thickened secretions. Results suggest the treatment could offer advantages to standard OWV use, with or without supplementary oxygen, as well as to HFT-T without a OWV, for weaning from mechanical ventilation and tracheostomy. However, for definitive treatment recommendations, randomized clinical trials are needed.