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.     

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.     

Timing of elective surgery and risk assessment after SARS-CoV-2 infection: an update

The impact of vaccination and new SARS-CoV-2 variants on peri-operative outcomes is unclear. We aimed to update previously published consensus recommendations on timing of elective surgery after SARS-CoV-2 infection to assist policymakers, administrative staff, clinicians and patients. The guidance remains that patients should avoid elective surgery within 7 weeks of infection, unless the benefits of doing so exceed the risk of waiting. We recommend individualised multidisciplinary risk assessment for patients requiring elective surgery within 7 weeks of SARS-CoV-2 infection. This should include baseline mortality risk calculation and assessment of risk modifiers (patient factors; SARS-CoV-2 infection; surgical factors). Asymptomatic SARS-CoV-2 infection with previous variants increased peri-operative mortality risk three-fold throughout the 6 weeks after infection, and assumptions that asymptomatic or mildly symptomatic omicron SARS-CoV-2 infection does not add risk are currently unfounded. Patients with persistent symptoms and those with moderate-to-severe COVID-19 may require a longer delay than 7 weeks. Elective surgery should not take place within 10 days of diagnosis of SARS-CoV-2 infection, predominantly because the patient may be infectious, which is a risk to surgical pathways, staff and other patients. We now emphasise that timing of surgery should include the assessment of baseline and increased risk, optimising vaccination and functional status, and shared decision-making. While these recommendations focus on the omicron variant and current evidence, the principles may also be of relevance to future variants. As further data emerge, these recommendations may be revised.     

Circulating angiotensin converting enzyme 2 and COVID-19

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a widespread outbreak since December 2019. The SARS-CoV-2 infection-related illness has been dubbed the coronavirus disease 2019 (COVID-19) by the World Health Organization. Asymptomatic and subclinical infections, a severe hyper-inflammatory state, and mortality are all examples of clinical signs. After attaching to the angiotensin converting enzyme 2 (ACE2) receptor, the SARS-CoV-2 virus can enter cells through membrane fusion and endocytosis. In addition to enabling viruses to cling to target cells, the connection between the spike protein (S-protein) of SARS-CoV-2 and ACE2 may potentially impair the functionality of ACE2. Blood pressure is controlled by ACE2, which catalyzes the hydrolysis of the active vasoconstrictor octapeptide angiotensin (Ang) II to the heptapeptide Ang-(1-7) and free L-Phe. Additionally, Ang I can be broken down by ACE2 into Ang-(1-9) and metabolized into Ang-(1-7). Numerous studies have demonstrated that circulating ACE2 (cACE2) and Ang-(1-7) have the ability to restore myocardial damage in a variety of cardiovascular diseases and have anti-inflammatory, antioxidant, anti-apoptotic, and anti-cardiomyocyte fibrosis actions. There have been some suggestions for raising ACE2 expression in COVID-19 patients, which might be used as a target for the creation of novel treatment therapies. With regard to this, SARS-CoV-2 is neutralized by soluble recombinant human ACE2 (hrsACE2), which binds the viral S-protein and reduces damage to a variety of organs, including the heart, kidneys, and lungs, by lowering Ang II concentrations and enhancing conversion to Ang-(1-7). This review aims to investigate how the presence of SARS-CoV-2 and cACE2 are related. Additionally, there will be discussion of a number of potential therapeutic approaches to tip the ACE/ACE-2 balance in favor of the ACE-2/Ang-(1-7) axis.