Identification of RAD51–BRCA2 Inhibitors Using N-Acylhydrazone-Based Dynamic Combinatorial Chemistry

RAD51 is an ATP-dependent recombinase, recruited by BRCA2 to mediate DNA double-strand breaks repair through homologous recombination and represents an attractive cancer drug target. Herein, we applied for the first-time protein-templated dynamic combinatorial chemistry on RAD51 as a hit identification strategy. Upon design of N-acylhydrazone-based dynamic combinatorial libraries, RAD51 showed a clear templating effect, amplifying 19 N-acylhydrazones. Screening against the RAD51–BRCA2 protein–protein interaction via ELISA assay afforded 10 inhibitors in the micromolar range. Further ¹⁹F NMR experiments revealed that 7 could bind RAD51 and be displaced by BRC4, suggesting an interaction in the same binding pocket of BRCA2. These results proved not only that ptDCC could be successfully applied on full-length oligomeric RAD51, but also that it could address the need of alternative strategies toward the identification of small-molecule PPI inhibitors.     

Mast cells and tumour angiogenesis: new insight from experimental carcinogenesis

Histopathologic examination and clinical observations of solid and haematological malignancies indicates mast cells as key host cells in the tumour infiltrate, with important consequence on tumour-associated angiogenesis and tumour growth. Data suggest indeed that tumour-infiltrating mast cells may exert a prominent function in the angiogenic "switch", which is essential for the progression of early tumours. The experimental approach has substantially increased our understanding of the role of tumour-infiltrating mast cells in the process of angiogenesis that accompanies tumour development. This review will focus on the crucial contribution of mast cells in promoting tumour neovascularization as it emerges from the most recent observations of experimental carcinogenesis in in vivo and in vitro models.     

Influence of fluoride concentration and ethanol pre-treatment on the reduction of the acid susceptibility of enamel

Objective

To determine the association between KOH-soluble and structurally bound fluoride uptake and the erosion resistance of enamel, respectively. Additionally, the effect of enamel pre-treatment with ethanol before fluoridation was assessed.

Methods

Sixty bovine incisors (4 specimens/tooth) were randomly allocated to six groups (A-F). Samples 1 and 2 remained untreated, serving as control at baseline. Pre-treatment of the samples was performed for 5 min with 99% ethanol (groups A, B and C) or physiologic saline (groups D, E and F). Samples 3 and 4 were treated either with 0.5% (groups A and D), 1.0% (groups B and E) or 1.5% (groups C and F) fluoride solution. In samples 1 and 3, uptake of KOH-soluble and structurally bound fluoride was determined. Samples 2 and 4 were used for the determination of acid susceptibility by immersion in 1 ml HCl for 30 s. Calcium release into HCl was assessed by atomic absorption spectroscopy. Differences between the groups were calculated by unpaired t-tests (p < 0.05).

Results

Mode of pre-treatment showed no influence on fluoride acquisition. KOH-soluble and structurally fluoride uptake increased with increasing fluoride concentrations. Highest acid resistance was observed after treatment with 1% fluoride solution for both kinds of pre-treatment followed by 1.5% and 0.5% fluoride solution.

Conclusion

Dose-dependency was observed for enamel fluoride acquisition but not for acid resistance.     

Nonopioid perioperative analgesia in head and neck cancer surgery: A systematic review

ObjectiveManagement of postoperative pain after head and neck cancer surgery is a complex issue, requiring a careful balance of analgesic properties and side effects. The objective of this review is to discuss the efficacy and safety of multimodal analgesia (MMA) for these patients.MethodsPubmed, Cochrane, Embase, Scopus, and clinicaltrials.gov were systematically searched for all comparative studies of patients receiving MMA (nonsteroidal anti‐inflammatory drugs (NSAIDs), acetaminophen, anticonvulsants, local anesthetics, and corticosteroids) for head and neck cancer surgeries. The primary outcome was additional postoperative opioid usage, and secondary outcomes included subjective pain scores, complications, adverse effects, and 30‐day outcomes.ResultsA total of five studies representing 592 patients (MMA, n = 275; non‐MMA, n = 317) met inclusion criteria. The most commonly used agents were gabapentin, NSAIDs, and acetaminophen (n = 221), NSAIDs (n = 221), followed by corticosteroids (n = 35), dextromethorphan (n = 40), and local nerve block (n = 19). Four studies described a significant decrease in overall postoperative narcotic usage with two studies reporting a significant decrease in hospital time. Subjective pain scores widely varied with two studies reporting reduced pain at postoperative day 3. There were no differences in surgical outcomes, medical complications, adverse effects, or 30‐day mortality and readmission rates.ConclusionMMA is an increasingly popular strategy that may reduce dependence on opioids for the treatment of postoperative pain. A variety of regimens and protocols are available for providers to utilize in the appropriate head and neck cancer patient.     

Risk of Death in Comorbidity Subgroups of Hospitalized COVID-19 Patients Inferred by Routine Laboratory Markers of Systemic Inflammation on Admission: A Retrospective Study

Our study objective was to construct models using 20 routine laboratory parameters on admission to predict disease severity and mortality risk in a group of 254 hospitalized COVID-19 patients. Considering the influence of confounding factors in this single-center study, we also retrospectively assessed the correlations between the risk of death and the routine laboratory parameters within individual comorbidity subgroups. In multivariate regression models and by ROC curve analysis, a model of three routine laboratory parameters (AUC 0.85; 95% CI: 0.79–0.91) and a model of six laboratory factors (AUC 0.86; 95% CI: 0.81–0.91) were able to predict severity and mortality of COVID-19, respectively, compared with any other individual parameter. Hierarchical cluster analysis showed that inflammatory laboratory markers grouped together in three distinct clusters including positive correlations: WBC with NEU, NEU with neutrophil-to-lymphocyte ratio (NLR), NEU with systemic immune-inflammation index (SII), NLR with SII and platelet-to-lymphocyte ratio (PLR) with SII. When analyzing the routine laboratory parameters in the subgroups of comorbidities, the risk of death was associated with a common set of laboratory markers of systemic inflammation. Our results have shown that a panel of several routine laboratory parameters recorded on admission could be helpful for early evaluation of the risk of disease severity and mortality in COVID-19 patients. Inflammatory markers for mortality risk were similar in the subgroups of comorbidities, suggesting the limited effect of confounding factors in predicting COVID-19 mortality at admission.     

Predictors of respiratory failure after thoracic surgery: a retrospective cohort study with comparison between lobar and sub-lobar resection

ObjectiveOnly approximately 15% of patients with lung cancer are suitable for surgery and clinical postoperative outcomes vary. The aim of this study was to investigate variables associated with post-surgery respiratory failure in this patient cohort.MethodsPatients who underwent surgery for lung cancer were retrospectively studied for respiratory function. All patients had undergone lung resection by a mini-thoracotomy approach. The study population was divided into two subgroups for comparison: lobectomy group, who underwent lobar resection; and sub-lobar resection group.ResultsA total of 85 patients were included, with a prevalence of lung cancer stage IA and adenocarcinoma histotype. Lobectomy (versus sub-lobar resection), the presence of chronic obstructive pulmonary disease (COPD), and a COPD assessment test (CAT) score >10, were all associated with an increased risk of respiratory failure. The partial pressure of arterial oxygen decreased more in the lobectomy group than in the sub-lobar resection group following surgery, with a significant postoperative between-group difference in values. Postoperative CAT scores were also better in the sub-lobar resection group.ConclusionsPost-surgical variations in functional parameters were greater in the group treated by lobectomy. COPD, high CAT score and surgery type were associated with postoperative development of respiratory failure.     

UK guidelines for the management of bone sarcomas

This document is an update of the British Sarcoma Group guidelines published in 2010. The aim is to provide a reference standard for the clinical care of patients in the UK with bone sarcomas. Recent recommendations by the European Society of Medical Oncology, The National Comprehensive Cancer Network and The National Institute for Health and Care Excellence have been incorporated, and the literature since 2010 reviewed. The standards represent a consensus amongst British Sarcoma Group members in 2015. It is acknowledged that these guidelines will need further updates as care evolves. The key recommendations are that bone pain or a palpable mass should always lead to further investigation and that patients with clinico-radiological findings suggestive of a primary bone tumour at any site in the skeleton should be referred to a specialist centre and managed by a fully accredited bone sarcoma multidisciplinary team. Treatment recommendations are provided for the major tumour types and for localised, metastatic and recurrent disease. Follow up schedules are suggested.