Quercetin alters the DNA damage response in human hematopoietic stem and progenitor cells via TopoII‐ and PI3K‐dependent mechanisms synergizing in leukemogenic rearrangements

Quercetin (Que) is an abundant flavonoid in the human diet and high‐concentration food supplement with reported pro‐ and anti‐carcinogenic activities. Topoisomerase II (TopoII) inhibition and subsequent DNA damage induction by Que was implicated in the mixed lineage leukemia gene (MLL) rearrangements that can induce infant and adult leukemias. This notion raised concerns regarding possible genotoxicities of Que in hematopoietic stem and progenitor cells (HSPCs). However, molecular targets mediating Que effects on DNA repair relevant to MLL translocations have not been defined. In this study we describe novel and potentially genotoxic Que activities in suppressing non‐homologous end joining and homologous recombination pathways downstream of MLL cleavage. Using pharmacological dissection of DNA‐PK, ATM and PI3K signalling we defined PI3K inhibition by Que with a concomitant decrease in the abundance of key DNA repair genes to be responsible for DNA repair inhibition. Evidence for the downstream TopoII‐independent mutagenic potential of Que was obtained by documenting further increased frequencies of MLL rearrangements in human HSPCs concomitantly treated with Etoposide and Que versus single treatments. Importantly, by engaging a tissue engineered placental barrier, we have established the extent of Que transplacental transfer and hence provided the evidence for Que reaching fetal HSPCs. Thus, Que exhibits genotoxic effects in human HSPCs via different mechanisms when applied continuously and at high concentrations. In light of the demonstrated Que transfer to the fetal compartment our findings are key to understanding the mechanisms underlying infant leukemia and provide molecular markers for the development of safety values.     

Topoisomerase I and II activity in human breast,cervix, lung and colon cancer

The identification of human DNA topoisomerases as cellular targets for active anti-cancer drugs has stimulated further interest in topoisomerase function in tumour biology. Topoisom-erase I and II catalytic activity is detectable in many normal and malignant tissues. However, little is known about the expression of topoisomerases in most human solid tumours. The present study evaluated topoisomerase I and II activity in biopsy samples from 86 patients with breast, lung, cervix or colon cancers. Significant intra- and inter-tumour variation in topoisomerase expression was observed. Topoisomerase I activity was relatively high in cervix and colon tumours in comparison to lung and breast cancers. Topoisomerase II activity was high in cervix, colon and lung cancers relative to breast cancer. Topoisomerase I and II activity co-segregated in individual colon tumour samples, but no correlation was observed in cervix, lung or breast tumours. The large heterogeneity in both topoisomerase I and II activity within a tumour type suggests a mechanism for variable response to topoisomerase-directed therapy. The differences in activity between tumour groups suggest that the potential efficacy of inhibitors of topoisomerase I in colon and cervical tumours may be greater than in lung and breast tumours. Future in vivo evaluation is required to establish the clinical relevance of the observed heterogeneity in topoisomerase activity.     

Time-of-day effects on eyewitness reports in morning and evening types

Our performance varies throughout the day as a function of alignment with our circadian rhythms. The current experiment tested whether similar performance patterns can be observed in eyewitness memory performance. One-hundred-and-three morning-type and evening-type participants watched a stimulus event, provided a free report and answered cued questions in the morning and the evening hours, respectively. We expected eyewitness reports to be more detailed and more accurate at participants’ circadian peaks than at circadian troughs. Contrary to our predictions, time of testing did not significantly affect quantity and accuracy of eyewitness statements. Future studies might investigate whether matching chronotype with time of day would be beneficial when encoding or retrieval conditions are suboptimal or when eyewitnesses are vulnerable.     

Safety of mTOR inhibitor continuation in pediatric heart transplant recipients undergoing surgical procedures

mTOR inhibitors have been associated with SWC when used in the perioperative period. Limited literature is available to guide providers in managing chronic mTOR inhibitor use in the perioperative period, especially in the pediatric setting. The primary aim of this study was to describe the prevalence of SWC with mTOR inhibitor continuation during the perioperative period for major surgeries. Heart transplant recipients ≤25 years old at the time of primary heart transplant receiving sirolimus maintenance therapy during a surgical procedure and within the study period were included. Surgeries identified within the study period included otolaryngology procedures (46.2%), such as tonsillectomies with or without adenoidectomies, cardiac surgeries (30.8%) including a sternal revision, pulmonary vein repair, and pacemaker placement in two patients, orthopedic surgeries (15.4%) including a posterior spinal fusion and an Achilles tendon lengthening with ankle and subtalar joint release, and a neurosurgery (7.7%), which was a ventriculoperitoneal shunt revision. Thirteen surgical encounters were examined. One SWC was observed, an infected pacemaker requiring systemic antibiotics and removal of the device. The results of this study suggest that sirolimus may be continued in the perioperative period based on the low rate of SWC observed.     

Omega-9 Modifies Viscoelasticity and Augments Bone Strength and Architecture in a High-Fat Diet-Fed Murine Model

The influence of diet on the development of osteoporosis is significant and not fully understood. This study investigated the effect of diets of varying lipid profiles and ω-3, ω-6 and ω-9 composition on the structural and mechanical properties of bone. The hypothesis studied was that a diet high in saturated fat would induce osteoporosis and produce an overall increased detrimental bony response when compared with a diet high in unsaturated ω-6, or ω-9. Male C57BL/6J mice were fed either a control diet, 50:50 mix (saturated:unsaturated) high in ω-9 (HFD^50:50), a diet high in saturated fat (HSF) or a polyunsaturated fat diet high in ω-6 (PUFA) over an 8-week duration. Tibiae were retrieved and evaluated using DMA, 3-point-bending, histomorphometry, and microCT. Mice fed a HSF diet displayed key features characteristic of osteoporosis. The loss tangent was significantly increased in the HFD^50:50 diet group compared with control (p = 0.016) and PUFA-fed animals (p = 0.049). HFD^50:50-fed mice presented with an increased viscous component, longer tibiae, increased loss modulus (p = 0.009), and ultimate stress, smaller microcracks (p < 0.001), and increased trabecular width (p = 0.002) compared with control animals. A diet high in ω-9 resulted in an overall superior bone response and further analysis of its role in bone health is warranted.     

Analysing the Porosity Distribution in Stone Surfaces by Means of Unilateral NMR after Long-Term Outdoor Weathering

Porosity changes in the near-surface area of sandstones due to long-term weathering can produce deterioration. Therefore, porosity analyses on weathered sandstones are significant for detecting possible influences on the pore structure. Classical methods for determining the porosity and pore size distribution in sandstones can only investigate the entire sample volume. In contrast, in this publication, the porosity was analysed in 0.2 mm steps over a depth of 5 mm by means of single-sided NMR measurements on water-saturated sandstones under vacuum. Evaluations of Obernkirchener and Schleeriether Sandstones that were weathered outdoors in Germany for over 30 years are presented. The results showed that the water content in Vol.-% strongly correlated with the normalised NMR signal. The unweathered sandstones showed a uniform distribution of micro and capillary pores throughout the stone depth. As a result of 30 years of outdoor weathering, changes in the pore structure occurred at the sandstone surface due to weathering down to depths of about 0.6 mm. The porosity of the Schleeriether Sandstone samples, mainly the microporosity, clearly increased in this region. Due to the dominance of capillary pores in the Obernkirchener Sandstone, the changes were not as pronounced, but a shift towards smaller pores in the surface area was observable.     

Epidemiology,aetiology and knowledge,attitudes, and practices relating to burn injuries in Palestine: A community‐level research

The aim of this study was to identify the epidemiology, aetiology as well as the knowledge, attitudes, and practices relating to burn injuries in Palestine. A mixed‐method approach was used. A survey was distributed to a total of 1500 households selected by randomised approach. The survey was standardised based on World Health Organisation''s guidelines for conducting community surveys on injury. Additionally, there were 12 focus group discussions and 10 key informant interviews to collect rich qualitative data. In the West Bank and Gaza, 1.5% of Palestinians had experienced serious burn injuries in the 12 months. The total sample of 1500 yields a margin of error (plus/minus) = 2.5% at a 95% level of confidence and a response distribution (P = 50%) with 3% non‐response rate. Of the 1500 households approached, 184 reported a total of 196 burn injuries, with 87.2% occurring inside the home: 69.4% were females and 39.3% were children. The main source of reported cause of burn was heat and flame (36%), electric current (31.6%), hot liquid (28.6%), and chemicals (2.7%). The most common first aid for burns was pouring water (74.7%). People in rural, refugee, and Bedouin settings had the highest incidence of burns. This study provides the burn prevalence rate, explanatory factors that contribute to the frequency of burns in Palestine. Making burn prevention a higher priority within the national policy is crucial.