Discovery and antiproliferative evaluation of new quinoxalines as potential DNA intercalators and topoisomerase II inhibitors

In continuation of our previous work on the design and synthesis of topoisomerase II (Topo II) inhibitors and DNA intercalators, a new series of quinoxaline derivatives were designed and synthesized. The synthesized compounds were evaluated for their cytotoxic activities against a panel of three cancer cell lines (Hep G‐2, Hep‐2, and Caco‐2). Compounds 18b, 19b, 23, 25b , and 26 showed strong potencies against all tested cell lines with IC₅₀ values ranging from 0.26 ± 0.1 to 2.91 ± 0.1 µM, comparable with those of doxorubicin (IC₅₀ values ranging from 0.65 ± 0.1 to 0.81 ± 0.1 µM). The most active compounds were further evaluated for their Topo II inhibitory activities and DNA intercalating affinities. Compounds 19b and 19c exhibited high activities against Topo II (IC₅₀ = 0.97 ± 0.1 and 1.10 ± 0.1 µM, respectively) and bound the DNA at concentrations of 43.51 ± 2.0 and 49.11 ± 1.8 µM, respectively, whereas compound 28b exhibited a significant affinity to bind the DNA with an IC₅₀ value of 37.06 ± 1.8 µM. Moreover, apoptosis and cell‐cycle tests of the most promising compound 19b were carried out. It was found that 19b can significantly induce apoptosis in Hep G‐2 cells. It has revealed cell‐cycle arrest at the G2/M phase. Moreover, compound 19b downregulated the Bcl‐2 levels, indicating its potential to enhance apoptosis. Furthermore, molecular docking studies were carried out against the DNA–Topo II complex to examine the binding patterns of the synthesized compounds.     

Iron overload in non-transfusion-dependent thalassemia: a clinical perspective

Iron overload due to increased intestinal iron absorption represents an important clinical problem in patients with non-transfusion-dependent thalassemia (NTDT), particularly as they advance in age. Current models for iron metabolism in patients with beta (β)-thalassemia intermedia (TI) suggest that suppression of serum hepcidin results in increased iron absorption and release of iron from the reticuloendothelial system, leading to depletion of macrophage iron, relatively low levels of serum ferritin, and liver iron loading. The clinical consequences of iron overload in patients with NTDT are multifactorial and include endocrinopathy, bone disease, thromboembolism, pulmonary hypertension, cerebrovascular and neuronal damage, liver fibrosis or cirrhosis, and increased risk of hepatocellular carcinoma. Although serum ferritin levels correlate with liver iron concentration (LIC), they underestimate iron load in these patients compared with transfusion-dependent patients with equivalent LIC. Therefore, direct measurement of LIC is recommended with chelation therapy as indicated.     

Protective effect of curcumin on N-nitrosodiethylamine and carbon tetrachloride-induced hepatocarcinogenesis in Sprague–Dawley rats

Curcumin, the yellow spice derived from the roots (rhizomes) of the plant Curcuma longa, has been reported to have a chemoprotective effect against several neoplasms. The protective effect of curcumin during N-nitrosodiethylamine- and carbon tetrachloride-induced hepatocarcinogenesis in Sprague–Dawley rats and its effect on the expression of IkappaB-alpha mRNA were evaluated. Sixty male rats were randomly assigned into four experimental groups. Group A animals received a single i.p. injection of N-nitrosodiethylamine (200 mg/kg b.w.). After 1 week, the animals received weekly s.c. injections of carbon tetrachloride (3 ml/kg b.w./week) for 6 weeks. Group B was given diet containing 0.2 % curcumin 2 weeks before the injection of N-nitrosodiethylamine and continued throughout the experimental period (20 weeks). Group C was given only a diet containing 0.2 % curcumin for the whole period of the experiment. Group D animals served as control. The level of IkappaB-alpha (IкB-α) mRNA was determined by semiquantitative PCR. Administration of diet containing 0.2 % curcumin, 2 weeks before the injection of N-nitrosodiethylamine and throughout the period of experiment, decreased percentage of preneoplastic foci in hepatic parenchyma and inhibited the development of hepatocellular carcinoma, cholangiofibrosis, and cystic cholangioma in rat liver. Moreover, curcumin administration decreased the number and size of the preneoplastic foci induced by N-nitrosodiethylamine and carbon tetrachloride in the liver. The densitometric analysis of the IкB-α mRNA bands revealed that curcumin administration blocked the decrease of IкB-α mRNA induced by N-nitrosodiethylamine and carbon tetrachloride. These results concluded that curcumin inhibited hepatocarcinogenesis induced by N-nitrosodiethylamine and carbon tetrachloride through blocking IкB-α degradation.     

Implementing the National Hip Fracture Database: An audit of care

Background

Hip fractures are common injuries in the elderly, with significant associated morbidity and mortality rates. The National Hip Fracture Database (NHFD) was implemented to audit care according to national standards thus improving its clinical and cost-effectiveness.

Patients and methods

We retrospectively examined the care pathway for all hip fractures after its introduction at our centre over 1 year, with an audit of care according to the BOA-BGS ‘Blue Book’ guidelines. Data between the first (period 1: initial audit) and second (period 2: re-audit) six months of the study period were compared.

Results

There were 372 patients (28% male, 72% female) in total with 190 in period 1 and 182 in period 2. For all patients, the median age was 85 years (range 33–101) and the median time to surgery was 24.5 h (1–519.3), with 251 (67.5%) within 36 h. Surgical delay was mainly due to lack of theatre space (37.6%) and medical reasons (54.7%). The median length of stay was 11 days (2–92) and the inpatient mortality rate was 6.2% (23). When comparing the two study periods, there were significantly more patients undergoing falls (p < 0.01) and bone protection (p < 0.01) assessments in period 2. Lack of theatre space was a significantly less common (p < 0.01), with a significantly shorter median time to surgery (p = 0.01) and length of stay (p < 0.01) in period 2. More patients were discharged to rehabilitation units and the mortality rate was non-significantly lower in period 2 (7.4% vs. 5%). The best practice tariff was met in 45.3% and 70.3% (p < 0.001) of patients in periods 1 and 2 respectively providing a total income of £95230.00 (GBP).

Conclusions

Implementing the NHFD has led to an improvement the quality of hip fracture care according to national guidelines. More patients were assessed by an orthogeriatrician, with a shorter time to surgery and length of stay following re-audit. There is potential for an improvement in mortality rates as well as significant financial income for hospitals.