Design,synthesis and biological evaluation of 6‐substituted quinolines derived from cabozantinib as c‐Met inhibitors

Based on the cabozantinib scaffold, novel c‐Met inhibitors were rationalized from the limited knowledge of structure‐activity relationships for the quinoline 6‐position. Emphasis was given to modifications capable of engaging in additional polar interactions with the c‐Met active site. In addition, ortho‐fluorinations of the terminal benzene ring were explored. Fifteen new molecules were synthesized and evaluated in a c‐Met enzymatic binding assay. A wide range of substituents were tolerated in the quinoline 6‐position, while the ortho‐fluorinations performed were shown to give considerable reductions in the c‐Met binding affinity. The antiproliferative effects of the compounds were evaluated in the NCI60 cancer cell line panel. Most notably, compounds 15b and 18b were able to inhibit cell proliferation more efficiently than cabozantinib in leukemia, CNS, and breast cancer cell lines. The in vitro data agreed well with the in silico docking results, where additional hydrogen bonding was identified in the enzymatic pocket for the para‐amino substituted 15b and 18b .     

Pro‐inflammatory effects of extracellular Hsp70 on NCI‐H292 human bronchial epithelial cell line

Extracellular Hsp70 (eHsp70) exerts its biological actions via Toll‐like receptors 2 and 4, and is increased in sera of chronic obstructive pulmonary disease (COPD) patients. The aim of this study was to explore the pro‐inflammatory effects and cytotoxicity of eHsp70 alone and in combination with bacterial components lipoteichoic acid (LTA) and lipopolysaccharide (LPS) on NCI‐H292 airway epithelial cells. NCI‐H292 cells were treated with recombinant human Hsp70 protein (rhHsp70), LPS, LTA and their combinations for 4, 12, 24 and 48 hours. IL‐6, IL‐8 and TNF‐α levels were measured by an ELISA method. Cell viability was determined by the MTS method, and caspase‐3/7, caspase‐8 and caspase‐9 assays. rhHsp70 induced secretion of IL‐6 and IL‐8 in a concentration‐ and time‐dependent manner, with the highest secretion at 24 hours. rhHsp70 combined with LTA had antagonistic and with LPS synergistic effect on IL‐6 secretion, while the interactions between rhHsp70 and LPS or LTA on IL‐8 were synergistic. TNF‐α was not detected in the applied conditions. rhHsp70, LPS or LTA did not affect cell viability, and rhHsp70 even suppressed caspase‐3/7 activities. We suggest that pro‐inflammatory effects of eHsp70, together with other damaging molecules and/or COPD risk factors, might contribute to the aggravation of chronic inflammation in human bronchial epithelium.     

Clinical Presentation and Outcome of Retinoblastoma among Children Treated at the National Cancer Institute (NCI) in Gezira,Sudan: A single institution experience

Background: Retinoblastoma (RB) is a rare and unique cancer that affects the eyes of very young children. There are few reports on RB in Sudan.

Materials and Methods: We performed a retrospective study of data from patients diagnosed with retinoblastoma between January 1999 and December 2009 at the National Cancer Institute in Gezira (NCI-Gezira).

Results: Of the 519 cases of childhood cancer treated at NCI-Gezira during the study period, 25 (4.8%) were retinoblastoma. Of these 25 patients with retinoblastoma, there were 13 boys and 19 cases were unilateral. The median age at diagnosis was 36 months (range, 8–60 months). The disease was localized in 9 patients, regional in 5 patients, and metastatic in 11 patients. The most frequent symptoms were enlarged eye (n?=?14) and leukocoria (n?=?8). Nine patients (36%) have been lost to follow-up; 9 were alive at last follow-up (7 in remission, 2 progressed); and 7 have died (5 from disease and 2 from unrelated causes). Twenty-two eyes were enucleated in 16 patients (6 bilateral and 10 unilateral). Pathologic examination of the enucleated eyes could only be completed in 11 patients. Diagnostic imaging in the form of computerized tomography scans or ultrasonography of the brain and orbit was done for 10 patients (40%).

Conclusions: Although these findings are not surprising, and similar to reports from other developing countries, we hope our work will provide a foundation for strategies to improve outcome for retinoblastoma in our center such as proper training, public awareness, team approach, and twinning.     

A case study in misidentification of cancer cell lines: MCF-7/AdrR cells (re-designated NCI/ADR-RES) are derived from OVCAR-8 human ovarian carcinoma cells

Multidrug-resistant MCF-7 breast adenocarcinoma cells (originally named MCF-7/AdrR cells and later re-designated NCI/ADR-RES) have served as an important and widely used research tool during the last two decades. However, the real identity of these cells has been in doubt since 1998 and has since been debated. The origin of NCI/ADR-RES cells has now been revealed by SNP and karyotypic analyses, carried out at the Sanger Institute and the NCI, respectively. The results of these analyses, recently posted on the Web, show that NCI/ADR-RES cells are derived from OVCAR-8 ovarian adenocarcinoma cells. The case of NCI/ADR-RES cells highlights a wide-spread problem of cell line cross-contamination and misidentification. Fortunately, this is a tractable problem that can be avoided by scrupulous genotyping of cell stocks and adoption of a few simple rules in cell culture practice.     

Employment in the community for people with and without autism: A comparative analysis

Employment in the community continues to be a major barrier for many people with disabilities in the United States. Analyzing the 2008–09 National Core Indicators Adult Consumer Survey, this study investigates community employment of working age (18–65) individuals with and without autism spectrum disorder (ASD) who receive services in the intellectual and developmental disability (IDD) service systems in 19 states. The findings show that 18.2% of adult service users of IDD services had a community job. People with ASD and people with ID had significantly lower odds of being employed in the community compared to those without ASD, after controlling for age, health, mobility, gender, level of ID, and challenging behavior. Results are presented in the context of current employment research and the implications of these findings are discussed.     

Improved prognosis for granulocytopenic patients with gram-negative bacteremia

The grave prognosis associated with gram-negative bacteremia occurring in granulocytopenic patients with cancer suggests that granulocyte transfusions are frequently indicated. We have evaluated 67 episodes of gram-negative bacteremia, studied in four consecutive antibiotic trials, in order to correlate prognostic determinants of recovery. These patients had a median absolute granulocyte count of 100/μl at the time of bacteremia. Empiric antibiotic regimens were begun at the first evidence of suspected infection. Granulocyte transfusions were employed only as clinically indicated by inadequate patient response to antibiotic therapy. Among the 29 patients who had an increase in their granulocyte count of ?100/μl over the subsequent 14 days, 27 (93 per cent) recovered whereas among 38 patients who had no appreciable increase in their granulocyte count, 21 (55 per cent) improved (p = 0.006). In this latter group of patients with no granulocyte recovery, the susceptibility of the pathogen(s) to the initial empiric antibiotic regimen was of major importance. None of four patients responded when the pathogen was resistant to both antibiotics initially utilized, six of 14 (44 per cent) patients responded when there was susceptibility to one antibiotic, and 15 of 20 (75 per cent) patients responded when there was susceptibility to both antibiotics (p < 0.025). We conclude that patients with gramnegative bacteremia and persistent granulocytopenia will often respond to antimicrobial therapy alone provided the initial choice of empiric antibiotics is appropriate and that their use is instituted promptly. Granulocyte transfusions need not be added unless clinical evaluation indicates inadequate response.     

An anticancer strategic dilemma: to kill or to contain. The choice of the pharmaceutical industry in 2009

For decades, the fight against cancer was based on oncolytic drugs aimed at eradicating malignant cells (killing strategy). The main flaws of this approach were its toxicity and the consequent emergence of resistance. New views on tumour biology consider tumours as complex organs involving dynamic interactions between their components. This implies the existence of dormant states and thus of a new therapeutic strategy aimed at inducing or extending tumour dormancy (containment strategy). The aim of this overview was to quantify the relative importance of these two strategies among the clinical trials (240 phase 1 and 186 phase 2 trials), launched or still in the pipeline and sponsored by the pharmaceutical industry in 2009. The most frequently targeted molecular entities are vascular endothelial growth factors (VEGFRs) (19 drugs), ErBBs (17 drugs), c‐met (14 drugs), tubulin (12 drugs), IGFRs (12 drugs). The main result of this overview is that the killing strategy is still largely prevailing since 326 drugs in 2009 (77% of the drugs tested in clinical trials in 2009) referred to this strategy, whereas 100 drugs could be attributed to the containment or mixed strategies in 2009. To obtain a dynamic view of the repartition of drugs between the killing strategy and the containment or mixed strategies, the present work should be renewed every 3–4 years.