TRAIL/bortezomib cotreatment is potentially hepatotoxic but induces cancer-specific apoptosis within a therapeutic window

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a novel promising anticancer biotherapeutic. However, TRAIL-resistant tumor cells require combinatorial regimens to sensitize tumor but not normal cells for TRAIL-induced apoptosis. Here, we investigated the mechanism of the synergistic antitumor effect of bortezomib in combination with TRAIL in hepatoma, colon, and pancreatic cancer cells in comparison to the toxicity in primary human hepatocytes (PHH). TRAIL cotreatment at high but clinically relevant concentrations of bortezomib caused toxicity in PHH which potentially limits the clinical applicability of bortezomib/TRAIL cotreatment. However, at low concentrations of bortezomib TRAIL-resistant hepatoma, colon and pancreatic cancer cell lines but not PHH were efficiently sensitized for TRAIL-induced apoptosis. RNA interference and TRAIL receptor blockage experiments revealed that in bortezomib-treated hepatoma cells TRAIL-R1/TRAIL-R2 up-regulation, enhanced TRAIL DISC formation and cFLIPL down-regulation in addition to accumulation of Bak cooperatively sensitized for TRAIL. Bim, although accumulated upon bortezomib treatment, did not play a causal role for TRAIL sensitization in Hep3b cells. Combined treatment with bortezomib and TRAIL massively reduced the clonogenic capacity of hepatoma cells in vitro. Surviving clones could be resensitized for repeated TRAIL treatment. CONCLUSION: Bortezomib/TRAIL cotreatment bears the risk of severe hepatotoxicity at high but clinically relevant concentrations of bortezomib. However, within a wide therapeutic window bortezomib sensitized different cancer cells but not PHH for TRAIL-induced apoptosis.     

Completeness of malaria notification in Tunisia assessed by capture recapture method

ObjectiveTo estimate the completeness of malaria notification to the public healthcare system (PHCS) and to describe retrospectively data of malaria cases in Tunisia.MethodsWe conducted a retrospective epidemiological survey using a standardized questionnaire for all cases of malaria reported to PHCS and those diagnosed in parasitological laboratory or infectious disease service between January 2002 and December 2007. To estimate the total number of cases, we used a two sources capture-recapture analysis.ResultsAfter record-linkage and cross-validation 317 cases of malaria were identified, of whom 231 were notified, resulting in an observed under-notification of 17%. The estimated number of malaria cases using capture-recapture analysis was 366.3 (95% CI: 335.8-396.8) for the period of study with a completeness of 63.1% which increased from 44.8% for 2002 to 78.7% for 2007. One hundred and sixty two patients (51.1%) had been born in sub-Saharan Africa, 113 (35.6%) in Tunisia, 35 (11.0%) in North Africa and 7 (2.2%) in Europe with predominance of men (87.1% of all cases). The median age was 25.0 years (21-30) for sub-Saharan Africans, 38.0 years (23.5-45.5) for North Africans, 38.5 years (30.75-38.5) for Tunisian and 39.0 (26-43) for European (P<0.01). The most predominant malaria species was Plasmodium falciparum with 216 cases (72.5%), and the most frequent area of acquisition was sub-Saharan Africa. In our study, information on compliance with malaria prophylaxis was only sporadically available and 34% of infected individuals had not used any chemoprophylaxis. Our study showed delayed identification of malaria that indicated a deficit in medical awareness and management of this infection.ConclusionsOur survey has marked variety in the type and availability of key data and shown an underreporting of malaria cases. Furthermore, it demonstrates that the two different sources of malaria registration are substantially incomplete. Of particular interest is the observation that a considerable number of patients could only be found in the records of PHCS, they were unknown to the laboratories, although malaria confirmation by thick or thin smear is obligatory in Tunisia.     

Paget disease: MR imaging findings

Magnetic resonance (MR) images of 13 patients with Paget disease were reviewed, and findings were correlated with those from computed tomographic (CT) scans, radiographs, and, in two patients, surgical biopsy. MR imaging findings correlated with CT and radiographic findings of cortical thickening, increased size of bone, and coarse thickened trabeculae. Focal or diffuse decreased signal intensity, representing dense bone, was seen on images obtained with short and long repetition times (TRs) and echo times (TEs); high-signal foci, representing fat collections, were seen on short TR/TE images; and high-signal foci, representing fibrovascular marrow in active Paget disease, were seen on long TR/TE images. Complications of Paget disease-including basilar invagination, spinal stenosis, and sarcoma--were well identified on MR images. Although MR imaging is not generally used in diagnosis of Paget disease, the disease will be encountered more frequently as more MR imaging examinations are performed. An awareness of the range of findings in Paget disease is useful in evaluating MR images of the musculoskeletal and other systems.