KRAS2 oncogene overexpression in myelodysplastic syndrome with translocation 5;12

The factors that initiate and maintain the abnormal hematopoietic clone in the myelo-dysplastic syndromes (MDS) remain largely unknown. We describe a patient with MDS associated with an abnormal karyotype, 46,XY,t(5;12)(q31;p12). According to the FAB cooperative group classification, the patient was classified as chronic myelomonocytic leukemia. Because of the particular chromosomal translocation, the structure-function relationship of three genes relevant to the translocation breakpoints, CSF2, FMS, and KRAS2, was studied in bone marrow and peripheral blood lymphocytes in this patient. No major structural alterations were observed at these three genetic loci. Although the levels of expression of the CSF2 and FMS genes remained unaltered, the KRAS2 oncogene was overexpressed approximately six-fold in bone marrow cells from the MDS patient compared with normal donors. We postulate that the RAS oncogene activation may be instrumental in the genesis of MDS.     

Pharmacokinetics and chemotherapeutic efficacy of adriamycin encapsulated in immunoliposomes against avian myeloblastosis virus infection

Immunoliposomes were prepared using rabbit anti-AMV gp80 IgG for the targeted chemotherapy of avian myeloblastosis virus infection. Adriamycin was encapsulated into immunoliposomes and used for in vivo studies. Comparative pharmacokinetics of free drug, drug encapsulated in free liposomes and of drug encapsulated in immunoliposomes in the virus-infected cells revealed that (i) the drug encapsulated in liposomes was cleared from the plasma slowly, and (ii) the drug encapsulated in immunoliposomes accumulated in the target tissue, the bone marrow, 5- and 8.5-fold more than the drug encapsulated in free liposomes and free drug, respectively. The drug encapsulated in immunoliposomes inactivated the virus and exhibited more chemotherapeutic efficacy as compared to controls when injected up to 24 h post-infection. However, when injected 48 h post-infection the drug encapsulated in immunoliposomes did not offer any protection against the virus infection. There is no detectable antibody response against immunoliposomes in the infected animals.     

Retrieving the Amplatz retrievable vena cava filter

The new Amplatz retrievable filter was placed 15 times into the inferior vena cava (IVC) of 7 dogs. Retrieval of the filter was attempted in 11 cases after 1 week and in 3 cases after 2 weeks. The retrieval was successful and without complication in all 14 cases. The 15th placement resulted in thrombotic occlusion of the IVC, and no retrieval was attempted.     

Initial experience with laparoscopic bypass for upper gastrointestinal malignancy: a new option for palliation of patients with advanced upper gastrointestinal tumors

BACKGROUND: The majority of patients with upper gastrointestinal (UGI) tract malignancy present at a stage where cure of disease is not possible. The aim of treatment in these patients is effective palliation. Various interventions have been described for the palliation of biliary and gastric outlet obstruction including open surgery, endoscopic and transparietal stent placement. Laparoscopic bypass appears to have the advantage of decreased postoperative pain and shorter hospital stay as well as offer effective palliation. The aim of this study was to assess the safety and efficacy of laparoscopic bypass in patients with incurable UGI tract malignancy. PATIENTS AND METHODS: Between August 2000 and April 2002 laparoscopic gastric and biliary bypass concurrently or alone was attempted in 19 consecutive patients with unresectable carcinoma of the head of the pancreas, adenocarcinoma of the stomach, cholangiocarcinoma of the distal common bile duct, or adenocarcinoma of the duodenum. The operative time, length of postoperative stay, complications, and the effectiveness of the procedure in terms of the ability to sustain oral nutrition and or the relief of obstructive jaundice were recorded and used as outcome measures. RESULTS: Laparoscopic bypass was successful in 18 out of 19 cases. The mean operative time for a single bypass was 164 minutes while the average postoperative hospital stay was 11 days. All patients were able to sustain oral nutrition during the course of their hospital stay and or had effective relief from their obstructive jaundice. Two patients died from procedure unrelated causes within 30 days of the operation. CONCLUSION: Laparoscopic bypass appears to be a safe and effective means of palliation for patients with unresectable UGI tract tumors and should replace open surgical palliation in this group of patients.     

Export of RNA silencing from C. elegans tissues does not require the RNA channel SID-1

Double-stranded RNA (dsRNA) triggers RNA interference (RNAi) to silence genes of matching sequence. In some animals this experimentally induced silencing is transported between cells, and studies in the nematode Caenorhabditis elegans have shown that the dsRNA channel SID-1 is required for the import of such transported silencing signals. Gene silencing can also be triggered by endogenously expressed RNAi triggers, but it is unknown whether such silencing is transported between cells. Here, we show that, in C. elegans, SID-1 is required for efficient silencing of multicopy transgenes, indicating that mobile silencing signals contribute to transgene silencing. Further, most tissues can transport silencing initiated by the tissue-specific transgenic expression of RNAi triggers to other tissues, consistent with expressed RNAi triggers generating mobile silencing signals. Whereas the import of silencing signals requires SID-1, we found that mobile silencing signals generated by transgene-expressed RNAi triggers are exported to other tissues through a SID-1-independent mechanism. Furthermore, when RNAi triggers are expressed in ingested Escherichia coli, silencing signals can be transported to internal tissues from the gut lumen across gut cells that lack SID-1. Thus, C. elegans can transport endogenous and exogenous RNA silencing signals between many different tissues via at least 2 SID-1 independent export pathways.     

Nearby inverted repeats fuse to generate acentric and dicentric palindromic chromosomes by a replication template exchange mechanism

Gene amplification plays important roles in the progression of cancer and contributes to acquired drug resistance during treatment. Amplification can initiate via dicentric palindromic chromosome production and subsequent breakage–fusion–bridge cycles. Here we show that, in fission yeast, acentric and dicentric palindromic chromosomes form by homologous recombination protein-dependent fusion of nearby inverted repeats, and that these fusions occur frequently when replication forks arrest within the inverted repeats. Genetic and molecular analyses suggest that these acentric and dicentric palindromic chromosomes arise not by previously described mechanisms, but by a replication template exchange mechanism that does not involve a DNA double-strand break. We thus propose an alternative mechanism for the generation of palindromic chromosomes dependent on replication fork arrest at closely spaced inverted repeats.     

Von Hippel-Lindau-coupled and transcription-coupled nucleotide excision repair-dependent degradation of RNA polymerase II in response to trabectedin

PURPOSE: Ecteinascidin 743 (Et743; trabectedin, Yondelis) has recently been approved in Europe for the treatment of soft tissue sarcomas and is undergoing clinical trials for other solid tumors. Et743 selectively targets cells proficient for TC-NER, which sets it apart from other DNA alkylating agents. In the present study, we examined the effects of Et743 on RNA Pol II. Experimental Design and RESULTS: We report that Et743 induces the rapid and massive degradation of transcribing Pol II in various cancer cell lines and normal fibroblasts. Pol II degradation was abrogated by the proteasome inhibitor MG132 and was dependent on TC-NER. Cockayne syndrome (CS) cells and xeroderma pigmentosum (XP) cells (XPD, XPA, XPG, and XPF) were defective in Pol II degradation, whereas XPC cells whose defect is limited to global genome NER in nontranscribing regions were proficient for Pol II degradation. Complementation of the CSB and XPD cells restored Pol II degradation. We also show that cells defective for the VHL complex were defective in Pol II degradation and that complementation of those cells restores Pol II degradation. Moreover, VHL deficiency rendered cells resistant to Et743-induced cell death, a similar effect to that of TC-NER deficiency. CONCLUSION: These results suggest that both TC-NER-induced and VHL-mediated Pol II degradation play a role in cell killing by Et743.     

Intensity-modulated radiation therapy for prostate cancer: late morbidity and results on biochemical control.

PURPOSE: To report on late morbidity and biochemical relapse-free survival (bRFS) after intensity-modulated radiation therapy (IMRT) for prostate cancer. METHODS: Between 1998 and 2005 133 patients were treated with IMRT for T(1-4) N0 M0 prostate cancer. The median follow-up time was 36 months. In a first cohort, patients received a median planning target volume (PTV) dose of 74 Gy with a hard constraint on maximum rectum dose of 72 Gy (74R72, n=51). Later, median PTV and maximum rectum dose were increased to 76 and 74 Gy, respectively (76R74; n=82). We defined low-risk (n=20), intermediate-risk (n=70) and high-risk (n=43) groups. Androgen deprivation was given to patients in the intermediate- and high-risk group. Late gastro-intestinal (GI) and genito-urinary (GU) morbidity and biochemical relapse, in accordance with the ASTRO consensus, were recorded. RESULTS: We observed grade 2 GI (17%) and GU (19%), grade 3 GI (1%) and GU (3%) late toxicities. Except for hematuria, the median duration of side-effects was 6 months. Biochemical relapse-free survival (bRFS) at 3 and 5 years was 88% and 83%, respectively, with a significantly better 3-year bRSF for the 76R74 than for the 74R72 group (p=0.01). Five-year bRFS for patients in the low-risk, intermediate-risk and high-risk group was 100%, 94% and 74%, respectively (p<0.01). CONCLUSION: IMRT for localized or locally advanced prostate cancer combines low morbidity with excellent biochemical control.