Pitx2 participates in the late phase of the pathway controlling left-right asymmetry

BACKGROUND: We have studied the role of the different MHC (RT1) subregions in acute natural killer (NK) cell-mediated bone marrow allograft rejection in lethally irradiated, bone marrow cell (BMC) reconstituted rats. METHODS: We employed a series of MHC congenic and intra-MHC recombinant rat strains so that effects of mismatches in defined RT1 subregions could be studied systematically. BMC allograft survival was measured as 125IUdR uptake in the spleen between day 5 and day 7 after irradiation and BMC reconstitution. RESULTS: We found that in certain RT1 haplotype combinations, nonclassical RT1.C disparities by themselves could determine graft rejection (i.e., in the u/av1 recombinant haplotypes), whereas in another combination (between the av1 and c haplotypes) a mismatch for an isolated classical RT1.A region was decisive for engraftment. Thus, PVG.R1 BMC failed to proliferate in PVG rats, differing in the RT1.A region only, whereas in PVG.1U rats rejection could be determined by isolated differences in the RT1.C region (LEW.1WR1). Also, RT1 homozygous rats (RT1.U) rejected semi-allogeneic F1 hybrid BMC. The acute rejection of BMC was mediated by NK cells, as athymic nude rats, lacking alloreactive T cells but with normal alloreactive NK cells, showed the same patterns of rejection as did normal rats. Nude rats also rejected allogeneic lymphocytes, a previously documented NK-mediated phenomenon, with identical requirements of MHC disparity. CONCLUSIONS: This investigation shows that rat effector NK cells are radioresistant, independent of the thymus, and capable of recognizing and rejecting MHC mismatched transplanted BMC on the basis of mismatches in both classical and nonclassical class I regions in vivo. The studies underline the importance also of NK cells in determining BMC allograft survival.     

Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program

PURPOSE: The CD20 antigen is expressed on more than 90% of B-cell lymphomas. It is appealing for targeted therapy, because it does not shed or modulate. A chimeric monoclonal antibody more effectively mediates host effector functions and is itself less immunogenic than are murine antibodies. PATIENTS AND METHODS: This was a multiinstitutional trial of the chimeric anti-CD20 antibody, IDEC-C2B8. Patients with relapsed low grade or follicular lymphoma received an outpatient treatment course of IDEC-C2B8 375 mg/m2 intravenously weekly for four doses. RESULTS: From 31 centers, 166 patients were entered. Of this intent-to-treat group, 48% responded. With a median follow-up duration of 11.8 months, the projected median time to progression for responders is 13.0 months. Serum antibody levels were sustained longer after the fourth infusion than after the first, and were higher in responders and in patients with lower tumor burden. The majority of adverse events occurred during the first infusion and were grade 1 or 2; fever and chills were the most common events. Only 12% of patients had grade 3 and 3% grade 4 toxicities. A human antichimeric antibody was detected in only one patient. CONCLUSION: The response rate of 48% with IDEC-C2B8 is comparable to results with single-agent cytotoxic chemotherapy. Toxicity was mild. Attention needs to be paid to the rate of antibody infusion, with titration according to toxicity. Further investigation of this agent is warranted, including its use in conjunction with standard chemotherapy.     

Assessment of the biodistribution and metabolism of 5-fluorouracil as monitored by 18F PET and 19F MRI: a comparative animal study

The effective clinical use of the anticancer drug 5-fluorouracil (5-FU) requires the non-invasive assessment of its transport and metabolism, particularly in the tumor and the liver, where the drug is catabolized to alpha-fluoro-beta-alanine (FBAL). In this study, the potentials and limitations of dynamic 18F PET and metabolic 19F MRI examinations for noninvasive 5-FU monitoring were investigated in ACI and Buffalo rats with transplanted MH3924A and TC5123 Morris hepatomas, respectively. Selective 5-[19F]FU and [19F]FBAL MR images were acquired 5 and 70 min after 5-FU injection using a CHESS MRI sequence. After administration of 5-[18F]FU, the kinetics of the regional 5-[18F]FU uptake were measured by dynamic PET scanning over 120 min. To allow a comparison between PET and MRI data, standardized uptake values (SUV) were computed at the same points in time. The TC5123 hepatoma showed a significantly (p < 0.002) higher mean SUV at 5 and 70 min post-5-FU injection than the MH3924A cell lines, whereas there were no significant differences between the mean SUV measured in the liver of both animal populations. In contrast to the PET data, no significant differences in the mean 5-[19F]FU and [19F]FBAL MR signal values in the tumor of both models were observed. The MR images, however, yielded the additional information that 5-FU is converted to FBAL only in the liver and not in the hepatomas.     

Three-dimensional respiratory-gated MR angiography of coronary arteries: comparison with conventional coronary angiography

OBJECTIVE: MR coronary angiography is most often performed using two-dimensional techniques. Although three-dimensional (3D) acquisitions do have important advantages, they take too long for a single breath-hold and are thus susceptible to respiratory motion artifacts. The purpose of this study was to investigate the accuracy of a unique respiratory-gated 3D MR angiographic technique in identifying the proximal coronary arteries in patients suspected of having coronary artery disease. In addition, we investigated the capability of this technique to detect proximal stenoses. SUBJECTS AND METHODS: We performed a prospective blinded study in 20 patients who were referred for conventional coronary angiography. A cardiac-gated 3D gradient-echo sequence with fat suppression was used. Retrospective respiratory gating was performed using navigator echoes of the diaphragm position. Using multiplanar reformatting, two independent readers blindly analyzed the data sets for visualization of major coronary arteries, lengths of imaged segments, and detection of significant stenoses (> 50% occlusion of the luminal diameter by conventional angiography). RESULTS: Seventy-seven of 80 (96%) coronary arteries were positively identified. In one patient, an anomalous coronary anatomy was readily identified and confirmed by conventional angiography. The average lengths of the imaged segments of the right, left main, left anterior descending, and left circumflex coronary arteries were 58 +/- 13 mm, 9 +/- 5 mm, 59 +/- 16 mm, and 24 +/- 10 mm, respectively. Overall sensitivity for the detection of stenoses was low (38%), with a specificity of 95%. Interobserver agreement was 0.92, with a kappa value of 0.65. CONCLUSION: Respiratory-gated 3D MR angiography allows accurate identification of proximal coronary arteries and may be valuable for 3D imaging of coronary anomalies. Further technical improvements are required to enhance the value of the technique in detecting stenoses.     

Electronic structure calculations of vacancies and their influence on materials properties

We provide two examples to illustrate how electronic structure calculations contribute to our understanding of vacancies and their role in determining materials properties. Diffusion and electromigration in aluminium are known to depend strongly on vacancies. Electronic structure calculations show that the vacancy-impurity interaction oscillates with distance, and this leads to an explanation for both the increased electromigration resistance and the slow impurity diffusion for copper in aluminium. Calculations of vacancies in plutonium have been used in conjunction with positron annihilation lifetime measurements to identify the presence of helium-filled vacancies. Helium stabilization of vacancies can provide the precursor for subsequent vacancy-related changes in materials properties.     

The impact of treatment time and smoking on local control and complications in T1 glottic cancer

Low frequency impedance measurements of pure egg lecithin (phosphatidylcholine) bilayers have revealed the presence of four layers which can be attributed to the acyl chain, carbonyl, glycerol bridge and phosphatidylcholine regions of the lecithin molecule. Measurements on bilayers formed in the presence of unoxidised-cholesterol revealed that cholesterol molecules were located in the hydrocarbon region of the bilayer with its hydroxyl groups aligned with the carbonyl region of the lecithin molecules. Measurements of oxidised-cholesterol lecithin bilayers revealed that these molecules protruded less into the hydrocarbon region and their polar hydroxyl group aligned with the glycerol bridge region of the lecithin molecule.