Is there a differential strength of specific HLA mismatches in kidney transplants?

In this article we attempted to identify whether there is a specific mismatched antigen that might be detrimental to kidney transplant outcome. The frequency of function versus failure of transplant cases was tallied within subpopulations among a subset of the 2006 United Network for Organ Sharing transplant dataset. We examined 7998 cadaveric and 11,420 living donor kidney transplants that were mismatched for a single class I antigen. When tested by five different criteria, the results were relatively similar for the HLA class I, A- and B-locus mismatches. HLA A1 was identified as the single most dominant immunogenic mismatch. However, when the P values were multiplied by 68, the number of comparisons, A1 was only marginally significant. We concluded that at least for class I specificities, the 68 specificities were about equal immunogenicity in kidney transplantation.

miR-151a induces partial EMT by regulating E-cadherin in NSCLC cells.

miR-151a and its host gene, focal adhesion kinase, FAK, are located in a region of chromosome 8q that is frequently amplified in solid tumors, including lung cancer. Lung cancer is the leading cause of cancer deaths worldwide and metastasis remains the major challenge in battling lung cancer mortality. Here, we demonstrate that miR-151a is overexpressed in non-small cell lung cancer (NSCLC) patient specimens, as compared to healthy lung. In addition, miR-151a overexpression promotes proliferation, epithelial-to-mesenchymal transition (EMT) and induces tumor cell migration and invasion of NSCLC cells. Blocking miR-151a expression using anti-miR-151a approaches significantly reduced NCSLC cell proliferative and motility potential. Furthermore, we determined that miR-151a significantly regulates E-cadherin expression. Finally, functional rescue experiments determined that overexpression of E-cadherin in miR-151a NSCLC cell lines potently repressed miR-151a-induced partial EMT and cell migration of NSCLC cells. In conclusion, our findings suggest that miR-151a functions as an oncomiR in NSCLC by targeting E-cadherin mRNA and inducing proliferation, migration and partial EMT.

Automatic segmentation of histological structures in mammary gland tissue sections.

Real-time three-dimensional (3-D) reconstruction of epithelial structures in human mammary gland tissue blocks mapped with selected markers would be an extremely helpful tool for diagnosing breast cancer and planning treatment. Besides its clear clinical application, this tool could also shed a great deal of light on the molecular basis of the initiation and progression of breast cancer. We present a framework for real-time segmentation of epithelial structures in two-dimensional (2-D) images of sections of normal and neoplastic mammary gland tissue blocks. Complete 3-D rendering of the tissue can then be done by surface rendering of the structures detected in consecutive sections of the blocks. Paraffin-embedded or frozen tissue blocks are first sliced and sections are stained with hematoxylin and eosin. The sections are then imaged using conventional bright-field microscopy and their background corrected using a phantom image. We then use the fast-marching algorithm to roughly extract the contours of the different morphological structures in the images. The result is then refined with the level-set method, which converges to an accurate (subpixel) solution for the segmentation problem. Finally, our system stacks together the 2-D results obtained in order to reconstruct a 3-D representation of the entire tissue block under study. Our method is illustrated with results from the segmentation of human and mouse mammary gland tissue samples.

Clonal deletion using total lymphoid irradiation with no maintenance immunosuppression in renal allograft recipients.

A total of 69 individuals received a kidney from a living donor after a TLI-based clonal deletion protocol with no post-transplant maintenance immunosuppression planned. If needed, immunosuppression was started on a patient-specific basis, adding one drug at a time, a strategy we AWN". call "Drugs Added When Needed," or "DAWN. Following this strategy, at last follow-up 40 of the 69 patients (58%) had to be rescued by conventional immunosuppression, 23 (33%) had to be started on daily prednisone and six (9%) remained with no maintenance immunosuppression. The overall rate of de novo donor-specific antibody produced was 36% (in 25 of the 69 patients), and mean time to detection was about four months. The incidence of acute rejection episodes that displayed humoral components was 27% (19 cases), of which 14 were pure antibody-mediated rejection, five combined antibody- and T-cell-mediated rejection, and six were episodes (9%) of pure T-cell-mediated rejection. Finally, this study shows that although complete clonal deletion was not achieved, an important proportion of patients--42%, or 29 of the original 69--could be maintained with prednisone alone or even with no immunosuppression for a total mean follow-up of 13.3 months. Moreover, 16 patients with recent follow-up are surviving with no maintenance immunosuppression or just on prednisone. The mean serum creatinine at last follow-up for these 16 patients is 1.33 +/- 0.2 mg/dL with a mean follow-up of 19.3 months. Clonal deletion can be used to transplant patients without maintenance immunosuppression, adding drugs only as needed.

Donor-specific HLA antibody response in clonal deletion.

1. A total of 61 patients were treated with a clonal deletion protocol and transplanted without planned post-transplant immunosuppression. 2. Twenty-nine (48%) patients did not develop any donor-specific anti-HLA antibodies after the transplant, with a median follow-up of 158 days and a mean sCr of 2.1 mg/dL at the last follow-up. 3. Only 23% of the patients who received a DST of 60 mL produced DSA after the transplant, while 68% of the patients who received a bigger DST dose did. 4. Small doses of donor-specific transfusions (60 mL) elicited smaller specific responses, allowing efficient deletion of the reacting clones, creating conditions in which donor-specific anti-HLA antibodies were not produced. 5. A better deleting agent is needed to achieve higher rates of success using the clonal deletion protocol.

Elimination of post-transplant donor-specific HLA antibodies with bortezomib.

We show the ability of bortezomib to remove donor-specific HLA antibody from kidney allograft patients, the drug acting as a proteasome inhibitor, providing targeted therapy against antibody-producing plasma cells. Ten out of thirteen patients (77%) experienced primary DSA reversal, and in the remaining three patients the MFI of their primary DSA was dramatically reduced. Bortezomib is a viable therapy to treat donor-specific HLA antibody in allograft recipients. The potential for long-term benefits--and complications--are still unknown. Prospective trials are being conducted at the University of Cincinnati, Cincinnati, OH; at the Mayo Clinic, Rochester, MN; and at IKDRC-ITS, Ahmedabad, India.