PIRCHE-II is related to graft failure after kidney transplantation

Individual HLA mismatches may differentially impact graft survival after kidney transplantation. Therefore, there is a need for a reliable tool to define permissible HLA mismatches in kidney transplantation. We previously demonstrated that donor-derived Predicted Indirectly ReCognizable HLA Epitopes presented by recipient HLA class II (PIRCHE-II) play a role in de novo donor-specific HLA antibodies formation after kidney transplantation. In the present Dutch multi-center study, we evaluated the possible association between PIRCHE-II and kidney graft failure in 2,918 donor-recipient couples that were transplanted between 1995 and 2005. For these donors-recipients couples, PIRCHE-II numbers were related to graft survival in univariate and multivariable analyses. Adjusted for confounders, the natural logarithm of PIRCHE-II was associated with a higher risk for graft failure [hazard ratio (HR): 1.13, 95% CI: 1.04-1.23, p = 0.003]. When analyzing a subgroup of patients who had their first transplantation, the HR of graft failure for ln(PIRCHE-II) was higher compared with the overall cohort (HR: 1.22, 95% CI: 1.10-1.34, p < 0.001). PIRCHE-II demonstrated both early and late effects on graft failure in this subgroup. These data suggest that the PIRCHE-II may impact graft survival after kidney transplantation. Inclusion of PIRCHE-II in donor-selection criteria may eventually lead to an improved kidney graft survival

PIRCHE-II Is Related to Graft Failure after Kidney Transplantation

Individual HLA mismatches may differentially impact graft survival after kidney transplantation. Therefore, there is a need for a reliable tool to define permissible HLA mismatches in kidney transplantation. We previously demonstrated that donor-derived Predicted Indirectly ReCognizable HLA Epitopes presented by recipient HLA class II (PIRCHE-II) play a role in de novo donor-specific HLA antibodies formation after kidney transplantation. In the present Dutch multi-center study, we evaluated the possible association between PIRCHE-II and kidney graft failure in 2,918 donor–recipient couples that were transplanted between 1995 and 2005. For these donors–recipients couples, PIRCHE-II numbers were related to graft survival in univariate and multivariable analyses. Adjusted for confounders, the natural logarithm of PIRCHE-II was associated with a higher risk for graft failure [hazard ratio (HR): 1.13, 95% CI: 1.04–1.23, p = 0.003]. When analyzing a subgroup of patients who had their first transplantation, the HR of graft failure for ln(PIRCHE-II) was higher compared with the overall cohort (HR: 1.22, 95% CI: 1.10–1.34, p &lt; 0.001). PIRCHE-II demonstrated both early and late effects on graft failure in this subgroup. These data suggest that the PIRCHE-II may impact graft survival after kidney transplantation. Inclusion of PIRCHE-II in donor-selection criteria may eventually lead to an improved kidney graft survival

Antibodies against ARHGDIB are associated with long-term kidney graft loss

The clinical significance of non‐HLA antibodies on renal allograft survival is a matter of debate, due to differences in reported results and lack of large‐scale studies incorporating analysis of multiple non‐HLA antibodies simultaneously. We developed a multiplex non‐HLA antibody assay against 14 proteins highly expressed in the kidney. In this study, the presence of pretransplant non‐HLA antibodies was corre

Allocation to highly sensitized patients based on acceptable mismatches results in low rejection rates comparable to nonsensitized patients

Whereas regular allocation avoids unacceptable mismatches on the donor organ, allocation to highly sensitized patients within the Eurotransplant Acceptable Mismatch (AM) program is based on the patient\'s HLA phenotype plus acceptable antigens. These are HLA antigens to which the patient never made antibodies, as determined by extensive laboratory testing. AM patients have superior long-term graft survival compared with highly sensitized patients in regular allocation. Here, we questioned whether the AM program also results in lower rejection rates. From the PROCARE cohort, consisting of all Dutch kidney transplants in 1995-2005, we selected deceased donor single transplants with a minimum of 1 HLA mismatch and determined the cumulative 6-month rejection incidence for patients in AM or regular allocation. Additionally, we determined the effect of minimal matching criteria of 1 HLA-B plus 1 HLA-DR, or 2 HLA-DR antigens on rejection incidence. AM patients showed significantly lower rejection rates than highly immunized patients in regular allocation, comparable to nonsensitized patients, independent of other risk factors for rejection. In contrast to highly sensitized patients in regular allocation, minimal matching criteria did not affect rejection rates in AM patients. Allocation based on acceptable antigens leads to relatively low-risk transplants for highly sensitized patients with rejection rates similar to those of nonimmunized individuals

Allocation to highly sensitized patients based on acceptable mismatches results in low rejection rates comparable to nonsensitized patients

Whereas regular allocation avoids unacceptable mismatches on the donor organ, allocation to highly sensitized patients within the Eurotransplant Acceptable Mismatch (AM) program is based on the patient's HLA phenotype plus acceptable antigens. These are HLA antigens to which the patient never made antibodies, as determined by extensive laboratory testing. AM patients have superior long-term graft survival compared with highly sensitized patients in regular allocation. Here, we questioned whether the AM program also results in lower rejection rates. From the PROCARE cohort, consisting of all Dutch kidney transplants in 1995-2005, we selected deceased donor single transplants with a minimum of 1 HLA mismatch and determined the cumulative 6-month rejection incidence for patients in AM or regular allocation. Additionally, we determined the effect of minimal matching criteria of 1 HLA-B plus 1 HLA-DR, or 2 HLA-DR antigens on rejection incidence. AM patients showed significantly lower rejection rates than highly immunized patients in regular allocation, comparable to nonsensitized patients, independent of other risk factors for rejection. In contrast to highly sensitized patients in regular allocation, minimal matching criteria did not affect rejection rates in AM patients. Allocation based on acceptable antigens leads to relatively low-risk transplants for highly sensitized patients with rejection rates similar to those of nonimmunized individuals

Automatic generation of in-circuit tests for board assembly defects

The components and the solder joints that are made during assembly to hold components to their printed circuit board can suffer from defects and therefore need to be tested. Many research papers on board-Assembly testing focus on boundary scan test, processor-controlled test, or other powered digital testing techniques that mostly ignore the indispensable passive circuits and that can incur damage that could have been avoided by executing a non-powered test first. In-circuit testing is a non-powered test method that applies stimuli and measures responses using probe needles. However, often used self-learning solutions for designing these tests need a known-good-board, entailing significant disadvantages. In this paper, a software tool is described that automatically generates in-circuit tests based on the product design files, without requiring probe access on every net. Furthermore, the tool indicates where on the board fault coverage is not maximal, and hence where extra probe access will improve the test quality

Automatic generation of in-circuit tests for board assembly defects

\u3cp\u3eThe components and the solder joints that are made during assembly to hold components to their printed circuit board can suffer from defects and therefore need to be tested. Many research papers on board-assembly testing focus on boundary scan test, processor-controlled test, or other powered digital testing techniques that mostly ignore the indispensable passive circuits and that can incur damage that could have been avoided by executing a non-powered test first. In-circuit testing is a non-powered test method that applies' stimuli and measures responses using probe needles. However, often used self-learning solutions for designing these tests need a known-good-board, entailing significant disadvantages. In this paper, a software tool is described that automatically generates in-circuit tests based on the product design files, without requiring probe access on every net. Furthermore, the tool indicates where on the board fault coverage is not maximal, and hence where extra probe access will improve the test quality.\u3c/p\u3

Automatic generation of in-circuit tests for board assembly defects

\u3cp\u3eThe components and the solder joints that are made during assembly to hold components to their printed circuit board can suffer from defects and therefore need to be tested. Many research papers on board-Assembly testing focus on boundary scan test, processor-controlled test, or other powered digital testing techniques that mostly ignore the indispensable passive circuits and that can incur damage that could have been avoided by executing a non-powered test first. In-circuit testing is a non-powered test method that applies stimuli and measures responses using probe needles. However, often used self-learning solutions for designing these tests need a known-good-board, entailing significant disadvantages. In this paper, a software tool is described that automatically generates in-circuit tests based on the product design files, without requiring probe access on every net. Furthermore, the tool indicates where on the board fault coverage is not maximal, and hence where extra probe access will improve the test quality.\u3c/p\u3

The presence of protective cytotoxic T lymphocytes does not correlate with shorter lifespans of productively infected cells in HIV-1 infection

OBJECTIVES AND DESIGN: CD8+ cytotoxic T lymphocytes (CTL) are important in the control of HIV infection. Although CTL are thought to reduce the lifespan of productively infected cells, CD8+ T-cell depletion in simian immunodeficiency virus-infected rhesus-macaques showed no effect on the lifespan of productively infected cells. As CD8+ T-cell responses that successfully delay HIV disease progression occur only in a minority of HIV-infected individuals, we studied the hypothesis that the ability of CTL to reduce the lifespan of productively infected cells is limited to protective CTL responses only. METHODS: We correlated features of CD8+ T cells that are associated with control of HIV infection, namely restriction by protective human leukocyte antigen (HLA) alleles, and/or a broad, high or poly-functional Gag-specific CD8+ T-cell response, to the lifespan of productively infected cells in 36 HIV-infected individuals, by measuring their plasma viral load declines immediately after start of combined antiretroviral therapy. RESULTS: The average lifespan of productively HIV-infected cells varied greatly between individuals, from 1.01 to 3.68 days (median 1.82 days) but was not different between individuals with or without the protective HLA molecules B27 or B57 (P=0.76, median 1.94 and 1.79 days, respectively). Although the CD8+ T-cell response against HIV Gag was the dominant HIV-specific T-cell response, its magnitude (r=0.02, P = 0.5), breadth (r = 0.03, P = 0.4), and poly-functionality (r = 0.01, P = 0.8), did not correlate with the lifespan of productively HIV-infected cells. CONCLUSION: The features of CD8+ T-cell responses that have clearly been associated with control of HIV infection do not correlate with a reduced lifespan of productively infected cells in vivo. This suggests that protective CD8+ T cells exert their effect on target-cells before onset of productive infection, or via noncytolytic mechanisms

Ccne1 Overexpression Causes Chromosome Instability in Liver Cells and Liver Tumor Development in Mice

BACKGROUND & AIMS: The CCNE1 locus, which encodes cyclin E1, is amplified in many types of cancer cells and is activated in hepatocellular carcinomas (HCCs) from patients infected with hepatitis B virus or adeno-associated virus type 2, due to integration of the virus nearby. We investigated cell cycle and oncogenic effects of cyclin E1 overexpression in tissues of mice. METHODS: We generated mice with doxycycline-inducible expression of Ccne1 (Ccne1T mice) and activated overexpression of cyclin E1 from age 3 weeks onwards. At 14 months of age, livers were collected from mice that overexpress cyclin E1 and non-transgenic mice (controls) and analyzed for tumor burden and by histology. Mouse embryonic fibroblasts (MEFs) and hepatocytes from Ccne1T and control mice were analyzed to determine the extent to which cyclin E1 overexpression perturbs S-phase entry, DNA replication, and numbers and structures of chromosomes. Tissues from 4-month-old Ccne1T and control mice (at that age were free of tumors) were analyzed for chromosome alterations, to investigate the mechanisms by which cyclin E1 predisposes hepatocytes to transformation. RESULTS: Ccne1T mice developed more hepatocellular adenomas and HCCs than control mice. Tumors developed only in livers of Ccne1T mice, despite high levels of cyclin E1 in other tissues. Ccne1T MEFs had defects that promoted chromosome missegregation and aneuploidy, including incomplete replication of DNA, centrosome amplification, and formation of non-perpendicular mitotic spindles. Whereas Ccne1T mice accumulated near-diploid aneuploid cells in multiple tissues and organs, polyploidization was observed only in hepatocytes, with losses and gains of whole chromosomes, DNA damage, and oxidative stress. CONCLUSIONS: Livers, but not other tissues of mice with inducible overexpression of cyclin E1, develop tumors. More hepatocytes from the cyclin E1-overexpressing mice were polyploid than from control mice, and had losses or gains of whole chromosomes, DNA damage, and oxidative stress - all of these have been observed in human HCC cells. The increased risk of HCC in patients with hepatitis B virus or adeno-associated virus type 2 infection might involve activation of cyclin E1 and its effects on chromosomes and genomes of liver cells