Targeting tumor multicellular aggregation through IGPR-1 inhibits colon cancer growth and improves chemotherapy.

Adhesion to extracellular matrix (ECM) is crucially important for survival of normal epithelial cells as detachment from ECM triggers specific apoptosis known as anoikis. As tumor cells lose the requirement for anchorage to ECM, they rely on cell-cell adhesion 'multicellular aggregation' for survival. Multicellular aggregation of tumor cells also significantly determines the sensitivity of tumor cells to the cytotoxic effects of chemotherapeutics. In this report, we demonstrate that expression of immunoglobulin containing and proline-rich receptor-1 (IGPR-1) is upregulated in human primary colon cancer. Our study demonstrates that IGPR-1 promotes tumor multicellular aggregation, and interfering with its adhesive function inhibits multicellular aggregation and, increases cell death. IGPR-1 supports colon carcinoma tumor xenograft growth in mouse, and inhibiting its activity by shRNA or blocking antibody inhibits tumor growth. More importantly, IGPR-1 regulates sensitivity of tumor cells to the chemotherapeutic agent, doxorubicin/adriamycin by a mechanism that involves doxorubicin-induced AKT activation and phosphorylation of IGPR-1 at Ser220. Our findings offer novel insight into IGPR-1's role in colorectal tumor growth, tumor chemosensitivity, and as a possible novel anti-cancer target.

Cost-benefit analysis and prediction of 24-hour proteinuria from the spot urine protein-creatinine ratio.

AIM: A prospective cross-sectional study was performed on 170 patients with various glomerular diseases to study the accuracy of predicting 24-hour proteinuria from the spot urine protein-creatinine ratio (Up/Uc). A cost-benefit analysis was performed for the New Zealand health economic system to obtain the best cut-off values for proteinuria. SUBJECTS, METHODS AND RESULTS: Two spot urine samples (Up/Uc1 and Up/Uc2) were collected on the same day as the collection of a 24-hour urine. A randomly chosen subsample of 50 patients provided a second set of urine samples. The correlation and precision of agreement between the two methods were examined. The predictive intervals were calculated for derived 24-hour proteinuria. The level of agreement was evaluated by the Bland-Altman method and concordance analysis. The limits of agreement were evaluated against the clinical limits of agreement. A cost-benefit analysis (CBA) was performed to obtain the optimum operating points on receiver operating characteristic (ROC) curves for the best decision threshold. Correlations of r = 0.97 and 0.99 were observed between Up/Uc1, Up/Uc2 and 24-hour proteinuria, respectively. The 95% predictive intervals were wide. A high concordance correlation coefficient was obtained. The most of the differences between the two methods fell within the clinical limits of agreement. The Up/Uc1 of 0.26 and 3.20 represent the best thresholds to detect normal and nephrotic proteinuria, respectively. CONCLUSIONS: Despite wide confidence intervals, a good correlation and precision of agreement were demonstrated between the two methods across the whole range of proteinuria, regardless of the level of renal function. The difference between the two methods was less than the biological variability in the protein excretion and its measurement, enabling the methods to be used interchangeably. The optimum thresholds for abnormal and nephrotic range proteinuria were obtained.

Acute renal failure in a renal transplant donor due to primary antiphospholipid syndrome.

Primary antiphospholipid antibody (APA) syndrome, a common prothrombotic disorder, has been known in dialysis patients and renal transplant recipients. We report a case of primary APA syndrome presenting as a posttransplant complication in a renal transplant donor. A renal donor presented with acute, painless anuria due to renal artery thrombosis 6 years following renal transplant surgery, subsequent thrombosis of jugular catheter and arteriovenous fistula occurred, despite anticoagulation treatment, due to primary APA syndrome. This incident represents the most catastrophic complication reported in a renal donor due to primary APA syndrome. The validity of a prothrombotic assay in an organ donor workup to detect predilection to hypercoagulable disorders and to prevent such complications is open to question. The actual significance of APA in the blood is unclear; hence, the presence of APA in a potential renal donor would pose an ethical and practical dilemma.

Predicting renal survival in primary focal glomerulosclerosis from the time of presentation.

UNLABELLED: Predicting renal survival in primary focal glomerulosclerosis from the time of presentation. BACKGROUND: To predict the risk of developing chronic renal failure in patients with primary focal glomerulosclerosis (FGS) using predictors available at the time of presentation, a retrospective analysis was performed on 111 patients who were diagnosed at Christchurch Hospital from 1965 to 1998. METHODS: The predictors of outcome included age, gender, systolic and diastolic blood pressure, serum albumin, plasma creatinine, presence of hematuria, and amount of proteinuria (all at the time of presentation). An injury score (combination of percentage of sclerosed glomeruli and proportion of tubulointerstitial fibrosis) was derived from a review of the initial kidney biopsy. Log-logistic accelerated failure time parametric models were used. RESULTS: The median renal survival was 16.4 years (Kaplan-Meier estimate). The best single variable model was that using the proportion of tubulointerstitial fibrosis (global chi-square 55.99, P < 0.0001). However, inclusion of plasma creatinine significantly improved the fit of the model (global chi-square 65.04, P < 0.0001). This joint model was superior to the single-variable model. Both of the models were validated using jackknifing. CONCLUSION: For a patient with primary FGS, these models can be used to predict the risk of developing chronic renal failure at any time and the median renal survival, given the proportion of tubulointerstitial fibrosis and plasma creatinine at the time of presentation.