The classic signs of acute cellular rejection during organ transplantation include the infiltration of mononuclear cells into the interstitium. This recruitment of leukocytes into the transplanted ...tissue is promoted by chemokines like RANTES. Since RANTES is a potent agonist for the CC chemokine receptor CCR1, we examined whether the CCR1 antagonist BX 471 was efficacious in a rabbit kidney transplant rejection model. BX 471 was able to compete with high affinity with the CCR1 ligands MIP-1α and RANTES for binding to HEK 293 cells expressing rabbit CCR1. BX 471 was a competitive antagonist of rabbit CCR1 in Ca
2+ flux studies. Two separate studies in which animals were subcutaneously implanted with slow release pellets of BX 471 demonstrated that animals implanted with BX 471 had increased survival compared with untreated controls or animals implanted with placebo. The mean survival time for the placebo group was 12.33±1.7 days. The animals in the BX 471 treated group had mean survival times of 16.9±2.1 and 16.0±1.7 days, respectively, for the two studies. Analysis of the combined data by Student
t-test gave a
P value of 0.03 that is significant at the 0.05 level. In addition, there was a marked reduction in the urea and creatinine levels in the BX 471 treated animals compared with the control and placebo groups in both studies. Finally, pathologic analysis of the kidneys in the rabbit renal transplantation model from animals in the different groups showed that BX 471 was similar to cyclosporin in its ability to prevent extensive infarction of transplanted kidneys. Based on the data from these studies, BX 471 shows clear efficacy at the single dose tested compared with animals treated with placebo.
A high-throughput RNA interference (RNAi) screen targeting 542 genes of the human kinome was used to discover regulators of RNAi. Here we report that the proto-oncogene
Akt-3/PKBγ
(Akt3) ...phosphorylates Argonaute 2 (Ago2) at Ser387 which down-regulates cleavage and up-regulates translational repression of endogenous microRNA (miRNA)-targeted mRNAs. We further demonstrate that Akt3 co-immunoprecipitates with Ago2 and that phosphorylation of Ago2 at Ser387 facilitates its interaction with GW182 and localization to cytoplasmic P-bodies, where miRNA-targeted mRNAs are thought to be stored and degraded. Therefore, Akt3-mediated phosphorylation of Ago2 is a molecular switch between target mRNA cleavage and translational repression activities of Ago2.
Morrissey and Spiegelman (1999, Biometrics55, 338–344) provided a comparative study of adjustment methods for exposure misclassification in case‐control studies equipped with an internal validation ...sample. In addition to the maximum likelihood (ML) approach, they considered two intuitive procedures based on proposals in the literature. Despite appealing ease of computation associated with the latter two methods, efficiency calculations suggested that ML was often to be recommended for the analyst with access to a numerical routine to facilitate it. Here, a reparameterization of the likelihood reveals that one of the intuitive approaches, the inverse matrix method, is in fact ML under differential misclassification. This correction is intended to alert readers to the existence of a simple closed‐form ML estimator for the odds ratio in this setting so that they may avoid assuming that a commercially inaccessible optimization routine must be sought to implement ML.
The effect of diabetes on survival after myocardial infarction (MI) was examined in a prospective population-based study of individuals hospitalized with MI in a bi-ethnic community of ...Mexican-Americans and non-Hispanic whites. Among Mexican-Americans, 54% (331 of 610) had diabetes compared with 33% (192 of 589) of non-Hispanic whites (P < 0.001). Among those with diabetes, the prevalence of a history of a cardiac event before the index admission was significantly higher (odds ratio = 1.4, 95% confidence interval CI 1.1-1.8) than among nondiabetic subjects. During the index hospitalization, diabetic subjects received cardiac catheterization less frequently than did nondiabetic subjects (45.1 vs. 51.5%, P = 0.03). Diabetic subjects had lower estimated ejection fractions, and the number of coronary arteries with significant obstruction (> 75%) was higher (P < 0.001). The peak creatine phosphokinase and creatine phosphokinase myocardial isoenzyme (CK-MB) levels were similar in diabetic and nondiabetic subjects. Despite a similar infarct size, diabetic subjects had a higher incidence of congestive heart failure (relative ratio = 2.2, 95% CI 1.7-2.8), more adverse indexes of short-term and long-term prognosis, and a longer average hospital stay (12.1 vs. 8.9 days, P < 0.01). After adjustment for age, sex, and ethnicity, the cumulative risk for total mortality, over 44 months of follow-up, was 37.4% among diabetic compared with 23.3% among nondiabetic subjects (P < 0.001). Diabetic subjects had a higher 28-day case-fatality rate post-MI as well as higher long-term mortality.
An increasing number of transplant centers are performing adult living donor liver transplantation (LDLT). We evaluated peoples' perspectives on possible outcomes of living donation, thresholds for ...donating, and views regarding the donation process. One hundred fifty people were surveyed; half were from a medical care group serving an indigent population and half were from a private clinic. Preferences about outcomes of adult living donation were ranked and quantified on a visual analogue scale. Thresholds for donation to a loved one were quantified. Sixty percent of the respondents suggested they would prefer to donate and die and have the transplant recipient live rather than forgo donation and have the potential transplant recipient die of liver failure. Participants' stated threshold for living donation was a median survival for themselves of only 79%. They would require that their loved one have a median survival of 55% with transplantation before they would agree to donate. Respondents from the medical care group reported higher survival thresholds for themselves and the transplant recipient, and race was the most statistically significant predictor of those thresholds. Sex was more predictive of threshold probabilities from the private clinic. Eighty-one percent of the respondents believed that the potential donor, not a physician, should have the final say regarding candidacy for living donation. In conclusion, the findings of this survey support the use of adult LDLT. Most respondents were willing to accept mortality rates that far exceed the estimated risk of donation and favored outcomes in which a loved one was saved. (
Liver Transpl 2001;7:335-340.)
Abstract 4574
CTCLs are generally incurable with conventional therapies. In particular, advanced mycosis fungoides (MF), Sézary syndrome (SS) and gamma delta varieties of CTCL have poor survival ...rates and are often refractory to traditional chemotherapy. Allogeneic SCT may provide a GVL effect and improve outcomes for these patients.
A retrospective analysis was performed at the University of Pennsylvania to identify all patients with CTCL who underwent allogeneic transplantation. 12 patients were identified who were transplanted between 2004 to 2010. A chart review was performed to obtain data about demographics, diagnosis, staging, treatment, transplantation and outcomes.
Median age at diagnosis was 49 yrs and M:F ratio was 5:7. Prior to transplantation, 4 had MF (stages IIB, IIIB, IVA1, IVB; 2 with nodal transformation), 4 had SS (one stage IVA1, three IVA2; 1 with nodal transformation), and 3 had gamma delta T-cell lymphoma (all T3b). Median time from diagnosis to transplantation was 3.3 yrs (range 0.5@02b97 yrs). Patients had received a median of 8 non-chemotherapy, and 2 chemotherapy-based treatment modalities before being transplanted. Only 3 patients were in complete remission (CR) at the time of conditioning and 9 had evidence of active disease. Reduced intensity conditioning (RIC) was used in 10 cases (Flu/Bu, Flu/Cy or Flu/Mel), and conventional myeloablative conditioning (Cy/TBI) was used in 2. GVHD prophylaxis consisted of calcineurin inhibitor and methotrexate in all patients.
The median follow up for all pts is 6.6 months (range 1.4 to 37.1 months) and 11.2 months for surviving patients. All patients engrafted with an ANC >500 a median 13 days after SCT. Median donor chimerism at day 100 after SCT in 10 evaluable pts was 97%. 7 of 12 patients developed acute GVHD, 4 of whom had grade 3 GVHD.
Two patients died within the first 100 days, from sepsis with active disease. At day 100, 7 of 10 evaluable patients were in CR, with an additional patient achieving CR shortly after; therefore transplant induced and maintained CR in 6 pts with active disease. 3 patients relapsed after achieving CR a median of 11.4 months (range 5.3–13.0 months) after SCT. 2 patients never achieved CR, and progressed within a month of transplantation. The median PFS for all pts was 31 wks, and 1 yr and 2 yr PFS were 48% and 32% without an obvious plateau. 2 year OS was 53% (Figure 1). Median OS is not reached.
6 patients have died from progression (5) and GVHD (1), 5 remain in CR and 1 is alive with active disease.
RIC SCT can provide long-term disease control in patients with advanced CTCL otherwise refractory to immunotherapy and chemotherapy. Given the limited TRM, consideration for earlier transplant should be given. Larger retrospective and ideally prospective studies will further define the role of allogeneic SCT in this disease.
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Rook:Therakos: Speakers Bureau; HY Biopharma: Consultancy. Kim:TenX: Research Funding; Biocryst: Research Funding; Genmab: Research Funding; Glouchester: Research Funding; Celgene: Research Funding; Eisai: Consultancy.
Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of non-Hodgkin lymphomas that are considered incurable. The role of allogeneic hematopoietic stem cell transplantation (HSCT) in the ...treatment of CTCL is not well defined but may provide potent graft-vs-lymphoma (GVL) activity independent of the conditioning therapy. We present outcomes of 12 extensively-pretreated patients with CTCL who underwent allogeneic HSCT using, most commonly, a reduced intensity conditioning (RIC) regimen. Median age at diagnosis of CTCL was 49 yrs, and median time to transplantation from diagnosis was 3.3 years. Transplant induced and maintained CR in 6 patients with active disease supporting the presence of a GVL effect. Transplant related mortality was low, and 42% of patients were alive and disease-free a median duration of 22 months after transplant. Two patients showed strong and direct evidence of a GVL effect with a direct response to withdrawal of immunosuppression or to donor leukocyte infusion (DLI). Our data show that HSCT can provide long-term disease control in patients with advanced CTCL otherwise refractory to immunotherapy and chemotherapy.
Sphingolipid synthesis is initiated by condensation of Ser with palmitoyl-CoA producing 3-ketodihydrosphinganine (3-KDS), which is reduced by a 3-KDS reductase to dihydrosphinganine. Ser ...palmitoyltransferase is essential for plant viability. Arabidopsis thaliana contains two genes (At3g06060/TSC104 and At5g19200/TSC1OB) encoding proteins with significant similarity to the yeast 3-KDS reductase, Tsc10p. Heterologous expression in yeast of either Arabidopsis gene restored 3-KDS reductase activity to the yeast tsc10∆ mutant, confirming both as bona fide 3-KDS reductase genes. Consistent with sphingolipids having essential functions in plants, double mutant progeny lacking both genes were not recovered from crosses of single tsc10A and tsc10B mutants. Although the 3-KDS reductase genes are functionally redundant and ubiquitously expressed in Arabidopsis, 3-KDS reductase activity was reduced to 10% of wild-type levels in the loss-of-function tsc10a mutant, leading to an altered sphingolipid profile. This perturbation of sphingolipid biosynthesis in the Arabidopsis tsc10a mutant leads an altered leaf ionome, including increases in Na, K, and Rb and decreases in Mg, Ca, Fe, and Mo. Reciprocal grafting revealed that these changes in the leaf ionome are driven by the root and are associated with increases in root suberin and alterations in Fe homeostasis.
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