Mismatches Research Articles

Aspects of ‘English language education’ policies in Iran: ‘Our own beliefs’ or ‘out of who you are’?

ABSTRACTThe worldwide English language teaching enterprise is mostly known by its professional and practical features such as teaching methodology and proficiency tests which tend to overshadow the cultural politics of language education and broader policy-level issues. To probe aspects of such less-addressed concerns and with a consideration of the crucial role of policies in education, including English language education, in this paper we explore officially stated English teaching policies in Iran as well as implicitly embraced de facto policy orientations in this area and their possible (mis)matches. Four major national documents bearing policy messages for English language education are examined as sources of overt national policies in this regard. Moreover, to observe parts of the related covert policies, we employ data obtained from interviews with teachers of private language teaching institutes as representative settings of real-life English teaching in Iran. Based on the illustration of the two types of policies and specifically considering the sociocultural implications of embracing or avoiding elements of these policies, we raise some concerns regarding the overall direction of English language education in Iran that could apply to the wider non-English-speaking world as well.

Impact of HLA-A-B-DR Matching in Kidney Transplantation: Graft and Patient Survival During Five Years

Objectives: A successful outcome of renal transplantation depends on various components, with one primary factor being donor and recipient ABO and human leukocyte antigen (HLA) compatibility. The primary aim of our investigation was to determine the impact of HLA-A-B-DR matching on overall and five-year graft and patient survival and to evaluate and improve kidney transplant outcomes. Methods: A total of 70 adult, immunologically low-risk, first-transplant recipients were enrolled in our retrospective study. HLA-A-B-DR typing was performed by the polymerase chain reaction sequence specific primer (PCR-SSP) method. Results: HLA compatibility was carefully matched before transplantation resulting in 81.4% renal transplants with 0-3 HLA mismatches (MM). Overall graft and patient survivals were 52 (74.3%) and 60 (85.7%), respectively, in 70 cases. Five-year graft and patient survivals were 23 (67.6%) and 29 (85.3%), respectively, in 34 cases. A significantly higher rate of graft and patient overall survivals were revealed in the 0-1 MM group compared with those in the 2-3 MM and 4-6 MM groups (p = 0.030 and p = 0.015, respectively). Conclusion: A highly statistically significant correlation of HLA matching enhancing kidney graft and patient survival rates was determined in our analysis. Better HLA matching was associated with better graft and patient survival. Despite the current era of potent immunosuppressive therapy and improved patient management, the data continue support organ sharing based on HLA matching in kidney transplantation.

Identification of Optimal Donor-Recipient Combinations Among Human Immunodeficiency Virus (HIV)-Positive Kidney Transplant Recipients.

For some patient subgroups, human immunodeficiency virus (HIV) infection has been associated with worse outcomes after kidney transplantation (KT); potentially modifiable factors may be responsible. The study goal was to identify factors that predict a higher risk of graft loss among HIV-positive KT recipients compared with a similar transplant among HIV-negative recipients. In this study, 82 762 deceased donor KT recipients (HIV positive: 526; HIV negative: 82 236) reported to the Scientific Registry of Transplant Recipients (SRTR) (2001-2013) were studied by interaction term analysis. Compared to HIV-negative recipients, the hepatitis C virus (HCV) amplified risk 2.72-fold among HIV-positive KT recipients (adjusted hazard ratio [aHR]: 2.72, 95% confidence interval [CI]: 1.75-4.22, p < 0.001). Forty-three percent of the excess risk was attributable to the interaction between HIV and HCV (attributable proportion of risk due to the interaction [AP]: 0.43, 95% CI: 0.23-0.63, p = 0.02). Among HIV-positive recipients with more than three HLA mismatches (MMs), risk was amplified 1.80-fold compared to HIV-negative (aHR: 1.80, 95% CI: 1.31-2.47, p < 0.001); 42% of the excess risk was attributable to the interaction between HIV and more than three HLA MMs (AP: 0.42, 95% CI: 0.24-0.60, p = 0.01). High-HIV-risk (HIV-positive/HCV-positive HLAwith more than three MMs) recipients had a 3.86-fold increased risk compared to low-HIV-risk (HIV-positive/HCV-negative HLA with three or fewer MMs)) recipients (aHR: 3.86, 95% CI: 2.37-6.30, p < 0.001). Avoidance of more than three HLA MMs in HIV-positive KT recipients, particularly among coinfected patients, may mitigate the increased risk of graft loss associated with HIV infection.

Sensitization trends after renal allograft failure: the role of DQ eplet mismatches in becoming highly sensitized.

Sensitization following renal allograft failure (AF) is highly variable. Some patients remain non-sensitized (NS), while others become highly sensitized (HS). We studied 66 NS patients who experienced AF after initial kidney transplantation. Post-failure, two main groups of NS panel reactive antibody (PRA) class I and II <10% and HS patients (PRA class I or II ≥80%) were identified. The impact of acute rejection (AR), immunosuppression withdrawal (ISW) at AF, allograft nephrectomy, graft intolerance syndrome (GIS), and both standard serologic and eplet-based mismatches (MM) in inducing HS status after failure was examined. Late PRA testing post-failure revealed 18 patients remained NS and 34 patients became HS. African American recipients, ISW at AF, DQB1 eplet MM, and presence of GIS were associated with becoming HS. Presence of total zero eplet MM, zero DQA1/B1 eplet MM, continuation of immunosuppression after failure, and a hyporesponsive immune status characterized by recurrent infections were features of NS patients. DQ eplet MM represents a significant risk for becoming HS after AF. Studies comparing ISW vs. continuation in re-transplant candidates with high baseline DQ eplet MM burden should be performed. This may provide insights if sensitization post-AF can be lessened.

Impact of HLA of Winning Cord Blood Unit on Outcomes after Double Umbilical Cord Blood Transplantation in Adults with Acute Leukemia: A Retrospective Study on Behalf of Eurocord, the Cord Blood Committee Cellular Therapy and Immunobiology Working Party and the Acute Leukemia Working Party of the EBMT

Umbilical cord blood transplantation (UCBT) from unrelated donor is a valid alternative for patients (pts) with acute leukemia (AL) who lack an HLA matched donor. Double UCBT (dUCBT) has extended the use of UCBT to adults. In the majority of the cases, chimerism analysis shows that one unit emerges as the sole source of long term hematopoiesis in the recipient (rcp) following dUCBT. However, no clear factor has yet been identified to reliably predict which unit will emerge as the predominant one.With the aim of analyzing factors that may predict cord blood unit (CBU) predominance and the impact of the winning CBU characteristics on outcomes after dUCBT, we studied adults with AL who underwent dUCBT as first transplant between 2004 and 2013 at EBMT centres. We selected pts who achieved engraftment and who had available chimerism data assessed within day 130 after dUCBT, with one of the CBUs representing at least 50% of the rcp hematopoiesis (winCBU). According to these criteria, 347 pts were included: 323 had full donor (18 being dual chimera) and 24 had mixed chimerism (>5% of donor cells). At diagnosis, 35% had ALL and 65% AML. At dUCBT 45% were in first complete remission (CR), 44% in second CR and 11% had more advanced disease. Overall, 33% had high risk cytogenetic features. Median time from diagnosis to dUCBT was 12 months (range, 2-202), median age was 40 years (y) (18-76). Conditioning regimen (CT) was reduced intensity (RIC) in 52%. Cyclophosphamide+fludarabine+total body irradiation was the most frequent CT (63%). Anti-thymoglobulin (ATG) was administrated in 25% of the transplants. Median number of total nucleated cells (TNC) and CD34+ cells at cryopreservation were 5.1x107/Kg (range, 2.3-13.7) and 1.3x105/Kg (range, 0.4-10.7), respectively. Considering the unit with the highest number of HLA mismatches (MMs) with the rcp, 73% of the donors were matched at 4 or less loci (≤4/6). For winCBUs, median number of TNC and CD34 cells at cryopreservation were 2.5x107/Kg (range, 0.95-6) and 1x105/Kg (range, 0.06-10), respectively. Only 4% of the winCBUs were 6/6 HLA-matched to the rcp, while 37% were 5/6, 55% were 4/6 and 4% were 3/6 HLA-matched. Overall, 54% of the winCBUs were gender matched and 38% were ABO compatible with the rcp. WinCBUs median age was 3.4 years (range, 0.2-14). As for inter unit characteristics, 50% of the pts received gender matched units. Units were ABO compatible in 40% of the cases, while 30% had minor and 30% had major ABO incompatibility.In our study population, median follow-up for survivors was 35 months (range, 3-99). All pts engrafted with neutrophil >0.5x109/L in a median time of 25 days (range, 6-66) post DCBT. No secondary graft failure was reported. The cumulative incidence (CI) of acute GvHD grade II-IV at 100 days was 41% with a median time of onset of 29 days (range, 7-106). The 3y-CI of chronic GvHD was 41% (50% of the pts had extensive). The 3y-CI of relapse (RI) and transplant related mortality (TRM) were 27% and 24%, respectively. At 3y, leukemia free survival (LFS) was 49% and overall survival (OS) was 54%.In multivariate analysis (MVA) including unit characteristics (HLA and gender matching, type of HLA MMs, number of TNC and CD34 cells at cryopreservation, ABO compatibility and unit age) and inter unit features (gender match, ABO compatibility), no significant factor predicting the winCBU was identified.Analyzing the impact of winCBU on dUCBT outcomes, the HLA matching between CBU and the rcp was the only characteristic related to the winCBU significantly affecting results. The 3y-LFS for pts with 6/6 or 5/6 HLA-matched winCBUs was 56% as compared to 44% for those with 4/6 (p=0.03), while OS was 62% versus 49% (p=0.01), respectively. Acute GvHD was increased in pts receiving a 4/6 HLA-matched winCBU (46% versus 35% for those 6/6 or 5/6, p=0.04). In MVA, 4/6 HLA-matched winCBU was associated with decreased LFS (HR 1.5, p=0.03) and OS (HR 1.5, p=0.03), and with increased TRM (HR 1.9, p=0.03) and acute GvHD (HR 1.7, p=0.01). Notably, older winCBUs (>3.4y) were associated with higher acute GvHD (48% versus 35%; HR 1.6, p=0.02). Other factors associated with poor outcomes were advanced disease status and the use of ATG.Although we failed to identified any factor predicting CBU predominance, we were able to demonstrate that a 4/6 HLA matched winCBU is associated with poor outcomes. Therefore, selecting units with lower number of HLA MMs for dUCBT may improve final outcomes. DisclosuresRussell:Therakos: Other: shares. Mohty:Riemser: Honoraria, Research Funding. Nagler:Biokine LTD: Consultancy.

Why do some 100% CPRA renal transplant candidates get more offers with the new KAS than others?

Aim In the 5 months after implementation of the new kidney allocation system (KAS), import kidney offers to 100% cPRA renal transplant candidates (RTC) have increased due to prioritization with an additional 212 points. We noted that while some RTC were receiving multiple provisional offers, other patients were not receiving any. We hypothesized that the patients receiving fewer offers had more unacceptable antigens (UA) entered in UNet, had a less common blood type, or had UA against broad specificities. Methods Active RTC with 100% cPRA from a single center were examined for: total numbers of class I and class II UAs; high frequency broad UAs such as Bw4, Bw6, DR52, etc.; wait time on 12/4/14; expected post-transplant survival (EPTS) score; and ABO blood type. DQA and DPB UAs were also examined, although they can’t be entered in UNet. RTC were stratified by number of offers into 3 groups (0, 1–2, and ⩾ 4 offers), with differences analyzed using Students t-test. Three RTC transplanted within 1 month of KAS were omitted. Results Comparisons are shown in Table 1. The group with 0 offers had a significantly greater number of class I UAs compared to the other groups. For class II UAs, the 0 and 1–2 groups had a significantly greater number than the ⩾ 4 group (p = 0.002). Closer analysis of class II UAs showed that the ⩾ 4 group had a lower incidence of DR52 UA (17%) vs the other groups (50% and 63%). DR51 UA had an incidence of 50% in the 2 groups with the fewest offers, compared to 33% in the ⩾ 4 group. DR53, Bw4, Bw6, Cw, DQ, DPB, mean EPTS score, wait time, and ABO were not significantly different between groups. Conclusion Although this is a single center study with small numbers, these findings may be reproduced with national data. RTC with many UAs may have an extremely narrow window of acceptable mismatches (MM). Donors with 0 MM at one or more loci or with unusual HLA phenotypes may be their only source of offers. Additional strategies may be needed, including sufficient additional points to achieve allocation when there are 0MM at the HLA-A or -B loci. Download : Download full-size image

A QOS Based Load Balanced Switch

The simple architecture with high forwarding capacity bandwidth is load balancing switch is build with two stage switch fabric to eliminate the mis sequencing problems and kept packets of the same flow in the order of load balanced two stage switch. Before load balancing two stages has perform with the Full frame first algorithm and use centralized scheduler to eliminate those mis sequencing problemsand getting the 100% throughput result. There comes at some additional cost and needs costly online scheduling algorithms and need for a complex scheduler and quality being reduced. In this paper we introduce the two stage switch fabric with round robin scheduling algorithmis used to solve mis sequencing problems and two maximum weight matching algorithms Longest queue first(LQF) and Oldest cell first(OCF) to achieve 100% throughput results. Theoretical analysis and simulation results shows that using these algorithms, achieve all the possible outcome results in the switch. � The simple architecture with the load balancing scheme perform with interesting two different stage switch fabric to eliminate the mis sequencing problems and kept packets of the same flow to the destination path in the order of load balanced two stage switch fabric. The two stage load balancing switch is more scalable than the any other switch in the network architecture. Hardly load balanced switch got some problem with that, on sending and receiving the data in wired or wireless networks(8), the major problem with that is mis sequencing problems has arised to loss of data packets or mis matched data formats. Somehow in earlier they are tired to clear those problems with the algorithms named, Full frame first algorithm to get mis sequencing problems and they put the centralized schedular to achieve the 100% throughput results(4)(2) in their data packets.Oftenly they got the perfect data packets arrival in destination, but the problem with that methodology is the quality of data is reduced to lower. And manually they they need costly online scheduling algorithms to rectify the mis matching of data and need more complex schedular to achieve the 100% throughput result of outcome data. We introduce in this paper to rectify the mis sequencing problems(1) and avoid the costly online scheduling algorithms, we use Round robin scheduling algorithms(RRS) to rectify the mis matching of data packets in the tcp applications and two maximum weight matching algorithms namely, Longest queue first(LOQ) and Oldest cell first(OCF) to achieve 100% throughput result for all independent arrival packets.(11)These algorithms are used to eliminate the complex schedular and needs of online costly scheduling algorithm to schedule the data packets in the destination node. The another approach of this proposed is to get the high quality of data packets in destination node which is the data which is send by sender, the receiver also got the same quality of data(9) without defragmentation and reduction of quality. We observed that in the algorithms and methodolgy of using those above like, RRS, LOQ and OCF, not only to solve mis sequencing problems and also get quality of data packets service of the same aaplication(10). Yet we are consider more algorithm to get the quality of data packets. Our idea is to just keep packets

A New HLA Allocation Procedure of Kidneys From Deceased Donors in the Current Era of Immunosuppression

IntroductionIt has recently been proposed to replace the current Eurotransplant kidney allocation based primarily on mismatches (MM) at the 3 HLA loci by a simpler system based on full HLA-DR compatibility. The present study analyzes this system in the current era of immunosuppression. MethodsFrom 1999 to 2012, 723 renal grafts were performed on 586 patients who were treated with a calcineurin inhibitor, mycophenolate mofetil, and in most cases antilymphocyte globulins. Four groups of HLA MM were compared: (A) A+B 2-4/DR 1-2 MM (n = 397), (B) A+B 2-4 MM/DR 0 MM (n = 106), (C) A+B 0-1 MM/DR 1-2 MM (n = 138), and (D) A+B 0-1/DR 0 MM (n = 82). ResultsAcute rejection episodes were less frequent during the first post-transplantation year in group D than in the other groups (P = .018). Patient survival was lower in group A than in the other groups (P = .008). Immunologic graft survival was higher in group D than in the other groups in univariate (P = .015) and multivariate analyses (P = .033; 96.4% vs 90.1% at 10 years). ConclusionsIn the current era of immunosuppression, allocation of kidneys from deceased donors could be performed primarily according to full DR compatibility then to the best A+B matching, affording excellent graft outcome to most recipients.

Targeting microRNAs: Towards a new tailored therapy for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains a significant unmet medical need with very limited therapeutic options available. Although microRNA-21 (miR-21) has been shown to be upregulated in HCC, its contribution as an onco-miR to the maintenance of tumorigenic phenotype in liver cancer remains poorly understood. We have developed potent and specific single-stranded oligonucleotide inhibitors of miR-21 (anti-miR-21) and used them to interrogate dependency on miR-21 in a panel of 20 commercially available HCC cell lines in vitro. Upon lipid-mediated transfection, anti-miR-21, but not its mismatched (MM) control, caused significant de-repression of known direct targets of miR-21, inhibited survival of a large subset of HCC cell lines. Sensitive HCC cell lines showed dose- and time-dependent induction of caspase 3/7 activity upon treatment with anti-miR-21. In contrast, non-responder HCC cell lines failed to significantly upregulate caspase activity and maintained viability in the presence of anti-miR compound. To better understand the consequences of miR-21 suppression in HCC, we carried out global gene expression profiling of anti-miR-21 treated sensitive liver cancer cells. Striking enrichment in miR-21 targets was noted among upregulated transcripts. Key cellular processes affected by miR-21 inhibition, including deregulation of metabolic pathways, were identified by gene ontology analysis. In summary, our data suggest that inhibition of miR-21 merits further investigation in the treatment of hepatocellular carcinoma.

The functions and the developments of the dual form in Maltese

This paper investigates the functions associated with the dual form in Maltese. This is established by the positing of (morpho)syntactic tests which help identify what NUM value is realized by specific dual forms within different noun categories. These tests show that while specific dual forms still realize a DU value, other dual forms have developed as PL or SG exponents. It is specifically by analysing the synchronic behaviour of the body part class of dual form-taking nouns that reconstructions of how the function of the dual form has developed are proposed. Moreover, the dual form’s realization of a specific value is also highly dependant on the paradigmatic context it occurs in. Considering the distinct dual form–function (mis)matches present within distinct paradigmatic contexts challenges binary-based overdifferentiated vs. non-overdifferentiated labels and highlights a correlation between canonicity and markedness. For the first time, Maltese dual data will be compared with data from different Arabic vernaculars.

Favorable effects of low-dose anti-thymocyte globulin in a partially-mismatched HLA group in an unrelated allogeneic stem cell transplantation setting.

The outcomes of unrelated stem cell transplantation (SCT) have improved with the use of anti-thymocyte globulin (ATG) to prevent graft-versus-host disease (GVHD) and graft rejection. Therefore, based on the HLA matching status classifications of well-matched (WM), partially-matched (PM), and mismatched (MM), the current study evaluated the role of ATG use among these 3 HLA groups in an unrelated SCT setting. Data from a total of 92 patients who received allogeneic SCT from unrelated donors (65 peripheral blood and 27 bone marrow) were retrospectively analyzed. Among the 92 patients, 19 were classified as WM, 42 as PM, and 31 as MM. Fifty-seven patients (61.9%) received ATG as GVHD prophylaxis. The overall survival (OS) rate was higher for the WM group (83%) when compared to the PM group (54%) and MM group (34%, p=0.076). For the PM group, the OS was significantly improved with ATG (83.3% vs. 38.6%, p=0.018). However, there was no difference in OS with or without ATG for the MM group (32.4% vs. 41.7%, p=0.215). The use of ATG lowered the cumulative incidence of grade 3-4 acute GVHD (10% vs. 40.2%, p=0.068) and severe chronic GVHD (21.2% vs. 52.2%, p=0.037). Use of ATG effectively improved the survival rate for the PM group in an unrelated SCT setting. However, this report has a major limitation in confirming the role of ATG for unrelated transplantation because the number of patients in each group was too small to compare therapy with ATG and without ATG, and a heterogeneous population was included in the current study. A larger study comparing different doses of ATG for unrelated PBSCT in a homogenous population will be needed to confirm the role of ATG.

Prognostic Factors and Outcomes in Allogeneic Hematopoietic Stem Cell Transplant Vs. Non-Transplant Chronic Lymphocytic Leukemia (CLL) Patients: A Comparative Analysis with the Leukemia/BMT Program of British Columbia (BC) and the BC Provincial CLL Database

Background: Chronic Lymphocytic Leukemia (CLL) patients (pts) have significant (sig) heterogeneity; survival ranges from decades to <5 years (yrs). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is promising treatment (tx) for high-risk pts. Ideally, predictive (pred) tools would allow clinicians to recognize such pts early, permitting transplant performance to maximize benefit and minimize procedure associated risk. Factors with significant (sig) pred capacity are not, however, entirely clarified. Moreover, limited studies compare CLL pts who have/have not received HSCT in terms of differences (diff) in characteristics (char) at diagnosis (dx), population (pop) composition and outcomes. This study evaluates pred factors for outcomes post allo-HSCT, and compares dx char between (bn) tx CLL pts who did /did not receive HSCT by evaluating a large pop-based CLL cohort (n= 1044) from the BC Provincial CLL Database (BCPCD).Methods: 102 CLL pts (71M, 31F) had consecutive allo-HSCT (01-91 to 03-13, L/BMT Program of BC). Median (med) age (range) at dx:HSCT was 50 (26-65):57 (32-68) yrs; med interval dx to HSCT 5.8 yrs (0.5 to 29). Most pts (78, 76%) received non-ablative therapy; (n=61 [60%] reduced-intensity fludarabine /busulfan [flu/bu] based [RIC], n=17 [17%] non-myeloablative flu-cyclophosphamide based [NMA]); 24 pts had myeloablative (MA) conditioning (CON). Donor status was 50% unrelated (UD) (51UD:51RD); 73M, 28 F.Results: With median (med) follow up (FU) (range) post allo-HSCT of 2 yrs (0.5-18); post dx of 9 yrs (1-38), 67 (50%) pts survive. 70 (69%) achieved CR post-HSCT a med of 187 (28-1274) days (d). 27 had CLL PROG a med of 339 (25-4367) d; 18 of 27 (67%) survive a med of 3 (0.5-18) yrs post HSCT. Factors pred OS post HSCT (KM p=; UVA HR=) (p<0.05) were: pre-HSCT FISH deletion 17p (del 17p) (0.005; 2.9), Dohner rank (0.02), HSCT specific comorbidity index (CoI) >3 vs. 0-2 (0.04; 2.5), HLA mismatched (MM) donor (0.03;2.3), pre-HSCT tx with alemtuzumab (alem) (0.005;3.0), CON (MA vs NMA or RIC) (0.046; 3.0), acute (A) graft vs host disease (GVHD) grade (g) 3-4 vs 0-2. (<0.001; 4.5), dn chim <90% (0.001; 5.2), abn FISH not clear post-HSCT (0.009; 2.6), yr of HSCT (pre- vs post-2010) (0.03; 3.13) and lack of CR post HSCT (<0.001; 10.5).The following sig pred for (OR; p=): >90% dn chim: no B symptoms at dx (2.5; 0.004), CON (RIC vs. NMA, (2.6; 0.006); clear FISH abn post-HSCT: CR post-HSCT (4.6; 0.004); CR post-HSCT: B symptoms at dx (0.4; 0.02), <=1 FISH abn (1.7; 0.045), rituximab (R) pre-HSCT (2.5; 0.001), clear FISH abn (2.5; 0.01), flu sensitivity (S) pre-HSCT (1.8; 0.03), S to last tx pre-HSCT (1.7; 0.03), CON (MA vs. RIC or NMA) (3.2; <0.001); PROG: Richter’s transformation ( Rich trans) pre-HSCT (3.5; 0.008), graft failure (3.3; 0.008), CoI >3 vs. 0-2 (6.9; 0.006), no R pre-HSCT (6.7; 0.01), CON (MA vs. NMA or RIC), (0.2; 0.03); NRM: pre-HSCT alem (2.7; 0.03), CoI >3 vs. 0-2 (2.7; 0.049), HLA MM (2.8; 0.01), CON (MA vs. rest) (3.0; 0.007), AGVHD g 3-4 vs. 0-2 (5.9; <0.001), FISH abn not clear (2.6; 0.04), and no CR (6.5; <0.001).Comparison bn allo-HSCT and BCPCD CLL pts showed sig diff at dx for Dohner FISH rank: more del 17p (23% vs.11%) and 11q (23% vs. 9%) in allo-HSCT pts (n=84 with pre-HSCT FISH); less +12 (13% vs. 17%), del 13q (24% vs.41%) or normal (22% vs 18%), p<0.001 than non-HSCT pts (n=952); Age at dx (med, range) was lower in HSCT (50, 26-65) vs non (62, 25-96), p<0.001; lymphocyte (lymph) count higher (14, 1-300 vs.11, 1-662, p=0.03), tx-free survival (TFS) from dx to 1st tx shorter at 0.75 (0-9.3) vs. 2.86 (0-20.6) yrs. Rich trans was more frequent in HSCT pts (8%) vs. non (3%), p=0.015.OS was sig better for HSCT pts (n=103) (med 17.6, SE 4.5, CI 95% 8.8-26) compared to non (n=494) (med 14.4, SE 1.1, CI 95% 12.1-16.6) (p=0.03).Conclusion: CLL allo-HSCT pts have sig diff than non including higher lymph at dx, shorter time to 1st tx, and higher risk FISH abn. 17p del remains high-risk with allo-HSCT. Pre-HSCT R increased post HSCT CR. Strategies to optimize post-HSCT CR and dn chim are important; these milestones are crucial to best outcome. PROG post-HSCT does not confer worse OS; rescue strategies are successful and deserve further study. Comparison of this large allo HSCT and pop-based BPCDB cohort indicate improved OS for allo-HSCT tx CLL pts vs. other, with a survival plateau. This data indicates early recognition of high-risk CLL patients for HSCT is likely to yield best long-term outcome. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Abstract 4787: Targeting miR-21 in hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) remains a significant unmet medical need with few therapeutic options available. Micro RNA 21 (miR-21) has been shown to be upregulated in HCC, however, contribution of this onco-miR to the maintenance of tumorigenic phenotype in liver cancer remains poorly understood. We have developed potent and specific single-stranded oligonucleotide inhibitors of miR-21 (anti-miR-21) and used them to interrogate dependency on miR-21 in a panel of 20 commercially available HCC cell lines in vitro. Upon lipid-mediated transfection, anti-miR-21, but not its mismatched (MM) control, caused significant de-repression of known direct targets of miR-21 (ANKRD46, DDAH1, RECK1) and inhibited survival of a large subset of HCC cell lines. Treatment of these sensitive HCC cell lines with anti-miR-21 resulted in dose- and time-dependent induction of caspase 3/7 activity. In contrast, non-responder HCC cell lines failed to significantly upregulate caspase activity and maintained viability in the presence of anti-miR compound. Further analysis of responder cell lines revealed robust induction of cell death, inhibition of cell migration and suppression of clonogenic growth upon treatment with miR-21 inhibitor. To better understand the consequences of miR-21 suppression in HCC, we carried out global gene expression profiling of anti-miR-21 treated sensitive liver cancer cells. Striking enrichment in miR-21 targets was noted among upregulated transcripts. Gene ontology analysis identified key cellular processes affected by miR-21 inhibition, including deregulation of metabolic pathways. In addition to the induction of direct miR-21 targets, cyclin H was found to be significantly downregulated upon miR-21 inhibition in the majority of responder cell lines. We hypothesize that inhibition of cyclin H expression, while an indirect effect of miR-21 suppression, could contribute to the activity of anti-miR-21 compounds. In summary, our data suggest that inhibition of miR-21 merits further investigation in the treatment of hepatocellular carcinoma. Citation Format: Sonya Zabludoff, Timothy Wagenaar, Francisco Adrian, Charles Allerson, Heike Arlt, Raffaele Baffa, Bal Bhat, Hui Cao, Scott Davis, Carlos Garcia-Echeverria, Kathrin Heermeier, Shih-Min Huang, Lan Jiang, Eric Marcusson, Christiane Metz-Weidmann, Adam Pavlicek, Jack Pollard, Jennifer Rocnik, Sabine Scheidler, Chaomei Shi, Fangxian Sun, Tatiana Tolstykh, Qunyan Yu, Gang Zheng, Dmitri Wiederschain. Targeting miR-21 in hepatocellular carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4787. doi:10.1158/1538-7445.AM2014-4787

Patient and graft outcome in current era of immunosuppression: a single centre pilot study

Objectives:The present single centre study aims at analyzing the impact on renal allograft outcome of the important changes which occurred in the transplant population and immunosuppressive therapy during the last two decades.Methods:From 2000 to 2013, 779 single kidney transplantations were performed on 635 patients who all received on an intent-to-treat basis steroids, a calcineurin inhibitor, mycophenolate mofetil and an induction therapy with either antithymocyte globulin or an antagonist directed to the interleukin (IL)-2 receptor. Uni- and multivariate analyses of patient and immunologic graft survival were conducted.Results:The sole factor predicting patient survival is recipient’s age: 10-year survival rates are 94·7, 81·6 and 57·9% for the <45, 45–60 and >60 years age groups, respectively (P<0·001). Peak (>50% panel reactive antibodies) anti-human leucocyte antigens (HLA) sensitization, cold ischaemia time and HLA-B and -DR mismatches (MM) influence graft outcome: at 10 years, the difference in 10-year survival rates is 5·9% between grafts from sensitized and not sensitized patients (90·9 vs 96·8%, P = 0·002), 3·8% between grafts with <18 and ≧18 hours cold ischaemia (96·6 vs 92·8%, P = 0·003), 7·3% between grafts with no MM and either B or DR MM versus those with B and DR MM (96·8 vs 89·5%, P = 0·002).Conclusion:In our single centre experience, graft survival was most strongly determined by HLA matching, offering excellent long term graft outcome to most patients.

HLA-DR Matching Is Associated With Improved Graft Survival in Recipients of Deceased Donor Kidneys. Review of OPTN Data.

Purpose: In May of 2003, Organ Procurement and Transplantation Network (OPTN) policy was amended to allow candidates for deceased donor kidneys HLA allocation points only for DRB1 (DR) matching; points for HLA-A and -B were removed. Candidates are given 2 points if there are no mismatched (MM) DR antigens. To assess the efficacy of this policy change the OPTN Histocompatibility Committee reviewed 8 yr. outcomes data stratified by the degree of DR MM. Methods: Results from 16,329 deceased donor (DD) kidney transplants performed from 2005-2007, with up to 8 years follow up, were analyzed. Recipients were excluded if they received a multi-organ transplant or if the level of DR mismatch (MM) was unknown. Pair-wise comparisons were made between 0, 1, and 2 DR MM groups. All results are based on OPTN data. Results: During this time, 20.9% of patients received 0-DR MM grafts, 41.5% 1 DR MM, and 37.6% 2 DR MM. Graft survival (GS) was significantly better for 0 DR MM transplants compared to 1 or 2 MMs (p <0.001). A single DR MM was sufficient to confer a statistically significant decrease in GS which was evident within 4 yrs. post transplant. For 0 DR MM transplants, 57% were also 0 AB MM. Interestingly, among the 0 MM DR group; 69% were also 0 MM for HLA DQ.Figure: No Caption available.Conclusions: These data demonstrate the GS benefit of DR matching among recipients of DD kidneys and supports the utility of awarding allocation points for DR match. Recipients with lower DR MMs enjoyed significantly better GS by 4 years post transplant. Importantly, more than half of the 0 DR MM group was also 0 AB MM suggesting that the 0 MM allocation policy is a predominant factor resulting in better DR matching. These results support the continued use of allocation points for DR matching and warrant additional analyses to determine if the current point values are adequate given the improved GS.

HLA Mismatching Is an Independent Risk Factor for Worse Patient Survival Among Lung Transplant Recipients in the United States.

Currently HLA donor/recipient mismatches are not considered in lung donor allocation or in risk adjustment models for assessing performance of transplant programs. We analyzed patient survival in lung transplant recipients by HLA mismatches (MM). Methods: Adult recipients reported to the Scientific Registry of Transplant Recipients (SRTR) database (01-11) were stratified by number of HLA-A,-B,-DR MM. Patient survival was assessed by Kaplan-Meier analysis. Cox proportional hazards regression determined predictors of patient survival. Multivariable analysis was conducted to assess the independent effect of MM adjusted for donor age, gender, race and cause of death, recipient primary diagnosis, use of ventilator, FVC, age, race, gender, primary diagnosis, size of transplant program and year of transplant. Results: The study includes 14,860 adult (18+) recipients, 56 % males, 86% Caucasian, 32% with OPD/Emphysema as primary diagnosis, median donor age 33 yrs and median recipient age 53 years. The proportion of 2-Ag MM was 51, 70, 54% at loci HLA-A, B, DR, respectively. The median follow up was 24 months (0-120) and the overall 5 year patient survival was 54%. Four percent of recipients had 0- 2/6 MM. Five-year patient survival among patients with 0-2 MM was 62% compared to 54% among patients with 3-6 MM (Figure 1).Figure: No Caption available.Higher MM was independently associated with diminished patient survival (AHR= 1.27, 95% CI. 1.07-1.51 p= 0.006). Among the 3 HLA loci, this effect was strongest and also independently associated with 2-HLA-DR MM (AHR= 1.17, 95% CI. 1.01-1.35, p= 0.03). Conclusion: HLA MM is an independent risk factor for poor patient survival after lung transplant. Although HLA matching may not be feasible for lung organ allocation, it could be important for risk stratification in individual patient clinical management. MM may also be an important consideration for more accurate evaluation of transplant center performance.

Mismatched HLA Eplets: Potential Predictor of Donor Specific Antibody Development Risk in Heart Transplantation.

Objectives: Donor Specific HLA antibody (DSA) is associated with poor graft survival. Recent studies suggest that mismatched (MM) HLA eplets may be associated with higher incidents of post-transplant (tx) DSA. Our aim was to investigate whether greater numbers of MM eplets expose heart tx recipients to an increased risk of DSA development and to evaluate whether assessment of MM eplets may provide clinicians with additional tools for more effective monitoring and treatment of DSA. Methods: We evaluated 35 heart recipients transplanted from 2010 to 2013 using solid phase antibody assays. The HLAMatchmaker program was used to calculate the number of donor-recipient HLA MM eplets. Sera were collected at 1, 3, 6, and 12 months or when clinically indicated. DSA were characterized using solid phase assays. Results: The cohort consisted of 71% males and 29% females with a mean age of 48yr. Out of 35 patients (pts), 7 developed DSA (20%) within 18 months post-tx. Among the 7 pts, 5 developed de novo DSA (dnDSA) and 2 had increased levels of historic DSA that were negative at the time of tx. No pts developed DSA against Cw, DR51, or DR52. One pt developed DSA against B and 1 against DR53. For HLA antigens including A, DR, and DQ, the number of MM donor eplets was higher in pts who developed either dnDSA or increased levels of historic DSA. Our data suggest that the number of MM eplets contributing to DSA development may be locus specific. For example, having 8 MM A eplets may be sufficient to induce DSA; in comparison, more than 14 MM DQ eplets appear to be needed. Conclusions: Our results suggest that a higher number of MM eplets may be associated with increased DSA against A, DR, and DQ antigens. Therefore, pts transplanted with a high MM eplet load may require close monitoring for post-tx DSA and early intervention. Further study on a larger population of heart tx pts is required to confirm this finding.Figure: No Caption available.

Sensitization Trends After Renal Allograft Failure: What Causes Patients to Become Highly Sensitized?

Purpose: There is lack of systematic analyses to help minimize sensitization in renal allograft failures (AF). Some patients remain non sensitized (NS) while others become highly sensitized (HS). Our ongoing study analyzes acute rejection (AR), immunosuppression withdrawal (IW) at AF, allograft nephrectomy (AN), Graft Intolerance syndrome (GIS) and HLA mismatches (MM) in NS and HS renal AF. Methods: Seventy NS patients with AF post initial kidney transplantation (KT) were studied. Panel Reactive Antibody (PRA) methodology changed from T cell Anti Human Globulin for Class I to Luminex® platform for HLA Class I and II during study period. Post AF, two main groups comprising of NS (PRA class I & II≤9%) and HS (PRA Class I or II≥80%) were identified. Epitope based method (http://www.HLAmatchmaker.net) to assess overall immunogenicity of MM for NS and HS is also in progress. Results: Latest PRA testing in these 70 patients after AF revealed 19 (27%) to be NS and 38(54%) becoming HS.Figure: No Caption available.Presence of African American (AA) ethnicity, IW at AF, HLA and DR MM, GIS after AF lead to HS status.Table: No Caption available.All cause AN and AR rates were similar between NS and HS groups. Conclusions: IS withdrawal at AF, HLA MM, GIS after AF and AA ethnicity are risk factors leading to HS status. Sensitization traditionally linked to AN may be an epiphenomenon related to GIS. This merits a prospective study to assess if sensitization can be lessened.

Looking Behind the Curtain: Pre-Transplant Mismatched Eplet Load May Better Predict Increases in Post-Transplant DSA.

Purpose: Patients receiving renal transplants in the presence of donor specific HLA antibodies (DSA) are at increased risk for antibody mediated rejection (AMR) as well as decreased graft survival. For highly sensitized patients, transplanting in the presence of low/moderate DSA may be the only viable option. We looked at which characteristics of pre-existing DSA are associated with poor post-transplant(tx) outcomes. Methods: We identified 11 patients (mean cPRA=87+7%) with DSAs from a cohort of 165 consecutive renal txs performed between 10/2012 and 12/2013. Patients were desensitized using plasmapheresis(PP) and IVIg and received standard induction and maintenance therapy post-tx. DSA titers and MFI were determined by solid phase assays (pre-Tx, day 3, weekly 1-4, months 2, 3, 6, 9, 12). Donor-recipient eplet mismatches (MM) in the DSA-associated HLA antigens were determined using HLA Matchmaker. Results: Post-tx, 5 of the 11 (45.5%) desensitized patients no longer had clinically significant DSA. Increased DSA were found in the remaining 6 (55.5%) within 2 weeks (MFI=3469-15000, titers 1:16->1:1024) and 5 developed de novo DSA. No association between pre-tx MFI values, positive xmatch (T or B), or previous tx and increased post-tx DSA was found. In contrast, patients with negative DSA post-tx averaged 6.4+3.6 eplet MM in pertinent HLA antigen, whereas those with increasing DSA post-tx averaged 16.8+5.6 MM eplets.Expression of Cytosolic DoubleFigure: No Caption available.Increased DSA were successfully reversed in 2 patients with PP and IVIg and in 1 with increased basal immunosuppression. The remaining 3, after treatment, have DSA levels that are stable or slightly lower with surviving but sub-optimal graft function. Conclusions: Renal transplants may be performed successfully in presence of DSA, but remain at increased risk for graft failure or poor function. Our data suggest that mismatched eplet load is predictive of clinically significant post-tx DSA and may identify patients in need of frequent monitoring and aggressive early intervention to minimize DSA load and improve outcomes.

Poor HLA Matching and Post-Operative Blood Transfusions Are Associated With the Development of De Novo DSA Post Renal Transplantation.

Introduction. De novo donor specific antibodies [dnDSA] are associated with antibody mediated rejection and allograft loss. In the first study of its kind, we have undertaken a detailed multivariate analysis of pre- and post- transplant factors associated with the development of dnDSA. Methods. We retrospectively analysed 871 ABO/HLA compatible renal transplant recipients who received a tacrolimus based immunosuppressive protocol with monoclonal antibody induction. Results. 159/871[18.3%] patients developed dnDSA. Pre-transplant factors associated with dnDSA on univariate analysis were the presence of HLA Abs [OR: 1.48(1.0-2.17), p=0.049], being mismatched (MM) at both the class I and II HLA loci [OR: 3.84(2.52-6.36), p<0.01] and having a DQ HLA MM [OR: 2.96(1.92-4.54), p<0.01]. Post-transplant factors analysed included blood transfusion [OR: 2.15(1.33-3.49),p=0.002], delayed graft function [OR: 1.25(0.8-1.95),p=0.33], culture positive infection [OR: 0.95(0.63-1.42),p=0.80], non-compliance (assessed by the coefficient of variance of tacrolimus levels) [OR: 1.29(0.9-1.84), p=0.17] and biopsy proven rejection [OR: 1.81(1.16-2.84),p=0.01]. On multivariate analysis, factors found to be independently associated with dnDSA are shown below.Table: No Caption available.Conclusion. Poor HLA mismatching and post-operative blood transfusions are strongly associated with dnDSA and are therefore potentially avoidable.