Journal articles on the topic 'Art. 52 c. 4 c.p'

To date, there have been no studies examining the role of hepatitis B virus (HBV) genotypes on the response to lamivudine therapy and the development of YMDD mutations. The present study aimed at determining any differences in the antiviral response and risk of YMDD mutations between lamivudine-treated patients with HBV genotype B and genotype C. Eighty-two patients receiving lamivudine were recruited. HBV genotypes at baseline and YMDD mutations at week 52 were determined by line probe assays (LiPA). HBV DNA levels were determined by the Cobas Amplicor HBV Monitor Test. Seventeen (20.7%) and sixty-four (78%) patients had single genotypes of B and C, respectively. At both week 24 and 52 there were no differences in the median reduction of HBV DNA levels (median 4 logs drop), the median reduction of alanine aminotransferase (ALT) levels, and the proportion with normalization of ALT [8/8 (100%) vs 26/37 (70.3%), P=0.19] between patients with genotypes B and C. The rate of HBeAg seroconversion [3/17 (17.6%) vs 6/64 (9.4%), P=0.39] and the chance of YMDD mutation development [3/17 (17.6%) vs 12/64 (18.8%), P=1.0] at week 52 were also similar between patients with genotype B and C, respectively. In conclusion, there was no difference in the antiviral response and the rate of development of YMDD mutations in Chinese patients with genotype B and C after 1 year of lamivudine. Determination of HBV genotypes before lamivudine therapy was probably not an important pre-treatment investigation to predict antiviral responses in Chinese patients.

Objective. To analyze the course of chronic hepatitis C (CHC) and efficacy of its treatment in children with HIV infection. Patients and methods. This study included 29 children aged 12 to 17 years (mean age 15.1 ± 0.2 years) with perinatal HIV infection and CHC. HIV stages were distributed as follows: stage 4A in 24 individuals (82.8%), stage 4B in 4 individuals (13.8%), and stage 4B in 1 individual (3.4%). All 29 patients received antiretroviral therapy. The distribution of children by HCV genotypes was as follows: 1a in one child (3.4%), 1b in 12 children (41.4%), and 3a in 16 children (55.2%). Antiviral therapy for CHC included glecaprevir/pibrentasvir (3 tablets; 100 mg + 40 mg) once a day for 56 days. Data analysis was performed using the Statistica for Windows software (version 10.0). Results. The mean HCV RNA level was 595,666 ± 34,734 IU/mL (range: 1,100–3,863,025 IU/mL). After 4, 8, or 12 weeks of antiviral therapy for HCV, HCV RNA clearance was achieved in all study participants (p = 0.01). Before treatment initiation, mean CD4+ count was 738 ± 34 cells/μL (above 500 cells/μL), which indicated the absence of immunodeficiency in the group analyzed. Successful antiviral therapy for HCV (sustained virologic response at week 12; SVR 12) also resulted in increase of the CD4+ lymphocytes level, which was considered as a positive effect of glecaprevir/pibrentasvir (p = 0.15). We observed significant differences in the level of liver enzymes (ALT and AST) (p = 0.01) between samples collected before antiviral therapy initiation and those collected during treatment, as well as 12 weeks after its completion (SVR12). All children demonstrated good tolerance of glecaprevir/pibrentasvir; none of them had adverse events, complaints, or clinical/laboratory changes. Conclusion. Thus, all children with HIV infection and CHC achieved SVR12 after the 8-week course of antiviral therapy with glecaprevir/pibrentasvir regardless of HCV genotype. Clinical manifestations (hepatosplenomegaly in 62.1%; asthenovegetative syndrome in 31.0%) were eliminated after 8 weeks of therapy. Laboratory manifestations (hepatic cytolysis (AST/ALT)) were normalized after 4 weeks of therapy. Antiviral treatment for HCV resulted in some increase in the level of CD4+ lymphocytes. We observed no adverse events caused by glecaprevir/pibrentasvir (neither clinical symptoms nor changes in complete blood count or liver function tests), which confirms the safety of this treatment regimen. Key words: antiretroviral therapy, HIV infection, children, direct-acting antivirals, chronic hepatitis C

Abstract Deferasirox is an oral iron chelator approved for the management of iron overload in thalassemia major (TM). However, there are some concerns for its effect on renal function. Cystatin C (Cys-C) is a cysteine protease inhibitor, which is considered as a sensitive marker of GFR. Inflammation process has been recently implicated in TM pathophysiology. The aim of this study was to evaluate the effect of deferasirox on renal function and inflammatory cytokines in 52 TM patients. Deferasirox was administered at a dose between 10–30 mg/kg/day for a 12-month period. Serum Cys-C, serum creatinine (Cr), clearance of Cr (Ccr), albuminuria and inflammatory cytokines including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), IL-1α, IL-1β, IL-4, IL-10 and transforming growth factor (TGF)-β1 and β2, were measured at baseline and then after 6 and 12 months post-deferasirox therapy. Standard hematology and biochemistry was evaluated monthly. Serum Cys-C was measured using a latex particle-enhanced nephelometric immunoassay (Dade Behring, Liederbach, Germany). Serum levels of the above cytokines were determined using ELISA (R&D Systems, Minneapolis, MN, USA, for ILs, and Diaclone, Bensancon, France for TNF-α, TGF-β1 and TGF-β2). Ten healthy blood donors were also evaluated as control group. At baseline, TM patients had elevated values of Cys-C (p<0.0001) compared with controls. Specifically, 21/52 patients (40%) had higher Cys-C values than the upper normal limit according to manufacturer (0.95 mg/L), while no patient had increased levels of serum Cr (>1.4 mg/dl) and only 6 (11.5%) had low Ccr (<80 ml/min). Before deferasirox administration, TM patients had also increased levels of IL-6 (p=0.008), IL-1α (p=0.015), TGF-β2 (p=0.017), IL-10 (0.021), IL-4 (p=0.039), and a borderline increase of TNF-α (p=0.05) compared with controls (Table). Serum levels of Cys-C correlated strongly with Cr (r=0.657, p<0.0001), and Ccr (r=−0.625, p<0.0001) but also with IL-6 (r=0.441, r<0.001) and proteinuria (r=0.261, p=0.037). Il-1a correlated with Hb (r=−0.417, p<0.001) and IL-4 (r=0.474, p<0.001), while IL-6 correlated with TNF-α (r=0.37, p<0.01). After 6 and 12 months of therapy, deferasirox produced a dramatic reduction of ferritin, SGOT and SGPT compared with baseline values (p<0.0001), but concomitantly we observed an increase of Cys-C and Ccr during the same period (p<0.0001). In particular at the end of the study 32/52 patients (61.5%) had increased Cys-C values, while 10 (19.2%) had low Ccr and only one high serum Cr. Interestingly serum levels of TNF-α reduced post-deferasirox administration (p=0.01), while the levels of all other cytokines remained unchanged during therapy (Table). Our study suggests that deferasirox is an effective chelator in TM. However, its effect on renal function is not insignificant and needs further investigation. Inflammatory cytokines seem to have a role in the pathogenesis of TM but further studies are needed to fully elucidate this role as well as the effect of deferasirox, if any, on inflammation. Table 1. Characteristics of patients & controls (mean values ± SD) Parameters Controls (n=10) Patients-baseline values (n=52) p-value (patients vs. controls) Patients-12-month values p-value patients (baseline vs. 12 m) Age(years) 40.8±11.7 39.5±10.9 0.782 Gender(Male/Female) 4/6 22/30 0.346 Hb(g/dL) 14.8±2.6 8.8±1.4 <0.0001 8.7±1.5 AST(U/L) 29.3±10.1 46.7±23.9 <0.0001 35.5±19.2 <0.0001 ALT(U/L) 23.8±12.5 50.7±28.6 <0.0001 34.3±22.1 <0.0001 Ferritin(μg/L) 88±34.2 2355±1380 <0.0001 1516±1320 <0.0001 Serum Creatinine (mg/dL) 0.8±0.1 0.7±0.1 0.823 0.8±0.2 0.001 Creatinine Clearance (ml/min/1.732) 125.2±22.7 126.5±29.9 0.227 117.0±31.1 0.005 Proteinuria(mg/24h) 55.4±28.2 322.9±461.6 <0.0001 323.4±417.0 0.976 Cystatin-C (mg/L) 0.76±0.11 0.93±0.26 <0.0001 1.12±0.37 <0.0001 Inflammatory Cytokines IL-1α (pg/mL) 0.08±0.19 0.65±0.80 0.015 1.06±1.13 0.114 IL-1β (pg/mL) 2.30±2.54 1.68±2.37 0.475 2.05±2.82 0.571 IL-4 (pg/mL) ND 0.78±1.83 0.039 0.28±0.59 0.167 IL-6 (pg/mL) 0.09±0.21 2.50±4.42 0.008 3.00±7.51 0.752 TNF-α (pg/mL) 1.13±2.05 3.85±7.48 0.05 0.46±1.40 0.015 TGF-β1 (ng/mL) 87.1±21.7 107.5±53.6 0.180 112.1±74.0 0.678 TGF-β2 (pg/mL) 5.62±10.5 19.5±26.4 0.017 15.8±29.7 0.318

SARS-CoV-2 infection may precede and cause various autoimmune and inflammatory diseases, including multisystem inflammatory syndrome in children (MIS-C). Therefore, we aimed to observe the clinical presentation and laboratory, instrumental and other constellations in children with MIS-C, including liver involvement. We present the outcomes from a single-center prospective observational study in which 89 children was included (60 with proven COVID-19, 10 symptomatic with confirmed COVID-19 contact and 19 diagnosed with MIS-C). Laboratory, instrumental, immunological, and clinical investigations were performed. Only 12% (n = 4) from the COVID-19 group (except the ICU cases), we found elevated AST and/or ALT (up to 100). All of the children with elevated transaminase were overweight or obese, presenting along with moderate COVID-19 pneumonia. The majority of children with MIS-C showed typical laboratory constellations with higher levels of IL-6 (120.36 ± 35.56 ng/mL). About half of the children in the MIS-C group (52%, n = 11) showed elevated transaminases. Eleven children (57.9%) presented with abdominal pain, eight (42.1%) with ascites, two (10.5%) with hepatosplenomegaly, and four (21.1%) with symptoms such as diarrhea. Mesenteric lymphadenitis was observed more often in patients with elevated LDH (327.83 ± 159.39, p = 0.077). Ascites was associated with lymphopenia (0.86 ± 0.80, p = 0.029) and elevated LDH. Hepato-splenomegaly was also more frequent in children with lymphopenia (0.5 ± 0.14, p = 0.039), higher troponin (402.00 ± 101.23, p = 0.004) and low ESR. Diarrhea was more frequent in patients with lower CRP (9.00 ± 3.44 vs. 22.25 ± 2.58, p = 0.04), and higher AST and ALT (469.00 ± 349.59 vs. and 286.67 ± 174.91, respectively, p = 0.010), and D-dimer (4516.66 ± 715.83, p = 0.001). Our data suggest that the liver can also be involved in MIS-C, presenting with typical laboratory and instrumental outcomes.

5537 Background: p38 mitogen-activated protein kinase (MAPK) regulates cytokine production in the tumor microenvironment and enables therapeutic resistance of cancer cells. Ralimetinib (R) is a selective small-molecule inhibitor of p38α and p38β MAPKs. Methods: Main inclusion criteria: ≥18 y; recurrent platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal, cancer after first-line treatment. Phase (Ph)1b was to determine the recommended Ph2 dose (RP2D) of R administered 12-hourly (Q12H) on Days 1-10 (21-day cycle [Q21D]) in combination with gemcitabine (G: 1000 mg/m2 on Days 3 and 10) and carboplatin (C: AUC 4 on Day 3) for 6 cycles. In Ph2, patients (pts) were randomized double-blind, 1:1 to RP2D R+GC or placebo (P)+GC, for 6 cycles, followed by R 300 mg Q12H or P on Days 1-14, Q28D until disease progression. The stratified log-rank test compared progression-free survival (PFS; primary endpoint) between treatment groups in Ph2, at a 1-sided α level of 0.2. ClinicalTrials.gov, NCT01663857. Results: 118 pts received ≥1 dose of R or P (safety population); 8 in Ph1b and 110 in Ph2 (R+GC N = 58; P+GC N = 52). The RP2D for R in combination with GC was 200 mg Q12H. The study met its primary objective (median PFS: R+GC 10.3 mo vs P+GC 7.9 mo; HR = 0.773, 2-sided p = 0.246). The secondary objectives of median overall survival (R+GC 29.2 mo vs P+GC 25.1 mo; HR = 0.827, p = 0.469) or overall response rate (R+GC 46.6% vs P+GC 46.2%; p = 0.967) were not statistically significant, and 32.4% vs 25.0% of pts had normalized CA125 at the end of cycle 6. Most pts (safety population) experienced ≥1 Grade 3/4 treatment-emergent adverse event (TEAE: R+GC 63/66 [95.5%]; P+GC 48/52 [92.3%]). Decreased neutrophil count (60.6% vs 76.9%), platelet count (43.9% vs 38.5%), and white blood cell count, (30.3% vs 26.9%), anemia (22.7% vs 25.0%), and increased alanine aminotransferase (ALT) (19.7% vs 3.8%) were the Grade 3/4 TEAEs in ≥10% of pts in the R+GC and P+GC arms, respectively. Conclusions: Addition of ralimetinib to GC resulted in modest improvements in PFS. Grade 3/4 elevated ALT was more common in the ralimetinib arm. Clinical trial information: NCT01663857.

128 Background: We have recently completed accrual of 63 patients (pts) to our study combining lenalidomide (L), with bevacizumab (B), docetaxel (D), and prednisone (P) (ART-P). Due to the lack of improved survival and the increased toxicity of anti-angiogenic docetaxel combinations in the MAINSAIL and CALGB 90410 trials we attempted to contrast and compare our studies with the failed phase III trials. Methods: Among the first 52 pts on the ART-P, 3 received L 15 mg daily, 3 had 20 mg daily, and the rest had 25 mg daily for 14 days of every 21−day cycle (C). We later enrolled 11 more pts at L 15 mg. All pts received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and enoxaparin daily throughout each C. Pegfilgrastim was given on day 2. Patients on CALGB 90410 received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and on MAINSAIL received D 75 mg/m2, L 25 mg daily for 14 days of every 21−day cycle with daily P. Patients on CALGB 90410 and MAINSAIL did not receive enoxaparin or pegfilgrastim prophylactically. Results: Median number of Cs in ART-P was 16 (3−38). PFS was 22 months and median OS has not been reached. Pts with measurable disease had 1 CR and 25 PR (86.7% RR). Two patients (3%) had deep vein thromboses. Of 1,219 cycles given, 14 cycles were complicated by febrile neutropenia (FN) (1.1%). There were no treatment related deaths. In comparison, median number of Cs in MAINSAIL L+DP arm was 6, with a PFS of 45 weeks and an OS of 77 weeks. Thirty-four pts (6.5%) developed pulmonary emboli and there were 2 deaths due to toxicity in the experimental arm. Nearly 12% of Cs were complicated by FN. In the experimental arm of CALGB 90410 trial, median OS was 22.6 months with median PFS of 9.9 months. Median number of Cs was 8, and 19 pts developed thromboses/emboli (3.6%). In addition, 7% of patients developed FN and treatment related deaths were reported at 4%. Conclusions: The use of supportive care allows the ART-P combination to be given for more cycles than were given in MAINSAIL and CALGB 90401 potentiating a longer PFS, RR and possibly OS with an improved toxicity profile. This data demonstrates the potential importance of supportive measures and is hypothesis generating for future combination studies. Clinical trial information: NCT00942578.

e16017 Background: We have completed accrual of 63 patients (pts) to our study combining lenalidomide (L), with bevacizumab (B), docetaxel (D), and prednisone (P) (ART-P) in mCRPC. Due to the lack of improved survival and the increased toxicity of anti-angiogenic docetaxel combinations in the MAINSAIL and CALGB 90401 trials, we attempted to compare and contrast our studies with these failed phase III trials. Methods: Among the first 52 pts on ART-P, 3 received L 15 mg daily, 3 received 20 mg daily, and the others received 25 mg daily for 14 days of every 21−day cycle (C). We then enrolled 11 pts at L 15 mg. All pts received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and enoxaparin daily. Pegfilgrastim was given on day 2. Patients on CALGB 90401 received D 75 mg/m2 and B 15 mg/kg on day 1, with P 10 mg. On MAINSAIL, pts received D 75 mg/m2, L 25 mg daily for 14 days of every 21−day cycle with daily P. Patients on CALGB 90401 and MAINSAIL did not receive enoxaparin or pegfilgrastim prophylactically. Results: The median number of Cs on ART-P is 18 (1-52). Median PFS is 19.1 months. Twenty-seven pts had a PR, and one pt with measurable disease had a CR. Two patients (3%) had deep vein thromboses. Of 1,334 Cs given, 14 cycles were complicated by febrile neutropenia (FN) (1%). There were no treatment related deaths. In comparison, median number of Cs in MAINSAIL L+DP arm was 6, with a PFS of 45 weeks and an OS of 77 weeks. Thirty-four pts (6.5%) developed pulmonary emboli and there were 2 deaths due to toxicity in the experimental arm. Nearly 12% of Cs were complicated by FN. In the experimental arm of CALGB 90401 trial, median OS was 22.6 months with median PFS of 9.9 months. The median number of Cs were 8 and 19 pts developed thrombosis/emboli (3.6%). In addition, 37 patients developed FN and treatment related deaths were reported at 4%. Conclusions: The use of supportive care allowed longer treatment duration with the ART-P combination as compared to D+L (MAINSAIL) and D+B (CALGB 90401), potentiating a longer PFS, RR and possibly OS with an improved safety profile. This data demonstrates the potential importance of supportive measures and is hypothesis generating for future combination studies. Clinical trial information: NCT00942578.

BackgroundBelimumab (BEL) is approved for the treatment of active autoantibody-positive systemic lupus erythematosus (SLE).1 Four Phase 3 studies have consistently demonstrated greater SLE Responder Index (SRI) response rates with BEL vs placebo (PBO).2-5 This robust dataset allows for additional exploration of the onset of efficacy of BEL and response rates by patient (pt) characteristics.ObjectivesTo perform a post hoc analysis evaluating the effect of BEL on SRI-4 response across a large, pooled population and pt subgroups.MethodsThe Belimumab Summary of Lupus Efficacy (Be-SLE) integrated analysis evaluated data from adults with SLE from 5 double-blind, PBO-controlled BEL trials: BLISS-76, BLISS-52, BLISS-NEA, BLISS-SC, and EMBRACE.2-6 Pts were randomised to BEL (monthly intravenous 10 mg/kg or weekly subcutaneous 200 mg) or PBO, plus standard therapy. Data were collected every 4 weeks (wks) from baseline (BL) to Wk 52. The SRI-4 response rate (a composite measure that includes ≥4-point reduction in Safety of Estrogens in Lupus Erythematosus National Assessment - SLE Disease Activity Index [SELENA-SLEDAI] score, stable Physician Global Assessment [PGA] increase of <0.3, and no new British Isles Lupus Assessment Group [BILAG] 1A/2B organ domain scores) by visit and time to first SRI-4 response maintained through Wk 52 were determined for both treatment groups. SRI-4 response rates at Wk 52 were evaluated by BL characteristic subgroups: SELENA-SLEDAI score; SLE International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) score; disease duration; biomarker levels (anti-dsDNA, complement [C]3/C4); glucocorticoid (GC), immunosuppressant (IS), and antimalarial (AM) use.ResultsOverall, 3086 pts were included (BEL, n=1869; PBO, n=1217). Most were female (94.4%); mean (standard deviation [SD]) age was 37.0 (11.6) years. Mean (SD) SLE duration was 6.4 (6.4) years.At Wk 52, in the overall population, significantly more BEL vs PBO pts were SRI-4 responders (Figure 1). A significantly greater proportion of SRI-4 responders was observed with BEL vs PBO as early as Wk 8 (38.4% vs 33.3%; odds ratio, OR [95% confidence interval, CI] 1.25 [1.07, 1.46]; p=0.0060), which continued to increase to Wk 52 (54.8% vs 41.6%; OR [95% CI] 1.70 [1.46, 1.98]; p<0.0001). At Wk 52, more BEL vs PBO pts had a 4-point reduction in SELENA-SLEDAI (56.3% vs 43.1%; OR [95% CI] 1.71 [1.47, 2.00]; p<0.0001), no worsening in PGA (76.6% vs 67.9%; OR [95% CI] 1.52 [1.28, 1.79]; p<0.0001), and no new BILAG 1A/2B organ domain scores (77.1% vs 69.4%; OR [95% CI] 1.47 [1.25, 1.74]; p<0.0001). Pts on BEL were 52% more likely to experience an SRI-4 response that was maintained through Wk 52 (hazard ratio, HR [95% CI] 1.52 [1.36, 1.69]; p<0.0001).Figure 1.SRI-4 response at Wk 52 in the overall population and by BL characteristic subgroups.*OR (95% CI) and p-value are from a logistic regression model for BEL vs PBO comparison with covariates of treatment group, study and BL SELENA-SLEDAI score (≤9 vs ≥10)SRI-4 response rates were significantly higher with BEL vs PBO in most subgroups, with the highest response rates observed in pts with SELENA-SLEDAI score of ≥10, low C3 and/or C4 + anti-dsDNA ≥30 IU/ml, and low C3 and/or C4 at BL (Figure 1).ConclusionSignificantly more pts receiving BEL had SRI-4 response rates that occurred from Wk 8 and were maintained through Wk 52 compared with pts receiving PBO. The efficacy of BEL was consistent across multiple pt subgroups, with higher response rates in pts with SELENA-SLEDAI scores of ≥10, low C3 and/or C4 + anti-dsDNA ≥30 IU/ml and low C3 and/or C4 at BL. These results further substantiate the benefits of BEL in the treatment of adults with SLE.References[1]GlaxoSmithKline. Benlysta US prescribing information. 2021[2]Furie R, et al. Arthritis Rheumatol 2011;63(12):3918–30[3]Navarra SV, et al. Lancet 2011;377(9767):721–31[4]Stohl W, et al. Arthritis Rheum 2017;69(5):1016–27[5]Zhang F, et al. Ann Rheum Dis 2018;77(3):355–63[6] Ginzler E, et al. Arthritis Rheum 2021; doi: 10.1002/art.41900AcknowledgementsThis analysis was funded by GlaxoSmithKline (GSK). Medical writing support was provided by Lulu Hill, MPharmacol, Fishawack Indicia Ltd. UK, part of Fishawack Health, and was funded by GSK.Disclosure of InterestsMichelle A Petri Consultant of: GSK, Grant/research support from: GSK, George Bertsias Speakers bureau: Pfizer, Aenorasis, UCB, Novartis, Lilly, SOBI, Consultant of: Novartis, GSK, AstraZeneca, Grant/research support from: GSK, Pfizer, Mark Daniels Shareholder of: GSK, Employee of: GSK, Norma Lynn Fox Shareholder of: GSK, Employee of: GSK, Bevra H. Hahn Consultant of: UCB, GSK, Anne Hammer Shareholder of: GSK, Employee of: GSK, Julia Harris Shareholder of: GSK, Employee of: GSK, Holly Quasny Shareholder of: GSK, Employee of: GSK, Chiara Tani Speakers bureau: GSK, AstraZeneca, Anca Askanase Consultant of: AstraZeneca, Aurinia Pharmaceuticals Inc., Amgen, AbbVie Inc., BMS, GSK, Grant/research support from: AstraZeneca, Eli Lilly and Company, GSK, Idorsia Pharmaceuticals Ltd, Janssen Pharmaceuticals, Pfizer

Abstract The biologic effects of erythropoietin (EPO) are mediated by its cellular receptor EPOR, a member of the cytokine receptor superfamily. EPOR expression in non-hematopoietic cells is associated with novel biologic effects for EPO in diverse organ systems. We recently demonstrated functional EPOR expression in adult rat cardiac myocytes and found that recombinant EPO exerts a rapid cardioprotective effect during ischemia-reperfusion injury of the isolated, perfused heart. Here we investigated the mechanisms of the cardioprotective effect of EPO using Langendorff-perfused rat hearts while left-ventricular-developed pressure (LVDP) was measured continuously to assess contractile function. Hearts were treated directly with EPO in the presence or absence of inhibitors of specific signal transduction pathways prior to normothermic global ischemia followed by reperfusion. Post-ischemic recovery of contractile function was determined by measuring LVDP at the end of reperfusion and expressed as a percentage of the baseline pre-treatment measurement. We investigated EPO-mediated activation of signal transduction pathways in the isolated, perfused heart and observed phosphorylation of p44/p42 MAP kinases ERK 1/2 (Thr202/Tyr204) and protein kinase B/Akt (Ser473), a downstream target of the phosphatidylinositol 3-kinase (PI3K) signaling pathway. Furthermore, EPO treatment of the isolated, perfused heart was associated with translocation of protein kinase C (PKC) ε and δ isoforms to the membrane fraction. We investigated the role of specific signaling pathways in EPO-mediated cardioprotection by employing inhibitors targeting PI3K, PKC and MAP kinase kinase (MEK1). PI3K inhibitors LY294002 and wortmannin attenuated EPO-induced phosphorylation of Akt but had no effect on EPO-mediated cardioprotection. MEK1 inhibitor U0126 had no effect on EPO-mediated cardioprotection. The PKC catalytic inhibitor chelerythrine (chel) significantly inhibited EPO-mediated improvement in post-ischemic recovery of LVDP (figure 1). Hearts pre-treated with EPO exhibited significantly improved post-ischemic recovery of LVDP compared to control hearts (mean±SE: 72±3 in EPO-treated versus 35±3% in control hearts, P<0.05 by ANOVA and Bonferroni post-hoc test, n=10 experiments each group) and the protective effect of EPO was significantly inhibited in chel-treated hearts (52±4% in EPO+chel versus 72±3% in EPO-treated hearts, P<0.05, n=10). As a control, treatment of the hearts with chelerythrine alone had no significant effect on LVDP (49±4%) compared to control hearts. These data demonstrate that EPO-mediated activation of the PKC signaling pathway is required for the cardioprotective effect of EPO during ischemia-reperfusion injury. Figure Figure

Since the early days of the semiconductor industry, defect control has been key to the successful development of devices and circuits. It requires a thorough understanding of their formation and the impact on the electrical material parameters. This has only been possible by the invention of powerful structural, chemical and electrical characterization tools, with the device itself perhaps as the most sensitive probe. This evolution was paralleled by the development of ab initio calculation methods, based on Density Functional Theory and more recently, also TCAD tools allowing more and more refined modelling of the impact of defects on the electrical characteristics of devices. The implementation of other materials than Si and SiO2 in CMOS through the hetero-epitaxial growth on a silicon substrate for example, has renewed the interest in defect engineering during the last two decades, leading to single-defect analysis methods like Random Telegraph Noise (RTN) [1] or novel growth schemes like Aspect Ratio Trapping (ART) [2] for the removal of extended defects from the device active regions. In this presentation, some state-of-the-art analysis techniques will be highlighted, including Deep Level Transient Spectroscopy (DLTS) [3], Generation-Recombination (GR) noise and RTN spectroscopy [1,4] and p-n diode lifetime analysis [5]. These methods will be applied to several case studies. As shown in Fig. 1, threading extended defects impact the recombination lifetime of lowly-doped n-type In0.47Ga0.53As starting from a density of a few 107 cm-2. Likewise, it will be demonstrated that the GR noise observed in GaN-on-Si MOSHEMTs (Fig. 2) most likely originates from threading dislocations [6]. It is concluded that when hetero-epitaxial layers can be grown with a sufficiently low defect density, their impact will be more on the variability of the electrical parameters rather than on the effective values. In addition, the position of the defect with respect to strategic nodes like a p-n junction or depletion region largely determines its electrical impact, as has been validated by TCAD simulations. References [1] E. Simoen and C. Claeys, “Random Telegraph Signals in Semiconductor Devices”, The Institute of Physics, Bristol, UK (2016). [2] J. Z. Li et al., Appl. Phys. Lett., 91, p. 021114 (2007). [3] E. Simoen, J. Lauwaert and H. Vrielinck, Semiconductors and Semimetals, Eds. L. Romano, V. Privitera and C. Jagadish, 91, pp. 205-250, Elsevier 2015. [4] D. Boudier et al., Solid-St. Electron., 128, pp. 102-108 (2017). [5] Po-Chun (Brent) Hsu et al., J. Phys. D: Appl. Phys., 52, p. 485102 (2019). [6] K. Takakura et al., IEEE Trans. Electron Devices, 67, pp. 3062-3068 (2020). Figure 1

1010 Background: Trabectedin ([T]; Yondelis) binds to the minor groove of DNA; its cytotoxicity is determined by the synergistic action of two DNA repair mechanisms, the efficient nucleotide excision repair (NER) and deficient homologous recombination repair (HRR) machinery. T has EMEA authorization in soft tissue sarcoma after failure of standard treatment. Preliminary data have shown activity of T as single agent in MBC. Clinical and preclinical data suggested T may display specific activity among certain NER-intact or HRR-deficient MBC, and prompted this phase II trial dedicated to 3 subgroups: triple-negative (TN), HER-2-overexpressed, and BRCA1/2 germline-mutated MBC. Methods: T was given at 1.3 mg/m2 as a 3- hour iv infusion every 3 weeks to pts with pretreated progressive MBC: Group A: TN; Group B: HER-2+++; Group C: BRCA1/2 mutation carriers. Endpoints were objective response (OR) rate by RECIST, duration of response, progression free survival (PFS), tumor volume changes, safety and exploratory pharmacogenomics (PGx). Results: A total of 95 women (median [med] age 52, ECOG 0/1 48/52%) have been enrolled (A:50, B:24, C:21) with data available for 72 pts. Med number of prior chemotherapy regimens: 4 (1–10). Med number of T cycles administered: 2 (1–12) for all groups. The most commonly reported grade 3/4 AEs are neutropenia (29/21%), ALT (28/2%) and AST (13/0). Alopecia/stomatitis, only G1, was reported in <2% each. Long-lasting disease stabilizations were described in all groups. While OR were rare among TN MBC pts (2PR/43 evaluable), preliminary analysis by investigator shows efficacy in group C (4PR/11 evaluable). Tissue samples from 36 pts were collected for RNA expression analysis (XPG + ERCC1 + BRCA1). Preliminary results show high XPG is associated with longer PFS: 4.1 months (95% CI 2.6-not reached) versus 1.3 months (95% CI 1.2–3.7), p = 0.01. Analyses are ongoing. Conclusions: Trabectedin shows a manageable safety profile in the 3 groups of MBC with promising efficacy in certain DNA-repair machinery sub-categories defined molecularly. TN group was closed due to low response. More mature PGx results will be discussed to help selecting the patients who are at highest chance for response. [Table: see text]

New methods are presented for determining the role of coupled ocean-atmosphere model climate bias on the strength and variability of the El Nino-Southern Oscillation (ENSO) and on the seasonal ensemble prediction of El Nino and La Nina events. An intermediate complexity model with a global atmosphere coupled to a Pacific basin ocean is executed with parallelised algorithms to produce computationally efficient year-long forecasts of large ensembles of coupled flow fields, beginning every month between 1980 and 1999. Firstly, the model is provided with forcing functions that reproduce the average annual cycle of climatology of the atmosphere and ocean based on reanalysed observations. We also configure the model to generate realistic ENSO fluctuations. Next, an ensemble prediction scheme is employed which produces perturbations that amplify rapidly over a month. These perturbations are added to the analyses and give the initial conditions for the ensemble forecasts. The skill of the forecasts is presented and the dependency on the annual and ENSO cycles determined. Secondly, we replace the forcing functions in our model with functions that reproduce the averaged annual cycles of climatology of two state of the art, comprehensive Coupled General Circulation Models. The changes in skill of subsequent ensemble forecasts elucidate the roles of model bias in error growth and potential predictability.
 
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STEAM-based learning is a global issue in early-childhood education practice. STEAM content becomes an integrative thematic approach as the main pillar of learning in kindergarten. This study aims to develop a conceptual and practical approach in the implementation of children's education by applying a modification from STEAM Learning to R-SLAMET. The research used a qualitative case study method with data collection through focus group discussions (FGD), involving early-childhood educator's research participants (n = 35), interviews, observation, document analysis such as videos, photos and portfolios. The study found several ideal categories through the use of narrative data analysis techniques. The findings show that educators gain an understanding of the change in learning orientation from competency indicators to play-based learning. Developing thematic play activities into continuum playing scenarios. STEAM learning content modification (Science, Technology, Engineering, Art and Math) to R-SLAMETS content (Religion, Science, Literacy, Art, Math, Engineering, Technology and Social study) in daily class activity. Children activities with R-SLAMETS content can be developed based on an integrative learning flow that empowers loose part media with local materials learning resources.
 Keyword: STEAM to R-SLAMETS, Early Childhood Education, Integrative Thematic Learning
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The article presents multicolor emission observed in poly(methyl methacrylate) specimens co-doped by trivalent terbium and europium ions. The bright luminescence was obtained using organometallic complexes of lanthanides and energy transfer antenna effect. Spectroscopic characterization exhibit wide excitation spectrum according to chelating structure of used complexes and characteristic Tb3+ and Eu3+ emission peaks in luminescence spectra. The calculated CIE 1931 chromaticity coordinates confirm that colorful emission from green to red can be obtained using proposed materials. Full Text: PDF ReferencesJ.-H. Jou, M.-C. Sun, H.-H. Chou, C.-H. Li, "White organic light-emitting devices with a solution-processed and molecular host-employed emission layer", Appl. Phys. Lett. 87, 043508 (2005). CrossRef R. Mac Ciarnain, D. Michaelis, T. Wehlus, A. F. Rausch, N. Danz, A. Brauer, A. Tünnermann, "Emission from outside of the emission layer in state-of-the-art phosphorescent organic light-emitting diodes", Organic Electronics 44, 115 (2017). CrossRef G. Williams, C. Backhouse, H. Aziz, "Integration of Organic Light Emitting Diodes and Organic Photodetectors for Lab-on-a-Chip Bio-Detection Systems", Electronics 3, 43 (2014). CrossRef P. Miluski, D. Dorosz, M. Kochanowicz and J. Żmojda, "Fluorescent polymeric optical fibre illuminator", Electronics Letters, 52, 18 (2016). CrossRef L. Bilro, N. Alberto, J. L.Pinto, R. Nogueira, "Optical Sensors Based on Plastic Fibers", Sensors 12, 12184 (2012). CrossRef P. Miluski, D. Dorosz, J. Żmojda, M. Kochanowicz, J. Dorosz, "Luminescent Polymer Optical Fibre Sensor for Temperature Measurement", Acta Phys. Pol. A 127, 730 (2015) CrossRef C. Lethien, C. Loyez, J. P. Vilcot, N. Rolland, P. A. Rolland, "Exploit the Bandwidth Capacities of the Perfluorinated Graded Index Polymer Optical Fiber for Multi-Services Distribution", Polymers 3, 1006 (2011). CrossRef J. Zubia, J. Arrue, "Plastic Optical Fibers: An Introduction to Their Technological Processes and Applications", Opt. Fiber Technol. 7, 101 (2001). CrossRef N. Sultanovaa, S. Kasarovaa, I. Nikolov, "Dispersion Properties of Optical Polymers", Acta Physica Polonica A 116, 585 (2009). CrossRef J. Arrue, F. Jiménez, I. Ayesta, M. Asunción Illarramendi, J. Zubia, "Polymer-Optical-Fiber Lasers and Amplifiers Doped with Organic Dyes", Polymers 3,1162 (2011). CrossRef P. Miluski, M. Kochanowicz, J. Żmojda, "Spectroscopic investigation of organic co-doped PMMA for optical fiber technology", Journal Of Optoelectronics And Advanced Materials, 19, 379 (2017). DirectLink P. Miluski, M. Kochanowicz, J. Żmojda, and D. Dorosz, "Emission properties and energy transfer in Perylene-Rhodamine 6 G co-doped polymeric fiber", Chinese Optics Letters 14, 12, 121602 (2016). CrossRef H. Liang, Z. Yang, L. Xiao, F. Xie, " Radiative transition probability of a europium (III) chelating polymer", Optoelectronics And Advanced Materials ? Rapid Communications 4, 9, 1396 (2010). CrossRef H. Jiu, J. Ding, Y. Sun, J. Bao, C. Gao, Q. Zhang, "Fluorescence enhancement of europium complex co-doped with terbium complex in a poly(methyl methacrylate) matrix", Journal of Non-Crystalline Solids 352, 197 (2006). CrossRef K. Kuriki, S. Nishihara, Y. Nishizawa, A. Tagaya, Y. Koike, Y. Okamoto, "Spectroscopic properties of lanthanide chelates in perfluorinated plastics for optical applications", Journal of the Optical Society of America B 19, 8, 1844 (2002). CrossRef P. Miluski, M. Kochanowicz, J. Żmojda, D. Dorosz, "Luminescent properties of Tb3+-dopedpoly(methyl methacrylate) fiber" Chinese Optics Letters, 15, 7, 070602 (2017). DirectLink P. Miluski, M. Kochanowicz, J. Żmojda, D. Dorosz, "Properties of Eu3+ doped poly(methyl methacrylate) optical fiber", Optical Engineering, 56, 2, 027106 (2017). CrossRef D. Oh, N. Song and J.-J. Kim, "Plastic optical amplifier using europium complex", Proc. SPIE, 4282, (2001). CrossRef X. Xu, H. Ming, Q. Zhang, "Optical-transition probabilities of Nd3+ ions in polymer optical fibers", Optics Communications 199, 369 (2001). CrossRef Z.-Q. Zheng, H. Liang, H. Ming, Q.-J. Zhang, X.-H. Han, G.-Z. Wang, J.-P. Xie, "Optical Transition Probability of Sm 3+ Ions in a Polymer Optical Fibre", Chin. Phys. Lett. 21, 2, 291 (2004). CrossRef

Abstract Objectives The aim was to assess the diagnostic accuracy of APRI and FIB-4 in assessing the stage of liver fibrosis in end stage renal disease (ESRD) patients with chronic viral hepatitis and to compare the two tests with standard tru-cut liver biopsy. Material and Methods The study was conducted at Sindh Institute of Urology and Transplantation Karachi (SIUT) from May 2010 to May 2014. All ESRD patients, being considered as candidates for renal transplantation and in whom liver biopsy was performed were included. Fibrosis stage was assessed on liver biopsy using Ishak scoring system. The serum transaminases and platelet counts were used to calculate APRI and FIB-4 scores. Results Out of 109 patients, hepatitis C and B virus infections were present in 104 (95.4%) and 3(2.8%), respectively, while 2 (1.8%) patients had both infections. The mean Ishak fibrosis score was 1.95 ± 2. Advanced fibrosis was noted in 37 (34%) patients. Univariate analysis showed that advanced liver fibrosis was associated with lower platelets counts (P=0.001) and higher aspartate aminotransferase (AST) (P=0.001), alanine aminotransferase (ALT) (P=0.022), APRI score (P=0.001) and FIB-4 score (P=0.001). On logistic regression analysis, only APRI score (P < 0.001) was found to be the independent variable associated with advanced liver fibrosis. APRI score cutoff ≥1 indicating advanced fibrosis showed sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 91.9%, 90.3%, 82.9%, 95.6%, respectively with area under the curve (AUC) of 0.97. Similarly, a FIB-4 score cutoff ≥1.1 had sensitivity, specificity, PPV and NPV of 70.27%, 66.67%, 52% and 81.36%, respectively with AUC of 0.74. Conclusion APRI is more accurate noninvasive test for assessing advanced liver fibrosis in ESRD patients as compared to FIB-4. It can be used to obviate the need for liver biopsy in this high risk population.

This review provides the results of a recent analysis of the Islet Transplant Registry on clinical adult islet transplants performed worldwide through June 30, 1992. Between December 12, 1893 and June 30, 1992, 167 adult islet transplants were performed at 25 institutions worldwide, including 104 at 9 institutions in North America, 62 at 15 institutions in Europe, and 1 elsewhere. The total number of diabetic patients reported to be insulin independent after adult islet allotransplantation through June 30,1992, was 19. In an analysis by era, the percentage of patients that showed positive basal C-peptide levels (i.e. ≥ 1 ng/mL at ≥ 1 mo) posttransplant, and that became insulin independent (>1 wk) in the 1985-1989 era (n = 35 cases) were 20% and 6%, and in the 1990-1992 era (n = 69 cases) were 64% and 20%, respectively, and thus have improved significantly (p < 0.001 and p < 0.05). For the 1990-1992 period, the percentage of patients who showed positive basal C-peptide levels post-transplant, and who became insulin independent in the single donor pancreas group (n = 31 cases) were 52% and 13%, and in the multiple donor pancreata group (n = 36 cases) were 75% and 28%, respectively. Islet graft function rates were nearly identical for grafts prepared from pancreata stored ≤6 h (n = 27) and >6 ≤ 12 h (n = 29), so that 67% and 72% showed positive basal C-peptide levels, and 30% and 21% of the recipients became insulin independent, respectively. No single patient showed islet graft function sufficient to allow withdrawal from insulin, if the pancreata have been stored for more than 12 h. In regard to recipient category for the six groups, namely IAK (islet after kidney), SIK (simultaneous islet kidney transplantation), SIL (simultaneous islet liver transplantation), SIL(C) (simultaneous islet liver transplantation after cluster operation), SIKL (simultaneous islet kidney liver transplantation), and SIH-L (simultaneous islet heart-lung transplantation), the number of patients who showed positive basal C-peptide levels post-transplant was 11 (58%), 17 (57%), 5 (83%), 8 (80%), 1 (50%), and 0 (0%), and the number of insulin independent patients was 4 (21%), 4 (13%), 0 (0%), 6 (60%), 0 (0%), and 0 (0%), respectively. Comparing the two largest recipient categories, namely IAK and SIK, no difference in the outcome of these transplants was apparent. The only sites of transplantation in the period between 1990-1992 were the liver, epiploic flap, and spleen, with the total number of recipients being 60 (90%), 4 (6%), and 3 (4%), respectively. For these three groups, the number of patients who showed positive basal C-peptide levels was 38 (63%), 2 (50%), and 1 (33%), and the number of insulin independent patients was 13 (22%), 0 (0%) and 0 (0%), respectively. In the overwhelming majority of cases, recipient selection was not based on prospective HLA donor/recipient matching. In different categories of HLA mismatching (i.e., AB-, DR-, BDR-, and ABDR-mismatch) no obvious tendency or difference in outcome could be demonstrated. In the 1990-1992 period, 16 patients (24%) received OKT3, 26 patients (39%) received ALS, ALG, or ATG, and 25 patients (37%) received neither monoclonal nor polyclonal T-cell antibodies for induction immunosuppression. For the three groups mentioned, the number of patients who showed positive basal C-peptide levels was 12 (86%), 16 (62%), and 15 (60%), and the number of insulin independent patients was 2 (14%), 6 (23%), and 6 (24%), respectively. A synopsis of all pretransplant C-peptide-negative Type I diabetic patients who succeeded in insulin independence revealed certain common characteristics, such as transplantations of ≥8000 islet equivalents per kilogram body weight, a purity of transplanted islets ≥ 50% (in all but one case), the liver as implantation site, and OKT3 or ALG/ ALS/ATG for induction immunosuppression (“state of the art” cases). Because it has been unequivocally proven that islet transplantation can be performed successfully in association with other organ transplants, more attention should be drawn to the nonuremic, nonkidney Type I diabetic patients, who have not been reported in a single case since 1990. This is the real target group, that could benefit most from islet replacement. However, islet transplantation in this recipient category will only have an undisputable indication, if low-risk, but effective methods other than life-long immunosuppression to protect the islet graft from rejection can be developed.

Reduced graphene oxide is a very attractive material for sensor applications. It exhibits high conductivity at room temperature and high specific surface area. Since it can be produced in many ways, its properties can be influenced by the fabrication method. In this paper, we investigated the influence of graphite precursors (flake, scalar and synthetic) on the size of reduced graphene oxide. We have shown that the size of the precursor determines the size of the obtained rGO. We have noted that the larger graphite size, the larger rGO size. Full Text: PDF ReferencesR. Peng, Y. Li, T. Liu et al., "Reduced graphene oxide/SnO2@Au heterostructure for enhanced ammonia gas sensing", Chem. Phys. Lett., 737, 136829 (2019). CrossRef S. Pei and H. M. Cheng, "The reduction of graphene oxide", Carbon N. Y., 50, 9 (2012). CrossRef N. Sharma, V. Sharma, R. Vyas et al., "A new sustainable green protocol for production of reduced graphene oxide and its gas sensing properties", J. Sci. Adv. Mater. Devices, 4, 3 (2019) CrossRef R. Tarcan, O. Todor-Boer, I. Petrovai, C. Leordean, S. Astilean, I. Botiz, "Reduced graphene oxide today", J. Mater. Chem. C, 8, 4 (2020). CrossRef X. Jiao, Y. Qiu, L. Zhang, and X. Zhang, "Comparison of the characteristic properties of reduced graphene oxides synthesized from natural graphites with different graphitization degrees", RSC Adv., 7, 82 (2017). CrossRef J.A. Quezada-Renteria, C.O. Ania, L.F. Chazaro-Ruiz, J.R. Rangel-Mendez, "Influence of protons on reduction degree and defect formation in electrochemically reduced graphene oxide", Carbon N. Y., 149 (2019). CrossRef H. Gao, Y. Ma, P. Song, J. Leng, Q. Wang, "Characterization and cytocompatibility of 3D porous biomimetic scaffold derived from rabbit nucleus pulposus tissue in vitro", J. Mater. Sci. Mater. Electron., 32, 8 (2021). CrossRef A.T. Lawal, "Graphene-based nano composites and their applications. A review", Biosens. Bioelectron., 141, 111384, (2019). CrossRef E. Aliyev, V. Filiz, M.M. Khan, Y.J. Lee, C. Abetz, V. Abetz, "Structural Characterization of Graphene Oxide: Surface Functional Groups and Fractionated Oxidative Debris", Nanomaterials, 9, 8 (2019). CrossRef S. Sali, H.R. Mackey, A.A. Abdala, "Effect of Graphene Oxide Synthesis Method on Properties and Performance of Polysulfone-Graphene Oxide Mixed Matrix Membranes", Nanomaterials, 9, 5 (2019). CrossRef G. Lu, L.E. Ocola, J. Chen, "Reduced graphene oxide for room-temperature gas sensors", Nanotechnology, 20, 44 (2009). CrossRef C. Botas, P. Alvarez, C. Blanco et al., "Critical temperatures in the synthesis of graphene-like materials by thermal exfoliation–reduction of graphite oxide", Carbon N. Y., 52, 2013. CrossRef

Background:Type I interferons such as Anifrolumab have been implicated in Systemic lupus erythematosus (SLE) pathogenesis on the basis of increased interferon-stimulated gene expression and genetic susceptibility. Little is known regarding its efficacy and safety profile.Objectives:To assess the efficacy and safety of Anifrolumab in patients with SLE.Methods:Electronic databases (PubMed, Embase, Scopus, Cochrane) were searched from inception until December 15th, 2020. Unadjusted odds ratios (OR) were calculated from dichotomous data using Mantel Haenszel (M-H) random-effects with statistical significance to be considered if the confidence interval excludes 1 and p<0.05. The primary outcome of interest was British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA). Secondary outcomes included the proportion of patients who achieved an SLE responder index of 4 (SRI-4) reduction of 50% or more in the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), reductions in the glucocorticoid dose and adverse effects.Results:A total of three studies1,2,3 with 839 participants (Anifrolumab=372, Placebo=467) were included in our analysis. Follow-up duration was at week 52. A statistically significant different was observed in the Anifrolumab arm in terms of BICLA response (OR 0.44 95%CI 0.34-0.59;p < 0.00001, I2=4), ≥50% reduction in CLASI activity score (OR 0.36 95%CI 0.21-0.60;p=0.0001, I2=0), glucocorticoid reduction (OR 0.41 95%CI 0.28-0.59;p<0.00001; I2=0) and SRI-4 response (OR 0.52 95% CI 0.30-0.90; p=0.02, I2=75). However, Adverse events were less likely in the placebo arm as compared to Anifrolumab (OR 1.54 95%CI 1.05-2.25; p=0.03; I2=0).Conclusion:Anifrolumab was found to be more effective than placebo for the management of SLE, but may also cause more severe adverse effects.References:[1]Morand EF, Furie R, Tanaka Y, Bruce IN, Askanase AD, Richez C, Bae SC, Brohawn PZ, Pineda L, Berglind A, Tummala R; TULIP-2 Trial Investigators. Trial of Anifrolumab in Active Systemic Lupus Erythematosus. N Engl J Med. 2020 Jan 16;382(3):211-221. doi: 10.1056/NEJMoa1912196. Epub 2019 Dec 18. PMID: 31851795.[2]Furie R, Khamashta M, Merrill JT, Werth VP, Kalunian K, Brohawn P, Illei GG, Drappa J, Wang L, Yoo S; CD1013 Study Investigators. Anifrolumab, an Anti-Interferon-α Receptor Monoclonal Antibody, in Moderate-to-Severe Systemic Lupus Erythematosus. Arthritis Rheumatol. 2017 Feb;69(2):376-386. doi: 10.1002/art.39962. PMID: 28130918; PMCID: PMC5299497.[3]Furie RA, Morand EF, Bruce IN, et al. Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. Lancet Rheumatol 2019; 1(4):e208-e219.Disclosure of Interests:None declared

Background and aim: Progress in laboratory diagnostics of IgE-mediated allergy is the use of component-resolved diagnosis. Our study analyses the results of specific IgE to 295 allergen reagents (117 allergenic extracts and 178 molecular components) in patients suffering from atopic dermatitis (AD) with the use of ALEX2 Allergy Explorer. Method: The complete dermatological and allergological examination, including the examination of the sensitization to molecular components with ALEX2 Allergy Explorer testing, was performed. The statistical analysis of results was performed with these methods: TURF (total unduplicated reach and frequency), best reach and frequency by group size, two-sided tests, Fisher’s exact test, and chi-square test (at an expected minimum frequency of at least 5). Results: Altogether, 100 atopic dermatitis patients were examined: 48 men, 52 women, the average age 40.9 years, min. age 14 years, max. age 67 years. The high and very high level of specific IgE was reached in 75.0% of patients to 18 molecular components: from PR-10 proteins (Aln g 1, Bet v 1, Cor a1.0103, Cor a1.0401, Fag s 1), lipocalin (Can f 1), NPC2 family (Der f 2, Der p 2), uteroglobin (Fel d 1), from Alternaria alternata (Alt a 1), Beta expansin (Lol p 1, Phl p 1), molecular components from Timothy, cultivated rye (Secc pollen) and peritrophin-like protein domain Der p 23. The high and very high level of specific IgE to other lipocalins (Fel d 7, Can f 4), to arginine kinase (Bla g 9, German cockroach), and to allergen extracts Art v (mugwort), and Cyn d (Bermuda grass) reached 52.0% of patients. The severity of AD is in significant relation to the sensitization to molecular components of storage mites (Gly d 2, Lep d 2—NPC2 family), lipocalins (Can f 1, Can f 2, Can f 4, and Can f 6), arginine kinase (Asp f 6, Bla g 9, Der p 20, Pen m 2), uteroglobin (Fel d 1, Ory c 3), Mn superoxide dismutase (Mala s 11), PR-10 proteins (Fag s 1, Mal d 1, Cor a 1.0401, Cor a 1.0103), molecular components of the peritrophin-like domain (Der p 21, Der p 23), and to Secc pollen. In the subgroup of patients suffering from bronchial asthma, the significant role play molecular components from house dust mites and storage mites (Lep d 2, Der p 2, Der f 2—NPC2 family), cysteine protease (Der p 1), peritrophin-like protein domain (Der p 21, Der p 23), enolase from Alternaria alternata (Alt a 6), and Beta expansin Phl p 1. Conclusion: The results of our study demonstrate the detailed profile of sensitization to allergens reagents (allergen extract and molecular components) in patients with atopic dermatitis. We show the significance of disturbed epidermal barrier, resulting in increased penetration of allergens. We confirmed the significant relationship between the severity of AD, the occurrence of bronchial asthma and allergic rhinitis, and high levels of specific IgE to allergen reagents. Our results may be important for regime measures and immunotherapy; Der p 23 shall be considered as an essential component for the diagnosis and specific immunotherapy of house dust mite allergy.

Abstract BACKGROUND: S-adenosyl-L-methionine (AdoMet or SAM-e®) is a commonly used nutritional supplement available in the United States since 1999. AdoMet is metabolized to homocysteine (Hcy), a potential cardiovascular risk factor. A few open-label, single-arm studies have reported on the effect of exogenous AdoMet on the levels of Hcy in humans; however, this has not been tested in a double-blind, randomized clinical trial. As a nutritional supplement, AdoMet is subject only to limited regulation by the FDA, despite being used to treat clinical diseases such as depression and osteoarthritis. AdoMet is the methyl donor for small molecule, DNA, RNA, and protein methylation reactions; therefore, further understanding the biology of the AdoMet/Hcy system is important. We hypothesized that exogenous AdoMet would increase plasma Hcy levels. METHODS: In a double-blind, placebo-controlled, randomized clinical trial, 93 healthy human subjects were screened and 52 were treated with placebo (26) or 800 mg per day AdoMet (26) pills for 4 weeks. Pre- and post-treatment Hcy levels were measured. The primary endpoint was change in Hcy level. Secondary endpoints included an interim Hcy level, high sensitivity C-reactive protein (hsCRP) levels, lipid profile, and transaminases. Exclusion criteria included pregnancy and concurrent use of medications associated with changes in Hcy. RESULTS: Of 52 subjects enrolled, 45 were evaluable at the end of treatment. Subject characteristics and dropout rates were similar between placebo and control groups. Adverse events were minor and were not different between placebo and AdoMet. The primary endpoint, change in Hcy, was not significantly different between the groups (mean (umol/L), baseline: 7.43 (placebo), 8.25 (AdoMet), P=0.358; 4 week: 7.66 (placebo), 8.06 (AdoMet), P = 0.683; Baseline − 4 week: 0.23 (placebo), −0.19 (AdoMet), P = 0.427). No statistically significant difference in change in Hcy or hsCRP at 2 or 4 weeks was noted. This was true for both absolute differences as well as relative percent changes. A small decrease in ALT was observed at 2 weeks in the AdoMet group compared to the placebo group (P = 0.027). AdoMet is used in the treatment of liver diseases. There was a small, but statistically significant (P = 0.028) decrease in total cholesterol in the AdoMet group as compared to the placebo group. Interestingly, a subject with the highest baseline Hcy level had a decline in Hcy on AdoMet. Study limitations include no evaluation of AdoMet serum levels or measurement of the effect of AdoMet on DNA methylation patterns. CONCLUSIONS: AdoMet seems well tolerated and in a dose of 800 mg/day for 4 weeks does not appear to significantly affect Hcy levels in the blood. Future clinical trials of AdoMet should monitor Hcy levels with extended use of AdoMet to confirm its safety with long term use. Clinicaltrials.gov ID: NCT00284011.

Abstract Abstract 4638 Introduction: Acute myeloid leukemia (AML) is a heterogeneous group of aggressive disease with complex process,gene mutations play an important role in AML pathogenesis. Several genes have been identified in AML,such as FLT3, c-KIT, NPM1 and JAK2. Indeed, some mutations have revealed prognosis subgroups and modified the therapeutic management of these leukemias. Recently,novel mutations in IDH1(amino acid R132)and IDH2 (R140 and R172)have been found in patients with AMLs,but the frequency and impact on biological and prognostic features in Chinese patients with AMLs remain unknown. We aimed at studying the potential significance of IDH1 and IDH2 mutations in AML and analyzed their interaction with other mutations in Chinese patients with de novo AMLs. Methods: We searched 163 Chinese patients with de novo AML for mutations in the IDH1,IDH2, JAK2, NPM1, FLT3-ITD,C-KIT genes.Female/male ratio was 98/65 and age ranged from 17.0–74.0years (median, 41.0years).Genomic DNA was extracted from diagnostic marrow specimens,FLT3 internaltandem duplication(FLT3 –ITD) and JAK2V617F mutations were screened using polymerase chain reaction (PCR),c-KIT, NPM1 and IDH genes were assessed by PCR followed by direct sequencing, according to previously described protocols. Results: Overall, IDH mutations were found in 25 patients (15.3%) —IDH1 in 7 patients (4.29%) and IDH2 in 18 patients (11.04%). A total of 4 types of IDH1 mutations were identified(c.395G>A, p.R132H,n=4 Gc.394C>A, p.R132S,n=1 Gc.394C>G, p.R132G,n=1 Gc.315C>T, n=1),six out of the seven patients with the missense mutations and the overall frequency of missense mutations in IDH1 was 3.68% (6/163). Both synonymous substitution (c.315C>T; rs11554137) in IDH1 and IDH2R140 mutation occurred in one patient. No mutated cases had both IDH1 and IDH2 missense mutations, suggesting that the mutations are mutually exclusive. IDH2 mutations caused changes of R140 (c.419G>A,p.R140Q,n=18), R172 mutation was not found in our study. The NPM1 mutation in exon 12 was present in 18.35% (n=29 29/158), 25 cases had FLT3-ITD(15.8% 25/158),One case had frame insertion/deletions of c-KIT in exon 8,7 cases had the substitution of a single amino acid in exon 17(4.57%,7/153),none of them had JAK2V617F mutation. IDH- mutated cases showed a higher frequency of concurrent NPM1 mutation compared with wildtype cases (48.3% 14/29 vs 10.8% 11/129), IDH mutations were also more frequent in FLT3-ITD mutation vs FLT3-ITD wildtype (44.0% 11/25 vs 10.5%14/133).10 patients had both FLT3-ITD and NPM1 mutations, concurrent mutations in NPM1, FLT-ITD were detected in 5 cases with the IDH mutation. None of all cases had both IDH and C-KIT mutations. IDH mutations were more often in cytogenetically normal AML cases(20.5% 15/73 vs5.8% 3/52. Patients with IDH mutations were older (51:40 P=0.003), whereas, there were no differences in sex,WBC and platelet count for IDHmut and IDHwt. Conclusion: Our results show that IDH mutations, especially IDHR140 were frequent genetic alterations in Chinese patients with de novo AMLs, and associated with older age, normal karyotype at diagnosis.There was strong association of IDH mutations with NPM1 and FLT3-ITD mutations, suggesting that IDH mutations may act cooperatively in leukemogenesis. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Biopsy diagnoses of benign breast disease (BBD) confer a 1.5- to 4-fold increased risk of developing breast cancer (BC) compared with women without BBD. Previously, we reported that decreased numbers of specific immune cell types in lobules of BBD biopsies predicted increased BC risk, suggesting the promise of future tissue biomarker studies to define BC risk markers among BBD patients. Thus, we applied protein-based GeoMx® Digital Spatial Profiling (DSP) to BBD biopsies preceding BC (cases) and to BBD biopsies from cancer-free patients (controls) to identify possible BC risk markers, which we then evaluated in subsequent BC tissues and in surrounding normal lobules of cases. Methods: Archived pathology slides of BBD biopsies were reviewed and used to guide preparation of TMAs containing 1.0-mm diameter FFPE cores of lobules from an age- and cohort-period-matched set of 91 cases and 88 controls from the Mayo Clinic BBD Cohort. For patients who later developed BC, we prepared TMAs of BC tissue and surrounding mapped normal lobules. We applied GeoMx® DSP (immune and canonical signaling proteins) to both sets of TMAs. Following QC and data normalization, associations of case status with log-transformed biomarker expression in lobules of BBD biopsies were carried out using linear mixed modeling approaches, accounting for multiple ROIs per individual. Biomarkers significantly associated with case status (p<0.05) were further examined in BCs and adjacent normal lobules, using similar approaches. Results: The mean age at BBD biopsy was 52 years, and at BC diagnosis of cases, 61.4 years (mean time from BBD to BC was 10.2 years). A family history of BC was more frequent among cases (70% versus 43%; chi-square p=0.002). Of 72 biomarkers tested, 46 (64.4%) were evaluable after QC and normalization and 5 were associated with BC risk after adjustment for family history of BC: BCL2 (p=0.005), STING (p=0.006), CD44 (p=0.02), S100 protein (p=0.03) and pan-AKT (p=0.05); each showed higher levels in lobules of BBD biopsies of controls than cases. Three unique patterns appeared when examining these biomarkers across tissue type within cases: for BCL2 (p=5 x 10-9) and STING (p=2 x 10-19), levels were high in both BC and lobules surrounding BC but low in preceding BBD; for GAPDH (p=4 x 10-53) and pan-AKT (p=2 x 10-33), levels were high in BC, low in preceding BBD, and moderate in lobules surrounding BC; and for CD44 (p=2 x 10-6) and S100B (p=2 x 10-49), levels were low in BC, high in lobules surrounding BC and moderate in preceding BBD. Conclusions: Using a novel TMA of lobules in combination with DSP, we preliminarily identified immune-based and PI3 kinase-related protein biomarkers in BBD biopsies associated with BC risk. In case-only analyses, these markers demonstrated complex differences between lobules in BBD biopsies, subsequent BCs and adjacent normal lobules. Citation Format: Robert Alan Vierkant, Jodi M. Carter, Stacey J. Winham, Chen Wang, Jennifer M. Kachergus, Ji Shi, Raymond M. Moore, Bryan M. McCauley, Laura M. Pacheco-Spann, E A. Thompson, Derek C. Radisky, Amy C. Degnim, Mark E. Sherman. Towards prediction of breast cancer risk in benign biopsies with high-plex GeoMx spatial protein profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2203.

BackgroundNumerous cytokines that influence disease activity in psoriatic arthritis (PsA) are modulators of the Janus Kinases/Signal Transducers and Activators of Transcription (JAK/STAT) pathway. The JAK1/STAT1/STAT3/STAT5 network can drive the expansion of Th17 and regulatory T cells via proinflammatory cytokines in PsA joints,[1], [2] while hyperphosphorylation of STAT3 in immune cells has previously been shown to promote PsA pathogenesis through the Interleukin (IL)-23/IL-17/IL-22 axis.[3] Therefore, the phosphorylation status of STAT molecules in leucocytes of PsA patients may indicate active disease and could potentially guide treatment with JAK inhibitors.ObjectivesTo analyse phosphorylated STAT (pSTAT) levels of circulating leucocyte subsets in PsA patients with active and inactive diseaseMethodsWhole blood was drawn on consecutive PsA patients fulfilling the CASPAR criteria[4] to perform flow cytometry analysis using the BD FACSLyric platform. Disease activity was assessed using the Disease activity for psoriasis arthritis (DAPSA) score.[5] All steps from storage of drawn blood to cell fixation were performed at 4°C to prevent auto-activation of leucocytes. The geometric mean fluorescence intensities (gMFI) of pSTATs in granulocytes, monocytes, B cells and CD4+/- naïve/memory T cells were compared between patients with moderate to high (MoDA/HDA) and remission to low disease activity (REM/LDA). Correlation analysis between gMFIs and DAPSA scores were performed.ResultsForty-two patients (female ratio: 0.48) with established PsA (median ± standard deviation, age: 56 ± 12.54 years, disease duration: 8.50 ± 7.10 years) were included in this study. Twenty-one percent of patients were in MoDA/HDA, while the remaining 79% were in REM/LDA. Patients in MoDA/HDA showed significantly higher pSTAT3 levels in CD4+ naïve (gMFI median ± standard deviation: 284.5 ± 79.9 vs 238 ± 92.9, p = 0.011), CD4- naïve (297 ± 107.5 vs 238 ± 98.4, p = 0.04), CD4+ memory (227 ± 62.9 vs 190.5 ± 72.2, p = 0.009) and CD4- memory T cells (209 ± 66.8 vs 167.0 ± 64.9, p = 0.036). On the other hand, PsA patients in remission or low disease activity displayed higher pSTAT1 levels in granulocytes (2509 ± 1887 vs 1330.5 ± 784.1, p = 0.040) and monocytes (255 ± 230 vs 144 ± 62.5, p = 0.049). Positive correlations were found between DAPSA scores and pSTAT3 in CD4+ naïve and memory T cells (Spearman’s correlation coefficient rho (ρ) = 0.5, p = 0.0012 and ρ = 0.47, p = 0.0025 resp.) whereas pSTAT1 in granulocytes and monocytes were negatively correlated with the DAPSA scores (ρ = -0.45, p = 0.0074 and ρ = -0.34, p = 0.05).ConclusionDifferential phosphorylation of STAT3 and STAT1 molecules in circulating leucocyte subsets indicates PsA disease activity. Further studies to examine the value of STAT phosphorylation patterns guiding JAK inhibitor therapy are underway.References[1]U. Fiocco et al., “Ex vivo signaling protein mapping in T lymphocytes in the psoriatic arthritis joints,” J. Rheumatol., vol. 93, pp. 48–52, 2015, doi: 10.3899/jrheum.150636.[2]S. K. Raychaudhuri, C. Abria, and S. P. Raychaudhuri, “Regulatory role of the JAK STAT kinase signalling system on the IL-23/IL-17 cytokine axis in psoriatic arthritis,” Ann. Rheum. Dis., vol. 76, no. 10, pp. e36–e36, 2017.[3]E. Calautti, L. Avalle, and V. Poli, “Psoriasis: A STAT3-centric view,” International Journal of Molecular Sciences, vol. 19, no. 1. MDPI AG, Jan. 06, 2018, doi: 10.3390/ijms19010171.[4]W. Taylor, D. Gladman, P. Helliwell, A. Marchesoni, P. Mease, and H. Mielants, “Classification criteria for psoriatic arthritis: Development of new criteria from a large international study,” Arthritis Rheum., vol. 54, no. 8, pp. 2665–2673, 2006, doi: 10.1002/art.21972.[5]M. M. Schoels, D. Aletaha, F. Alasti, and J. S. Smolen, “Disease activity in psoriatic arthritis (PsA): Defining remission and treatment success using the DAPSA score,” Ann. Rheum. Dis., vol. 75, no. 5, pp. 811–818, 2016, doi: 10.1136/annrheumdis-2015-207507.Disclosure of InterestsBarbara Dreo: None declared, Daniel Ruben Pietsch: None declared, Rusmir Husic Speakers bureau: MSD, Lilly und Abbvie, Angelika Lackner: None declared, Johannes Fessler: None declared, Janine Rupp: None declared, Anirudh Subramanian Muralikrishnan: None declared, Jens Thiel Speakers bureau: GSK, BMS, AbbVie, Novartis, Consultant of: GSK, Novartis, Grant/research support from: BMS, Martin Stradner Speakers bureau: Eli Lilly, Pfizer, MSD, BMS, AbbVie, Janssen, Consultant of: Eli Lilly, AbbVie, Janssen, Philipp Bosch Grant/research support from: Pfizer

Abstract Background: Hepatitis C virus (HCV) chronic infection has been associated with increased risk of non-Hodgkin lymphoma (NHL) in people living with human immunodeficiency virus (HIV) as well as with a trend of inferior overall survival (OS) in HIV-associated NHL in the modern antiretroviral therapy (ART) era (Besson 2020). The recent introduction of interferon (IFN)-free direct-acting antivirals (DAAs) led to the achievement of sustained virologic response (SVR) in nearly all treated patients (pts) with negligible toxicity in all settings, including HIV/HCV coinfected pts, in which, however, careful attention to interactions with ART is required. We recently showed that DAAs' administration after immuno-chemotherapy (I-CT) may improve long-term outcome in HIV-negative HCV-associated diffuse large B-cell lymphomas (DLBCL) pts (Merli 2019), however, only scant data have been reported so far about the use of DAAs in HIV/HCV coinfected NHL pts. METHODS: We retrospectively collected clinical and virological features, treatments and outcome data of all consecutive pts with NHL and HIV/HCV co-infection, diagnosed and treated at 13 Italian centers between 2005 and 2021, with a special focus on pts affected by DLBCL and treated with DAAs. Only pts who received ART were included. The primary endpoints were SVR rate after DAAs and 2-year OS in HIV/HCV-positive NHL pts. RESULTS: Overall, we collected data of 74 HIV/HCV coinfected pts with NHL (69 males, 93%), including 52 DLBCL, 13 Burkitt lymphoma (BL), 5 plasmablastic lymphoma (PL), 1 anaplastic large-cell ALK negative, 1 T lymphoblastic, 1 gastric MALT and 1 lymphoplasmacytic lymphoma (Table 1). Median age was 51 years (22-57). Previous AIDS defining event was recorded in 16 cases (22%). The main HIV transmission group was represented by intravenous drug users (69%). Stage was III-IV in 63 pts (85%) and aaIPI was ≥2 in 57 pts (77%). At NHL diagnosis 38% of pts had CD4+ <200/mmc and 31% ≥400 HIV-RNA copies/ml. ARL-IPI score was intermediate or high in 49 pts (64%). HCV genotype was 1 in 26 pts (58%), 3 in 12 (27%) and 4 in 7 (15%). Cirrhosis was present in 39% of pts (Child-Pugh B or C in 25%). Overall, 70 pts underwent curative first line therapy alongside ART, including (R-)CHOP-like in 50 (71%), (R-)EPOCH in 9 (13%), (R-)CODOX-M/IVAC in 8 (11%). Rituximab was used in 53% of cases (60% in DLBCL). 46 pts (66%) achieved a complete response (CR), 7 (10%) a partial response (PR), while 17 (24%) did not respond or progressed. At a median follow-up of 1.8 years (95%CI 0.1-12.3), 33 pts (45%) progressed, with a 2-year PFS of 53.5% (95%CI 40.7-64.8), and 38 (51%) died (30 due to NHL, 7 to infections and 1 to hepatocellular carcinoma), with a 2-year OS of 58.2% (95%CI 45.7-78.9). Two-year OS for DLBCL was 61.4% (95%CI 46.3-73.4), significantly higher than BL (39%, 95%CI 14.1-62.8; p=.0.47, Fig. 1). Considering anti-HCV therapy, 13 pts received IFN-based regimens, 5 of whom achieved SVR (38%). After 2016, 21 pts (14 DLBCL, 3 BL, 2 indolent and 2 T-cell lymphoma), including 4 who previously failed IFN, received various DAAs regimens after I-CT (sofosbuvir-based in 20). Toxicity of DAAs was minimal, with only 2 grade (G) ≥2 adverse events (1 G2 peripheral neuropathy and 1 G2 insomnia). SVR was achieved in 20/21 pts (95%): notably, the only non-responder had discontinued DAAs autonomously. DAAs use was associated with improved OS in all pts (p=0.01) and in DLBCL (p=0.04) and with better PFS (p=0.01) in all pts. Similarly, the achievement of SVR after either DAAs or IFN predicted a better OS (Fig.2) and PFS in all pts (p=0.005 and p=0.008, respectively) and in DLBCL (p=0.018 and p=0.047, respectively). The impact of DAAs and SVR on OS remained significant also if considering only pts who achieved CR or PR after I-CT (p<0.05). At univariate analysis, age >60 years (p=0.02), ARL-IPI (p=0.013), PS ECOG ≥2 (p=0.018) were associated with inferior OS. By applying multivariate Cox regression analysis, age >60 years (HR 67.9, 95% CI 7.2- 643.3, p<0.001), ARL-IPI (HR 2.87, 95%CI 1.03-8.06, p=0.044) and SVR after IFN or DAAs (HR 0.30, 95%CI 0.12-0.75, p=0.01) retained independent prognostic influence on OS. CONCLUSIONS: In this very high risk series of HIV/HCV coinfected pts with NHL, mainly represented by DLBCL, the administration of DAAs after I-CT resulted feasible and effective (SVR 95%), and displayed an independent favourable influence on OS. These results strongly support DAAs' use in this hard to treat population. Figure 1 Figure 1. Disclosures Tisi: Incyte: Membership on an entity's Board of Directors or advisory committees; BWS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zilioli: Roche, Italfarmaco: Consultancy, Honoraria; MSD, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations; Takeda: Other: travel expenses, accommodation; Gentili, Takeda, Gilead, Servier: Consultancy, Speakers Bureau. Passamonti: AbbVie: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Arcaini: Celgene, Roche, Janssen-Cilag, Gilead: Other: Travel expenses; Bayer, Celgene, Gilead Sciences, Roche, Sandoz, Janssen-Cilag, VERASTEM: Consultancy; Gilead Sciences: Research Funding; Celgene: Speakers Bureau.

The Magnesium battery is considered a potential a high energy, sustainable successor to the lithium-ion battery, due to an almost two-fold increase in the volumetric capacity of magnesium compared to lithium (Li), decreased probability of dendritic growth, cheaper raw material costs, and high natural abundance.[1]–[3] Current electrolytes have been found to be insufficiently stable towards the Mg electrode, leading to reduction of the electrolyte and formation of a solid electrolyte interphase (SEI), which is believed to be detrimental to performance.[4]–[6] Our previous study [7] indicated a cycling mechanism at Mg surface in a Mg(TFSI)2-based electrolyte occurring through Mg deposits and an evolution of interphase chemistry during conditioning that is critical for stable cycling in the Mg(TFSI)2-glyme electrolyte. However, unlike Li metal batteries,[8], [9] where the Li plating and nucleation mechanism has been studied in depth, this is not the case for Mg batteries. In this study, we have combined electrochemical analysis with state-of-the-art cryo-focus ion beam scanning electron microscopy (FIB-SEM) and energy-dispersive X-ray spectroscopy (EDX), aiming to give insight into the Mg nucleation & growth mechanism. In doing so, we are able to reveal the detailed chemical and structural composition of the Mg deposits for the first time. Our studies are performed in Mg(TFSI)2-tetraglyme electrolyte as the leading base electrolyte for the battery. By linking the structure of Mg deposits to their state of charge and cycling performance, we can conclusively demonstrate the origin of the high overpotential in the battery. In addition, we show how Mg is reversibly plated and stripped within the deposit and demonstrate how the structure and size of the Mg deposit fluctuates to accommodate this process. Image caption: Electron microscopy images of the cross -section of a Mg particle after discharge etched using cryo-FIB-SEM, showing. a) secondary electron images of the exposed cross-section and b) In lens secondary electron images highlighting the distinct regions of the particle: Mg-rich inner core, MgO-rich outer core and interphase. References: [1] G. N. Newton, L. R. Johnson, D. A. Walsh, B. J. Hwang, and H. Han, ACS Sustain. Chem. Eng., vol. 9, no. 19, pp. 6507–6509, May 2021 [2] M. Fichtner, Magnesium Batteries: Research and Applications, vol. 2020, no. 23. Royal Society of Chemistry, 2019 [3] J. W. Choi and D. Aurbach, Nat. Rev. Mater., vol. 1, no. 4, p. 16013, 2016 [4] J. Muldoon, C. B. Bucur, and T. Gregory, Chem. Rev., vol. 114, no. 23, pp. 11683–11720, Dec. 2014 [5] A. Ponrouch, J. Bitenc, R. Dominko, N. Lindahl, P. Johansson, and M. R. Palacin, Energy Storage Mater., vol. 20, no. pp. 253–262, Feb. 2019 [6] R. Attias, M. Salama, B. Hirsch, Y. Goffer, and D. Aurbach, Joule, vol. 3, no. 1, pp. 27–52, 2019 [7] C. Holc, K. Dimogiannis, E. Hopkinson, and L. R. Johnson, ACS Appl. Mater. Interfaces, vol. 13, no. 25, pp. 29708–29713, Jun. 2021 [8] Z. Yu et al. Nat Energy, vol 5, pp.526–533 Jun. 2020 [9] B. Liu, J. G. Zhang and W. Xu, Joule, vol 2, no. 16, pp. 833-845, May 2018 Figure 1

This presentation focuses on a transdisciplinary approach to innovative and collaborative learning practices driven by technology. It highlights two salient elements associated with industry practices and processes in relation to learning and educational contexts: empowerment of individuals and communities of practice through technology, and a broader consideration of industrial approaches to the concept of learning and teaching enhanced within a digital environment.
 More precisely, this presentation will feature some of the key theoretical frameworks used in three different settings of learning and teaching in France with regards to the life-long learning approach thanks to Social and Emotional Learning (SEL) (WEF, 2016). It will also discuss the positive effect of the Internet and its affordances (Southerton & Taylor, 2020) on reducing the differences between theoretical and applied knowledge via professional-focused communities (Danvers, 2003). Thus, it will briefly explain that spatial and cognitive learning proximities (Lave & Wenger 1991; Fruchter, 2001) can be reduced by virtue of technology (Anders, 2016; Antonczak, 2019; Glazewski & Hmelo-Silver, 2019) and that ‘computer-supported collaborative learning’ methods can facilitate social and shared problem-solving (Sawyer, 2005; Levallet & Chan, 2018; Presicce et al., 2020) without the ‘restriction of time and place’ (Cheng et al., 2019, 489). Additionally, it will point out some aspects of problem-solving through ‘emancipatory learning and social action’ (Merriam, 2001, 9) through the use of ‘actual’ content and ‘actionable feedback’ (Woods & Hennessy, 2019) enhanced by digital tools and tactics.
 Next, it will focus on three case studies by concisely presenting key specifics for each of the courses, including the various digital tools used and followed by some quick interim reflections.
 Then it will summarise the challenges and the barriers encountered across the different practices such as virtual delivery, the size of the students' groups and some connectivity considerations. It will be followed by the principal advantages and opportunities, like the professionalisation dimension through interactive and authentic learning enhanced by affordances. And it will conclude with some managerial recommendations as experiential and practical methods (knowledge codification) thanks to industry-based teaching supported by digital technologies.
 The presentation will close with the overall conclusion in relation to digital technology and some of the key 21st-century career skills. In general, the findings will be of interest to academics, practitioners and policymakers. The added value of this transdisciplinary investigation is that it improves research on collaborative innovation and collective knowledge by creating a bridge between the fields of Education and Business.
 
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Language skills are significant predictors of early academic and social-emotional outcomes of children and are important predictors of school readiness. This study aims to improve children's language skills through the application of mind mapping learning methods. This classroom action research used Kemmis and Taggart's cycle model. The research subjects were 12 children in group B consisting of eight boys and four girls. The data was collected through observation, interviews, and documentation with the validity of the data using source triangulation and method triangulation. This research uses data analysis techniques in the form of data condensation, data presentation, and drawing conclusions. The results showed that the children's language skills through the application of the mind mapping method in the first cycle were 75%, and in the second cycle had increased to 92%. Based on the results of teacher observations in the implementation of cycle I, the children's language skills obtained a percentage value of 61.5%, and in cycle II increased to 92.3%. While the results of observations of children's activities in the implementation of the first cycle obtained a percentage of 54%, and in the second cycle, it increased to 85%. This study found that the teacher's assessment of this mind mapping method was an easy method to understand so that it was easy to apply in classroom learning. The implication of this research is that it is necessary to carry out further research on the application of the mind mapping method for other aspects of development.
 Keywords: Early Childhood, language Skills, Mind Mapping Learning Methods
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Abstract In order to analyse the incidence of iron overload after allo BMT and assess the role of venesection in preventing complications, we retrospectively analysed 168 consecutive patients undergoing allo BMT at our institution from 1998–2003 surviving at least one year. Iron studies were performed routinely pre-BMT, at D100, one & two years post BMT. Iron overload was defined by at least one of the following criteria i)liver biopsy (n=24), one of : a) dry weight iron concentration >80μmol/g; b) iron index >1.9; c) Perl’s stain grade 3 or 4, ii) CT liver iron >1.0mg/ml (n=13) iii) raised ferritin >1000 μg/L and transferrin saturation >55% on 2 occasions, persisting >6/12 post BMT (n=11), iv) venesection >5g iron (n=1). Using these criteria, iron overload occurred in 49/168 (29%) pts. 12/119 in the non-overloaded group had further investigation but did not meet the criteria; liver biopsy (n=10) or CT (n=2). Elevated ferritin, particularly early post-transplant, did not reliably predict for iron overload, with 55/91 evaluable patients having values >1000μg/L at D100 not fulfilling the criteria for iron overload. There was no difference between overloaded and non-overloaded patients with respect to age or sex. Acute (15/49 vs. 26/113) or chronic liver GVHD (25/46 vs. 47/105) was not different between the two groups (both p>0.05). Only 3 patients were hepatitis B sAg+ or hepatitis C Ab+. The iron overloaded group was more likely to i) have been transplanted for acute leukaemia (29/49 vs. 33/119; p 0.0002) ii) be C282Y heterozygotes (11/46 vs. 10/110, p 0.02) (iii) been transfused more units of red cells (mean 42 vs. 19; p<0.0001) and iv) have persistently abnormal liver function post-transplant, ALT (IU/ml; normal <55) at 1 year 77 vs. 52 and at 2 years 67 vs. 37 (all p<0.05). There was no effect of hetero- or homozygosity for H63D. 63 patients were analysed for the S65C, V59M and Q283P mutations. One patient was heterozygous for the S65C mutation (non-overloaded group). A mean of 12.3 units were venesected in 22 patients (range 2–46), all of whom had received >25 units of red cells. ALT fell significantly (mean pre venesection 189 IU/ml, post 36, p<0.05), as did transferrin saturation (mean pre venesection 68%, post 29%, p<0.05). We conclude that tissue iron overload is common after BMT, that biochemical measures of iron stores (ferritin and transferrin saturation) may be unreliable in this context, particularly in the early post BMT period and that radiological or histological assessment to distinguish hyperferritinaemia due to inflammation from true tissue iron overload may be required. Patients at risk of iron overload (transfusions >25 units, C282Y heterozygotes) should be closely monitored and early venesection therapy instituted to minimise organ damage.

BackgroundCoronavirus disease causes a proximal tubule dysfunction of kidneys, inducing uric acid loss [1]. It has been established that several changes in laboratory markers (C-reactive protein (CRP), ferritin, interleukin-6 (IL-6)) can predict the severity of Covid-19 [2]. The purpose of this retrospective study was to analyze whether uric acid could act as another predictor of severe Covid-19.ObjectivesTo evaluate the relationship between the severity of Covid-19 and uric acid levels on admission to the hospital.MethodsThis retrospective study included 150 hospitalized patients with confirmed Covid-19 (mean age 60.3±14.6 years; 52% were men), the severity of which was determined by the presence and type of oxygen support: (1) without O2, (2) O2 by mask or nasal cannula, (3) continuous positive airway pressure, (4) positive bi-pressure in the airways or high-flow oxygen, (5) invasive ventilation. Among them, 90 subjects required oxygen support, and 60 people didn’t. The mortality rate in our study was 9.3%. The average uric acid level was compared with patients without Covid-19 (40 subjects). The study included patients who didn’t receive urate-lowering therapy. Levels of CRP, ferritin, IL-6, D-dimer were also determined on admission. The Spearman’s rank coefficient was used for measuring correlation.ResultsThe mean uric acid level in patients with coronavirus disease was 251.5±104.1 µmol/L; without Covid-19 it was significantly higher — 328.6±96.9 µmol/L (p<0.001). Approximately one in four (24.6%) Covid-19 patients had uric acid levels below the lower limit of normal (208 µmol/L for men, 155 µmol/L for women). A decrease in serum uric acid levels was also observed in patients suffering from asymptomatic hyperuricemia or gout. However, there was no correlation between uric acid levels and disease severity (r=0.01, p=0.88). Also, uric acid levels did not correlate with other laboratory markers of severe Covid-19 (CRP: r=0.07, p=0.73; ferritin: r=0.15, p=0,07; IL-6: r=0.11, p=0,22; D-dimer: r=0.02, p=0,79).ConclusionLow uric acid levels are common in patients with Covid-19, but are not predictive of a more severe course of this disease. A correlation between uric acid and the level of other laboratory markers of severe Covid-19 was not found.References[1]Dufour, I., Werion, A., Belkhir, L. et al. (2021). Serum uric acid, disease severity and outcomes in COVID-19. Crit Care 25, 212 https://doi.org/10.1186/s13054-021-03616-3[2]Huang, I., Pranata, R., Lim, M. A., et al. (2020). C-reactive protein, procalcitonin, D-dimer, and ferritin in severe coronavirus disease-2019: a meta-analysis. Therapeutic advances in respiratory disease, 14, 1753466620937175. https://doi.org/10.1177/1753466620937175Disclosure of InterestsNone declared

Ocean literacy is currently at the forefront of the development of the notion of marine environmental sustainability. It is critical to compare ocean literacy ideas in curriculum standards. Comics Convey various messages of maritime insight content on integrated, contextual, and meaningful learning. This study aims to design STEAM (to R-SLAMET; Religion, Science, Literacy, Art, Math, Engineer, and Technology) learning that contains ocean literacy messages in a comic media. Through the qualitative research method with study case type, researchers seek to aid early childhood education (ECE) educators in designing R-SLAMET learning through the media to overcome maritime cultural literacy problems. The participants of this study consisted of three educators and 43 children. The findings show that the natural play experience of early childhood can be a source of inspiration to find ocean literacy through R-SLAMET learning activities. Contextual play by children becomes a reference for designing comic-based R-SLAMET learning. Comic media can integrate R-SLAMET learning in improving children's ocean literacy.
 Keywords: children ocean literacy, comic media, STEAM to R-SLAMET learning design
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Abstract Bosutinib (SKI-606) is an orally bioavailable dual Src/Abl inhibitor demonstrating inhibitory activity against BCR-Abl phosphorylation, and is 200 times more potent than imatinib but with minimal inhibition of platelet-derived growth factor receptor (PDGFR) or c-kit. The phase I portion of this study identified a treatment dose of 500 mg daily and showed evidence of clinical efficacy. The phase II portion of the study to investigate the efficacy and safety of bosutinib in patients (pts) with CP Ph+ CML who have failed imatinib therapy is ongoing. Preliminary data for 283 treated pts, median age 54 yrs (range 18 – 91 yrs) and 52% male are reported. A subset of pts received treatment in addition to imatinib, including interferon (91 pts), dasatinib (71 pts), nilotinib (7 pts) and stem cell transplant (13 pts). Among pts who failed imatinib (and received no other tyrosine kinase inhibitor treatment), 137 were imatinib-resistant (all received imatinib ≥600mg) and 64 pts were imatinib-intolerant; median duration of bosutinib treatment to date is 7.7 mos (range 0.2 – 28.2 mos) and 4.5 mos (range 0.5 – 21.5 mos), respectively. Among 67 imatinibresistant pts evaluable for hematological response, 53 (79%) had complete hematological response (CHR). Of 84 imatinib-resistant pts evaluable for cytogenetic response, 34 (40%), achieved a major cytogenetic response (MCyR), including 24 (29%) with a complete cytogenetic response (CCyR). Of 34 pts with MCyR, 31 have maintained their response to date. Of 60 evaluable imatinib-resistant pts, 20 (33%) achieved major molecular response, 10 (17%) of which were complete. Among imatinib-intolerant pts, 22 of 29 evaluable (76%) achieved CHR, and 13 of 22 evaluable (59%) achieved MCyR, including 11 (50%) with CCyR. Of 25 evaluable imatinib-intolerant pts, 7 (28%) achieved major molecular response, 5 (20%) of which were complete. Of 105 pts with baseline samples tested for mutations, 17 different mutations were found in 45 pts (43%). CHR occurred in 5/6 pts (83%) with P-loop mutations and 13/17 (76%) with non-P-loop mutations; MCyR occurred in 3/6 pts (50%) and 11/24 pts (46%), with P-loop and non-P-loop mutations, respectively. Treatment was generally well tolerated. The most common adverse events among treated pts (n=283) were gastrointestinal (nausea, vomiting, diarrhea), these were usually grade 1 – 2, manageable and transient, diminishing in frequency and severity after the first 3 – 4 weeks of treatment. Grade 3 – 4 non-hematologic toxicity occurring in ≥5% of pts were diarrhea (8%), rash (8%) and increased ALT (5%). 27 pts (10%) reported grade 1/2 fluid retention adverse events, including 21 pts with edema, and 6 pts with effusions: 4 pleural, 1 pericardial, and 1 pleural and pericardial. A single patient experienced grade 3 pleural effusion possibly related to bosutinib with concomitant pneumonia and a pre-treatment history of recurrent pleural effusions. Grade 3 – 4 hematologic laboratory abnormalities included thrombocytopenia in 65 pts (23%), neutropenia in 37 pts (13%) and anemia in 17 pts (6%). 124 pts (44%) had at least 1 temporary treatment interruption and 85 pts (30%) had at least 1 dose reduction due to toxicity. 37 pts (13%) have permanently discontinued treatment due to adverse event. Bosutinib is effective in pts with CP CML with resistance or intolerance to imatinib across a range of mutations. Unlike other tyrosine kinase inhibitors, bosutinib does not significantly inhibit PDGFR or c-kit, and this may be responsible for the relatively favorable toxicity profile with few pts experiencing hematologic toxicity or fluid retention.

5006 Background: TITAN was designed to determine whether APA, a selective next-generation androgen receptor inhibitor, plus ADT improves radiographic progression-free survival (rPFS) and overall survival (OS) compared with PBO plus ADT in pts with mCSPC. Methods: In this randomized, double-blind phase 3 study, pts with mCSPC regardless of extent of disease were randomized (1:1) to APA (240 mg/d) or PBO, added to ADT, in 28-day cycles. Pts with prior treatment (tx) for localized disease or prior docetaxel for mCSPC were allowed. All pts received continuous ADT. Dual primary end points were rPFS and OS. Secondary end points were time to a) initiation of cytotoxic chemotherapy, b) pain progression, c) chronic opioid use, d) skeletal-related event. Time-to-event end points were estimated by Kaplan-Meier and Cox proportional hazards methods. This first planned OS interim analysis took place after ~50% of expected events. Results: 525 pts were randomized to APA and 527 to PBO. Median age was 68 y; 8% had prior tx for localized disease; 11% had prior docetaxel. 63% and 37% had high- or low-volume disease, respectively. At median 22.6 mo follow-up, 66% APA and 46% PBO pts remained on tx. APA significantly improved rPFS (HR, 0.48; 95% CI, 0.39-0.60; p < 0.0001), with a 52% reduction in risk of death or radiographic progression; benefit was observed across all subgroups analyzed. Median rPFS was not reached in the APA group and 22.1 mos in the PBO group. APA also significantly improved OS (HR, 0.67; 95% CI, 0.51-0.89; p = 0.0053), with a 33% reduction in risk of death. Median OS was not reached in the APA or PBO group. Time to initiation of cytotoxic chemotherapy was significantly improved with APA (HR, 0.39; 95% CI, 0.27-0.56; p < 0.0001). Based on these results, the independent data monitoring committee recommended unblinding to allow crossover of PBO pts to receive APA. Rates of grade 3/4 adverse events (AEs) (42% APA, 41% PBO) were similar, and discontinuations due to AEs (8% APA, 5% PBO) were low. Conclusions: In the TITAN study in pts with mCSPC, including pts with high- and low-volume disease and prior docetaxel, addition of APA to ADT significantly improved rPFS and OS, and the safety profile was tolerable. These results support the addition of APA to ADT for tx of pts with mCSPC. Clinical trial information: NCT02489318.

Rare variants in the γ-globin (HBG2 and HBG1) promoters cause sustained postnatal expression of fetal hemoglobin (HbF, α2γ2) in red blood cells (RBCs). This benign condition is termed hereditary persistence of fetal hemoglobin (HPFH). Individuals with HPFH variants are protected from β-hemoglobinopathies including sickle cell disease and β-thalassemia. Our group and others have used CRIPSR/Cas9-mediated non-homologous end joining to generate HPFH-like insertion-deletion (indel) mutations in the γ-globin promoter. However, simultaneous double-stranded breaks (DSBs) in the tandem duplicated γ-globin genes can result in loss or inversion of the intervening genetic material and/or chromosomal rearrangements. More generally, Cas9-associated DSBs can elicit a cytotoxic DNA repair response leading to cell death or evoke p53 loss with malignant transformation. Base editor (BE) proteins represent a promising approach to install precise nucleotide substitutions without DSBs. Adenosine base editors (ABEs), consisting of catalytically impaired Cas9 fused to a modified adenosine deaminase, create targeted A:T-to-G:C mutations. Here we describe the use of ABEs to recapitulate naturally occurring HPFH variants in hematopoietic stem cells (HSCs). We electroporated ABE7.10-single guide (sg) RNA ribonucleoprotein (RNP) complex into mobilized peripheral blood CD34+ hematopoietic stem and progenitor cells (HSPCs) to recreate 3 different HPFH variants in the HBG1/2 promoters (-198 T>C, -175 T>C and -113 A>G). Measured editing frequency was maximal on day 10 after electroporation and transferred to erythroid differentiation media. 20% editing efficiency was observed for the -198 site, 58% for -175 and 50% for -113. Indel frequencies were <2% at each of the three sites, reflecting a low rate of DSBs. Fetal hemoglobin levels in erythroid cells generated in vitro from A base-edited CD34+ HSPCs were 26±4% (-198 T>C), 60±10% (-175 T>C), and 42±7% (-113 A>G) versus14±2% in unedited control cells. Base editing at the -175 site in sickle cell disease (SCD) donor CD34+ HSPCs resulted in the induction of HbF to 55% in erythroid progeny compared to 6% in controls. After exposure to hypoxia (2% oxygen), reticulocytes generated from -175 T>C-edited CD34+ HSPCs exhibited sickling rates of 24%, compared to 52% in controls. Thus, creation of this variant, which generates a de novo binding site for the transcriptional activator TAL1, reactivates erythroid cell HbF to levels that inhibit sickle hemoglobin polymerization and cell sickling. To assess base editing in HSCs, we used ABE RNP to modify the -175 site in SCD donor CD34+ HSPCs, followed by transplantation into NBSGW mice. The editing frequency in CD34+ HSPCs before transplantation was ~30% and declined to approximately 20% in bone marrow-repopulating donor cells at 16 weeks post-transplantation. Editing frequencies were similar in CD34+ donor cell-derived myeloid, erythroid, and B cells, indicating that hematopoietic differentiation was not altered. Bone marrow erythroblasts derived from base-edited and control CD34+ HSPCs exhibited similar maturation profiles and enucleation. Erythroblasts generated in vivo from SCD patient HSPCs exhibited 32±2% HbF compared to unedited controls (4±1%) (n=4, P>0.0001). Our studies provide proof of concept that adenosine base editors can be used therapeutically for β-hemoglobinopathies. Specifically, generation of the -175 T>C HPFH mutation in patient HSCs followed by autologous transplantation represents a new therapeutic approach for SCD and β-thalassemia. Disclosures Yen: Beam Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Sharma:Spotlight Therapeutics: Consultancy; Magenta Therapeutics: Other: Research Collaboration; CRISPR Therapeutics, Vertex Pharmaceuticals, Novartis: Other: Clinical Trial PI. Liu:Pairwise Plants: Consultancy, Patents & Royalties; Editas Medicine: Consultancy, Patents & Royalties; Beam Therapeutics: Consultancy, Patents & Royalties; Prime Medicine: Consultancy, Patents & Royalties. Weiss:Beam Therapeuticcs: Consultancy, Current equity holder in private company; Esperion Therapeutics: Consultancy, Current equity holder in private company; Novartis: Consultancy, Current equity holder in private company; Cellarity Inc.: Consultancy, Current equity holder in private company; Rubius Inc.: Consultancy, Current equity holder in private company.

5020 Background: The HSD3B1(1245A > C) variant allele, whose frequency varies by race, encodes a missense sequence that stabilizes the rate-limiting enzyme responsible for extragonadal androgen synthesis, thus enhancing intratumoral dihydrotestosterone (DHT) synthesis. Multiple retrospective studies have found that men inheriting the HSD3B1(1245C) variant allele exhibit early resistance to ADT. We sought to validate these findings with prospective data from the Chemohormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED). Methods: Men with newly metastatic PCa were randomized to receive either ADT plus docetaxel at a dose of 75 mg/m2 every 3 weeks for 6 cycles (arm A) or ADT alone (arm B). We determined germline HSD3B1 genotype in the subset of men with LV disease ( < 4 bone metastases, no visceral metastases). We analyzed freedom from castration-resistant prostate cancer (CRPC) and OS according to HSD3B1 genotype using Cox and Kaplan-Meier methods. Results: 197 patients with LV disease had blood samples available and were genotyped, including 97 in arm A and 100 in arm B. Docetaxel did not improve OS of LV men. Of the 197 men, 47% were homozygous wild-type (WT), 43% were heterozygous, and 10% were homozygous variant. When all 197 men were analyzed as one goup, the median time to CRPC was 39.7 mos. in homozygous WT men vs. 25.0 mos. in men with one or more copies of the variant allele (HR 1.27, 95% CI 0.89 to 1.82; p = 0.187). Although OS data are still maturing, at 52 months OS was 83% (95% CI 75% to 91%) in homozygous WT men vs. 64% (95% CI 55% to 74%) in men with one or more variant alleles. There was a suggestion that docetaxel delayed development of CRPC among men with at least 1 variant allele (20.3 vs. 40.7 mos.; HR 0.66, 95% CI 0.40 to 1.04; p = 0.08). Benefit for men with high-volume disease was not evident. Conclusions: Inheritance of the HSD3B1(1245C) allele that augments DHT synthesis may be associated with lower OS in men treated with ADT with or without docetaxel for LV newly metastatic PCa. Additional study is warranted in patients with LV disease. Clinical trial information: NCT00309985.

The purpose of this study was to assess the clinical and genetic features of the course of hypertension, complicated by a hypertensive crisis in the inhabitants of the Aral Sea region. Methods and Results: The study included 132 patients (52 men and 80 women) with AH who applied at least 5 times (4.9±2.4) during 1 year to the Nukus Emergency Medical Care Center with a diagnosis of “Uncomplicated hypertensive crisis.” The mean age of the patients was 57.2±11.6 years, the mean duration of AH ‒ 8.85±3.4 years. The control group consisted of 50 healthy people (mean age of 52.7±6.4 years), women and men in equal proportions. A cardio Hypertension Panel of multiplex RT-PCR assay was used to detect 4 SNP [ADD1 rs4961 (G460T), GNB3 rs5443 (C825T), AGT rs4762 (C521T), and AGT rs699 (T704C)]. To assess the strength of the association between a genetic marker and AH, measured by the OR, we used multiplicative and additive models. According to the results of office BP measurement, the average SBP corresponded to AH Grade 3 (200.8±22.6 mmHg), and DBP corresponded to AH Grade 2 (105.4±7.62 mmHg). All AH patients, regardless of gender, were diagnosed with left ventricular hypertrophy and increased carotid intima-media thickness. Microalbuminuria was detected in 89 (67.4%) patients, proteinuria in 39 (29.6%) patients. Among AH patients, 88% had a high salt taste sensitivity threshold (STST) and 12% had a medium STST (χ²=269.455, P=0.0001). Analysis of the multiplicative and additive models for the AGT rs699 (Т704С) SNP showed a significant risk of AH with the carriage of the T allele (OR=3.70, 95% CI: 1.88-7.26, P=0.000) and the homozygous TT genotype and heterozygous CT genotype (OR=12.55, 95% CI: 0.72-218.80, P=0.000, and OR=2.67, 95% CI: 1.24-5.74, P=0.000, respectively). At the same time, the carriage of the C allele and CC genotype may be protective against the development of AH in individuals of the Aral Sea region. Analyzing the additive models, we also found a significant risk of AH with the carriage of the homozygous CC genotype of the AGT rs4762 (C521T) SNP (OR=5.92, 95% CI: 2.78-12.63, P=0.000). For the ADD1 rs4961 (G460Т) SNP and the GNB3 rs5443 (C825T) SNP, we did not find associations with the risk of AH. The presence of ethnic differences in the prevalence and associative links of AH candidate genes with the development of the salt-sensitivity phenotype require further extended searches in this direction, especially in the Aral Sea region.

The high-temperature proton exchange membrane fuel cell (HT-PEMFC) conducts protons through the hydrogen bond network established by the polymer and phosphoric acid (PA), which reduces the dependence on humidity and allows its operating temperature to be higher than 100°C [1]. A higher operating temperature is conducive to improve catalyst activity, reducing carbon dioxide adsorption on the catalyst thus reducing the requirement for hydrogen purity, and convenient water management [2]. As the most widely commercialized HT-PEMFC proton exchange membrane material, the performance and durability of Polybenzimidazole (PBI) still need to be improved. In particular, it has insufficient proton conductivity, insufficient mechanical properties, and phosphoric acid leaching issues under high acid doping level [3] [4] [5]. The doping of functionalized graphene oxide in the PBI membrane can build additional proton transfer channels, promote proton hopping and act as a trap for PA to reduce its leaching by virtue of abundant functional groups of functionalized GO [6] [7] [8]. Among the groups that can be used for functionalization, the phosphoric acid group has become one of the most promising due to its strong hydrogen bonding and water retention ability [9] [10] [11]. Phosphonated graphene oxide (PGO) is usually synthesized by further phosphonation of GO obtained by chemical exfoliation [6] [7]. Chemical exfoliation methods usually require the long-term action of strong acids and strong oxidants [12]. The safety and environmental issues caused by those methods can not be underestimated. And the two-step synthesis method of PGO has a long reaction period. This work achieved the rapid, safe, and large-yield production of electrochemically exfoliated PGO by using a 3D printed reactor, ammonium dihydrogen phosphate as the electrolyte and natural graphite flakes as the raw material. The two-step electrochemical exfoliation method of producing GIC with concentrated sulfuric acid as the first electrolyte is also used to synthesize electrochemical exfoliated (E)GO. 1.5wt% EGO or PGO was doped in the PBI membrane to explore the effect of different GO on the performance and durability of the PBI- membrane-based HT-PEMFC. Compared with pure PBI, the doping of EGO and PGO increases the peak power density of HT-PEMFC by 17.4% and 35.4%, respectively. [1] Y.-L. Ma, J.S. Wainright, M.H. Litt, R.F. Savinell, Journal of The Electrochemical Society 2004, 151, A8. [2] H. Su, S. Pasupathi, B. Bladergroen, V. Linkov, B.G. Pollet, International Journal of Hydrogen Energy 2013, 38, 11370. [3] S. Galbiati, A. Baricci, A. Casalegno, R. Marchesi, International Journal of Hydrogen Energy 2013, 38, 6469. [4] S.H. Eberhardt, F. Marone, M. Stampanoni, F.N. Büchi, T.J. Schmidt, Journal of Synchrotron Radiation 2014, 21, 1319. [5] Q. He, X. Yang, W. Chen, S. Mukerjee, B. Koel, S. Chen, Physical Chemistry Chemical Physics 2010, 12, 12544. [6] J. Yang, C. Liu, L. Gao, J. Wang, Y. Xu, R. He, RSC Advances 2015, 5, 101049. [7] C. Xu, Y. Cao, R. Kumar, X. Wu, X. Wang, K. Scott, Journal of Materials Chemistry 2011, 21, 11359. [8] Y. Cai, Z. Yue, S.X.-J. of A.P. Science, undefined 2017, Wiley Online Library 2017, 134, 44986. [9] E. Abouzari-Lotf, H. Ghassemi, A. Shockravi, T. Zawodzinski, D. Schiraldi, Polymer 2011, 52, 4709. [10] E. Abouzari-Lotf, M. Zakeri, M.M. Nasef, M. Miyake, P. Mozarmnia, N.A. Bazilah, N.F. Emelin, A. Ahmad, Journal of Power Sources 2019, 412, 238. [11] S. Some, I. Shackery, S.J. Kim, S.C. Jun, Chemistry - A European Journal 2015, 21, 15480. [12] C. Xu, Y. Cao, R. Kumar, X. Wu, X. Wang, K. Scott, Journal of Materials Chemistry 2011, 21, 11359.

The present study aimed to estimate the trend in road traffic injury mortality in older adults (60 years of age or older) and comparison with those <60 years of age in Ecuador (1990-2018). Official death records and population projections were used to calculate mortality rates per 100,000 population, rate ratios, years of potential life lost (YPLL), and trends. Those under 60 years of age had mortality rates of 16.7 (per 100,000) compared to 36.2 (per 100,000) for older adults, with an increasing trend in YPLL. Older adults recorded fewer deaths than the younger population. However, it is necessary to develop road safety strategies oriented to the progressive aging of the Ecuadorian population.
 Keywords: older adults, traffic accidents, mortality, trends, Ecuador.
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Композиты на основе полианилина и CuCl2·2H2O/ZrOCl2·8H2O, в качестве модифицирующих добавок получены методом химической полимеризации без добавления кислоты. Особенности электронной структуры и химических связей образцов исследованы методами ИК спектроскопии и спектроскопии рентгеновского поглощения. Микроструктура поверхности композитов исследовалась методом сканирующей электронной микроскопии. Полианилин в состав композитов входит в частично окисленной форме, степень окисления полимера зависит от типа модифицирующей добавки. Добавление CuCl2·2H2O/ZrOCl2·8H2O в процессе синтеза увеличивает электропроводность образцов
 
 
 
 
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Abstract Chnages in hemostasis are often seen in children with ALL. Although increased thrombin generation is already present at diagnosis, thromboembolism is reported only after start of therapy, indicating a relationship between disease and treatment. We present results of a prospective study on coagulation and fibrinolysis in 64 children with newly diagnosed ALL. The DCOG ALL-9 remission induction protocol consists of weekly vincristine IV and oral dexamethasone 6 mg/m2 during 4 weeks. From day 29, dexamethasone is tapered and Asparaginase Paronal® is introduced, twice weekly at 6000 IU/m2 IV for 2 weeks. Results from the introduction of Paronal are given as medians (25th – 75th perc): Day 29 Paronal 1 Day 33 Paronal 2 Day 36 Paronal 3 Day 40 Paronal 4 Day 43 *1 p<0.0001; *2p=0.001; *3p=0.003; *4p=0.0007 Fibr mg/L 1.1 (0.8–1.6) 00.9 *1 (0.6–1.2) 0.8 (0.5 – 1.3) 1.1 (0.5 – 1.6) 1.5*3 (0.9 – 2.2) F V IU/ml 1.35 (1.24–1.5) 1.38 (1.14–1.77) 1.37 (1.0–1.58) 1.37 (1.13–1.62) 1.41 (1.15–1.63) F II 1.33 (1.2–1.47) 1.17*1 (1.0–1.34) 1.17 (0.96–1.29) 1.17 (0.95–1.3) 1.17 (0.94–1.3) F VII 1.12 (0.8–1.4) 1.48*1 (1.16–1.67) 1.46 (1.28–1.62) 1.54 (1.31–1.95) 1.52 (1.29–1.89) F IX 1.68 (1.47–2.0) 1.1*1 (0.83–1.37) 1.1 (0.82–1.35) 0.95 (0.73–1.15) 0.88 (0.66–1.17) F X 1.47 (1.25–1.81) 1.25*1 (1.1–1.48) 1.26 (0.96–1.47) 1.24 (1.1–1.48) 1.2 (0.87–1.41) AT III 1.47 (1,41–1.66) 1.1*1 (0.95–1.2) 0.95*1 (0.87–1.1) 0.9*2 (0.75–1.1) 0.84 (0.71–1.0) Prot C act 1.68 (1.44–2.0) 1.21*1 (1.1–1.41) 1.15*4 (0.94–1.31) 1.1 (0.92–1.32) 1.0 (0.8–1.18) Prot C ag 1.5 (1.22–1.73) 1.0*1 (0.84–1.29) 1.0 (0.8–1.23) 0.93 (0.78–1.21) 0.93 (0.76–1.1) Prot S total 1.0 (0.92–1.16) 0.8*1 (0.69–0.94) 0.8 (0.65–0.9) 0.79 (0.67–0.95) 0.84 (0.62–0.95) Prot S free 1.0 (0.85–1.16) 0.66*1 (0.55–0.78) 0.59*2 (0.47–0.74) 0.59 (0.46–0.71) 0.56 (0.42–0.7) F 1+2 mmol/L 1.1 (0.77–1.49) 1.1 (0.80–1.48) 1.19 (0.73–1.59) 1.1 (0.8–1.46) 1.15 (0.87–1.6) TAT μg/L 4.4 (3.1–9.1) 3.9 (2.65–6.1) 3.15 (2.3–5.3) 3.0 (2.5–4.35) 4.1 (2.70–9.3) Alpha–2 AP 1.29 (1.17–1.41) 0.96*1 (0.84–1.11) 0.98 (0.8–1.1) 0.9 (0.69–1.1) 0.9 (0.7–1.1) Plasminogen 1.16 (1.0–1.31) 0.78*1 (0.64–0.98) 0.78 (0.65–0.91) 0.79 (0.65–1.0) 0.82 (0.63–1.1) PAP μg/L 215 (117.5–428) 91*1 (59.5–187.5) 93 (56–163) 88 (62–141) 82 (52–170.5) Four weeks of dexamethasone results in hypofibrinogenemia, which decreases further during Paronal infusions. AT III and prot C show an initial rise during dexamethasone, and a subsequent significant decrease during Paronal, never in ‘thrombogenic ranges’. However, median prot S values of 0.59 IU/ml are thrombogenic. The significant decrease of α2-AP, plasminogen and PAP point to a decreased fibrinolytic potential. The increased thrombin generation (increased F1+2 and TAT) can be attributed to both disease and treatment. We conclude that the hypercoagulable situation during dexamethasone is in part counterbalanced by low fibrinogen levels. However, addition of Paronal increases the risk for thrombosis by low concentrations of prot S and a decreased fibrinolytic potential due to decreased levels of α2-AP and plasminogen.

Background:Cardiovascular (CV) and cerebrovascular (CVB) risk have not been adequately examined in the setting of patients with small vessel vasculitides. In particular, data on CV/CVB surogate markers are scarce and the diagnostic value of traditional CV risk scores, such as the Systematic COronary Risk Evaluation (SCORE) and ist EULAR modified version (mSCORE) is unknown.Objectives:Aims of this study were to examine gold standard surrogates of CV risk and subclinical atherosclerosis (1), as well as novel duplex-sonographic markers of CVB risk in a cohort of patients with small vessel vasculitides. Moreover, we sought to evaluate for the first time the diagnostic value of SCORE and mSCORE in identifying patients at high CV and CVB risk.Methods:SCORE/mSCORE and the gold standard marker of aortic stiffness (carotid-femoral pulse wave velocity; cfPWV) were examined in patients with small vessel vasculitides and healthy controls across 3 Rheumatology Centers. Moreover, sonography of the common- (CCA), internal- (ICA) and external- (ECA) carotid arteries was performed in subsets of both groups, evaluating carotid intima-media-thickness (cIMT), plaque presence and duplex-sonographic indices of CBV risk, such as the resistance- (RI) and pulsatility-index (PI). Disease characteristics, clinical and serological activity markers, as well as traditional CV risk factors were also documented.Results:We recruited 46 patients with small vessel vasculitides [granulomatosis with polyangiitis (n=33), eosinophilic granulomatosis with polyangiitis (n=6), microscopic polyangiitis (n=4), cryoglobulinemic vasculitis (n=1), urticaria vasculitis (n=2): 76.1% female, median age 61.5 years (52-72.25, IQR)] and 105 healthy controls [76.1% female, median age 61.5 years (52-72.25, IQR)]. cfPWV was significantly higher in the patient group compared to the control group, even after statistical corrections for confounding factors (i.e. age, gender: different in the two groups) (8.4 m/s vs. 6.8 m/s; padj<0.001). Moreover, carotid sonography revealed higher CVB surrogates in the patient subgroup, compared to controls.According to SCORE and (EULAR)-mSCORE, 0.9% and 15.8% of the patients had high CV risk (defined as SCORE/mSCORE >5), respectivelly. However, cfPWV revealed an increased CV risk in 28.2% of the patients. Moreover, carotid sonography showed signs of subclinical carotid arteriosclerosis in 50% (plaques) and 71.7% (cIMT >0.9 mm) of the patients, respectively.Conclusion:Herein, we could show that patients with small vessel vasculitides had higher aortic stiffness and subclinical carotid atherosclerosis, compared to controls and could thus have higher CV and CVB risk. Moreover, we were able to demonstrate for the first time that SCORE/mSCORE performed poorly in identifying patients at high CV risk and carotid atherosclerosis compared to cfPWV and carotid sonography respectively. Thus, cfPWV and carotid sonography could improve CV and CBV screening in patients with small vessel vasculitides.Table 1.Descriptive characteristics.Controls(n=105)Patients(n=46)Significance(p)cfPWV† (m/s)6.80 (6.05-7.5)8.40 (7.26-10.66)<0.001*Age† (years)50 (39.50-56.5)61.50 (52-72.25)<0.001*Gender(female)95 (90.5%)35 (76.1%)0.019*Nicotin(smokers)21 (20%)5 (11.1%)0.190Antihypertensive drugs18 (17.1%)27 (65.9%)<0.001*BMI†23.73 (21.1-27.1)25.14 (22.81-28.70)0.074Mean art. pressure¶93.45±10.6896.19±10.680.150ESR† (mm/h)-20.00 (11– 41.5)-ANCA-25 (54.3%)-Creatinine†0.77 (0.72-0.81)0.94 (0.8-1.31)<0.001*Cholesterol¶ (mg/dL)-216.88±40.16 -Prednisolone† (mg)-5.63 (1.75-16.38)-Lung involvement17 (37%)-Kidney involvement17 (37%)-Ear-nose-throat (ENT)16 (34.8%)-†median (IQR): Mann Whitney test¶ mean±standard deviation: t test*p<0.05References:[1]Vlachopoulos C et al., Prediction of Cardiovascular Events and All-Cause Mortality With Arterial Stiffness: A Systematic Review and Meta-Analysis. J Am Coll Cardiol 2010 30;55(13):1318-27Disclosure of Interests:Konstantinos Triantafyllias Speakers bureau: Pfizer, Novartis, Janssen, Chugai, Leif-Erik Thiele: None declared, Michele De Blasi: None declared, Andreas Schwarting: None declared

Abstract Basis. Abnormalities in chromosome 8 (8p-/8q+) are observed in 2-5% of CLL patients. Microarray studies have revealed up to 30-40% of 8 alterations in del(17p) patients and an independent association with poor outcome. Large series assessing CLL patients with 8p-/8q+ are scarce. Aims. 1. To describe the frequency of 8q gains (8q+) and 8p losses (8p-) in CLL patients with del(17p); 2. To compare cytogenetic and clinical characteristics between patients with 8p-/8q+ (Alt-chr8) and those with normal chromosome 8 (N-chr8); 3. To assess their prognostic value. Patients and methods. From 2,249 patients included in the Spanish CLL database, 75 del(17p) cases were selected. Gains of MYC (8q24) and losses of LPL (8p22) were studied by FISH. Clinical and cytogenetic data of Alt-chr8 and N-chr8 were compared. Results. 8p- and/or 8q+ were found in 21/75 patients (28%). In the Alt-chr8 group, 8q+ was more frequent than 8p- (71% vs. 52%) and 29% showed concomitance of both abnormalities, suggesting the presence of i(8q). Six different FISH patterns were identified, some of them coexisting in the same patient (Table 1). Conventional cytogenetics data were available in 47 cases (15 Alt-chr8 and 32 N-chr8). Alt-chr8 group showed a higher median number of alterations and frequency of complex karyotypes (P=0.048 and P=0.013). In the Alt-chr8 group, the karyotype revealed 8p-/8q+ in 3 patients and in 9 cases with abnormal karyotype, the presence of marker chromosomes, added material and/or cryptic alterations would explain the FISH results (Table 1). From 66 cases, routine FISH data (13q, 12 and 11q) were available and no significant differences were detected among Alt-chr8 and N-chr8, as with other clinical and analytical parameters at diagnosis. Of note, shorter Overall Survival (OS) was observed for Alt-chr8, although differences were only significant for patients with 8p- (P=0.012, Figure 1). Interestingly, for 3 patients of Alt-chr8 group, previous non-del(17p) samples already presented 8p-/8q+. Conclusions. 1. In CLL patients with del(17p), detection of 8p- and/or 8q+ is associated with an increased karyotypic complexity and a worse outcome; 2. 8p-/8q+ could act as a primary event that trigger del(17p). More cases are required to confirm this hypothesis. Acknowledgments.PI11/01621; RD12/0036/0044, RD12/0036/0069; 2014/SGR585; Fundació La Caixa. Table 1. Karyotypes and FISH results of patients with del(17p) and Alt-chr8. Conventional Cytogenetics FISH ID Karyotype % del(17p) Chromosome 8 alteration % Pattern* 1 46,XX,del(8)(p21),add(10)(q26),add(17)(p13),+2ac[5]/47,XX,+12,add(17)(p13),del(18)(q21),add(22)(q13)[3] 80 20 1O2G 8p- 2 - 95 75 3 46,XX,add(6)(q24),add(14)(q32,3),i(17)(q10)[6]/46,XX[8] 95 75 4 - 76 50 5 45,XY,-5,-9,-15,add(17)(p13),+18,-21,+2mar[13]/46,XY[37] 70 17 6 46,X,der(X),add(8)(p23),del(13)(q12q22),add(17)(p13)[11]/46,XX[13] 10 32 1O3G 8p- and 8q+ 7 - 95 64 8 45,XY,add(3)(q29),del(4)(q26q35),der(7)(1p36-1p32::7p22-7q32::15q22-15q26), -8,der(9),del(13)(q21q34),-15,-17,-18,+19,add(19)(p13),+2mar,+ac[17]/46,XY[3] 78 34/21 1O3G/2O3G 9 44,X,-X,-6,der(13;15)(q10;q10),add(17)(p13),-20,+mar[13]/46,XX[7] 95 10/23 1O3G/1O2G 10 - 95 66/31 11 45,XY,add(6)(q22),del(11)(q11q22),-17[15]/44,XY,add(6)(q22),del(11)(q11q22),-17,-20,-22,+mar[2] 87 40/24 12 46,XX,del(13)(q14q21)[2]/45,X,-X,del(13)(q14q21)[3]/45,XX,add(3)(q27), t(9;10)(q21;q22),+12,der(12)t(12;17)(q11;p11),del(13)(q14q21),-14,-17[7]/46,XX[8] 70 62 2O3G 8q+ 13 46,XY[30] 14 88 14 46,XY[13] 80 82 15 47,XY,+12[8]/46,XY,add(1)(p34),add(2)(q34),t(11;22)(p14;q11),+12,-22[15]/46,XY[11] 75 18 16 43,X,-X,del(2)(p15),+4,-7,add(11)(q21),-12,-13,add(14)(q32),add(17)(p11)[6]/46,XX[9] 19 14 17 45,XY,del(6)(q?),-9,add(14)(q32),-22,+mar[9]/ 46,XY,del(6)(q?),add(17)(p13),add(19)(q13)[21] 55 23 18 45,XY,add(6)(p11),-22[13]/46,XY,i(17)(q10)[5]/46,XY[16] 16 57 19 - 70 66 2O4G 20 - 90 81 2OnG 21 46,XY[11] 43 60 4O4G Tetraploid *O: LPL signal in orange, G: MYC signal in green. Figure 1. Kaplan Meier plots for OS and (A) 8p- and/or 8q+, (B) 8p- or (C) 8q+. Figure 1. Kaplan Meier plots for OS and (A) 8p- and/or 8q+, (B) 8p- or (C) 8q+. Disclosures No relevant conflicts of interest to declare.

Abstract Activation of the canonical Wnt signaling pathway by Wnt3a has been implicated in hematopoietic stem cell (HSC) self-renewal (Reya et al., Nature, 2003). Wnt5a has been observed to inhibit Wnt3a signaling (Topol et al., J Cell Biol, 2004). We hypothesized that Wnt3a and 5a act as antagonists on HSC function. 1 x 106 lineage negative cells (lin−) were cultured for 4 days in the presence of 50 ng/ml SCF and Flt3L (control) plus 100 ng/ml rmWnt3a and/or 500 ng/ml rmWnt5a (all factors added on day 0 and day 2). Control lin− cell numbers expanded more than lin− cells cultured with Wnt3a, 5a, or both (control 8.3 ± 0.3-fold; Wnt3a 6.9 ± 0.2-fold (p < .01); Wnt5a 4.8 ± 0.2-fold (p < .001); Wnt3a and 5a 2.6 ± 0.6-fold (p < .001); n = 3). After 4 days, cells were analyzed for myeloid colony formation. Control cells and cells cultured in Wnt3a had similar numbers of CFU-GM/5000 lin− cells (control 13.1 ± 11.1; Wnt3a 21.8 ± 15.3; p = .21; n = 8), while cells cultured in Wnt5a and Wnt3a and 5a had 2-fold and 5.9-fold more CFU-GM/5000 lin− cells than control (Wnt 5a 26.8 ± 13.3 (p = .04); Wnt3a and 5a 77.9 ± 48.3 (p < .01); n = 8). To analyze repopulating ability, 4 x 105 lin− Ly5.1 cells, cultured under the same conditions, were transplanted with 2 x 106 Ly5.2 bone marrow cells into lethally-irradiated Ly5.2 recipients. 16 weeks after transplant, repopulation by control lin− cells increased 2-fold compared to lin− cells cultured in Wnt3a or Wnt5a (control 7.3 ± 3.8%; Wnt3a 3.37 ± 1.2% (p < .01); Wnt5a 3.6 ± 1.1% (p < .01); n = 9-10). However, lin− cells cultured in Wnt3a and 5a showed normal repopulating activity (n = 10; 8.7 ± 5.3%; p = .52). 1 x 104 HSCs (lin−, c-kitHI, Sca-1HI, IL-7Rα −) were cultured for 6 days with SCF, Flt3L, Wnt3a and 5a (factors added on day 0 and day 3) as described above. Control HSC numbers expanded more than HSCs cultured with Wnt3a, Wnt 5a, or both (control 20.7 ± 10.4-fold; Wnt 3a 7.0 ± 4.1-fold (p = .05); Wnt5a 1.7 ± 1.7-fold (p = .01); Wnt3a and 5a 1.2 ± 1.0-fold (p < .01); n = 4). Similar numbers of control HSCs and HSCs cultured with Wnt3a or 5a were lin+ (control 21.7 ± 0.2%; Wnt 3a 15.4 ± 5.3% (p = .10); Wnt5a 14.4 ± 5.2% (p = .07); n = 3). However, culturing HSCs with Wnt3a and 5a resulted in a 50% decrease in the number of lin+ cells compared to control (12.3 ± 2.0% (p = .001)). Cultured Ly5.1 HSCs were transplanted with Ly5.2 bone marrow cells at a 1:100 ratio. There was no difference in repopulation between control HSCs and HSCs cultured with Wnt3a (control 5.8 ± 6.1%; Wnt3a 3.6 ± 0.4%; p = .43; n = 5). To examine the effects of enforced expression of Wnt ligands in HSCs, 5-FU treated bone marrow was transduced with Wnt3a-IRES-GFP, Wnt5a-IRES-dsRED, or IRES-GFP retroviral vectors. Sorted IRES-GFP+, Wnt3a-GFP+ and Wnt5a-dsRed+ cells (Ly5.1) were transplanted with equal numbers of mock-transduced cells and 3 x 105 Sca-1− bone marrow cells (Ly5.2) into lethally-irradiated Ly5.2 mice. 16 weeks later, recipients of IRES-GFP+ and Wnt5a-dsRed+ cells contained a similar number of engrafted cells expressing the vector (3.4 ± 1.8% GFP+ Ly5.1 and 3.5 ± 0.4% dsRed+ Ly5.1 respectively; n = 8). In contrast, no GFP+ Ly5.1 cells were detected in Wnt3a-GFP+ recipients (n = 8). 33.4 ± 3.7% of bone marrow cells were Ly5.1+ indicating successful engraftment and retroviral DNA was detected by PCR, suggesting that transduction had occurred but that only cells in which the vector was silenced survived. We conclude that activation of the canonical Wnt pathway in HSCs promotes differentiation of primitive hematopoietic cells and that other signals, such as Wnt5a, are required to maintain the balance between HSC differentiation and self-renewal.

The Plant Disease Diagnostic Laboratory of the Pennsylvania Department of Agriculture received diseased geranium (Pelargonium × hortorum) samples from several Pennsylvania (PA) greenhouses in 1999 and 2000 and from one Delaware (DE) greenhouse in 1999. Originating from Guatemala, plants exhibited yellowing, wilting, stunting, and bacterial oozing from the vascular tissues. Isolations on yeast dextrose-CaCO3 (YDC) and triphenyl-tetrazolium-chloride (TTC) agars resulted in off-white mucoid colonies and white, fluidal colonies with pink centers, respectively. Such colonies are typical of Ralstonia solanacearum (1). The disease was similar to a bacterial wilt of geranium caused by an unidentified biovar of R. solanacearum (3). Preliminary tests using Biolog MicroLog 3 (Hayward, Ca; 4.01A) and enzyme-linked immunosorbent assay (ELISA) (Agdia Inc., Elkhart, IN; BRA 33900/0500) identified the organism as R. solanacearum. For pathogenicity tests, a 10-μl droplet of water suspension containing 1 × 106 CFU of each of five geranium strains (PDA 22056-99, 81849-99, 81862-99, 51032-00, and 64054-00) per milliliter was placed on a stem wound made by cutting off the terminal growth of each of 4 6-leaf stage plants of geranium ‘Orbit Scarlet’, tomato ‘Rutgers’, potato ‘Russet Norkotah’, and eggplant ‘Black Beauty’ in a growth chamber at 28°C, 86% relative humidity, and 12 h light/dark cycle. Water was included as a control. The five strains caused severe yellowing and wilting within 10 days. Colonies typical of R. solanacearum were reisolated from symptomatic tissue on YDC and TTC. To determine the specific biovar, 20 pathogenic geranium strains from PA and DE plus a strain of R. solanacearum originally isolated from a geranium plant of Guatemalan origin received from Connecticut in 1995 were grown up to 28 days on Ayers mineral medium supplemented with a 1% final concentration of D-cellobiose, dextrose, meso-inositol, lactose, maltose, D-ribose, trehalose, mannitol, sorbitol, or dulcitol (1). Acid was produced by 21 test strains from the first five carbohydrates only. Such carbohydrate utilization is typical of bv 2 (1). Bv 2 identification was confirmed by real-time polymerase chain reaction using bv 2-specific primers and probes (N. Schaad, unpublished) designed from a bv 2-specific DNA fragment (2). All tested strains were positive using ELISA. In contrast, strains of bv 2 from geraniums in Wisconsin and South Dakota were reported to be negative using ELISA (4). From our results, it appears that bv 2 was introduced into the United States on geraniums from Guatemala in 1995 and 1999. This cool climate bv 2, a regulated agent by the Agricultural Bioterrorism Protection Act of 2002, has caused extensive crop loss in potatoes in Europe, but has not been found in potatoes in the United States. References: (1) T. P. Denny and A. C. Hayward. Ralstonia solanacearum. Pages 151–174 in: Lab Guide for Identification of Plant Pathogenic Bacteria. N. W. Schaad et al. eds. 3rd ed. The American Phytopathological Society, St. Paul, MN, 2001. (2) M. Fagen et al. Development of a diagnostic test based on the polymerase chain reaction (PCR) to identify strains of R. solanacearum exhibiting the Biovar 2 genotype. Pages 34–43 in: Bacterial Wilt Disease: Molecular and Ecological Aspects. P. H. Prior et al. eds. Springer-Verlag, Berlin, 1998. (3) D. L. Strider et al. Plant Dis. 65:52, 1981. (4) L. Williamson et al. (Abstr.) Phytopathology 91 (Suppl.):S95, 2001.

e18678 Background: The Coronavirus Disease 2019 (COVID- 19) has been nominated as a pandemic by the World Health Organization short after has spreaded globally. Unfortunately, even after several effective vaccines approved by FDA, COVID-19 cases are still surging. Compared to the general population, patients with cancer are more susceptible to COVID-19 for many aspects. Therefore, better understanding of the clinical characteristics of cancer patients with COVID-19 is urgently needed to spare these vulnerable patients from severe disease course. Methods: This retrospective study was completed in Capital Health Regional Medical Center, New jersey, USA. Adult patients with COVID-19 diagnosed between March 2020 and May 2021 were included in this study. All selected COVID-19 patients were stratified as two groups: Patients with cancer and patients without cancer. Other variables were included as age at diagnosis, gender, race/ethnicity, insurance status, obesity, comorbidity score, treatment of COVID-19, oxygen requirement and vital status. The Charlson Comorbidity Index was used to calculate the comorbidity score. Results: A total of 562 COVID-19 patients were included in this study; 67 (12%) patients diagnosed with cancer. Patients with cancer were more likely to be older (73 vs. 62 years, p < 0.001), overweight (BMI 25-29.9) (39% vs 28%, p = 0.02), and have higher comorbidity score > 3 (58% vs 15%, p < 0.001) than patients without cancer. Patients with cancer more frequently received steroid therapies (52% vs. 34%, p = 0.003), remdesivir (21% vs. 4%, p < 0.001), and convalescent plasma (21% vs. 10%, p = 0.009). The rate of high flow oxygen therapy was higher in patients with cancer than patients without cancer (30% vs. 16%, p = 0.02). The days of mechanic ventilation, hospital stay, ICU admission were similar between two groups. Patients without cancer had better survival rate compared to patients with cancer (77% vs. 64%, p = 0.02). Patients with cancer had increased D-dimer level (2.4 vs. 1.6 mg/L, p = 0.08) compared to patients without cancer but it was not significantly different. Other laboratory findings were also similar between two groups, including WBC, neutrophils, lymphocytes, lactate, lactate dehydrogenase, creatine kinase, d-dimer, C-reactive protein, procalcitonin, fibrinogen, BNP, troponin, sodium, AST, ALT, and ferritin. Multivariable logistic regression analysis showed that patients with cancer were associated with increased odds of higher than 3 comorbidity score (OR 7.09 [3.85-13.05], p < 0.001) and oxygen therapy with nasal cannula up to 6 liters (OR 3.7 [1.04-13.5], p = 0.04). Conclusions: This present analysis showed that patients had increased risk of mortality compared to counterpart. Our results emphasize that cancer patients as a group are at higher risk due to advanced age and preexisting conditions.

Introduction. Ibrutinib, a small molecule inhibitor of Bruton's tyrosine kinase (BTK), has proven to be an efficient treatment for chronic lymphocytic leukemia (CLL). A distinct characteristic of ibrutinib therapy is transient lymphocytosis. Recently, we have demonstrated that CLL patients with high levels of CD49d show reduced lymphocytosis and inferior nodal response under ibrutinib due to residual activity of BCR-induced inside-out activation of the CD49d/CD29 integrin VLA-4 (Tissino E et al. J Exp Med. 2018;215(2):681-697). Here, we used Tcl1 transgenic (tg) mice as a model to further validate the observation of VLA-4 activation under ibrutinib and to study involved signaling pathways and the effect of VLA-4 inhibition in vivo. Methods. Surface receptor expression analysis of various receptors was performed by flow cytometry. The phosphorylation of signaling molecules was measured by phosflow and western blotting. VLA-4 affinity state was determined by a real-time kinetic assay described in Chigaev A et al. J Biol Chem. 2001;276(52):48670-8. To analyze the distribution of individual VLA-4 molecules on the cell surface, immunofluorescence approaches and superresolution microscopy (STORM, Abbelight) were employed. Mouse treatment studies were performed upon transplantation of TCL1-tg splenocytes to wild-type C57BL/6J mice using the small molecule VLA-4 inhibitor firategrast in drinking water. Tumor infiltration of different organs was measured by flow cytometry. Results. Analyzing the surface expression of CD49d and other homing receptors, we found that TCL1-tg mice correspond with the CD49d-high CLL cohort. We found that both CLL cells from TCL1-tg mice and human CD49d-high CLL show similar CD49d expression levels as the corresponding healthy B cells (human: N = 116 CD49d-high CLL and 32 healthy donor, P = 0.8717; mouse: N = 12 per group, P = 0.6845). Next, we analyzed the impact of BCR pathway inhibitors on the phosphorylation of signaling molecules involved in the BCR pathway after activation by anti-IgM (aIgM) in TCL1-tg leukemic cells. Ibrutinib and idelalisib showed specific patterns of inhibition of BTK and PI3K, respectively. The combination of ibrutinib and idelalisib proved to be the most efficient in reducing the phosphorylation of BTK, SYK, ERK1/2 and Akt upon IgM activation, compared to the phosphorylation of stimulated cells without inhibition (N = 6, P = 0.0003, 0.0305, 0.0039, 0.0019, respectively). IgM stimulation induced VLA-4 high affinity as well as a reorganization of VLA-4 molecules on the cell surface, forming areas of high VLA-4 density. BCR-induced inside-out activation of VLA-4 remained functional upon treatment with ibrutinib (N = 5, cnt vs aIgM P = 0.0017, cnt vs ibrutinib+aIgM P = 0.0499), while idelalisib reduced VLA-4 activation more effectively (N = 5, cnt vs aIgM P = 0.0014, cnt vs idelalisib+aIgM P = 0.0803), suggesting a pivotal role of PI3K in the transmission of the exogenous antigen signal to the integrin. Finally, to analyze the potential of VLA-4 blockage in a tumor setting similar to VLA-4-high CLL patients, we treated wild-type C57BL/6J mice (N = 6 mice per group), which were transplanted with TCL1-tg splenocytes, with the CD49d inhibitor firategrast. This treatment reduced the tumor load in spleen and bone marrow. Conclusion. We found that the TCL1-tg mouse model is adequate to study the activity of the BCR-VLA-4 axis in CLL. Using this model, we show that a) BCR stimulation induces both, an increase in VLA-4 affinity as well as avidity (clustering), b) that PI3K is an essential transmitter between BCR and VLA-4, and c) that VLA-4 inhibition alters tumor infiltration patterns in vivo. Synergies of VLA-4 blockage with established therapy options as a possible way of reducing microenvironment-induced resistance development are currently been investigated. Disclosures Egle: Celgene: Honoraria, Other: Advisory board and Travel support. Greil:Eisai: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Sandoz: Honoraria; Genentech: Honoraria, Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Honoraria; Janssen-Cilag: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; GSK: Research Funding; Boehringer Ingelheim: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Ratiopharm: Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding.

e3293014Current Brazilian legislation defines the gifted as those who have high ability and high involvement in areas of human knowledge (intellectual, leadership, psychomotor, arts, and creativity), whether in isolation or in combined areas. The law nº 9.394/1996, integrates these students to the public of Special Education and assures them education appropriate to their needs, the possibility of acceleration of studies, specialized educational assistance, and special education for work. However, the estimates indicate that a large number of these students are unassisted, without them being at least identified by the educational systems. The historical recovery of the legal guidelines that guided and guide the educational service of the gifted in Brazil reveals that the national legislation was preceded by isolated pedagogical practices, which began in the first half of the twentieth century. Initiatives in favor of the gifted have gained strength after the law nº 5.692/1971 explicitly mention this pupil. At that time, the Federal Council of Education issued opinions aimed at meeting the needs of this public, but the expansion of care has occurred in a gradual and modest way, so that, despite a series of legal documents issued in the last decades, the gifted remain with their potentialities and needs ignored.ResumoA legislação brasileira atual define os estudantes com altas habilidades/superdotação como aqueles que possuem alta potencialidade e elevado envolvimento em áreas do conhecimento humano (intelectual, de liderança, psicomotora, de artes e criatividade), seja isoladamente, seja em áreas combinadas. A Lei nº 9.394/1996 integra esses discentes ao público da Educação Especial e assegura-lhes ensino adequado às suas necessidades, possibilidade de aceleração de estudos, atendimento educacional especializado e educação especial para o trabalho. No entanto, as estimativas apontam que grande parcela desses estudantes se encontra desassistida, sem que eles sejam, ao menos, identificados pelos sistemas de ensino. O resgate histórico das diretrizes legais que orientaram e orientam o atendimento educacional dos estudantes com altas habilidades/superdotação, no Brasil, objetivo deste ensaio teórico, revela que a legislação nacional foi antecedida por práticas pedagógicas isoladas, as quais tiveram início na primeira metade do século XX. As iniciativas em favor desse alunado ganharam força após a Lei nº 5.692/1971, sem mencioná-los, explicitamente. Nessa época, o Conselho Federal de Educação emitiu pareceres voltados à atenção das necessidades desse público, mas a ampliação do atendimento tem ocorrido de modo gradativo e modesto, de maneira que, a despeito de uma série de documentos legais expedidos nas últimas décadas, tais estudantes permanecem com suas potencialidades e necessidades ignoradas.ResumenLa legislación brasileña actual define a los superdotados como aquellos que poseen alta potencialidad y alto involucramiento en áreas del conocimiento humano (intelectual, liderazgo, psicomotora, artes y creatividad), sea aisladamente o en áreas combinadas. La Ley nº 9.394/1996, integra estos discentes al público de la Educación Especial y les asegura una enseñanza adecuada a sus necesidades, posibilidad de aceleración de estudios, atención educativa especializada y educación especial para el trabajo. Sin embargo, las estimaciones apuntan que una gran parte de estos estudiantes se encuentra desasistida, sin que ellos, al menos, sean identificados por los sistemas de enseñanza. El rescate histórico de las directrices legales que orientaron y orientan la atención educativa de los superdotados en Brasil revela que la legislación nacional fue precedida por prácticas pedagógicas aisladas, las cuales comenzaron en la primera mitad del siglo XX. Las iniciativas en favor de los superdotados ganaron fuerza después de la Ley nº 5.692/1971 mencionar, explícitamente, ese alunado. En esa época, el Consejo Federal de Educación emitió opiniones orientadas a la atención de las necesidades de ese público, pero la ampliación de la atención ha ocurrido de modo gradual y modesto, de manera que, a pesar de una serie de documentos legales expedidos en las últimas décadas, los superdotados permanecen con sus potencialidades y necesidades ignoradas.Palavras-chave: Educação especial, Diretrizes da educação, Superdotação.Keywords: Special education, Education guidelines, Giftedness.Palabra clave: Educación especial, Pautas educativas, Superdotación.ReferencesALMEIDA, L. S.; ARAÚJO, A. M.; SAINZ-GÓMES, M.; PRIETO, M. D. Challenges in the identification of giftedness: Issues related to psychological assessment. Anales de psicologia, v. 32, n. 3, p. 621-627, 2016.ALMEIDA, M. A.; CAPELLINI, V. L. M. F. Alunos talentosos: possíveis superdotados não notados. Educação, Porto Alegre, v. 55, n. 1, p. 45-64, 2005.ALVARENGA, R. Entrevista virtual com Helena Antipoff: a psicóloga de Minas Gerais. Belo Horizonte: Minas Gerais, 2014.ANTIPOFF, C. A. Uma proposta original na educação de bem-dotados: ADAV – Associação Milton Campos para Desenvolvimento e Assistência de Vocações de Bem Dotados em sua primeira década de funcionamento: 1973-1983. 2010. 239f. Dissertação (Mestrado em Educação) – Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil, 2010.BRASIL. Decreto nº 1.426, de 12 de Setembro de 1854. Coleção de Leis do Império do Brasil - 1854, 1, pt I, p. 295 (Publicação Original). Disponível em: http://www2.camara.leg.br/legin/fed/decret/1824-1899/decreto-1428-12-setembro-1854-508506-publicacaooriginal-1-pe.html. Acesso em: 21 set. 2015.BRASIL. Lei n. 4.024, de 20 de dezembro de 1961. Fixa as Diretrizes e Bases da Educação Nacional. Disponível em: http://wwwp.fc.unesp.br/~lizanata/LDB%204024-61.pdf. Acesso em: 05 out. 2015.BRASIL. Lei n. 5.692, de 11 de agosto de 1971. 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Abstract Background Advances in the multidisciplinary care of hormone-receptor positive (HR+) early breast cancer (eBC) have markedly improved clinical outcomes: however, disease recurrence may still occur, particularly in patients (pts) with moderate or high-risk cancers at the time of diagnosis. The use of CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) is a standard of care for advanced breast cancer, supporting the rationale to study CDK4/6i in the eBC setting. Here we present the final protocol-planned analyses of the global phase III PALLAS trial investigating whether the addition of the CDK4/6i palbociclib (P) to adjuvant ET improves outcomes over ET alone for HR+/HER2- eBC. Methods PALLAS (PALbociclib CoLlaborative Adjuvant Study, NCT02513394) is a randomized phase III open-label trial in which pts with stage II-III HR+/HER2- eBC were randomized to receive either 2 years of P with adjuvant ET (P+ET) or ET alone. The primary endpoint is invasive disease-free survival (iDFS); secondary endpoints include distant recurrence-free survival (DRFS), locoregional recurrence-free survival (LRRFS), overall survival (OS), and safety. Mandatory biospecimen collection has supported the creation of an expansive translational science program, and long-term follow-up is planned. Revised sample size calculations required recruitment of 5600 pts in order to detect a 25% iDFS improvement in patients receiving P+ET with 85% power; this final protocol-planned analysis was planned after 469 iDFS events. Results From September 1, 2015 to November 30, 2018, 5,761 pts (median age 52 years, range 22-90) were randomized in 406 centers in 21 countries worldwide. 1,014 (17.6%) had stage IIA disease (capped) and 4,728 (82.1%) stages IIB/III. 4,754 (82.5%) had received prior (neo)adjuvant chemotherapy. After a protocol-planned 2nd interim analysis in May 2020 crossed the futility threshold, 349 P+ET pts still on active treatment stopped P and were transferred to follow-up. At the time of final analysis cutoff date (November 20, 2020), after a median follow-up of 31 months and 516 events recorded, iDFS was similar between the two arms, with 3-year iDFS of 89.3% (95% CI: 87.8-90.6%) for Palbo+ET, and 89.4% (88.0-90.7%) for ET alone (hazard ratio 0.96, 95% CI: 0.81-1.14). There was no statistically significant difference in secondary outcome endpoints. Subgroup analyses revealed no significant interactions between treatment effect and other factors (including risk category). The safety profile of P was as expected, with grade 3 or 4 neutropenia the most common side effect (safety population: 1759/2841 [61.9%] vs 11/2902 [0.4%]). Overall 42% of pts. discontinued P prior to the planned 2-year duration, 28.2% of Palbo+ET pts discontinued therapy due to adverse events, without an observed impact on survival outcomes. Conclusions Now with the full number of events, this analysis of the PALLAS trial shows that the addition of 2 years of P to ongoing adjuvant ET did not improve survival endpoints for pts with stage II-III HR+/HER2- eBC. Whether P is beneficial in the adjuvant setting for certain sub-groups of pts will be further evaluated with longer-term follow-up and by the ongoing translational science program. Support: ABCSG; AFT; Pfizer; ClinicalTrials.gov Identifier: NCT02513394; https://www.abcsg.org; https://acknowledgments.alliancefound.org Citation Format: Michael Gnant, Amylou C Dueck, Sophie Frantal, Miguel Martin, Hal Burstein, Richard Greil, Peter Fox, Antonio C Wolff, Arlene Chan, Eric Winer, Christian Singer, Kathy Miller, Marco Colleoni, Michelle Naughton, Gabor Rubovszky, Judith Bliss, Ingrid A Mayer, Guenther G Steger, Zbigniew Nowecki, Olwen Hahn, Norman Wolmark, Hope Rugo, Georg Pfeiler, Hannes Fohler, Otto Metzger, Céline Schurmans, Kathy P Theall, Dongrui R Lu, Kathleen Tenner, Christian Fesl, Angela DeMichele*, Erica L Mayer, *shared last authorship. Adjuvant palbociclib in HR+/HER2- early breast cancer: Final results from 5,760 patients in the randomized phase III PALLAS trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS1-07.

The government incurs huge costs because of low literacy rates, which are associated with higher crime rates, poor health, and higher welfare costs, therefore the stimulation of basic literacy from an early age is important. This study aims to examine the effectiveness of animated motion learning media and songs that are interesting, innovative, and effective for improving basic literacy aspects of early childhood. This mixed-method design with the research and development stages of the ADDIE model was tested for the effectiveness of the media through a paired sample test. The research was divided into three stages, starting from needs analysis, product development, and product evaluation, involving 11 respondents in the effectiveness test. The data collection technique was carried out using a basic literacy instrument grid questionnaire, for child development, while for the feasibility of the media or products being developed it was also through a questionnaire from experts. Data were analyzed qualitatively and quantitatively. The results of the study show that there is a significant increase in basic literacy values through learning media. The findings of the integration of quantitative and qualitative data form the basis for preparing the final product to revise and complement the deficiencies of movement and song-learning media.
 Keywords: basic literacy, animation media, motion, and song, early childhood
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447 Background: We previously reported that TP53 status may predict C benefit in patients with locally advanced rectal cancer treated with neoadjuvant chemotherapy and chemoradiotherapy (CRT) and this effect appeared to be independent of KRAS. Recent studies indicate that NRAS mutations and KRAS mutations beyond exons 2-3 may also preclude benefit from anti-EGFRs. We analyzed whether the predictive value of TP53 in EXPERT-C was independent of RAS. Methods: 164 patients received 4 cycles of CAPOX followed by CRT, surgery, and 4 cycles of adjuvant CAPOX (n=81) or the same regimen plus C (CAPOX-C, n=83) and were analyzed for KRAS (exons 2-3) and NRAS (exon 3). TP53 mutations (exons 4-9) were screened for by CE-SSCA. KRAS (exon 4) and NRAS (exons 2 and 4) mutations were screened for by bi-directional Sanger sequencing. Progression-free survival (PFS) and overall survival (OS) were estimated with Kaplan-Meier methods and log-rank analysis was used to compare the treatment arms. The interaction between treatment and TP53 was adjusted for prognostic variables and RAS in a multivariate model. Results: 75/144 (52%) eligible patients had a TP53 mutation. 81/86 patients with known KRAS (exons 2-3) and NRAS (exon 3) wild-type (WT) status were analyzed for the remaining RAS mutations. Of these, 11 (13%) had tumours with mutation in KRAS exon 4 (11%) or NRAS exons 2/4 (2%). Overall, 75/144 (52%) patients were RAS WT (CAPOX, n=39; CAPOX-C, n=36). After a median follow-up of 65 months, no difference in PFS (HR 1.21, p=0.59) and OS (HR 0.97, p=0.94) was observed between TP53 mutant patients treated with CAPOX or CAPOX-C. In TP53 WT patients, the addition of C was associated with a statistically significant improvement in PFS (HR 0.23, p=0.02) and OS (HR 0.16, p=0.02). A significant interaction between TP53 status and C effect was found (PFS, p=0.029; OS, p=0.036). In multivariate analyses, this interaction remained significant even after adjusting for RAS status (PFS, p=0.026; OS, p=0.033). Conclusions: In EXPERT-C, the value of TP53 as predictive biomarker for C benefit was independent of RAS. The value of monoallelic vs. biallelic TP53 inactivation will be presented at the meeting.