Aza Group Research Articles

Synthesis of Oxaazaisowurtzitane Derivatives Via Condensation of p‐Toluenesulfonamide With Glyoxal

ABSTRACTThis work presents the study results on the acid‐catalyzed cascade condensation of p‐toluenesulfonamide with glyoxal in H2SO4 in order to synthesize aza‐ and oxaazaisowurtzitanes—a platform for promising high‐energy‐density compounds—and explore their formation processes. The effects of the ratio of starting reactants, acidity, reaction medium concentration, and temperature on this process were studied in detail. Five novel compounds were derived, including four oxaazaisowurtzitanes comprising one to three aza groups, and one condensation intermediate. The most favorable conditions for the formation of the resultant caged compounds were established and some new regularities of the process were revealed. For instance, the reaction medium concentration was discovered for the first time to influence the generation process of oxaazaisowurtzitanes via direct condensation. The limiting stage of the cage formation process of oxaazaisowurtzitanes was identified. The formation rate of the oxaazaisowurtzitanes was shown to be dependent on their structure. The factor dramatically reducing the yield of the oxaazaisowurtzitanes at elevated synthesis temperature was also revealed.

Prophylactic therapy using epigenetic agents for RUNX1::RUNXT1-positive high-risk AML after Allo-HSCT.

Disease recurrence is the leading cause of treatment failure in patients with RUNX1::RUNXT1-positive acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Post-transplant maintenance therapy, guided by monitoring minimal residual disease (MRD), is commonly administered; however, relapse rates remain high. This prospective study aimed to assess the effectiveness and safety of epigenetic agents as prophylactic therapy in patients with RUNX1::RUNXT1-positive AML. Thirty high-risk patients received prophylactic therapy (n = 17 and n = 13 in the chidamide and AZA groups, respectively) between January 2019 and July 2023. 34 high-risk patients who received preemptive treatment due to molecular relapse were included in the analysis. The two-year relapse-free survival (RFS) and overall survival (OS) were significantly higher in the prophylactic group compared to the preemptive group (82.82% vs. 51.38%, P = 0.014; 86.42% vs. 56.16%, P = 0.025, respectively); 2-year cumulative incidence of relapse rates were 13.8% and 36.40%, respectively (P = 0.037). In conclusion, prophylactic therapy with epigenetic agents may improve long-term prognosis and is well-tolerated in patients with RUNX1::RUNXT1-positive high-risk AML. Timely post-transplant prophylactic therapy may be more effective than preemptive therapy based on positive MRD results.

Zn, Cd and Cu Coordination Polymers for Metronidazole Sensing and for Ullmann and Chan-Lam Coupling Reactions.

Five compounds, [Zn2(bpe)(BPTA)2(H2O)2] ⋅ 2H2O (1); [Zn(bpe)(BPTA)] (2); [Cd(bpe)(BPTA)H2O] (3); [Cd(BPTA) (bpmh)] ⋅ 2H2O (4); and Cu2(BPTA)2(bpmh)3(H2O)2] ⋅ 2H2O (5) were prepared employing 2,5-bis(prop-2-yn-1-yloxy)terephthalic acid (2, 5 BPTA) as the primary ligand and 1,2-di(pyridin-4-yl)ethane (4, 4' bpe) (1-3) and 1,2-bis(pyridin-3-ylmethylene)hydrazine (bpmh) (4-5) as the secondary ligands. Single crystal studies indicated that the compounds 1, 3 and 5 have two-dimensional layer structures and compounds 2 and 4 three-dimensional structures. The luminescence behaviour of the compounds 2 and 3 were explored for the sensing of metronidazole in aqueous medium. The studies indicated that the compounds can detect metronidazole in ppm level both in solution as well as simple paper strips. The Cu compound 5 was found to lose the coordinated water molecule at 100 °C without any structural change. The coordinatively unsaturated Cu-centre were examined towards the Lewis acidic character by carrying out the Ullmann type C-C homocoupling reaction of the aromatic halide compounds. The compounds, 4 and 5, also have the Lewis basic functionality arising out the =N-N=, aza groups. The bifunctional nature of the coordination polymers (CP) was explored towards the Chan-Lam coupling reaction between phenyl boronic acid and aniline derivatives in the ethanol medium. In both the catalytic reactions, good yields and recyclability were observed. The present studies illustrated the rich diversity that the transition metal containing compounds exhibit in extended framework structures.

Efficacy and safety of venetoclax-based combination therapy for previously untreated acute myeloid leukemia: a meta-analysis

ABSTRACT Purpose: To explore the efficacy and safety of venetoclax-based combination therapy for older patients with newly diagnosed acute myeloid leukemia (AML). Methods: We performed a systematic review and meta-analysis of clinical trials comparing venetoclax plus hypomethylating agents (HMAs) or low-dose cytarabine (LDAC) with mono-HMAs or LDAC. The random or fixed effects model was applied to the studies based on heterogeneity. Dichotomous data were summarized using the risk ratio (RR) and 95% confidence interval (CI). Continuous variable data were reported as weighted mean differences (WMDs). Results: Nine studies, including a total of 1232 patients, were included in this meta-analysis. Thec complete remission (CR)/complete remission with incomplete hematological recovery (CRi) rate of the venetoclax (Ven) + azacytidine (Aza) group was significantly greater than that of the Aza monotherapy group (RR: 2.42; 95% CI: 1.85–3.15; P < 0.001). Similarly, the CR/CRi rate of the Ven + LDAC group was also significantly greater than that of the LDAC monotherapy group (RR: 2.57; 95% CI: 1.58–4.17; P = 0.00). The same results were observed for OS among these groups. However, the incidence of febrile neutropenia was greater in the Ven + Aza group than in the Ven + Decitabine (Dec) or monotherapy Aza group (RR: 0.69; 95% CI: 0.53–0.90; P = 0.006 and RR: 2.19; 95% CI: 1.58–3.03; P < 0.001, respectively). In addition, the Ven + LDAC group had significantly greater rates of constipation, diarrhea, nausea, and vomiting than the LDAC monotherapy group, with RRs and CIs of 0.61 (95% CI 0.44–0.83, P = 0.002), 1.81 (95% CI 1.22–2.67, P = 0.003), 1.39 (95% CI 1.06–1.82, P = 0.016), and 1.80 (95% CI 1.19–2.72, P = 0.005), respectively. Conclusion: Venetoclax combined with azacitidine, decitabine, or LDAC significantly improved the CR/CRi and OS of patients with previously untreated AML. However, venetoclax plus azacitidine or LDAC was more likely to lead to increased febrile neutropenia and gastrointestinal toxicity.

Azathioprine Plus Exclusive Enteral Nutrition Versus Azathioprine Monotherapy for the Prevention of Postoperative Recurrence in Patients with Crohn's Disease: An Open-Label, Single-Centre, Randomized Controlled Trial.

Azathioprine [AZA] effectively prevents postoperative endoscopic recurrence [ER] in Crohn's disease [CD]. However, the efficacy of AZA emerges after 3 months. Exclusive enteral nutrition [EEN] can maintain remission in CD. The present trial investigates whether AZA plus postoperative 3-month EEN is superior to AZA alone in preventing ER of CD. In total, 84 high-risk CD patients undergoing intestinal resection received AZA alone or AZA plus 3 months of EEN [AZA + EEN] postoperatively. The primary endpoint was the rate of ER at 12 months. Secondary endpoints included the rate of ER at 3 months, clinical recurrence [CR], CD activity index [CDAI] scores, faecal calprotectin [FC], and C-reactive protein [CRP]. Quality of life was assessed using Short Form-36 [SF-36] and the Inflammatory Bowel Disease Questionnaire [IBDQ]. Patients in the AZA + EEN group exhibited significantly lower rates of ER compared to the AZA group at both 12 months (33.3% [13/39] vs 63.2% [24/38], P = 0.009) and 3 months (8.6% [3/35] vs 28.1% [9/32], P = 0.037) post-surgery. The rates of CR between the two groups at 3 and 12 months were similar. CDAI scores, FC, albumin level, and CRP were all comparable between the two groups. Quality of life was significantly higher in the AZA group than in the AZA + EEN group at 3 months but became comparable from 5 to 12 months postoperatively. In high-risk CD patients, combining AZA with postoperative 3-month EEN reduces 1-year ER but may temporarily impact quality of life. Further large-scale, long-term studies are warranted. NCT05214430.

Synthesis of Seven Indolizine-Derived Pentathiepines: Strong Electronic Structure Response to Nitro Substitution in Position C-9.

Seven new 1,2,3,4,5-pentathiepino[6,7-a]indolizines were synthesized in which the pentathiepine moieties bear an indolizine backbone that is derivatized from C-H to F-, Cl-, Br-, I-, NO2-, and CH3-substitutions, respectively, in a meta position relative to the aza group on the pyridine moiety. Their preparation took place via two common steps: (i) a Sonogashira coupling between (4-substituted) 2-bromo- or 2-chloropyridines and propynyl 3,3-diethylacetal, and (ii) a ring closing reaction mediated by a molybdenum oxo-bistetrasulfido complex and elemental sulfur. The latter simultaneously facilitates the 1,2,3,4,5-pentathiepino chain/ring- and indolizine ring-formations. The fluoro derivative was addressed with 2-bromo-5-aminopyridine as the starting material via a Sandmeyer reaction. The iodo derivative was obtained from 5-bromo-2-alkynylpiridine using a metal-assisted variation of the Finkelstein reaction. The requirement to explore different reaction conditions and the varied respective yields of the final products are discussed. The influence of the distinct substitutions on the pyridine moieties, their electronic structures, and respective chemical properties was investigated through a set of spectroscopic/analytical characterizations. Intriguingly, in all cases, the nitro-substituted derivative exhibited a distinct behavior compared to the six other investigated derivatives, which was also addressed computationally. All seven new pentathiepines were crystallized, and their respective molecular structures were determined using single crystal X-ray diffraction. These structures are compared and discussed as are their respective packing patterns.

The Notch1/Hes1 signaling pathway affects autophagy by adjusting DNA methyltransferases expression in a valproic acid-induced autism spectrum disorder model

As a pervasive neurodevelopmental disease, autism spectrum disorder (ASD) is caused by both hereditary and environmental elements. Research has demonstrated the functions of the Notch pathway and DNA methylation in the etiology of ASD. DNA methyltransferases DNMT3 and DNMT1 are responsible for methylation establishment and maintenance, respectively. In this study, we aimed to explore the association of DNA methyltransferases with the Notch pathway in ASD. Our results showed Notch1 and Hes1 were upregulated, while DNMT3A and DNMT3B were downregulated at the protein level in the prefrontal cortex (PFC), hippocampus (HC) and cerebellum (CB) of VPA-induced ASD rats compared with Control (Con) group. However, the protein levels of DNMT3A and DNMT3B were augmented after treatment with 3,5-difluorophenacetyl-L-alanyl-S-phenylglycine-2-butyl ester (DAPT), suggesting that abnormal Notch pathway activation may affect the expression of DNMT3A and DNMT3B. Besides, our previous findings revealed that the Notch pathway may participate in development of ASD by influencing autophagy. Therefore, we hypothesized the Notch pathway adjusts autophagy and contributes to ASD by affecting DNA methyltransferases. Our current results showed that after receiving the DNA methyltransferase inhibitor 5-Aza-2′-deoxycytidine (5-Aza-2'dc), the VPA + DAPT+5-Aza-2'dc (V + D + Aza) group exhibited reduced social interaction ability and increased stereotyped behaviors, and decreased expression of DNMT3A, DNMT3B and autophagy-related proteins, but did not show changes in Notch1 and Hes1 protein levels. Our results indicated that the Notch1/Hes1 pathway may adjust DNMT3A and DNMT3B expression and subsequently affect autophagy in the occurrence of ASD, providing new insight into the pathogenesis of ASD.

Determination of lipophilic marine biotoxins in aquatic products by liquid chromatography coupled with triple quadrupole mass spectrometry

Lipophilic marine biotoxins include Azaspiracid-1 (AZA-1), Azaspiracid-2 (AZA-2), Azaspiracid-3 (AZA-3), Pectenotoxin-2 (PTX 2), Okadaic acid (OA), Dinophysistoxin-2 (DTX-2), Dinophysistoxin-1 (DTX-1), Yessotoxin (YTX), and 1-Homoyessotoxin (Homo-YTX) were extracted with methanol, followed by cleaning up with solid phase extraction technique (SPE). Lipophilic toxins were confirmed and quantified by liquid chromatography coupled with triple quadrupole mass spectrometry (LC/MS/MS) using calibration curves on the solvent. The quantification limits of this method satisfied the requirements of the European Maximum Residue Limit (MRLs) with 25 &amp;micro;g/kg for the YTX group and 10 &amp;micro;g/kg for AZA, OA, and PTX groups. To validate the effectiveness of this method, matrices of clams, fish, and mixed seafood were collected and analyzed (recovery ranged from 92.4 - 101.5%, and relative standard deviation was less than 20%). The method was used successfully to participate in a proficiency testing program organized by Quasimeme (z-score in the range of &amp;plusmn;2)

Abstract 6001: Epigenetic regulation of BARD1 confers resistance to anti-VEGF therapy in ovarian cancer

Abstract Introduction: Vascular endothelial growth factor (VEGF) is a key promoter of angiogenesis and disease progression in epithelial ovarian cancer (OC). Bevacizumab, a humanized anti-VEGF monoclonal antibody, is approved for treatment of patients with ovarian and other cancers. Despite the wide use of anti-VEGF therapy for cancer treatment, most patients develop resistant disease. Therefore, new combinations/strategies are needed to reduce adaptive resistance to anti-VEGF antibody (AVA) therapy. Our aim is to determine the potential role of epigenetic changes in AVA-adaptive resistance. We identified and characterized epigenetic changes in BARD1, a tumor suppressor, at the emergence of AVA resistance. Methods: To define epigenetic changes during AVA therapy induced resistance, we performed series of in vitro (methylation array, RNA sequencing) and in vivo (orthotopic OC (PDX-MDA-OVCA1, immunocompetent-IG10, and immunocompromised-SKOV3) and fibrosarcoma-HT1080, an inherently VEGF resistant model) experiments. The biological effects of DNA methylation agent (5`-Azacytidine; 5`-Aza) with B20 (murine anti-VEGF antibody) treatment were subsequently tested using in vivo models. Results: To determine whether 5`-Aza can enhance the efficacy of AVA therapy and overcome resistance to AVA in OC, we established AVA-resistant SKOV3 model. In AVA-resistant mice treated with B20 + 5`-Aza, there was a statistically significant reduction in tumor weight (p=0.03). Next, we performed a Human 450k methylation and mRNA arrays from xenografts of SKOV3 tumors. Based on both analyses, we demonstrated that BARD1 was one of the top candidate which was highly expressed (p=0.02) and less methylated (p&amp;lt;0.05) in the combination of B20 and 5`-Aza group compared to B20 alone. Our data also showed that BARD1 expression was restored in the combination therapy. The sequential treatment with 5`-Aza reverted the resistance towards the AVA therapy in SKOV3 model. Furthermore, the combination of B20 and 5`-Aza significantly decreased tumor weight in SKOV3 (p=0.005), IG10 (p&amp;lt;0.05), MDA-OVCA1 (p=0.01), and HT1080 (p&amp;lt;0.05). BARD1 expression levels were substantially increased in combination therapy compared to the B20 alone group (&amp;gt;4-fold, p=0.006). Tumor weight and BARD1 expression were inversely correlated. To determine the biological significance of BARD1, we knockdown BARD1 using Tet-inducible shRNA system. Our data showed a significant reduction in tumor weight in the BARD1 knockdown group in SKOV3 model (p=0.021). RNA-sequencing of BARD1 knockdown showed an enrichment of the angiogenesis pathway. Moreover, BARD1 expression levels were decreased in hypoxic conditions both in vitro and in vivo. Conclusion: Our findings indicate a previously unrecognized role for BARD1 in mediating resistance to AVA therapy. Use of epigenetic drugs to control the expression of tumor suppressor genes may enhance the efficacy of AVA therapy in OC. Citation Format: Emine Bayraktar, Cristian Rodriguez-Aguayo, Sudhir Kumar, Elaine Stur, Lingegowda S. Mangala, Stephen Baylin, Gabriel Lopez-Berestein, Sunila Pradeep, Anil K. Sood. Epigenetic regulation of BARD1 confers resistance to anti-VEGF therapy in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6001.

Conformational preferences of aza-proline residues and their impact on the relative stability of polyproline structures

The collagen model peptide Ac-(Hyp-Gly-Pro)2-NMe2 with the replacement of Pro3 by azPro in the middle of the sequence well adopted polyproline II structures with RMSD = 0.6 Å in water.

ELN Risk Stratification Is Not Predictive of Outcomes for Treatment-Naïve Patients with Acute Myeloid Leukemia Treated with Venetoclax and Azacitidine

Background: Venetoclax (Ven), a highly selective oral BCL-2 inhibitor, in combination with hypomethylating agents (HMAs) such as azacitidine (Aza), is approved for the treatment of patients (pts) with newly diagnosed acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy (IC). An open-label, non-randomized phase 1b trial (NCT02203773) and the confirmatory VIALE-A phase 3 randomized trial (NCT02993523), both enrolling pts with intermediate and poor risk cytogenetics per NCCN Guidelines, demonstrated that the combination of Ven+Aza led to high rates of complete remission and longer overall survival (OS) than Aza alone (median OS of 14.7 months [mo] vs 9.6 mo), with similar safety profiles. In this exploratory post hoc analysis of the pooled treatment-naïve, IC ineligible pts treated with Ven+Aza in the phase 1b and phase 3 trials, patients were stratified according to the 2017 ELN risk classification system (which is based on data from patients receiving IC and utilizes cytogenetic and molecular determinants commonly associated with AML). We report clinical outcomes for these patients per ELN 2017 risk group, which will also be updated using the newly published ELN 2022 criteria. Methods: For the phase 1b trial, our analysis includes pts who were enrolled to evaluate safety and efficacy of Ven+Aza at a daily dose of 400 mg for VEN. For the phase 3 trial, pts were randomly assigned in a 2:1 ratio to the Ven+Aza group or placebo (Pbo)+Aza group. All pts received a standard dose of Aza (75 mg/m2 SC or IV on days 1-7 every 28-day cycle). Ven (400 mg) or Pbo was administered orally, once daily, in 28-day cycles. Pts with favorable risk cytogenetics such as t(8;21), inv(16), t(16;16) or t(15;17) as per the NCCN Guidelines Version 2 were excluded from the study. The pooled group of pts from the two trials having both site-reported cytogenetic data and bone marrow aspirate with centrally determined molecular data allowing for ELN genetic risk classification were included in this analysis. Pts were retrospectively classified per the ELN 2017 criteria as favorable-, intermediate-, or adverse-risk AML. Results: Inclusion of central molecular data allowed the reclassification of patients according to ELN 2017 recommendations (Figure 1). 63 of the 67 Ven 400mg + Aza pts enrolled in the phase 1b trial, and 329 of the 431 total pts enrolled in the VIALE-A trial were evaluable for inclusion in this analysis (279/353 in the pooled Ven+Aza group and 113/145 in the Pbo+Aza control group from the phase 3 study). In the Ven+Aza and Pbo+Aza groups, 46 (16.5%) and 20 (17.7%) pts had favorable-risk AML, 65 (23.3%) and 19 (16.8%) had intermediate-risk AML, and 168 (60.2%) and 74 (65.5%) had adverse-risk AML, respectively, by ELN. In favorable-risk AML pts, CR+CRi was achieved in 69.6% with VEN+AZA vs in 20% with Pbo+Aza; for intermediate-risk AML, CR+CRi was achieved in 75.4% vs 42.1%; for adverse-risk AML, CR+CRi was achieved in 61.3% vs 25.7%. Median OS was longer with Ven+Aza in all three risk categories when compared to Pbo+Aza: 21.09 vs. 12.96 mo, HR = 0.45 [95% CI: 0.24, 0.83] in the favorable-risk group; 23.26 vs. 13.14 mo, HR = 0.62 [95% CI: 0.35, 1.08] in the intermediate-risk group; 11.53 vs. 7.43 mo, HR = 0.59 [95% CI: 0.43, 0.82] in the adverse-risk group. The median OS was similar for favorable and intermediate risk groups who received Ven+Aza (21.09 mo and 23.26 mo, respectively; Figure 2). While the median OS of the Ven+Aza adverse risk group was lower (11.53 mo), two subgroups with distinct outcomes are apparent: adverse risk pts with a TP53 mutation (36.3% [61/168]) and adverse risk pts with a RUNX1 mutation (40.5% [68/168]) (one pt had both TP53 and RUNX1). The median OS for adverse risk pts with a RUNX1 mutation and TP53 WT was 22.9 mo while the median OS for adverse risk pts with a TP53 mutation and RUNX1 WT was 5.42 mo. Conclusions: ELN 2017 risk groups, based on younger patients who received IC regimens, are not prognostic in patients receiving Ven+Aza. This exploratory analysis suggests little OS distinction between favorable and intermediate risk groups. Furthermore, adverse risk ELN groups can be further refined to determine mutationally-defined cohorts with more favorable outcomes. A modified risk stratification system is needed for pts receiving newer therapies, such as Ven+Aza, that uses determinants that are prognostic for pts treated in the context of these regimens with distinct mechanisms of actions from IC. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Identification of Predictive Factors for Overall Survival and Response during Hypomethylating Treatment in Very Elderly (≥75 Years) Acute Myeloid Leukemia Patients: A Multicenter Real-Life Experience.

Simple SummaryIntensive induction strategies are rarely used for older patients in community on-cology practice, with comorbidities being the major cause of contraindication. We conducted a multicentric retrospective study to evaluate activity and safety in a real-life setting of hypomethylating drugs (HMAs) in patients older than 75 years with AML. In multivariate analysis, age (≥80), Charlson comorbidity index (≥3), creatinine clearance and the type of best response (≥PR) during treatment maintained independent significance in predicting survival. Furthermore, our data show that HMAs have similar efficacy compared to pivotal trials and are well tolerated in a setting of very elderly patients with several co-comorbidities.Elderly patients represent the most challenging and hard-to-treat patient population due to dismal characteristics of the disease, such as secondary-acute myeloid leukemia (AML), enrichment of unfavorable molecular genes (TP53) and comorbidities. We conducted a multicentric retrospective study to evaluate activity and safety in a real-life setting of hypomethylating drugs (HMAs) in patients older than 75 years with AML. Between September 2010 and December 2021, 220 patients were treated, 164 (74.5%) received AZAcitidine and 56 DECitabine; most patients (57.8%), received more than four cycles of HMAs. The best response obtained was CR in 51 patients (23.2%), PR in 23 (10.5%) and SD in 45 (20.5%); overall transfusion independence was obtained in 47 patients (34%), after a median of 3.5 months. The median OS (mOs) was 8 months (95% CI 5.9–10.2), with 1- and 2-years OS of 39.4% (95% CI 32.7–46) and 17.4% (95% CI 11.7–23.1), respectively; similar mOS was observed according to HMA treatment (AZA 8.3 vs. DEC 7.8 months, p = 0.810). A subset of 57 long survivors (44 in AZA group and 13 in DEC group) received at least 12 cycles of HMAs, their mOS was 24.3 months. In multivariate analysis, age (≥80), Charlson comorbidity index (≥3), creatinine clearance and the type of best response (≥PR) during treatment maintained independent significance in predicting survival. Infectious complications, most frequently pneumonia (35) and septic shock (12), were lethal in 49 patients (22.2%). Our data show that HMAs have similar efficacy compared to pivotal trials and are well tolerated in a setting of very elderly patients with several co-comorbidities.

Outcomes in Patients with Poor-Risk Cytogenetics with or without TP53 Mutations Treated with Venetoclax Combined with Hypomethylating Agents

Outcomes in Patients with Poor-Risk Cytogenetics with or without TP53 Mutations Treated with Venetoclax Combined with Hypomethylating Agents

Randomized Maintenance Therapy with Azacitidine (Vidaza) in Older Patients (≥ 60 years of age) with Acute Myeloid Leukemia (AML) and Refractory Anemia with Excess of Blasts (RAEB, RAEB-t). Results of the HOVON97 Phase III Randomized Multicentre Study (EudraCT 2008-001290-15)

Purpose: The prevention of relapse is the major therapeutic challenge in older patients with acute myeloid leukemia (AML) who have obtained a complete remission on intensive chemotherapy. There is no established post-remission treatment for prevention of relapse in this setting, except allo HSCT. This randomized phase III study (HOVON97) in older patients (≥ 60 years) with AML or MDS-RAEB in CR/CRi after at least 2 cycles of intensive chemotherapy assessed the value of azacitidine as post remission therapy (in comparison to observation) with respect to the disease free survival (primary endpoint) and overall survival (secondary endpoint).Patients and methods: In total 117 patients were randomly 1:1 assigned to either observation (control group ) or azacitidine maintenance (aza group), 50 mg/m2, s.c., day 1-5, q 4 weeks, until relapse for a maximum of 12 cycles. The study was powered to detect improvement in disease free survival (DFS) after 1 year from 40% to 60% (power 80%, two-sided test at 5% significance). The current pre-final evaluation after study closure is based on the first 109 patients with at least one year follow-up. The 2 arms (56 control patients vs 53 aza maintenance patients) were comparable with regard to age (60-81 years, median 69 years), performance status, peripheral blood counts and cytogenetics. Although all patients had < 5% bone marrow blasts at randomization, one patient in the aza group had a relapse prior to start aza maintenance.Results: A total of 52 patients received at least 1 cycle of aza. Subsequently, 44, 40, 34 and 32 patients received at least 3, 6, 9 and 12 cycles respectively. The maintenance treatment with aza was feasible, as, during the first 4 cycles, most treatments could be given according to schedule (87% < 30 days interval and 9% 30-40 day interval), at full dose (98%) and without transfusions (95%). The absolute number of AE's grade ≥ 2 were 417 in the control group and 474 in the aza group. The difference in DFS between the two arms was statistically significant in the cohort of patients in this pre-final analysis (Cox regression; p=0.005). The 12 months DFS was estimated at 39% for the control group and at 63% for the aza group. The difference in overall survival (OS) between the two groups currently is not statistically significant in the cohort of patients in this pre-final analysis (Cox regression; p=0.35). In total 31 patients in the control group and 11 patients in the aza group received therapy while off protocol after relapse (control group vs aza group: 7 vs 2 patients received azacitidine; 18 vs 5 patients received other chemotherapy; 6 vs 4 patients received other treatment; 8 vs 1 patients received allogeneic hematopoietic cell transplantation (HCT)). One of the control patients received allogeneic HCT in CR. After censoring patients who received an allogeneic HCT (n=9 and n=1 in control group and aza group respectively) the difference in OS was statistically different (Cox regression; p=0.04). The 12 months OS (after censoring allo transplanted patients) was estimated at 64% for the control group and 83% for the aza group. A planned subgroup analysis (CR vs CRi at inclusion) revealed that patients with platelet count ≥ 100 x 109/L had a significant better OS in favor of aza maintenance treatment (logrank; p=0.01).Conclusion: Post-remission treatment with aza in older AML patients in CR/CRi after at least 2 cycles of intensive chemotherapy significantly improves DFS (p=0.005). When patients who received an allo HSCT were censored at time of transplant, the difference in OS between both arms was also significantly different (p=0.04), in favor of aza maintenance treatment [Display omitted] DisclosuresHuls:Celgene: Consultancy; J&J: Consultancy. Kuball:Miltenyi: Research Funding; Gadeta (www.gadeta.nl): Consultancy, Equity Ownership, Patents & Royalties: on gdT cells and receptors and isolation strategies , Research Funding. Ossenkoppele:J&J: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Roche: Honoraria; Karyopharm: Consultancy, Research Funding; Novartis: Research Funding.

Rational design of organic semiconductors with low internal reorganization energies for hole and electron transport: position effect of aza-substitution in phenalenyl derivatives.

Amphoteric-redox phenalenyl radical (PLY) is a suitable candidate used to design ambipolar organic materials. Because the singly occupied nonbonding molecular orbital (NBMO) of PLY has a perfect local nonbonding character, its internal reorganization energy (λ) for transporting holes (λ+) or electrons (λ-) is known to be small. Herein, PLY is employed to study the position effect of the aza group on the λ. By adding or extracting an electron from the NBMO, the bond length alterations can be minute. Therefore, the PLY derivatives are also an excellent candidate to study the contributions from the bond angle alterations to the λ. Substituting the aza groups at the β- or α-positions of PLY shows two different trends. When consecutively substituting the aza group at the three β-positions of PLY, the λs are consistently decreased. Contrarily, a series of double functionalization of aza groups at the four α-positions of PLY, the λs are increased. It is because the local bonding or antibonding character in frontier orbitals (FMO) is observed in α2N-PLY and α4N-PLY. As the FMOs of the three β-substituted PLYs and α6N-PLY have perfect local nonbonding character, we found the bond angle alterations are the main contributors of λ. The λs for most aza-PLYs were smaller than 100 meV. Thus, we propose a design rule for substituting aza groups on the parent molecules with strong local nonbonding character in their FMOs. Based on the adiabatic ionization potential and electron affinity, two π-extended PLY derivatives with small λ were recommended for fabricating air-stable ambipolar OFET.

Higher risk of tuberculosis in combination therapy for inflammatory bowel disease: A nationwide population-based cohort study in South Korea.

Inflammatory bowel disease (IBD) in Asia has become increasingly prevalent. As a treatment of IBD, many immunomodulators and biological agents were introduced and shown to be effective in inducing and maintaining remission. However, many cases with treatment failure were reported. To overcome the failure, combination therapy of immunomodulatory and biologics have emerged, showing better outcomes by optimizing biologic pharmacokinetics and minimizing immunogenicity. Adversely, rates of tuberculosis (TB) have been increased as a result. The aim of this study is to compare the risk of TB according to the therapy using large population data.We used data from the South Korean Health Insurance and Review Agency over the period 2008–2016 and calculated the hazard ratio (HR) for TB in IBD. We compared the risk of TB according to the medication: infliximab only, azathioprine only (AZA), combination of azathioprine and infliximab (CAI), azathioprine monotherapy and infliximab monotherapy (AIM), and azathioprine and infliximab whether simultaneously or separately (AISS).In IBD patients, a total of 249 patients were identified as active TB. After one-to-one matching with age, sex and disease duration, the risks of TB were significantly higher in AZA group (HR, 2.06; 95% CI, 1.35–3.12, P < .001), AIM group (HR, 3.26; 95% CI, 1.18–9.05, P = .02), AISS group (HR, 3.50; 95% CI, 1.92–6.37, P < .001), and CAI group (HR, 5.67; 95% CI, 2.42–10.21, P < .001), and the HR increased gradually in this order. In UC patients, the results were in similar pattern, but this pattern was not observed in CD patients in our study.Our study shows that Korean IBD patients are at risk of TB, and the risk increases with usage of IBD medication; moreover, the risk is the highest if combination therapy is used. These results highlight the importance of screening for TB in IBD patients, especially in combination therapy.

P0451TEN-YEAR OUTCOME DIFFERENCES IN LUPUS NEPHRITIS PATIENTS TREATED WITH CYCLOPHOSHAMIDE AND MYCOPHENOLATE- BASED TREATMENT REGIMEN

Abstract Background and Aims Lupus nephritis (LN) poses a considerable impact on the morbidity and mortality of SLE patients. Long term comparative outcome data with cyclophosphamide (CYP) and mycophenolate mofetil (MMF) based regimen from the Indian subcontinent is sparse. We assessed the renal and patient survival of these patients for the types of induction CYP or MMF and the two maintenance therapies – MMF or Azathioprine. We determined the predictors of death and dialysis dependency in the study population. Method In this retrospective study, we analysed outcomes of 100 LN patients, total 67 (26 class III, 25 class IV, 6 class III+V, and 10 class IV+V)) treated with CYP (euro lupus-40 and NIH- Dharmendra Bhadauria 27), and 33 with MMF based regimen with the steroid between July 2008 to June 2018. The class distribution of the patients in the two groups was similar. The data were archived regarding demography, clinical, histopathological features, and the treatment given of all 100 biopsy-proven LN patients. Outcomes between two regimens CYP and MMF in terms of remission, dialysis dependency, and patient survival were compared. The renal survival and patient survival at the end of follow-up between two groups were also analysed. Results The clinical characteristics were similar in both groups, except the activity index was high in CYP patients (6.13 ±4.48 Vs. 4.61 ± 2.80); however, the chronicity index was similar. The overall remission was 70% at the end of induction. The CR, PR, and NR in the CYP group was 46.2%, 23.9 %, 29.9% respectively; however, in the MMF group was 57.6%, 12.1%, and 30.3%, respectively. More patients died in CYP (14.9%) than those in MMF (9.1 %) patients. The 1-, 2-, 3-, 4-, 5- and 10-years patient survival in the CYP induction was 89.5%, 86.2%, 86.2%,83.8%, 83.8% and 83.8% however in MMF was 93.9%, 93.9%, 89%, 89%, 89% and 89% respectively. The most common cause of death was sepsis 9/13(69.2%), followed by uremia. The high serum creatinine, low Hb, male, thrombocytopenia, microscopic haematuria, leukocyturia, nephrotic proteinuria, lack of remission in 12 months, dialysis, doubling of creatinine on follow-up were significant predictors of mortality. The 1-, 2- 3-, 4-, 5- and 10- years renal survival (event death-censored, but dialysis dependency) in CP group was 98.5%, 96.7%, 94.7%, 92.4%, 92.4% and 84 % respectively however in the MMF was 96.8 %, 96.8%, 91.9%, 91.9%, 91.9%, and 78.8% respectively. (Figure 1)At the end of the study, dialysis dependency in the MMF group and CYP group was 7.5% and 12.1 %, respectively (NS). In the maintenance therapy, 3/56(5.3%) had to double of creatinine in MMF, and 7/34 (20.5%) in the AZA group (p=0.03). Conclusion Long term outcomes in terms of patient and renal survival of LN patients treated with CP and MMF based induction is similar. Serum creatinine doubling was more with MMF than AZA based maintenance. The majority of death occurred during induction, and sepsis was the most common cause of death.

P0363ANTIPROLIFERATIVE AGENTS IN ADDITION TO STEROIDS IN IGA NEPHROPATHY: A SINGLE-CENTER COHORT STUDY

Abstract Background and Aims IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide. The optimal approach to its treatment remains a significant challenge; despite recent evidence suggesting that immunosuppressive (IS) therapy does not offer significant benefits over supportive treatment alone, many nephrologists continue to offer steroids and other IS drugs to patients in order to reduce proteinuria and prevent progressive kidney dysfunction. Anti-proliferative agents have been used in combination with steroids to treat IgAN, but data regarding their efficacy are controversial, especially in Caucasian patients. Method We conducted an observational, single center retrospective cohort study to compare the efficacy of different IS regimens in the treatment of IgAN. We included 48 patients (98% Caucasians) with a histological diagnosis of IgAN and without crescentic glomerulonephritis. Patients were divided into three groups according to treatment: steroids alone (ster, n=11), steroids + mycophenolate mophetil (ster+MMF, n=28) and steroids + azathioprine (ster+aza, n=9). Data regarding histological characteristics at diagnosis (MEST-C score, percentage of interstitial fibrosis/tubular atrophy), serum creatinine and proteinuria/creatininuria (P/C) during follow-up, and progression to end stage kidney disease (ESKD) were collected for all patients; adverse events were registered. As primary outcome we considered the complete response at 24 months, defined as a composite outcome of proteinuria/creatininuria &amp;lt; 0.3 and &amp;lt;20% reduction of eGFR during follow-up. Secondary outcomes were: differences in time-averaged proteinuria (TAP), 50% reduction of P/C from baseline, eGFR&amp;lt;30 ml/min, development of ESKD. Results Mean follow-up for our cohort was 53.88 months. Clinical baseline characteristics did not differ significantly among groups, apart for male sex, more expressed in the steroid group (see table 1). Groups were comparable for histological characteristics at diagnosis (table 2). Interestingly, the addition of anti-proliferative agents did not lead to a reduction of total steroid dose (table 3). Time to complete response in the first 24 months, estimated with Kaplan-Meier method with log-rank test, was not different between the three groups (p=0.44, see figure 1). Moreover, we encountered no differences in TAP measured at 6-months periods for the first two years (figure 2). Groups were also comparable in time to 50% reduction in P/C from baseline, time to eGFR&amp;lt;30 ml/min, time to ESKD (figure 3). No significant adverse events were registered, apart from a higher incidence of diarrhea in the ster+MMF (14%) and ster+aza (11%) groups compared to the ster group. At multivariate logistic regression after adjusting for age and sex, only P/C at baseline was predictive of the absence of complete response (figure 4). Conclusion In our study, the combination of MMF or aza plus steroid treatment did not offer any benefit over steroids alone in terms of reduction of proteinuria and reduction of eGFR in IgAN patients. Even if safe in terms of severe complications (only mild to moderate diarrhea was reported in the anti-proliferative groups), currently evidence is lacking to support their use in Caucasian patients. Limitations of our study include its retrospective and single-center design, and the relatively low number of patients.

Synthesis of oxaazaisowurtzitanes by condensation of 4-dimethylaminobenzenesulfonamide with glyoxal

This study was focused on investigating the formation of N-polysulfonylsubstituted aza- and oxaazaisowurtzitanes via condensation of 4-dimethylaminobenzenesulfonamide with glyoxal and discovering new polyheterocyclic caged systems. More specifically, we explored how a donor substituent incorporated into the para position of the phenylsulfonamide molecule would influence the formation of cage products. Four new oxaazaisowurtzitane derivatives bearing one to three aza groups in the cage were consequently synthesized. A side reaction was found to take place, leading to a product having a non-isowurtzitane structure and four 4-dimethylaminobenzenesulfonyl moieties. The side product was analyzed by X-ray diffraction.

A Comparison of Azathioprine and Mycophenolate Mofetil as Adjuvant Drugs in Patients with Pemphigus: A Retrospective Cohort Study.

IntroductionAzathioprine (AZA) and mycophenolate mofetil (MMF) are both first-line steroid-sparing agents used for the treatment of pemphigus in combination with a corticosteroid, but few studies to date have directly compared these two combination treatment modalities. The aim of this study was to compare the efficacy and safety of each of these agents as adjuvant therapy with the corticosteroid prednisolone for the treatment of pemphigus, using standardized outcome parameters.MethodsThis was a retrospective study of patients with pemphigus who received corticosteroid therapy in combination with either AZA or MMF at the Autoimmune Blistering Skin Diseases Clinic of Ramathibodi Hospital (Bangkok) between January 2007 and July 2017. The treatment response was evaluated using early [end of the consolidation phase (ECP)] and late endpoints [complete remission (CR) on therapy, CR off therapy and immunological remission]. Cumulative steroid use, relapse rate and adverse events in each treatment group were also compared.ResultsOf the 62 patients with pemphigus included in the study, 37 were treated with prednisolone plus AZA as adjuvant (AZA group) and 25 patients were treated with prednisolone plus MMF as adjuvant (MMF group). The majority of patients in both treatment groups reached the ECP (AZA group 88.2%; MMF group 71.4%; between-group difference not statistically significant at p = 0.156); the median time required to achieve this early endpoint was also comparable (p = 0.362). A high percentage of patients in both the AZA and MMF groups attained CR on therapy (AZA 73%; MMF 72%). The total number of patients who achieved CR on and off therapy were comparable in the two groups (p = 0.933 and p = 0.690, respectively). However, the median time for patients to achieve CR on therapy was significantly shorter for those on MMF than for those on AZA (7.3 vs. 12.5 months; p = 0.019), and the cumulative steroid dose required for patients to achieve CR both on and off therapy was significantly lower in the MMF group than in the AZA group (p = 0.007 and p = 0.043, respectively).ConclusionWhile corticosteroid in combination with either AZA or MMF is an effective therapeutic regimen for the treatment of pemphigus, MMF demonstrates a shorter time to achieve CR on therapy and has a significantly higher steroid-sparing effect.