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Journal articles on the topic "B 20.5 UL 2011"
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Alvarado, Yesid, Michael J. Keating, Susan O'Brien, Hagop M. Kantarjian, William G. Wierda, Troy Sneed, Nitin Jain, and Guillermo Garcia-Manero. "Azacytidine and Vorinostat in Patients with Chronic Lymphocytic Leukemia (CLL) Diagnosed with Therapy-Related Myelodysplastic Syndromes/Acute Myeloid Leukemia (t-MDS/AML)." Blood 124, no. 21 (December 6, 2014): 5627. http://dx.doi.org/10.1182/blood.v124.21.5627.5627.
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Abstract Background: There is evidence of a leukemogenic effect of purine analogues, mainly when combined with DNA-damaging agents. Various series report an approximately 5% rate of t-MDS/AML in patients treated with a fludarabine-based regimen. Patients are generally old, and old age is associated with worse outcomes. To date, there is no established standard therapy recommendation for this group of patients, and results of prospective treatment evaluations are scarce. Aim: To determine the characteristics and treatment outcomes of patients with CLL and t-MDS/AML. Methods: We analyzed a group of 6 patients with newly diagnosed t-MDS/AML who were treated in our institution from September 2011 to July 2014. Patients were enrolled in a phase II trial of azacitidine (75 mg/m2 IV daily x 5 days) in combination with vorinostat (200 mg orally three times daily x 5 days) (Arm A) or azacitidine alone (Arm B), with courses repeated every 3-8 weeks. This trial was designed to uniformly treat patients not eligible for other leukemia protocols due to comorbidities. Results: At baseline, all patients had an underlying diagnosis of CLL that was in remission or minimally active. The median percentage of CLL bone marrow involvement was 10% (range 0-60%), and ALC was 0.9 K/uL (range 0.2-9.79). The median number of prior CLL treatments was 2 (range 0-3). All patients had previously received fludarabine-based regimens. The median time from chemotherapy to t-MDS/AML diagnosis was 10 years (range 4-10). All patients were male, and the median age was 72 years (range 52-72). All patients had 3-line cytopenia, with median WBC 2.3 K/uL (range 0.8-8.9), ANC 0.55 K/uL (range 0-1.22), hemoglobin 9.6 G/DL (range 8.3-10.4), platelets 39 K/uL (range 6-80), and bone marrow blast percentage of 5% (range 1-18%). The karyotype was complex in all patients. Molecular studies showed that 3 patients had TP53 gene mutations. Five patients received treatment in Arm A, and only 1 patient was randomized to Arm B. Patients received a median of 4 cycles (range 2-7) and remained in the study for a median time of 216 days (range 86-329) before progression. None of the patients achieved remission, but stable disease was observed in 5 out of 6 patients. At the time of this analysis, 4 patients are dead and 2 are still alive: one discontinued treatment because of prolonged myelosuppression and is receiving best supportive care, and the other is recovering from cycle number 4 of treatment. The median survival in the group from the time of treatment initiation was 10.1 months and from the time of study discontinuation was 3.1 months. Further therapy was attempted in 3 patients without response. Conclusion: This is a group of patients with poor prognostic features. Azacytidine and vorinostat have been previously reported to be a safe combination (Garcia-Manero et al. ASH 2010, abstract 604) and may constitute a reasonable treatment alternative. Further prospective studies involving larger numbers of patients are required. Abstract 5627. Table 1: Baseline Patient Characteristics. Patient Age WBC K/uL Hb G/DL Plt K/uL BM Blast % CLL BM % Cytogenetic Molecular Prior CLL Treatments Treatment Arm Best Response 1 52 11 9.6 6 18 60 -3,-4,-5q,-6,-7, -7p,-12, +16 TP53 mutation 1.FCR x 62. Rituximab + Lenalidomide A NR 2 74 1 10 41 3 10 -3p,-5q,-7,-15,-17,-19 TP53 mutation 1. FCR x 42. FCR x 53. BR x 2 A SD 3 68 2.2 9.4 27 6 30 +7,-7p,t(7,21) Negative 1. FCR x 62. FCR x 4 B SD 4 73 2.3 9.7 39 6 0 +2,-5q,+8,-17,-18,+19,+20,-Y Negative 1. FCR x 6 A SD 5 71 0.8 8.3 39 4 0 +2,+4,t(5;17),+6,-7,-9, +13, +15,-16,-17,+18,+19,-20,+21 Negative 1. FR x 12. BR x43. MEDI-551 A SD 6 74 2.4 10.4 80 1 10 t(1;3),inv3,-5q,-18 TP53 mutation 1. R-CHOP x 62. BR x 13. FCR x 4 A SD WBC: White blood cells, Hb: hemoglobin, Plt: Platelets, BM: Bone Marrow, CLL: Chronic Lymphocytic Leukemia, F: Fludarabine, C: Cyclophosphamide, R: Rituximab, B: Bendamustine, MEDI-551: anti-CD19 antibody, NR: no response, SD: stable disease. Disclosures O'Brien: Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Kantarjian:ARIAD, Pfizer, Amgen: Research Funding.
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Storek, Jan, Rob Woolson, Paul K. Wallace, Gregory Sempowski, Peter A. McSweeney, Maureen Mayes, Leslie Crofford, Sharon LeClercq, Richard A. Nash, and Keith M. Sullivan. "Low Blood Counts of Memory/Effector CD8 T Cells, Gamma/Delta T Cells, Memory B Cells and Plasmacytoid Dendritic Cells and High Counts of Th2 Cells in Systemic Sclerosis." Blood 118, no. 21 (November 18, 2011): 4917. http://dx.doi.org/10.1182/blood.v118.21.4917.4917.
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Abstract Abstract 4917 Introduction: Systemic sclerosis (SSc) is presumed to result from aberrant activation of autoreactive T cells. However, the exact pathogenesis of SSc is not known. Patients and Methods: To contribute to the understanding of the immunopathology of systemic sclerosis (SSc), we compared blood counts of multiple lymphocyte subsets between 20 adult SSc patients not treated with immunomodulatory drugs and healthy controls. The patients had to fit entry criteria for SCOT trial (Scleroderma – Cyclophosphamide or Transplantation?, www.sclerodermatrial.org), i.e, 1. symptoms for no longer than 5 years (except for Raynaud's phenomenon), 2. diffuse scleroderma, and 3. either moderate lung involvement (forced vital capacity (FVC) or diffusion of carbon monoxide (DLCO) between 45 and 70% predicted) or moderate kidney involvement (history of hypertensive renal crisis, but normal renal function at study entry). Multiparameter flow cytometry was used for the determination of the lymphocyte subset counts. Results: Counts of the following subsets were significantly lower in the patients compared to the controls: total T cells (median 1316 vs 2088/ul, p=0.015), total CD8 T cells (273 vs 580/ul, p<0.001), central memory CD8 T cells (23 vs 87/ul, p<0.001), effector memory CD8 T cells (17 vs 39/ul, p=0.015), effector CD8 T cells (28 vs 68/ul, p=0.001), gamma/delta T cells (31 vs 77/ul, p<0.001), switched (IgM/DàIgG/A isotype switched) memory B cells (6 vs 26/ul, p<0.001), non-switched memory B cells (7 vs 17/ul, p=0.004), and plasmacytoid dendritic cells (2 vs 6/ul, p=0.002). Counts of Th2-biased (producing interleukin-4 upon polyclonal stimulation) CD4 as well as CD8 T cells were significantly higher in the patients compared to the controls (248 vs 139/ul for CD4, p=0.002, and 259 vs 164/ul for CD8, p<0.001). Conclusion: Immunopathology of SSc is complex. Low blood counts of memory/effector CD8 T cells, gamma/delta T cells, memory B cells and plasmacytoid dendritic cells and Th2-biased T cells may play a role in the pathogenesis of SSc. However, cause and effect relations need to be established. Given previous reports of increased numbers of CD8 and gamma/delta T cells in the affected tissues of patients with systemic sclerosis and increased numbers of plasmacytoid dendritic cells in the affected tissues of patients with autoimmune diseases (compared to healthy individuals) (Prescott RJ et al: J Pathol 166 (1992) 255–63, Atamas SP et al: Arthritis Rheum 42 (1999) 1168–78, Giacomelli R et al: Arthritis Rheum 41 (1998) 327–34, Yurovski VV et al: J Immunol 153 (1994) 881–91, Nestle FO et al: J Exp Med 202 (2005) 35–43, Farkas L et al: Am J Pathol 159 (2001) 237–43), it is possible that the low blood counts of CD8 T cells, gamma/delta T cells and plasmacytoid dendritic cells result from redistribution of these cells from blood to affected tissues. Disclosures: No relevant conflicts of interest to declare.
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Roesch, Erin Elizabeth, and Catherine Broome. "Complement Blockade with C1 Esterase Inhibitor in Refractory Immune Thrombocytopenia." Blood 126, no. 23 (December 3, 2015): 2253. http://dx.doi.org/10.1182/blood.v126.23.2253.2253.
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Immune thrombocytopenia (ITP) is an acquired thrombocytopenia due to autoantibody-mediated destruction of platelets. Multiple therapies targeting antibody production, the reticuloendothelial system and platelet production are used to treat ITP, including glucocorticoids, intravenous immune globulin (IVIG), Rituximab, splenectomy and thrombopoietin-receptor agonists. The response to therapy is heterogeneous, supporting the concept that multiple mechanisms are ultimately responsible for thrombocytopenia. In vitro complement fixation assays have shown that serum obtained from 50% of patients with ITP is able to fix complement to the platelet surface. Autoantibodies to platelet surface antigens GPIIb/IIIa and/or GPIb/IX have also been shown to activate complement via the classical pathway. We suspect that complement fixation/activation plays an important role in platelet destruction in ITP. Proposed mechanisms include C3b deposition on the platelet surface leading to opsonization, direct damage to platelets by C5b-9, and a role for complement in the imbalance in T-cell regulator/effector activity. T-cell activity has been proposed to stimulate B-cell production of autoantibodies against platelet surface antigens. C1 esterase inhibitor (C1INH) is a member of the serine protease inhibitor family and interacts with C1 esterase to block activation of the classical pathway of complement activation. Case reports have demonstrated that C1INH can prevent C3-mediated lysis of PNH erythrocytes (DeZern 2014) and attenuate hemolysis in a patient with DAT C3d positive autoimmune hemolytic anemia (Wouters 2013). Based on these data, we hypothesized 1) complement activation/deposition may play an important role in persistent thrombocytopenia in refractory ITP, and 2) blockade of the classical pathway with C1INH may lead to prolonged platelet survival. Two female patients with a history of autoimmune disease (systemic lupus erythematosus (SLE) and Sjogren's) and primary refractory ITP [steroids, IVIG, Rituximab, and Romiplostim (23-38 days)] were treated with C1INH, Berinert 20 units/kg. Within 8 hours of first C1INH dose, platelet count improved significantly in both patients. Given the rapid increase in platelet count, each patient received two additional doses of C1INH. Both patients demonstrated a continued increase in platelet count with no further C1NH therapy. In patient 1, platelet count normalized on day 63 and remains normal without additional therapy 194 days post C1INH treatment. In patient 2, platelet count has risen to 568K 14 days after C1INH administration. These cases clinically illustrate a thought provoking relationship between antigen/antibody complexes, complement activation, and platelet destruction in ITP. We suspect a potential biphasic response to C1INH therapy. We hypothesize immediate inhibition of the classical pathway and subsequent decrease of C3b deposition on platelet surface may be responsible for the acute rise in platelet count, while a reset of T-cell regulatory/effector function via complement blockade may be accountable for the longevity of platelet count increase and normalization seen in our patients. Refractory ITP may involve antibody-mediated complement activation via the classical pathway. The destruction of platelets may be driven by C3b-mediated phagocytosis and/or by C5b-9-mediated membrane damage, as well as by modulation of the immune system and T regulator cell function. In our patients, the commercially available C1INH, Berinert, was well-tolerated and platelet count improvement was noted almost immediately after administration and has appeared to be sustained. Future studies evaluating treatments that target inhibition of the complement pathway may be an effective alternative or adjunctive therapy for refractory immune thrombocytopenia. Table 1. Platelet Counts Baseline Diagnosis Prior to 1st C1NH dose 8 hours post 1st C1NH dose Prior to 2nd C1NH dose 8 hours post 2nd C1NH dose Prior to 3rd C1NH dose Post 3rd C1NH dose 7 days post 1st C1NH dose 10 days post 1st C1NH dose 14 days post 1st C1INH dose Patient 162yo F H/O SLE 160 K/UL 0 K/UL 2 K/UL 12 K/UL 5 K/UL 9 K/UL 15 K/UL 30 K/UL 38 K/UL 105/UL 139K/UL Patient 247yo F H/O Sjogren's Unknown 1 K/UL 4K/UL 8K/UL 9 K/UL 18 K/UL 18 K/UL 25 K/UL 122 K/UL 469 K/UL 568 K/UL Disclosures Off Label Use: Berinert and its use in ITP.. Broome:Alexion Pharmaceuticals: Consultancy, Honoraria, Research Funding.
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Ramadas, Poornima, Jennifer Leibovitch, and Teresa Gentile. "Hemophagocytic Lymphohistiocytosis: A Single Institution Experience." Blood 134, Supplement_1 (November 13, 2019): 4877. http://dx.doi.org/10.1182/blood-2019-127517.
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Background: Hemophagocytic lymphohistiocytosis [HLH], is a rare life-threatening syndrome of excessive immune activation. It can be primary due to genetic predisposition or secondary due to infections, immune disorders or malignancies. With nonspecific clinical presentation, a high index of suspicion is required to make the diagnosis. Prompt treatment of underlying etiology and HLH specific therapy is warranted to prevent adverse clinical outcome. Methods: After IRB approval, we conducted a retrospective chart review of adult patients (pts) ≥ 18 years diagnosed with HLH between January 1st, 2010 and June 30th, 2019. We recorded age at diagnosis, gender, cause of HLH, symptoms, laboratory testing, bone marrow pathology, imaging, treatment and outcome. Results: We found a total of 15 patients in the time interval. Pt age ranged from 22 to 64 years with a median of 46 years. 60% were females and 40% were males. 14 pts had secondary HLH and one pt tested positive for HLH gene mutations. Etiology of HLH was malignancy in 6 (40%), infection in 5 (33%), rheumatological disease in 3 (20%) and cause was unclear in one pt but suspected to be an infection. One pt had prior allogenic stem cell transplant and one pt developed HLH even after completion of treatment for lymphoma. On presentation, 14 (93%) had fever, 6 (40%) had respiratory symptoms, 6 (40%) had neurological symptoms, 2 (13%) had a skin rash, 2 (13%) had bleeding manifestations and 3 (20%) required pressor support. Hemoglobin ranged from 5.5 to 13.3 g/dL on presentation, with median of 10.1 g/dL and 14 (93%) had Hb <9 g/dL. Absolute neutrophil count ranged from 0.3 to 16.94 x 103/uL with median of 2.87x103/uL and decreased to < 1000x103/uL in 11 (73%) and < 500x103/uL in 7 (46%). Platelet counts on presentation ranged from 18 to 244x103/uL with median of 82x103/uL and decreased to <100x103/uL in 14 (93%) and <20x103/uL in 8 (53%). 14 (93%) had bicytopenia. Initial ferritin levels ranged from 1,552 to 2,62,080 ng/ml with median of 5,515 ng/ml and increased to >10,000 ng/ml in 10 (66%) and highest level was 4,57,970 ng/ml. All 15 pts had some degree of hepatic dysfunction and one pt had acute kidney injury. Triglyceride levels were >265 mg/dL in 6 (40%). 10 (66%) had laboratory evidence of disseminated intravascular coagulation (DIC), one pt had clinical DIC. Blood cultures were negative in everyone, except 2 pts who developed infection during the hospital course, one with Candida krusei and the other with methicillin sensitive staphylococcus aureus. Bone marrow biopsy was performed in 14 (93%) and all of them demonstrated hemophagocytosis. 3 (20%) underwent lumbar puncture and 2 had elevated CSF protein. 11 (73%) had immunological testing and all of them had elevated soluble IL-2 receptor alpha (sCD25 or sIL-2R). Of the 3 pts who had HLH genetic testing, one had HLH associated mutations. Organomegaly was noted in 11 (73.3%) (4 had hepatosplenomegaly, 6 had splenomegaly, one had hepatomegaly). 6 (40%) had lung infiltrates. MRI brain was done in 5 (33%) and 2 had patchy hyperintensities. 11 (73.3%) were treated with HLH-94 protocol with etoposide and dexamethasone. One pt had matched unrelated donor Allogenic stem cell transplant. 13 (86.6%) had initial recovery. At the time of data cut off, 10 (66%) were alive. Of the 3 pts who initially recovered, one pt died of relapsed lymphoma, one died of HLH relapse and one developed Clostridium difficile infection with bowel perforation. [Refer to Table 1]. Conclusion: Even though literature suggests that malignancy associated HLH has a worse prognosis, our small series did not suggest that. We also noted that HLH associated with rheumatological diseases leads to a superior outcome if the underlying disease is adequately treated. The most significant finding in our series was a patient with diffuse large B cell lymphoma who was diagnosed to have primary HLH with HLH associated mutations. Typically, primary HLH presents in the first few years of life. This patient case points to the fact that patients with primary HLH can have a late presentation and can also be associated with immunological disorders with a predisposition to malignancy. This finding suggests that all patients diagnosed with HLH should have genetic testing done for HLH associated mutations, as this will impact treatment decisions and these patients will benefit from more intense treatment which may include an allogenic stem cell transplant. Disclosures No relevant conflicts of interest to declare.
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Qiao, Junjing, Dandan Zhao, Le Xuan Truong Nguyen, Herman Wu, Gang Liu, Shanshan Suo, Huafeng Wang, et al. "Spred1 Insufficiency in the Hematopoietic and/or Vascular Compartments of the Bone Marrow (BM) Niche Promotes Aggressive Leukemogenesis in Chronic Myelogenous Leukemia (CML)." Blood 134, Supplement_1 (November 13, 2019): 3791. http://dx.doi.org/10.1182/blood-2019-127616.
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Spred1, a member of the Sprouty family of proteins and a negative regulator of RAS-MAPK signaling, is highly expressed in normal hematopoietic stem cells (HSCs) where it negatively regulates self-renewal activity. Lack of Spred1 function has been associated with aberrant hematopoiesis (Tadokoro, 2018). Spred1 knocked-out (KO) mice fed with high-fat diet develop a myeloproliferative phenotype (Tadokoro, 2018), and lower SPRED1 expression in acute myeloid leukemia associates with a poor outcome (Li, 2015; Olsson, 2014; Pasmant, 2015), suggesting a potential role of this gene as a tumor suppressor in myeloid malignancies. In CML, however, the role of Spred1 has not been fully dissected. Thus, we generated Spred1 KO CML (i.e., Spred1-/-SCLtTA/BCR-ABL) mice by crossing Spred1 KO (a gift from Dr. Yoshimura, Japan) with inducible SCLtTA/BCR-ABL CML mice. Spred1 KO mice showed increased cell cycling of BM long-term HSCs (LTHSCs; Lin-Sca-1+c-kit+Flt3-CD150+CD48-; G0: 62% vs 76%), and increased white blood cell (WBC) counts [14 vs 5.9 k/ul at 12 weeks (w) old, n=15 per group, p<0.0001], as compared to wt mice. Upon B/A induction by tetracycline withdrawal, Spred1-/-SCLtTA/BCR-ABL mice had higher WBC (102.5 vs 12 k/ul at 4 w, n=15 per group, p<0.0001), more pronounced splenomegaly (spleen weight: 0.28g vs 0.19g, n=4 per group, p=0.06) and a significantly shorter survival (median: 39 vs 83 days, n=23 per group, p<0.0001) than Spred1 wt CML mice. In Spred1-/-SCLtTA/BCR-ABL mice, we observed a more rapid expansion of circulating mature myeloid cells (CD11b+Gr-1+ cells: 63% vs 25%, n=8 per group, p<0.01) and a deeper decrease of BM LTHSCs (1,385 vs 2,164 per femur, n=5 per group, p<0.01) and increase of spleen LTHSCs (27330 vs 18546, n=5 per group, p<0.01) at 4 w after B/A induction compared with Spred1 wt CML mice. Further, we found a higher fraction of Spred-/-SCLtTA/BCR-ABL mice (33% vs 10%) developed lymph node enlargement, with infiltration with pro-B lymphoblastic cells (B220+CD43+CD19+IgM−) compared with Spred1 wt CML mice. Altogether these features suggested that Spred1 insufficiency accelerates CML development and evolution to more aggressive phases of the disease. Since upregulation of Spred1 reportedly disrupts vascular integrity (Fish, 2008; Wang 2008), a finding that we have also confirmed in the BM niche, in order to evaluate separately the leukemogenic effect of Spred1 expression on different compartments of the BM niche, we generated the following conditional Spred1 KO strains: Spred1flox(f)/fMxl-cre+ (Spred1 KO in HSCs, hereafter called Spred1HSCΔ/Δ), Spred1f/fTie2-cre+ [Spred1 KO in endothelial cells (ECs), hereafter called Spred1ECΔ/Δ], Spred1HSCΔ/ΔSCLtTA/BCR-ABL and Spred1ECΔ/ΔSCLtTA/BCR-ABL by crossing SCLtTA/BCR-ABL with the above Spred1 KO mice. LTHSCs from Spred1HSCΔ/ΔSCLtTA/BCR-ABL mice showed an increase in cell cycling, RAS/MAPK/ERK activity and Bcl-2 levels, and higher engraftment in recipient mice (blood: 9.7% vs 26.5% at 6w, 14.8% vs 42% at 8w, 14.7% vs 48% at 12w, n=10 per group, p<0.01), compared to Spred1 wt CML LTHSCs. Spred1HSCΔ/ΔSCLtTA/BCR-ABL mice (n=15) showed enhanced leukemia progression (WBC: 19 vs 12 k/ul, p=0.004; CD11b+Gr-1+ in blood: 36% vs 25%, p=0.04 at 4 w after B/A induction) and a significantly shorter survival (median: 49.5 vs 83 days, p=0.01) compared to Spred1 wt CML mice (n=20). However, the disease in these mice appeared to be overall less aggressive than global Spred1 KO CML (i.e., Spred1-/-SCLtTA/BCR-ABL) mice (WBC: 19 vs 102 k/ul; CD11b+Gr-1+ in blood: 36 vs 63%; Survival: 49.5 vs 39 days), suggesting that Spred1 depletion in other non-hematopoietic cell compartments may also be important for leukemogenesis. In fact, Spred1ECΔ/ΔSCLtTA/BCR-ABL mice (n=8) showed enhanced leukemia progression (WBC: 26 vs 9.8 k/ul at 4 w after B/A induction, p=0.02), a trend for a reduced survival (median: 56 vs 83 days, p=0.09), and increased arteriolar vascularization, compared to Spred1 wt CML mice (n=20). Mechanistic studies on how endothelial Spred1 insufficiency co-participates in leukemogenesis are ongoing. Altogether our results support a role of Spred1 insufficiency in distinct BM niche compartments to produce a more aggressive CML phenotype, likely through different, but complementary mechanisms. Spred1 may therefore emerge as a novel target for advanced CML. Disclosures No relevant conflicts of interest to declare.
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Beltran, Brady E., Erick Cotacallapa, and Jorge J. Castillo. "Survival and Clinicopathological Characteristics of EBV-Positive Diffuse Large B-Cell Lymphoma." Blood 120, no. 21 (November 16, 2012): 1588. http://dx.doi.org/10.1182/blood.v120.21.1588.1588.
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Abstract Abstract 1588 Background: EBV-positive diffuse large B-cell lymphoma (EBV+ DLBCL) of the elderly is a provisional entity included in the 2008 WHO Classification of Lymphomas. Diagnostic criteria include age >50 years, DLBCL morphology and EBV expression in lymphomatous cells. However, these criteria are evolving as several patients are <50 years and a specific cut-off for the percentage of EBV expression has not been defined. The goal of this retrospective study is to evaluate clinical and pathological characteristics of EBV+ DLBCL from Peruvian patients. Methods: Between January 2002 and January 2012, all patients meeting criteria for EBV+ DLBCL were included in the analysis. Patients with evidence of immunosuppression were excluded. All cases re positive for the presence of EBV-encoded RNA (EBER) by in situ hybridization, and CD20 and/or PAX-5 expression by immuno-histochemistry. Clinical data were reviewed retrospectively and patient's biopsies were analyzed for the expression of BCL6, CD10, CD30 and MUM-1/IRF4 using a tissue microarray (TMA) technique. The overall survival (OS) curves were calculated using the Kaplan-Meier method, and compared using the log-rank test. Results: A total of 43 EBV+ DLBCL patients are included in this study. The median age was 73 years (range 25–95 years). Four patients (9% ) were <50 years. The male:female ratio was 2.2:1. B symptoms occurred in 59%, ECOG >21 in 60%, advanced stage (III/IV) in 58%, elevated LDH levels in 44%, and lymphocyte count <1000/uL in 35%. The International Prognostic Index (IPI) score was 0–2 in 39% and 3–5 in 61% of the patients. Extranodal disease occurred in 20 patients (46%): stomach (n=3), tonsil (n=3), pleura (n=2), palate (n=2), cecum (n=2), bone marrow (n=2), ileum (n=1), bone (n=1), skin (n=1), lung (n=1), meninges (n=1), breast (n=1) and peritoneum (n=1). Three patients had central nervous system involvement (7%), one at presentation and two at relapse. Based on the Hans classification, 76% had non-germinal center profile. Ki67 expression was >80% in 53% of the patients. Eleven evaluated patients had a c-myc-negative status. Chemotherapy was received in 75% of the cases due to poor performance status. The overall response rate with conventional chemotherapy was 46%, with complete response in 39%, partial response in 7%, and no response in 54%. The median survival was 7.5 months. The Oyama score was: 0 factors (13%), 1 factor (47%), and 2 factors (40%) with median OS of 41, 11 and 1.5 months respectively (p=0.07). A lymphocyte count <1000/uL was a prognostic factor for OS (p=0.001). Conclusions: Based on our study, which is the largest cohort in Latin-America, EBV+ DLBCL is an aggressive entity with frequent extranodal disease and poor response to conventional chemotherapy. The overall survival remains poor. Lymphopenia, as defined as lymphocyte count <1000/uL, appears as a prognostic factor for OS. Disclosures: No relevant conflicts of interest to declare.
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Kline, Justin, Aaron P. Rapoport, Adam M. Petrich, Kenneth S. Cohen, Sachdev P. Thomas, Sreenivasa Nattam, Krishna Rao, et al. "Phase II Study of Temsirolimus and Lenalidomide in Patients with Relapsed and Refractory Lymphomas: Final Analysis of NCI 8309." Blood 128, no. 22 (December 2, 2016): 4147. http://dx.doi.org/10.1182/blood.v128.22.4147.4147.
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Abstract Background: mTOR inhibitors, including temsirolimus (TEM), have demonstrated activity in patients (pts) with relapsed/refractory (rel/ref) lymphomas (J Clin Oncol 2010;28(31):4740). Lenalidomide (LEN) is an immunomodulatory agent with activity in a number of lymphoma subtypes with potential additive or synergistic effects. We previously reported phase I results of TEM/LEN in patients with relapsed/refractory lymphomas and showed good tolerability and evidence of clinical activity (J Clin Oncol 2012;30 suppl; abstract 8075). Recommended phase II doses of TEM 25 mg weekly and LEN 20 mg daily (D1-21, q28D) were tested in 3 histology-based cohorts with final results presented here. Methods: Pts with rel/ref lymphomas having received > 1 cytotoxic regimen were eligible. Other criteria included ANC > 1000/uL, platelets > 75,000/uL, and normal renal and hepatic function. Pts were enrolled into 3 cohorts: DLBCL (cohort A), FL (cohort B), and other lymphomas (cohort C). CLL/SLL was excluded due to poor single-agent TEM activity. TEM was administered at 25 mg IV weekly, and LEN at 20 mg PO daily (D1-21, q28D). Pts received therapy for up to 1 year, or until disease progression or development of toxicities requiring treatment cessation. All pts received ASA prophylaxis. Response assessments were performed after cycle 2, and every 3 months thereafter. Results: 93 pts (31 female, 62 male), mean age 57 years (range, 23-78 years) were enrolled onto cohort A (n=39 DLBCL), cohort B (n=15 FL), or cohort C (n=39; 20 HL, 9 T-NHL, 5 MCL, 4 MZL, 1 WM). The median number of prior treatments was 4 (range, 1-14). 28 pts had relapsed following autologous stem cell transplantation (ASCT). The median number of cycles delivered was 4 (range, 1-12). Grade 3 or higher non-hematologic adverse events (AE) were uncommon with only fatigue and hypokalemia occurring in >10% of pts; ≥ grade 3 hematologic toxicity included anemia (n=27), lymphopenia (n=40), neutropenia (n=44) and thrombocytopenia (n=42). Three grade 5 AEs were observed (colonic perforation, myocardial infarction and sepsis). The overall response rates (ORR) were 25.6% (5 CR; 5 PR), 46.6% (5 CR; 2 PR), and 64.1% (7 CR; 18 PR) for pts in cohorts A, B, and C, respectively. Of note, cohort B (FL) was closed prematurely due to poor accrual. Median progression-free survival (PFS) for pts in cohorts A and C was 6.0 months (95% CI 3.1 - 8.0 months), and 7.3 months (4.2 - 10.8 months), and median duration of response (DOR) was 11.3 months (2.6 months - not reached) and 5.5 months (2.3 months - not reached), respectively. Median overall survival (OS) for pts in cohorts A and C was 10.2 months (5.9 - 20.6 months), 25.5 months (10.1 - not reached), respectively. Among 20 heavily-treated HL pts in cohort C (median prior treatments 6, range 3-14), all of whom progressed on brentuximab vedotin (BV), and 13 of whom had received a prior ASCT, the ORR was 80% (7 CR; 9 PR), and the median PFS, DOR and OS was 9.2 months, 8.1 months, and 25.5 months, respectively. Conclusions: The combination of TEM/LEN therapy was well-tolerated and showed encouraging activity in pts with rel/ref lymphomas. The most significant activity was observed in rel/ref HL, with an 80% response rate, including in pts with prior BV exposure and in those relapsed after ASCT. For DLBCL, the addition of LEN did not improve ORR compared to historical experience with single-agent TEM, but we note a provocative prolongation of both PFS and DOR for this otherwise aggressive disease. Further evaluation of mTOR pathway inhibition and immunomodulatory agents in relapsed HL patients is warranted based on these results. This study was conducted through the University of Chicago Phase II Consortium, supported by NCI contract N01-CM-2011-00071C Disclosures Kline: Vasculox: Research Funding; Merck: Honoraria, Research Funding. Petrich:AbbVie: Employment. Rao:Novocure: Consultancy. Smith:TGTX: Consultancy; Juno: Consultancy; Portola: Consultancy; Amgen: Other: Educational lecture to sales force; Genentech: Consultancy, Other: on a DSMB for two trials ; Pharmacyclics: Consultancy; Celgene: Consultancy; Gilead: Consultancy; AbbVie: Consultancy.
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delMoral-Diez, Juan J., Elena Juventina Tuna-Aguilar, Alvaro Aguayo, Antonio Olivas-Martinez, and Gladys P. Agreda-Vasquez. "Prognosis in Patients with Human Immunodeficiency Virus Infection and Advanced Clinical Stage Classic Hodgkin's Lymphoma." Blood 134, Supplement_1 (November 13, 2019): 5281. http://dx.doi.org/10.1182/blood-2019-123792.
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Classic Hodgkin's lymphoma (cHL) represents 95% of all Hodgkin lymphomas, and is responsible of 0.5% of all cancer types (Siegel, Miller & Jemal, 2016). In HIV positive patients, the incidence of cHL is high (5-20 fold). The use of combination antiretroviral therapy (CART) and CD4 count >200 cells/uL appears to increase the risk; nonetheless, the risk for developing cHL in HIV infected patients remains high, regardless of CD4 count. The median patients' age of HIV-associated classic Hodgkin's lymphoma (HIV-cHL) ranges from 40 to 49 years old, slightly higher than the age observed in general population. It is more common in men, and tends to manifest with extranodal disease (67% vs 32%), B-symptoms (77% vs 43%), and stage III or IV disease (82% vs 42%) (Shiels et al, 2014). Recent recommendations state that HIV-cHL should receive first-line ABVD chemotherapy treatment while continuing CART (Blanca et al, 2007)(Montoto et al, 2012). To determine the prognosis of de novo advanced stage HIV-cHL and compare it with non-HIV-cHL, we designed an observational, descriptive study, including all HIV-cHL (WHO 2016 criteria) from August 2004 to December 2018, paired with a non-HIV-cHL group by clinical stage and gender. Clinical features between positive and negative HIV groups were compared by standard statistical methods. Overall survival (OS) and relapse-free survival (RFS) were calculated by Kaplan-Meier methodology. Analysis for mortality predictors was performed with a univariate Cox regression model. Data was collected from 21 patients with HIV-cHL, all male and with advanced clinical stage, and compared with 58 non-HIV-cHL patients with the same characteristics. The mean age observed was 42.9 (± 10.88) years in HIV-cHL, and 45.1 (± 17.56) years in non-HIV-cHL (p = 0.50). Among the clinical characteristics, the presence of B symptoms was documented in 85.7% of HIV-cHL, and in 91.4% of non-HIV-cHL (p = 0.43). Among biochemical characteristics in both groups, we observed a significantly lower leucocyte count in HIV-cHL (4.6x103 cells/uL) compared with non-HIV-cHL (6.7x103 cells/uL) (p = 0.02). In the monocyte line, we found that HIV-cHL had lower absolute counts (340 cells/uL) than non-HIV-cHL (708 cells/uL) (p = 0.01). A high IPS was reported in 66.7% of HIV-cHL, and in 67.2% of non-HIV-cHL (p = 1.00). The most common reported histologic subtype was mixed cellularity for both groups, with a prevalence of 38.1% and 38.9%, respectively (p = 0.25). The positivity for Epstein-Barr virus was tested in the biopsies of 18 HIV-cHL, and was 100%. Regarding HIV status in infected patients, a 40-month period was the median time between HIV and cHL diagnosis. The median CD4 cell count was 109 cells/uL. 90.5% of patients were treated with CART at time of cHL diagnosis. Other clinical, biochemical and prognostic characteristics are in Table 1. The median follow-up time for all patients was 31 months; the median follow-up time for HIV-cHL was 10 months, shorter than the median follow-up time for non-HIV-cHL (45 months) (p = 0.01). 85.7% of HIV-cHL and 96.6% of non-HIV-cHL received chemotherapy, with a median of 6 cycles (p = 0.11). Complete response (CR) was documented in 61.1% of HIV-cHL, and in 66.1% of non-HIV-cHL (p = 0.77). RFS was 36.5 months for all patients, being less for HIV-cHL (24 months) compared with non-HIV-cHL (51 months) (p = 0.03). The OS median at the time of last follow-up had not yet been reached in all patients (Figure 1). The univariate analysis showed that age ≥45 years old and stage IV cHL are adverse prognostic factors (p = 0.02, p = 0.03, respectively). IPS ≥4 was an adverse outcome factor for mortality, with statistical significance (p = 0.01) (Figure 2). At last follow-up, 22 (27.8%) patients had died, 6 (28.6%) HIV-cHL and 16 (27.6%) non-HIV-cHL (p = 1.00). Clinical, biochemical and prognostic variables, as well as treatment outcomes were similar between HIV-cHL and non-HIV-cHL. Although follow-up time in the HIV-cHL group is shorter, prognosis in terms of OS is similar. RFS is statistically different between both groups and is shorter in HIV-cHL, but as the OS in both groups remains similar, it is possible that rescue chemotherapy is effective in relapsed patients. There was no difference observed in the likelihood of achieving CR in both groups. IPS ≥4 and CR were independent prognostic factors for OS. IPS as an adverse factor and CR as a favorable one. Prognosis of advanced stage HIV-cHL is similar to non-HIV-cHL patients. Disclosures No relevant conflicts of interest to declare.
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Yang, Yanqin, Yubo Zhang, Jun Zhu, Catherine E. Lai, Jingrong Tang, Lisa J. McReynolds, Amy P. Hsu, et al. "Development of Somatic NRAS Mutation Associated with Rapid Transition from Germline GATA2 Mutation Associated Myelodysplastic Syndrome to Acute Myeloid Leukemia." Blood 126, no. 23 (December 3, 2015): 3616. http://dx.doi.org/10.1182/blood.v126.23.3616.3616.
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Abstract There is increasing recognition of the role of inherited germline predisposition for myeloid disorders such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The additional somatic genetic events required for development of a malignant phenotype are however poorly understood. A 25 year old woman was referred to the NHLBI hematology branch in March 2014 for a seven year history of pancytopenia. Her medical history included recurrent pneumonias, oral ulcers, severe varicella infection and arthralgias. Prior bone marrow examinations at ages 21 and 23 at outside institutions reported normocellular marrow, tri-lineage hematopoiesis and mild dyspoiesis. Cytogenetics were remarkable for trisomy 8 in 80% (aged 21) or 90% (aged 23) of metaphases. Previously unrecognized lymphedema was noted on examination. Peripheral blood counts showed WBC 2.28 K/ul [normal range: 3.98-10.04], HGB 9.9 g/dL [11.2-15.7], PLT: 67 K/ul [173-369], ALC: 0.36 K/ul [1.18-3.74] and AMC: 0.06 [0.24-0.86]. Peripheral blood flow cytometry demonstrated decreased CD3+ CD4+ (T) cells, CD19+ (B) cells and NK cells. HLA-DR15 negative. Bone marrow examination showed trilineage hematopoiesis, 50-60% cellularity, mild erythroid predominance and mildly increased, mildly atypical megakaryocytes. Blasts less than 5%. Bone marrow flow cytometry revealed severely decreased B-cells and monocytes, absent B-cell precursors, absent dendritic cells, inverted CD4:CD8 ratio, and atypical myeloid maturation pattern. Cytogenetics demonstrated stable trisomy 8 in 90% of metaphases. On the basis of this assessment the diagnosis of MDS was confirmed. Sanger sequencing revealed a GATA2 L375S mutation in the second zinc finger of known pathogenic significance. Four months later she developed increased fatigue and easy bruising with worsening thrombocytopenia (PLT: 10K/ul). Bone marrow was dramatically changed; now markedly hypercellular (90-100%) with diffuse sheets of immature cells consistent with blasts having fine chromatin, distinct or prominent nucleoli, and visible cytoplasm. Blasts were positive for CD33, CD56, CD64, CD123, and CD163; and were negative for CD34, CD14, and myeloperoxidase. Cytogenetics showed a new trisomy 20 in 65% of metaphases, in addition to previously seen trisomy 8 in 100%. A diagnosis of acute monoblastic leukemia (M5a subtype) was made. At both clinic visits bone marrow aspirate was collected on an IRB approved research sample acquisition protocol. Whole exome sequencing of 1ug DNA was performed using Agilent SureSelect v5 Exome enrichment Kits on an Illumina HiSeq 2000 with 100-bp paired-end reads (Macrogen, Rockville, MD). Data was mapped to hg19 (BWA) and processed using an in-house pipeline (Samtools/Picard/GATK/VarScan/Annovar). Mean read depth of target regions was 157 and 149. There was high correlation between both samples with the exception of a NRAS:NM_002524:exon3:c.C181A:p.Q61K mutation (57 of 180 reads) seen only in the later sample. Confirmatory ultra-deep sequencing for NRAS was performed using Illumina TruSight Myeloid Sequencing Panel on an Illumina MiSeq. No evidence of the NRAS Q61K mutation was found in the earlier March MDS bone marrow sample even when sequenced to a depth greater than 1750 reads (see figure). The mutation was confirmed in the August AML sample at a variant allele frequency of 35%. If heterozygous this would reflect a clone size of 70%, consistent with data from both cytogenetics (new trisomy 20 in 65% of metaphases) and the 76% blasts documented by bone marrow aspirate smear differential. We report here the rapid progression to AML in a patient with germline GATA2 MDS associated with development of a new trisomy 20 karyotype and a NRAS Q61K mutation. The NRAS mutation was not detectable after the patient achieved a complete remission following induction chemotherapy further supporting this association. This NRAS mutation has been implicated in the pathogenesis of multiple cancers by constitutive activation of proliferative signaling. GATA2 associated MDS is a high-risk pre-leukemic condition with the potential for rapid evolution to AML. This is the first report of acquired somatic mutations in the RAS/RTK signaling pathway in the context of germline GATA2 insufficiency associated with acute leukemic transformation. Figure 1. Figure 1. Disclosures Townsley: Novartis: Research Funding; GSK: Research Funding.
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Badar, Talha, Hagop M. Kantarjian, Susan O'Brien, Guillermo Garcia-Manero, Elias Jabbour, Rebecca Garris, Naveen Pemmaraju, et al. "Clinical Outcome of De Novo Adult Acute Lymphoblastic Leukemia (ALL) with 11q23/Mixed Lineage Leukemia (MLL) Gene Rearrangements." Blood 124, no. 21 (December 6, 2014): 5342. http://dx.doi.org/10.1182/blood.v124.21.5342.5342.
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Abstract Introduction: The MLL gene on located on 11q23 plays an essential role in positive regulation of gene expression in early embryonic development and hematopoiesis. Fusion genes, such as MLL-AF4 resulting from t(4:11)(q21;q23), alter normal cellular proliferation and differentiation, favoring leukemogenesis. The DOT1L histone methyltransferase associated with MLL appears to be required for maintenance of ALL. MLL-AF4 is detected in about 10% of de novo B-lymphoblastic leukemia or 30=40% of pro-B ALL subtypes. The 11q23/MLL subtype of ALL has been associated with extremely poor outcomes. We conducted a retrospective analysis of de novo adult ALL with 11q23/MLL gene rearrangements. Methods: Overall the database included 74 pts with 11q23/MLL gene rearrangements referred to our institution between 1980 and 2014. Of these, 20 (27%) pts were relapsed/refractory, 4 (5%) were minimally pretreated, 5 (7%) were inevaluable for response, 3 (4%) had concomitant Philadelphia chromosome, 2 (3%) were T-lineage, 2 (3%) were mature B-ALL. The remaining 38 cases comprised the study cohort evaluated with respect to pretreatment characteristics and outcome measures such as response to therapy, remission duration (CRD), and survival (OS). Results: Baseline characteristics of the cohort included median age 44 yrs (range, 20-75); 26% were older than 60 yrs. Ten (26%) pts had a prior malignancy and were designated secondary ALL. Five (13%) pts had CNS disease at presentation. Median WBC count was 69.8 K/uL (range, 0.5-612); 24 (63%) pts had WBC > 30 K/uL. Nineteen (50%) pts had serum LDH > 1400 U/L. Co-expression of myeloid markers (CD13, CD33 +/- CD117) was noted in 6 (16%) pts. Distribution of the 11q23/MLL gene aberrancies were: t(4;11) (q21; q23) in 25 (66%) pts, 11q23 without translocation partner in 10 (26%) pts, and t(11;19)(q23;p13.1) in 3 (8%) pts. Thirty two (84%) pts were treated per the hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high dose methotrexate and cytarabine) regimen (3 [10%] received concurrent rituximab) and 6 (16%) pts were treated per the augmented BFM regimen. Overall response rate was 95%; complete remission (CR) in 92% and CR without platelet recovery (CRp) in 3%. Overall median CRD was 26.3 mos (range 0.2-93+ mos); median OS was 24.2 mos. Overall, the 5-yr CRD and OS rates were 19% and 26%, respectively, with a median follow-up of 60 mos (range, 4.8-173+ mos). Median OS in pts with 11q23 without chromosomal translocation was 48.5 mos, compared with 24 mos for t(11; 19) and 13.3 mos for t(4; 11) (p= 0.07) (Fig. 1). There were no differences in outcomes by older age or designation as secondary ALL. Conclusion: The 11q23/MLL positive B-lymphoblastic subsets are associated with differentially inferior outcomes, although MLL-AF4 remains the ALL subset associated with highest risk of disease recurrence particularly in the absence of allogeneic stem cell transplantation; the relatively rarity of these subsets poses challenges in establishing the optimal treatment strategies. Therapeutic approaches incorporating hypomethylating agents, histone deacetylase inhibitors, and CAR-T cells could improve these dismal outcomes; targeted agents such as DOT1L inhibitors are under investigation in clinical trials. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
Book chapters on the topic "B 20.5 UL 2011"
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Taber, Douglass F. "Intramolecular Diels-Alder Cycloaddition: 7-Isocyanoamphilecta- 11(20),15-diene (Miyaoka), (–)-Scabronine G (Kanoh), Basiliolide B (Stoltz), Hirsutellone B (Uchiro), Echinopine A (Chen)." In Organic Synthesis. Oxford University Press, 2015. http://dx.doi.org/10.1093/oso/9780190200794.003.0078.
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The amphilectane diterpenes, exemplified by 7-isocyanoamphilecta-11(20),15-diene 3, have been little investigated. In the course of a synthesis of 3, Hiroaki Miyaoka of the Tokyo University of Pharmacy and Life Sciences took advantage (Synlett 2011, 547) of the kinetic enolization and silylation of 1 to convert it into a trienone that spontaneously cyclized to 2. Scabronine G 6, isolated from the mushroom Sarcodon scabrosus, was found to enhance the secretion of neurotrophic factors from 1321N1 astrocytoma cells. To set the absolute configuration of the two quaternary centers that are 1, 4 on the cyclohexane ring of 6, Naoki Kanoh and Yoshiharu Iwabuchi of Tohoku University cyclized (Org. Lett. 2011, 13, 2864) 4 to 5. Although described by the authors as a double Michael addition, this transformation has the same connectivity as an intramolecular Diels-Alder cycloaddition. The diterpenes isolated from the genus Thapsia, represented by basiliolide B 9, induce rapid mobilization of intracellular Ca2+ stores. Brian M. Stoltz of Caltech effected (Angew. Chem. Int. Ed. 2011, 50, 3688) Claisen rearrangement of 7 to give an intermediate that cyclized to 8 as a mixture of diastereomers. A significant challenge in the synthesis was the assembly of the delicate enol ether/lactone of 9. Hirsutellone B 12, isolated from Hirsutella nivea, shows significant antituberculosis activity. Hiromi Uchiro of the Tokyo University of Science found it useful (Org. Lett. 2011, 13, 6268) to protect the intermediate unsaturated keto ester by intermolecular cycloaddition with pentamethylcyclopentadiene before constructing the triene of 10. Simple thermolysis reversed the intermolecular addition, opening the way to intramolecular cycloaddition to give 11. The tetracyclic ring system of the diterpene echinopine A 15 represents a substantial synthetic challenge. David Y.-K. Chen of Seoul National University approached this problem (Org. Lett. 2011, 13, 5724) by Pd-mediated cyclization of 13 to the diene, which then underwent intramolecular Diels-Alder cycloaddition to give 14, with control of the relative configuration of two of the three ternary centers of 15. Double bond migration followed by oxidative cleavage of the resulting cyclohexenone then set the stage for the intramolecular cyclopropanation that completed the synthesis of 15.
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Taber, Douglass F. "Substituted Benzenes: The Piers/Lau Synthesis of Hamigeran B." In Organic Synthesis. Oxford University Press, 2013. http://dx.doi.org/10.1093/oso/9780199965724.003.0064.
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Govindasamy Sekar of the Indian Institute of Technology, Madras, developed ( Chem. Commun. 2011, 47, 5076) an environmentally friendly procedure for the amination of 1 to 2. Jens-Uwe Peters of Hoffmann-La Roche, Basel, showed (Tetrahedron Lett. 2011, 52, 749) that the Udenfriend protocol could be used to convert drugs such as 3 to their hydroxylated metabolites. Suman L. Jain and Anil K. Sinha of the Indian Institute of Petroleum reported (Chem. Commun. 2011, 47, 1610) complementary conditions for arene hydroxylation. Dimethyl aniline has been used, inter alia, as a nucleophile in enantioselective MacMillan conjugate addition. Zhong-Xia Wang of USTC established (Angew. Chem. Int. Ed. 2011, 50, 4901) that the quaternized salt 5 could participate in Negishi coupling. Mark R. Biscoe of the City College of New York discovered (Org. Lett. 2011, 13, 1218) that with a Ni catalyst, the secondary organozinc 9 will couple without rearrangement. Igor V. Alabugin of Florida State University devised (J. Org. Chem. 2011, 76, 1521) a radical-based protocol for replacing a phenolic OH with alkyl, to give 12. Petr Beier of the Academy of Sciences of the Czech Republic used (J. Org. Chem. 2011, 76, 4781) vicarious nucleophilic substitution followed by alkylation to convert 13 to 15. Robin B. Bedford of the University of Bristol developed (Angew. Chem. Int. Ed. 2011, 50, 5524) a Pd-catalyzed procedure for the ortho bromination of an anilide 16. Jin-Quan Yu of Scripps/La Jolla took advantage (J. Am. Chem. Soc. 2011, 133, 7652) of the energetic N-O bond of 19 to drive the functionalization of 18 to 20. Lei Liu of Tsinghua University devised (Org. Lett. 2011, 13, 3235) a Rh-mediated oxidative ortho coupling of the carbamate 21 with 22. Kohtaro Kirimura of Waseda University inserted (Chem. Lett. 2011, 40 , 206) the DNA for a novel Trichosporon decarboxylase into Escherichia coli and found that the resulting fermentation efficiently converted 24 into 25. The alternative Kolbe-Schmitt reaction requires high temperature and pressure. Sometimes, usually with more highly substituted benzene rings, creating the ring is worthwhile.
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Taber, Douglass F. "Organocatalyzed C-C Ring Construction: The Thomson Synthesis of Streptorubin B." In Organic Synthesis. Oxford University Press, 2013. http://dx.doi.org/10.1093/oso/9780199965724.003.0072.
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Jinxing Ye of the East China University of Science and Technology used (Tetrahedron Lett. 2011, 52, 2715) the Hayashi catalyst to direct the addition of 2 to 1, to give the cyclopropane 3. Jia-Rong Chen and Wen-Jing Xiao of Central China Normal University employed (J. Org. Chem. 2011, 76, 281) a urea catalyst for the addition of 5 to 4. Yasumasa Hamada of Chiba University devised (Tetrahedron Lett. 2011, 52, 987) a different urea catalyst for the addition of 7 to 8, to control both the absolute and relative configuration of 9. Jiyong Hong of Duke University showed (Tetrahedron Lett. 2011, 52, 2468) that the imidazolium-mediated cyclization of 10 proceeded with high diastereoselectivity to give 11. Yixin Lu of the National University of Singapore optimized (J. Am. Chem. Soc. 2011, 133, 1726) a dipeptide-derived phosphine to catalyze the addition of 12 to 13. Karl A. Scheidt of Northwestern University combined (Angew. Chem. Int. Ed. 2011, 50, 1678) a triazolium catalyst with super-stoichiometric Ti(O- i Pr)4 to effect the addition of 15 to 4, to give 16. En route to malyngamide C, Xiao-Ping Cao of Lanzhou University condensed (J. Org. Chem. 2011, 76, 3946) the prochiral commercial monoketal 17 with nitrosobenzene, using proline as a catalyst, to prepare 18. Hong Wang of Miami University showed (Angew. Chem. Int. Ed. 2011, 50, 3484) that a lanthanide-complexed α-amino amide was effective for catalyzing the addition of the prochiral 19 to 4, to give 20. Alexandre Alexakis of the Université de Genève and John C. Stephens of the National University of Ireland, Maynooth, established (Angew. Chem. Int. Ed. 2011, 50, 5095) that the Hayashi catalyst was effective for mediating the addition of 22 to 21, to give the diene 23. Ying-Chun Chen of Sichuan University and Karl Anker Jørgensen of Aarhus University used (J. Am. Chem. Soc. 2011, 133, 5053) the same catalyst for the addition of 24 to 25. The Hayashi catalyst appeared again in the report (Chem. Comm. 2011, 47, 3828) by Magnus Reuping of RWTH Aachen University of the addition of 27 to 28.
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Taber, Douglass F. "The Fuwa Synthesis of Didemnaketal B." In Organic Synthesis. Oxford University Press, 2017. http://dx.doi.org/10.1093/oso/9780190646165.003.0097.
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Didemnaketal B 3 may be an artifact of isolation, derived from didemnaketal C, in which one of the methyl esters is instead an ethylsulfonate. Nevertheless, it is B, not C, that is a potent inhibitor of HIV protease. Haruhiko Fuwa of Tohoku University has provided (Chem. Eur. J. 2014, 20, 1848) a detailed account of the synthesis of 3, including the necessary revision of the absolute configuration of seven of the stereogenic centers. A central feature of the modular synthesis of 3 was the cyclization of 1 to the thermodynamically most favorable diastereomer of the spiroketal 2. Three components were combined for the synthesis of 3. The upper sidechain was prepared from commercial citronellal 4. Reduction followed by protection and ozonolysis delivered the aldehyde 5, that was carried on to the alkyne 6. Hydroiodination using the method previously reported by the authors (OHL May 30, 2011) gave 7, that was oxidized to 8 and then to the ester 9. Lactone formation by ring-closing metathesis is difficult because of the substantial preference for the extended conformation of the ester. As illustrated by the conversion of 10 to 11, this can be overcome by complexation with a Lewis acid. Conjugate addition followed by phosphorylation completed the preparation of the enol phosphate 12. The third component of 3 was the lactone 15, prepared by deprotonation/kinetic protonation with 14 of 13. This was carried on to the sulfone 16, that was coupled with 17. Although the Julia–Kocienski reaction usually strongly favors the E alkene, in this case it was necessary to optimize both the base and the solvent. Sharpless asymmetric dihydroxylation followed by coupling with the enol phosphate 12 then completed the preparation of the diol 1. Addition of the ketene silyl acetal 18 to the aldehyde derived from 2 proceeded to give the undesired diastereomer 19. This was overcome by oxidation to the ketone followed by enantioselective reduction. The iodide 9 was added to the aldehyde 20 to give a 1.8:1 mixture of diastereomers, the major one of which was didemnaketal B 3. This full paper is worth reading in detail. The work reported underlines the importance of powerful protocols for carbon–carbon bond formation that maintain high diastereocontrol in stereochemically complex environments.
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Taber, Douglass F. "C–N Ring Construction: The Harrity Synthesis of Quinolizidine (–)-217A." In Organic Synthesis. Oxford University Press, 2015. http://dx.doi.org/10.1093/oso/9780190200794.003.0054.
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David M. Jenkins of the University of Tennessee devised (J. Am. Chem. Soc. 2011, 133, 19342) an iron catalyst for the aziridination of an alkene 1 with an aryl azide 2. Yoshiji Takemoto of Kyoto University cyclized (Org. Lett. 2011, 13, 6374) the prochiral oxime derivative 4 to the azirine 5 in high ee. Organometallics added to 5 syn to the pendant ester. Hyeung-geun Park of Seoul National University used (Adv. Synth. Catal. 2011, 353, 3313) a chiral phase transfer catalyst to effect the enantioselective alkylation of 6 to 7. Yian Shi of Colorado State University showed (Org. Lett. 2011, 13, 6350) that a chiral Brønsted acid mediated the enantioselective cyclization of 8 to 9. Mattie S.M. Timmer of Victoria University of Wellington and Bridget L. Stocker of Malaghan Institute of Medical Research effected (J. Org. Chem. 2011, 76, 9611) the oxidative cyclization of 10 to 11. They also showed (Tetrahedron Lett. 2011, 52, 4803, not illustrated) that the same cyclization worked well to construct piperidine derivatives. Jose L. Vicario of the Universidad del País Vasco extended (Adv. Synth. Catal. 2011, 353, 3307) organocatalysis to the condensation of 12 with 13 to give the pyrrolidine 14. Jinxing Ye of the East China University of Science and Technology used (Adv. Synth. Catal. 2011, 353, 343) the same Hayashi catalyst to condense 15 with 16 to give 17. André B. Charette of the Université de Montreal expanded (Org. Lett. 2011, 13, 3830) 18, prepared by Petasis-Mannich coupling followed by ring-closing metathesis, to the piperidine 20. Marco Bella of the “Sapienza” University of Roma effected (Org. Lett. 2011, 13, 4546) enantioselective addition of 22 to the prochiral 21 to give 23. Ying-Chun Chen of Sichuan University and Chun-An Fan of Lanzhou University cyclized (Adv. Synth. Catal. 2011, 353, 2721) 24 to 25 in high ee. Andreas Schmid of TU Dortmund showed (Adv. Synth. Catal. 2011, 353, 2501) that ω-laurolactam hydrolases could be used to cyclize the ester 26, but not the free acid, to the macrolactam 27.
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Taber, Douglass F. "Advances in Alkene Metathesis: The Kobayashi Synthesis of (+)-TMC-151C." In Organic Synthesis. Oxford University Press, 2015. http://dx.doi.org/10.1093/oso/9780190200794.003.0033.
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Shazia Zaman of the University of Canterbury and Andrew D. Abell of the University of Adelaide devised (Tetrahedron Lett. 2011, 52, 878) a polyethylene glycol-tagged Ru catalyst that is effective for alkene metathesis in aqueous mixtures, cyclizing 1 to 2. Bruce H. Lipshutz of the University of California, Santa Barbara developed (J. Org. Chem. 2011, 76, 4697, 5061) an alternative approach for aqueous methathesis, and also showed that CuI is an effective cocatalyst, converting 3 to 5. Christian Slugovc of the Graz University of Technology showed (Tetrahedron Lett. 2011, 52, 2560) that cross metathesis of the diene 6 with ethyl acrylate 7 could be carried out with very low catalyst loadings. Robert H. Grubbs of the California Institute of Technology designed (J. Am. Chem. Soc. 2011, 133, 7490) a Ru catalyst for the ethylenolysis of 9 to 10 and 11. Thomas R. Hoye of the University of Minnesota showed (Angew. Chem. Int. Ed. 2011, 50, 2141) that the allyl malonate linker of 12 was particularly effective in promoting relay ring-closing metathesis to 13. Amir H. Hoveyda of Boston College designed (Nature 2011, 471, 461) a Mo catalyst that mediated the cross metathesis of 14 with 15 to give 16 with high Z selectivity. Professor Grubbs designed (J. Am. Chem. Soc. 2011, 133, 8525) a Z selective Ru catalyst. Damian W. Young of the Broad Institute demonstrated (J. Am. Chem. Soc. 2011, 133, 9196) that ring closing metathesis of 17 followed by desilylation also led to the Z product, 18. Thomas E. Nielsen of the Technical University of Denmark devised (Angew. Chem. Int. Ed. 2011, 50, 5188) a Ru-mediated cascade process, effecting ring-closing metathesis of 19, followed by alkene migration to the enamide, and finally diastereoselective cyclization to 20. In the course of a total synthesis of (–)-goniomitine, Chisato Mukai of Kanazawa University showed (Org. Lett. 2011, 13, 1796) that even the very congested alkene of 22 smoothly participated in cross metathesis with 21 to give 23. En route to leustroducsin B, Jeffrey S. Johnson of the University of North Carolina protected (Org. Lett. 2011, 13, 3206) an otherwise incompatible terminal alkyne as its Co complex 24, allowing ring closing methathesis to 25.
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Taber, Douglass F. "Alkaloid Synthesis: (–)-α-Kainic Acid (Cohen), Hyacinthacine A2 (Fox), (–)-Agelastatin A (Hamada), (+)-Luciduline (Barbe), (+)-Lunarine (Fan), (–)-Runanine (Herzon)." In Organic Synthesis. Oxford University Press, 2015. http://dx.doi.org/10.1093/oso/9780190200794.003.0058.
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The intramolecular ene cyclization is still little used in organic synthesis. Theodore Cohen of the University of Pittsburgh trapped (J. Org. Chem. 2011, 76, 7912) the cyclization product from 1 with iodine to give 2, setting the stage for an enantiospecific total synthesis of (–)-α-kainic acid 3. Intramolecular alkene hydroamination has been effected with transition metal catalysts. Joseph M. Fox of the University of Delaware isomerized (Chem. Sci. 2011, 2, 2162) 4 to the trans cyclooctene 5 with high diastereocontrol. Deprotection of the amine led to spontaneous cyclization, again with high diastereocontrol to hyacinthacine A2 6. Yasumasa Hamada of Chiba University devised (Org. Lett. 2011, 13, 5744) a catalyst system for the enantioselective aziridination of cyclopentenone 7. The product 8 was carried on to the tricyclic alkaloid (–)-agelastatin A 9. Guillaume Barbe, now at Novartis in Cambridge, MA, effected (J. Org. Chem. 2011, 76, 5354) the enantioselective Diels-Alder cycloaddition of acrolein 11 to the dihydropyridine 10. Ring-opening ring-closing metathesis later formed one of the carbocyclic rings of (+)-luciduline 13, and set the stage for an intramolecular aldol condensation to form the other. Chun-An Fan of Lanzhou University employed (Angew. Chem. Int. Ed. 2011, 50, 8161) a Cinchona-derived catalyst for the enantioselective Michael addition to prepare 14. Although 14 and 15 were only prepared in 77% ee, crystallization to remove the racemic component of a later intermediate led to (+)-lunarine 16 in high ee. Seth B. Herzon of Yale University used (Angew. Chem. Int. Ed. 2011, 50, 8863) the enantioselective Diels-Alder addition with 18 to block one face of the quinone 17. Reduction of 19 followed by methylation delivered an iminium salt, only one face of which was open for the addition of an aryl acetylide. Thermolysis to remove the cyclopentadiene gave an intermediate that was carried on to (+)-runanine 20.
Conference papers on the topic "B 20.5 UL 2011"
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Ramakrishna, P. V., and M. Govardhan. "Studies on Downstream Stator With Rotor Re-Staggering and Forward Sweeping in a Subsonic Axial Compressor Stage." In ASME 2011 International Mechanical Engineering Congress and Exposition. ASMEDC, 2011. http://dx.doi.org/10.1115/imece2011-65101.
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The present numerical work studies the flow field in subsonic axial compressor stator passages for: (a) preceding rotor sweep (b) preceding rotor re-staggering (three stagger angle changes: 0°, +3° and +5°); and (c) stator sweeping (two 20° forward sweep schemes). The following are the motives for the study: at the off-design conditions, compressor rotors are re-staggered to alleviate the stage mismatching by adjusting the rows to the operating flow incidence. Fundamental to this is the understanding of the effects of rotor re-staggering on the downstream component. Secondly, sweeping the rotor stages alters the axial distance between the successive rotor-stator stages and necessitates that the stator vanes must also be swept. To the best of the author’s knowledge, stator sweeping to suit such scenarios has not been reported. The computational model for the study utilizes well resolved hexahedral grids. A commercial CFD package ANSYS® CFX 11.0 was used with standard k-ω turbulence model for the simulations. CFD results were well validated with experiments. The following observations were made: (1) When the rotor passage is closed by re-staggering, with the same mass flow rate and the same stator passage area, stators were subjected to negative incidences. (2) Effect of stator sweeping on the upstream rotor flow field is insignificant. Comparison of total pressure rise carried by the downstream stators suggests that an appropriate redesign of stator is essential to match with the swept rotors. (3) While sweeping the stator is not recommended, axial sweeping is preferable over true sweeping when it is necessary.
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EL-Bagory, Tarek M. A. A., Maher Y. A. Younan, and Hossam E. M. Sallam. "Limit Load Determination and Material Characterization of Cracked Polyethylene Miter Pipe Bends." In ASME 2011 Pressure Vessels and Piping Conference. ASMEDC, 2011. http://dx.doi.org/10.1115/pvp2011-57587.
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The quality of Natural Gas Piping Systems, NGPS, must be ensured against manufacturing defects. The main purpose of the present paper is to investigate the effect of loading mode and load angle (30°,45°, and 60°) on the limit load of miter pipe bends, MPB, under different crack depths a/W = 0 to 0.4 at a crosshead speed 500 mm/min. The geometry of cracked and un-cracked multi miter pipe bends are: pipe bend angle, α = 90°, pipe bend factor, h = 0.844, standard dimension ratio, SDR = 11, and three junctions, m = 3. The material of the investigated pipe is a high-density polyethylene, HDPE, which is commonly used in natural gas piping systems. The welds at the miter pipe junction are produced by butt-fusion welding. For all loading modes the limit load is obtained by the tangent intersection method, TI, from the load deflection curves produced by the specially designed and constructed testing machine at the laboratory. Tensile tests are conducted on specimens longitudinally extruded from the pipe with thickness, T = 10, 30 mm, at different crosshead speeds (5–500 mm/min), and different gauge lengths (G = 20, 25, and 50 mm) to determine the mechanical properties of welded and un-welded specimens. The fracture toughness is determined on the basis of elastic plastic fracture mechanics, EPFM. Curved three-point bend specimens, CTPB, are used. All specimens are provided with artificially pre-crack at the crack tip, a/W = 0.5. The effect of specimen thickness variation (B = 10, 15, 22.5, 30, 37.5, and 45mm) for welded and un-welded specimens is studied at room temperature (Ta = 23°C) and at different crosshead speeds, VC.H, ranging from 5 to 500 mm/min. The study reveals that increasing the crack depth leads to a decrease in the stiffness and limit load of MPB for both in-plane, and out-of-plane bending moment. In case of combined load (out-of-plane and in-plane opening; mode) higher load angles lead to an increase in the limit load. The highest limit load value occurs at a loading angle, φ = 60°. In case of combined load (out-of-plane and in-plane closing; mode) the limit load decreases with increasing load angles. On the other hand, higher limit load values are proved at a load angle, φ = 30°. For combined load opening case; higher values of limit load are obtained. The crosshead speed has a significant effect on the mechanical behavior of both welded and un-welded specimens. The fracture toughness, JIC, is greater for un-welded than welded specimen.
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Song, Feng, Rongxi Peng, Zijiao Zhang, and Yixi Li. "Extending the concept of the morphological frame: a case study of Tangshan old military airport." In 24th ISUF 2017 - City and Territory in the Globalization Age. Valencia: Universitat Politècnica València, 2017. http://dx.doi.org/10.4995/isuf2017.2017.5686.
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Extending the concept of the morphological frame: a case study of Tangshan old military airport Rongxi Peng, Zijiao Zhang, Yixi Li, Feng Song* College of Urban and Environmental Sciences, Peking University. 100871 Beijing E-mail: pengrongxi@pku.edu.cn, 411148973@qq.com, elaine9565@yeah.net, songfeng@urban.pku.edu.cn*(corresponding author)Telephone Number: +86 132-6990-0350, +86 139-1013-6101* Keywords: China, morphological frame, three-dimensional view, airport Conference topics and scale: Urban form and social use of space/ City transformations/ Stages in territorial configuration The concept of the morphological frame is important in urban morphology, but it has been discussed much less than other critical concepts, such as the fringe belt and the fixation line. Passing its features on as inherited outlines, the morphological frame contains not only the linear fixation line, but also ground plan and three-dimensional aspects. In this research, the linear, ground plan, and three-dimensional morphological frame of Tangshan old military airport during the expansion of the city after the removal of the airport is identified. The former boundary roads of the airport exert obvious influences on the division of plots. The former arterial roads also function as a linear morphological frame. In relation to the ground plan, property rights and plots containing important buildings have an impact on the consequent town plan. The distinct feature of the morphological frame of the airport is its three-dimensional constraint, i.e. the vertical clearance requirement, which restricted the height of surrounding buildings. The impact of this institutional limit can last a very long time owing to the high cost of demolishing the old surrounding buildings or adding extra storeys even if the limit ceased to exist with the removal of the airport. Based on this case study, this paper refines and extends the connotation of the concept of the morphological frame and further discusses the relationship between function and form. References Conzen, M. P. (2009) ‘How cities internalize their former urban fringes: a cross-cultural comparison’, Urban Morphology 13(1), 29. Conzen, M. R. G. (1969) Alnwick, Northumberland: a study in town-plan analysis (Institute of British Geographers, London). Lin, Y., De Meulder, B. and Wang, S. (2011) ‘From village to metropolis: a case of morphological transformation in Guangzhou, China’, Urban Morphology 15(1), 5-20. Whitehand, J. W. R. (2001) ‘British urban morphology: the Conzenion tradition’, Urban Morphology 5(2), 103-109. Whitehand, J. W. R., Conzen, M. P. and Gu, K. (2016) ‘Plan analysis of historical cities: a Sino-European comparison’, Urban Morphology 20(2), 139-158.
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Zhang, Ye, Xiangya Xie, and Jie Zhang. "Exploring transformation of small and medium-sized historical towns in China with network analysis and user-generated open data." In 24th ISUF 2017 - City and Territory in the Globalization Age. Valencia: Universitat Politècnica València, 2017. http://dx.doi.org/10.4995/isuf2017.2017.6000.
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Ye ZHANG1, Xiangya XIE2, Jie ZHANG2 1 Department of Architecture, School of Design and Environment, National University of Singapore, 4 Architecture Drive, Singapore 117566 2 School of Architecture, Tsinghua University, Beijing100084, P. R. China E-mail: akizy@nus.edu.sg; xiexy15@mails.tsinghua.edu.cn; zjzhangjie@tinsghua.edu.cn Keywords (3-5): urban transformation, small and medium-sized historical Chinese cities, big data While an increasing number of research on transformation and conservation of historical areas of major Chinese cities have been witnessed in recent years (e.g. Whitehand et al, 2011; Whitehand et al 2014; Whitehand et al 2016, among many others), endeavours to studying more ordinary and small and medium-sized historical towns in China are rare. In the near future, those historical towns will be confronted with a new wave of developments, given that urbanisation of small and medium-sized cities and towns is high on China’s 13th five-year plan (2016-2020). This will pose a serious challenge to the conservation of their already vulnerable traditional urban fabric. This study aims to develop an accurate description of the transformation of built form, in particular street and block patterns, of the small and medium-sized historical towns, and how this is associated with the change of spatial distribution of urban activities. A total number of 36 towns in Zhejiang province, China are selected as case studies. Transformation of the urban fabric is examined based on cartographical maps of different historical periods using combined methods of urban network analysis and field survey. A large amount of user-generated geo-referenced open data, such as social media reviews, point-of-interest mapping, microblogs and night time illumination maps, are harnessed to produce a detailed description of urban activity patterns, of which the relationships to the transformation of urban form are investigated using multi-variate regression models. The results show how basic built form parameters such as spatial integration, between-ness centrality, block size and block depth can effectively and accurately describe the transformation of the small and medium-sized historical towns and how the formal changes are linked to the geographical shift of different urban activities. In which ways the findings can inform decision making in urban conservation practice to better address the tension between conservation and developments is discussed at the end.References: Whitehand Jeremy WR, Gu Kai, and Whitehand Susan M. (2011). "Fringe belts and socioeconomic change in China." Environment and Planning B: Planning and Design 38 (1):41-60 Whitehand Jeremy WR, Gu Kai, Conzen Michael P, and Whitehand Susan M. (2014). "The typological process and the morphological period: a cross-cultural assessment." Environment and Planning B: Planning and Design 41 (3):512-533. Whitehand Jeremy WR, Conzen Michael P, and Gu Kai. 2016. "Plan analysis of historical cities: a Sino-European comparison." Urban Morphology 20 (2):139-158.