bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pilot Study of Peginterferon Alfa-2a (PEGASYS®) Concurrent Administration during Induction Chemoradiotherapy and Maintenance Therapy in Patients with EBV-Associated Extranodal NK/T Cell Lymphoma
Authors: Cho Seok-Goo , Kim Sung-Won , Park Kyung-Sin , Lim Ji-Hyang , Min Chang-Ki , Kim Yong-Goo , Lee Jong-Wook , Min Woo-Sung 
Published: April 2020

Abstract
Extranodal NK/T-cell lymphoma, nasal type is common in Asians rather than in Western populations. This special subtype responds poorly to intensive chemotherapy regimens or has a significant relapse rate in spite of low IPI and loco-regional staging. The presence of the EBV genome within tumor cells raised the possibility of developing therapeutic strategies directed at viral targets. The primary objectives of this prospective, single center, nonrandomized phase II trial are the evaluation of efficacy by determination of progression-free survival after concurrent administration of peginterferon alfa-2a (PEGASYS®, provided by Roche Korea) and chemoradiotherapy in patients with extranodal NK/T cell lymphoma. In addition, we evaluated the efficacy of peginterferon alfa-2a maintenance therapy for 3 years. All seven patients with newly diagnosed CD56+ EBV+ extranodal NK/T-cell lymphoma were enrolled onto a prospective clinical trial. Step 1; PEGASYS® 180 mcg was administered once weekly on D1, D8 of ProMACE-CytaBOM. 1, 2 cycles. Step 2; PEGASYS® 180 mcg will be administered once weekly on D1, D8, D15, D22 of involved-filed irradiation 3600 cGy (180 cGy × 20, for 4 weeks). Step 3; PEGASYS® 180 mcg will be administered once weekly on D1, D8 of ProMACE-CytaBOM. 3, 4 cycles. Step 4; PEGASYS® 180 mcg will be administered every two weeks after hematologic recovery of high-dose therapy and autologous PBSCT for 3 years. In case of advanced stage and non-nasal lesion, Step 2 was omitted and ProMACE-CytaBOM was extended to 6 cycles. EBV DNA copy based on real-time PCR was monitored. Of all 7 patients, 6 patients achieved complete response and 1 patient was dead due to pneumonia during chemotherapy. With a median follow-up of 26 months (3–36 months), the 3-year PFS were 67%. Of 6 assessable patients, five patients extended to peginterferon alfa-2a maintenance therapy and four patients showed PFS. Among two relapsed patients, one patient refused a peginterferon alfa-2a maintenance therapy and eventually relapsed 3 months later. Titer of EBV DNA copy in whole blood was significantly decreased compared with the titer on initial diagnosis. The main toxicities of peginterferon alfa-2a were mild flu-like symptoms. This pilot study suggests that larger prospective randomized studies are needed to define the role of peginterferon alfa-2a concurrent administration during induction therapy and maintenance therapy in EBV-associated extranodal NK/T-cell lymphoma.
Trans-Cinnamaldehyde Induces Granulocytic Differentiation and Impairs Survival and Migration of Acute Myeloid Leukemic Cells
Authors: Liu Liqiong , Wang Ping , Wang Xingbin , Gu Junxia , Li Xiaoqing , Huang Shiang 
Published: April 2020

Abstract
Trans-cinnamaldehyde (TCA), the major active component of oil isolated from the stem bark of Cinnamomum cassia traditionally used to treat dyspepsia, gastritis and inflammatory disease world widely, has been shown to inhibit proliferation and promote apoptosis in a number of cancer cells. However, the functional roles TCA plays in hematopoietic system have not been fully investigated. In this study, we show the effects of TCA on acute promyelocytic leukemia (APL) cell line HL60 and primary bone marrow mononuclear cells (BMMNC) as well as bone marrow stromal cells (BMSC) from acute myeloid leukemia (AML) patients. We found that TCA affected HL60 cells in a time-and dose-dependent fashion. Low concentration of TCA (20 μM) arrested HL60 cells at G0/G1 phase at 72 h without significant apoptosis. Middle concentration of TCA (60 μM) accumulated HL60 cells at G2/M at 24 h with increased apoptosis when the treated time was prolonged. Both low and middle concentrations of TCA induced HL60 cells to differentiate toward mature granule cells characterized with up-regulation of CD11b on cells accompanied by decreased c-Myc protein and increased p27 protein. Consistently, the expression and cellular distribution of p16 and Cdc6 were also significantly changed in differentiated HL60 cells treated with TCA. On the other hand, high concentration of TCA (100 μM) rapidly inhibited NF-kappaB activity and induced apoptosis in HL60 cells. Importantly, TCA induced apoptosis of AML CD34+ cells and suppressed colony formation of AML BMMNC, while its cytotoxicity on normal BMMNC was minor. In addition, TCA synergized with AraC to kill AML BMMNC and AML CD34+ cells. Finally, TCA also decreased CXCR4 expression on HL60 cells, consistent with it ability to depress migration and invasion of HL60 cells induced by rhSDF-1α as well as the adhesion of HL60 cells to AML BMSC. Of note, TCA also impaired survival and SDF-1α secretion of AML BMSC, which may further suppress the interaction of HL60 with AML BMSC. Taken together, our data show that TCA is an effective agent for the treatment of hematopoietic malignancies, not only being the direct inducer of terminal differentiation and apoptosis of acute myeloid leukemic cells, but attenuating the protective effect of AML BMSC on leukemia cells via inhibiting SDF-CXCR4 axis, which highlights the potential of TCA to be a promising therapeutic agent for hematopoietic malignancies treatment.
Interferon-γ Enhances PML Protein Expression in Acute Promyelocytic Leukemia Cells and Cooperates with All-Trans Retinoic Acid to Induce Maturation of NB4 and MR2 Cells
Authors: He Pengcheng , Zhang Mei , Wang Xiaoning , Qi Jun , Xi Jieying , Li Jing , Wu Di , Cao Yunxin 
Published: April 2020

Abstract
More than 90% patients with untreated acute promyelocytic leukemia(APL) obtain complete remission clinically by using All-trans retinoic acid(ATRA), a strong differentiation inducer. However, the rapid development of ATRA-resistance brings a new problem to the treatment of APL. Interferon(IFN), as an important cytokine, has broad biological activities. It can not only inhibit the growth of tumor cells, but also reverse the drug-resistance of chemotherapy. As proved by some research, the mechanisms of ATRA-resistance are probably related to lacking some important proteins which synthesized by Interferon-γ (IFN-γ). In order to explore a new way to solve the problem of ATRA-resistance in APL, we investigate the effect and mechanisms of IFN-γ in combination with ATRA on the proliferation/differentiation of NB4 cells(APL cell line with ATRA-sensitiveness) and MR2 cells(APL cell line with ATRA-resistance) respectively. ATRA, IFN-γ and IFN-γ in combination with ATRA were incubated with NB4 and MR2 cells respectively. The cell proliferation was tested by MTT assay, the cell differentiation was tested through light microscope, by NBT reduction test and flow cytometry(FCM). The results showed that ATRA could inhibit the growth of NB4 cells significantly (P&lt;0.05), but it had no effect on the growth of MR2 cells (P&gt;0.05). IFN-γ could inhibit the growth of both NB4 cells and MR2 cells slightly (P&lt;0.05). Moreover, the growth inhibition effect of IFN-γ in combination with ATRA on NB4 and MR2 cells was obviously stronger than that of any single drug group (P&lt;0.05). The results of cell morphology observation, NBT reduction test and CD11b antigen detection showed that ATRA could induce differentiation of NB4 cells significantly (P&lt;0.05), but it had no effect on MR2 cells (P&gt;0.05). Although IFN-γ alone had no effect on the differentiation of either NB4 or MR2 cells (P&gt;0.05), it could augment the differentiation of NB4 cells induced by ATRA (P&lt;0.05) and induce the differentiation of MR2 cells slightly (P&lt;0.05) when it combined with ATRA. Furthermore, we have observed the expression of promyelocytic leukemia(PML) protein by indirect immune fluorescent test. The results showed that the number of fluorescent particles in both NB4 and MR2 cells’ nucleus was increased significantly (P&lt;0.05) when they were incubated with IFN-γ respectively, which indicated IFN-γ could induce the expression of PML protein, a tumor growth inhibitor. It can be seen that IFN-γ could augment the proliferation inhibition effect of ATRA on NB4 and MR2 cells through enhancing the expression of PML protein. Moreover, IFN-γ in combination with ATRA not only can strengthen the induction differentiation effect of ATRA on NB4 cells, but also can partially induce the maturation of MR2 cells with ATRA-resistance.
Upregulation of XAF1 by 5-Aza-2′-Deoxycytidine Sensitizes Busulfan-Resistant Human CML Cells; Implications for Pretransplant Conditioning Therapy in Myeloid Leukemia
Authors: Valdez Benigno C. , Li Yang , Murray David , Champlin Richard E. , Andersson Borje S. 
Published: April 2020

Abstract
The DNA-alkylating drug busulfan (Bu) is commonly used in myeloablative pretransplant conditioning therapy in patients with chronic myelogenous leukemia (CML). A major obstacle to successful treatment is inherent or acquired cellular Bu-resistance. We hypothesized that cellular Bu-resistance can be reversed by epigenetic upregulation of pro-apoptotic genes. We established a Bu-resistant CML cell line B5/Bu2506 which is 4-fold more resistant to Bu than the parental B5 cells but 4-fold collaterally more sensitive to DNA demethylating agent 5-aza-2′-deoxycytidine (DAC). Exposure to DAC synergistically increased Bu-mediated cytotoxicity in B5/Bu2506 cells as evaluated by the MTT assay and analyzed by the median-effect method (combination index CI &lt; 0.5). The DAC-induced sensitivity to Bu of B5/Bu2506 cells was associated with PARP1 cleavage, phosphorylation of histone 2AX and activation of caspase 8. Real-time PCR and immunostaining analyses of the expressions of various pro-apoptotic genes, which are known to be epigenetically regulated, showed a highly significant increase (approximately 40-fold) in the expression of XAF1 (X-linked inhibitor of apoptosis protein (XIAP)-associated factor 1) in B5/Bu2506 cells that were exposed to 0.5 microM DAC for 48 hrs. Analysis of the XAF1 promoter by methylation-specific PCR showed a significant decrease in its methylation status which correlates with the alteration in its gene expression in the presence of DAC. These findings will be discussed relative to our analysis of XAF1 gene methylation status in leukemia cell samples obtained from patients who underwent allogeneic stem cell transplantation after high dose Bu-based conditioning therapy and either remained in remission for more than one year or who experienced rapidly progressive leukemia. Our results suggest that DNA methylation status (eg. XAF1 gene) may be used to identify leukemia patients who could benefit from Bu-DAC combinations to achieve improved leukemic cytoreduction with the conditioning program.
A Newly Developed IAP Inhibitor (IAPi) Induces Apoptosis of Human Myeloma Cells and Synergises with Conventional and Novel Anti-Myeloma Therapeutics
Authors: Khong Tiffany T. , Spencer Andrew 
Published: April 2020

Abstract
The IAPs (inhibitor of apoptosis proteins) are a family of 8 structurally related caspase inhibitors that efficiently block the execution phase of apoptosis induced by various stimuli including death receptor activation. Based on reports of elevated expression of IAPs in multiple myeloma (MM) we evaluated the therapeutic potential of a novel IAP (IAPi) in MM. A panel of 9 genetically heterogeneous human myeloma cell lines (HMCL) were screened and found to be sensitive to IAPi with an IC50 of 25 to 50μM in a dose and time dependent manner. Induction of cell death was confirmed by Annexin V and propidium iodide staining of treated HMCL. Mechanistic studies were then undertaken utilising 3 HMCL with high (NCI H929), intermediate (LP-1) or low (OPM2) sensitivity to IAPi with QRT-PCR demonstrating the highest expression of XIAP in the most IAPi sensitive HMCL NCI H929. In all 3 HMCL IAPi exposure was associated with rapid cleavage of caspase 3, caspase 7, ROCK-1, cytosolic degradation of ICAD, nuclear translocation of CAD and PARP cleavage confirming cell death via apoptosis. Replicate experiments utilising caspase specific inhibitors and siRNA knock-down of caspases 3 and 7 confirmed this to be both caspase 3 and caspase 7 dependent. Co-culture of HMCL with conditioned media from the human stromal cell line HS-5 or primary MM bone marrow mononuclear cells reproducibly demonstrated enhanced IAPi-induced HMCL apoptosis with a median increase in HMCL killing of 1.2 fold compared to HMCL treated in standard culture media. Similarly, IAPi activity was not abrogated but enhanced in the presence of either IL-6 or IGF-1 (1.1 and 1.3 fold, respectively) when compared to HMCL treated without the addition of exogenous growth factors. Primary MM cells from 9 multiply relapsed MM patients were treated with IAPi in an autologous bone marrow co-culture assay with concentrations of IAPi ranging from 10–100μM inducing a median of 23% (range, 8–56% as determined by Apo2.7 staining) MM cell killing at 48 hours. Finally the anti-MM activity of IAPi in combination with other conventional (etoposide, adriamycin, velcade) and novel (HSP90 inhibitor, agonistic TRAIL DR5 monoclonal antibody) therapeutics was investigated against both HMCL and primary MM tumour samples. All combinations showed synergistic cell killing with Combination Indices of &lt;1 (Calcusyn) when compared to either agent alone. We conclude that IAPi induces apoptosis of MM cells via a caspase 3 and caspase 7 dependent process. Furthermore, IAPi retains anti-MM activity in the context of pro-survival cytokine exposure and induces synergistic killing of MM cells when combined with both conventional and novel anti-MM therapeutics. Based on these preliminary observations further investigation of the role of IAPi as a potential tumour sensitising agent for the therapy of MM is justified.
Circulating MUC1 Levels (CA15.3) in Myeloproliferative Disorders (MPD)
Authors: Rughetti Aurelia , Fama Angelo , von Mensdorff-Pouilly Silvia , Taurino Federica , Rahimi Hassan , Ribersani Michela , Natalino F. , D’Elia G.M. , Bizzoni L. , Latagliata Roberto , Breccia Massimo , Foà Robin , Alimena Giuliana , Girelli Gabriella , Frati Luigi , Nuti Marianna , Tafuri Agostino 
Published: April 2020

Abstract
MUC1 is a glycoprotein expressed on the luminal surface of simple epithelia. In carcinoma, MUC1 overexpression is associated with malignancy. In breast cancer patients, increased levels of circulating MUC1 (CA 15.3 tumor marker) are associated with poor prognosis (Tumour Biol.2005; 26:217–20). In myeloma, MUC1 overexpression correlates with apoptosis resistance. We have previously shown (Br J Haematol.2003; 120:344–52) that MUC1 is selectively found in differentiating erythroid cells suggesting a possible role as cross-talk molecule between erythroblasts and bone marrow microenvironment during erythropoiesis. In CD34+ cells cultured in the presence of EPO and SCF, MUC1 is expressed before Glycophorin A (GlyA) during the erythroid differentiation process, and disappears following GlyA up-regulation. Aiming to evaluate the role of MUC1 in the erythroid counterpart present in neoplastic haemopoiesis, we studied MUC1 serum circulating levels in patients affected by Ph-negative Myeloproliferative Chronic Disorders (MPD). We analysed serum samples from 42 MPD patients affected by Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF) (N 25, 14, and 3, respectively). CA15.3 (soluble MUC1) levels were determined using the commercially available ADVIA Centaur CA 15.3 assay (Bayer Corporation, NY) and cut off level was set at 25 U/mL. As control group serum samples from healthy donors, matched for sex and age, were also analyzed. Evaluation of the humoral immune response to MUC1 protein core was performed in ELISA. Results indicated that CA15.3 levels were statistically higher in MPD patients than in the control group (p&lt;0.005), this difference was more evident in PV patients (p&lt;0.001) and in female cases (p&lt;0.001). The JAK2V617F mutation status was not associated with CA15.3 values; similarly, neither the clinical or hematological features nor the clinical complications (thrombosis) were influenced byCA15.3 levels. Analysis of the humoral immune response to MUC1 core protein showed no substantial changes in serum anti-MUC1 IgG titers in PV patients, suggesting that in PV increase of soluble MUC1 does not induce immune responses against this self-antigen. Further studies are ongoing to investigate the significance of MUC1 in the development and onset of myeloproliferative disorders. In conclusion, MUC1 levels seem to be increased in PV patients, suggesting that further evaluations on large series of cases should include this test in the diagnostic work-up to PV patients.
Peripheral Blood Disease Monitoring in Marginal Zone Lymphoma Using Flow Cytometry
Authors: de Tute Ruth , Rawstron Andy C , Owen Roger G , Jack Andrew 
Published: April 2020

Abstract
The use of sensitive flow cytometric techniques for the primary diagnosis and monitoring of patients with B-CLL is now well established. The aim of this study is to examine the feasibility of extending this approach to other indolent B-cell lymphoproliferative disorders. Such a technique, particularly if applicable to peripheral blood samples, would have significant benefits in allowing minimally invasive sequential monitoring of treatment responsiveness and early detection of relapse. Using a similar statistical approach to that used in the design of the CLL minimal disease flow cytometry panels we identified LAIR1, CCR6, CXCR5 and CD10 as markers that allowed discrimination between normal and neoplastic B-cells. These markers were incorporated into a 2 tube 8 colour assay together with CD19, CD5, CD20, CD22, CD45, kappa and lambda. Leucocytes were prepared using ammonium chloride lysis, incubated with these antibodies and washed before acquisition of 500,000 events on a FacsCanto flow cytometer (BD BioSciences, Oxford). As part of the evaluation of the technique we investigated peripheral blood samples from a total of 28 patients (14 male, median age 69.1 years and 14 female, median age 73.4 years), 22 with Marginal Zone Lymphoma/Waldenstrom’s Macroglobulinaemia (MZL) and a further 6 with Extranodal Marginal Zone Lymphoma (EMZL). Of the 22 MZL patients, 8 had active disease, 5 had stable disease that was untreated, 1 was on treatment and 8 were in remission. Of the extranodal MZL patients 1 had stable untreated disease, with 2 on treatment and 3 in remission. 77% (10/13) of MZL patients with active or stable untreated disease had detectable circulating tumour cells. Abnormal B-cells represented a median 2% of leucocytes (range 0.08 – 39%). The median absolute abnormal B-cell count was 0.34 ×109/l (range 0.003–9.6 ×109/l). The phenotypes of the cells detected showed a high level of heterogeneity. Abnormal cells were detectable in 22% (2/9) of cases on treatment or in remission, with a median % abnormal B-cells of 0.88% (range 0.35–5.37%) and a median absolute B-cell count of 0.09×109/l (range 0.02–0.386×109/l). None of the EMZL patients had abnormal cells detectable. Circulating tumour cells were detectable down to a level of 0.003×109/l and were found in a proportion of patients on treatment or considered to be in clinical remission. Methods used to monitor patients with indolent lymphoproliferative disorder need to take into account the phenotypic diversity found in marginal zone lymphoma compared to CLL. However the results demonstrate the feasibility of extending the use of flow cytometric residual disease assays to marginal zone lymphoma.
IL-6 and Tumor Susceptibility Alleles of Strain BALB/C Cause Phenotypic Shift of MYC-Driven Lymphomas in Mice from Diffuse Large B-Cell Lymphoma (DLBCL) to Plasmacytoma (PCT)
Authors: Neppalli Vishala T. , Janz Siegfried , Rutsch Sebastian , Goldschmidt Hartmut 
Published: April 2020

Abstract
Aims: Deregulation of cellular oncoprotein MYC (c-Myc) and the plasma cell growth, differentiation and survival cytokine, interleukin-6 (IL-6), are key pathogenetic factors in human high grade B-cell lymphomas (Burkitt lymphoma and DLBCL) and PCT respectively. Genomic instability, as a consequence of this deregulation, is poorly understood. Transgenic expression of these factors in the B-cell lineage, in mice, generates a pre-clinical model system of great relevance for human B-cell lymphoma counterparts. In this study we evaluated for the incidence of lymphomas in transgenic mouse models, with deregulated CMYC and IL-6. We performed a morphologic classification and correlation of the malignant lymphoid proliferations with the underlying genetic lesions.
Materials & Methods: Deregulation of CMYC was observed in gene-targeted C57BL/6 mice that harbor a His6-tagged mouse Myc cDNA gene in themouse immunoglobulin heavy-chain locus (B6.iMyc mice). A double transgenic mouse model, using BALB/c mice, carry the same gene insertion, in addition to a widely expressed human IL-6 transgene (C.iMyc/IL-6 mice). Tumor tissue from the mice was processed by formalin fixation and embedded in paraffin. Sections from the paraffin blocks were stained with hematoxylin and eosin and evaluated for morphology. The morphologic evaluation of the lymphomas was performed blind to the genetic make up of the host, followed by genetic correlation with morphology.
Results: B6.iMyc mice developed nodal and extranodal lymphomas. Tumor incidence was 50% (70/140) at 18 months of age. The lymphomas demonstrated sheets of large cells with centroblastic morphology, consistent with diffuse large B-cell lymphoma. The mitotic index was high, with the presence of frequent atypical mitotic figures and apoptotic debris laden macrophages, giving a starry sky pattern. C.iMyc/IL-6 mice developed nodal and extra nodal plasma cell tumors (PCT). Tumor incidence was 100% (20/20) at 4–5 months of age. PCT demonstrated sheets of monotonous and atypical plasma cells with prominent nucleoli. In lymphoid tissue containing germinal centers, the sheets of plasma cells were located in the interfollicular areas. There was no bone marrow involvement.
Conclusions: Our findings demonstrate that
B6.iMyc mice with CMYC deregulation develop high grade B-cell lymphomas similar to human DLBCL. The activity of deregulated IL-6 appears to enhance and accelerate the oncogenic potential of deregulated CMYC, in the pathogenesis of lymphoid malignancy. IL-6 and/or tumor susceptibility alleles of strain BALB/c cause a remarkable shift in the phenotype of MYC-driven lymphomas from DLBCL to PCT.