bluuebunny/crossref_metadata_2025_split huggingface dataset:
SU11657 Cooperates with Doxorubicin To Increase Survival of Leukemic Mice.
Authors: Sevcikova Sabina , Lee Brian D. , Kogan Scott C. 
Published: April 2020

Abstract
Acute promyelocytic leukemia (APL) is characterized by t(15,17) resulting in fusion of RARα to PML; in rare cases, RARα may be fused to other partners. The PML-RARα fusion initiates APL-like disease in mice, including a response to ATRA. FLT3, a receptor tyrosine kinase, is mutated in a large number of human AMLs and roughly 40% of cases of human APL. In our mouse model of APL, we previously introduced activated FLT3 (ITD mutation) into bone marrow of PML-RARα transgenic mice and observed rapid development of AML. This disease is transplantable into sublethally irradiated mice with onset of disease between 3–6 weeks, creating a system suitable for therapeutic study.
There has been considerable effort focused on the development of small molecule inhibitors of FLT3 as therapeutics for hematological malignancies, in particular, AML; some of these inhibitors are currently in clinical trials. SU11657 is a multi-targeted inhibitor of class III/V receptor tyrosine kinases, including FLT3. We previously observed a synergistic effect of SU11657 in combination with ATRA in our PML-RARα/FLT3 model. We set out to use this model to assess the effectiveness of anthracycline chemotherapy in combination with SU11657. This model is in vivo resistant to the maximum tolerated dose of doxorubicin (3 mg/kg/day).
We found that the median survival of untreated and doxorubicin-treated mice with PML-RARα/FLT3 leukemia was not significantly different (42 and 45 days, respectively). SU11657 increased the median of survival to 55 days, whereas the combination therapy increased median survival to 62 days (P=0.003). Neither agent alone or in combination significantly increased survival of mice with PML-RARα leukemia lacking activated FLT3. These results suggest that the use of targeted therapeutics, such as a FLT3 inhibitor, can overcome chemoresistance to traditional therapies in AMLs.
Inhibitory Effect of ssRNA40, a Toll-Like Receptor-8 Agonist, on the Proliferation of Acute Myeloid Leukemia Cells.
Authors: Wang Xingbing , Xiong Fang , Liu Jun , Huang Shiang 
Published: April 2020

Abstract
Acute myeloid leukemia (AML) is a malignant hematopoietic disorder with considerable impairment of the immune system. We have previously reported that the T-cell-mediated immunity in AML patients could be in part damaged by the increased prevalence of CD4+CD25high regulatory T cells (T-regs). Toll-like receptors (TLR), found on many immune cells, including T-regs, have been shown to be important molecules in both innate and adaptive immune responses. Recent studies demonstrated that synthetic and natural ligands for human TLR8 could completely reverse the suppressive function of T-regs and enhance antitumor immunity, which provides a possible application of TLR8 ligands in immunotherapy for a patient with AML. However, an important question is whether the TLR8 ligands could also have direct impacts on the AML cells. In this study, we first examined the expression of TLR8 on fresh leukemic cells from 11 AML bone marrow samples and a human AML cell line (U937) by using RT-PCR analysis. We found that U937 cells and the majority of the AML patients (8+/11) expressed TLR8. To further investigate the functional role of TLR8, the cell line U937 was stimulated with ssRNA40, a Toll-like receptor-8 agonist, and analyzed by the measurements of cell proliferation, apoptosis and co-stimulatory molecules (CD80 and CD86) expression. The proliferation of U937 was detected by cell counting kit-8 (CCK-8) and the apoptosis was examined by AnnexinV and PI. Interestingly, the proliferation of U937 cells could be inhibited in a dose-dependent manner, whereas apoptosis and co-stimulatory molecules expression were not significantly changed with ssRNA40 stimulation. In the same condition, the inhibitory effect of ssRNA40 was not revealed on the proliferation of K562 CML cell line, even though TLR8 was also expressed on the cells. This might suggest that a specific pathological pathway in AML was blocked by ssRNA40. The signaling pathway that can restrain AML cells from proliferation is currently being studied. In conclusion, the present data may offer a unique therapeutic potential for ssRNA40 as an inhibitor, by which we will be able to directly inhibit the proliferation of AML cells and simultaneously enhance the patients’ immune response against the malignant cells.
Utility of Bone Marrow Biopsy, Bone Marrow Aspirate, Flow Cytometry, and Molecular Testing in the Clinical Staging of Lymphoma: An Institutional Experience.
Authors: Dumont Randall J. , Fernandez Louis A.V. , Juskevicius Ridas 
Published: April 2020

Abstract
Lymphomas are a diverse group of solid tumors of lymphoid cells that are broadly subdivided into Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) categories. In the Western world, lymphoma is the most common hematologic malignancy. Complete and accurate staging of the patient with lymphoma is essential in determining the extent of initial disease. Bone marrow biopsy (BMB) remains the gold standard for assessing bone marrow involvement by lymphoma. It allows morphological diagnosis as well as the use of immunohistochemistry in difficult cases. At the time of BMB, other specimens are often gathered for use in ancillary investigations that can aid in diagnosis and/or staging. These investigations include bone marrow aspirate (BMA), flow cytometry (FC), and molecular studies (M) such as PCR. The objectives of this study were to evaluate the performance characteristics of BMA, FC, and M relative to BMB in lymphoma staging, to determine how frequently ancillary testing is positive for bone marrow involvement with lymphoma while BMB is negative, as well as to determine the clinical significance of this situation. Retrospective analysis was performed on 294 lymphoma cases from 1997 to 2002 at a single adult tertiary care center. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), pre-test probability (PreTP), post-test probability given a positive test result (PTP+), and post-test probability given a negative test result (PTP−) were determined. Chart review was performed to determine clinical significance of the situation when BMB is negative and one or more ancillary investigations are positive. The number of cases positive for lymphoma by BMB, BMA, M, and FC was 157,113, 109, and 111, respectively. The performance characteristics are indicated in Table I. Twelve cases in which one or more ancillary investigations were positive when BMB was negative were identified. Clinical management was not altered in these cases. In staging of lymphoma, BMB remains the gold standard for the determination of bone marrow involvement. When compared to BMB, ancillary investigations have a high specificity and PPV, but only moderate sensitivity and NPV. Ancillary bone marrow investigations appear to add little information to lymphoma staging, and may not be fiscally justified.
Table I. Performance Characteristics Of Ancillary Bone Marrow Investigations In The Staging Of Lymphoma Parameter Bone Marrow Aspirate Molecular FlowCytometry Abbreviations: PPV = positive predictive value; NPV = negative predictive; PreTP = pre-test probability; PTP+ = post-test probability given a positive test result; PTP− = post-test probability given a negative test result Sensitivity 71% 64% 68% Specificity 98% 93% 96% PPV 97% 92% 95% PreTP 53% 53% 53% PTP+ 97% 92% 95% PTP− 26% 31% 28%
Absence of Chlamydial Infection in Japanese Patients with Ocular Adnexal MALT Lymphoma.
Authors: Yakushijin Yoshihiro , Kodama Toshio , Takaoka Ikue , Tanimoto Kazushi , Bessho Hiroko , Yamanouchi Jun , Azuma Taichi , Narumi Hiroshi , Hato Takaaki , Hasegawa Hitoshi , Yasukawa Masaki 
Published: April 2020

Abstract
The extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is a distinct type of B-cell lymphoma that develops in extranodal sites and usually has an indolent clinical course as a localized disease. Recent clinicopathological studies suggest a strong relationship between MALT lymphoma and inflammatory diseases of the epithelium such as autoimmune diseases and infections (Sjogren’s syndrome, Hashimoto’s thyroiditis, Helicobacter pylori infection, and etc.), because chronic antigen stimulation has been causally linked to the development of lymphoproliferative diseases in B cells. MALT lymphoma grows in extranodal lymphoid tissue and exists in epithelium tissues, and it is often difficult to distinguish malignant lymphoid tissue from benign inflammation. However, this is only one of the possible causes; recent positive and negative correlations between ocular adnexal MALT lymphomas and chlamydial infections reported by different researchers indicate several different possible explanations. Here, we analyze twenty-three cases of ocular adnexal MALT lymphoma whose monoclonality was confirmed by immunoglobulin heavy chain gene rearrangement and/or the analysis of cell surface antigens for evidence of expected causative factors, using both ELISA analysis to detect antibodies and specific PCR gene amplification followed by Southern blot analysis. Our series of patients did not show any serological relations to the Epstein-Barr virus, the Hepatitis C virus, or to Chlamydophila psittaci. Two cases had positive serum antibodies for autoimmunity, another two cases had positive antibodies against Chlamydia trachomatis. None of our cases showed the presence of chlamydial 16S rRNA or 16S-23S spacer rRNA genes (C. psittac, C trachomatis, C. pneumoniae, and C. felis) after PCR amplification. These results indicate that the inflammatory agents are still unknown in our series of ocular adnexal MALT lymphomas, and that some types of chlamydial infections are not associated with ocular adnexal MALT lymphoma in southern regions of Japan.
Ki-67 Expression Level Is Not a Significant Prognostic Factor in Korean Diffuse Large B-Cell Lymphoma.
Authors: Sym Sun-Jin , Lee Sung Sook , Kim Min Kyoung , Kim Shin , Suh Cheolwon 
Published: April 2020

Abstract
The cell proliferation rate of tumors from patients with non-Hodgkin’s lymphomas has been shown to correlate with survival in previous studies. The aim of this study was to evaluate the independent prognostic value of Ki-67 expression level and the significance of cell proliferation rate as an outcome predictor. To this end, we reviewed the hospital case records and histopathological materials of 92 patients diagnosed with diffuse large B-cell lymphoma in a single center. The cell proliferative rate was expressed as percentage of Ki-67 positive cells (Ki-67 labeling index). All patients were available Ki-67 expression level. High Ki-67 labeling index was defined as nuclear Ki-67 expression in ≥ 70% of malignant cells. A cutoff point of 70% was used because this divided the group of cases into two subgroups of similar size (Ki-67 labeling index &lt; 70, n = 46, Ki-67 labeling index ≥ 70, n = 46). The median age was 57 years (range, 15 to 83 years). The median follow-up time was 14 months. Sixty-nine (75%) patients were treated R-CHOP regimen initially and 13 (14%) patients were CHOP regimen. In a univariate analysis, age (p =.003), performance (p =.001), serum LDH (p =.020) were significant prognostic factors for overall survival. But Ki-67 had no statistical significance (p =.554). Multivariate analysis used Cox’s multivariate regression model revealed that serum LDH (relative risk estimate 6.7; 95% confidence interval, 1.5, 30.5), age (relative risk estimate 7.0; 95% confidence interval, 1.9, 26.4) were independent prognostic factors for overall survival. Taking all the results into consideration, it seems that Ki-67 expression level has no significance as outcome predictor in Korean diffuse large B-cell lymphoma.
SCFβ-TRCP Mediates Ubiquitination and Degradation of the Erythropoietin Receptor and Controls Cell Proliferation.
Authors: Verdier Frederique , Meyer Laure , Deau Benedicte , Forejtnikova Hana , Dumenil Dominique , Lacombe Catherine , Mayeux Patrick 
Published: April 2020

Abstract
Control of intensity and duration of erythropoietin (Epo) signalling is necessary to tightly regulate red blood cells production. After Epo stimulation of erythroid cells, 2 types of signal are transduced via the Epo receptor (Epo-R): positive signals involved in survival and proliferation, and negative signals involved in signal arrest. We have recently shown that the ubiquitin/ proteasome system plays a major role in the control of Epo-R signalling duration and desensitisation processes. Indeed, after Epo stimulation the Epo-R is ubiquitinated and its intracellular part is degraded by the proteasome, preventing further signal transduction. The remaining part of the receptor, together with associated Epo is internalised and degraded by the lysosomes (Walrafen et al 2005 Blood, 105, 600-608). Our aim was to identify the E3 ubiquitin ligase involved in Epo-R ubiquitination. The Epo-R contains a putative β-Trcp binding site in its intracellular domain. Interestingly, this putative binding sequence is located in a region of the Epo-R that is deleted in erythroid progenitors from patients with familial polycythemia. We show that β-Trcp is responsible for Epo-R ubiquitination upon Epo stimulation.
After Epo stimulation, β-Trcp binds to the Epo-R and this binding is dependent on Jak2 activation. Mutation of the Ser 462 residue of the Epo-R, located in the consensus β-Trcp binding site abolished β-Trcp binding, Epo-R ubiquitination and EpoR cleavage by the proteasome. Activation of the mutated Epo-R is prolonged in comparaison with Epo-R WT and BaF3 cells expressing this mutated receptor unable to bind β-Trcp are hypersensitive to Epo. Whether the removal of the β-Trcp binding site contributes to the hypersensitivity to Epo in familial polycythemia is currently under study.]
2-Methoxyestradiol Sensitizes B-NHL Cells to TRAIL-Mediated Apoptosis Via Inhibition of HIF-1α, NF-κ B, YY1 and Induction of DR5 Expression.
Authors: Huerta-Yepez Sara , Vega Mario I. , Baritaki Stavroula , Suzuki Eriko , La Vallee Theresa , Bonavida Benjamin 
Published: April 2020

Abstract
There have been many advances in the treatment of B-NHL by both chemotherapy and immunotherapy. However, many patients experience recurrences and relapses and develop resistance to further treatments. Therefore, there is a need for new therapies. TRAIL and mAbs directed against DR4 or DR5 are currently being examined clinically, either alone or in combination with other therapies, for the treatment of resistant cancers. The objective of our study is to examine whether B-NHL can be sensitized to respond to TRAIL. 2-Methoxyestradiol (2ME2), a naturally occurring metabolite of estradiol, is known to have apoptotic activity and anti-angiogenic activity and has been examined for its therapeutic efficacy, both preclinically and in humans. Further, we and others have shown that 2ME2 can sensitize solid tumors to TRAIL-induced apoptosis. Thus, we hypothesized that 2ME2 may also sensitize B-NHL cells to TRAIL-induced apoptosis and that 2ME2-induced microtubule disruption and inhibition of NF-κ B activity may be involved in 2ME2-induced sensitization. The present study examined the role of 2ME2 in TRAIL-sensitization of the B-NHL cell line, Ramos, as a model for B-NHL. Ramos cells were treated with 2ME2 (0.1, 1.0 μ m for 5 h) and then treated with TRAIL (2.5–10 ng/ml for 18 h). The cells were harvested and examined for apoptosis by Annexin V/PI and for activation of caspase-3. The findings demonstrate that, while single agents were not cytotoxic, the combination treatment resulted in significant cytotoxicity demonstrating synergy in apoptosis. The synergy was obtained with very low concentrations of 2ME2 (0.1μ m) and TRAIL (2.5 ng/ml), concentrations that were not effective in other tumor cell lines studied. We examined the potential mechanism involved in synergy induced by 2ME2 and TRAIL. Surface DR-5 expression was upregulated following treatment with 2ME2. In addition, the transcription repressor YY1 protein expression was inhibited as assessed by Western and immunohistochemistry (IHC). Microtubule disruption by 2ME2 results in inhibition of HIF-1α transcriptional activity through impairment of HIF-1α nuclear accumulation. Additionally, we have found that 2ME2 inhibits HIF-1α accumulation in the nucleus as assessed by IHC. Inhibition of HIF-1α has been shown to regulate apoptosis via upregulation of BID and phosphorylyzation of Bcl-2. The present findings demonstrate, for the first time, that 2ME2 sensitizes B-NHL cells to TRAIL-induced apoptosis via inhibition of both HIF-1α and YY1 and upregulation of DR5. The findings support potential therapeutic combination studies of 2ME2 with TRAIL for the treatment of resistant B-NHL In addition, we suggest that HIF-1α, YY1, and DR5 may serve as targets for therapeutic intervention and potentially as biomarkers for activity.
International Prognostic Score (IPS) Is Not Useful in Stages I–II Hodgkin’s Lymphoma (HL) - An Experience of the Buenos Aires Leukemia Group (BALG).
Authors: Tartas Norma E. , Zerga Marta , Santos Maria I. , Alfonso Graciela , Amoroso Maria 
Published: April 2020

Abstract
The International Prognostic Factors Project on advanced HL developed a prognostic score to predict treatment outcome in patients with advanced disease treated with modern chemotherapy,with or without radiotherapy (RT).The score incorporates seven adverse prognostic factors (APF): age ≥45yrs old, male sex, stage IV, hemoglobin&lt;10.5,serum albumin &lt;4 g/dl,leukocytosis≥ 15×109/L and lymphocytopenia (&lt; 0.6× 109/L). Patients with ≤ 2 APF have a two year freedom from progression of 80% while those with 3 or more APF have a worse outcome, each additional factor reduces the prognosis by about 8%.
To study the utility of IPS in less advanced disease, we looked into our patients included in the HD 98 protocol for stages I–II HL.According to this protocol, patients without bulky disease,B symptoms or N&lt; 3, received 4 cycles of standard ABVD plus IFRT.Patients with one or more of the unfavourable characteristics received 6–8 cycles of standard ABVD plus RT in areas of bulky or residual disease.Since December 98, ninety two patients have been included, 91 are evaluable for this report.Patient characteristics were as follows: 44 males,47 females, Age 30yr (15–80).Histologic subtypes were: LP:5, NS:64, MC:21, LR:1. Clinical stages IA:13, IAX: 3, IB:1, IBX:3, IIA:34, IIAX:13, IIB:19, IIBX:5.
Looking to IPS impact in freedom from progression we have simply considered two subgroup of patients: low risk (&lt;3APF) and high risk (≥ 3APF).Only 6/91 patients belonged to the high risk group. With ABVD 92% of the patients got a CR.Four patients were considered to be primary resistant, we have lost follow up of two patients, three persons have relapsed and two of them got a second CR. Currently 85/91 are alive, with a median FU of 56 months .All patients with a high IPS obtained a prolonged CR . Three patients have relapsed at 7,13 and 30 months;all belonged to the low risk IPS group.Four patients with primary resistant HL have died, three of them had had an autologus bone marrow transplant .All primary resistant HL belonged to the low risk IPS group.
We think that IPS is not useful in stages I–II HL, because it is only significantly altered in less than 10% of the patients. One possible explanation might be, that IPS relies on laboratory parameters such as white cell counts in peripheral blood, hemoglobin levels and serum albumin which are less affected, in early stages of the disease .Interestingly 5/6 patients with high risk IPS had B symptoms and 3/5 had bulky or N3 disease, consequently they received 6–8 cycles of ABVD. These facts, might have had influence in our results.
In our experience resistance to ABVD have a dismal prognosis in HL. IPS was not a good predictor of progression or resistance in this cohort of patients.
Hodgkin’s Lymphoma Reed Sternberg Cells over Express the T-Cell Inhibitory Carbohydrate-Binding Lectin, Galectin 1: Role of AP-1 and Likely Mechanism of Tumor Immune Escape.
Authors: Juszczynski Przemyslaw , Ouyang Jing , Kutok Jeffery L. , Monti Stefano , Chen Wen , Cin Paola Dal , Abramson Jeremy S. , Takeyama Kunihiko , Golub Todd R. , Aster Jon C. , Rabinovich Gabriel A. , Shipp Margaret A. 
Published: April 2020

Abstract
Primary Hodgkin lymphomas (HL) contain small numbers of neoplastic Reed-Sternberg (RS) cells within an extensive host inflammatory infiltrate, which includes few cytotoxic T-cells. The lack of an effective host anti-tumor response prompts speculation regarding the mechanisms that HL RS cells use to evade immune surveillance. To identify novel HL-specific T-cell inhibitory molecules, we compared the gene expression profiles of a series of HL and diffuse large B-cell lymphoma (DLBCL) cell lines. The HL cell lines overexpressed galectin-1 (GAL1), a carbohydrate-binding lectin that selectively induces the apoptosis of cytotoxic T cells. GAL1 mRNA abundance was 5- to 33- fold higher in HL cell lines than in DLBCL lines. GAL1 protein expression was also uniformly high in HL cell lines and low or undectable in DLBCL lines by western blotting.
Immunohistochemical staining of primary tumors revealed abundant GAL1 expression in HL RS cells whereas DLBCLs were uniformly negative. To elucidate the mechanisms responsible for GAL1 over expression in HL, we analyzed the GAL1 locus and identified a candidate AP1 enhancer element 1.5 kb downstream of the GAL1 transcription start site. The predicted enhancer element increased the expression of a reporter gene (luciferase) 5-fold in a HL cell line but had no effect in either a DLBCL or fibroblast cell line. In electrophoretic mobility studies, AP1 bound to the predicted GAL1 enhancer element in a cell-type specific manner. In addition, mutation of the AP1 binding site in the GAL1 enhancer abolished its activity. Since the AP1 components, cJUN and JUN-B, are known to be overexpressed in HL, we analyzed cJUN and JUN-B copy numbers and transcript abundance in the HL cell lines using 100K high-density SNP arrays and oligonucleotide RNA microarrays. We found increased copy numbers of cJUN and/or JUN-B in all HL cell lines tested and confirmed these findings using fluorescence in situ hybridization (FISH). Increased cJUN and JUN-B copy numbers were associated with significantly higher transcript abundance in the HL cell lines. In additional functional assays, we confirmed previous reports that recombinant GAL1 induced the apoptosis of CD3+ PHA-stimulated lymphoblasts in a dose- and time-dependent manner. Taken together, these studies indicate that HL RS cells selectively over express GAL1, at least in part, via AP1-mediated induction of the GAL1 enhancer. Given the profound effects of GAL1 on cytotoxic T cells, RS-specific expression of GAL1 likely inhibits the host anti-tumor response in HL.