bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Comparison of Efficacy Between MVEP Chemotherapy and R- MVEP Chemotherapy in Patients of Refractory and Relapsed Non-Hodgkin Lymphoma
Authors: Qian Meihua , Wang Wensong 
Published: April 2020

Abstract
To observe the efficacy and toxicity of two groups of MVEP Chemotherapy and R-MVEP Chemotherapy in patients of Refractory and relapsed Non-Hodgkin Lymphoma. 19 cases patients of refractory and relapsed Non-Hodgkin Lymphoma, 9 females and 10 male, between 17–75 years of age (mean age 45.5 years), 2 cases IIa,, 11caseIII (9IIIa and 2IIIb), 6 cases IV(4 IVa and 2 IVb).Most of patients showed the enlargement of superficial and/or deep multiple lymph nodes, 4 cases had fever and the enlargement of spleen and/or liver, 2 cases with hydrothorax and ascites, 3 cases with bone marrow infiltration and 1 case with multiple lumps in liver, other 1 case with autoimmune hemolytic anemia (AIHA)and one with pericardial effusion. All patients were treated with chemotherapy included COP (or COPP), CHOP, BCAOP (or BECAOP), etc. and 2 patients of them Had been treated by radiotherapy before they were treated by MVEP Chemotherapy and R- MVEP Chemotherapy. In this experiment, A group of 13 patients were treated by MVEP Chemotherapy and G-CSF ( MVEP, Mitoxantrone 8mg/m2/d1, VP16 O.1/d1 ‘d5 (or,Wumon 0.1/d1 ‘d3),Vinorelbinum 20mg/m2/d1,Prednison 60mg/d1 ‘d7,or DXM 8mg/m2d1 ‘d7), other group of 6 patients were therapied by Rituximab plus MEVP Chemotherapy and G-CSF,( R-MVEP, Rituximab 375 mg/m2/d1,Mitoxantrone 8mg/m2/d3, Wumon 0.1/d3 ‘d5 (or VP16 O.1/d3 ‘d7),Vinorelbinum 20mg/m2/d3,Prednison 60mg/d3 ‘d9 (or DXM 8mg/m2d3 ‘d9 ), G-CSF 100 ‘300/d were injected when the number of WBC was &lt;2.0×109/L after chemotherapy. Each cycle was 28–35 days and assessment was given after 2 cycles. The result is, The overall response rate and complete remission was 61.5 % and 38.4% respectively in treat group of MVEP, The overall response rate and complete remission was 83.3% and 50 % respectively in group of R- MVEP. One of patients of NHL with AIHA after a treating cycle achieved complete remission(all of enlarged lymph nodes disappeared and Hemoglobin return to normal).The main toxicity was mylosuppression, the minimum of WBC after chemotherapy reached 0.5 ‘1.4*109/L, few patients vomited during chemotherapy, All toxicity was no different in two groups of MVEP and R-MVEP BOur study result indicates: MEVP Chemotherapy and G-CSF is an Effective, safety and economy on patients of Refractory and relapsed Non-Hodgkin Lymphoma, but Rituximab in Combination with MEVP Chemotherapy and G-CSF is could improve the efficacy of MEVP Chemotherapy only in patients of Refractory and relapsed Non-Hodgkin Lymphoma. The efficacy of Rituximab in Combination with MEVP Chemotherapy is much better than that of MVEP Chemotherapy only on patients of Refractory and relapsed Non-Hodgkin Lymphoma, the treatment method of R-MVEP are suitable for old patients.
Characterization of Antibodies Direct against the Idiotypic VK3 Chain of HCV-Related Type-II Mixed Cryoglobulinemia and B-Cell Proliferations
Authors: De Re Valli , Simula Maria Paola , Pavan Alessandro , Marin Dolores , Caggiari Laura , Toffoli Giuseppe 
Published: April 2020

Abstract
Autoimmune type-II cryoglobulinemia (MC) is sustained by clonal/oligoclonal B-cell populations such the disease may be considered an “indolent B-cell lymphoma (NHL) “ and may favor overt NHL development. HCV-antigen driven mechanism induces B-cell proliferations. Clonal B-cells demonstrate a restricted used of variable genes to construct the B-cell receptor (BCR) and a homology between BCR functional regions and autoimmune rheumatoid factor (RF) activity. We underline the BCR unique repertoire with frequent rheumatoid factor activity also in other autoimmune disorders associated to NHL development as Sjogren’s syndrome and rheumatoid arthritis. All together these BCRs are characterized by their high degree of idiotypic (Id) cross reactivity. Particularly the K chain V3-20/15 is frequently found in subject with positive HCV antibody. Id is a clonamarker expressedby B cells, thus is an ideal target for immunotherapy. The evidence of few Id presented in the NHL subgroup above reported constitute the rational for the development of antibodies and recombinant proteins that use shared Id among different NHL. Five monoclonal antibodies have been produced in our laboratory toward the VK3-20 region of a subject HCV+ with NHL. Epitopes recognized has been performed using epitope excision approach. A fine determination of the antibodies activities toward specific amino acids, possibly common to different individuals, are in progress. Monoclonal antibodies reactivity has been tested in vitro in ELISA, western blot and cytofluorimetry. Apoptosis and SyK/ERK phosphorylation pathways induced following BCR cross-linking of antiId murine IgG will be performed. All the antibodies were reactive in Elisa against the VK3-Ig light chain. Two of these antibodies showed a reactivity against the light chain of cryoprecipitated immunocomplexes from several patients in western blot, and by cytofluorimter they recognised two lymphoma B-cell lines.
Rituximab Therapy for HIV-Negative Multicentric Castleman’s Disease: Seven Years’ Experience at a Single Institute
Authors: Ide Makoto , Kawachi Yasunori , Izumi Yoichiro 
Published: April 2020

Abstract
Background: Multicentric Castleman’s disease (MCD) is an indolent lymphoproliferative disorder of unknown etiology, and is classified into three types: hyaline-vascular type, plasma-cell type, and mixed type. Recently, we reported the use of rituximab therapy for HIV-negative patients with MCD, after obtaining the informed consent of the patient and the approval of the Institutional Review Board (Br J Haematology 121, 818–819, 2003, Eur J Haematology 76. 119–123. 2006). Therefore, we tried to review the long-term follow-up (nine to 75 months) of all patients at a single institute.
Patients and Methods: Over seven years, 5 HIV-negative patients with MCD (3 men and 2 women; median age: 39, range: 26–61 years) were referred to Takamatsu Red Cross hospital. After clinical evaluation (chest and abdominal computed tomography scans, magnetic resonance imaging and Ga67 citrate scintigrams), lymphnode biopsy was performed for histological diagnosis. Rituximab was administered intravenously at a standard dose of 375 mg/m2 weekly, for 4 or 8 times without chemotherapy, and we analyzed the clinical course of MCD after rituximab therapy. During the follow-up, clinical symptoms were recorded. At a median follow-up of 49 months, biologic parameters (complete blood count, C-reactive protein, immunoglobulin G), and cytokines (soluble interleukin-2 receptor, Interleukin-6) were determined at different time points by standard procedures.
Results: Three of the five patients had histological evidence of hyaline-vascular type MCD, and two patients had plasma-cell type MCD. Two (both with hyaline vascular type) of the five MCD patients (40%) with MCD achieved almost complete remission with rituximab therapy when followed up for 50 to 75 months. Three (one with hyaline vascular type and two with plasma-cell type) of the five patients did not show clinical remission after riruximab administration.
Conclusion;Rituximab treatment provides a durable response in a some MCD (especially those with hyaline-vascular type) patients, but is not always successful.
A Novel Clinical Syndrome Associating Severe Congenital Neutropenia and Complex Developmental Aberrations Caused by Deficiency of G6PC3
Authors: Boztug Kaan , Appaswamy Giridharan , Ashikov Angel , Schäffer Alejandro A , Salzer Ulrich , Diestelhorst Jana , Germeshausen Manuela , Brandes Gudrun , Lee-Gossler Jacqueline , Noyan Fatih , Gatzke Anna-Katherina , Minkov Milen , Greil Johann , Kratz Christian , Petropoulou Theoni , Pellier Isabelle , Bellanne-Chantelot Christine , Rezaei Nima , Mönkemöller Kirsten , Irani-Hakimeh Noha , Bakker Hans , Gerardy-Schahn Rita , Zeidler Cornelia , Grimbacher Bodo , Welte Karl , Klein Christoph 
Published: April 2020

Abstract
We here describe a previously unrecognized nosological entity in 12 patients from 8 unrelated pedigrees. All patients presented with severe congenital neutropenia and severe invasive bacterial infections. In addition, patients had a variety of additional syndromic features such as congenital heart disease (8/12), urogenital malformations (5/12), inner ear hearing loss (2/12), and myopathy (1/12). Furthermore, most patients (10/12) showed increased visibility/angiectasia of subcutaneous veins. The bone marrow smear was characterized by a typical “maturation arrest” due to premature apoptosis of mature neutrophils. Similar to Kostmann’s disease secondary to mutations in HAX1, myeloid cells from patients with this novel syndrome showed increased susceptibility to apoptosis. Myeloid progenitor cells revealed an abnormally enlarged rough endoplasmic reticulum and increased endoplasmic reticulum stress evidenced by increased expression of BiP. A genome-wide linkage study, performed in two consanguineous pedigrees, gave statistical evidene of a linkage interval on chromosome 17q21 (LOD score 5.74). We identified homozygous missense mutations in G6PC3, a ubiquitously expressed paralog of glucose-6-phosphatase. Biochemical studies confirmed deficient enzymatic activity. Using retroviral G6PC3-gene transfer into primary hematopoietic stem cells and in vitro differentiation into myeloid cells, the phenotype of increased susceptibility to apoptosis could be reverted. Eight distinct biallelic mutations were found, including missense and nonsense mutations. G6PC3-deficient myeloid cells showed a predominance of the unphosphorylated form of GSK3beta, a key molecule controlling cellular differentiation and apoptosis. As a consequence of increased GSK3beta activity, increased phosphorylation of the antiapoptotic molecule Mcl1 was detected, explaining increased susceptibility to apoptosis in neutrophils. In summary, our study describes a novel disease, determines its molecular etiology, and sheds light on the role of glucose-dependent pathways in controlling the homeostasis of the endoplasmic reticulum and control of apoptosis.
Treatment of CD 20+ Hodgkin Lymphoma (Lymphocyte Predominant) with Monoclonal Antibody Rituximab after First-Line Treatment Is Effective and Might Improve the Outcome
Authors: Genadieva-Stavrik Sonja , Pivkova Alexandra , Ivkovski Ljube , Cevreska Lidija 
Published: April 2020

Abstract
Lymphocyte-predominant Hodgkin disease (LPHD) presents as early-stage disease with slow disease progression and excellent initial response to conventional chemotherapy. Although 96% of LPHD patients experience a complete remission (CR) upon first line treatment, many relapses occur. Residual tumor cells in Hodgkin’s patients can survive standard therapy and cause relapse. Thus, the elimination of minimal residual disease after first line treatment might improve the outcome in Hodgkin disease. CD20+ is strongly expressed by malignant cells in LPHD, but so far there is limited information regarding the efficacy of Rituximab in this patient population. A 66 year-old woman presented with bilateral inguinal lymphadenopathy in 2004 and complained on malaise and weight loss. Lymph node biopsy confirmed a diagnosis of LPHD and immunohistochemistry confirmed that CD20 antigen was expressed on more than 30% of malignant cells. Staging revealed II B disease. There were lymph node enlargements in the pelvis on CT. Her blood count, erythrocyte sedimentation rate, and albumin were normal with elevation of and lactate dehydrogenase and alkaline phoshatase. She was treated with ABVD regiment 8 cycles and CR was achieved. After standard chemotherapy patient with CD20+ LPHD received four weekly doses of Rituximab at 375 mg/m2 and maintenance therapy with additional four doses of Rituximab every three months for the next year. Treatment was well tolerated without any complications. Evaluation of disease assessment included physical examination and computed tomography, bone marrow biopsy and routine analyses, after the end of treatment and every 3 months after for the first two years, and on six months for the following year. There were no abnormalities on CT after the end of the treatment. Patient was in complete remission. CT after 36 months showed no detectible tumor mass. Patient remains still in complete remission three years after chemotherapy without detectible tumor mass.
Our case report suggests that Rituximab is both safe and effective in patients with CD20+ LPHD. The optimal treatment for patients with LPHD remains uncertain. Current research aims to identify alternative treatment approaches that possess significant activity but less toxicity. Radiotherapy for early-stage patients and chemotherapy or combined modality treatment for advanced-stage patients remains to be standard of care. Initial observed benefit of Rituximab treatment in this group of patients suggests that there is a role for monoclonal antibodies in optimal treatment approach, especially in improving the outcome. Further studies with Rituximab are warranted in this patient population.
Targeting Early Events of B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia: Suppressed Syk and PLCγ2 Activities Predict Apoptotic Response of Leukemic Cells to Dasatinib
Authors: Wang Y. Lynn , Song Zibo , Lu Pin , Leonard John P. , Coleman Morton , Martin Peter , Wu Chaowei , Lee Francis Y. , Knowles Daniel M. , Furman Richard 
Published: April 2020

Abstract
B cell receptor (BCR) signaling plays an essential role in the pathogenesis of chronic lymphocytic leukemia. In a subset of patients with a poor clinical outcome, BCR ligation leads to increased cell metabolism and cell survival (Cancer Research66, 7158–66, 2006). Based on these findings, we tested whether targeting BCR signaling with dasatinib, an inhibitor of Src kinase, would interfere with the signaling cascade and cause death of CLL B cells. CLL leukemic cells were isolated from 34 patients and were incubated with or without dasatinib at a low dose of 128 nM. Among 34 cases, viability of leukemic cells was reduced by 2% to 90%, with an average of ~50% reduction on day 4 of ex vivo culture. Further study showed that CLL B cells undergo death by apoptosis via the intrinsic pathway which involves the generation of reactive oxygen species. Analysis of the Src family kinases showed that phosphorylation of Src, Lyn and Hck was inhibited by dasatinib not only in those cases that responded to dasatinib with apoptosis, but also in those that did not respond well (&lt;20% apoptosis). Further analysis revealed that suppressed activity of two downstream molecules, Syk and PLC
Statistical analysis showed a significant correlation between CLL dasatinib response and their IgVH mutation and ZAP70 status. Cases with worse prognoses by these criteria have a better response to the kinase inhibitor. Lastly, we have also found that ZAP70 positive cases showed a greater degree of PLC
Design and Synthesis of Novel Derivatives of ATRA Demonstrate the Combined Importance of Acid Moiety and Conjugated Double Bonds in Its Binding to PMLRAR-Alpha Oncogene in Acute Promyelocytic Leukemia
Authors: Goel Swati , Schinke Carolina , Bhagat Tushar , Mo Yongkai , Zhou Li , Heuck Christoph , Alencar Christina , Pahanish Perry , Anguiano Jaime , Kabalka George , Platanias Leonidas C , Verma Amit , Das Bhaskar 
Published: April 2020

Abstract
All trans retinoic acid (ATRA) is the treatment of choice for Acute Promyelocytic Leukemia (APL) and binds to the transcriptional repressor PML-RAR-alpha oncogene. The binding of ATRA to RAR-alpha relieves transcriptional repression and leads to induction of genes important for myeloid differentiation. ATRA consists of an acid moiety at position 15 and is also characterized by conjugated double alkene bonds (Fig1A). The exact contributions of these structural components of ATRA in its clinically important binding to RAR-alpha receptor are not very well studied. In an effort to improve the therapeutic index and to study its binding mechanism, we synthesized novel retinoic acid analogs (retinoids). Our objective was to construct retinoids to test these structure functional correlates. 3 novel retinoids created were synthesized as follows:
Compound 13a (Fig1B): consisting of modifying conjugated alkene backbone while keeping acid moiety intact.
Compound 13b (Fig1C): consisting of modifying conjugated alkene backbone and converting acid to ester moiety.
Compound 13c (Fig1D): consisting of modifying conjugated alkene and cycloalkene ring backbone and keeping acid moiety intact.
We tested the ability of these newer retinoids to bind to RAR-alpha as well as inhibit the proliferation of PML-RAR-alpha containing acute promyelocytic leukemic cell line NB4. Reporter assays using a RAR- luciferase demonstrated that Compound 13a successfully relieved transcriptional repression by RAR-alpha and led to downstream gene induction. This was significantly less compared to wild type ATRA demonstrating the importance of C9–C10 double bonds in this binding. Compounds 13b and 13c could not relieve RAR mediated repression of gene induction demonstrating that the acid moiety plays a important role in this binding. Functional studies were consistent with these observations and showed that both ATRA and 13a were able to inhibit the proliferation of APL cells while 13b, 13c were not. Flow cytometry showed that 13a led to partial differentiation of NB4 cells, as evident from CD11b expression after five days of culture. 13b and 13c did not lead to any differentiation, while ATRA led to the greatest expression of CD11b.
Our results demonstrate that both the acid moiety and conjugated double bonds are important in binding to RAR-alpha and the subsequent transcriptional repression by retinoic acid. These insights will be important in future efforts to improve the stability and efficacy of ATRA and also have implication in efforts focused on treating ATRA resistant cases of APL.
Figure Figure
Effects of Imatinib on the Pharmacokinetics of Acetaminophen in Korean Patients with Chronic Myelogenous Leukemia (CML)
Authors: Kim Dong-Wook , Park Sa-Hee , Jin Yu , Hayes Michael , Wang Yanfeng 
Published: April 2020

Abstract
Background: Drug-drug interactions between imatinib (IM) and drugs which are substrates of CYP2C9, CYP2D6- and CYP3A4/5 isozymes have been characterized in clinical studies as IM has demonstrated an inhibitory effect on these isozymes in vitro in human liver microsomes [Gleevec® Prescribing Information]. IM also exhibited a weak in vitro inhibitory effect on UGTs-mediated O-glucuronidation using acetaminophen as a probe substrate (Ki 58.5 μM). The present study evaluates the clinical significance of PK interactions between IM 400 mg/d and acetaminophen, an often used analgesic/antipyretic medicine, in CML patients.
Methods: Newly diagnosed CML patients (n=12) treated at St Mary’s Hospital, the Catholic University of Korea first received a single oral dose of acetaminophen 1000 mg on day 1 after an overnight fasting. On days 2–8, IM 400 mg was administered daily (qd). On day 8, another 1000 mg dose of acetaminophen was administered together with IM 400 mg. Blood and urine samples over 24 hours were collected following the morning dose on days 1 and 8 to determine the plasma PK and renal excretion of acetaminophen and its glucuronide (G) and sulfate (S) conjugate metabolites (two major metabolites of acetaminophen). Additional blood samples were collected on day 8 to measure the plasma exposure of IM and its major metabolite CGP74588 (CGP) in patients.
Results: Preliminary results from 6 patients showed that the plasma Cmax and AUC values of acetaminophen and the AUC ratios of conjugate G and S to acetaminophen were all similar between day 1 (Control) and day 8 (with IM) (Table 1). The renal clearance values for acetaminophen and its two conjugate metabolites were also similar between days 1 and 8. Following 7 days treatment at IM 400 mg qd, the IM plasma Cmax and AUC values were 2040±477.7 ng/mL and 31.8±8.68 μg*hr/mL, respectively. The oral clearance of IM in these Korean patients, 13.4±3.6 L/hr, was comparable to that reported in Caucasian CML patients, 10–14 L/hr [Schmidli 2005]. PK samples from an additional six patients have been collected, and results will be available for reporting by December 2008.
Acetaminophen (A) Cmax (μg/mL) AUC (μg*hr/mL) G/A AUC ratio S/A AUC ratio Day 1 (n=6) 15.6±8.3 52.4±24 2.66±0.75 0.77±0.11 Day 8 (n=6) 12.0±5.0 49.0±19.6 2.70±0.96 0.85±0.17 Day 8/Day 1 ratio 0.92±0.42 0.95±0.08 1.0±0.11 1.1±0.15 Imatinib (IM) Cmax (ng/mL) AUCt (μg*hr/mL) Cmin (ng/mL) CGP/IM AUC ratio Day 8 (n=6) 2040±477.7 31.8±8.68 947±323 0.15±0.035
Conclusion: Preliminary results showed that coadministration of imatinib 400 mg/d had no effect on the PK and metabolism of acetaminophen 1000 mg in newly diagnosed CML patients.
Research of Apoptosis Induction by the Application of Magnetic Nanoparticle of Fe3O4 Loaded with Daunorubicin and 5-Bromotetrandrine in K562/A02 Leukemic Cells
Authors: Chen Bao-An , Shen Ming-fang , Cheng Jian , Gao Feng , Xu Wen-lin , Shen Hui-lin , Ding Jia-hua , Gao Chong , Sun Yun-Yu , Wang Jun , Zhao Gang , Song Hui-hui , Bao Wen , Sun Xin-chen , Cheng Hong-yan , Deng Yu-xia , Li Guo-hong , Liu Li-jie , Chen Wen-ji , Wang Jue-qiong , Yuan Peng , Pei Xiao-ping , Chen Ning-na , Wang Xue-mei 
Published: April 2020

Abstract
Objective: To observe the apoptosis of K562/A02 cells induced by application of Fe3O4-Magnetic Nanoparticle (Fe3O4-MNPs) loaded with Daunorubicin(DNR) and 5-Bromotetrandrine (BrTet) and to explore its possible molecular mechanism.
Methods: We detected the apoptosis of K562/A02 cells after treatment with Fe3O4-MNPs and BrTet with DNR alone or their combination by flow cytometry(FCM),Wright staining and DNA ladder. The expression of Bax and Bcl-2 protein was measured by Western blot.
Results: The result showed apoptotic characteristics after treated with this composite for 48 hours. Flow cytometry assay showed the percentage of apoptotic cells which were treated with Fe3O4-MNPs and BrTet with DNR alone or their combination for 48 hours increased from (7.9%±0.35)% to (15.5%±0.87)%, (19.7%±1.04)% and(40.8%±1.74)%, (P&lt;0.05. After treated with this composite, the typical apoptotic morphological features appeared: condensation of cells and nuclear, disintegration of nuclear chromatin, and apoptotic body could be observed under microscope; DNA agarose gel electrophoresis showed ladder bands; the expression level of Bax protein increased (P &lt; 0.01) and Bcl-2 protein decreased markedly (P &lt; 0.01).
Conclusion: Our results suggest that Fe3O4-MNPs or BrTet with DNR induces apoptosis in K562/ADM cells, and when used together,they have distinct synergism. The up-regulation of Bax protein and the down-regulation of Bcl-2 protein may play important roles.