bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Lymphoid Cell Surface Receptor NTB-A: A Novel Monoclonal Antibody Target for Leukemia and Lymphoma Therapeutics.
Authors: Korver Wouter , Singh Shweta , Zhao Xiaoxian , Hsi Eric D. , Abo Arie 
Published: October 2019

Abstract
NTB-A is a CD2-related cell surface protein expressed primarily on lymphoid cells including B-lymphocytes from Chronic Lymphocytic Leukemia (CLL) and lymphoma patients. We have generated a series of murine and chimeric mAbs against NTB-A and assessed their therapeutic potential for CLL. Selective mAbs to NTB-A were further tested in functional Complement Dependent Cytotoxicity (CDC) and Antibody Dependent Cellular Cytotoxicty (ADCC) assays in cell lines and B lymphocytes freshly isolated from CLL patients. While lower levels of NTB-A were detected in T and NK cells, CDC and ADCC activity was demonstrated primarily in B cells isolated from CLL patients and B lymphoma cell lines. Knockdown of NTB-A by siRNA in target cells results in lower cytotoxicity, demonstrating the specificity of the mAbs. Furthermore, anti-NTB-A mAbs demonstrated anti-tumor activity against CA46 human lymphoma xenografts in nude mice and against systemically disseminated Raji human lymphoma cells in SCID mice. Taken together, these results demonstrate NTB-A as a potential new target for immunotherapy of leukemia and lymphomas.
Anti-Cancer Effects of Rapamycin on U937 Cell Line.
Authors: Jin Lina , Fu Chenchen , Cen Jiannong , Chen Peishuai , Wu De Pei 
Published: October 2019

Abstract
Purpose: Cytotoxicity of rapamycin alone or in combination with arsenic trioxide in lymphoma cell line U937 was assessed, for the study of Anti-cancer effects of rapamycin.
Methods: cell vability and proliferation was analyzed by MTT and cell counting, clone formulating ability was analyzed by semisolid medium, cell cycle was analyzed by Propidium Iodide/RN-ase stain, the phosphorylation level of mammalian target of rapamycin (mTOR) was detected after marked by Phospho-mTOR antibody (Ser2448) and FITC. Expression of P27 was assessed by western- blot.
Result: 1.MTT measurement showed with increasing concentrations of RAPA (10 nM 100 nM, 1000 nM) cell proliferation inhibition rate was follwed 16.2%, 25.5%, 47.8%. Clonogenic assay showed the U937 proliferation inhibition rate was 80.5% in a 7-day leukemia colony-forming assay with concentration of 10 nM RAPA.2 RAPA 10nM, As2O3 0.6uM, As2O3 0.9uM alone, RAPA 10nM in combination with As2O3 0.6uM and 0.9uM, cell proliferation inhibition rate was followed 13%, 26%, 35%, 43%, 54%. 3. Propidium Iodide/RN-ase measurement showed RAPA resulted in U937 cell arrested in G1-phase, and was blocked in S-phase. 4. FCM showed the phosphorylation level of mTOR down-regulated significantly after treated by rapamycin (10 nM),5.The expression of P27 enhanced after treatd by rapamycin (10 nM)
Conclutions: From the experiment we can see rapamycin alone can inhibit the proliferation and clone formulating ability of U937 cell line. mTOR kinase is involved in the regulation of cell growth and proliferation. Rapamycin can down-regulate the phosphorylation level of mTOR, which can induce increasing expression of P27, As a result U937 arrest in G1-phase and block in S-phase. Interestingly rapamycin exert additive effect in proliferation experiment when combind with As2O3, higher than rapamycin or As2O3 alone.
Optimal Treatment for Patients after Dasatinib or Nilotinib: Comparison of Preclinical Activities of Approved and Promising Investigational Kinase Inhibitors Against BCR-ABL Kinase Domain Mutations That Confer Clinical Resistance to Dasatinib or Nilotinib.
Authors: Kasap Corynn , Weier Christopher , Shah Neil P. 
Published: October 2019

Abstract
The optimal management of patients with chronic myeloid leukemia (CML) is increasingly reliant upon molecular studies. Loss of response to imatinib in CML is most commonly associated with selection for a limited number of BCR-ABL kinase domain mutations that impair the ability of imatinib to effectively bind to BCR-ABL Molecular understanding of imatinib resistance mechanisms has led to the development of effective “second generation” BCR-ABL kinase inhibitors, such as dasatinib and nilotinib, which have clinical activity against most, but not all, drug-resistant mutations. Analysis of the BCR-ABL kinase domain in patients who develop resistance to second-generation inhibitors has implicated further selection of drug-resistant BCR-ABL kinase domain mutants in nearly all cases reported to date. Encouragingly, the number of resistant mutations capable of conferring clinical resistance to the most clinically-advanced second-generation agents, dasatinib (approved by the US FDA and EMEA) and nilotinib (approved in Mexico and Switzerland), appears to be restricted to a relatively small number of amino acid substitutions. As clinical experience with dasatinib and nilotinib grows, an understanding of the relative sensitivities of dasatinib- and nilotinib-resistant BCR-ABL mutants to other kinase inhibitors, both approved and investigational, is critical to optimize clinical outcomes in patients with resistance to dasatinib or nilotinib. At the present time, kinase inhibitor therapy options for patients with resistance to one of these agents include the investigational options bosutinib and MK-0457 (VX-680), as well as dasatinib and nilotinib (for patients not yet exposed to one of these agents) and re-exposure imatinib. It is likely that the success of therapeutic intervention in these cases can be predicted based upon the preclinical sensitivity of the mutation(s) involved with the agent chosen. We have therefore conducted a thorough biochemical and biological cross-analysis of the activities of each of these clinically-useful kinase inhibitors against mutations that confer clinical resistance to dasatinib or nilotinib. These studies provide clinicians with a useful reference for choosing an appropriate kinase inhibitor based upon the identity of the resistant BCR-ABL kinase domain mutation(s) detected at the time of relapse when faced with a patient who has lost response to dasatinib or nilotinib. It is hoped that the application of such “personalized medicine” strategies to the clinical management of CML cases will further improve outcomes in patients treated with kinase inhibitor therapy.
Expression Profiles in Chronic Lymphoid Leukemia by Hematochip Analysis.
Authors: Alvarez Patricia , Leon Virginia , Caballero Gonzalo , Rubio-Martinez Araceli , Pocovi Miguel , Giraldo Pilar 
Published: October 2019

Abstract
Aim: The gene expression analysis system is a good tool to identify biomarkers related to prognosis or response predictors of therapy in haematological malignancies. Low density microarrays are an useful technology to obtain genetic expression profiles in different neoplastic disorders. Recently we have designed an oligonucleotide biochip (Hematochip, Alvarez et al, Clin Chem2007;53:259) useful for study peripheral blood in hematological malignancies. Chronic Lymphoid Leukemia (CLL) is a frequent clonal lymphocyte disorder characterized by clinical diversity and that have known prognosis markers but a more accurate subclassification could be required. Our objective was to define CLL subgroups with differential genetic profile expression. Patients and
Methods: Analytical, prospective study in 49 consecutive CLL patients diagnosed since January 2003 to December 2004 in the Hematology Department of Miguel Servet University Hospital. Zaragoza. Spain. At diagnosis demographic, clinical stage, analytical, immunophenotype expression, genetic aberrations and mutational status of IgVH were collected at electronically data base. Simultaneously, peripheral blood from 20 healthy donors and all CLL patients were collected in PAXgene tubes (PreAnalytix). cDNA was generated from total RNA and double-strand cDNA was used as a template to generate biotinylated cRNA by in vitro transcription using the MEGA-script T7 High Yield Transcription kit (Ambion). Fragmented cRNA was denatured and hybridized using a Ventana Discovery Station (Ventana Medical Systems). Arrays were stained with Cy3-conjugated streptavidin (Amersham Biosciences) and scanned using a ScanArray 4000 scanner (Perkin-Elmer). The data were treated and analyzed by GeneSpring clusters method. The expression profiles were compared and stratified with clinical stability or progression, gender, ZAP 70 expression, associated neoplasia, time free of therapy and response or not to Fludarabine.
Results: The Hematochip has identified 9 probes obtained with filtered data and statistical significance (p<0.01), related to stable or progressive disease. The results had been validated by RT-PCR.
Comments: the study of genetic profiles by Hematochip could be a useful analysis to predict the stability or progression of CLL patients at diagnosis. Further studies analyzing more cases will be necessary in order to validate these results. This work has been partially sponsorized by grants: Mutua Madrilena del Automovil, Fundacion para el Estudio de la Hematologia y Hemoterapia de Aragon and I+CS.
Leukemic Meningitis as the Presenting Manifestation of Chronic Lymphocytic Leukemia (CLL) in a Young Man.
Authors: Sousa Aida B. , Veiga Joana , Ferreira Gilda , Rodrigues Antonio S. , Silva Madalena , Gouveia Joaquim 
Published: October 2019

Abstract
Meningeal infiltration is extremely rare in CLL. Moreover, part of the cases found in the literature occurred in fact in patients with prolymphocytic leukemia. In the few CLL cases, this complication was reported at late stages of the disease, in elderly patients. A previously healthy 30-year-old man was referred to the emergency department for evaluation of blurred vision and headache that developed 2 weeks earlier. Bilateral papilledema was observed, with no other neurological abnormality. CT and MRI of the head and orbits disclosed thickening of both optic nerves. Hemoglobin and platelet count were within normal limits. The WBC count was 41800/μl with 83% small lymphocytes, which were SmIg+ λ(weak) CD19+, CD5+, CD23+, CD20+, CD79b+, CD11c+, bcl2+, CD38+, ZAP70+ and CD10 negative. Moderately enlarged cervical lymph nodes were present. A diagnosis of Binet stage A, Rai stage I B-CLL was made. Bone marrow aspiration and biopsy showed 95% lymphocytes, with a diffuse pattern of infiltration. No metaphases were obtained for karyotyping. FISH disclosed a rearranged IgH, and was negative for trisomy 12 and for deletions of 11q, 13q and 17q. Abdominal CT showed retroperitoneal lymphadenopathy. Serology for HIV and EBV was negative. The cerebrospinal fluid (CSF) revealed >1000 lymphocytes/μl which were immunophenotypically identical to the peripheral blood cells. Systemic corticosteroids and intrathecal chemotherapy (methotrexate and dexamethasone) followed by cranial irradiation led to resolution of headache, but blurred vision persisted. Clearance of leukemic cells from the CSF was slow, a normal CSF being achieved only after 6 alternate day intrathecal injections. Systemic chemotherapy and stem cell transplantation are planned. To our knowledge this is the first reported case of CLL presenting as meningeal infiltration. Two possible reasons for the apparent rarity of CLL meningitis can be put forward: meningeal invasion would frequently be clinically silent, a hypothesis that is strengthened by autopsy findings; and it would usually occur in very advanced stages of CLL (with misinterpretation of neurological symptoms in erderly patients) making underdiagnosis easy.
Distinctive IgVH Gene Segments Usage and Mutation Status in Chinese Patients with Chronic Lymphocytic Leukemia.
Authors: Chen Lijuan , Zhang Yaping , Zheng Wenjuuan , Li Jianyong , Ruan Changgeng 
Published: October 2019

Abstract
Chronic lymphocytic leukemia (CLL) is characterized by the relentless accumulation of monoclonal B cells with the appearance of small mature lymphocytes and a characteristic CD5 and CD19 co-expression immunophenotype. The incidence of CLL in Asian countries is lower than that in the Western ones, where CLL is the most common leukemia. To evaluate the frequency and mutation status of immunoglobulin (Ig) variable heavy chain gene (IgVH) expression in Chinese patients with CLL. We investigated IgVH gene segments usage and mutation status by multiplex RT-PCR in 52 CLL patients, and analyzed the relationship between IgVH somatic mutation status and the expression of CD38, ZAP-70 and CLLU1. 38 patients had mutated IgVH, and 14 had unmutated IgVH. The most frequently expressed VH gene family was found to be VH3 (46.2%) followed by VH4 (40.4%), VH1 (5.8%), VH2 (5.8%) and VH7 (1.9%), with no expression of VH5 and VH6 gene families. VH1-69 and VH3-21 which commonly overused in Western CLL weren’t detected in our cohort. The frequency of IgVH gene families indicates significant difference in Chinese CLL patients compared with Western patients, suggesting involvement of ethnic and/or environmental factors in CLL disease initiation. IgVH gene mutation status was significantly associated with the expression of CD38 and CLLU1. The expression of them may be simple and reliable surrogates for the identification of IgVH mutations.
VH gene family usage and mutation status VH family n Mutated VH gene Unmutated VH gene VH1 3 3 0 VH2 3 2 1 VH3 24 19 5 VH4 21 16 5 VH5 0 0 0 VH6 0 0 0 VH7 1 0 1
Symptomatic Waldenstrom’s Macroglobulinemia (WM) in Young Patients: Disease Characteristics and Outcome.
Authors: Kastritis Efstathios , Eleftherakis-Papaiakovou Evangelos , Migkou Magdalini , Gika Dimitra , Terpos Evangelos , Zervas Konstantinos , Kyrtsonis Marie Christine , Anagnostopoulos Nicolaos , Delimpassi Sossana , Symeonidis Argiris , Dimopoulos Meletios Athanasios 
Published: October 2019

Abstract
Introduction: WM is a disease of the elderly with a median age of 70 years in most series. Advanced age is recognized as an adverse prognostic feature and age > 65 years has been included among the 5 adverse covariates in the recently reported International prognostic Scoring System for WM (Morel et al, ASH 2006). There is little information regarding the incidence of disease features and outcomes after treatment of young patients (≤ 50 years of age) with symptomatic WM.
Patients and methods: Our database includes 220 patients with previously untreated, symptomatic WM. These patients were separated in two groups according to age ≤ 50 years and >50 years at the time of initiation of treatment. Clinical and laboratory characteristics, response to treatment, overall survival (OS) and disease-specific survival (DSS) were compared among the two groups.
Results: Twenty-two patients (10%) were ≤ 50 years of age at the time of initiation of treatment. The incidence of clinical and laboratory features was similar among young and older patients: gender (p=0.3), B-symptoms (p=0.3), splenomegaly (p=0.9), lymphadenopathy (p=0.1), anemia (p=0.3), median serum IgM level (p=0.6), hyperviscosity syndrome (p=0.7), elevated β2-microglobulin (p=0.3) and IgM related disorders (p=0.6). primary treatment consisted of chlorambucil, nucleoside analogs or rituximab-based regimens with equal distribution among young and older patients. At least partial response was observed in 73% of young patients and in 57% of older patients (p=0.16). The median OS was not reached in young patients and it was 106 months in older patients (p=0.07). The median DSS was not reached in young patients and it was 116 months in older patients (p=0.2).
Conclusion: 10% of patients with WM are ≤50 years at the time of treatment initiation. Their clinical and laboratory features and response to treatment are similar to those of older patients. Overall survival tend to be longer in young patients, but when deaths unrelated to WM or complications of treatment are excluded, survival times among young and older patients are similar.
An Open-Label Study of Pegylated Liposomal Doxorubicin, Vincristine and Reduced-Dose Dexamethasone Combination Therapy in Newly Diagnosed Multiple Myeloma Patients in Chinese Population.
Authors: Shen Yang , Shen Zhixiang , Jiang Bin , Hou Jian , Zhan Rong , Qiu Lugui , Wu Yongji , Jin Jie , Li Juan , Meng Fanyi , Zou Ping , Liu Ting , Li Jianyong , Wang Chun , Wu Depai , Ma Jun 
Published: October 2019

Abstract
BACKGROUND: Pegylated liposomal doxorubicin (CAELYX®) is a liposomal formulation of doxorubicin sterically stabilized by the grafting of segments of polyethylene glycol (PEG) onto the liposomal surface. Given the demonstrated efficacy of VAD (vincristine and doxorubicin and oral dexamethasone) in Multiple Myeloma (MM) patients and the potential for CAELYX® to extend the duration of bone marrow exposure to therapeutic levels of doxorubicin, a combination regimen of CAELYX®, vincristine, and reduced-dose dexamethasone (DVD) has been actively investigated in MM patients. Studies showed that substituting CAELYX® for doxorubicin in the VAD regimen and reducing the dose of dexamethasone in MM patients improves the safety profile and convenience of the treatment regimen without compromising efficacy. Due to potential differences in metabolism of these patients, safety and efficacy results may vary. Thus, we carried out this study in 82 newly diagnosed MM patients in China, in order to demonstrate the efficacy and safety profiles of DVD.
METHODS: Patients (n=82) from 15 sites were recruited in this study. CAELYX® (40mg/m2) was infused intravenously over 60-minutes, administered every 28 days. Vincristine (2.0mg) was administered intravenously on Day 1 of each cycle. Dexamethasone (40 mg) was administered from Day 1- Day 4 of each cycle orally or intravenously. The treatment was repeated every 28 days for 4 cycles.
RESULTS: Upon ITT analysis, the overall response rate was approximately 68% (56/82); 11% of the patients achieved complete remission (CR), 40% achieved partial response (PR), 17% achieved minimal response; 15% had stable disease (SD), and 12% o had progressive disease (PD) after the treatment. The cumulative 4-month progression-free survival (PFS) was 88%. The incidence of all the adverse events was 46%. The most common non-hematological toxicities were palmar-plantar erythrodysesthesia (13.4%) and stomatitis (6.1%), respectively.
CONCLUSION: Pegylated liposomal doxorubicin, vincristine and reduced dose dexamethasone combination (DVD) regimen is an effective and safe regimen in newly diagnosed multiple myeloma patients in Chinese population.
Rb Intrinsically Promotes Erythropoiesis by Coupling Cell Cycle Exit with Mitochondrial Biogenesis.
Authors: Sankaran Vijay G. , Walkley Carl R. , Spiegelman Bruce M. , Orkin Stuart H. 
Published: October 2019

Abstract
Regulation of the cell cycle is intimately linked to erythroid differentiation, yet how these processes are coupled at the molecular level is not well understood. In order to gain insight into this coordinate regulation, we examined the role that the retinoblastoma gene product (Rb), a central regulator of the cell cycle, plays in erythropoiesis. A conditional (floxed) Rb gene was specifically deleted in the erythroid compartment by means of EpoR-GFPcre, or in other hematopoietic compartments (with LysM-Cre and Mx1-Cre) in mice. We found that Rb serves a cell-type intrinsic and autonomous role in erythropoiesis. Deletion of Rb in the erythroid compartment results in an anemia due to ineffective erythropoiesis. A partial block in differentiation occurs at the transition from early to late erythroblasts. Unexpectedly, we found that in addition to a failure to properly exit the cell cycle, mitochondrial biogenesis fails to be upregulated at this transition point. The disturbance in mitochondrial activities was established through gene expression analysis, measures of respiratory function, as well as measurements of mtDNA content in sorted cell populations. The failure to upregulate mitochondrial biogenesis appears to contribute to the block in differentiation. The link between erythroid differentiation and mitochondrial function was validated by chemical inhibition of mitochondrial biogenesis and knockdown of the mitochondrial transcriptional coactivator PGC-1beta in cultured erythroid cells. The ineffective erythropoiesis seen in erythroid cells lacking Rb closely resembles the features of the refractory anemia seen in the context of the myelodysplastic syndromes (MDS). Prior work has demonstrated the presence of defects in cell cycle regulation as well as mitochondrial function in MDS. Our work demonstrates how these seemingly disparate pathways may play a role in coordinately regulating cellular differentiation.
Results of a Prospective Phase II Trial of Limited and Extended Rituximab Treatment in Nodular Lymphocyte Predominant Hodgkin’s Disease (NLPHD).
Authors: Horning Sandra J. , Bartlett Nancy L. , Breslin Sheila , Advani Ranjana H. , Hoppe Richard T. , Ekstrand Bradley C. , Lucas Jennifer B. 
Published: October 2019

Abstract
Background: NLPHD represents a unique clinical entity characterized by limited peripheral nodal disease, an indolent behavior with a frequent relapse pattern following radiotherapy or chemotherapy, and late treatment-related effects. Distinct from classical HD, the malignant cells of NLPHD are universally CD20+ and we therefore postulated that rituximab may have activity with fewer adverse effects.
Methods: In this prospective phase II trial, patients (pt) with untreated or relapsed CD20+ NLPHD and measurable disease were eligible to receive four weekly doses of rituximab at 375 mg/m2. Restaging studies after completion of all treatment were performed at 1, 3 and 6 months (mo), and every 6 mo thereafter to progression. Endpoints were estimated response rate, freedom from progression (FFP) and safety. We previously reported that FFP was less than 1 year despite the fact that all patients responded to a limited, weekly × 4 treatment (Ekstrand et al. Blood101:4285, 2003). The protocol was then modified to repeat 4 weekly 375 mg/m2 doses at 6 mo intervals for 2 yr. One patient received an extended rituximab course after progression on the limited course.
Results: Pt received limited (n=23, 12 previously untreated) or extended (n=16, 9 previously untreated) rituximab. Median age at treatment was 44 yr (17–71) with 26 males. Among 21 previously untreated pt, stages were I (6), II (8), or III (7). Median follow-up is 60 months (mo) for all pt, 72 mo for limited and 30 mo for extended treatment pt. Treatment-related adverse events were minimal and no grade 3 or 4 toxicities were reported. All but 1 pt responded (OR 97%) with CR/CRu in 27 (69%), and PR in 11 (28%) and SD in 1 (3%). CR/CRu was achieved in 56% limited and 88% extended rituximab pt (p=0.08). No difference was observed in previously treated v untreated pt. To date, 17 progressions (15 limited, 2 extended rituximab) have been recorded. Median FFP was 24 mo for limited and not reached for extended rituximab (p=0.03). FFP at 30 months was estimated at 52% for limited rituximab and 88% for extended rituximab pt. Four pt transformed to large cell lymphoma (one after multiple relapse treatments). Three deaths occurred, one each due to colon cancer, acute leukemia (pt heavily pre-treated with radiation and MOPP), and large cell lymphoma. For all 38 pt, median follow-up from diagnosis is 7.5 yr (range (<1–38) and survival from diagnosis is estimated at 97% at 10 yr and 85% at 20 yr.
Conclusions: Rituximab is an effective treatment in de novo or recurrent NLPHD that may be associated with fewer adverse effects than conventional therapy. FFP is prolonged with an extended treatment but additional follow-up is needed to better assess the duration of benefit.