bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cytosolic Histone H1 Releasing under Different Apoptotic Stimuli in Chronic Lymphocytic Leukemia (CLL).
Authors: Gine Eva , Crespo Marta , Montserrat Emili , Bosch Francesc 
Published: April 2020

Abstract
Recently, it has been demonstrated that nuclear histone H1 could be released into cytoplasm when apoptosis is induced by DNA double-strand breaks, this process being dependent of p53 functional status. In addition, cytosolic histone H1.2 was shown to induce cytochrome C release in a Bak-dependent manner. The aims of this study were: 1) to analyze the presence of histone H1.2 in the cytosol of peripheral blood purified CLL cells during apoptosis induced by different chemotherapeutic drugs or ionizing radiation in CLL cells in culture; 2) to correlate the presence of cytosolic histone H1 with the p53 functional status. FISH analysis was used to select samples with (n=2) or without (n=4) p53 deletion. Peripheral blood purified CLL cells were cultured for 24 hours with no treatment, after irradiation (25 Gy), in the presence of fludarabine and mitoxantrone (FM) (1mg/ml and 0.5 mg/ml respectively), or with etoposide (5.8 mg/ml). Cell viability and analysis of apoptosis were performed by annexin V/PI staining and FACscan analysis. Cytosolic and nuclear fractions were separated with the Nuclear/Cytosol Fractionation kit (Biovision). The presence of histone H1 in the cytosolic fraction was assessed by Western Blott using the anti-histone H1 antibody (Upstate). Nuclear contamination of this fraction was detected by using anti-ribonucleoprotein (hnRNP) antibody (Abcam). In p53 wild-type CLL cases, increased apoptosis was observed under all stimuli, being the FM combination the most effective. In contrast, CLL cases with p53 deletion displayed a lower or no response to the different treatments. In p53 wild-type CLL cases, histone H1 was only observed in cytosolic fractions at 24 hours when irradiation or etoposide treatment was applied, but not with FM treatment. Interestingly, cytosolic histone H1 was also present in the control cells at 24h of culture, indicating that H1 was also involved in the spontaneous apoptosis observed due to the microambient deprivation of CLL cells in culture. This histone H1 traffic was also confirmed using immunofluorescence analysis. Conversely, in p53 deleted CLL cases histone H1 was not detected into cytosolic fractions with any treatment. In conclusion, cytosolic histone H1 appeared in CLL cases in a p53 dependent manner when DNA double-strand breaks were induced. These results suggest that histone H1 plays an important role in the p53-dependent cytosol apoptotic signaling.
Expression of Cannabinoid Receptors on the Neoplastic Lymphocytes in Patients with Chronic Lymphocytic Leukemia.
Authors: Piszcz Jaroslaw A. , Pietruczuk Miroslawa , Kloczko Janusz S. , Dabrowska Milena , Galar Marzenna , Milewski Marek P. 
Published: April 2020

Abstract
Endocannabinoids take part in the physiology of neural and immune systems. The latest data showed that these compounds and their receptors play an important role in proliferation and apoptosis of various neoplastic cells. Cannabinoids were shown to increase apoptosis in human leukemia and lymphoma cell lines and culture of neoplastic cells obtained from patients with T-cell acute lymphoblastic leukemia. The aim of the study was an assessment of cannabinoid receptors expression on lymphocytes B derived from patients with CLL. The study group contains newly diagnosed, untreated adult patients with B-cell chronic lymphocytic leukemia; 13 male and 7 female, aged from 44 to 65. All of the patients were in B or C stage according to Binet. Peripheral blood samples from 10 healthy adult donors were used as the control group. The patients were hospitalized in the Department of Haematology, Medical University in Bialystok, Poland. Diagnosis of CLL in all cases was confirmed by routine immunophenotyping study. For flow cytometric analysis 1x105 – 1x106 of peripheral blood cells were incubated with 10ul of anty CB1 and anty CB2 polyclonal antibodies (American Diagnostics). Then 10ul of monoclonal antibodies IgG1-FITC and CD19-PE (Becton Dickinson) were added and the samples were incubated for 20 min in dark in 4°C. The samples were lysed, fixed and stabilized using Immuno-Prep (Coulter procedure) and assessed by flaw cytometry (Epics XL, Coulter). Statistical analysis was performed using non parametric U Mann-Whitney and Wilcoxon Tests. The conducted study revealed high expression of CB1 and CB2 receptors on the surface of neoplastic lymphocytes. The percentage of CB1/CD19 and CB2/CD19 positive cells in CLL patients were significantly higher, compared to the control group respectively (81.2±9,8% vs 12.0±9,3% p&lt;0,05; 94,8±11,0 % vs 9,9±4,0%, p&lt;0,05). No difference was noticed between the percentage of lymphocytes with CB1 and CB2 receptors expression in CLL and control group. Fluorescent intensity of CB2 receptors was about ten folds higher than CB1 receptors in both groups. The study demonstrated the presence of both types of cannabinoid receptors (CB1 and CB2) on neoplastic cells derived from patients with chronic lymphocytic leukemia. The higher percentage of B-lymphocytes expressing cannabinoid receptors in CLL patient suggests that the cannabinoid system may take part in CLL development. High intensity of CB2 receptor may be another target in CLL treatment.
Chronic Lymphocytic Leukemia Cells May Become Less Dependent on Nurse-Like Cells during Later Stages of Disease.
Authors: Endo Tomoyuki , Nishio Mitsufumi , Rassenti Laura , Kater Arnon P. , Kipps Thomas J. 
Published: April 2020

Abstract
A subset of blood mononuclear cells from patients with B-cell chronic lymphocytic leukemia (CLL) can differentiate into large, adherent cells, termed “nurse-like cells” (NLC), that can attract CLL cells and protect them from undergoing apoptosis in vitro. When removed from NLC in vitro, CLL cells often undergo spontaneous apoptosis. We observed that the relative viability of isolated CLL cells cultured without versus with NLC appeared constant for any one sample in different experiments and did not vary with the source of the NLC used in any one experiment. Furthermore, the isolated CLL cells from some patients could survive in vitro without NLC better than could the leukemia cells of other patients. We examined for characteristics associated with CLL cells that were more or less reliant on NLC for survival in vitro. For this, we defined CLL cell populations as having “low dependency” on NLC when the relative leukemia cell viability after two days culture without NLC was less than one half-log (33%) lower than that of the same CLL cells co-cultured with NLC. Using a Multiplex Ligation-dependent Probe Amplification (MLPA) assay, we examined CLL cell populations with low dependency (n = 4) versus samples with high dependency (n = 5) for expression of 40 distinct mRNA that encoded known pro-apoptotic or anti-apoptotic proteins. CLL cells with low dependency expressed significantly higher levels of BCL-2, and significantly lower levels of BAX-2 than CLL cells with high NLC dependency. There was no significant difference between the mean white blood cell counts of patients whose CLL cells had low-dependency versus those whose cells had high dependency on NLC in vitro. However, in the high dependency group there was a significantly higher proportion of cases that expressed ZAP-70 than in the group with low dependency. This association, however, could reflect the fact that many of the samples with low dependency were acquired from patients who had long-established disease, a characteristic that typically was not associated with patients who have CLL cells that expressed ZAP-70. The mean time from diagnosis to the date of sample collection was significantly longer (m = 66.6 ± 47.0 months, median = 49 months, n=30) for samples with low dependency than it was for those cases with high dependency (m = 41.2 ± 25.1 months, median = 39.5 months, n=20) (p=0.017). Furthermore, evaluation of serial samples collected over years from the same patients (n = 5) revealed that the relative dependency of CLL cells on NLC could decrease significantly over time. In none of the serial samples did we observe increased dependency of the CLL cells on NLC over time or over that observed for the CLL cells isolated from the initial sample collection. These data suggest that over the course of the disease CLL cells might acquire less dependency on NLC, and potentially also on its stromal microenvironment.
CD11b Is Useful in the Diagnosis of Chronic Lymphocytic Leukemia/Prolymphocytic Leukemia, Mixed Chronic Lymphocytic Leukemia, and Prolymphocytic Leukemia.
Authors: Fricke William 
Published: April 2020

Abstract
CD11b is well known as an integrin, Mac-1, is often complexed with CD18, and is found on monocytes, granulocytes, and natural killer cells. It also serves as a receptor for iC3b. However, its occurrence in B cell chronic lymphoproliferative disorders is not generally recognized and has not been fully evaluated. To address this issue, a series of B cell leukemias and lymphomas referred for primary diagnosis was evaluated for the presence of CD11b. The purpose was to determine the frequency of its expression on these tumors and to evaluate its diagnostic value.
Consecutive cases referred for flow cytometry as possible lymphoproliferative disease were analyzed. Included were bone marrow, peripheral blood, and lymph nodes. All cases were diagnosed according to the WHO classification based on immunophenotypic, morphologic, and clinical findings. The morphologic criteria of Melo (1986) and Bennett (1989) were used for classification of chronic lymphocytic leukemia (CLL), CLL/prolymphocytic leukemia (CLL/PLL), mixed CLL, and PLL. Cases identified as not related to chronic lymphocytic leukemia or prolymphocytic leukemia were recorded but not further analyzed. Similarly, lymph node and spleen-based tumors were excluded from the final analysis.
CD11b was present on cells from 32 of 123 cases, including occasional follicular lymphoma, (5/35); mantle cell lymphoma, (1/8); diffuse large B cell lymphoma, (3/9); hairy cell leukemia, (3/5); multiple myeloma, (1/2); lymphoplasmacytic lymphoma, (2/2); nodal marginal zone lymphoma, 0/1); and splenic marginal zone lymphoma, (1/1). However, it was most consistently expressed on CLL that contained increased numbers of prolymphocytes or large cells and on PLL. A total of 16 such cases were found. Morphologic assessment showed them to include 8 CLL/PLL, 3 mixed CLL, 4 PLL, and 1 typical CLL. The typical CLL case included both large cells and prolymphocytes but did not have more than 10% PLs. Five of the 16 cases (31%) were negative for CD5, CD23, and CD38 but were positive for FMC-7. In contrast, the other 11 cases were all CD5(+) and CD23(+); 3/11 were positive for CD38; and 5/11 were positive for FMC-7. Forty-five CLLs also were identified during the study, of which 27 had sufficient data for comparison. Twenty-six of the 27 CLLs were morphologically typical. The remaining case was mixed CLL. All of the CLLs were CD11b(−), CD5(+) and CD23(+); 15/43 were CD38(+), and 6/43 were FMC-7(+).
The findings show that CD11b is expressed on chronic B cell lymphoproliferative disorders. In particular, it is expressed on almost all CLL cases that contain large cells or prolymphocytes and on PLL. Inclusion of CD11b in routine screening panels of possible chronic B cell leukemiaa will improve diagnosis of these disorders.
Leukotriene B4 Plays a Pivotal Role in CD40 Dependent Activation of Chronic B Lymphocytic Leukemia Cells.
Authors: Claesson Hans-Erik , Runarsson Gudmundur , Liu Anquan , Mahshid Yilmaz , Feltenmark Stina , Klein Eva , Bjorkholm Magnus 
Published: April 2020

Abstract
Biosynthesis of leukotrienes occurs in human myeloid cells and B lymphocytes. However, the function of leukotrienes in B lymphocytes is unclear. Here we report that B-cell chronic lymphocytic leukemia (B-CLL) cells produce leukotriene (LT) B4 and that specific leukotriene biosynthesis inhibitors counteracted CD40-dependent activation of B-CLL cells. Studies on the expression of the high affinity receptor for LTB4 (BLT1) by flow cytometry analysis showed that the receptor was expressed, to a varying degree, in all investigated B-CLL clones. The drugs BWA4C (a specific 5-lipoxygenase inhibitor) and MK-886 (a specific 5-lipoxygenase activating protein inhibitor), at a concentration of 100 nM, markedly inhibited CD40-induced DNA synthesis (45% and 38%, respectively) and CD40-induced expression of CD23, CD54 and CD150. Addition of exogenous LTB4 (150 nM) almost completely reversed the effect of the inhibitors on DNA synthesis and antigen expression.
Taken together, the results of the present study suggest that leukotriene biosynthesis inhibitors may have a therapeutic role in B-CLL.
Cytoplasmic PML Function in TGF-β Signaling.
Authors: Lin Hui-Kuan , Bergmann Stephan , Pandolfi Pier Paolo 
Published: April 2020

Abstract
TGF-β is a pluripotent cytokine that controls key tumor suppressive functions such as cell growth inhibition, induction of apoptosis, cellular senescence and differentiation. Cancer cells are often unresponsive to TGF-β. Blasts from several leukemia subtypes including acute promyelocytic leukemia (APL) display resistance to TGF-β-growth inhibitory and differentiating activity. As TGF-β, the PML tumor suppressor of APL is also known to modulate key tumor suppressive functions. PML is found to accumulate in the PML-nuclear body, although cytoplasmic isoforms of unknown function have also been described. The PML-RARα fusion oncoprotein of APL is found to accumulate both in the nucleus and cytoplasm and is thought to act as a dominant negative PML mutant in view of its ability to heterodimerize with PML. Given the functional similarities between PML and TGF-β and their functional loss in APL, we asked whether PML would modulate TGF-β function. Here we show that cytoplasmic Pml is an essential modulator of TGF-β signaling. Pml-null primary cells of diverse histological origins are resistant to TGF-β-dependent growth arrest, induction of cellular senescence and apoptosis. Induction of TGF-β target genes such as p21 and p15, as well as Smad2 and Smad3 phosphorylation and nuclear translocation is also dramatically impaired in the absence of Pml. Cytoplasmic Pml is induced by TGF-β and its add-back to Pml-null cells can fully rescue these biological and biochemical defects. Furthermore, we find that cytoplasmic PML physically interacts with Smad2/3 and SARA (Smad anchor for receptor activation), colocalizes with these proteins in cytosolic regions and is required for association of Smad2/3 with SARA and for the accumulation of SARA and TGF-β receptor in the early endosome. We demonstrate that the PML-RARα oncoprotein of APL can antagonize cytoplasmic PML function and that APL blasts display defects in TGF-β signaling similar to that observed in Pml-null cells, which can be overcome by retinoic acid (RA) and As2O3, drugs that induce PML-RARα degradation and are effective in APL treatment. Our findings identify cytoplasmic PML as a critical TGF-β regulator, and further implicate deregulated TGF-β signaling in cancer pathogenesis.
Pharmacokinetics of Single-Agent Lumiliximab (Anti-CD23 Antibody) in Patients with Chronic Lymphocytic Leukemia.
Authors: Woodworth James , Leigh Bryan R. , O’Brien Susan , Flinn Ian , Kipps Thomas J. , Weiss Mark A. , Rai Kanti , Thall Aron , Wynne Dee , Byrd John C. 
Published: April 2020

Abstract
CD23 is highly expressed on the cell surface of certain B-cell malignancies including chronic lymphocytic leukemia (CLL). Lumiliximab (L-mab), a macaque-human chimeric anti-CD23 antibody, has been reported to have antitumor activity against CLL in preclinical studies. In this 46 patient, Phase I, multicenter study, single-agent L-mab was evaluated as a treatment for patients with relapsed or refractory CLL. Therapy consisted of intravenous L-mab given as 6 regimens: (1) 125 mg/m2/wk for 4 weeks; (2) 250 mg/m2/wk for 4 weeks; (3) 375 mg/m2/wk for 4 weeks; (4) 500 mg/m2/wk for 4 weeks; (5) 500 mg/m2 for 3 doses during Week 1, then 500 mg/m2/wk during Weeks 2 to 4; and (6) 500 mg/m2 three times a week for 4 weeks. Pharmacokinetics (PK) and pharmacodynamic measurements were evaluated in patients with adequate data. L-mab and anti-L-mab antibody concentrations in plasma were measured by ELISA. L-mab coating of CLL cells and CD23 density on CLL cells were evaluated by flow cytometry. The absence of sustained L-mab concentrations did not allow PK calculations at the 125 mg/m2/wk and 250 mg/m2/wk dose levels. Doses at 375 mg/m2/wk or higher resulted in coating of CD23 binding sites on CLL cells and saturable PK (see table). Anti-L-mab antibody formation was not detected. CD23 density on CLL cells did not change during or after L-mab treatment. In summary, L-mab exhibits saturable PK, low clearance, and low volume of distribution without an immunogenic response. No down regulation of CD23 expression was observed on CLL cells in any dose group, and complete coating of CD23 sites was observed.
Median Pharmacokinetic Parameters
Treatment Group n C max(μ g/mL) Clearance (mL/m2/day) Volume of Distribution (mL/m2) Half-life (days) 1 3 39 - - - 2 3 84 - - - 3 8 180 310 3.02 7.9 4 9 245 335 3.22 7.3 5 8 430 406 3.45 5.4 6 9 654 293 3.58 10.6
Thalidomide Is Active Alone and in Combination with Fludarabine in Fludarabine-Relapsed and Refractory Chronic Lymphocytic Leukemia.
Authors: Furman Richard R. , Allen Steven L. , Leonard John P. , Coleman Morton , Markis Jessica M. , Gabrilove Janice L. 
Published: April 2020

Abstract
Background: CLL is a lymphoproliferative disease characterized by an accumulation of malignant lymphocytes due to a defect in apoptosis. CLL lymphocytes demonstrate increased NF-κB activity, which may play a role in mediating resistance to fludarabine. Additionally, several cytokines have been linked to enhanced CLL survival, including TNF-α, bFGF, and VEGF. Given thalidomide’s ability to inhibit these cytokines and NF-κB activity, we investigated whether thalidomide, either alone or in combination with fludarabine, is an effective treatment for pts with CLL previously treated with fludarabine.
Methods: CLL pts requiring therapy as defined by NCI-WG criteria and who were previously treated with fludarabine were eligible. Pts were randomized to receive either thalidomide alone (T) or in combination with fludarabine (FT). Thalidomide was started at a dose of 200 mg qHS and adjusted as tolerated. Pts assigned to FT started thalidomide prior to receiving fludarabine at a dose of 25 mg/m2 each day x 5 days x 6 cycles.
Results: 13 pts have been enrolled, 8 men/5 women, median age=60, (range 48–68), 4 pts refractory to fludarabine, randomized to receive either T (6) or FT (7). The median dose of thalidomide was 200 mg qHS (range 50–450). Of the 10 evaluable pts, there have been 1 CR (FT), 3 PRs (1T, 2FT), and 2 hematologic improvements (1T/1FT). Of interest, 5 pts on T developed tumor flares, characterized by fevers, increased size and tenderness of lymph nodes, increased lymphocyte counts, and decreased hemoglobin and platelet counts. These symptoms resolved with either continued treatment (3 pts) or temporarily discontinuing the thalidomide and re-introducing it at a dose of 50 mg (2 pts). Patients on T demonstrated hematologic improvement (HI) prior to decreases in lymph node size. Figs 1 and 2 illustrate two patients with tumor flares followed by marked HI, but only minimal improvement in LAD. Pt in fig 1 continued on T, while pt in fig 2 had T held for 4 weeks. Overall, therapy was tolerated, with grade 3 toxicities being: neuropathy(2)(requiring T dose reduction), sedation(1), catheter thrombosis(1), febrile neutropenia(1), infection(3), none requiring discontinuation of therapy.
Conclusion: Thalidomide demonstrates activity alone and in combination with fludarabine as treatment for CLL. Further data are required to see if FT can increase the response rate over historical controls for patients who relapse after fludarabine. The addition of F to T appears to ameliorate the development of a tumor flare.
Etodolac Induces Apoptosis and Inhibits Cell Adhesion to Bone Marrow Stromal Cells in Human Myeloma Cells.
Authors: Nakamura Satoki , Kobayashi Miki , Shibata Kiyoshi , Sahara Naohi , Shigeno Kazuyuki , Shinjo Kaori , Naito Kensuke , Ohnishi Kazunori 
Published: April 2020

Abstract
Cyclooxygenase-2 (COX-2) is reported to regulate apoptosis and to be an important cellular target for therapy. In this study, we demonstrated that etodolac, a COX-2 inhibitor, inhibited proliferation and induced apoptosis in myeloma cell lines (RPMI 8226 and MC/CAR cells), expressing the COX-2 enzyme. In both cell lines, etodolac more strongly induced apoptosis compared with thalidomide or meloxicam. Etodolac induced down-regulation of bcl-2 protein and mRNA, activation of caspase-9, -7 and -3, down-regulation of caspase inhibitors, cIAP-1 and survivin, and loss of mitochondrial membrane potential in a dose-dependent manner. In addition, our data demonstrated that when myeloma cells were coincubated with 50 mM etodolac on bone marrow stromal cells (BMSC), myeloma cell adhesion to BMSC was significantly inhibited compared with thalidomide or meloxicam coincubation, and the adhesion molecules VLA-4, LFA-1 (CD11a), CXCX4, and CD44 were suppressed on myeloma cells treated with etodolac. Moreover, we found that 100 mM R-etodolac, S-etodolac, and the combination of R- and S-etodolac, which are the stereoisomers of etodolac, slightly inhibited the proliferation of myeloma cells, while 50 to 100 mM etodolac significantly inhibited the proliferation of myeloma cells. In conclusion, our findings indicate that etodolac induced apoptosis via a bcl-2 dependent pathway, suppressed the expression of adhesion molecules, and inhibited myeloma cell adhesion to BMSC compared with thalidomide or meloxicam. Thus, the activities of etodolac potentially extend to the treatment of patients with myeloma resistant to standard chemotherapy, including thalidomide.
P53 Gene Deletion Detected by Fluorescence In Situ Hybridization Is an Adverse Prognostic Factor for Patients with Multiple Myeloma Following Autologous Stem Cell Transplantation.
Authors: Qi Xiao Ying , Yi Qi Long , Reece Donna , Stewart A. Keith , Chang Hong 
Published: April 2020

Abstract
We investigated the relevance of p53 deletions to the clinical outcome of multiple myeloma (MM) patients treated with high-dose chemotherapy and autologous stem cell transplantation. Hemizygous p53 gene deletions were detected by cytoplasmic Ig-enhanced interphase fluorescence in situ hybridization (cIg-FISH) in 10 of 105 (9.5%) patients studied. p53 deletions were associated with higher serum calcium (p=0.0062) and creatinine (p=0.013) levels but there were no association with patient age, gender, β-2 microglobulin, C-reactive protein, hemoglobin, albumin, bone lytic lesions, or immunoglobulin isotype. There were no association of p53 deletions with chromosome 13q deletions, translocation t(11;14) or t(4;14). The overall response rates were similar in patients with and without p53 deletions (67% vs 71%). However, patients with p53 deletions had significantly shorter progression free (median 7.9 vs. 25.7 months, p=0.0324) and overall survival (median 14.7 vs. 48.1 months, p=0.0008) than patients without a p53 deletion. A multivariate analysis confirmed p53 deletion was an independent prognostic factor predicting shortened progression free (p=0.0009) or overall survival (p=0.0002) in myeloma patients after high-dose chemotherapy and autologous stem cell transplantation.