bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multikinase Inhibition by Sorafenib in B and T NHL Cell Lines: Increasing Cytostatic Efficacy after Prolonged Exposure
Authors: Chapuy Bjoern , Schuelper Nikolai , Kaehler Elisabeth , Truemper Lorenz H. , Wulf Gerald 
Published: April 2020

Abstract
Introduction: A substantial fraction of patients with relapsed or primarily refractory Non Hodgkin Lymphoma (NHL) can still not be cured with current chemotherapy regimens. Therefore, we evaluated the efficacy of tyrosinkinase inhibition by sorafenib against NHL cells in vitro.
Methods: Phosphorylation of RAF/MEK/ERK pathway members as well as of PDGF and VEGF receptors was analyzed by western blot with phospho-antibodies in a panel of cell lines, i.e. aggressive B-NHL (Balm3, Karpas422, Raji, Ramos, SuDHL4), mantle cell lymphoma (Granta, Jeko, Mino), and T cell lymphoma (CEM, HPB-ALL, Jurkat, Molt4). Cell viability under sorafenib exposure was tested by tetrazolium-based (MTT) assays and the proapoptotic and antiproliferative mechanisms were evaluated by annexin V and cell cycle assays, respectively. Clonogenic potential after long-term (10 days) exposure to sorafenib was analyzed by colony formation in inhibitor-free semisolid media.
Results: Sorafenib reduced cell viability at clinically relevant concentrations with IC50 between 3.7 and 10.9 μM in seven cell lines, whereas four cell lines (Balm3, CEM, HPB-ALL, Granta) were less susceptible requiring IC50 of &gt;15 μM. Most sensitive were the diffuse large B cell lines, SUDHL4 and Karpas422, and the Burkitt cell lines, Ramos and Raji. Induction of apoptotic death through an annexin V positive intermediate was documented in the responding cell lines (range 20–90% at 10.9 μM) after short-term exposure (24 through 72 h). After prolonged exposure (&gt;10 days), apoptosis increased significantly, with proportions of annexin V positive cells at 7.3 μM above 75% in all cell lines except Jeko (39% ± 1.2%). In the remaining cells, we found cell cycle arrest to occur, leading to a complete loss of in vitro clonogenicity after cessation of sorafenib exposure in all cell lines (7.3 μM). Activation of the RAF/MEK/ERK-pathway was inhibited to variable degrees in all cell lines. Intensity of RAF and ERK phosphorylation inhibition alone, however, did not predict susceptibility to sorafenib after short-term exposure, suggesting a heterogeneous and time-dependent pattern of sorafenib targets to be involved.
Conclusions: Sorafenib has significant in vitro efficacy against B and T cell lymphoma cells, especially after prolonged exposure.
ITF2357, a Novel Histone-Deacetylase Inhibitor, Is Effective against Peripheral T-Cell Lymphomas in Vivo
Authors: Piccaluga Pier Paolo , Rossi Maura , Esposito Aurora , Tazzari Pier Luigi , Ricci Francesca , Nicoletti Giordano , Landuzzi Lorena , Fanti Stefano , Ambrosini Valentina , Leoni Flavio , Mascagni Paolo , Gazzola Anna , Lollini Pier Luigi , Zinzani Pier Luigi , Pileri Stefano A. 
Published: April 2020

Abstract
Background. Recently, gene expression profiling (GEP) indicated histone-deacetylases (HDAC) as potential therapeutic targets in peripheral T-cell lymphomas (PTCL) not otherwise specified (NOS), the commonest PTCL type. Consistently, phase II trials demonstrated the efficacy of some HDAC inhibitors (HDACi), including SAHA, which was approved for cutaneous T-cell lymphomas (CTCL) treatment.
Aims and methods. We investigated the anti-tumour effects of ITF2357 (Italfarmaco, Italy), a novel hydroxamic acid HDACi, on PTCL primarily-cultured cells and cell lines (HH and FEDP), and in a xenografted mouse-model of CTCL.
Cultured cells were incubated with different dosages of ITF2357 and SAHA (ranging from 0.5 to 2.5 mM). Cell viability, assessed by trypan-blue exclusion assay, cell-cycle progression, assessed by bromodeossiuridine assay, and apoptotic rate, determined by flow-cytometry analysis of annexin-V binding populations were determined at 48, 72 and 120 hours. Nude mice, injected with HH cells, received ITF2357 (10–20mg/Kg, per os) for 14 days. Micro-PET scan was adopted for disease measurement and treatment response evaluation. Finally, GEP of cell lines exposed to ITF2357 and SAHA were generated to elucidate their mechanisms of action.
Results. Cell viability of HH cells treated with ITF2357 ranged from 50% (0.5 mM, at 48 h), to &lt;10% (0.5–2.5 mM, at 72–120 h), in comparison to untreated cells. Differently, cell viability of HH cells treated with SAHA ranged from 80% (0.5 mM, at 48–120 h) to 25% (2.5 mM at 48 h). Analogue effects were documented in FEDP and primarilycultured PTCL cells. Conversely, viability of normal T-lymphocyte was not significantly affected. Interestingly, exposure to ITF2357 was associated to G0/G1 cell-cycle arrest and apoptosis induction. Finally, ITF2357 determined significant reduction of tumoral masses and survival benefit in a xenografted mice-model inoculated with HH cells.
Conclusion. Taken together, these data demonstrate that ITF2357 is effective against PTCLs ex vivo and in vivo, by nominating it for clinical evaluation in this setting.
Simvastatin Sensitizes Bcl-2-Negative DLBCL Cell Lines to CHOP: A Finding with Possible Clinical Implications for Treatment of Bcl-2-Negative DLBCL?
Authors: Ageberg Malin , Linderoth Johan , Lindén Ola , Jerkeman Mats , Drott Kristina 
Published: April 2020

AbstractIt has previously been shown that addition of rituximab overcomes bcl-2-associated resistance to CHOP in DLBCL patients (Mounier 2003). However, the role of rituximab in the treatment of bcl-2 negative DLBCL is presently unclear. To better understand the molecular mechanisms for CHOP-resistance, the DLBCL cell lines Karpas 422, ULA, WSU-NHL, SU-DHL-8 and SU-DHL-5 were characterised with regard to CHOP- and rituximab-sensitivity. As compared to the other cell lines, Karpas 422 and ULA were CHOP-refractory and WSU-NHL showed an intermediate response to CHOP-treatment. However, SU-DHL-8 and SU-DHL-5 were sensitive to low levels of CHOP. Interestingly, the response to rituximab did not correspond to CHOP-sensitivity, as CHOP-refractory ULA were sensitive to rituximab alone while CHOP-sensitive SU-DHL-8 were refractory. Moreover, when assayed for expression of bcl-2 protein by western blot, SU-DHL-8 and SU-DHL-5 showed a low or undetectable expression while Karpas 422, ULA and WSU-NHL expressed high levels of bcl-2 protein. Hence, low levels of bcl-2 correlated to CHOP-sensitivity and with rituximab-resistance, consistent with results from clinical studies. The HMG-CoA reductase inhibitor simvastatin can induce apoptosis of Hodgkin lymphoma and myeloma cell lines, and statin use was associated with reduction in lymphoma risk in the international case-control study EPILYMPH (Fortuny 2006). Yet, statins have been shown to impair the antitumour effects of rituximab by inducing conformational changes of CD20 (Winiarska 2008), questioning the concomitant use of statins and rituximab. To evaluate the effect of simvastatin on the cell death of bcl-2-expressing and –non-expressing cell lines, ULA, SU-DHL-8 and Karpas 422 were incubated with increasing levels of simvastatin. Interestingly, already at levels as low as 2 μM (corresponding to a daily intake of 10 mg simvastatin), bcl-2-negative SU-DHL-8 cells showed signs of increased cell death. However, bcl-2 expressing ULA and Karpas 422 cells were resistant to levels of simvastatin as high as 50 μM. Moreover, low levels of simvastatin sensitized SU-DHL-8 cells to CHOP treatment. Taken together, our results may suggest that replacement of rituximab with simvastatin during CHOP-treatment of bcl-2 negative DLBCL could improve treatment responses. However, further studies are warranted to bring this notion to clinical reality.
Inhibition Effects of baicalin on Lymphoma Cell Line CA46 in Vitro and in Vivo
Authors: Hu Jian Da , Huang Yi , Chen Yingyu , Wei Tiannan , Liu Tingbo , Lv Lianhuang 
Published: April 2020

Abstract
Baicalin is a traditional Chinese medicine with multiple biological effects. Some researches showed baicalin has anti-tumor effects in solid tumor, such as prostate cancer. In order to investigate its effects on proliferation inhibition and apoptosis induction in human lymphoma cell, we treated Burkitt lymphoma cell line CA46 with baicalin in vitro and in vivo of CA46 xenograft. Baicalin remarkably inhibited the cell proliferation, with an IC50 value of 10μM. Apoptosis was remarkably induced by baicalin in a dose-dependent manner, which was detected by Annexin V FITC/PI double staining analysis, TUNEL labeling method and DNA fragmentation respectively. Furthermore, RT-PCR showed that the mRNA expressions of c-myc and bcl-2 in treated CA46 cell decreased in a time-dependent manner. Western-Blot showed that the protein expressions of c-myc, bcl-2, procaspase-3 and PARP(116KD) in baicalin treated CA46 cell were down-regulated, while the expression of PARP(85KD) increased. Based on the results in vitro, we investigated in vivo efficacy of baicalin, alone or in combination with cytotoxic drug VP16, for treatment in CA46 nude mice xenograft. Baicalin with the dosage of 40mg/kg/d and 80kg/mg/d could remarkably inhibit the growth of the tumor compared with control group. Combination of baicalin and VP16 had better anti-tumor effects. Histological examination of tumor samples showed more necrotic cells in treated groups. And obvious apoptosis could be observed by electron microscope. No adverse events were found in treated groups. From above we could conclude that baicalin could efficiently induce proliferation inhibition and apoptosis of CA46 cells in vitro and in vivo, which may be related with the down-regulation of c-myc and bcl-2 expressions, as well as the up-regulation of caspase-3 activity.
Molecular Biological Mechanisms of Cyclosporine a, Tetrandrine and Their Combination on the Reversion of Multidrug Resistance in Leukemia Cell Line
Authors: Chen Bao-An , Guo Jing-jing , 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 Previous researches confirmed that multidrugresistance(MDR) plays an important role in the failure of chemotherapy on malignant tumors. This study was to investigate the molecular biological mechanisms of cyclosporine A(CsA), tetrandrine(Tet) and their combination on multidrug resistance cell line K562/A02.
Methods K562/A02 cells were treated with cyclosporine A and (or) tetrandrine. The intracellular DNR concentration and the expression of P-glyco-protein (P-gp) were observed by flow cytometry (FCM) assay. The mRNA expression of mdr-1 was measured by fluorescent semi-quantitative reverse transcriptase polymerase chain reaction(RT-PCR).
Resulds CsA and Tet (alone or combination) elevated the intracellular DNR concentration in K562/A02 cells(the fluorescence intensity of intracellelar DNR in K562/A02 cells was 60%,65% and 98% respectively of that in K562 cells); The fluorescence intensity of P-gp in K562 and K562/A02 cells was 0.5% and 97.97%. The P-gp expression was down after treated with CsA,Tet and both(75.32%,76.86% and 48.61%); mdr1 mRNA was also down regulated, and the effect of their combination was greater.
Conclusion Multidrug resistance (MDR) can be partially reversed by CsA or Tet, the combination of both drugs shows a great synergistic reversal effect.
Five New Pedigrees with Inherited RUNX1 Mutations Causing Familial Platelet Disorder with Propensity to Myeloid Malignancy (FPD/AML)
Authors: Owen Carolyn J , Toze Cynthia L , Koochin Anna , Forrest Donna L. , Smith Clayton A. , Jackson Shannon C , Poon Man-Chiu , Sinclair Gary D. , Leber Brian , Johnson Peter , Macheta Anthony , Yin John AL , Barnett Michael J. , Lister T. Andrew , Fitzgibbon Jude 
Published: April 2020

Abstract
Familial platelet disorder with propensity to myeloid malignancy (FPD/AML) is an autosomal dominant syndrome characterised by platelet abnormalities and a predisposition to myelodysplasia (MDS) and/or acute myeloid leukemia (AML). The disorder, caused by inherited mutations in RUNX1, is uncommon with only 14 pedigrees reported. We screened 10 families with a history of more than one first- degree relative with MDS/AML and detected inherited mutations in RUNX1 in 5 of these pedigrees. Several affected members had normal platelet counts or platelet function, features not previously reported in FPD/AML. The median incidence of MDS/AML among carriers of RUNX1 mutation was 35%. Individual treatments varied but included hematopoietic stem cell transplantation (HSCT) from siblings before recognition of the inherited leukemogenic mutation. Transplantation was associated with a high incidence of complications including early relapse, failure of engraftment and post-transplantation lymphoproliferative disorder. As acquired trisomy 13 and 21 and FLT3-ITD have all been associated with RUNX1 mutation in sporadic MDS/AML, a combination of single nucleotide polymorphism profiling and mutation analysis was performed to determine whether these secondary genetic events were implicated in the onset of overt malignancy in FPD/AML. Five disease (MDS and/or AML) samples from 4 of our pedigrees with FPD/AML were screened and in all cases, these abnormalities were excluded. Therefore, the secondary mutations that promote MDS/AML in individuals with germline RUNX1 mutations are distinct from those reported in sporadic cases and require further investigation. The small size of modern families and the clinical heterogeneity of the FPD/AML syndrome may have resulted in the diagnosis being previously overlooked. Based on our data, FPD/AML may be more prevalent than previously recognized and therefore, it would appear prudent to screen young patients with MDS/AML for RUNX1 mutation, particularly prior to consideration of sibling HSCT.
Proposal of a New Prognostic Scoring System for Myelodysplastic Syndromes (MDS) Based on the Immunophenotypic Features of CD34+ Myeloid Precursors
Authors: Sandes Alex Freire , Orfao Alberto , López Antonio , Chauffaille Maria de Lourdes L.F. , Oguro Tsutomu , Flores Juan , Matarraz Sergio , Kimura Eliza YS , Silva Marçal CA , Yamamoto Mihoko 
Published: April 2020

Abstract
Introduction. Myelodysplastic Syndromes (MDS) are hemopoietic clonal disorders characterized by a heterogeneous clinical course, which is currently predicted on the basis of clinical, morphologic and cytogenetic data. Only a few reports have studied the impact of flow cytometry immunophenotypic data on the prognosis of the disease.
Objectives: To evaluate the immunophenotypic characteristics of CD34+ myeloid precursor cells in MDS and their association with the prognosis of the disease.
Material & Methods: Overall, 39 patients with MDS - 8 with refractory anemia (RA), 9 RA with ringed sideroblasts (RARS), 12 refractory cytopenias with multilineage dysplasia (RCMD), 2 RA with excess of blasts (RAEB)-1, 5 RAEB-2, 2 with 5q- Syndrome and one unclassifiable MDS - were studied. Bone marrow cells were stained with an extensive panel of MoAbs.
Results: the most frequent phenotypic abnormalities on CD34+ myeloid cells were: CD7+ (36%), CD25+ (33%) and CD56+ (15%) followed by overexpression of CD13 and/or CD33 (33%). Abnormal expression of CD7, CD25, CD13 and CD33 were evenly distributed within the WHO and IPSS subgroups of the disease, although CD56 expression was more frequently detected in low risk IPSS cases. From the prognostic point of view, patients that showed altered expression of CD25, CD56 and CD33 had a shorter median overall survival (OS): 30 vs 109 months (p = 0.0003), 19 vs 102 months (p=0.009), and 21 vs 102 months (p=0.009), for CD25, CD56 and CD33, respectively. Reactivity for CD7 and overexpression of CD13 did not influence OS. A phenotypic score was built where a score of 1 was given to abnormal CD25, CD56 or CD33 expression. Significantly different median OS rates (p&lt;0.04) were found for cases with a score of 0 (101±11 months), 1 (47 ±6 months) and &gt;1 (15 ± 5 months).
Discussion: Our results show that flow cytometry immunophenotyping of CD34+ myeloid precursors provides clinically useful information for the prognostic stratification of MDS patients. Further studies including larger number of patients with a longer follow-up are necessary to confirm these results.
Impact of Age on Transfusion Independence Response, Survival, and Transformation to Acute Myeloid Leukemia in Patients with Deletion 5q: A Sub-Analysis of the MDS-003 Study
Authors: Battiwalla Minoo , Fu Tommy , Knight Robert D. , List Alan F. 
Published: April 2020

Abstract
Introduction: Recent data have demonstrated that lenalidomide reduced transfusion requirements and reversed cytologic and cytogenetic abnormalities in patients who have myelodysplastic syndrome (MDS) with the chromosome 5q31 deletion (List et al NEJM 2006). Previous studies have demonstrated that age may impact on survival rates in cancer patients, but the impact of age on patients treated with lenalidomide for deletion 5q [del(5q)] MDS has not been investigated. This sub-analysis investigated the impact of age on transfusion independence (TI) response, survival, transformation to acute myeloid leukemia (AML), and cytopenias in patients with deletion 5q who were treated with lenalidomide.
Methods: Transfusion-dependent, Low/Int-1-risk patients with primary MDS and del(5q) with/without additional cytogenetic abnormalities were treated with lenalidomide 10 mg daily or for 21 days every 28 days. Patients were treated until disease progression, treatment failure, or treatment-limiting adverse events. For this analysis, patients were subdivided into two categories: ≤75 and &gt;75 years of age. The relationship between age and TI response, survival, progression to AML, and cytopenias were analyzed.
Results: A total of 148 patients were included in the study: 103 patients aged ≤75 years and 45 patients aged &gt;75 years (Table). The TI response was 68% for patients aged ≤75 years and 60% for patients aged &gt;75 years (P=0.35). As expected, median survival was shorter for older patients (P=0.01). There was no difference in the progression to AML with 22% progressing for patients aged ≤75 years and 16% for patients aged &gt;75 years (P=0.65). Cytopenias were reported in 84% and 76% of patients aged ≤75 and &gt;75 years, respectively (p=0.42).
Conclusion: Patients aged &gt;75 years had a similar TI response to patients aged ≤75 years of age. Survival was shorter as is to be expected in an older age group with a lower average life expectancy. There was no difference in the rate of progression to AML when compared with patients aged ≤75 years. The rates of cytopenias were not influenced by patient age.
≤75 years (n = 103) &gt;75 years (n = 45) P CI, confidence interval; NA, not yet reached. TI response, n/N (%) 70/103 (68) 27/45 (60) 0.35 Median survival, years (95% CI) NA (3.186–NA) 2.52 (2.13–3.09) 0.01 AML progression, n/N (%) 23/103 (22) 7/45 (16) 0.65 Cytopenias, n/N (%) 87/103 (84) 34/45 (76) 0.42
Activity of Azacitidine (AZA) in Chronic Myelomonocytic Leukemeia (CMML)
Authors: Abdulhaq Haifaa , Haq Bushra , Rossetti James M. , Shadduck Richard K. , Sahovic Entezam , Christianson Dijana , Lister John 
Published: April 2020

Abstract
Background: CMML is a distinct clinicopathologic entity recognized by the World Health Organization (WHO). Treatment of CMML by AZA was approved by the US Food and Drug Administration on the basis of a phase III randomized trial conducted by the Cancer and Leukemia Group B, for the treatment of myelodysplastic syndromes (MDS). Only 14 patients with CMML were included in the pivotal trial.
Methods: We retrospectively reviewed our institutional experience of CMML treatment with AZA. 39 patients were treated between May 1996 and January 2006. AZA was given at 75 mg/m2 subcutaneously daily for seven days every 4 weeks or 100 mg/m2 daily for 5 days every 4 weeks. Patients who received at least 2 cycles of therapy were considered evaluable for response (N=34). All patients were evaluated for toxicity. The modified International Working Group standardized response criteria for MDS were used for evaluation. The response to AZA, duration of response, tolerability and survival are presented.
Results: Patients had a median age of 68.5 years (range: 46–83); male: female ratio was 4.5:1. 28 patients (72%) had a WBC &gt;12,000/μl (myeloproliferative form of CMML). 6 patients had 20–30% blasts in their bone marrow. The International Prognostic Scores were as follows: Low (N=3), Intermediate-1 (N=13), Internediate-2 (N=14), High (N=7), unknown in 2 patients (due to lack of aspirate particles in one and cytogenetics in the other). CMML was secondary to chemotherapy/radiotherapy in 5 patients. Overall response was seen in 14 patients (41%): 5 patients (15%) had a complete response (CR), 9 patients (26%) had hematologic improvement. Mean duration of response was 16.2 months (range: 3–50+); 2 patients are still alive and being treated with CR for &gt;50 months. Average number of cycles to respond was 2.4 cycles (range: 1–6). Splenomegaly was present in 8 patients (20%). Treatment resulted in normalization of spleen size in 1 patient, decrease in 3 patients and no effect in 4 patients. Mean overall survival was 13.2 months (range 1–72). Average survival in responders was 23.5 months (5–72) while average survival in non-responders was 7.48 months (&lt;1–23). Treatment was well tolerated. The most common non-hematological toxicities were nausea and fever.
Conclusions: AZA appears to be effective and well tolerated in CMML.