bluuebunny/crossref_metadata_2025_split huggingface dataset:
Triggered Release of Nanoparticulate Arsenic Trioxide for Treatment of Malignant Lymphomas: Preclinical Studies
Authors: Winter Jane N. , Waterhouse Dawn , Ahn Richard , Chen Haimei , Gordon Leo I. , Jovanovic Borko , Bally Marcel , O’Halloran Thomas 
Published: April 2020

Abstract
Lipid encapsulation of chemotherapeutic agents facilitates local delivery of highly concentrated antineoplastics to tumors while ensuring an adequate duration of drug exposure and reducing systemic toxicity. Using novel technology, we have encapsulated nanoparticulate (100 nM) arsenic trioxide (ATO) at high density in “nanobins,” biocompatible lipids and polymers that undergo a change in permeability when exposed to intracellular conditions, releasing drug cargo into the acidic tumor microenvironment (J. Am. Chem. Soc.2006, 128: 13348-9). At low concentrations, ATO is an effective agent in the treatment of acute promyelocytic leukemia, causing differentiation and turnover of PML. At higher but potentially toxic concentrations, ATO induces programmed cell death through the generation of reactive oxygen species and its effects on other proapoptotic signaling pathways. A preliminary dose-range finding study was completed comparing the toxicity profiles of free ATO and nanobin formulations of arsenic based on loading procedures using either cobalt (Co) or nickel (Ni). Female Balb/c mice were injected intraperitoneally with either a single dose of free or nanobin formulations of ATO at 20, 40, 60, 100 or 200 μmol/kg of elemental As. Mice were assessed daily for the first 5 days after injection and then every second day thereafter for a total study duration of 14 days and monitored for body weight and clinical signs. The maximum tolerated doses for both the Co- and Ni-ATO formulations were approximately 100 – 200 μmol/kg as a single intraperitoneal injection. Efficacy experiments for the Ni-ATO-nanobins were conducted in a murine (RAG2-M) xenograft model in which the mantle cell lymphoma cell line Z138C was injected subcutaneously. On day 21, when the average tumor volume was 50–100 mg, weekly injections of saline, empty nanobins, or the Ni-ATO nanobins at 60 μmol/kg were begun. Cohorts of mice received either two or three weekly injections. Mice bearing tumors of 1000 mm3 or greater were sacrificed. Results were normalized to the tumor size at the time that treatment was initiated (day 21) and are represented as fold-increase in tumor measured with calipers three times weekly. The results of the three weekly injections are illustrated below. Following two injections, the curves began to separate showing a significant inhibition of tumor growth that persists for two weeks beyond the last injection (p &lt; 0.001). Two weekly injections also impacted tumor growth significantly (p &lt; 0.01; data not shown). These results provide rationale for further preclinical investigation of this novel therapeutic.
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Prolonged Bone Marrow Failure Following Rituximab Therapy of Follicular Lymphoma
Authors: Debatin Laura , Veelken Hendrik , Schmitt-Graeff Annette 
Published: April 2020

Abstract
Prolonged Bone Marrow Failure following Rituximab Therapy of Follicular Lymphoma Laura Debatin, Annette Schmitt-Graeff*, Hendrik Veelken Depts. of Hematology/Oncology and *Pathology, University Medical Center Freiburg Rituximab (R) is a mainstay in B-NHL therapy. Apart from infusional reactions and prolonged B cell depletion, severe R side effects are relatively rare. A 65 year-old, previously healthy woman presented with anemia (Hb 9.3 mg/dl), thrombocytopenia, and cervical lymphadenopathy. A submandibular lymph node biopsy showed CD20+CD10+CD79a+ follicular infiltrates. Diagnosis of follicular lymphoma was supported by detection of an IgH-BCL2 gene rearrangement by FISH. CT scans revealed generalized lymphadenopathy and hepatosplenomegaly. The BM was infiltrated with 68% clonal CD20+CD10+CD79a+ B cells. Due to advanced (stage IVA) and high-risk disease (FLIPI 4/5), 200 mg/m2 cyclophosphamide/100 mg prednisone/day (d) were given for 5 days, followed by a single dose of 375 mg/m2 R. Grade 4 neutropenia developed 4 days later and precluded the planned CHOP chemotherapy. A BM biopsy on d+21 post R showed marked BM hypoplasia consistent with drug-induced changes, but no residual lymphoma. Serologic testing ruled out Parvovirus B19, HBV, HCV and HIV infections. Leukocytes recovered to &gt;1/nl 3,5 weeks after R administration. No further cytoreduction was given due to prolonged cytopenia and documented PR. Despite this history, Bendamustin/R (200 mg) was given for eventual BM relapse at a different hospital 11 months later. Grade 4, filgrastim-refractory cytopenia with the same BM histology developed promptly and lasted for 4 weeks. The patient was transferred to our institution because of multiple opportunistic infections including pulmonary aspergillosis, E. faecium sepsis, and destructive mucor mycosis of the right maxillary sinus. Posaconazole and liposomal amphotericin were given for 5 months. 13 months after the 2nd R infusion, the patient had to undergo reconstructive surgery with a flap plasty to cover an extensive, disfiguring facial and maxillary necrosis. Since different alkylators were given at moderate doses, a causal relationship to similar episodes of rapid-onset, extended BM failure appears unlikely. R, administered immediately prior to both episodes, appears to be the causative agent in this case. Since hematopoietic precursors and the myeloid lineage do not express CD20, the mechanism for this near-fatal BM failure is unknown and suggestive of an idiosyncratic component. The BM findings are incompatible with a metamizol-type allergic agranulocytosis. Severe BM failure appears to be a rare but grave potential side-effect of rituximab.
Evaluation of the Pharmacokinetics, Immunogenicity, and Safety of XmAb®2513 in the Ongoing Study XmAb2513-01: A Phase 1 Study of Every Other Week XmAb2513 to Evaluate the Safety, Tolerability, and Pharmacokinetics in Patients with Hodgkin Lymphoma or Anaplastic Large Cell Lymphoma
Authors: Younes Anas , Zalevsky Jonathan , Blum Kristie A. , Smith Mitchell R , Fung Henry C. , Ramies David A , Lawrence Chris E , Combs Daniel , Bloss Jeffrey 
Published: April 2020

Abstract
XmAb2513 is a novel second-generation humanized monoclonal antibody (mAb) directed against the human cell surface antigen CD30, with an Fc region engineered to enhance cell killing activity via recruitment of effector cells through increased binding affinity to Fcγ receptors (FcγRs). The CD30 antigen (Ki-1) is a member of the tumor necrosis factor superfamily and was originally identified as a cell surface antigen on primary and cultured Reed-Sternberg cells of Hodgkin Lymphoma (HL). Expression of CD30 is a hallmark for the identification of HL and a subset of T-cell lymphomas, including Anaplastic Large Cell Lymphoma (ALCL). Preclinical in vitro data demonstrated XmAb2513 to be more potent with regards to antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP) than the first generation anti- CD30 antibodies MDX-060 and SGN-30. Studies in cynomolgus monkeys demonstrated that XmAb2513 exposure was proportional to dose with half-lives (t½) ranging from 5 to 9 days in single dose studies and 12 to 17 days in repeat dose studies. The exposure and t½ data from these cynomolgus monkey studies supported an every other week dosing interval in clinical trials. Based on these favorable features, a Phase 1 study has been initiated to examine the safety and efficacy of XmAb2513 in patients with relapsed and refractory classical HL and ALCL. This ongoing Phase 1 Study is currently evaluating every other week dosing of XmAb2513 using a dose-escalation study design to establish the maximum tolerated dose (MTD). The dose levels under evaluation are 0.3, 1.0, 3.0, 6.0, 9.0, and 12.0 mg/kg, given intravenously over two hours. To date, seven patients are enrolled on the study in the first three dose levels. Pre-study simulation of human exposure based on the pharmacokinetic (PK) parameters obtained from cynomolgus monkeys predicted that 0.3 mg/kg XmAb2513 in humans would result in serum trough levels of 1–1.5 μg/mL after four infusions given every other week. Interim PK and immunogenicity results from the treated patients have been analysed and the results observed thus far are on track with these simulations. Additionally, immunogenicity assessment for human anti-XmAb2513 (HAHA) showed that the treated patients are so far negative for HAHA. Importantly XmAb2513 was well tolerated. As dose escalation continues, results for human PK, immunogenicity, and safety for additional dose cohorts of HL patients, and preliminary safety and response assessment data will be presented.
Experience in Using Hypercvad Combined with Alemtuzumab in Treating Peripheral T-Cell and T/NK-Cell Neoplasms
Authors: Kuan Jew Win , Lau Ngee Siang , Chang Kian Meng , Tan Sen Mui , Ong Tee Chuan , Purushothamaný Visalachy 
Published: April 2020

Abstract
Peripheral T-cell and T/NK-cell neoplasms (T/NK-cell neoplasms) are rare, representing less than 15% of non-Hodgkin lymphoma in the western hemisphere. The optimal therapy for peripheral T-cell and T/NK-cell neoplasms is an area of controversy due to rarity of the diseases, their variable clinical course, and the lack of randomized trials. Fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (hyperCVAD) alternating with high doses of methotrexate and cytarabine has proven to be an effective cytoreductive regimen in patients with aggressive histopathologic variants of mantle cell lymphoma. Alemtuzumab (Campath®) is a humanized monoclonal antibody that targets CD52, a cell surface protein present at high density on most normal and malignant B and T lymphocytes. We report our experience in using six cycles of hyperCVAD in combination with alemtuzumab D1 +/− D4 for the treatment of newly diagnosed peripheral T-cell and T/NK-cell neoplasms in our institution. Seven females and five males diagnosed with peripheral T-cell and T/NK-cell neoplasms (NT and T/NK-cell lymphoma = 5, NT-cell leukemia = 5, NNK-cell leukemia = 2) from 2006 to 2008 were treated with alemtuzumab-hyperCVAD regime. Three patients completed alemtuzumab-hyperCVAD regime and achieved response within four cycles. Among the three patients who completed hyperCVAD regime with only three to five doses of alemtuzumab, two achieved complete response and one had progressive disease. There were six patients who did not complete the alemtuzumabhyperCVAD regime. Three of them stopped at fifth cycle due to cytomegalovisrus (CMV) complication. Two patients died after forth cycle due to neutropenic sepsis although they achieved complete response after two cycles. The other patient did not respond to the treatment, hence discontinued. Both the NK-cell leukemia patients did not respond to the treatment. It was noted that patients with at least one dose of alemtuzumab per hyperCVAD cycle were more likely to survive (62.5%) than the other (25.0%) (95%CI of difference = −0.176 – 0.689). Among the complete respondents, the median disease free duration (from the day achieved response to date or relapse) is 216 days. CMV reactivation occurred in four out of seven patients who received at least five doses of alemtuzumab. In conclusion, alemtuzumab-hyperCVAD seems to be useful in treating peripheral T-cell lymphoma, T/NK-cell lymphoma and T-cell leukemia but not NK-cell leukemia. At least one dose of alemtuzumab per hyperCVAD cycle should be administered to achieve favourable survival. Although CMV complication is common in alemtuzumab-hyperCVAD regime, it does not seem to affect the outcome of the treatment. A proper randomized controlled trial should be conducted to evaluate the effectiveness of alemtuzumab-hyperCVAD in the treatment of peripheral T-cell and T/NK-cell neoplasms.
A Novel Microarray Gene Expression Analysis of Murine AML Cell Lines Provides Clues to the Development of Drug Resistance to Ara-C
Authors: Rathe Susan K , Largaespada David 
Published: April 2020

Abstract
Acute myeloid leukemia (AML) has the ability to evade cell death in the presence of chemotherapeutic cocktails containing cytosine arabinoside (Ara-C). This lab previously developed two highly resistant murine AML cell lines, B117H and B140H, by introducing increasing concentrations of Ara-C to their parental cell lines, B117P and B140P, respectively. B117H and B140H can tolerate Ara-C concentrations ~1000X that of their drug sensitive parental cell lines. mRNA from all four cell lines were used in gene expression microarrays for the purpose of comparing Ara-C drug resistant murine AML cell lines with their Ara-C drug sensitive parental lines. A novel algorithm was developed to evaluate the changes in gene expression between the drug resistant and drug sensitive cells. The algorithm differed from more conventional algorithms in two key ways. First, the detection data was normalized by using ribosomal subunit 9 (Rsp9) as the normalization gene, and secondly it calculated fold change by comparing the minimum value of one population to the maximum value of the other population. The output of this algorithm was a list of genes with significant gene expression changes. These genes were next submitted to the Ingenuity Pathway Analysis (IPA) process. IPA implicated nuclear factor-κB (NFκB) in the Ara-C resistance process. Cell growth assays confirmed that the Ara-C drug resistant B117H cell line was significantly more sensitive to NFκB inhibition than its Ara-C sensitive parental cell line. This leads us to believe that the selection of Ara-C resistance may also concomitantly make some AML cells highly sensitive to killing by NFκB inhibition. This theory is being tested further through the use of drug combination assays, to determine if a synergistic or antagonistic relationship exists between Ara-C and various drugs that affect the NFκB pathway.
Pml and TAp73 Interacting at Nuclear Body and Activated p38MAPK Mediate Imatinib-Induced p53-Independent Apoptosis of Chronic Myeloid Leukemia Cells
Authors: Liu Jin-Hwang , Liu Chin-Cheng , Yen Chueh-Chuan , Gau Jyh-Pyng , Tzeng Cheng-Hwai 
Published: April 2020

Abstract
Imatinib induces apoptosis in chronic myeloid leukemic (CML) cells even with mutant p53. Ras provokes promyelocytic leukemia protein (pml), which promotes apoptosis and senescence in untransformed cells. In CML cells, ras is usually activated; however, the function of pml seems inadequate to induce apoptosis without imatinib. In both BCR-ABL+ p53mutant K562 and Meg-01 CML cells but not in BCR-ABL− HL60 cells, we found imatinib upregulated phosphorylation of p38 mitogen-activated protein kinase (MAPK), checkpoint kinase 2 (chk2) and transactivation-competent (TA) p73, formation of PML-nuclear body (NB), co-localization of TAp73/PML-NB, and expression of bax. Co-immpunoprecipitation of TAp73 and pml was also consistent with the TAp73/PML-NB co-localization. The induced co-localization also occurred to primary CML cells from three out of six patients, including the two with p53mutant. In K562 cells, both inhibiting p38MAPK with SB203580 and silencing pml or TAp73 with short interfering RNAs (siRNAs) abolished the imatinib-induced apoptosis whereas interferon alpha-2a induced additively with imatinib the apoptosis. Notably, interferon alpha-2a increased additively while SB203580 hindered the imatinib-induced phosphorylation of TAp73 and the TAp73/PML-NB co-localization. Together, imatinib induced in some CML cells, especially with mutant p53, a p53-independent proapoptotic mechanism via a p38MAPK/chk2-pml/TAp73 signaling.
The Antileukemic Potential of New Derivatives of 5-Fluoro-1H-Indole-2,3-Dione-3-Thiosemicarbazone on in Vitro Cell Lines
Authors: Kuruca Serap Erdem , Karali Nilgun , Cetin Beyza , Karadenizli Sabriye , Karakas Zeynep 
Published: April 2020

Abstract
1H-Indole-2,3-dione (isatin) is an endogenous compound identified in many organisms, possesses a wide range of biological activities. Biological properties of isatin include a range of actions in brain and offer protection against certain types of infections. This molecule has a versatile moiety that displays diverse biological activities, including anticancer activity. The discovery of numerous biologically active 3-substituted 2-indolinones led in the past decade to extensive synthesis of related compounds and as a result, anticancer agents were developed. In particular, among the 5-substituted analogs tested in the growth inhibitions against several human cancer cell lines, 5-halide, methoxy and trifluoromethoxy groups containing 3-substituted 2-indolinones show high antiproliferative effects. For this purpose, we first synthesized twelve 5-fluoro-1H-indole-2,3-dione-3-thiosemicarbazones that antituberculosis activities were shown previously by our teamwork and we researched anticancer drug potential in this study. The cytotoxic effects of twelve thiosemicarbazone derivatives were investigated by MTT assay in chronic myeloid leukemia cell lines (K562, HL60), B-lymphoma cell lines (P3HR1) and in vincristine resistant forms. The IC50 values (IC50 is a concentration that kills 50% of cells) were calculated from dose-response curve according to cytotoxicity index. The effectiveness of thiosemicarbazone derivatives were evaluated by comparing IC50 values in leukemic cell lines. All of the compounds were found cytotoxic in B-lymphoma cell lines (P3HR1, P3HR1Vin) in range 0.95–2.41 μM. However, the allyl derivative of thiosemicarbazones has cytotoxic activity in all the cancer cell lines (K562, K562Vin, HL-60, P3HR1, P3HR1Vin) that were tested. As a result, 5-fluoro-1H-indole-2,3-dione-3-thiosemicarbazones derivates might have chemotherapeutic drug potential in B-lymphoma patients. The allyl derivative of thiosemicarbazones has benefit both B-lymphoma and chronic myeloid leukemia patients in a large spectrum.
MYC Responsible for down-Regulation of CD33 Expression in Human Myeloma Cells
Authors: Shamsasenjan Karim , Otsuyama Ken-ichiro , Iqbal Mohd S. , Mahmoud Maged S. , Kawano Michio M. 
Published: April 2020

Abstract
Human myeloma cells from about 10% of cases with multiple myeloma expressed CD33 and have monocytoid morphology with convoluted nuclei, and all these patients had no increase in serum CRP values. In CD33(+) myeloma cells as well as myeloma cell lines, CD33 expression levels were correlated with the increased expression levels of CEBPA (C/EBPα) gene. This correlation was confirmed by the finding that transfection with the CEBPA gene induced CD33 expression in a CD33(−) myeloma cell line. As suggested by the lack of an increase in serum CRP values in CD33(+) myelomas, IL-6 down-regulated the expression of CD33 in CD33(+) myeloma cell lines along with the down-regulation of CEBPA gene expression. Cucurbitacin I (STAT3 inhibitor) but not U0126 (MAPK inhibitor) could abolish the effect of IL-6. Furthermore, IL-6 up-regulated the expression of MYC via STAT3 phosphorylation and MYC bound to the promoter region of CEBPA gene followed by the down-regulation of the CEBPA expression. It was confirmed that introduction of shRNA for MYC into a CD33(+) myeloma cell line blocked the IL6-induced down-regulation of CD33 and CEBPA expression. Therefore, these results indicate that IL-6 can reverse the expression level of CD33 by up-regulating MYC followed by the down-regulation of CEBPA expression.
Nonsense Suppression Approaches in Treating Hemophilia
Authors: Liu Yi-Lin , Margaritis Paris , Khazi Fayaz , Downey Harre , Kadauke Stephan , Hasbrouck Nicole , Sheedy Josephine , Welch Ellen , Weetall Marla , High Katherine A. 
Published: April 2020

Abstract
Genetic diseases can result from nonsense mutations that cause premature translation termination. Nonsense mutations account for ~10–15% of all cases of hemophilia A and B and this population may benefit from small molecule-induced readthrough of nonsense codons. Recent studies document the ability of an orally bioavailable small molecule, PTC124, to facilitate dose-dependent readthrough of nonsense codons in a variety of in vitro and in vivo systems, including reporter gene constructs, mdx mice (a murine model of Duchenne muscular dystrophy; Nature447:87–91, 2007), and in a mouse model of cystic fibrosis (PNAS105: 2064–2069, 2008). PTC124 was well-tolerated in healthy human volunteers (J. Clin. Pharmacol.47:430–444, 2007) and in patients with cystic fibrosis (The Lancet, online August 21, 2008). We previously constructed murine models of severe hemophilia B with nonsense mutations in a transgenic human factor IX (hF.IX) gene resulting in nonsense codons at amino acid positions 29 or 338 (R29X and R338X; Blood104:2767–2774, 2004). These mice have no circulating hF.IX detectable by ELISA. To evaluate the effect of small molecules on readthrough in the hemophilia B model, we administered PTC124 to mice carrying the R338X mutation by subcutaneous injection for three days. Measurable plasma levels of hF.IX were detected by ELISA (n=3) and high levels of hF.IX were detected in the liver by immunohistochemistry in the single mouse that was sacrificed. Following oral administration of PTC124 to R338X mice for three days, 20% of mice demonstrated detectable circulating hF.IX levels in the range of 3–5 ng/mL. In a separate experiment, we administered another small molecule, PTC-EMK, by IP injection for three days to R338X mice. With this regimen, 40% of mice showed detectable circulating hF.IX levels. To examine the effect of PTC124 or PTC-EMK on other nonsense mutations, we prepared ten of the most frequently reported nonsense mutations in the hF.IX gene (R29X, R116X, W194X, R248X, R252X, Y266X, W310X, R333X, R338X, and W407X) and transiently transfected these constructs into HEK293 cells. The cells were treated with PTC124 or PTCEMK at various concentrations for 72 hrs and the level of hF.IX protein in the medium was quantified using the ELISA. Of the nonsense containing constructs analyzed, 6/10 mutants showed positive responses with the largest response noted for cells containing the R29X mutation treated with PTC-EMK. In summary, our results demonstrate the ability of PTC124 and PTC-EMK to read through nonsense codons in the hF.IX mRNA and support the potential use of orally bioavailable small molecules as a therapeutic option for patients with hemophilia due to nonsense mutations.
Proteomic Analysis of Multiple Myeloma Cells Targeted with Bortezomib
Authors: Cumova Jana , Potacova Anna , Kasalova Irena , Sedo Ondrej , Konecna Hana , Zdrahal Zbynek , Hajek Roman 
Published: April 2020

Abstract
Introduction: Multiple myeloma (MM) is still an incurable disease characterized by clonal expansion of malignant plasma cells. New anticancer drugs further improve prognosis of myeloma patients. Despite promising clinical activity, some patients with MM failed to respond to bortezomib therapy. The aim of this study was to evaluate changes in protein expression of myeloma cell line ARH-77 after bortezomib treatment.
Materials and methods: Myeloma cell line ARH-77 was treated with bortezomib (5–20nM) for various periods of time. The proteins contained in total myeloma cell lysate were separated by 2-dimensional polyacrylamide gel electrophoresis (2-DE) and the differentially expressed proteins between the untreated (control) and treated cell lines were excised and identified by mass spectrometry.
Results: There were analyzed 94 proteins differentially expressed between treated and control cells; total of 34 protein spots were upregulated: proteins involved in regulation of apoptosis, chaperons/stress related proteins, proteolysis of ubiquitin/protein degradation and cytoskeleton proteins. Sixty protein spots were downregulated: proteins involved in synthesis, regulation of apoptosis, chaperons/stress related proteins, regulation of cell cycle proteins, proteins connected to glycolysis and proteolysis of ubiquitin/protein degradation and antioxidant/redox proteins.
Conclusion: Employing optimized proteomic approach we identified 94 proteins with altered expression after bortezomib treatment.