bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human Langerhans-Type Dendritic Cells Break Tolerance against the Tumor Antigen, WT1, by a Largely IL-15-Dependent Mechanism.
Authors: Romano Emanuela , Silva Rosa Barreira da , Chandrasekar Sharanya , Münz Christian , Heller Glenn , Young James W. 
Published: April 2020

Abstract
The Wilms’ tumor 1 (WT1) gene encodes a transcription factor essential for cell growth and development, but overexpression in many leukemias, myelodysplastic syndromes, and solid tumors correlates with poor prognosis. The WT1 protein could therefore serve as a therapeutic target, if tolerance could be broken against this self-differentiation, tumor-associated antigen (TAA). Vaccination protocols using peptide-pulsed dendritic cells (DCs) to induce anti-tumor responses present only defined epitopes restricted to certain human leukocyte antigens (HLA). In contrast, vaccination with mRNA-electroporated DCs supports processing and presentation of multiple TAA epitopes tailored to patient-specific HLA. Human Langerhans-type dendritic cells (LCs) derived from CD34+ hematopoietic progenitors are superior to other conventional DC subtypes, like monocyte-derived DCs (moDCs), in producing IL-15 to generate MHC-restricted, Ag-specific cytolytic T lymphocytes (CTL). Mature LCs transcribe 3 to 5-fold higher amounts of IL-15R-alpha mRNA and express the highest levels of IL-15R-alpha protein compared with other conventional DCs as measured by real-time RT-PCR, Western blot, and immunofluorescence microscopy (P&lt;0.001 to 0.05, n=3–4 independent expts). Anti-IL-15R-alpha blockade also significantly reduces but does not completely eliminate the capacity of LCs to stimulate CTL. This indicates that LCs have a greater capacity than moDCs for presenting IL-15 in trans to stimulate lytic T cell responses. We therefore compared the ability of LCs and moDCs electroporated with WT1 mRNA to break tolerance against this self-differentiation TAA by generating CTLs against WT1+ tumor cells. After a single 7-day round of stimulation at T cell:LC ratio of only 10:1 to 30:1 and in the absence of exogenous IL-15, T cells stimulated by WT-1-electroporated LCs lyse 85–95% of a WT-1+ tumor cell line. MoDCs are completely incapable of generating WT-1-specific CTL under comparable conditions and require exogenous IL-15 10ng/ml to generate 70–80% specific lysis of WT-1+ targets. Lysis of a WT-1- HLA-A*0201+ target cell line or NK cell-sensitive LCL721.221 targets is at background levels (&lt;5%) in all cases. Most importantly, WT-1-electoporated LCs also induce 63% lysis (+/− 11 SEM) of primary WT1+ HLA-A*0201+ blasts from a patient with AML after 7 days’ coculture at a T cell:LC ratio of 10:1 without exogenous IL-15. These results demonstrate a major role for the IL-15R-alpha-IL-15 complex on LCs in expanding anti-tumor cytolytic T cells and breaking tolerance against self-differentiation Ags like WT1. These data also support the use of IL-15-producing LCs in active immunization or expansion of T cells ex vivo for adoptive immunotherapy.
A Phase I/II Trial of the Kinesin Spindle Protein (KSP) Inhibitor SB- 743921 Administered on Days 1 and 15 Every 28 Days without and with Prophylactic G-CSF in Non-Hodgkin or Hodgkin Lymphoma.
Authors: Gerecitano John , O’Connor O. , Van Deventer H. , Hainsworth J. , Leonard J. , Goy A. , Afanasyev B. , Chen M. , Saikali K. , Conlan M. G , Escandon R , Wolff A 
Published: April 2020

Abstract
Background: KSP is a mitotic kinesin essential for cell cycle progression. SB-743921 (SB-921), a selective KSP inhibitor, blocks mitotic spindle assembly with cell cycle arrest in mitosis and cell death. Since neurons lack a mitotic spindle, neurotoxicty, common with anti-tubulins, is not expected. In the first-in-humans (FIH) trial, the maximum tolerated dose (MTD) was 4 mg/m2 q21 days (d), a dose density of 0.2 mg/m2/d. Since neutropenia was the major dose-limiting toxicity (DLT), with nadir at ~d8 and recovery by ~d15, a q14d schedule without (−GCSF) and with prophylactic G-CSF (+GCSF) is being explored in this trial.
Methods: In Phase I of this Phase I/II trial, the MTD of SB-921 (−GCSF) and (+GCSF) will be determined. In Phase II, efficacy and safety of the MTD will be further explored. Eligible patients (pts) have relapsed or refractory Hodgkin (HL) or non-Hodgkin (NHL) lymphoma, aggressive (a) or indolent (i), have had at least 1 prior chemotherapy (CT) regimen, and have relapsed after or were not candidates for autologous stem cell transplant. SB-921 is given to cohorts of 3 on d1/d15 q28d, starting at 2 mg/m2 and escalating by 1 mg/m2. Cohorts expand to 6 if 1/3 pts have DLT. Once DLT (−GCSF) is identified, (+GCSF) dosing begins at the (−GCSF) MTD, escalating in 1 mg/m2 increments until (+GCSF) DLT is identified.
Results: The (−GCSF) cohort included 39 pts treated at 6 dose levels (2–7 mg/m2) of SB-921. DLT was reported in 4 pts: 2/10 at 6 mg/m2 (both neutropenia with sepsis) and 2/7 at 7 mg/m2 (both Grade 4 neutropenia lasting &gt;5d). MTD (−GCSF) was 6 mg/m2. Ten pts have been treated with SB-921 (+GCSF) at 6 (n=4), 7 (n=3) and 8 (n=3) mg/m2, with no DLT. Enrollment at 9 mg/m2 is ongoing. Among the first 39 pts treated with SB-921 (−GCSF), mean age was 47 yr, 49% were male, histology was 46% HL, 28% aNHL, and 26% iNHL, 67% had ≥3 prior CT regimens. The most common Grade 3/4 adverse event (AE) was neutropenia (42% of pts treated at or above MTD). Other Grade 3/4 AEs were uncommon. No neuropathy or alopecia &gt;Grade 1 was reported. Demographics and AEs in the (+GCSF) cohort are similar with less Grade 3/4 neutropenia. Two partial responses (PRs) have been reported, both in elderly pts with HL, 1 at 6 mg/m2 (−GCSF) after 2 cycles and 1 at 8 mg/m2 (+GCSF) after 2 cycles.
Conclusions: The MTD of SB-921 (−GCSF) on a d1/d15 q28d schedule was 6 mg/m2 (dose density = 0.42 mg/m2/d). The current MTD (+GCSF) is ≥8 mg/m2 and dose escalation is continuing. This dose density (0.57 mg/m2/d) is nearly 3-fold higher than observed in the FIH trial with a q21d schedule (0.2 mg/m2/d). SB-921 is well tolerated with few Grade 3/4 AEs other than hematologic. Activity has been observed in HL, with 2 PRs at doses ≥ the (−GCSF) MTD.
Tolerability and Efficacy of Bortezomib Added to CVP-R for Previously Untreated Advanced Stage Follicular Lymphoma: Interim Analysis of a Phase II Study by the NCIC Clinical Trials Group.
Authors: Sehn Laurie H , Macdonald David A , Rubin Sheldon H. , Rubinger Morel , Imrie Kevin R , Chapman Judy-Anne W , Djurfeldt Marina , Shepherd Lois , Couban Stephen , Crump Michael 
Published: April 2020

Abstract
Background: Despite recent improvements in therapy, follicular lymphoma (FL) remains incurable with standard treatment, warranting investigation of new approaches. Bortezomib, the first-in-class proteasome inhibitor has demonstrated promising efficacy as a single agent in heavily pretreated patients (pts) with FL. This is the first study to evaluate the safety and efficacy of the addition of bortezomib to cyclophosphamide, vincristine, prednisone and rituximab (CVP-R).
Methods: This is a phase II multi-center open-label trial adding bortezomib (1.3 mg/m2 day 1&8) to standard dose C(750 mg/m2) V(1.4 mg/m2, capped at 2 mg) P(40 mg/m2 × 5) –R(375 mg/m2) for up to 8 cycles in pts with newly diagnosed stage III/IV FL requiring therapy. Planned accrual is 90 patients. A two-stage design was employed with a planned interim analysis of the first 28 patients to ensure an acceptable level of neurotoxicity (defined as less than 5/28 patients with grade 3/4 neurotoxicity after the first 4 cycles) and meaningful response rate (more than 12/28 patients with a complete response following 8 cycles), prior to enrolling remaining patients.
Results: Median age of the first 28 patients was 55 years (range, 30–73). Fifty percent were male and 79% had stage IV disease. FLIPI score at study entry: low 14%, intermediate 43%, high 43%. Overall, the combination of bortezomib and CVP-R was extremely well tolerated. To date, no pts have developed grade 4 neurotoxicity and only 1/28 (4%) has developed grade 3 neurotoxicity within the first 4 cycles (neuropathic pain which resolved without need for treatment modification). The incidence of grade 1 and 2 neurotoxicity was 54% and 25% respectively. Only 3 pts discontinued therapy prematurely (2 pt refusal, 1 progressive disease). Ninety-four percent of planned bortezomib treatments in the first four cycles and 93% of vincristine doses were administered without dose reduction. Hematologic toxicity was mild, with no pts experiencing grade 3/4 anemia or thrombocytopenia. Only 2 episodes of febrile neutropenia occurred and no grade 3/4 infections were noted. Although it is too early to report on efficacy in this ongoing trial, response objectives for stage I have been met, and enrollment to stage 2 is underway.
Conclusions: The addition of bortezomib to standard dose CVP-R is very well tolerated, with an acceptable level of neurotoxicity, without compromising the delivery of bortezomib or vincristine. This ongoing study will provide toxicity and efficacy data to facilitate the development of a planned phase III trial.
Anti-Tumor Activity of the Aurora a Inhibitor MLN8237 in Diffuse Large B-Cell Lymphoma Preclinical Models.
Authors: Huck Jessica J , Zhang Mengkun , Hyer Marc L , Manfredi Mark G 
Published: April 2020

Abstract
Aurora A kinase is a serine/threonine protein kinase that is essential for normal transit of cells through mitosis. In many tumor types the Aurora A gene is amplified and/or the protein is over-expressed. The Aurora A small-molecule inhibitor MLN8237 demonstrated robust tumor growth inhibition in xenograft models of solid tumors grown subcutaneously (S.C.) in immunocompromised mice. Here we explored the antitumor activity of MLN8237 in models of diffuse large B-cell lymphoma (DLBCL) both in vitro and in vivo. In vivo three established DLBCL xenograft models (OCI-Ly7, OCI-Ly19, and WSU-DLCL2; all cells expressing luciferase) and a primary DLBCL tumor model PHTX-22-06 were tested using MLN8237 at different doses. Rituximab, an anti-CD20 monoclonal antibody that is active against CD20+ malignant B cells and is a standard of care agent was used for comparison. Using these model systems, tumor cells were injected either I.V. (to evaluate disseminated disease), or S.C. in severe combined immunodeficient mice (SCID). Animals were dosed orally for 21 days with MLN8237 (QD or BID) at various doses, or Rituximab dosed at 10mg/kg IV (once/week) and tumor growth inhibition was monitored using either bioluminescent imaging for the disseminated models or vernier calipers for the S.C. models. Tumor growth inhibition by MLN8237 was dose dependent with 20 mg/kg bid being the most efficacious dose (TGI&gt;100% in both disseminated OCI-Ly19 and WSU models). All animals in the OCI-Ly19 disseminated model 20 mg/kg BID treatment group demonstrated regressions and remained disease free until the end of the study, day 65. In this study the Rituximab treated animals were euthanized on day 31 due to a high level of tumor burden. In the primary tumor model, PHTX-22-06, MLN8237 dosed at 20 mg/kg BID was also the most efficacious with a TGI of 95%. Moreover, tumor growth inhibition was durable as determined by prolonged tumor growth delay (&gt;50 days). Significant efficacy was achieved in all models tested, whether grown as disseminated or subcutaneous models. A noted increase in durability of response was observed with MLN8237 treatment when compared with previous data from solid tumor models. In vitro, MLN8237 treatment increased levels of apoptosis in the OCI-Ly19 cells in comparison to the solid tumor cell line HCT-116 (colon). Greater Annexin V positive cells and greater cleaved PARP and Caspase-3 signals were detected in the MLN8237 treated OCI-Ly19 cells when compared to HCT-116 cells. The demonstration of robust and durable anti-tumor activity in preclinical models treated with MLN8237 provides the basis for its clinical evaluation as a treatment option for DLBCL. MLN8237 is currently in multiple Phase I clinical trials.
Adenanthin Upregulates c/ebp β Expression with Induction of Differentiation of the ATRA-Sensitive and -Resistant leukemic Cells.
Authors: Wu Ying-Li , Liu Chuan-Xu , Chen Guo-Qiang 
Published: April 2020

Abstract
Application of all-trans retinoic acid (ATRA) has significantly improved the outcome of patients with acute promyelocytic leukemia (APL), a unique subtype of acute myeloid leukemia (AML) characterized with the reciprocal translocation t(15;17) that results in the expression of leukemia-promoting promyelocytic leukemia-retinoic acid receptor-α (PML-RARα) protein. However, most patients usually relapsed in a short period and followed by generation of retinoid resistance. Therefore, it is imperative to explore agents to overcome the resistance. In this work, we found that adenanthin, a diterpenoid compound extracted from medicinal herbs, could induce monocytic differentiation of ATRA-sensitive APL-derived NB4 cells. Especially, the differentiation-inducing effect could also be seen in the agent-treated ATRA-resistant NB4-LR1, NB4-LR2 cells, as evidenced by the morphology and the increased expression of cell surface differentiation antigens CD11b and CD14. Based on this discovery, we also found that adenanthin significantly upregulated the expression of CCAAT enhancer–binding protein beta (C/EBPβ), but not the C/EBPα and C/EBPε at its transcription and protein levels, which was accompanied by the activation of c-Jun N-terminal kinases signal pathway. On the other hand, silence of C/EBPβ by specific small-interfering RNA abrogated the adenanthin induced differentiation in NB4 cells. All these data proposed the role of C/EBPβ in adenanthin induced differentiation. Furthermore, we investigated the potential combinational effects of the natural compound with other known differentiation-inducing agents including ATRA and 1, 25-dihydroxy vitamin D3. The results demonstrated that adenanthin strikingly enhanced ATRA (10nM) induced granulocyte differentiation and 1, 25-dihydroxy vitamin D3 (1nM) induced monocytic differentiation. These results suggest that adenanthin may be a potential antileukemia agent for the ATRA-sensitive and -resistant APL and deserves to be further investigated in the future.
The Para-Isomer of Nitric Oxide-Donating Acetylic Salicylic Acid (p-NO-ASA) Effectively Induces Cell Death in B-Cell Chronic Lymphocytic Leukemia (CLL) Cells at Low Micromolar Concentrations.
Authors: Razavi Regina , Paesler Julian , Gehrke Iris , Erdfelder Felix , Hertweck Magdalena , Filipovich Alexandra , Gandhirajan Rajesh Kumar , Hallek Michael , Kreuzer Karl Anton 
Published: April 2020

Abstract
Introduction: B-cell chronic lymphocytic leukemia CLL is characterized by an accumulation of mature, non functional B cells. We and others have shown that WNT/β-catenin (CTNNB1) signaling appears to be constitutively activated in these cells. Furthermore, it is already long known that several compounds related to the non-steroidal antiinflamnmatory drugs (NSAID) can inhibit CTNNB1 stability and/or function. However, so far clinical studies with such substances generated disappointing results which is likely to the fact that therapeutic plasma concentrations could not be reached without producing significant toxicities. Recently, nitric oxide donating derivatives of acetylic salicylic acid (NO-ASA) have been shown to be well tolerated in humans. In addition NO-ASA could disrupt complexation of CTNNB1 and TCF-4 in vitro, whereas the latter belongs to the transcription factors which posses a central function in mediating WNT signaling. The aim of our study was to evaluate whether the para- and meta-isomers of NO-ASA selectively induce apoptosis in CLL cells.
Methods: Primary CLL cells as well as healthy peripheral blood monocytes (PBMC) were treated with varying concentrations of p- and m-NO-ASA for different time periods. Cytotoxicity was assessed by microscopic cell viability testing and an ATP assay. Induction of apoptosis was investigated by immunoblotting of PARP, caspases 3 and 9. Further, CTNNB1 protein amount was measured by immunoblotting and expression of WNT effector proteins like cyclin D1 (CCND1), C-MYC and LEF-1 was evaluated with immunoblot analysis as well.
Results: The meta-isoform of NO-ASA did not have any effect on CLL cells whereas the para-isomer showed a selective cytotoxic effect. Mean lethal concentration (LC50) values were 4.83 μM and 4.64 μM in CLL cells, respectively. LC50 values for healthy controls were more than 25-fold higher. Immunoblot analysis revealed that p-NO-ASA cleaves PARP; caspase 3 and caspase 9, decreases CTNNB1 protein levels and downregulates WNT pathway target genes in a concentration dependent manner.
Conclusion: Our findings show that the para- but not the meta-isomer of NO-ASA induces caspase-mediated apoptosis by inhibition of WNT signaling in CLL cells. NO-ASA, consisting of a traditional molecule of ASA where the NO moiety is covalently bound via a spacer, has been shown to exhibit a lower gastric toxicity than traditional NSAIDs. Therefore p-NO-ASA might be a valuable compound for the treatment of CLL. More investigations of the exact mechanism of action and the specific difference between the positional isomers are indicated.
Berberine Induces Apoptosis in Acute Lymphoblastic Leukemia Cells through Downregulation of the MDM2 Oncoprotein.
Authors: Zhang Xiaoling , Gu Lubing , Shah Noopur , Zhou Muxiang 
Published: April 2020

Abstract
Berberine, an isoquinoline alkaloid derived from a plant used in Chinese herbal medicine, has a wide range of biological and pharmacological activities that include anti-proliferative and pro-apoptotic effects on human cancer. However, the mechanism of berberine’s anticancer action is not clearly defined. Herein, we report that berberine induces apoptosis in acute lymphoblastic leukemia (ALL) cells through downregulation of the MDM2 oncoprotein. In studying a set of ALL cell lines, we found that the cytotoxic and apoptotic effects of berberine were positively associated with the expression levels of MDM2 by those cells, regardless of their p53 status. However, most potent apoptosis induced by berberine was seen in ALL cells with wild-type (wt) p53 and MDM2 overexpression, while no pro-apoptotic effect of berberine was detected in MDM2-negative ALL cells that had a p53-null phenotype. Berberine induced apoptosis in wt-53/MDM2-overexpressing cells through downregulation of MDM2 and a concomitant stabilization of p53, with induction of its pro-apoptotic target PUMA. This berberine-induced p53 activation in the wt-p53/MDM2-overexpressing ALL differed from that induced by the chemotherapeutic drug doxorubicin, which activates p53 without prior MDM2 downregulation or even with a late upregulation of MDM2 due to a p53-mediated increase in transcription. The berberine’s downregulation of MDM2 in ALL cells occurred at the post-translational level through modulation of DAXX, which promotes MDM2 self-ubiquitination. Because wt-p53/MDM2-overexpressing ALL cells are commonly chemo-resistant due to MDM2-regulated repression of the p53 function, the potent killing of these cells by berberine through direct targeting of MDM2 suggests that this agent may be a novel therapeutic for refractory ALL.
HERG K+ Channel Is Essential for Leukemic Cell Migration Induced by SDF-1.
Authors: Li Huiyu , Du Yi-Mei , Guo Linlin , Guo Tiannan , Jie Shenghua , Du Wen , Chen Xiangjun , Liu Wei , Zhang Jiahua , Fan Linlin , Zou Anruo , Zhang Songyu , Huang Shiang 
Published: April 2020

Abstract
Background: Recent studies suggest that HERG K+ channel is an important regulator of non excitable cell proliferation and migration, and has been found in tumor cells including acute myeloid leukemia(AML), where HERG K+ channel is generally considered to be absent from their healthy counterparts. Bone marrow stromal cells constitutively secrete the stromal cell-derived factor-1 (SDF-1) which is a homeostatic chemokine that signals through CXCR4, SDF-1/CXCR4 axis and plays an important role in hematopoiesis development and leukemic cells migration. In this study, we investigated whether SDF-1-induced leukemic cell migration associated with HERG K+ channel.
Methods: primary CD34+/CD38− leukemic stem cells (LSCs) were isolated by cell sorting using a FACS Vantage. Transwell was used to assess the effect of E-4031, a specific HERG K+ channel inhibitor, on leukemic cell migration, the lower chamber was filled with serum-free RPMI-1640 with 100ng/ml SDF-1. Flow cytometry was used to analyze the CXCR4 expression as well as phenotypical analysis of leukemia samples. HERG K+ channels were expressed in Xenopus oocyte by microinjection and the resulting currents were measured using the standard two microelectrode voltage clamp techniques.
Results: numbers of HL-60 cells with and without E-4031 treatment migrated towards SDF-1 in the lower chamber were 1.58±0.98 ×104 and 3.47±0.81 ×104 respectively, indicating E-4031 significantly blocked the cell migration induced by SDF-1. The similar results were also observed in primary leukemic cells (n=7) and leukemic stem cells(n=3). From a holding potential of −80 mV varying potentials from −70 mV to +50 mV in 10 mV increments (2s) were applied to elicit activating currents. Each pulse was followed by a constant return pulse to −50 mV (2s) to evoke outward tail currents. 100 ng/ml SDF-1 increased HERG K+ current expressed in oocytes, for example, at +50 mV, HERG current increased about 30% (n=5). The HERG K+ current increase by SDF-1 might contribute to the mechanism of SDF-1 induced leukemic cell migration. There were no significant changes of CXCR4 expression on both HL-60 cells and primary leukemic cells regardless of untreated and treated with E-4031 for 24 hours (p&gt;0.05), suggesting that the leukemic cell migration induced by SDF-1 were specifically associated with HERG K+ channel, not by regulating CXCR4 expression.
Conclusion: the data showed that HERG K+ channel was essential for leukemic cell migration induced by SDF-1. SDF-1 enhanced herg current suggested that SDF-1 promotes leukemic cell migration. Blocking HERG K+ channel with specific inhibitor could decrease leukemic cell and leukemic stem cell migration caused by SDF-1. Prospectively, HERG K+ channel may be a potential therapeutic target with specific inhibitors in leukemia treatment.