bluuebunny/crossref_metadata_2025_split huggingface dataset:
Posttransplant Lymphoproliferative Disorder in Liver Transplant Recipients: A Report of Seventeen Cases.
Authors: Patel Himisha , Vogl Dan , Aqui Nicole , Stadtmauer Edward A. , Olthoff Kim , Tsai Donald E. 
Published: April 2020

Abstract
Posttransplant lymphoproliferative disorder (PTLD) is a major complication of liver transplantation. The optimal approach to these patients remains to be determined. We report a retrospective analysis of seventeen consecutive cases of PTLD seen at the University of Pennsylvania Medical Center. A total of 1179 liver transplants have been performed, of which 15 (1.3%) patients developed PTLD. There were two additional patients in this series that received their transplant elsewhere. The most common indications for liver transplantation were viral hepatitis (35%) and/or alcoholic cirrhosis (29%). Of the seventeen PTLD patients identified, most were Caucasian (76%) and/or male (76%). The median age at PTLD diagnosis was 50 yrs (range 20–65 yrs) with a median time from liver transplantation to PTLD diagnosis of 25 months (range 3–75 months). The most common presenting symptoms included fevers (47%), weight loss (47%), anorexia (47%), and pain (70%). PTLD location was frequently extranodal (71%) and/or involved the transplanted liver (41%). At diagnosis, immunosuppressive medications included OKT3 (12%), steroids (71%), azathioprine (41%) or mycophenolate mofetil (12%), and cyclosporine (65%) or tacrolimus (35%). PTLD histology consisted of 9 (53%) monomorphic and 8 (47%) polymorphic. EBV was detected by in situ hybridization in 11 (79%) of 14 cases evaluated. Stage at diagnosis was I (29%), II (35%), III (12%), and IV (12%). Initial therapy included reduction in immunosuppression (RI) alone in 13 (76%) of 17 patients. The remaining 4 patients were treated with retransplantation, rituximab + RI, alpha interferon, or chemotherapy. RI alone resulted in 6 (46%) CR and 7 (54%) PD. The addition of rituximab to RI in 1 patient resulted in an additional CR. R±CHOP was used as initial therapy in one patient and in 2 patients as salvage after relapse with all attaining a CR. Current median follow-up is 6 months (range 7 days to 9 years) with PFS of 6 months. Median overall survival following PTLD diagnosis was 6 months (range 7 days to 9 years). Of the 12 expired patients, 6 (50%) died from progressive PTLD, 3 (25%) from liver failure, 2 (17%) from infection, and 1 (8%) from cardiomyopathy. Currently, 5 patients are alive in CR (follow-up times of 6 months, 3.5 yrs, 4.5 yrs, 6 yrs and 8.5 yrs). Although the detection and treatment of PTLD in liver transplant recipients remains problematic and the upfront mortality is still high, long-term survival is possible. Further studies are necessary to better define treatment strategies.
The Anti-FLT3 Monoclonal Antibody EB10 Is Cytotoxic to FLT3 Inhibitor Resistant Cells In Vivo.
Authors: Piloto Obdulio , Griesemer Melissa , Nguyen Bao , Li Li , Li Yiwen , Witte Larry , Hicklin Daniel J. , Small Donald 
Published: April 2020

Abstract
The class III receptor tyrosine kinase, FLT3, has been shown to play a role in leukemogenesis, particularly in acute myeloid leukemias (AML) and acute lymphoblastic leukemias (ALL). This finding has spurred the development of tyrosine kinase inhibitors (TKI) targeting wild-type and mutant FLT3, and these drugs have shown activity in clinical trials. However, as has been observed with Gleevac for treatment of chronic myeloid leukemia, continuous treatment with TKIs may select for resistant clones. Immunotherapy targeting FLT3 may prove efficacious against FLT3-expressing resistant cells since their mode of action is not dependent on FLT3 inhibition. To study resistance to TKIs against FLT3 we developed resistant human cell lines by co-culturing MOLM14 and SEM-K2 cells, expressing FLT3/ITD mutant and wild type FLT3, respectively, with increasing concentrations of the FLT3 inhibitor CEP-701. The resulting cell lines, MOLM14(R) and SEM-K2(R), are resistant to CEP-701 induced cytotoxicity as well as to other selective FLT3 TKIs, CEP-5214 and PKC412. Cross resistance to CEP-701, CEP-5214 and PKC412 was also observed when MOLM14 and SEM-K2 cells were co-cultured with CEP-5214 or PKC412, instead of CEP-701. Western blot analysis reveals that CEP-701, CEP-5214 and/or PKC412 still inhibit FLT3 and downstream STAT5, Akt and MAPK pathways in MOLM14(R) and SEM-K2(R) cells. Sequencing of FLT3 from the resistant clones confirmed that the resistance was not the result of drug resistance mutations in FLT3. This indicates that the observed resistance to CEP-701, CEP-5214 and PKC412 is due to selection of FLT3-independent clones during co-culture with anti-FLT3 TKIs. To see if anti-FLT3 immunotherapy would still be active against resistant cells, MOLM14(R) and SEM-K2(R) cells were injected into NOD/SCID mice and treated with IMC-EB10, an unconjugated monoclonal antibody against FLT3. These in vivo studies demonstrate that IMC-EB10 still reduces leukemic engraftment and prolongs survival of mice injected with the resistant cell lines, to comparable levels observed with the parent cell lines. In conclusion, our data indicates that culturing leukemic cells with increasing concentrations of selective FLT3 TKIs can result in clones that are FLT3 independent and that anti-FLT3 immunotherapy is still cytotoxic to these resistant cells in vivo. An approach combining FLT3 TKIs with anti-FLT3 antibodies may prove superior and result in reduced chance of developing resistance.
Sensitization of Rituximab-Sensitive and Rituximab-Resistant B-NHL Cell Lines/Clones to TRAIL-Induced Apoptosis by Bortezomib and NF-κB Inhibitors.
Authors: Jazirehi Ali R. , Bonavida Benjamin 
Published: April 2020

Abstract
Patients with B-NHL respond initially to conventional chemotherapy and/or to immunotherapy with rituximab (alone or in combination with chemotherapy). However, patients develop resistance to these modalities and novel approaches are needed. TRAIL is a cytotoxic molecule that exerts selective anti-tumor cytotoxic activity with minimal toxicity to normal tissues. Further, TRAIL or agonist monoclonal antibody (mAb) to TRAIL receptors, DR4 and DR5, are currently being tested clinically. The present study investigated the sensitivity of B-NHL cell lines to TRAIL-mediated apoptosis using the AIDS-related NHL (ARL) B-cell line, 2F7, and the B-NHL cell lines, Ramos and Daudi. Also, to recapitulate various aspects of acquired rituximab-resistance, we have generated rituximab-resistant (RR) clones from the parental wild type (wt) cells. Rituximab failed to chemo-sensitize the RR clones and the clones exhibited higher resistance to various drugs (e.g., CDDP, VP-16, ADR, Vincristine, Taxol) and to TRAIL (1–250 ng/ml-18 h) compared to the wt cells as analyzed by DNA fragment on assay. The findings demonstrate that the wild type and RR1 cells were resistant to TRAIL-mediated apoptosis at a wide range of TRAIL concentrations. We then examined means to reverse TRAIL resistance. We and others have reported that inhibition of NF-κB activity can sensitize TRAIL-resistant tumor cells to TRAIL-induced apoptosis. Hence, we examined the effect of the proteasome and NF-κB inhibitor, Bortezomib (Velcade), Bay 11–7085 and the specific NF-κB inhibitor DHMEQ (Kikuchi et. al, Cancer Research2003; 63:107). Pretreatment of the NHL tumor cells with Bortezomib, Bay 11–7085 or DHMEQ for 6 h followed by treatment with TRAIL for 18h resulted in significant augmentation of apoptosis and synergy was achieved. Both the rituximab-sensitive and rituximab-resistant tumor cells were sensitized by these inhibitors, though higher concentrations were required for sensitization of the RR clones. Interestingly, detailed analysis of the signaling pathways in the RR clones revealed constitutive hyper-activation of the NF-κB survival pathway leading to over-expression of anti-apoptotic gene products Bcl-2, Bcl-xL and Mcl-1. Based on the findings, we postulate that patients with resistant B-NHL can be treated with combination of TRAIL/anti-DR4 or DR5 mAb and NF-κB inhibitors. Alternatively, these patients can be treated with agents that up-regulate TRAIL expression on host effectors (e.g., T cells, NK cells) in combination with NF-κB inhibitors.
A Dual Bcr-Abl/Lyn Tyrosine Kinase Inhibitor, NS-187, Is a Novel Agent for Imatinib-Resistant Leukemia.
Authors: Kimura Shinya , Naito Haruna , Yokota Asumi , Kamitsuji Yuri , Kawata Eri , Ashihara Eishi , Nakaya Yohei , Naruoka Haruna , Wakayama Tatsushi , Asaki Tetsuo , Niwa Tomoko , Hirabayashi Kazuko , Maekawa Taira 
Published: April 2020

Abstract
Chemical modifications of imatinib mesylate made with the guidance of molecular modeling yielded several promising compounds. Among them, we selected a compound denoted NS-187 (elsewhere described as CNS-9) on the basis of its affinity to Abl, and also to Lyn, which may be involved in imatinib-resistance (Figure). The most striking structural characteristic of NS-187 is its trifluoromethyl (CF3) group at position 3 of the benzamide ring. The presence of the CF3 group strengthened the hydrophobic interactionss of the molecule with the hydrophobic pocket of Abl. Another possible merit of the CF3 group is that it may fix the conformation of the drug by hindering its rotation at the 4-position of the benzamide ring; as a result, a CF3-bearing molecule may be more potent than more flexible compounds such as imatinib. In fact, NS-187 was 25–55 times more potent than imatinib in vitro and and at least 10 times more potent than in vivo. NS-187 also inhibited the phosphorylation and growth of all Bcr-Abl mutants tested except T315I at physiological concentrations. Another special feature of NS-187, in addition to its increased affinity to Abl is its unique spectrum of inhibitory activity against protein kinases. At a concentration of 0.1 μM, NS-187 inhibited only four of 79 tyrosine kinases, that is, Abl, Arg, Fyn, and Lyn. Notably, at 0.1 μM NS-187 did not inhibit PDGFR, Blk, Src or Yes. The IC50 values of NS-187 for Abl, Src and Lyn were 5.8 nM, 1700 nM and 19 nM, respectively, and those of imatinib were 106 nM, &gt;10,000 nM and 352 nM, respectively. These findings indicate that NS-187 acts as a Bcr-Abl/Lyn inhibitor. In this respect, NS-187 may stand out among other novel Abl tyrosine kinase inhibitors, because BMS-354825 inhibits all members of the Src family, while AMN-107 inhibits none of the Src-family kinases. Our proposed docking models of the NS-187/Abl complex support the notion that NS-187 is more specific for Lyn than for Src. The amino acid at position 252 is either Gln or Cys in Src-family proteins. NS-187 inhibited the Gln252-bearing proteins Abl, Fyn and Lyn but had lower activity against the Cys252-bearing Src and Yes. This is probably because Gln, unlike Cys, readily forms hydrogen bonds. The distinguishing characteristic of NS-187, its high affinity for and specific inhibition of Abl and Lyn, may be useful in the treatment of Bcr-Abl-positive leukemia patients.
Figure Figure
Radiosensitization of Human Cancers by Smac Agonists.
Authors: Giagkousiklidis Stavros , Vogler Meike , Westhoff Andrew , Kasperczyk Hubert , Debatin Klaus-Michael , Fulda Simone 
Published: April 2020

Abstract
Resistance to current treatment regimens such as radiation therapy remains a major concern in oncology and may be caused by defects in apoptosis programs. Since “Inhibitor of apoptosis proteins” (IAPs), which are expressed at high levels in many tumors, block apoptosis at the core of the apoptotic machinery by inhibiting caspases, therapeutic modulation of IAPs could target a key control point in resistance. Here, we report for the first time that full length or mature Smac, an inhibitor of IAPs, significantly enhanced γ-irradiation-induced apoptosis and reduced clonogenic survival in neuroblastoma, glioblastoma or pancreatic carcinoma cells. Notably, Smac had no impact on DNA damage/DNA repair, activation of NF-κB, upregulation of p53 and p21 proteins or cell cycle arrest following γ-irradiation indicating that Smac did not alter the initial damage and/or cellular stress response. Smac enhanced activation of caspase-2, -3, -8 and -9, loss of mitochondrial membrane potential and cytochrome c release upon γ-irradiation. Inhibition of caspases also blocked γ-irradiation-induced mitochondrial perturbations, indicating that Smac facilitated caspase activation, which in turn triggered a mitochondrial amplification loop. Interestingly, mitochondrial perturbations were completely blocked by the broad range caspase inhibitor zVAD.fmk or the relatively selective caspase-2 inhibitor zVDVAD.fmk, whereas caspase-8 or caspase-3 inhibitors only inhibited the increased drop of mitochondrial membrane potential provided by Smac, suggesting that caspase-2 was acting upstream of mitochondria upon γ-irradiation. In conclusion, our findings provide evidence that targeting IAPs, e.g. by Smac agonists, is a promising strategy to enhance radiosensitivity in human cancers.
Overcoming Resistance to Imatinib Mesylate in a CML Cell Line by Downregulation of P-gp with siRNAs.
Authors: Lima Raquel T. , Guimaraes Jose E. , Vasconcelos M. Helena 
Published: April 2020

Abstract
Imatinib Mesylate (Gleevec, formely STI571 from NOVARTIS) is a highly selective drug, capable of inhibiting the BCR-ABL tyrosine kinase which is responsible for CML. However, resistance to this drug has been documented, mainly due to an overexpression of the BCR-ABL protein, to mutations in the tyrosine-kinase domain of BCR-ABL itself or to an overexpression of the multidrug resistance protein 1 (P-gp). In the current study we investigated if downregulation of P-gp expression with siRNAs, in a cell line resistant to Imatinib which overexpressed P-gp (K562Dox), would allow to overcome resistance to this drug. In order to optimise transfection of the siRNAs, we used a fluorochrome labelled control-siRNA and fluorescence microscopy to evaluate the % of uptake of the siRNA under different transfection conditions. The optimised conditions (200 nM siRNA using the jetSi™ transfection reagent) allowed us to obtain uptake of siRNAs in 53% of cells. In order to confirm if the siRNAs were capable of downregulating the expression of P-gp we carried out, 24h after transfection, Real-Time Quantitative PCR studies and Western Blots of cells: i) treated with medium only (Blank), ii) transfected with the siRNAs suspension buffer, iii) transfected with a control siRNA (CRNAi), iv) transfected with two different siRNAs for P-gp (MDR-FE or MDR-CR). We verified that in cells treated with the MDR-CR siRNA there was a reduction in the P-gp mRNA expression of 26%, when compared to the CRNAi. Furthermore, when cells were treated with the MDR-FE or MDR-CR siRNAs, protein levels were also reduced by 33% and 57% respectively, when compared to the CRNAi. It was then verified if this downregulation of MDR expression caused sensitization of cells to Imatinib, in comparison to control cells, using both viability (Trypan Blue) and apoptosis (TUNEL) assays. For this purpose, Imatinib Mesylate was added to the cells previously transfected with siRNAs (for P-gp or control siRNAs) and to cells in exponential growth (Blank cells). Results showed that there was an enhancement of the effect of Imatinib in cells previously transfected with both P-gp siRNAs (MDR-FE or MDR-CR). This increase in the effect of Imatinib was due to an increase in cellular apoptosis. Indeed, the % of apoptotic cells increased from 3 % in cells treated with solvent to 7 % in cells treated with 1 μM Imatinib. It was concluded that downregulation of P-gp protein expression by RNAi technology permitted sensitisation of CML cells to Imatinib, suggesting that P-gp inhibition may be considered as an adjuvant therapy in cases of Imatinib resistance mediated by this mechanism.
Gene Expression Profiling (GEP) in Multiple Myeloma (MM): Comparison of Purified MM Cells (PMM), Random Bone Marrow Biopsies (RBX) and Fine Needle Biopsies from Focal Lesions (FNBX).
Authors: Huang Yongsheng , Zhan Fenghuang , Barlogie Bart , Shaughnessy John 
Published: April 2020

Abstract
Background: GEP has become a useful tool for the distinction of genetic subgroups of patients with malignant disease of a common pathologic diagnosis, including MM. The aim of this study was to determine whether whole bone marrow biopsies could replace the laborious magnetic bead purification of CD 138-positive plasma cells, with the potential added advantages of: 1. less sample manipulation and thus facilitating shipping to a central processing and analysis facility; 2. encompassing the bone marrow micro-environment as an important contributor to MM survival and drug resistance.
Patients and Methods: Samples included paired PMM and RBX from 190 newly diagnosed patients treated on Total Therapy protocols TT2 (n = 85) and TT3 (n = 105); 29 of these patients also had CT-guided fine needle biopsies (FNBX); 5 subjects with MGUS and 5 normal donors were used for comparison. Total RNA was applied to Affymetrix U133 Plus2 microarray chips. Unsupervised hierarchical clustering (UHC) was performed on Log2 transformed GEP intensity values of probe sets with &gt;95% present detection calls and &gt;0.5 standard deviation.
Results: UHC analysis of RBX (MM, MGUS, normal) identified 2 major subgroups: one containing both normal and MGUS samples (“normal-like”, N-L) and the other comprising only MM samples (“myeloma-like”, M-L) (Figure 1). In the context of previously defined 7 GEP subgroups (Zhan et al, Blood 2004), the N-L group contained higher proportions of hyperdiploid and normal karyotype cases, whereas the M-L group comprised the majority of MAF/MAFB, FGFR3/MMSET and proliferation cases. Good-risk standard laboratory features (non-IgA isotype, lower B2M and CRP levels, higher Hb concentrations) were over-represented in the N-L group. When applied to TT2 patients with a median follow-up of 3 years, N-L patients had superior 3-yr EFS (85% vs 55% for M-L group; p=.02). A further UHC analysis addressed similarities/differences among PMM, RBX and FNBX samples available in 29 patients. The dendrogram had 2 major branches; one comprising all PMM samples and the other all BX with sub-branches separating RBX and FNBX subgroups. Finally, 90% of all MAF, MAFB, FGFR3, MMSET and CCND1 “spikes” identified in PMM (with well established prognostic implications) were also detectable in RBX and FNBX samples.
Conclusion: GEP analysis of RBX distinguished 2 subgroups, M-L and N-L, in the context of comparison with normal subjects and MGUS. Compared to M-L, N-L patients (comprising more favorable genetic and standard laboratory features) had superior EFS. Both RBX and FNBX were adequate tissue sources for the detection of prognosis- and possibly therapy-relevant translocation-associated “spiked” genes. Genes differentiating PMM, RBX and FNBX will be reported at the meeting. BX as tissue source should make GEP studies of MM feasible in the context of multi-institutional trials.
Risk of Monoclonal Gammopathy of Undetermined Significance (MGUS) and Subsequent Multiple Myeloma among African-American and White Veterans in the U.S.
Authors: Landgren Ola , Gridley Gloria , Turesson Ingemar , Caporaso Neil E. , Goldin Lynn R. , Baris Dalsu , Fears Thomas R. , Hoover Robert N. , Linet Martha S. 
Published: April 2020

Abstract
Background: The age-adjusted incidence of multiple myeloma (MM) is 2-fold higher in African-Americans than in Whites, which is paralleled by reports of a higher prevalence of monoclonal gammopathy of undetermined significance (MGUS) in African Americans. Etiological factors for MGUS and determinants for transformation of MGUS to MM are unknown, but data on the race-specific prevalence of MGUS and progression of MGUS to MM may provide clues to etiology.
Objective: To determine the prevalence and the probability of progression from MGUS to MM in African-Americans compared to Whites.
Patients and Methods: The cohort was identified from review of discharge diagnoses in hospital medical records for inpatient hospitalizations at 142 nationwide U.S. Veterans Affairs (VA) hospitals between October 1, 1980 and September 30, 1996. The target population for calculation of MGUS prevalence included all African-American (N=749,020) and White (N=3,248,795) veterans hospitalized at least once at age 18 or older. For estimating the risk of malignancy, all subjects without a prior discharge diagnosis of malignancy were followed from one year after index hospital discharge (MGUS diagnosis for MGUS cases, and first discharge for any reason for all others) until the diagnosis of a first malignancy, death, or the end of the observation period (September 30, 1996), whichever came first. Using the Kaplan-Meier procedure, we calculated the cumulative probability of developing MM among MGUS cases according to race, testing for statistical significance using the Wilcoxon-test appropriate for censored data. The Cox proportional hazards model was applied. Poisson regression was used for analyses comparing risk for MM among MGUS versus non-MGUS cohorts.
Results: We identified 734 cases of MGUS in African-Americans and 1,312 in Whites. The age-adjusted prevalence-rate for MGUS was 3.0-fold (2.7–3.3 95% CI) higher in African-Americans than in Whites. Among MGUS cases, the estimated cumulative risk of developing MM during the first 10 years of follow-up was similar (Wilcoxon-test P=0.37) for African-Americans (17%) and for Whites (15%). The risk of developing MM among all MGUS (versus non-MGUS) cases was very high (RR=89.1; 74.7–106.3, 95%CI).
Conclusions: In the largest study to date, we suggest that the excess risk of MM in African-Americans results from an increase in risk of MGUS rather than an increased risk of progression from MGUS to MM.