bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adaptor Protein Lnk Inhibits C-Fms Mediated Macrophage Function
Authors: Gueller Saskia , Goodridge Helen S. , Xing Hongtao , Gery Sigal , Serve Hubert , Koeffler H. Phillip 
Published: October 2019

Abstract
The macrophage colony-stimulating factor receptor (c-Fms) plays an important role in proliferation, differentiation and survival of macrophages and is involved in the regulation of distinct macrophage functions. Interaction with the ligand M-CSF results in activation of the intracellular tyrosine kinase domain and phosphorylation of tyrosine residues, thereby creating binding sites for several molecules containing Src homology 2 (SH2) domains. One such protein is the adaptor Lnk that negatively regulates several hematopoietic cytokine receptors including MPL, EpoR and c-Kit. Lnk belongs to a family of proteins sharing several structural motifs including a SH2 domain and a pleckstrin homology domain. The SH2 domain is known to be essential for its inhibitory effect which can be abolished by the point mutation R392E. In this study, we investigated the ability of Lnk to interact and modulate the function of c-Fms. In order to determine if Lnk can bind to c-Fms, immunoprecipitation was performed with lysates from 293T cells co-transfected with the cDNAs for c-Fms and Lnk. Only after exposure to M-CSF, Lnk bound to c-Fms, and binding was dependent on an intact SH2 domain. To elucidate further if Lnk exhibits biological and functional effects on macrophages, we examined both in-vitro differentiated macrophages derived from the bone marrow and also macrophages harvested from peritoneum from Lnk deleted (KO) and wild type (WT) mice. These cells appeared to be at a similar stage of differentiation because expression levels of myeloid and macrophage surface markers such as F4/80, CD11b and CD11c were the same in both bone marrow-derived and peritoneum-derived macrophages from Lnk KO and WT mice. Clonogenic assays demonstrated that the number of M-CFUs in the bone marrow were elevated in Lnk KO as compared to WT mice. Furthermore, the M-CSF-induced phosphorylation of AKT in these Lnk KO macrophages was increased and prolonged compared to WT macrophages. This was associated with prominent up-regulation of c-Fms in macrophages from Lnk KO mice. We found that Lnk additionally had several functional effects on bone marrow-derived macrophages. Production of reactive oxygen species (ROS) was dramatically increased in a M-CSF-dependent manner in Lnk KO macrophages upon stimulation with zymosan. In addition, knock-out of Lnk led to altered cytokine production of macrophages: Stimulation with zymosan caused increased levels of TNFalpha and IL-6 in the KO cells, while bacterial lipoproteins (Pam3CSK4) decreased levels of TNFalpha in KO compared to WT macrophages. Last, Lnk inhibited M-CSF-induced migration of macrophages in the Boyden chamber as Lnk KO macrophages showed a significantly higher migration capacity than WT macrophages. In summary, we show for the first time that Lnk can bind to c-Fms and can blunt the stimulation of M-CSF. Modulation of levels of Lnk in macrophages may provide a unique therapeutic approach to increase innate host defenses.
Long-Term Outcome of AIDS-Related Lymphoma Treated with Abbreviated Cycles of EPOCH-RR: A Prospective Study of 40 Patients
Authors: Dunleavy Kieron , Little Richard , Wayne Alan S. , Grant Nicole , Pittaluga Stefania , Jaffe Elaine S. , Steinberg Seth , Yarchoan Robert , Carrasquillo Jorge A. , Janik John E. , Wilson Wyndham H. 
Published: October 2019

Abstract
We hypothesized that the addition of rituximab to EPOCH chemotherapy could improve tumor kill, allowing delivery of fewer cycles of treatment and therefore reducing toxicity. Patients received EPOCH-RR (in mg/m2/d – etoposide 50, vincristine 0.4 and doxorubicin 10 all CIV d 1–5; cyclophosphamide 750 mg IV d 5; prednisone 60 po days 1–5 and rituximab 375 IV d 1,5 and G-CSF sc d 6–15) every 21 days. Prophylactic IT methotrexate was administered and HAART was suspended during therapy. Cyclophosphamide was adjusted based on absolute neutrophil count (ANC) nadir. Response was assessed by CT and FDG-PET scan and patients received 1 cycle beyond CR for a minimum of 3 cycles. Characteristics of 40 enrolled patients are: median (range) age 42 (9–60) years; IPI 3 (0–4); ECOG PS 1 (1–4), CD4 count 222 (0–835) cells/mm3; HIV viral load 34,766 (0–6,080000) RNA copies/mL; male sex 35 (88%); LDH > N 27 (68%); stage IV 27 (68%) and histology diffuse large B-cell lymphoma (DLBCL) 32 (80%) and Burkitt lymphoma (BL) 8 (20%). Of 38 evaluable patients (2NE), median (range) number of cycles given is 3 (3–5) with CR/CRu in 35 (92%) and PR in 1 (3%) patients. At 4 years median follow-up, PFS and OS are 86% and 70%, respectively. Eight patients with BL are in continuous CR. For patients with CD4 > and < 100 cells/mm3, PFS is 96% and 69%, respectively. IPI did not impact OS and PFS. Early PET scanning (after cycle 2) had a high negative predictive value (100%) but low positive predictive value (20%). Fever/neutropenia occurred on 30%, ANC < 500/mm3 on 40%, and platelets < 50,000/mm3 on 23% of cycles. EPOCH-RR was associated with less CD4 loss - median 128 cells/mm3 (range +154 to −639) compared to historical data with EPOCH alone (median 189 cells/mm3 (range +19 to −973). Patients with CD4 < 100/mm3 had good tumor control, but OS was only 31% due to late deaths from advanced AIDS. Patients with CD4 counts > 100/mm3 had an extremely good PFS and OS. The addition of rituximab did not appear to cause serious infection related complications or deaths. However, one treatment-related death occurred from complications of mycobacterium avium intercellulare. Abbreviated EPOCH-RR is highly effective and tolerable in ARL and enables the administration of fewer treatment cycles (median 3 versus 6). PET scanning has a very high negative but low positive predictive value for subsequent relapse, possibly due to HIV associated PET changes. Accrual continues.
Combined Epigenetic Therapy with the Novel Histone Methyl Transferase EZH2 Inhibitor 3-Deazaneplanocin and Histone Deacetylase Inhibitor Panobinostat Exerts Synergistic Activity against Human Mantle Cell Lymphoma Cells
Authors: Fiskus Warren , Wang Yongchao , Jillella Anand , Johnston Pace , Joshi Rajeshree , Rao Rekha , Sotomayor Eduardo , Tao Jianguo , Atadja Peter , Marqez Victor , Bhalla Kapil N. 
Published: October 2019

Abstract
Lysine specific histone methylation and deacetylation and DNA hypermethylation are involved in the epigenetic silencing of tumor suppressor genes (TSG), e.g., p16 and JunB. The multi-protein complex PRC (polycomb repressive complex) 2 that contains the three core proteins EZH2, SUZ12 and EED, has intrinsic histone methyltransferase (HMTase) activity. This is mediated by the SET domain of EZH2, which induces tri-methylation (3Me) of lysine (K)-27 on histone H3, as well as promotes cell proliferation and aggressiveness of neoplastic cells. EZH2 is preferentially overexpressed in proliferating but not resting Mantle Cell Lymphoma (MCL) cells. In the present studies we demonstrate that treatment with the S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin A (DZNep) dose-dependently (500 nM to 2.0 uM) depletes EZH2, SUZ12 and EED levels, as well as inhibits 3Me K27 on H3 while inducing K27 H3 acetylation. DZNep treatment also induces the levels of p21, p27, JunB and FBXO32, while depleting cyclin D1 and cyclin E levels in the cultured human MCL Jeko-1, MO2058 and Z138 cells and in primary patient-derived MCL cells. Treatment with DZNep induces PARP cleavage activity of the caspases and apoptosis in the cultured and primary MCL cells. DZNep promoted proteasomal degradation of EZH2 and SUZ12, since co-treatment with bortezpmib significantly restored EZH2 and SUZ12 levels in the MCL cells. We had previously reported that treatment with the pan-histone deacetylase (HDAC) inhibitor panobinostat (PS) (LBH589, Novartis Pharmaceutical Corp) depletes the levels of EZH2, SUZ12 and EED in cultured and primary AML cells (Mol Cancer Ther.2006; 5:3096). Within the PRC2 complex, EZH2 bound and recruited the DNA methyltransferases DNMT1, and treatment with PS also disrupted the interaction of EZH2 with DNMT1, attenuated DNMT1 levels and its binding to the EZH2-targeted gene promoters, e,g, JunB. Here, we also demonstrate that, PS treatment depletes DNMT1 levels and induces JunB levels in cultured MCL cells. As compared to treatment with either agent alone, co-treatment with DZNep and PS caused more depletion of EZH2 and SUZ12, but not of DNMT1, more induction of JunB, p21 and p27, as well as synergistically induced apoptosis of cultured MCL cells (combination indices < 1.0). Taken together, these findings indicate that DZNep and PS mediated targeting of EZH2 and the PRC2 complex is an effective epigenetic therapy of MCL, which also results in undermining several molecular determinants of MCL cell proliferation and survival. Additionally, combined epigenetic therapy with DZNep and PS exerts synergistic in vitro activity against human MCL cells, suggesting that this combination may be a promising novel treatment for MCL.
Selective Inhibition of CDK4 and CDK6 Primes Chemoresistant MCL Cells for Killing by Proteasome Inhibitor Bortezomib by Activating Cell Cycle-Coupled Apoptosis
Authors: Di Li berto Maurizio , Huang Xiangao , Chadburn Amy , Martin Peter , Niesvizky Ruben , Ely Scott , Leonard John P. , Kiang Selina Chen- 
Published: October 2019

Abstract
Mantle Cell Lymphoma (MCL) remains generally incurable, suggesting that more effective control of unrestrained tumor growth is essential. Loss of cell cycle control is a hallmark of cancer, in particular of MCL where cell cycle progression through G1 is accelerated due to elevation of cyclin-dependent kinase 4 (CDK4) and constitutive cyclin D1 expression. Thus, one rational approach to improve MCL therapy is to target CDK4/6 in combination with cytotoxic killing. Although success in targeting the cell cycle in cancer with broad-spectrum CDK inhibitors has been modest, PD 0332991, the only known CDK4/6-specific inhibitor with oral bioavailability, has been shown to selectively and potently inhibit CDK4/6 in MCL cells ex vivo. Additionally, in a proof-of-mechanism study in patients with recurrent MCL, we have found that PD 0332991 is well tolerated, and effective in inhibiting CDK4 and CDK6 and suppressing tumor growth in vivo. Of note, 50% of the patients (8/16) have achieved a stable disease for greater then 40 weeks (Leonard et al, abstract submitted to ASH 2008). These findings suggest that selective targeting of CDK4 and CDK6 with PD 0332991 is a promising therapy for MCL. To advance targeting of the cell cycle in cancer, we have developed two novel approaches to both inhibit tumor cell proliferation and activate cell cycle-coupled apoptosis in MCL. We show in primary MCL tumor cells and MCL cell lines by BrdU pulse labeling and DNA content analysis that selective inhibition of CDK4/6 with PD 0332991 leads to a complete G1 arrest, despite high level of c-Myc expression and extensive chromosomal abnormality. As PD 0332991 acts reversibly, removal of PD 0332991 immediately releases the G1 block and induces synchronous (>90%) G1-S cell cycle progression and S phase entry. This sensitizes chemoresistant MCL cells to killing by suboptimal doses of cytotoxic agents such as bortezomib, through activating cell cycle-coupled apoptosis during S phase entry. Synergistic killing of MCL cells by induction of cell cycle synchronization with PD 0332991 in combination with bortezomib is mediated by induction of mitochondrial membrane depolarization and activation of caspase-9. In a complementary study, we have demonstrated that selective targeting of CDK4 and CDK6 by PD 0332991 similarly primes chemoresistant primary myeloma cells for cytotoxic killing by activating cell cycle-coupled apoptosis, and induces synergistic tumor suppression in animal models. Selective targeting of CDK4 and CDK6 by PD 0332991 in combination with cytotoxic killing, therefore, represents a promising new strategy for cell cycle-based therapy for MCL and other hematopoietic malignancies.
Osteomyelosclerosis, Anemia and Extramedullary Hematopoiesis in Mice Deficient for the Transcription Factor NFAT (Nuclear Factor of Activated T Cells) c2
Authors: Kyttälä Satu , Bauer Wolfgang , Haase Michael , Habermann Ivonne , Ehninger Gerhard , Kiani Alexander 
Published: October 2019

Abstract
NFAT (Nuclear Factor of Activated T cells) is a family of five calcium-induced, calcineurin-dependent transcription factors, characterized as master regulators of inducible gene expression in T lymphocytes. In various tissues (including bone, cartilage and adipose tissue), NFAT factors have also been found to regulate processes of cellular adaptation and differentiation. NFAT family members are also expressed in human CD34+ hematopoietic progenitor cells as well as in mesenchymal stem cells; however, a biological function of NFAT in these cells, such as a role in hematopoietic differentiation, has not yet been described. To determine a potential role for NFAT in hematopoiesis, we characterized the steady-state hematopoiesis in NFATc2 knockout (KO) mice by analyzing peripheral blood, bone marrow and extramedullary tissue (spleen and liver) of KO and age-matched wildtype (WT) mice by cytology, histopathology as well as flow cytometry. No significant abnormalities were observed in KO mice of young age (6–12 weeks). NFATc2 KO mice of older age (>12 months), however, were found to be anemic, with a significant decrease in red blood cell counts as well as in hemoglobin and hematocrit values, and also showed decreased numbers of peripheral blood platelets as compared to the WT. In contrast, no significant differences between WT and KO were found in total counts of white blood cells or in leukocyte differentials. Femora of NFATc2 KO mice appeared macroscopically pale and, upon elutriation, gave yield to less than 50% of bone marrow cells compared to the WT, indicating bone marrow hypoplasia. Further analysis of bone marrow differentials by morphology and flow cytometry showed a profound decrease in erythroid cells as well as in megakaryocytes. Histopathological examination of KO bone marrow sections revealed evidence of bone marrow sclerosis, as indicated by an increase in bone trabeculae and osteoblasts within the marrow space. In some mice, an increase in reticulin fiber content was also noted. Interestingly, both liver and spleens of NFATc2 KO mice showed clear evidence for extramedullary hematopoiesis, suggesting that displacement of hematopoietic cells by the bone marrow stroma may be a possible cause of the observed cytopenias.
These results show that NFATc2 knockout mice over their lifespan develop a phenotype, which clinically resembles human osteomyelofibrosis/-sclerosis. The underlying mechanism for the observed hematopoietic abnormalities has to be defined, in particular the respective contribution of hematopoietic and bone marrow stroma cells. Given that NFAT factors are expressed at considerable levels in both hematopoietic progenitor cells and mesenchymal stem cells, our results should encourage further studies on the yet undefined role of these transcription factors within the bone marrow hematopoietic niche.
Sequential Chemotherapy Followed by High Dose Therapy and Autologous Stem Cell Rescue for Mantle Cell Lymphoma: Impact of MIB-1 on Outcome
Authors: Zelenetz Andrew D , Moskowitz Craig , Maragulia Jocelyn , Portlock Carol S. , Teruya-Feldstein Julie 
Published: October 2019

Abstract
Introduction: Optimal management of mantle cell lymphoma (MCL) remains undefined. However, recent data support the conclusion that upfront consolidation with high dose therapy with autologous stem cell rescue (HDT/ASCR) can improve the PFS (Dreyling, et al., 2005; Geisler, et al., 2008) and possibly OS (Geisler, et al. 2008). Based on gene expression profiling data, the proliferation signature has emerged as a critical determinant of prognosis in MCL (Rosenwald, et al., 2003). Immunohistochemical assessment of proliferation as estimated by MIB-1 (Ki-67) staining has been shown to predict outcome in patients with MCL treated with chemotherapy or immunochemotherapy. With conventional chemotherapy, the reported MIB-1 staining cutoff associated with poor prognosis reportedly varies from 10–30%. Since 1994 we have treated patients (pts) with MCL with sequential chemotherapy followed by HDT/ASCR. The current analysis is a retrospective review of our treatment program focused on the impact of upfront consolidation with HDT/ASCR on the prognostic significance of proliferation as measured by MIB-1 immunohistochemistry.
Methods: Seventy-nine patients underwent upfront consolidation with HDT/ASCR for MCL. Fifty-two patients had evaluation of proliferation by MIB-1 immunohistochemistry. MIB-1 expression was estimated visually and assigned a percentage. Patients were binned into quintiles of MIB-1 expression: 0–20% (n=32, 61.5%); 21–40% (n=5, 9.6%); 41–60% (n=5, 9.6%); 61–80% (n=5, 9.6%); and 81–100% (n=5, 9.6%). Outcomes were analyzed by the method of Kaplan-Meier and comparisons were by log-rank.
Results: The EFS and OS at 5 years was 65.1% and 61.4% respectively for the subset of patients with available MIB-1 staining (n=52); the outcomes for the entire group (n=79) did not differ from the subset. Outcomes (PFS, OS) were evaluated by MIB-1 quintile with successive cutoff values of 20%, 40%, 60% and 80%. MIB-1 cutoff values of 40% or less were not predictive of outcome. However, when the cutoff was 60% or 80%, both the PFS and OS were significantly worse for the high proliferation group. Nineteen percent of patients had a proliferation fraction of greater than 60%. For patients with MIB-1 staining of >60% the PFS was 4.2 years and was not reached for the group with staining ≤60% (p=0.004). Similarly, overall survival was significantly different, (p=0.031).
Conclusions: These findings suggest that upfront consolidation with HDT/ASCR can partially overcome the adverse impact of proliferation on outcome and the adverse outcomes are seen in a subgroup of approximately 20% of patients with MIB-1 staining of greater than 60%.
Arachidonic Acid Metabolism-Related Molecules as Candidate Markers in Subclassification of Lymphoma
Authors: Sjoberg Jan , Schain Frida , Schain Daniel , Mahshid Yilmaz , Porwit Anna , Xu Dawei , Sundstrom Christer , Claesson Hans-Erik , Bjorkholm Magnus 
Published: October 2019

Abstract
Arachidonic acid metabolites, like prostaglandins and leukotrienes, have been suggested to play an important role not only in inflammation but also in carcinogenesis. We have recently reported that the cysteinyl leukotriene receptor 1 (CysLT1) and 15-lipoxygenase-1 (15-LO-1), a sister enzyme to 5-LO (which is essential for leukotriene synthesis), are expressed by the malignant Hodgkin Reed-Sternberg cells of Hodgkin lymphoma (HL) and certain HL-derived cell lines, and that these cells convert arachidonic acid to the novel pro-inflammatory eoxins (Int J Cancer, 2008; FEBS J, 2008; PNAS, 2008). Given the pleiotropic effects of the CysLT1 receptor and 15-LO-1 and the fact that their expression is strictly regulated in a cell-type and tissue-specific manner, it was of interest to elucidate whether these proteins are exclusively expressed by the tumor cells of the classical HL entities. Therefore, the expression of these molecules was investigated by immunohistochemistry in a broad range of lymphomas (lymphocyte predominance (LP) HL, MALT lymphoma, T cell-derived anaplastic large cell lymphomas (ALCL), immunocytoma, mantle cell lymphoma, B-CLL, Burkitt lymphoma, follicular lymphoma, DLBCL, PTCL, primary mediastinal B cell lymphoma (PMBCL), T cell-rich B cell lymphoma; n=58). The tumor cells in one of four T cell-derived ALCLs, in contrast to all other studied non-Hodgkin lymphomas (NHLs) and LP HL tumors, strongly expressed 15-LO-1. PMBCL was the only NHL entity showing tumor cells positive for the CysLT1 receptor (9 of 10 tumors), and the PMBCL cell line Med-B1 expressed functional CysLT1 receptors, responding with a robust calcium signal upon cysteinyl leukotriene challenge. These findings further corroborate the pathologic overlap between PMBCL and classical HL. Although most cases of PMBCL are identified by routine diagnostics, the distinction between PMBCL and DLBCL may be challenging. After future careful validation in extended patient series, the CysLT1 receptor may be a potential additional marker to phenotypically distinguish these two lymphoma entities.
CD4 Cell Count of More Than 250/Microl in the Peripheral Blood Is Associated with Improved Overall Survival in Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Independent of the aaIPI
Authors: Borghaei Hossein , Smith Mitchell , Millenson Michael , Li Tianyu , Shafer Danielle , Al-Saleem Tahseen I. 
Published: October 2019

Abstract
Background: Interaction between lymphoma and the host immune system may influence patient outcomes. The predictive value of lymphocyte subsets in the peripheral blood of patients with DLBCL on survival has not been reported. We retrospectively reviewed the flow cytometry (FCM) data of the peripheral blood in patients with DLBCL and analyzed the effect of lymphocyte subsets on overall survival from the time of FCM.
Patients and Methods: Multicolor FCM was performed on 103 patients with DLBCL treated at Fox Chase Cancer Center (during 1996–2006). All pathology specimens were centrally reviewed. About half of these patients were treated by various regimens before referral to our center. Sixty-one males and 42 females with a median age of 64 years (19–89) were studied. Absolute lymphocyte count (ALC), NK cell (CD56+CD3−), CD3+CD4+ T cell and CD3+CD8+ T cell subsets were calculated. Median overall survival (OS) from time of FCM in all evaluable patients (91) was 22 months (range: 3 to 126 months). Median cell counts were as follows: NK cells 140, CD4+= 355, CD8+=224 and the ALC= 1064. Univariate analysis was done via Kaplan-Meier estimation and multivariate analysis via Cox proportional hazard model.
Results: We found, in univariate analysis, that OS from the date of initial FCM was significantly correlated with increased CD4+ T cell count and ALC, with cutoffs of 250 and 1000 cells/microL, respectively. No significant cut-off was found for CD56+ or CD8+ cells. The hazard ratio for OS by CD4+ T cell-count is 0.240 (95% CI 0.099–0.581; p = 0.0015) and for ALC is 0.44 (95% CI: 0.217–0.905; p = 0.0256). In multivariate analysis, for patients with either lower risk aaIPI (0–1) or higher risk (2–3), the only significant predictor of OS, based on FCM data, is the CD4+ T cell-count (p =0.0098 hazard ratio 0.251, 95% CI 0.0088 to 0.716).
Conclusion: In patients with diffuse large B-cell lymphoma referred for management at a tertiary cancer center regardless of prior therapy, CD4+ T cell levels of more than 250/microl predict improved overall survival independent of the IPI.