bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene Transfer of CD40-Ligand to Human Dendritic Cells Induces Growth Arrest and Apoptosis of Tumor Cells Mediated by Up-Regulated TRAIL and its Receptors.
Authors: Tomihara Kei , Kato Kazunori , Masuta Yukari , Noguchi Makoto , Hiratsuka Hiroyoshi , Hamada Hirofumi 
Published: October 2019

Abstract
Interaction of CD40 and its ligand CD40L is essential for the activation of dendritic cells (DC) followed by the induction of antigen-specific T-cell responses. Recent studies have also indicated that ligation of CD40 on tumor cells directly modulate tumor cell growth. In this study we examined whether gene transfer of CD40L to DC could exhibit direct anti-tumor effect on CD40-expressing tumors. First, we constructed a modified adenoviral vector driving human CD40L gene with CA promoter/enhancer and incorporating the integrin-binding motif, RGD, in the H1 loop of the fiber knob (AxCAhCD40L-F/RGD). At the same multiplicity of infection, cell surface expression of human CD40L on DC after infection with AxCAhCD40L-F/RGD (CD40L-DC) was induced to express superior higher levels of T-cell costimulatory molecules (CD80, CD86, and CD54), DC maturation markers (CD25 and CD83), MHC molecules and the production of IL-12 than soluble CD40L or TNF-a treated DC. In addition to the phenotypic alternation of CD40L-DC, we found that cultivation of tumor cells (including lymphoma, leukemia, glioma, head and neck carcinoma) with CD40L-DC significantly inhibited the expression of phospho-AKT and tumor cell growth in vitro. Importantly, these tumor cells in transwell cocultured with CD40L-DC, but not with TNF-a-treated DC or immature DC, were significantly induced to express apoptosis-inducing death receptors such as TRAIL-R1, TRAIL-R2 and Fas. The ability of CD40L-DC to inhibit tumor-cell growth and TRAIL receptor induction could not be abrogated by neutralizing antibodies specific for CD40L, IFN-b, IFN-g, and IL-12, indicating that these factors were not involved. Additionally, natural killer cells cocultured with CD40L-DC displayed marked up-regulation of TRAIL on their cell surface. To confirm the biological function of TRAIL and its receptors, we assessed the cytotoxic activity of NK cells to various tumors that were stimulated with CD40L-DC. Tumor cells stimulated with CD40L-DC were susceptible to apoptosis by recombinant TRAIL protein and natural killer cells expressing TRAIL. Overall, these results reveal that CD40L-transfected DC could induce direct tumor cell growth arrest mediated by AKT pathway and susceptibility of apoptosis by TRAIL, indicating that CD40L-DC have potential therapeutic implications which we were currently exploring.
Langerhans Cells and T Cells in Langerhans Cell Histiocytosis Have Distinct Cytokine and Growth Factor Gene Expression Profiles Depending on the Clinical Risk Groups.
Authors: McClain Kenneth L. , Yan Xiao-tian , Li Liunan , Hicks John , Peterson Leif E. 
Published: October 2019

Abstract
Langerhans cell histiocytosis (LCH) can present in several clinical forms with expected response to therapy categorized by the organ systems involved. Low Risk patients (unifocal bone, skin, or lymph nodes disease) are nearly always cured of the disease, patients with multifocal bone involvement are more likely to have relapses, and High Risk patients (involving liver, lung, spleen, or bone marrow) have only a 50% chance of cure. The etiology of LCH is unknown and controversy exists whether this is purely an immunologic dysfunction or a neoplastic disease since the Langerhans cells have been identified as a clonal proliferation. Understanding interaction of Langerhans cells (LC) with T lymphocytes and macrophages in the lesions of Langerhans cell histiocytosis (LCH) is critical to elucidating LCH pathophysiology. We have used laser capture microdissection to isolate CD1a+ LC and CD3+ T cells from frozen LCH lesions. RNA from the dissected cells was enzymatically amplified, hybridized to a cytokine/growth factor array and analyzed for quantity of gene expression after normalizing to b-actin. A complex expression profile has emerged:
Gene Expression in LCH Clinical Groups
Low Risk Multifocal Bone High Risk * to ***= low to high expression of a gene, VEGF:vascular endothelial growth factor, FGF: fibroblast growth factor CD1a Cytokines IL-9**, -11***, -17**, Leptin*,TGF- β IL-10**, IL-11**,TGF- β IL-9*,11*,Leptin** CD1a Growth Factors FGF-6*, VGEF*** FGF-6**, VEGF** FGF-6***, VEGF* CD3 Cytokines IL-9**, Lymphotoxin- α IL-9*,-10 IL-9*** Lymphotoxin- α** CD3 Growth Factors GM-CSF* GM-CSF** FGF-5* GM-CSF*** FGF-5**
Growth factor and cytokine interactions from these LCH patients with different clinical presentations illustrates the importance of both LC and T-cells as well as the known influence of macrophages on the type of LCH. Although previous studies have shown TNF-a is an important factor, our data illustrates that other cytokines and growth factors may play critical roles, because of their relative higher gene expression when compared with TNF-a. These data will facilitate development of in vitro systems to test our hypotheses that a combination of cytokines/growth factors may be important in varying LCH clinical presentations.
Primary Plasma Cells Expressing CD52 Are Efficiently Targeted In Vivo by Alemtuzumab.
Authors: Carlo-Stella Carmelo , Di Nicola Massimo , Longoni Paolo , Cleris Loredana , Milanesi Marco , Lavazza Cristiana , Milani Raffaella , Carrabba Matteo , Formelli Franca , Gianni Alessandro M. , Corradini Paolo 
Published: October 2019

Abstract
Salvage therapy options for multiple myeloma (MM) patients relapsing following autologous stem cell transplantation remain limited. New treatments targeting the malignant plasma cell (PCs) are therefore needed. Alemtuzumab is a humanized monoclonal antibody to CD52 capable of destroying CD52+ cells by antibody-mediated cellular cytotoxicity and complement fixation. In order to evaluate the therapeutic potential of alemtuzumab for MM patients, we initially examined CD52 expression on primary malignant marrow PCs as well as a panel of MM continuous cell lines (RPMI-8226, KMS-11, OPM-2, U-266, LP-1, ARH-77). In addition, the anti-myeloma activity of alemtuzumab was evaluated in vivo in a xenotransplant model of MM in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. PCs were enriched from the marrow of MM patients (n = 40) according to CD138 expression. By using an immunomagnetic technique (Miltenyi Biotec, Germany, EU), highly purified CD138+ cells (median purity = 93%; median recovery = 55%) were obtained and further characterized by 3-color (CD138/CD45/CD52) flow cytometry. Expression of CD52 on CD138-enriched cells was detected in 28/40 (70%) of MM patients, with a median of 95% PCs expressing CD52. Detection of CD52 was equally evident on CD138+CD45+ and CD138+CD45− PCs (P ≥ 0.05). Similarly to what observed for primary CD138+ cells, MM cell lines showed a rather heterogeneous CD52 expression, ranging from dim (KMS-11, OPM-2) to bright positivity (LP-1, ARH-77). Both on primary PCs and MM cell lines, expression of CD52 mRNA by quantitative PCR analysis strongly correlated with CD52 antigen detection by flow cytometry. The in vivo activity of alemtuzumab was evaluated in a xenotransplant model of MM in NOD/SCID mice. Mice were inoculated intravenously with KMS-11 cells (0.5 x 105 per mice) and were treated with alemtuzumab (3 x 1 mg/mouse, subcutaneously, days 2, 5, 7). All placebo-treated mice (n = 15) died, whereas mice treated with alemtuzumab (n = 15) showed a significant prolongation of median survival (P ≤0.009 by log rank test) and 27% of them were alive and well at 120 days. No mice experienced any apparent treatment-related toxicity. According to these data, we conclude that: (1) CD52 is expressed on the plasma cells of a significant proportion of MM patients; (2) alemtuzumab has a strong antitumor activity in vivo on CD52-positive MM cell lines; (3) alemtuzumab might have therapeutic potential in a subset of MM patients.
SDX-101 Is Cytotoxic and Overcomes Drug Resistance in Multiple Myeloma.
Authors: Hamasaki Makoto , Hideshima Teru , Ishitsuka Kenji , Yasui Hiroshi , Shiraishi Norihiko , Kumar Shaji , Raje Noopur , Roccaro Aldo M. , Tai Yu-Tzu , Shiringarpure Reshma , Leoni Lorenzo , Kanekal Sarath , Elliott Gary , Munshi Nikhil C. , Anderson Kenneth C. 
Published: October 2019

Abstract
SDX-101 is an oral antineoplastic agent, has been evaluated in a phase I/II study in B-cell malignancies. It induces cytotoxicity at least in part, by significantly inhibiting expression of Mcl-1, an anti-apoptotic Bcl-2 family protein which is highly expressed in CLL cells. Here, we examined the cytotoxicity of SDX-101 against multiple myeloma (MM) cell lines. SDX-101 significantly inhibited growth in MM.1S, U266, RPMI8226 MM cell lines using MTT assays in a time- and dose-dependent fashion, with IC50s of 0.6mM, 1.0mM, and 0.4mM, respectively. In contrast, SDX-101 did not induce cytotoxicity in normal peripheral mononuclear cells (PBMCs) at these concentrations. Importantly, SDX-101 induced cytotoxicity even in dexamethasone (MM.1R)-, doxorubicin (RPMI-Dox40)-, and melphalan (LR5)- resistant MM cell lines. SDX-101 (0.3–1.25mM) triggered apoptosis associated with pro-caspase-3, pro-caspase-8, and PARP cleavage, as confirmed by immunoblotting. Although, interleukin-6 (IL-6) and insulin-like growth factor (IGF)-1 completely abrogates Dex-induced MM cell apoptosis, neither protects against SDX-101-induced apoptosis in MM.1S and RPMI8226 cells. Moreover, dexamethasone, Melphalan, and AS2O3 augment apoptosis induced by SDX-101. Importantly, SDX-101 downregulated both b-catenin and cyclin D1 expression in RPMI8226 cells. Finally, our recent studies demonstrate that the bone marrow (BM) microenvironment promotes MM cell growth, survival, and drug resistance while SDX-101 inhibits viability even if MM cells adherent to BM stromal cells; an environment in which cytotoxic potency is lost with other anti-neoplastic agents. Our data therefore demonstrate that SDX-101 induces apoptosis in MM cells via a mechanism different from conventional MM drugs, and support clinical trials of this agent, alone or in combination with conventional and/or novel agents to improve therapeutic outcome in MM.
Randomized Comparison of Weekly Administration and Daily Courses of Cladribine in Patients with Hairy Cell Leukemia - Updated Results.
Authors: Robak Tadeusz , Kasznicki Marek , Gora-Tybor Joanna , Dwilewicz-Trojaczek Jadwiga , Dmoszynska Anna , Wojtaszko Maria , Zdziarska Barbara , Calbecka Malgorzata , Hellmann Andrzej , Stella-Holowiecka Beata , Sulek Kazimierz , Skotnicki Aleksander , Zawilska Krystyna , Kloczko Janusz , Warzocha Krzysztof , Konopka Lech 
Published: October 2019

Abstract
Cladribine is the drug of choice in the treatment of hairy cell leukemia (HCL). However, its optimal method of administration is still unknown. There are suggestions that weekly administration is less toxic than daily schedule. We, therefore, compared these two methods of 2-CdA administration in a prospective randomized study. One group was treated with 2-CdA 0.12 mg/kg/d in 2 h i.v. infusion for 5 consecutive days and the second group received the same doses once a week for six weeks. Inclusion and response criteria were those recommended by Grever et al (J. Clin. Oncol 1995, 13, 974). From January 1998 to December 2003 118 patients with previously untreated symptomatic HCL were included into the study.
Both complete response (CR) and overall response (OR) rates are similar in compared groups. Response duration has not reached median yet. There is no statistically significant difference in toxicity between groups except for thrombocytopenia. It seems, however, that daily administration of 2-CdA may more frequently induce neutropenia and lead to more frequent infections.
In conclusion, the updated results of our study suggest that weekly administration of cladribine in HCL may be equally effective but less toxic than daily courses.
Patients (n=118) OR CR Thrombocytopenia grIII/IV Neutropenia grIII/IV Infections Relapsed Died Daily (n=59) 50 (85%) 43 (73%) 8 (13.6%) 21 (35.6%) 14 (24%) 5 (8.5%) 6 (10.1%) Weekly (n=59) 49 (83%) 44 (76%) 2 (3.4%) 12 (20.3%) 6 (10.2%) 5 (8.5%) 4 (6.8%) p value 0.8 0.8 0.04 0.06 0.05 1.0 0.5
POKEMON Is a Proto-Oncogene Which Plays a Key Role in Lymphomagenesis.
Authors: Maeda Takahiro , Hobbs Robin , Merghoub Taha , Guernah Ilhem , Zelent Arthur , Teruya-Feldstein Julie , Pandolfi Pier Paolo 
Published: October 2019

Abstract
POKEMON (for POK, Erythroid, Myeloid ONtogenic factor, also known as LRF) was originally isolated as a homologue of PLZF (Promyelocytic Leukemia Zinc Finger) which can physically interact with the BCL6 (B Cell Lymphoma 6) proto-oncogene.
Analysis of Pokemon−/− mice demonstrates that this transcriptional repressor plays a key developmental role whose function is required for cellular differentiation in multiple tissues such as skin, adipose tissue and hematopoietic lineage cells. Taking advantage of Pokemon−/− MEFs (Mouse Embryonic Fibroblasts), we found that Pokemon is indispensable for cellular transformation mediated by oncogenes (such as BCL6, E1A, H-RasV12, c-Myc, or T-Ag) and Pokemon overexpression overcomes oncogene induced premature senescence and apoptosis leading to oncogenic transformation by repressing p19ARF tumor suppressor. Furthermore, Pokemon−/− MEFs showed a premature senescence phenotype in early passage which was rescued by inactivation of p19ARF. To explore the oncogenic role of Pokemon in vivo, we generated Lck/Eμ Pokemon transgenic mice in which Pokemon is over expressed in T and B lineage cells under the control of Lck/Eμ promoter/enhancer. Strikingly, about 50% of the mice developed T lymphoblastic lymphoma (CD4+, CD8+, CD44 + and TdT+) after a latent period of 2 to 4 months. As Pokemon expression proved essential for cellular transformation and is oncogenic when overexpressed in vivo, we analyzed the levels of POKEMON expression in human cancers, performing Tissue Microarray Analysis (TMA). We first analyzed human B-cell lymphomas as POKEMON is normally co-expressed with BCL6 in the B-cell within the germinal center, and may therefore cooperate with BCL6 in lymphomagenesis. We analyzed and scored a total of 123 cases of diffuse large B-cell lymphoma (DLBCL) and 290 cases of follicular lymphoma (FL) for POKEMON protein expression levels. POKEMON was highly expressed in 25–35% and moderately expressed in 40–50% of both DLBCL and FL clinical samples. Strikingly, as previously shown for BCL6, POKEMON positivity predicted a better prognosis of overall survival in DLBCL. Interestingly, the vast majority (approximately 80%) of BCL6 positive DLBCLs and FLs were found to be POKEMON positive. By contrast, not all the POKEMON positive lymphomas expressed BCL6. Importantly, coexpression of POKEMON and BCL6 in DLBCL predicted an even better clinical outcome, identifying a clinically distinct DLBCL subtype.
The Seasonal Incidence of Venous Thromboembolism (VTE): A Population-Based Cohort Study.
Authors: Kobbervig Catie E. , Heit John A. , Petterson Tanya M. , Christianson Teresa J. , Bailey Kent R. , Melton L. Joseph 
Published: October 2019

Abstract
If the incidence of VTE varies by season, then the etiology of VTE could be related to seasonal exposures. However, the few studies that estimated VTE incidence by season reached conflicting conclusions.
Objective: To estimate the incidence of VTE by month and by season of the year.
Methods: Using the resources of the Rochester Epidemiology Project, we identified the inception cohort of Olmsted County, MN, residents with a first lifetime VTE over the 30-year period, 1966–1995 (n=2761). For each case, we reviewed the complete medical records in the community for the date of VTE onset, date of birth, gender and 48 baseline clinical characteristics commonly accepted as risk factors for VTE. We categorized cases as idiopathic (n=305) if no such characteristics were present; remaining cases were categorized as secondary. Incidence rates were calculated using the number of overall, idiopathic or secondary VTE cases by month of onset as the numerator, and age- and sex-specific estimates of the monthly population of Olmsted County as the denominator (yearly population estimates divided by 12).
Results: The incidence of VTE did not vary appreciably by month of the year for overall, idiopathic or secondary VTE (all p-values >0.2). However, the overall incidence of VTE was higher in the 3 summer months (June, July, August) compared to the 3 winter months (December, January, February; 132.6 vs. 116.9 per 100,000 person-years, respectively, both age- and sex-adjusted to year 2000 U.S. Whites; p-value = 0.026). The same general pattern was true for both idiopathic and secondary VTE, but separately neither was statistically significant (p-value=0.48 and 0.15, respectively).
Conclusions: The incidence of VTE is higher in the summer compared to the winter months, suggesting the hypothesis that vector-borne (e.g., mosquito, tick) and/or enteroviral infection may play a role in the etiology of VTE.
Staphylococcus Epidermidis Induced Platelet Aggregation Is Mediated by the Fibrinogen Binding Surface Protein SdrG.
Authors: Brennan Marian P. , Devocelle Marc , Foster Timothy J. , Cox Dermot 
Published: October 2019

Abstract
S. epidermidis is normally present on the surface of the skin, however in a hospital setting, it is responsible for many infections involving implanted medical devices resulting in potentially fatal complications such as infective endocarditis and septicemia. S. epidermidis has previously been shown to induce platelet aggregation (Ohshima et al. Microbiol Immunol 1991) through an unknown mechanism. The surface protein SdrG (serine-aspartate repeat G protein) is important in the initial colonization of the device, as it binds fibrinogen, which is one of the first proteins to coat foreign devices. We thus postulated that this SdrG fibrinogen complex may mediate the S. epidermidis interaction with platelets. In order to investigate the specific effects of SdrG on platelets, we expressed SdrG in Lactococcus lactis which does not activate platelets. L. lactis SdrG was able to support platelet adhesion in the absence of fibrinogen, and to a greater extent in the presence of fibrinogen suggesting both a direct interaction with the platelet and an indirect interaction via a fibrinogen bridge. Fibrinogen dependent adhesion was inhibited by both abciximab and tirofiban confirming an interaction with GPIIb/IIIa. Furthermore, SdrG when expressed in L. lactis can induce platelet aggregation with a lag time of 1.5 ± 0.4 min. This aggregation was inhibited by abciximab suggesting that it is true aggregation rather than agglutination. We have also shown this to be dependent on cyclooxygenase signalling, as it is inhibited by aspirin. SdrG binds to the C-terminus of the beta chain of fibrinogen (Ponnuraj K et al. , Cell 2003). We synthesized a 15-mer peptide mimicking the binding region of the fibrinogen beta chain in order to determine whether fibrinogen binding was important for this aggregation. The native fibrinopeptide NEEGFFSARGHRPLD increased the lag time for aggregation to 9.2 ± 1.4 min, however, the control peptide NEEGFFAARGHRPLD did not affect aggregation (1.4 ± 0.3 min). The lag time did not increase further with saturating concentrations of peptide concentrations suggesting instability of the peptide, or a second mechanism involved in the aggregation which is consistent with the fibrinogen independent interaction seen in the adhesion assay. This work shows that SdrG alone is sufficient to support platelet adhesion and aggregation. SdrG mediates platelet activation through a novel mechanism via GPIIb/IIIa, and an as yet unknown direct interaction. Thus SdrG appears to be the dominant virulence factor for S. epidermidis induced thrombosis, therefore, inhibition of these interactions have potential for treatment of thrombotic complications associated with S. epidermidis infections.
Both 5′ and 3′ Distal Regulatory Elements Are Required for Human CD34 Gene Expression.
Authors: Okuno Yutaka , Levantini Elena , Tatetsu Hiro , Mitsuya Hiroaki , Tenen Daniel G. 
Published: October 2019

Abstract
In order to understand the controls of gene expression in hematopoietic stem cells (HSC), we have studied the regulation of human CD34, a cell surface glycoprotein used in isolation of HSC. We previously reported that regions 10 to 18 kb 5′ upstream of the transcription start site (TSS) and/or 17 to 26 kb 3′ downstream of the transcription termination site (TTS) of the human CD34 gene contain critical elements for expression in vivo. Mice transgenic for a human CD34 PAC clone (PAC54A19) that includes 18 kb of 5′ and 26 kb of 3′ human CD34 flanking sequences expressed human CD34 antigen in the majority of HSC. Because these transgenic mice also demonstrated downregulation of human CD34 gene expression with maturation of hematopoietic cells, we concluded that these critical cis-elements are necessary not only for human CD34 expression in immature cells, but also for downregulation in mature cells. To further delineate the distal cis-elements which regulate the human CD34 gene, we generated two deletion constructs which removed sequences either upstream from −12.8 kb (PmeI deletion) or downstream of +18.2 kb (FseI deletion) of the human CD34 gene. We used a murine myeloblastic cell line, 416B, to test these constructs. We first generated stable clones of 416B cells with PAC54A19; these stable clones expressed human CD34 RNA and protein. In contrast, neither PmeI nor FseI deletion constructs conferred human CD34 mRNA or protein expression in these 416B stable cell lines. Therefore, we conclude that both 5′ upstream and 3′ downstream distal cis-elements are necessary for proper human CD34 expression in cell lines. We also performed DNaseI hypersensitivity assays to localize open chromatin structures in the human CD34 gene in several human myeloblastic cell lines. We detected one DNaseI hypersensitive site (DHS) −12.5 kb upstream of the TSS and several DHS in the region located between +17 kb to +26 kb 3′ downstream of the human CD34 TTS in the human myeloblastic CD34+ KG1a cell line. In addition, we performed similarity searches of the −18 kb to −10 kb human CD34 5′ flanking sequence and +17 kb to +26 kb human CD34 3′ flanking sequence, comparing with the murine CD34 genomic sequence. We identified one conserved region in the −11.5 kb 5′ upstream region of the TSS and one highly conserved region located +19 kb 3′ downstream region of the TTS. To further localize distal cis-elements, we generated several deletion constructs in the parental PAC54A19 PAC clone using the ET cloning system, which facilitates manipulation of PACs by homologous recombination in bacteria. Using this method, we showed that deletion of a 600 bp region located 15 kb 5′ of the TSS or a 1000 bp sequence located 19 kb downstream of the human CD34 gene led to loss of human CD34 expression in 416B stable lines. Our current efforts are focused on identifying the transcription factors that bind to these regions to regulate the expression of human CD34 in stem cells.