bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coactivation of NF-κB and Notch signaling is sufficient to induce B-cell transformation and enables B-myeloid conversion
Authors: Xiu Yan , Dong Qianze , Fu Lin , Bossler Aaron , Tang Xiaobing , Boyce Brendan , Borcherding Nicholas , Leidinger Mariah , Sardina José Luis , Xue Hai-hui , Li Qingchang , Feldman Andrew , Aifantis Iannis , Boccalatte Francesco , Wang Lili , Jin Meiling , Khoury Joseph , Wang Wei , Hu Shimin , Yuan Youzhong , Wang Endi , Yuan Ji , Janz Siegfried , Colgan John , Habelhah Hasem , Waldschmidt Thomas , Müschen Markus , Bagg Adam , Darbro Benjamin , Zhao Chen 
Published: October 2019

AbstractNF-κB and Notch signaling can be simultaneously activated in a variety of B-cell lymphomas. Patients with B-cell lymphoma occasionally develop clonally related myeloid tumors with poor prognosis. Whether concurrent activation of both pathways is sufficient to induce B-cell transformation and whether the signaling initiates B-myeloid conversion in a pathological context are largely unknown. Here, we provide genetic evidence that concurrent activation of NF-κB and Notch signaling in committed B cells is sufficient to induce B-cell lymphomatous transformation and primes common progenitor cells to convert to myeloid lineage through dedifferentiation, not transdifferentiation. Intriguingly, the converted myeloid cells can further transform, albeit at low frequency, into myeloid leukemia. Mechanistically, coactivation of NF-κB and Notch signaling endows committed B cells with the ability to self renew. Downregulation of BACH2, a lymphoma and myeloid gene suppressor, but not upregulation of CEBPα and/or downregulation of B-cell transcription factors, is an early event in both B-cell transformation and myeloid conversion. Interestingly, a DNA hypomethylating drug not only effectively eliminated the converted myeloid leukemia cells, but also restored the expression of green fluorescent protein, which had been lost in converted myeloid leukemia cells. Collectively, our results suggest that targeting NF-κB and Notch signaling will not only improve lymphoma treatment, but also prevent the lymphoma-to-myeloid tumor conversion. Importantly, DNA hypomethylating drugs might efficiently treat these converted myeloid neoplasms.
Novel drivers and modifiers of MPL-dependent oncogenic transformation identified by deep mutational scanning
Authors: Bridgford Jessica L. , Lee Su Min , Lee Christine M. M. , Guglielmelli Paola , Rumi Elisa , Pietra Daniela , Wilcox Stephen , Chhabra Yash , Rubin Alan F. , Cazzola Mario , Vannucchi Alessandro M. , Brooks Andrew J. , Call Matthew E. , Call Melissa J. 
Published: October 2019

Abstract
The single transmembrane domain (TMD) of the human thrombopoietin receptor (TpoR/myeloproliferative leukemia [MPL] protein), encoded by exon 10 of the MPL gene, is a hotspot for somatic mutations associated with myeloproliferative neoplasms (MPNs). Approximately 6% and 14% of JAK2 V617F− essential thrombocythemia and primary myelofibrosis patients, respectively, have “canonical” MPL exon 10 driver mutations W515L/K/R/A or S505N, which generate constitutively active receptors and consequent loss of Tpo dependence. Other “noncanonical” MPL exon 10 mutations have also been identified in patients, both alone and in combination with canonical mutations, but, in almost all cases, their functional consequences and relevance to disease are unknown. Here, we used a deep mutational scanning approach to evaluate all possible single amino acid substitutions in the human TpoR TMD for their ability to confer cytokine-independent growth in Ba/F3 cells. We identified all currently recognized driver mutations and 7 novel mutations that cause constitutive TpoR activation, and a much larger number of second-site mutations that enhance S505N-driven activation. We found examples of both of these categories in published and previously unpublished MPL exon 10 sequencing data from MPN patients, demonstrating that some, if not all, of the new mutations reported here represent likely drivers or modifiers of myeloproliferative disease.
Long-term effects of intermittent interleukin 2 therapy in patients with HIV infection: characterization of a novel subset of CD4+/CD25+ T cells
Authors: Sereti Irini , Martinez-Wilson Hector , Metcalf Julia A. , Baseler Michael W. , Hallahan Claire W. , Hahn Barbara , Hengel Richard L. , Davey Richard T. , Kovacs Joseph A. , Lane H. Clifford 
Published: October 2019

AbstractThe long-term immunologic effects of intermittent interleukin 2 (IL-2) therapy were evaluated in a cross-sectional study by comparing 3 groups: HIV-seronegative volunteers, HIV-infected (HIV+) patients receiving highly active antiretroviral therapy (HAART), and HIV+ patients receiving HAART and intermittent IL-2. Whole-blood immunophenotyping was performed to study expression of the IL-2 receptor chains on T lymphocytes and natural killer cells and to further characterize CD4+/CD25+ T cells. Increased CD25 expression, especially in CD4+ T cells but also in CD8+ T cells, without increases in expression of the β and γ chains of the IL-2 receptor was detected in the IL-2 group. Up to 79% of naive CD4+ T cells (median, 61%) from patients in the IL-2 group expressed CD25, and the number of naive CD4+/CD25+ T cells correlated positively with both the total and naive CD4+ T-cell counts. A discrete population of CD45 double intermediate RA+/RO+CD4+ cells was also preferentially expanded in the IL-2 group, and the number of these cells strongly correlated with the total CD4+ count. Despite increases in CD25 expression, T lymphocytes from patients treated with IL-2 did not have increased expression of early (CD69) or late (CD95) activation markers or evidence of recent proliferation (Ki67). Both CD4+/CD25+ and CD4+/CD25− cells from IL-2–treated HIV+ patients proliferated in response to mitogens, specific antigens, and T-cell-receptor–mediated stimuli. Thus, intermittent administration of IL-2 in HIV+ patients leads to preferential expansion of a unique subset of CD4+ T cells that may represent a critical population in T-cell homeostasis.
Role for macrophage inflammatory protein (MIP)-1α and MIP-1β in the development of osteolytic lesions in multiple myeloma
Authors: Abe Masahiro , Hiura Kenji , Wilde Javier , Moriyama Keiji , Hashimoto Toshihiro , Ozaki Shuji , Wakatsuki Shingo , Kosaka Masaaki , Kido Shinsuke , Inoue Daisuke , Matsumoto Toshio 
Published: October 2019

AbstractMultiple myeloma (MM) cells cause devastating bone destruction by activating osteoclasts in the bone marrow milieu. However, the mechanism of enhanced bone resorption in patients with myeloma is poorly understood. In the present study, we investigated a role of C-C chemokines, macrophage inflammatory protein (MIP)–1α and MIP-1β, in MM cell-induced osteolysis. These chemokines were produced and secreted by a majority of MM cell lines as well as primary MM cells from patients. Secretion of MIP-1α and MIP-1β correlated well with the ability of myeloma cells to enhance osteoclastic bone resorption both in vitro and in vivo as well as in MM patients. In osteoclastogenic cultures of rabbit bone cells, cocultures with myeloma cells as well as addition of myeloma cell-conditioned media enhanced both formation of osteoclastlike cells and resorption pits to an extent comparable to the effect of recombinant MIP-1α and MIP-1β. Importantly, these effects were mostly reversed by neutralizing antibodies against MIP-1α and MIP-1β, or their cognate receptor, CCR5, suggesting critical roles of these chemokines. We also demonstrated that stromal cells express CCR5 and that recombinant MIP-1α and MIP-1β induce expression of receptor activator of nuclear factor-κB (RANK) ligand by stromal cells, thereby stimulating osteoclast differentiation of preosteoclastic cells. These results suggest that MIP-1α and MIP-1β may be major osteoclast-activating factors produced by MM cells.
Regeneration of Bone Marrow from Adipose-Derived Stromal Cells - a Novel Approach for the Treatment of Fibroblastic Bone Marrow Diseases.
Authors: Ogawa Rei , Mizuno Hiroshi , Hyakusoku Hiko , Migita Makoto , Shimada Takashi 
Published: October 2019

Abstract
BACKGROUND: Taking advantage of homogeneously marked cells from green fluorescent protein (GFP) transgenic mice, we have previously demonstrated that adipose-derived stromal cells (ASCs) and bone marrow-derived stromal cells (BSCs) differentiate into a variety of cell lineages both in vitro and in vivo. In the present study, we extended this approach to regenerate bone marrow.
METHODS: ASCs isolated from the inguinal fat pads of GFP mice were cultured in vitro for five passages and seeded onto hydroxyapatites with small pores. The hydroxyapatites including ASCs were subsequently implanted into immunocompetent mice subcutaneously. Two months later, the hydroxyapatites were extirpated for histological and immunohistochemical analyses.
RESULTS: The specimens were covered with adipose tissues including extensively developed microvessels and GFP+ cells. Histological examination showed that the pores were filled with typical bone marrow composed of adipocytes, hematopoietic cells, vasculatures, and matrix. Immunohistochemical analysis confirmed that the GFP+ ASCs had differentiated into osteoblasts and vascular endothelial cells, but not hematopoietic cells.
CONCLUSION: We demonstrated for the first time that bone marrow can be regenerated from ASCs. Bone marrow regeneration from non-bone-marrow-derived cells will have a great impact on the treatment of various bone marrow-related disorders, in particular idiopathic myelofibrosis and osteopetrosis, in which there is no place for hematopoietic stem cells to survive. Furthermore, in combination with gene transfer, bone marrow regeneration may be applied to the development of novel therapeutic approaches for various kinds of hematopoietic diseases.
IPI-504: A Novel hsp90 Inhibitor with In Vitro and In Vivo Anti-Tumor Activity.
Authors: Mitsiades Constantine S. , Mitsiades Nicholas , Rooney Melissa , Negri Joseph , Geer Corey C. , Pink Melissa , Pien Christine , Hideshima Teru , Chauhan Dharminder , Munshi Nikhil C. , Richardson Paul G. , Barrett John , Tong Jeffrey K. , Grayzel David , Palombella Vito , Adams Julian , Anderson Kenneth C. 
Published: October 2019

Abstract
We have previously shown that inhibitors of the hsp90 molecular chaperone (including geldanamycin, 17-allylamino-17-demethoxy-geldanamycin (17-AAG) and other members of the ansamycin family) potently induce growth arrest and apoptosis of a large panel of drug-sensitive and -resistant MM cell lines, as well as tumor cells freshly isolated from patients with relapsed refractory MM; and sensitize these cells to other pro-apoptotic anti-tumor agents. While multiple phase I clinical trials have shown that biologically active doses of 17-AAG can be administered without significant hsp90-related toxicities, the insolubility of this compound in most conventional clinical solvents, as well as the practical limitations of DMSO-based formulations that were used in the original clinical trials have generated the need to develop more effective and practical approaches to administer 17-AAG to patients. Herein we describe the in vitro and in vivo pre-clinical profile of IPI-504, a novel analog of 17-AAG, which is soluble in aqueous formulations and can bypass key limitations of the DMSO-based formulations for administration of 17-AAG. Our in vitro studies show that IPI-504 has anti-tumor activity against a broad panel of primary MM tumor cells as well as MM cell lines (including cells resistant to cytotoxic chemotherapeutics, proteasome inhibitor bortezomib, thalidomide or its immunomodulatory thalidomide derivatives, and/or Apo2L/TRAIL). Based on hierarchical clustering analyses, logistic and linear regression models, we observed that the profiles of drug sensitivity of MM cells to IPI-504 were consistent with the profiles of sensitivity to 17-AAG. Similarly, IPI-504 triggered a constellation of molecular sequelae that were consistent with hsp90 inhibition by 17-AAG, including suppression of cell surface expression and down-stream signaling (via PI-3K/Akt and Ras/Raf/MAPK) of receptors for IGF-1 and IL-6; decreased intracellular levels of several key kinases, including Akt, Raf, IKK-α; suppressed expression of several intracellular anti-apoptotic proteins (e.g. FLIP, XIAP, cIAP2); leading to tumor cell sensitization to other pro-apoptotic agents (e.g. cytotoxic chemotherapy or PS-341). Importantly, in our mouse model of diffuse MM bone lesions in SCID/NOD mice, IPI-504 (50 mg/kg, i.v. twice weekly) was able to prolong the survival of mice vs. vehicle-treated mice (p<0.01, log-rank test), without significant treatment-related toxicities. These results indicate that hsp90 inhibitors have significant anti-MM activity in vivo, which, coupled with our ex vivo mechanistic and molecular profiling studies, have provided the framework for upcoming clinical trials of this novel class of agents in patients with MM.
T-Cell Function in Patients with B-Cell Chronic Lymphocytic Leukemia (B-CLL) Following Alemtuzumab (Campath®) or Fludarabine Treatment.
Authors: Kiaii Shahryar , Mozaffari Fariba , Lundin Jeanette , Rezvany Reza , Chudhury Aniruddha , Mellstedt Håkan , Osterborg Anders 
Published: October 2019

Abstract
Fludarabine and alemtuzumab (humanized anti-CD52 antibody, Campath®) are both used as routine therapy for patients with B-CLL. Fludarabine and in particular alemtuzumab, in addition to their antitumor effects, induce long-lasting suppression of T-cell numbers in blood. T-cell suppression, in combination with advanced disease, may result in an increased risk of opportunistic and other infections. In addition to a decrease in circulating T cells, functional defects in T cells have been described following alemtuzumab therapy for non-malignant disorders; however, only a limited amount of information exists about the effect of alemtuzumab on T-cell function in patients with B-CLL. The aim of the present study was to characterize in detail various aspects of T-cell function in patients with B-CLL who were in stable unmaintained PR or CR following fludarabine (n = 9) and alemtuzumab (n = 10) treatment as well as in age-matched healthy control donors (n = 10). CD4 and CD8 T-cell subsets of freshly obtained peripheral blood mononuclear cells (PBMC) were analyzed by flow cytometry to measure the expression of TCR-CD3 ζ chain, p56Lck, p59Fyn, ZAP-70, and PI3 Kinase as well as intracellular production of IFN-γ and IL-4. Additional analyses were performed to measure the proliferative response capability to a recall antigen (PPD) in alemtuzumab-treated patients and (as a control) indolent, untreated B-CLL patients (n = 11). The expression of IFN-γ and IL-4 (measured as mean fluorescence intensity [MFI]), but not the total number of positive cells, was significantly higher in CD4 and CD8 T cells for both CLL groups compared to healthy donors with the highest expression observed in alemtuzumab-treated patients. The total number of T cells that expressed the five signaling molecules was significantly lower in treated patients versus control donors; however, there were no differences between fludarabine- and alemtuzumab-treated patients. MFI analysis showed a significant increase in the TCR-CD3 ζ chain in fludarabine-treated patients compared to control donors; however, MFI analysis revealed no other significant differences between control group patients and fludarabine- and alemtuzumab-treated patients. Moreover, the proliferative response to PPD was not significantly different in alemtuzumab-treated patients and indolent CLL patients. In conclusion, these results suggest that the intrinsic signal transduction machinery in T cells is relatively well-preserved, such that T cells remain functionally intact following fludarabine or alemtuzumab therapy despite a marked reduction in their numbers. These results provide a better understanding of the immune suppression induced by alemtuzumab and fludarabine therapy in B-CLL patients.
Identification of Thymus Settling Progenitors.
Authors: Schwarz Benjamin A. , Bhandoola Avinash 
Published: October 2019

Abstract
T cells develop in the thymus, but are ultimately derived from hematopoietic stem cells (HSCs) that reside in the bone marrow. In order to produce T cells throughout adult life, the thymus must be periodically seeded by bone marrow progenitors via the blood. The identity of progenitors that seed the adult thymus is unknown. To determine which bone marrow progenitors that have access to they thymus, we analyzed the blood of adult mice (Schwarz & Bhandoola, Nature Immunology 2004). We found that the only progenitors in blood with T lineage potential were lineage negative cells with high expression of Sca-1 and c-Kit (LSK). Such LSK cells in blood were potent T lineage progenitors, with the capacity to expand over a million fold in the thymus. Like the corresponding population in the bone marrow, the blood LSK population was heterogeneous, containing HSCs and downstream multipotent progenitors (MPPs) including RAG-expressing early lymphoid progenitors (ELPs) and CD62L+ cells. In order to determine which of these LSK subsets can settle in the thymus, we developed a quantitative assay for thymic seeding in normal adult mice. We find that the fraction of LSK cells that settle in the thymus from the blood is extremely small. Of the estimated 3,000 to 4,000 LSK cells that pass through the thymic circulation each day, less than 10 cells are able to settle in the thymus. Our data suggest that any decrease in thymic seeding, as may occur in aging, would lead to a decrease in total thymic output.
Enforced Expression of Pax-5 Results in Developmental Arrest, Immortalisation and Aberrant Expression of B Lineage Genes in Committed Myeloid Progenitors.
Authors: Anderson Kristina , Rusterholz Corinne , Mansson Robert , Jensen Christina , Bacos Karl , Sasaki Yutaka , Sigvardsson Mikael , Jacobsen Sten Eirik W. 
Published: October 2019

Abstract
The paired domain transcription factor Pax-5, has been demonstrated to play a crucial role in development and final commitment of the B cell lineage. In fact, otherwise committed B cell progenitors acquire multipotentiality (myelo-lymphoid) potential upon targeted deletion of Pax-5 expression (Nutt et al. Nature.1999; 401:556–562). Thus, in addition, to promoting B cell development through acting as an activator of transcription of B cell specific genes such as CD19, Pax-5 is also thought to act as a suppressor of transcription of genes involved in determination of other blood cell lineages. However, it remains unclear how Pax-5 might repress myeloid development. Thus, we investigated the effect of Pax-5 expression on lympho-myeloid differentiation by overexpressing human (h)Pax-5 (through retroviral transduction) in adult murine bone marrow Linlo/−Sca-1+c-kit+ (LSK) cells. When compared to cells transduced with a control vector, LSK cells ectopically expressing hPax-5 very efficiently developed into hPax-5+B220+CD19+ pro-B cells in response to flt3 ligand and interleukin-7 in vitro. In contrast, when hPax-5+ LSK cells were cultured under myeloid conditions, we consistently observed development of a highly proliferative and immortalised bi-phenotypic (B-myeloid) hPax-5+B220+Gr-1+Mac-1+ population that predominantly consisted of immature myeloblasts but also maturated granulocytes and monocytes. Global gene expression analysis by micro-array, and confirmation by RT-PCR, demonstrated that hPax-5+B220+Gr-1+Mac-1+ cells also possessed a bi-phenotypic gene expression pattern, characteristic for B-cell as well as myeloid lineages including the Pax-5 target B cell genes mb-1 and BLNK as well as GM-CSFRα and low levels of C/EBPα. Similar findings were observed when targeting committed myeloid progenitors. These findings suggest that in addition to promoting B cell development, Pax-5 is capable of inhibiting/blocking myeloid differentiation and inducing immortalization as well as expression of B cell specific genes in otherwise myeloid committed progenitors. These findings motivate a careful investigation of the potential involvement of Pax-5 also in myeloid leukemias.
High Level CD24 Expression Is Correlated to Higher Metastatic Potential of Breast Cancer Cells.
Authors: Park Gyeongsin , Kim Hae-Jung , Park Bo-Bae , Park Woo-Chan , Lee Kyo-Young , Kang Chang-Suk , Oh Il-Hoan 
Published: October 2019

Abstract
Cancer stem cells are subpopulations of cancer cells with potential to seed and develop new cancer mass causing recurrence and/or metastasis, but phenotypic characteristics of such cell populations remains uncertain. As an initial approach to identify heterogeneity in cancer mass, we performed comparative study using matched pairs of primary breast cancer masses and their immediate metastatic counterparts in regional LN.
First, in the gene expression study of primary tumor mass and their LN counterpart using cDNA microarray, about 100 genes showed differential expression between the two, but with variations depending on cases (3 Exp). In addition, when fresh individually matched surgical block from primary mass and LN mass were each inoculated into NOD/SCID mice, higher growth of LN-derived mass was observed supporting distinction between the two (2 Exp). In subsequent search for phenotypic difference between the two, 99 primary-LN tissue pairs with individual matching were immunostained for CD24, a newly proposed marker for cancer stem cell, and analysed by semiquantitative scoring (0, 1+, 2+, 3+, 4+). Among 73 cases with positive staining for CD24, higher level of CD24 expression in LN mass compared to its matched primary tumor tissue was observed in 38 cases (52.1%), while the opposite was for only 7 cases (9.6%). Furthermore, high level expression (4+) of CD24 was observed more frequently in LN tumor tissues (63.0%, 46/73) than in their primary tumor counterparts (26%, 19/73)( P = 0.000). These results support the notion that cancer cells in tumor mass are clonally heterogeneous and suggest that CD24 expression could be related to characteristic of metastatic cancer stem cells.
Significance of Marrow Fibrosis in Chronic Phase Chronic Myelogenous Leukemia (CML) Post Interferon-A Failure Treated with Imatinib Mesylate Therapy.
Authors: Alvarez Ricardo H. , Kantarjian Hagop M. , Bueso-Ramos Carlos , Talpaz Moshe , O’Brien Susan , Giles Francis , Rios Mary Beth , Shan Jianqin , Cortes Jorge 
Published: October 2019

Abstract
Background. Myelofibrosis in the setting of CML has been historically associated with poor prognosis and with transformation. Its significance in the context of imatinib therapy is unknown.
Study Aims. To evaluate the prognostic relevance of myelofibrosis in patients with chronic phase CML post interferon-a failure treated with imatinib.
Patients and Methods. 110 patients with Philadelphia chromosome (Ph)-positive CML were analyzed. Imatinib was given at 400 mg orally daily. Marrow biopsies obtained prior to imatinib were subjected to Snook’s reticulin staining and graded on a scale of 1 to 4 for the degree of reticulin fibrosis as previously reported (Dekmezian.Cancer 59:1739, 1987). Severe fibrosis included grades 3–4.
Results. Patients’ median age was 57 years (24 to 81). Median duration of chronic phase was 31 months (range 6–148). Reticulin fibrosis was grade 1 in 4%, grade 2 in 35%, grade 3 in 28% and grade 4 in 33%. Splenomegaly was more frequent with grade 3–4 fibrosis (p=0.04). However, patients with severe fibrosis had a similar incidence of complete cytogenetic response and survival as those with lesser degrees of fibrosis.
Parameter Fibrosis Grade 1–2 3–4 pvalue No. analyzed 43 67 No. cytogenetic CR (%) 25(58) 45(67) .45 Estimated cytogenetic CR (%) 88% 80% .27
Conclusions. Imatinib, being a highly effective therapy in CML, may have reduced or eliminated the previously known prognostic impact of myelofibrosis in CML.