bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrin alpha 6 Is Essential for Fetal Hematopoietic Progenitor, but Not Fetal Stem Cell Homing to Bone Marrow.
Authors: Qian Hong , Jacobsen Sten Eirik W. , Ekblom Marja 
Published: October 2019

Abstract
Homing of transplanted hematopoietic stem cells (HSC) in the bone marrow (BM) is a prerequisite for establishment of hematopoiesis following transplantation. However, although multiple adhesive interactions of HSCs with BM microenviroment are thought to critically influence their homing and subsequently their engraftment, the molecular pathways that control the homing of transplanted HSCs, in particular, of fetal HSCs are still not well understood. In experimental mouse stem cell transplantation models, several integrins have been shown to be involved in the homing and engraftment of both adult and fetal stem and progenitor cells in BM. We have previously found that integrin a6 mediates human hematopoietic stem and progenitor cell adhesion to and migration on its specific ligands, laminin-8 and laminin-10/11 in vitro (Gu et al, Blood, 2003; 101:877). Furthermore, integrin a6 is required for adult mouse HSC homing to BM in vivo (Qian et al., Abstract American Society of Hematology, Blood 2004 ). We have now found that the integrin a6 chain like in adult HSC is ubiquitously (>99%) expressed also in fetal liver hematopoietic stem and progenitor cells (lin−Sca-1+c-Kit+, LSK ). In vitro, fetal liver LSK cells adhere to laminin-10/11 and laminin-8 in an integrin a6b1 receptor-dependent manner, as shown by function blocking monoclonal antibodies. We have now used a function blocking monoclonal antibody (GoH3) against integrin a6 to analyse the role of the integrin a6 receptor for the in vivo homing of fetal liver hematopoietic stem and progenitor cells to BM. The integrin a6 antibody inhibited homing of fetal liver progenitors (CFU-C) into BM of lethally irradiated recipients. The number of homed CFU-C in BM was reduced by about 40% as compared to the cells incubated with an isotype matched control antibody. To study homing of long-term repopulating stem cells, BM cells were first incubated with anti-integrin alpha 6 or anti-integrin alpha 4 or control antibody, and then injected intravenously into lethally irradiated primary recipients. After three hours, BM cells of the primary recipients were analysed by competitive repopulation assay in secondary recipients. Blood analysis up to 16 weeks after transplantation showed that no reduction of stem cell reconstitution from integrin a6 antibody treated cells as compared to cells treated with control antibody. In accordance with this, fetal liver HSC from integrin a6 gene deleted embryos did not show any impairment of homing and engraftment in BM as compared to normal littermates. These results suggest that integrin a6 plays an important developmentally regulated role for homing of distinct hematopoietic stem and progenitor cell populations in vivo.
Cytogenetics in Adult De Novo Acute Myeloid Leukemia: An Institutional Experience of a Predominantly Minority Population.
Authors: Berko Ebenezer , Osafo David , Tamkus Deimante , Griza Decebal S. , Sloan Steven , Jajeh Ahmad , Kovarik Paula , Catchatourian Rose 
Published: October 2019

Abstract
Cytogenetic findings at diagnosis correlate with prognosis in adult AML. Data have been largely derived from Caucasian populations. The purpose of this study was to define the frequency of cytogenetic abnormalities in de novo AML in a predominantly minority population and compare the data with that reported in the literature. We performed a retrospective review of cytogenetic findings at diagnosis in 40 adult AML patients diagnosed between 1999 and 2005. 17 African Americans, 11 Hispanics, 7 Caucasians, 1 Asian and 4 unknown ethnicity made up this population (72.5% minority). The age range was between 15 and 82 years. 28 patients (70%) were less than 55 years and 15 (37.5%) were less than 35 years of age. 75% of patients had abnormal karyotypes and 25% had normal karyotypes. Prognostic group categorization showed that 45% of patients were in the adverse group, 35% in the intermediate group and 20% in the favorable group. The most common cytogenetic finding was complex abnormalities occurring in 37.5% of patients. The frequency of complex abnormalities with adverse prognosis found in this predominantly minority population is higher than that reported in the literature (12% in SWOG/ECOG study; 6% in MRC AML 10 trial). Our study is limited by its small sample size. Further studies with a larger sample size would be needed to clarify the role of race/ethnicity in cytogenetic aberrations in AML.
Homoharringtonine Induced Apoptosis of Leukemic Cell Line MUTZ-1 Cells Is Mediated by the Endoplasmic Reticulum Stress Pathway.
Authors: Cai Zhen , Hu Jie , He Donghua , Wu Wenjun , Gao Liang , Bao Hanying 
Published: October 2019

Abstract
The endoplasmic reticulum (ER) is the major organelle for protein synthesis and maturation as well as the regulation of intracellular calcium (Ca2+) homeostasis. The accumulation of unfolded proteins in the ER lumen or depletion of Ca2+ from the ER lumen leads to the ER stress response known as unfold protein response. This response enhances the ability of protein folding by inducing ER resident chaperones such as glucose-regulated stress protein 78 or immunoglobulin heavy-chain binding protein (GRP78/BIP) mRNA and protects the cell from ER stress by splicing of X-box binding protein 1 (XBP-1) mRNA, and synthesis of phosphatidylcholine, the primary phospholipid of the ER membrane. However, when the ER function is severely impaired, the organelle elicits apoptotic signals. One of the components of the ER stress-mediated apoptosis pathway is C/EBP homologous protein (CHOP), also known as growth arrest- and DNA damage-inducible gene 153. Homoharringtonine (HHT), one of the alkaloids from a Chinese natural plant, Cephalotaxus, has currently been used successfully in the treatment of acute and chronic myeloid leukemias and has been shown to induce apoptosis of different types of leukemic cells in vitro. But the mechanism of how HHT causes apoptosis remains unknown. In this study, we investigated the relationship between ER stress and apoptosis of MUTZ-1 cells (cell line of MDS) treated with HHT. HHT induced growth inhibition of MUTZ-1 cells was measured by MTT method. Apoptosis was detected by FACS and observed by light and electron microscopy. Concentration of cystosolic calcium was measured with the spectrofluorometer. The mRNA expression level of CHOP, BIP and XBP1 was detected by semi-quantitative RT-PCR. We found that after exposure of MUTZ-1 to HHT (rang 0.02~0.4ug/ml) for 24 to 72 hours, the IC50 and the percentage of apoptotic MUTZ-1 cells increased in a time and dose dependent manner. Typical apoptotic cells and release of Ca2+ from the cytosolic Ca2+ storage were observed. RT-PCR analysis revealed that mRNAs for ER stress-associated proapoptotic factor CHOP and an ER chaperone BiP, XBP1 are markedly increased at 4 hours after 0.05ug/ml HHT treated and reach the top level at 12hours, then decreased to the level before treatment at 24 hours. Induction of ER stress-responsive proteins (BIP and CHOP) was also observed at 12 hours. These results indicate that HHT could not only inhibit MUTZ-1 growth but also induce MUTZ-1 apoptosis and HHT-induced MUTZ-1 cell death is likely mediated by the ER stress pathway.
Myelofibrosis in a Patient with Sarcoidosis.
Authors: Abbasi Elham , Liu Enli , Mims Martha P. , Udden Mark M. 
Published: October 2019

Abstract
Secondary bone marrow fibrosis can be seen in several conditions such as hematological malignancy, metastatic malignancy and autoimmune disorders like lupus. We report here a 50 year old Middle Eastern female with a history of pulmonary sarcoidosis diagnosed by lung biopsy in January of 2004, beta thalassemia trait, hypertension and hypothyroidism. At the time of diagnosis she was started on bronchodilating inhalers. Nine months later she was referred to hematology for left lower quadrant pain and possible enlarged spleen on examination. CT scan revealed extensive mediastinal, retroperitoneal and inguinal adenopathy but no splenomegaly. Hemoglobin was 12.3 with a hematocrit of 38 and an MCV of 61, WBC was 7.8with a normal differential and Platelet count was 238. Her peripheral blood smear revealed moderate anisocytosis, polychromasia and some teardrops. Bone marrow biopsy showed significant fibrosis confirmed by reticulin staining. Biopsy of an inguinal node was consistent with her lung biopsy showing granulomatous disease. In the course of follow up she developed fever, fatigue, anemia, and splenomegaly proven by ultrasound (16cm). Her labs also revealed increased ACE and ESR levels. We started her on prednisone at 1mg/kg and her hemoglobin rose from 8.0 to 12.5. X-chromosome transcription-based clonality assays were employed to deteremine whether this patient had primary myelofibrosis with myeloid metaplasia, a myeloproliferative disorder characterized by clonal hematopoiesis or secondary myelofibrosis which is characterized by polyclonal hematopoiesis. Six exonic X-chromosome polymorphisms were tested to determine the clonality of the patient’s platelets and granulocytes (Liu, BLOOD 2003). Unfortunately, this patient was not informative in any of six exonic X-chromosome polymorphism markers, and we could not determine the clonality of hematopoiesis. Peripheral blood CD34 level; however, was low normal, consistent with reactive fibrosis rather than a primary myeloproliferative disease. To our knowledge this is the first report of secondary bone marrow fibrosis in sarcoidosis.
Therapy-Associated Immunosuppression and Opportunistic Infections in Multiple Myeloma Patients.
Authors: Schutt Philipp , Brandhorst Dieter , Stellberg Werner , Poser Miriam , Ebeling Peter , Muller Siemke , Buttkereit Ulrike , Opalka Bertram , Lindemann Monika , Grosse-Wilde Hans , Seeber Siegfried , Moritz Thomas , Nowrousian Mohammad R. 
Published: October 2019

Abstract
This study evaluates cellular and humoral immune parameters in myeloma patients focusing on the effect of treatment and the risk of opportunistic infections. Peripheral blood lymphocyte subsets and serum levels of nonmyeloma immunoglobulins (Ig) were analyzed in 480 blood samples from 77 myeloma patients. Untreated myeloma patients exhibited significantly reduced CD4+/45RO+, CD19+, CD3+/HLA-DR+, and natural killer (NK) cells as well as nonmyeloma IgA, IgG, and IgM. Conventional-dose chemotherapy (conv-CTX) resulted in significantly reduced CD4+ and even further decline of CD4+/CD45RO+ and CD19+ cells, most notably in relapsed patients. Patients treated with conv-CTX in combination with thalidomide showed significantly increased counts of monocytes as well as serum levels of nonmyeloma IgA and IgM as compared to patients on conv-CTX without additional thalidomide. Following high-dose chemotherapy (HD-CTX) prolonged immunosuppression was observed. While CD8+, NK, CD19+, and CD4+/CD45RO+ cells recovered to normal values within 60, 90, 360, and 720 days, respectively, CD4+ counts remaining reduced even thereafter. Nine opportunistic infections were observed including 5 cytomegalovirus (CMV) diseases, 1 pneumocystis carinii pneumonia (PCP), and 3 varicella zoster virus (VZV) infections with CMV diseases and PCP occurring exclusively after HD-CTX. Opportunistic infections were correlated with severely reduced CD4+ as well as CD4+/CD45RO+, and CD19+ counts. Thus, myeloma patients display cellular and humoral immunodeficiencies, which increase following conv- as well as HD-CTX and constitute an important predisposing factor for opportunistic infections.
Predictive Potential of Minimal Residual Disease Level after the First Imatinib Cycle on the Outcome of Allogeneic Stem Cell Transplantation in Adults with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.
Authors: Lee Seok , Kim Yoo-Jin , Min Chang-Ki , Cho Byung-Sik , Kim Sung-Yong , Eom Ki-Seong , Kim Heeje , Cho Seok-Goo , Kim Dong-Wook , Lee Jong-Wook , Min Woo-Sung , Kim Chun-Choo 
Published: October 2019

Abstract
Purpose: Previously, we demonstrated the positive impact of first-line imatinib interim therapy on the outcome of allogeneic stem cell transplantation (SCT) in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) (Blood2005;105:3449). Here, we analyzed for risk factors that affect transplantation outcome, and focused particularly on the prognostic relevance of minimal residual disease (MRD) during treatment course.
Patients and Methods: Fifty-two consecutive adults with Ph-positive ALL who completed SCT following imatinib therapy were enrolled in this prospective study. MRD assessment was performed using real-time quantitative polymerase chain reaction.
Results: Forty-three (87.8%) of the 49 evaluable patients showed a decrease in MRD after imatinib therapy. Molecular remission rates were 18.4% and 44.4% after the first and second imatinib cycles, respectively. Forty-eight (92.3%) of the 52 patients received SCT during first complete remission. With a median follow-up of 42 months after SCT, the actuarial 3-year relapse and disease-free survival (DFS) rates were 22.9% ± 6.6% and 67.3% ± 7.2%, respectively. An MRD level of ≥ 10−3 after the first imatinib cycle was found to be the most powerful predictor of relapse (47.5% ± 14.3% versus 11.4% ± 6.4%, P = .009) and DFS (45.0% ± 13.2% versus 80.9% ± 8.0%, P = .016). The presence of chronic graft-versus-host disease was also found to be associated with a lower relapse (5.3% ± 5.1% versus 37.6% ± 10.8%, P = .029) and better DFS (82.0% ± 9.5% versus 62.4% ± 10.8%, P = .039).
Conclusion: In the setting of allogeneic SCT following imatinib therapy, prospective MRD monitoring may allow us to identify subgroups of Ph-positive ALL patients at high risk of relapse at an earlier treatment stage.
High Engraftment Rate after Second Stem Cell Transplantation for Thalassemia: A Prospective Study.
Authors: Gaziev Javid , Lucarelli Guido , Sodani Pietro , Polchi Paola , Paciaroni Katia , Marziali Marco , Isgro Antonella , Alfieri Cecilia , Simone Maria Domenica , Roveda Andrea , Montuoro Aldo , De Angelis Gioia , Gallucci Cristiano 
Published: October 2019

Abstract
Unlike hematological malignancies patients with thalassemia have an increased risk of graft failure or rejection occurring in up to 15% of patients after myeloablative stem cell transplantation from HLA identical related donors. Patients who reject their grafts and have a return of thalassemic hematopoiesis could benefit from second transplantation with the prospect of cure. Our previous experiences of second SCT using BUCY conditioning regimen alone or in combination with antilymphocyte globulin or total lymphoid irradiation showed a higher graft failure rates (43% to 69%). In 2003 we devised a new preparative regimen in an attempt to improve engraftment rate after second transplantation for thalassemia. The treatment protocol (Protocol 26.1) consisted of pre-conditioning immunosuppression-cytoreduction with hydroxiurea 30 mg/kg/day, azathioprine 3 mg/kg/day (day -45 to -12) and fludarabine 30 mg/m2/day (day -17 to -13) and conditioning regimen with BU 14/16 TT10 CY200 ATG (Thymoglobulin)12,5/10. Thirteen patients with median age of 9 years (range, 4–20 years) were given a second SCT according to this protocol. The median time between the first and second transplant was 29 months (range, 8–204 months). As a stem cell source 4 patients received bone marrow and 9 patients unmanipulated peripheral blood stem cells (PBSC). All but two patients received stem cells from the same donor. Twelve out of 13 patients (92%) had sustained full donor engraftment. One patient had early graft failure and died from cerebral bleeding due to refractory thrombocytopenia despite an autologous back-up. Other two patients died from acute or chronic GvHD -related complications. The probability of survival, thalassemia-free survival, transplant related mortality and rejection were 76%, 76%, 18% and 8% respectively with a median follow-up of 26 months (range, 8–47 months). Four patients developed grade II–III and 1 patient grade IV acute GvHD responsive to steroids and 3 patients had extensive chronic GvHD. Both acute and chronic GvHD occurred in patients who received PBSC. The incidence of CMV and EBV reactivation was 62% and 38% respectively. None of these patients developed EBV related lymphoproliferative disorders. Six patients had BK virus- related hemorragic cystitis (2 moderate, 2 severe and 2 mild cystitis). In conclusion, the high engraftment rate observed in this study suggests that this new preparative regimen is effective curative treatment for second transplant in patients with thalassemia. Disclosure: No relevant conflicts of interest to declare.
Circulating Endothelial Cells as Noninvasive Marker of Angiogenesis in Patients with Chronic Lymphocytic Leukemia.
Authors: Gora-Tybor Joanna , Krawczynska Anna , Lech-Maranda Ewa , Szmigielska-Kaplon Anna , Jesionek-Kupnicka Dorota , Blonski Jerzy Z. , Robak Tadeusz 
Published: October 2019

Abstract
There is accumulating evidence that circulating endothelial cells (CECs) play an important role in angiogenesis. An increased neovascularisation has been documented in bone marrow and lymph nodes of patients with chronic lymphocytic leukemia (CLL). The aim of our study was to compare the number of CECs in peripheral blood of CLL patients and healthy donors and to correlate these numbers with bone marrow microvessel density (MVD). In addition we checked if the number of CECs correlates with the response to treatment. We analyzed the total (CECs), activated endothelial cells (aCECs), apoptotic endothelial cells (apoCECs) and endothelial precursors (CPECs) count by the four colour flow cytometry in the peripheral blood of 80 untreated CLL patients and 29 healthy donors. We also evaluated the MVD in the bone marrow biopsy in 21 CLL patients and 11 controls, using the hot spot analysis of vessels density (x200 HPS). In 34 patients treated with purine analogs (Cladribine or Fludarabine) as first line treatment, we analyzed the influence of the initial number of CECs on treatment results. We found significantly higher numbers of CECs, aCECs, apoCECs and CPECs in CLL patients than in healthy controls (p=0.0001, p=0.001, p=0.0001 and p=0.001 respectively). The total number of CECs was significantly higher in the group of patients with advanced disease (Rai stage 3–4) as compared to patients in Rai stage 0–2 (p=0.02). A correlation was found between CECs and apoCECs number and the β2-microglobulin level (r=0.4, p=0.01 and r=0.3, p=0.01 respectively). The MVD was significantly higher in the bone marrow of CLL patients (median 60, range 27–147) as compared to controls (median 20, range 10–60) (p=0.01). In addition, the number of aCECs correlated with the MVD in CLL patients (r= 0.5, p= 0.02). Moreover, the patients with CECs numbers above median had significantly lower probability to achieve response to treatment with purine analogs (p=0.048). In conclusion, the number of CECs is increased in CLL patients and correlates with vessel density and tumor stage. These findings indicate that analysis of CECs may be a suitable, noninvasive marker of angiogenesis in CLL patients. Evaluation of CECs could be useful to identify CLL patients with low probability of response to purine analogs that may benefit from alternative therapy including anti-angiogenic agents.
Importance of PI3 Kinase Family for Crosstalk between Chronic Lymphocytic Leukemia B Cells and the Stromal Microenvironment: Therapeutic Implications.
Authors: Niedermeier Matthias T.W. , Rawluk Justyna , Knight Zachary , Shokat Kevan , Wierda William G. , Keating Michael J. , Burger Jan A. 
Published: October 2019

Abstract
Nontumoral accessory cells such as marrow stromal cells (MSC) or nurselike cells (NLC), which constitute the leukemia microenvironment, constitutively secrete the chemokine stromal cell-derived factor-1 (SDF-1/CXCL12). CXCL12 transduces signals via its receptor CXCR4, which is expressed at high levels by Chronic Lymphocytic Leukemia (CLL) B cells. Via the CXCL12-CXCR4 axis, CLL cells migrate and adhere to stromal cells. Adhesion to stromal cells protects CLL cells from spontaneous and drug-induced apoptosis in a contact-dependent fashion. Signaling pathways regulating these processes in CLL B cells are largely unknown. Here, we examined the importance of phosphatidyl-inositide 3-kinases (PI3-K) for migration and viability of CLL B cells using non-specific and isoform-specific PI3-K inhibitors. The importance of PI3-K for migration of CLL cells to CXCL12 was determined by transwell chemotaxis and pseudoemperipolesis (PEP) assays. Inhibition of PI3-K resulted in a significant reduction of CLL cell migration in chemotaxis and PEP assays. In comparison to untreated CLL cells, Ly 294002 inhibited chemotaxis to 65 ± 4.6% of untreated controls. Using a panel of isoform-specific PI 3-K inhibitors (PI-103, PIK-90, IC87114, TGX-115, ZK-75), we observed inhibition of chemotaxis by the multi-targeted compounds PI-103 (51.4 ± 0.2%) and PIK-90 (57.5 ± 8.9%), whereas p110beta and delta inhibition had no effect. We conclude from this part of the study that PI3-kinases play an important role for CXCR4 signaling in CLL B cells, mediating migratory responses and protection from apoptosis. Experiments with inhibitors of PI3-K with higher target selectivity suggest a dominant role for the class I PI3-K p110alpha for migration in response to CXCL12. Because adhesion to stroma mediates protection from chemotherapeutic drugs, we tested PI3-K inhibitors alone and in combination with fludarabine in CLL-stroma co-cultures. Pre-treatment of CLL cells with the PI3-K inhibitors Ly 294002, PI-103, and PIK-90 resulted in a significant decrease in viability of CLL cells co-cultured with and without stroma. Moreover, PI3-K isoform specific inhibitors enhance the cytotoxicity of Fludarabine and partially reverse the protective effect of stromal cells on fludarabine-induced apoptosis. Collectively, this study establishes that PI3-Ks play an important role in CXCR4 signaling for CLL cell migration and adhesion to stromal cells. New, isoform-specific PI3-K inhibitors enhance the cytotoxicity of fludarabine in suspension cultures and in co-cultures with stromal cells. Therefore, the therapeutic potential of PI3-K inhibitors alone or in combination with fludarabine should further be investigated.
Figure. Figure.